Dr.

Zeeshan Ahmad Chattha

Endocrine Diseases
148 Chapter 8 Endocrine and metabolic disease

Diabetes mellitus
Insulin is necessary, even when fasting, to maintain glucose homeostasis and
balance stress hormones (e.g. adrenaline). It has two classes of action:
• Excitatory—stimulating glucose uptake and lipid synthesis
• Inhibitory (physiologically more important)—inhibits lipolysis,
proteolysis, glycogenolysis, gluconeogenesis, and ketogenesis.
Lack of insulin is associated with hyperglycaemia, osmotic diuresis, dehy-
dration, hyperosmolarity, hyperviscosity predisposing to thrombosis, and
increased rates of wound infection. Sustained hyperglycaemia is associated
with increased mortality, hospital stay, and complication rates.
Diabetes mellitus is present in 5% of the population.
• Type 1 diabetes (20%): immune-mediated and leads to absolute
insulin deficiency. Patients cannot tolerate prolonged periods without
exogenous insulin. Glycogenolysis and gluconeogenesis occur, resulting
in hyperglycaemia and ketosis. Treatment is with insulin.
• Type 2 diabetes (80%): a disease of adult onset, associated with insulin
resistance. Patients produce some endogenous insulin, and their
metabolic state often improves with fasting. The treatment may be diet
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control, oral hypoglycaemics, and/or insulin.

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General considerations
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Many diabetic patients are well informed about their condition and have
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undergone previous surgery. Discuss management with them. Hospital

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diabetic teams can be useful for advice. The overall aims of perioperative
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diabetic management are to maintain physiological glucose levels (above

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hypoglycaemic levels, but below those at which deleterious effects of

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hyperglycaemia become evident) and prevent hypokalaemia, hypomagnes-

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aemia, and hypophosphataemia.

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Preoperative assessment
• CVS: the diabetic is prone to hypertension, IHD (may be ‘silent’),
cerebrovascular disease, MI, and cardiomyopathy. Autonomic
neuropathy can lead to tachy- or bradycardia and postural hypotension.
• Renal: 40% of diabetics develop microalbuminuria, which is associated
with hypertension, IHD, and retinopathy. This may be reduced by
treatment with ACE inhibitors.
• Respiratory: diabetics are prone to perioperative chest infections,
especially if they are obese and smokers.
• Airway: thickening of soft tissues (glycosylation) occurs, especially in
ligaments around joints, leading to limited joint mobility syndrome.
Intubation may be difficult if the neck is affected or there is insufficient
mouth opening.
• GI: 50% of patients have delayed gastric emptying and are prone to
reflux.
• Diabetics are prone to infections.
Diabetes mellitus 149

Investigations
• Ensure that diabetic control is optimized prior to surgery.
• Measure glycosylated Hb (HbA1c), a measure of recent glycaemic
control (normal 20–48mmol/mol, 4–6.5%). If HbA1c is >69mmol/mol
(8.5%), refer to the team who manages their diabetes for optimization.
Surgery may then proceed with caution. A value >85mmol/mol (10%)
suggests inadequate control. Refer to the diabetic team, and only
proceed if surgery is urgent.
• Patients with hypoglycaemic unawareness should be referred to the
diabetes specialist team, irrespective of HbA1c.
Preoperative management
• Make an individualized diabetes management plan, agreed with the
patient, for the pre-admission and perioperative period.
• Ensure that co-morbidities are recognized and optimized prior to
admission.
• Place the patient first on the operating list, if possible.
• Individuals with type 1 diabetes should NEVER go without insulin, as
they are at risk of diabetic ketoacidosis.
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• The Enhanced Recovery Partnership Programme recommends

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high-carbohydrate drinks prior to surgery. This may compromise blood

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sugar control and is not recommended for people with insulin-treated

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diabetes.
• Avoid overnight preoperative admission to hospital wherever possible.
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• Patients with a planned short starvation period (no more than one
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missed meal in total) should be managed by modification of their usual

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diabetes regime, avoiding a variable-rate IV insulin infusion (VRIII)

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wherever possible.
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• Patients expected to miss >1 meal should have a VRIII.

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• For suggested perioperative management of insulin, see Table 8.1. For

suggested perioperative management of non-insulin diabetic medication,
see Table 8.2.
Perioperative management
• Monitor blood glucose on admission, and hourly during the day of
surgery. Aim for blood glucose level of 6–10mmol/L; 4–12mmol/L is
acceptable.
• If blood glucose is >12mmol/L either pre- or post-surgery, check
capillary blood ketones or urinary ketones. If capillary blood ketones
are >3mmol/L or urinary ketones > +++, cancel surgery.
• Consider an RSI if gastric stasis is suspected.
• Regional techniques may be useful for extremity surgery and to reduce
the risk of undetected hypoglycaemia. Document any existing nerve
damage.
• Autonomic dysfunction may exacerbate the hypotensive effect of
spinals and epidurals.
150 Chapter 8 Endocrine and metabolic disease

Table 8.1 Perioperative management of insulin therapy

Day of surgery
Patient for a.m. surgery Patient for p.m. surgery
Once daily (evening) No dose change
Once daily (morning) No dose change
Twice daily Halve the usual morning dose
Leave the evening meal dose unchanged
Twice daily—separate Calculate the total dose of both morning insulins,
injections of short-acting and give half as intermediate-acting only in
and intermediate-acting the morning
Leave the evening meal dose unchanged
3–5 injections daily Basal bolus regimens: Take usual morning
Omit the morning and insulin dose(s)
lunchtime short-acting Omit lunchtime
insulins. Keep the basal dose
unchanged, unless patient
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grazes all day when consider

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reducing by a third
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Premixed a.m. insulin

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Halve morning dose, and

omit lunchtime dose
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Reproduced from Dhatariya, K. et al., NHS Diabetes perioperative management guideline,

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Appendix 2, Diabetic Medicine © Crown Copyright 2012.

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Perioperative adjustment of insulin (short starvation

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period—no more than ONE missed meal)

Insulin should be taken as usual on the day before surgery.
Check blood glucose on admission.
Perioperative adjustment of non-insulin medication (short
starvation period—no more than ONE missed meal)
For well-controlled patients (HbA1c<69mmol/mol) undergoing surgery
with a short starvation period (one missed meal) and preoperative hyper-
glycaemia (blood glucose >12mmol/L):
• Type 1 diabetes: give SC rapid-acting insulin analogue. Assume that 1U
will drop blood glucose by 3mmol/L, but take advice from the patient
wherever possible. Recheck blood glucose hourly. If surgery cannot be
delayed, commence VRIII.
• Type 2 diabetes: give 0.1U/kg of SC rapid-acting insulin analogue, and
recheck blood glucose 1hr later to ensure it is falling. If surgery cannot
be delayed or the response is inadequate, commence VRIII.
Diabetes mellitus 151

Table 8.2 Perioperative management of oral diabetic medication

Day of surgery
Patient for a.m. surgery Patient for p.m. surgery
Acarbose Omit morning dose Give morning dose
if NBM if eating
Meglitinide Omit morning dose Give morning dose if
(repaglinide or nateglinide) if NBM eating
Metformin Take as normal Take as normal
(if procedure not requiring
use of contrast media*)
Sulfonylurea Once daily a.m. omit Once daily a.m. omit
(e.g. glibenclamide, Twice daily, omit a.m. Twice daily, omit a.m.
gliclazide, glipizide, etc.) and p.m.
Pioglitazone Take as normal Take as normal
DDP-4 inhibitor Omit on day of surgery Omit on day of surgery
(e.g. sitagliptin, vildagliptin,
saxagliptin)
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GLP-1 analogue Omit on day of Omit on day of

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(e.g. exenatide, surgery surgery

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liraglutide)
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* If contrast medium is to be used and estimated GFR <50mL.min/1.732, metformin should be

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omitted on the day of surgery and for the following 48hr.

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a.m., morning; DDP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; NBM, nil by
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mouth; p.m., afternoon.

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Reproduced from Dhatariya, K. et al., NHS Diabetes perioperative management guideline,

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Appendix 3, Diabetic Medicine © Crown Copyright 2012.

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Patients undergoing surgery with a long starvation period

(i.e. two or more missed meals)
• Commence VRIII on admission.
• If patient is already on a long-acting insulin analogue, these should be
continued, even if planning to use a VRIII through the perioperative
period.
• Glucose/insulin infusions should be administered through the same
cannula to prevent accidental administration of insulin without glucose.
Both infusions should be regulated by volumetric pumps, with an
anti-reflux valve on the IV glucose line.
• Hartmann’s solution should be used in preference to 0.9% saline in
those patients not requiring a VRIII.
152 Chapter 8 Endocrine and metabolic disease

Hypoglycaemia
• Blood glucose <4mmol/L is the main danger to diabetics
perioperatively. Fasting, recent alcohol consumption, liver failure, and
septicaemia commonly exacerbate this.
• Characteristic signs are tachycardia, light-headedness, sweating, and
pallor. This may progress to confusion, restlessness, incomprehensible
speech, double vision, convulsions, and coma. If untreated, permanent
brain damage will occur, made worse by hypotension and hypoxia.
• Anaesthetized patients may not show any of these signs. Monitor blood
sugar regularly, and suspect hypoglycaemia with unexplained changes in
the patient’s condition.
• If hypoglycaemia occurs, give 75mL of 20% glucose over 15min or
150mL of 10% glucose, and repeat the blood glucose after 15min.
Alternatively, give 1mg of glucagon (IM or IV); 10–20g (2–4 teaspoons)
of sugar by mouth or an NGT is an alternative.
Variable-rate intravenous insulin infusion
• The recommended 1st-choice solution for VRIII is 0.45% NaCl with
5% glucose, and either 0.15% potassium chloride (KCl) or 0.3% KCl;
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however, this is not always available.

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• 4% glucose and 0.18% NaCl, 10% glucose, or 5% glucose are

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acceptable. Whenever giving hypotonic parenteral fluids, beware of

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hyponatraemia. Preferably give 10% glucose at 60mL/hr, rather than

5% glucose at 120mL/hr (prevents water overload, particularly in the
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elderly).
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• If K+ <4.5mmol/L, add 10mmol KCl to each 500mL bag of glucose.

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• Start VRIII using a syringe pump. Adjust according to the sliding scale
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in Table 8.3. Test blood glucose hourly initially. Patients on >100U of

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insulin/day will need higher doses of insulin by infusion.

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Transferring from a variable-rate intravenous insulin

infusion to subcutaneous insulin or oral treatment
Restarting oral hypoglycaemic medication
• Recommence oral hypoglycaemic agents once the patient is ready to eat
and drink.
• Be prepared to withhold or reduce sulphonylureas if the food intake is
likely to be reduced.
• Metformin should only be recommenced if the estimated GFR (eGFR)
>50mL/min/1.732.
Restarting subcutaneous insulin for patients already established on insulin
• Conversion to SC insulin should be delayed until the patient is able to
eat and drink without nausea and vomiting.
• It should take place when the next meal-related SC insulin dose is due,
e.g. with breakfast or lunch.
Diabetes mellitus 153

Table 8.3 VRIII sliding scale

Blood glucose Initial rate of insulin infusion Insulin infusion rate if blood
(mmol/L) (U/hr) glucose not maintained
<10mmol/L (U/hr)
<4.0 0.5 0.5
(0.0 if a long-acting (0.0 if a long-acting
background insulin has been background insulin has been
continued), and treat as for continued), and treat as for
hypoglycaemia hypoglycaemia
4.1–7.0 1.0 2.0
7.1–9.0 2.0 3.0
9.1–11.0 3.0 4.0
11.1–14.0 4.0 5.0
14.1–17.0 5.0 6.0
17.1–20.0 6.0 8.0
>20 Check infusion running, Check infusion running, and
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and seek diabetes team or seek diabetes team or medical

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medical advice) advice

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• Restart the normal pre-surgical regime. Be aware that insulin

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requirement may change due to post-operative stress, infection, or

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altered food intake.

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• Consult the diabetes team if blood sugar is outside the acceptable range
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(4–12mmol/L) or if a change in diabetic management is needed.

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• Ensure overlap between the VRIII and the 1st injection of the fast-acting
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insulin. The fast-acting insulin should be injected SC with the meal, and
the VRIII discontinued 30–60min later.
For patients on basal bolus insulin
• If the patient was previously on a long-acting insulin analogue, such as
Lantus® or Levemir®, this should have been continued, and so the patient
only needs to restart their normal short-acting insulin at the next meal.
For patients on a twice-daily fixed-mix regimen
• The insulin should be only reintroduced before breakfast or before the
evening meal.
For patients on continuous subcutaneous insulin
• Commence the SC insulin infusion at their normal basal rate as long as
not at bedtime.
• VRIII should be continued until the next meal bolus has been given.
154 Chapter 8 Endocrine and metabolic disease

Intensive care unit admissions

• Manage patients admitted to ICU post-operatively to ensure blood
glucose between 5 and 10mmol/L. Previous evidence from Van den
Berghe et al.1 for tighter glucose control (4.4–6.1mmol/L), leading to
improved mortality and morbidity, has not been borne out by recent
evidence from the Glucontrol study2 and the VISEP study.3 These
showed no difference in outcomes, but significantly more hypoglycaemia
and the need for more nursing input to achieve this level of glycaemic
control safely.
Glucose–potassium–insulin regime (GKI or Alberti)
This is an alternative, simpler regime which does not require infusion
pumps, but may provide less accurate control of blood sugar. The original
regime, as described by Alberti,4 consists of:
• 500mL of 10% glucose
• Add 10–15U of soluble insulin, plus 10mmol of KCl per 500mL bag
• Infuse at 100mL/hr
• Provides insulin 2–3U/hr, K+ 2mmol/hr, and glucose 10g/hr.
Glucose 10% is not always available, so the following regime with 5% glu-
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cose can be used—infuse 5% glucose (500mL bags) at the calculated rate

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for the patient’s fluid maintenance requirements. Insulin and K+ should be

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added to each bag, as per Table 8.4. The bag may be changed according to
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2-hourly blood glucose measurements.

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Table 8.4 GKI infusions based on 5% glucose solution

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Blood glucose Soluble insulin Blood K+ (mmol/L) KCl (mmol) to

(mmol/L) (U) to be added to be added to each
each 500mL bag of 500mL bag of 5%
5% glucose glucose
<4 5 <3 20
4–6 10 3–5 10
6.1–10 15 >5 None
10.1–20 20
>20 Review If potassium level not
available, add 10mmol
KCl to each bag
Diabetes mellitus 155

References
1 Van den Berghe G, Wouters P, Weekers F, et al. (2001). Intensive insulin therapy in critically ill
patients. N Engl J Med, 345, 1359–67.
2 Preiser JC, Devos P, Ruiz-Santana S, et al. (2009). A prospective randomized multi-centre con-
trolled trial on tight glucose control by intensive insulin therapy in adult intensive care units: the
Glucontrol study. Intensive Care Med, 35, 1738–48.
3 Brunkhorst FM, Engel C, Bloos F, et al. (2008). Intensive insulin therapy and pentastarch resuscita-
tion in severe sepsis. N Engl J Med, 358, 125–39.
4 Alberti KGMM (1991). Diabetes and surgery. Anesthesiology, 74, 209–11.

Further reading
Dhatariya K, Levy N, Kilvert A, et al. (2011). NHS Diabetes guideline for the peri-operative manage-
ment of the adult patient with diabetes. Diabet Med, 29, 420–33.
Lobo DN, et al. (2012). The peri-operative management of the adult patient with diabetes.
M http://www.asgbi.org.uk.
Rehman HU, Mohammed K (2003). Peri-operative management of diabetic patients. Curr Surg, 60,
607–11.
Simpson AK, Levy N, Hall GM (2008). Perioperative IV fluids in diabetic patients—don’t forget the
salt. Anaesthesia, 63, 1043–5.
Sonksen P, Sonksen J (2000). Insulin: understanding its action in health and disease. Br J Anaesth,
85, 69–79.
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84

Diabetes: peri-operative management

An elderly patient with IDDM is scheduled for an axillo-femoral bypass
graft. What are the important features of a pre-operative assessment in
diabetic patients?

Glycaemic control
It is important to get a feel for the patient’s recent diabetic control,
assessing glucose control as well as hydration and acid–base balance.
Current hypoglycaemic agents should be reviewed. The patient will
undergo a period of starvation as well as a surge of catabolic hormone
secretion associated with the stress response to surgery.
Tight control of blood glucose has both short- and long-term advantages.
In the acute setting inadequately treated diabetes can cause symptomatic
hypoglycaemic episodes or severe dehydration with acidosis (lactic and/or
ketoacids). Raised blood sugar levels peri-operatively have been linked with
wound infection and poor neurological outcome in cardiac surgery.

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In the longer term, improved glucose control can reduce the
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microvascular and neuropathic complications of this disease.

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Assessment of diabetic Coronary artery disease

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complications Autonomic neuropathy

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Diabetic nephropathy
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Respiratory changes/airway assessment

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Associated endocrine disorders

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Are these complications of diabetes of concern to you as an anaesthetist?

Diabetics are four to five times as likely to have coronary heart disease as
non-diabetics and a proportion of these are asymptomatic.
Autonomic neuropathy occurs in up to 40% of type1 diabetics and can take
the form of postural hypotension, gastroparesis, diarrhoea and bladder
paresis. There can be unexpected tachycardia, arrhythmias and hypotension
(often unresponsive to atropine and ephedrine). Diabetics with autonomic
neuropathy show increased QT variability (i.e. regional variations in
ventricular recovery) and this may be a major factor in the ‘sudden death
syndrome’ recognized in this group. Gastroparesis causes an increase in the
volume of gastric contents with increased risk of aspiration. The degree of
autonomic neuropathy is difficult to quantify pre-operatively, but the
Valsalva manoeuvre and assessment of heart rate variability may be of
benefit.
Diabetic nephropathy increases the risk of peri-operative renal failure and
infection. Appropriate fluid and haemodynamic monitoring is essential.
Respiratory: diabetes is associated with a reduced FEV1 and FVC. It has been
estimated that 30%–40% of long-standing diabetics develop the ‘stiff joint
syndrome’ in which chronically raised blood sugar levels cause protein
glycosylation and reduced elasticity of connective tissues. This is associated
D Diabetic ketoacidosis 85

with poor neck extension and mouth opening and a higher incidence of
difficult intubation.

How would you manage this man’s glucose control peri-operatively?

This is an elderly man who is insulin dependent undergoing a major surgical
procedure. The main principles are:
Regular blood glucose monitoring.
Insulin and glucose infusions during the period of starvation.
There are many methods of providing continuous insulin/glucose infusions and
hospital policy may dictate the regimen chosen. The two main regimens are:
1. Separate infusions of insulin and glucose – the insulin rate is adjusted
according to the blood glucose level.
2. The Alberti regimen provides glucose, insulin and potassium in the same
solution, thus eliminating the potential for giving insulin without glucose
or vice versa.
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As indicated above, these regimens should be commenced and stabilised

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pre-operatively and continued until the patient has resumed eating/drinking

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and their normal hypoglycaemic agents.

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What is your preferred anaesthetic technique in this man?

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This man requires a general anaesthetic and, if gastric stasis is suspected, then
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a rapid sequence induction is the technique of choice. In an elderly man with

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known vascular disease, an arterial line inserted pre-induction would be

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prudent, especially if there is a question of autonomic neuropathy. A high-dose

opiate anaesthetic technique will reduce the sympathetic and hormonal
response to surgery, providing both metabolic and haemodynamic stability.

Bibliography
McAnulty GR, Robertshaw HJ, Hall GM. (2000). Anaesthetic management of patients with diabetes
mellitus. British Journal of Anaesthesia, 85(1), 80–90.

Diabetic ketoacidosis
What is the mechanism of ketone production in diabetes?
Ketones are produced from acetyl-CoA in the liver mitochondria and are used
as fuel by the brain and muscle. Acetyl-CoA is the end product of β-oxidation
of fatty acids. If there is excess fatty acid breakdown (as in diabetes and
starvation), then there will not be enough oxaloacetate to join with all the
acetyl-CoA in order for it to enter the citric acid cycle. In this situation the
excess acetyl-CoA is diverted into ketone production. The accumulation of
ketoacids (␤-hydroxybutyrate and aceto-acetate) cause a metabolic acidosis
86 Diabetic ketoacidosis D

when levels reach about 10 mmol/l. The rate of production is usually slow, but
can be as fast as 1 mmol/min.
Conditions required for ketone production

Insulin deficiency. However, only a very low level of insulin is required to

inhibit hepatic ketogenesis.
Counter-regulatory hormone excess (an increase in glucagon,
catecholamines and glucocorticoids)

Further pathophysiology . . .
Insulin lack accelerates glycogenolysis and gluconeogenesis. An osmotic
diuresis results from the high blood glucose and causes uncontrolled
urinary loss of K+ , Na+ and water. This decreased ECF volume leads to
pre-renal failure. Renal excretion of glucose is then inhibited, which
leads to a further increase in plasma glucose level. Hyperglycaemia
moves water out of cells into the ECF. This can decrease the serum [Na+ ].
Nausea and vomiting frequently complicate the biochemical picture.

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What are the actions of insulin?

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Insulin prevents proteolysis, glycogenolysis and lipolysis and promotes uptake

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and storage of fuel. It is an anabolic hormone. Insulin binds to a specific

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membrane-bound receptor and alters intracellular cAMP levels.

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Carbohydrate
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Increases glycogen synthesis (phosphofructokinase and glycogen synthase).

Inhibits glycogenolysis and gluconeogenesis.
The increased uptake of glucose into cells (such as adipose tissue and
muscles) by increased glucokinase activity is now considered much less
important.

Fat
Decreases triglyceride breakdown in adipocytes (triglyceride–lipase).
Increases fatty acid synthesis in the liver due to activation of acetyl CoA
carboxylase.
Activates lipoprotein lipase, which splits triglycerides enabling the fatty
acids to enter adipose tissue for storage.
Increases esterification of fatty acids with glycerol in adipose tissue.

Protein
Decreases proteolysis.
Increases uptake of amino acids into cells.
Increases mRNA translation.

Increased K+ and Mg2+ transport into cells

D Diabetic ketoacidosis 87

How would you manage a diabetic with ketoacidosis?

Treatment of DKA needs to address:

Fluid deficit/shock
Insulin deficiency
Hypokalaemia
Acidosis
Underlying/precipitating cause

History
Examination Sunken eyes
Reduced skin turgor
Acetone smell on breath
Kussmaul’s breathing
Low BP
Decreased conscious level
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Investigations
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Arterial blood gases for acid–base balance

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Anion gap
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Plasma glucose
Plasma Na+ concentration is usually low as an osmolar compensation for the
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high glucose. If the sodium is high, this represents severe water loss.
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Plasma K+ concentration may be high on presentation, but the total body

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potassium is low due to the absence of insulin allowing it to drift out of the
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cells.
Urea and creatinine Pre-renal failure from ECF depletion
Diabetic nephropathy
Osmolality of serum
Serum/urinary ketones (aceto-acetate). The ratio of ␤-hydroxybutyrate to
aceto-acetate is governed by pH. As the pH decreases, the ratio increases.
Conventional bedside tests for ketones only react with acetoacetic acid and
therefore it is possible to have a very high ␤-hydroxybutyrate concentration
and have the test only show a trace of ketones.
PO4 levels tend to follow K+ .
CXR, ECG, FBC, blood cultures, urine culture and sputum culture to look for
underlying cause.
Monitoring ECG/heart rate/BP/temp./resp. rate/urine output/NG tube
Regular blood glucose monitoring
HDU/ICU

Treatment
ECF volume should be replaced with normal saline (CVP line may be
needed).
Start with 1–2 litres in the first hour. More than 6 litres may be needed.
88 Diabetic ketoacidosis D

Insulin (actrapid) at 0.1 unit/kg bolus and then 0.1 unit/kg per hour.
Potassium replacement should begin when serum [K+ ] becomes less than
4.5 mmol/l. 20 mmol/hour if K+ is 4–5 mmol/l, 40 mmol/hour if 3–4 and
40–60 mmol/hour if <3 mmol/l.
5% or 10% Dextrose should be started when the plasma glucose falls below
14 mmol/l.
Bicarbonate therapy is controversial. Several centres use it if pH<7.0 or if
the [HCO3 − ] is <5.0 mmol/l.
The problems with it are: Large Na+ load
Increased CO2 production (may easily enter cells
and cause a paradoxical intracellular acidosis)
Hypokalaemia
Metabolic alkalosis as ketoacids disappear
Left-shift of oxyhaemoglobin dissociation curve
Phosphate therapy has no proven benefit.
The underlying cause must be treated (myocardial infarction, infection,
etc.).
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Anion gap
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= (Na+ + K+ ) – (HCO3 − + Cl− )

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Normal value = 10 – 18 mmol/l.

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Represents unmeasured anions, e.g. albumin, sulphate and phosphate.

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An increase is due to an unmeasured anion that is balanced by H+

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causing an acidosis, e.g. lactate or ketoacids.

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is

Complications
Shock and lactic acidosis
Coma
Cerebral oedema
Hypothermia
DVT
Iatrogenic electrolyte imbalance

Bibliography
Goguen JM, Josse RG. (1993). Management of diabetic ketoacidosis. Medicine International, 21(7),
275–8.
Kumar PJ, Clark ML. (1994). Clinical Medicine, 3rd edition. Baillière Tindall.
Sonksen P, Sonsken J. (2000). Insulin: understanding its action in health and disease. British Journal
of Anaesthesia, 85(1), 69–79.
Viallon A, Zeni F, Lafond P et al. (1999). Does bicarbonate therapy improve the management of
severe diabetic ketoacidosis? Critical Care Medicine, 27(12), 2690–3.
Weatherall DJ, Ledingham JGG, Warrell DA. (1996). The Oxford Textbook of Medicine, 3rd Edition.
Oxford University Press.
BJA Education, 17 (6): 198–207 (2017)

doi: 10.1093/bjaed/mkw075
Advance Access Publication Date: 22 February 2017
Matrix reference
1A02, 2A03, 3A06

Diabetes medication pharmacology

Daniel J Stubbs BA BMBCh MRCP FRCA1, Nicholas Levy MBBS BSc FRCA
FFICM2,* and Ketan Dhatariya MBBS MSc MD MS FRCP3
1
Department of Anaesthesia, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 0QQ, UK, 2Department of
Anaesthesia, West Suffolk Hospital, Hardwick Lane, Bury St Edmunds IP33 2QZ, UK and 3Elsie Bertram
Diabetes Centre, Norfolk and Norwich University Hospitals NHS Foundation Trust, Colney Lane, Norwich NR4

a
tth
7UY, UK

C s
ad ote
ha
*To whom correspondence should be addressed. E-mail: [email protected]
hm N
fo r P ale A am

Diabetes mellitus (DM) is a group of metabolic conditions

characterized by hyperglycaemia. It is the most common meta-
Key points
ot o S an x

bolic condition in the world, and the incidence is increasing. In

N ot f or sh a E

• People with Type1 Diabetes must always have a England, it is estimated that there are 2.8 million people over
constant source of exogenous insulin, otherwise n the age of 16 who have diabetes.1 There are several forms/
N ot f ee esi

diabetic ketoacidosis (DKA) will result. causes of diabetes. These include:

tio
• People with Type 2 Diabetes can be managed (i) Type 1 diabetes (T1DM) is characterized by an absolute
N r. Z th

bu

either with diet alone, or a combination of diet lack of insulin.

D es

and non-insulin glucose lowering drugs with or (ii) Type 2 diabetes mellitus (T2DM) is the most common
tri
ed t
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An

without insulin. form and is characterized by insulin resistance.

is

• Multiple formulations of insulin exist with markedly (iii) Gestational diabetes occurs during pregnancy and is asso-
ciated with conditions including pre-eclampsia, neonatal
diverse pharmacokinetic profiles. These diverse prep-
hypoglycaemia, and fetal abnormality.
arations are used by people with diabetes in a variety
(iv) Genetic defects of b-cell function (e.g. maturity-onset dia-
of different regimens with the aim of both ensuring
betes of the young).
sufficient background insulin, and to minimise pran-
(v) Endocrinopathies (e.g. Cushing syndrome and
dial hyperglycaemia. An understanding of the differ- phaeochromocytoma).
ent formulations and regimens is required to facili- (vi) Pancreatic disease (e.g. cystic fibrosis and chronic
tate safe perioperative use of insulin and to prevent pancreatitis).
complications from perioperative dysglycaemia. (vii) Drugs (e.g. glucocorticoids and b-adrenergic agonists).2
• Insulins must be prescribed by the brand name, the
The terms ‘insulin dependent’ and ‘non-insulin dependent’,
word units must be written in full, and when admin- or ‘juvenile-onset’ or ‘maturity-onset diabetes’ are no longer
istering, an insulin syringe must always be used. used. This is because a large number of people with T2DM re-
• There are currently eight different classes of non- quire insulin to maintain glycaemic control, and there are also
insulin glucose lowering medication, each with an increasing number of children (who are often obese) who
their own mechanism of action and side effects. have T2DM. Thus the terms ‘Type 1 DM’, ‘Type 2 DM’, and ‘Type
An understanding of the pharmacology is essen- 2 DM on insulin’, are now preferred.
tial to facilitate safe perioperative manipulation Unless the patient’s diabetes can be treated with diet, the
patient will require medication to control the hyperglycaemia.
and to promote optimal perioperative outcomes.
In the last 30 years, insulin pharmacology has been
revolutionized by the introduction of recombinant DNA

Editorial decision: October 19, 2016; Accepted: December 6, 2016

C The Author 2017. Published by Oxford University Press on behalf of the British Journal of Anaesthesia.
V
All rights reserved. For Permissions, please email: [email protected]

198
Diabetes medication pharmacology

technology and genetically engineered human insulin, which Naturally occurring short-acting insulin, be it of human or ani-
has replaced the animal-derived insulin preparations. In more mal origin, is known as soluble insulin.
recent years, the human insulins produced by recombinant
DNA technology, have been further modified by subtle molecu- Very rapid-acting insulin analogues
lar changes to produce insulins that have different systemic ab- Examples: insulin aspart (Novorapid), insulin lispro (Humalog),
sorption from the s.c. site of injection. These are known as insulin glulisine (Apidra).
insulin analogues. As these biological analogues come off pa- Very rapid-acting insulin analogues have had a small num-
tent, generic drugs are being marketed. These biological generic ber of amino acid substitutions made to the human insulin
drugs (which are known as ‘biosimilars’) are not identical in molecule that allow them to be absorbed at a faster rate than
their purity to the initial analogue preparation, and so to be human insulin when injected s.c. Their onset of action is within
licensed need to go through safety and comparative studies. 10–15 min of initial s.c. injection, and they have a peak of action
These studies have not demonstrated clinically important phar- within an hour and last for up to 4 h. They are usually given to
macokinetic or pharmacodynamic differences between the bio- cover the glucose excursion associated with meals (prandial in-
similar and the original analogue preparation. In 2015, sulin) as part of a basal bolus regimen. The rapid onset of action
Abasaglar, the first biosimilar, was licensed, which is the biosi- means that they can be administered immediately before or
milar of insulin glargine, a long-acting insulin analogue. within 30 min of a meal.
There are currently eight different classes of non- Owing to these pharmacokinetic properties, these are the in-
insulin glucose-lowering agents,3 with the majority being intro- sulins that the Joint British Diabetes Societies (JBDS) and the
duced in the last 20 years. The term ‘oral hypoglycaemic agents’ Association of Anaesthetists of Great Britain and Ireland
to describe the non-insulin glucose-lowering drugs has been (AAGBI) now recommend to treat transient hyperglycaemia in
rendered obsolete, as the relatively new glucagon like peptide-1 the surgical patient.4,5

a
analogues (GLP-1 analogues) are peptides, and thus need to be

tth
injected.

C s
Human soluble insulin

ad ote
Patients with diabetes require surgery more often than the Examples: Actrapid; Humulin S; Insuman rapid (Human Insulin

ha
general population, and recent studies suggest that 15% of the rDNA).
surgical population has diabetes. Anaesthetists need to have an
hm N
Human soluble insulins start working within half an hour of
understanding of the pharmacology of these agents to allow the s.c. injection and last for between 4 and 8 h. Even though they
fo r P ale A am

safe use and modification of the diabetes medication during the are an exact clone of human insulin their use is declining. This
surgical period.4,5 is because of their slow onset of action after s.c. administration.
ot o S an x

If they are administered immediately before a meal, patients

N ot f or sh a E

will be prone to postprandial hyperglycaemia owing to the

Insulin n length of time to reach peak action.
N ot f ee esi

Insulin is a peptide hormone produced by the b-cells in the pan- These are the insulins that are recommended to be used in
tio
creas. Within vertebrates the amino acid sequence is strongly the fixed rate and variable rate i.v. insulin infusions. To reduce
N r. Z th

bu

conserved. Bovine insulin differs to human insulin by only the incidence of error, it is recommended that the insulin is ad-
D es

three amino acids, whilst in porcine insulin the difference from ministered via a commercially prepared prefilled syringe with a
tri
ed t

concentration of 1 unit/ml.6
r R rin

human insulin is only one amino acid. Most patients are now
An

is

on human insulin produced by recombinant DNA technology.

There are many types of insulin commercially available. Background insulins
Insulins can be classified by:
There are two types of background human insulin:
(i) The speed of onset and length of action after s.c. injection
(i.e. short-acting insulin or background insulin). (i) Intermediate-acting insulin, also known as NPH (Neutral
(ii) The type of the insulin (i.e. bovine, porcine, or obtained Protamine Hagedorn [NPH]).
from human insulin using recombinant DNA technology). (ii) Long-acting insulin analogues.
(iii) Whether the preparation contains a single type of insulin These insulins are designed to ensure a steady systemic in-
or a mixture of different insulins. sulin concentration, to ensure that insulin is constantly acting
Table 1 summarizes the different insulin preparations and and to promote continuous cellular glucose uptake. The admin-
their pharmacokinetics. istration of these agents averts the use of fatty acids as a cellu-
lar energy substrate and thus prevents subsequent diabetic
ketoacidosis (DKA). There is little to choose between ‘old’ NPH
The different types of insulin insulin and the ‘new’ longer acting insulin analogues in terms
of glycated haemoglobin (HbA1c) reduction. However, there are
Short-acting insulins
suggestions that the rates of severe hypoglycaemia (i.e. requir-
There are three types of short acting insulin: ing help from a third party) are lower with the long-acting ana-
logue insulins. The newer long-acting insulin analogues are
(i) Very rapid-acting insulin analogues.
significantly more expensive than NPH.
(ii) Human soluble insulin.
(iii) Animal soluble insulin.
NPH insulin/intermediate-acting insulin
The short-acting insulins are usually given to cover the glu- Examples: Insulatard (NPH Insulin), Humulin I (Isophane insu-
cose excursion associated with meals (prandial insulin) as part lin); Insuman basal (Isophane insulin).
of a basal bolus regimen. The dose can be adjusted according to With the addition of the protamine molecule, these insulins
the size of the meal, the amount of carbohydrate in the meal, have delayed absorption and are clinically effective 90–120 min
the current glucose reading, and the planned activity levels. after s.c. injection, and exert their effect for 8–10 h. These

BJA Education | Volume 17, Number 6, 2017 199

200
Table 1 Summary of different types of insulin and their pharmacokinetic profiles

Type of insulin Onset (min) Peak activity Duration Pharmacokinetic profile Clinical use

• Rapid-acting analogue in- 10 min 15 min to 1 h 3–4 h • Bolus part of basal bolus regimen
sulins, e.g. • Bolus part of twice daily
• Novorapid (aspart) separate injections (rarely used
• Humalog (lispro) in this combination)
• Apidra (glulisine)
An
• CSIIs pump therapy
Diabetes medication pharmacology

D es
N r. Z th
N ot f ee esi
• Short-acting soluble 30 min 1–3 h 6–8 h • Bolus part of basal bolus regimen
human insulins, e.g. • Variable rate and fixed rate

BJA Education | Volume 17, Number 6, 2017

N ot f or sh a E
• Actrapid i.v. insulin infusions
•
ot o S an x
Humulin S
• Velosulin
fo r P ale A am
• Short-acting animal 30 min Within 60 min 6–8 h Reduced use in 21st century
(Bovine or Porcine), e.g.
r R rin hm N
• Hypurin
ed t ad ote
is C s
tri
• NPH insulin/Intermediate- 120 min 4–6 h 8–10 h • Basal part of twice daily
ha
acting insulin, e.g. separate injections
bu
• Humulin I • Basal part of basal bolus
tio tth
• Insultard n a regimen—can be given once
• Hypurin (Bovine or or twice in this regimen
Porcine) Isophane

• Long-acting analogue in- 120 min No peak 18–24 h • Once daily regimen for T2DM
sulins, e.g. • Part of basal bolus regimen
• Levemir (detemir)

(continued)
Table 1. (continued)
Type of insulin Onset (min) Peak activity Duration
An Pharmacokinetic profile Clinical use

• Lantus (glargine)
• Tresiba (degludec)
D es
N r. Z th
N ot f ee esi
N ot f or sh a E
ot o S an x
• Biphasic insulin As per Two peaks As per Twice daily regimen, although
fo r P ale A am
(Combinations of either components components occasionally given three
times per day
r R rin
rapid-acting or short-
hm N
acting soluble with an
ed t
intermediate-acting in-
ad ote
sulin), e.g.
is C s
• Humalog Mix 25 or Mix
tri
50
ha
• Humulin M3
bu
• Insuman comb 15,
tio tth
comb 25 n a
• NovoMix 30

BJA Education | Volume 17, Number 6, 2017

201
Diabetes medication pharmacology
Diabetes medication pharmacology

insulins are commercially available either alone or in combin- properties as human insulin, but are far more immunogenic,
ation with either a rapid acting (e.g. NovoMix 30), or a soluble and are subsequently associated with immune-mediated lipo-
insulin (e.g. Humulin M3). hypertrophy and lipoatrophy.

Human biphasic/mixed insulins Insulin regimens

Examples: NovoMix 30, Humulin M3, Insuman Comb 25. There are many different regimes depending on the need of the
There are some commercial preparations of premixed inter- patient, ranging from one injection a day to up to five injections
mediate- with a short-acting insulin. The short-acting insulin a day. The idea is to try to mimic the normal physiological con-
may be either a soluble insulin or a very rapid-acting insulin centrations of insulin. They are displayed graphically in Figures
analogue. The number in these insulin names refers to the pro- 1–4.
portion of short-acting insulin in the combination (e.g. NovoMix The different types of insulins can be given in any different
30 comprises 30% Insulin aspart (rapid-acting analogue) and combination.
70% Insulin aspart complexed with protamine (intermediate- Commonly used regimens:
acting). These mixed insulins are usually given twice daily, first
before breakfast and second before the evening meal. The (i) Once daily.
breakfast dose allows the short-acting insulin to cover the (ii) Twice daily.
increase in blood glucose associated with breakfast, with the (iii) Basal bolus.
intermediate-acting insulin covering the increasing glucose (iv) Three times per day regimen.
that would be associated with lunch. The second dose is usually (v) Continuous s.c. insulin infusions (CSIIs).
taken with the evening meal, with the short-acting insulin cov-
ering the increasing glucose concentration associated with the Once daily

a
tth
evening meal and the intermediate insulin covering the over-

C s
This is almost always used in people with T2DM where the indi-
night period.
ad ote vidual uses a once daily long-acting or intermediate-acting in-

ha
sulin at night in addition to their oral medication to overcome
Long-acting insulin analogues
hm N
the high hyperglycaemia associated with inappropriate hepatic
Examples: insulin glargine (Lantus), insulin detemir (Levemir), gluconeogenesis (see Fig. 1).
fo r P ale A am

and insulin degludec (Tresiba).

Insulin glargine was the first of these long-acting analogues
Twice daily
ot o S an x

and became available in 2003, whilst degludec only became

N ot f or sh a E

available in 2013. These insulins have a very long duration of This is a very commonly used regimen in both T1DM and T2DM
action—between 18 and 36 h. They take 2–3 days to reach a
n where a premixed insulin is injected at breakfast and evening
N ot f ee esi

steady state. They are usually injected once or twice a day. meal (see Fig. 2).
tio
They have relatively ‘flat’ profiles, and often described as
N r. Z th

bu

‘peakless’. Basal bolus

D es

tri

Four injections a day regimen is also called the basal bolus. This
ed t

Animal insulin
r R rin
An

is composed of a longer acting either intermediate- or long-act-

is

Example of short-acting (soluble) animal insulins: Hypurin neu-

ing insulin analogue given once daily, most frequently at night.
tral (bovine or porcine).
The additional three doses are normally composed of a very
Example of intermediate-acting animal insulin: Hypurin bo-
rapid-acting insulin analogue given at the time of the meal
vine protamine zinc; Hypurin isophane (bovine or porcine).
(however, some patients may use soluble). The basal dose usu-
Examples of mixed animal insulins: Hypurin 30/70 mix
ally equates to 50% of the total daily insulin dose (see Fig. 3).
(porcine).
Occasionally, the long-acting or intermediate insulin is split to
The number of patients on animal insulin (bovine, porcine)
be given 12 h apart; therefore the individual gives themselves
is diminishing. These are available as soluble (short-acting) or
five injections a day.
isophane (intermediate-acting) insulin. These are extracted
from the pancreas of slaughtered animals. It used to take 2 tons
of animal pancreases to produce 200 g of purified insulin. Three times per day
Animal insulin was the initial type of insulin after insulin was Although rarely used, this is the use of a premixed insulin given
identified in the 1920s. With the advent of human insulins in with each meal.
the 1980s, animal insulin is now rarely used. The few patients
who have continued to use it, do so because of patients’ fear of
hypoglycaemic unawareness on human insulins, but this fear
Continuous s.c. insulin infusions (CSII)
has never been substantiated. Hypoglycaemic unawareness is CSIIs (‘pumps’) are becoming more frequent. The UK National
the loss of symptoms of sympathetic overdrive (e.g. sweating, Institute for Health and Care Excellence guidelines7 state that
hunger, shaking, palpatations) when glucose levels drop. In for individuals with T1DM aged >12 yr, pumps are recom-
people without diabetes, or where the diabetes is well con- mended as a treatment option for those attempting to achieve
trolled, symptoms often start to occur when glucose concentra- target HbA1c concentrations <69 mmol mol1 (8.5%), but experi-
tions decline to approximately <3.8 mmol litre1, although it is ence disabling hypoglycaemia with multiple daily injections
very person specific. Hypoglycaemic unawareness most fre- despite intensive education. An insulin pump delivers a fixed
quently occurs in those who have long-standing insulin-treated hourly basal rate of a very rapid-acting insulin analogue. This
diabetes. rate can be changed on an hourly basis. The individual gives
Many people on these animal insulins will be on mixtures themselves bolus doses to cover their carbohydrate intake dur-
twice a day. They have essentially the same pharmacokinetic ing individual meals or snacks (see Fig. 4).

202 BJA Education | Volume 17, Number 6, 2017

Diabetes medication pharmacology

Insulin
activity

Breakfast Lunch Evening meal Bedtime

Fig 1 Insulin activity profile with a once daily injection of long-acting insulin.

a
tth
C s
Insulin
ad ote
ha
activity
hm N
fo r P ale A am
ot o S an x
N ot f or sh a E

Breakfast Lunch Evening meal Bedtime

n
N ot f ee esi

Fig 2 Insulin activity profile with twice daily injection of mixed (biphasic) insulin.
tio
N r. Z th

bu
D es

tri
ed t
r R rin
An

is

Insulin
activity

Breakfast Lunch Evening meal Bedtime

Fig 3 Insulin activity profile using a ‘basal bolus’ regimen.

A pump should only be used with close collaboration be- insulins; these include: the risk of inhaling a growth factor onto
tween the patient and the specialist diabetes team. a thin epithelium; the difficulty of prescribing in ‘milligrams’
not ‘units’; and unpredictable absorption in lung disease.
Whether or not this route of administration becomes viable re-
Inhaled insulin mains to be seen.

Administration of insulin via the inhaled route has been diffi-

cult to achieve. The first inhaled insulin, Exubera (Pfizer Ltd),
was withdrawn within a few months of launch—partly because
of very poor sales, but also because of a spike in lung cancers
Safe use of insulin
being reported in users of the drug.8 Newer inhaled insulins are Whilst insulin has the potential to be a life-saving drug, its pre-
in development and the first of these, ‘Afrezza’, was launched scription and administration, and its subsequent use is associ-
in the USA in 2015. There remain many challenges with inhaled ated with iatrogenic harm. Consequently, the national patient

BJA Education | Volume 17, Number 6, 2017 203

Diabetes medication pharmacology

Insulin
activity

Breakfast Lunch Evening meal Bedtime

Fig 4 Insulin activity profile using a CSII. Width of CSII activity shows programmable range of basal infusion. Boluses can be adjusted to carbohydrate load of individual
meals.

safety agency issued specific guidance to improve its safety in Essentially, these drugs work via four broad mechanisms:
2010.6 The guidance included the following facts:
(i) Increase release of endogenous insulin and cause a genu-
• All regular and single insulin (bolus) doses are measured ine reduction in the blood glucose (the sulphonylureas
and administered using an insulin syringe or commercial in- and meglitinides).

a
sulin pen device. I.V. syringes must never be used for insulin (ii) Affecting gastro-intestinal absorption and renal reabsorp-

tth
C s
administration. tion of glucose (intestinal alpha-glucosidase inhibitors

ad ote
• The term ‘units’ is used in all contexts. Abbreviations, such and the SGLT-2 inhibitors).

ha
as ‘U’ or ‘IU’, are never used. (iii) Drugs that alter effector site sensitivity to endogen-
hm N
• An insulin syringe must always be used to measure and pre- ous insulin and reduce gluconeogenesis/glycogenolysis
pare insulin for an i.v. infusion. Insulin infusions are admin- or endogenous metabolism (metformin and the
fo r P ale A am

istered in 50 ml i.v. syringes or larger infusion bags. thiazolidinediones).

Consideration should be given to the supply and use of (iv) Drugs acting on the incretin pathway (GLP-1 analogues
ot o S an x

ready to administer infusion products (e.g. prefilled syringes and the DPP4 inhibitors).
N ot f or sh a E

of fast-acting insulin 50 units in 50 ml 0.9% sodium chloride

It is vital to note that only the sulphonylureas and megliti-
solution).
n
N ot f ee esi

nides are associated with hypoglycaemia in the starved state,

• Policies and procedures for the preparation and administra-
tio
whilst the others are not. Thus the sulphonylureas and megliti-
tion of insulin and insulin infusions in clinical areas are re-
N r. Z th

nides should always be omitted in the perioperative period for

bu

viewed to ensure compliance with the above.

this reason.
D es

tri

Additionally, it is vital that the insulin is prescribed by the

ed t
r R rin
An

brand name rather than the generic name. Furthermore, newer

is

formulations of insulin are available that have different concen- Sulphonylureas

trations. Previously, the concentration was 100 units per ml, but Examples: glibenclamide, gliclazide, glimepiride, glipizide,
insulins are now available with concentrations 200 units per ml; tolbutamide.
300 units per ml and 500 units per ml in an attempt to help Sulphonylureas are insulin secretagogues and have been in
those who require large doses because of their extreme insulin the armamentarium of the diabetologist since the 1950s. They
resistance. Care needs to be taken to ensure that the correct act by binding on the sulphonylurea receptor in the pancreatic
dose is given when prescribing and administering these b-cell, closing KATP channels, which depolarizes the b-cell and
concentrated formulations. It is essential that insulin is causes an influx of calcium. This ultimately leads to exocytosis
never withheld from a patient with T1DM, otherwise DKA of insulin-containing vesicles and an increase in peripheral in-
will ensue. sulin concentration. The maximum HbA1c reduction is up to
13–14 mmol mol1 (1.5%).
The sulphonylureas rely on adequate b-cell function.
The non-insulin glucose-lowering drugs Additionally, because of the increase in insulin secretion there
is the risk of hypoglycaemia in the starved state. There are data
There are currently eight different classes of non-insulin glu-
to show that the rate of severe hypoglycaemia (i.e. needing
cose-lowering drugs. These are:
third party assistance) for those on sulphonylureas is 0.1 per pa-
(i) Sulphonylureas. tient year.9
(ii) Meglitinides. Sulfonylureas can have a very long half-life and some are
(iii) Intestinal alpha-glucosidase inhibitors. renally excreted, therefore their use in the elderly and in pa-
(iv) Sodium-glucose linked transporter inhibitors (SGLT-2 tients with renal impairment is discouraged. The older agents,
inhibitors). e.g. glibenclamide (half-life 10 h), should no longer be pre-
(v) Biguanides. scribed because of this increased risk, whilst the short-acting
(vi) Thiazolidinediones. and hepatic metabolized gliclazide is considered safer.
(vii) Incretin mimetics/GLP-1 analogues. Sulphonylureas are widely used as second-line agents after
(viii) The gliptins/dipeptidyl peptase-4 inhibitors (DPP4 metformin. This is because they are cheap and effective.
inhibitors). However, as there is now evidence that the long-term use of

204 BJA Education | Volume 17, Number 6, 2017

Diabetes medication pharmacology

sulphonylureas is associated with deterioration of glycaemic Biguanides

control, weight gain, and increased risk of cardiovascular harm,
Example: metformin.
other drugs are now advocated as second-line agents.10
Metformin is the biguanide that is advocated by several
international guidelines as the first-line treatment of people
Meglitinides with T2DM.3 This is because until recently, it was the only oral
hypoglycaemic agent that had evidence of cardiovascular
Examples: nateglinide, repaglinide. benefit.
These agents are short-acting insulin secretagogues. They Metformin will only work when there is circulating insu-
work in a similar manner to sulphonylureas but are rarely used lin present and it can be used in combination with other
because they are short acting and thus require more frequent oral agents or insulin. It is one of the few oral glucose-
dosing. They have a more rapid onset and shorter duration of lowering agents which is weight neutral, and the maximum
action than the sulphonylureas, which could have beneficial ef- HbA1c reduction is most studies is up to 13 or 14 mmol mol1
fects on decreasing late hypoglycaemia. Furthermore, repagli- (1.5%).
nide is non-renally excreted.11 The use of metformin was first described in animals in the
1920s and was eventually licensed in Europe for use in humans
in the late 1950s. Despite this long history of use, the exact
Intestinal alpha-glucosidase inhibitors
mechanism of action of metformin remains elusive, although
Examples: Acarbose. several mechanisms have been proposed.
The human gut is not designed to absorb disaccharides such Normally, in the fed state, there is suppression of endogen-
as sucrose and therefore an enzyme in the brush border called ous hepatic gluconeogenesis owing to activation of adenosine
alpha-glucosidase cleaves the disaccharides into its component monophosphate (AMP)-activated protein kinase. However, in

a
monosaccharides, which can then easily be absorbed. T2DM there is a failure to suppress hepatic gluconeogenesis in

tth
C s
Inhibition of this enzyme inhibits the absorption of monosac- the fed state, leading to inappropriate gluconeogenesis in the
ad ote
ha
charides, therefore limiting the rate of rise of plasma glucose face of hyperglycaemia. Metformin reactivates hepatic AMP kin-
concentrations and reducing the total quantity of carbohydrate ase and inhibits glucagon signalling, leading to a reduction in
hm N
absorbed. Acarbose also inhibits pancreatic alpha-amylase, glycogenolysis and endogenous glucose production. This is im-
which hydrolyses complex carbohydrates into oligosaccharides. portant because the predominant action of metformin is not to
fo r P ale A am

The HbA1c reduction achieved with acarbose is limited, about 8 lower blood glucose but to stop glucose from increasing.
mmol mol1 (0.75%). Metformin also has an ‘acarbose-like’ action. It inhibits in-
ot o S an x

Acarbose can be used in combination with sulphonylureas,

N ot f or sh a E

testinal disaccharidase, which leads to a delay in absorption of

metformin, or insulin. Its use is however limited by its gastro- monosaccharides and a reduction in the rate of increase of
intestinal side-effects. The flora that inhabit the large bowel
n blood glucose. The resultant disaccharide load to the large
N ot f ee esi

tio
lumen ferment the carbohydrate load, resulting in the common bowel and subsequent micro-organism fermentation causes
side-effects of bloating, diarrhoea, abdominal pain, and nausea. many of the gastrointestinal side-effects of metformin, includ-
N r. Z th

bu

It is for this reason, therefore, that the dose of the drug must be ing nausea, diarrhoea, bloating, and wind. Normally, the gastro-
D es

built up gradually. It is contraindicated in those individuals intestinal upset does resolve; however, should it continue to be
tri
ed t
r R rin

with inflammatory bowel disease or history of previous abdom- a problem then the use of modified release metformin has been
An

is

inal surgery. shown to reduce the rate of incidence of gastrointestinal side-

effects by 50%.
Metformin has also been shown to work by increasing insu-
Sodium-glucose transporter 2 inhibitors lin receptor expression and tyrosine kinase activity, thereby
Examples: canagliflozin, dapagliflozin, empagliflozin. increasing insulin sensitivity. This results in a reduction of
Glucose is filtered freely through the kidneys at about blood glucose but this effect is relatively minor compared with
180 g day1. Normally, very little glucose is lost in the urine be- the effect on suppression of hepatic gluconeogenesis. The in-
cause it is actively reabsorbed in the proximal convoluted renal crease in insulin sensitivity can be seen in patients treated with
tubule by a transport mechanism linking sodium and glucose, both insulin and metformin who need to stop their metformin;
SGLT2. This actively reabsorbs almost all the glucose that is the dose of insulin rapidly increases by between 25 and 35%,
filtered. showing the insulin-sparing effect of the drug.
The SGLT2 inhibitors are a class of drug which prevent glu- The feared complication of lactic acidosis is rare and most
cose reabsorption from the proximal convoluted tubules in an frequently occurs in patients who have contraindications to the
insulin-independent manner and give rise to the osmotic symp- use of metformin (e.g. renal and severe heart failure with low
toms of uncontrolled diabetes: polyuria, dehydration, subse- peripheral perfusion).14 It is postulated that it is not the metfor-
quent polydipsia, and candidiasis. They result in the loss of min that causes the lactic acidosis but the associated comorbid-
several grams of glucose in the urine every 24 h. There is a sub- ity. The dose of metformin should be reviewed if the eGFR <45
sequent reduction in HbA1c of about 11 mmol mol1. They are ml/min/1.73 m2 and should be stopped if the eGFR is <30 ml/
also associated with a modest weight loss, as well as a reduc- min/1.73 m2.
tion in cardiovascular mortality.12 Because they work independ- The summary of product characteristics for metformin15
ently of insulin there are currently studies looking at the use of suggests that that it should be stopped 48 h before surgery and
this drug in people with T1DM. the administration of iodinated contrast owing to the fear of the
Although the risk of hypoglycaemia in the starved state is metabolic complications of lactic acidosis and AKI. It is now
low, it is now advised that these drugs are stopped before sur- appreciated that this advice may deny many patients the bene-
gery, as there have sporadic cases of DKA that have been attrib- fits of glycaemic control that can be achieved with the use of
uted to the SGLT2 inhibitors.13 metformin, as metformin is not as toxic as once thought.

BJA Education | Volume 17, Number 6, 2017 205

Diabetes medication pharmacology

In the perioperative period, the fact that metformin does not is produced by the L cells of the upper GI tract in response to
cause hypoglycaemia and is safer than previously thought glucose in the gut lumen. It has multiple effects including:
allows for the JBDS and the AAGBI to recommend its continu-
(i) Enhancing glucose dependent insulin secretion from b-
ation in elective surgery with short fasting times, as long as
cells.
other risk factors for acute kidney injury are not present (e.g.
(ii) Inhibits glucagon secretion from a-cells.
the use of contrast medium, or other nephrotoxic agents).4,5
(iii) Reduces gastric emptying, slowing the rise in postprandial
The anaesthetic technique must be renoprotective (e.g. main-
glucose.
tain normal blood pressure, maintain normovolaemia, and
(iv) Promotes satiety and reduces appetite.
avoid other potential nephrotoxins).
People with T2DM have very low concentrations of GLP-1
compared with those without the condition.18
Thiazolidinediones Endogenous GLP-1 has a circulating half-life of 2 min be-
Examples: pioglitazone. cause it is broken down by an endogenous circulating enzyme
The thiazolidinediones act on the peroxisome proliferator- called DPP-4. Greater understanding of this pathway has led to
activated receptor-c, a transcription factor altering multiple two new drug classes to treat diabetes; the GLP-1 analogues and
genes that are involved in glucose and other substrate metabol- the DPP-4 inhibitors (see Fig. 5). The overall HbA1c reduction
ism. They increase the sensitivity of naturally released insulin, with both these classes of drug is in the region of 11 mmol
and so again the risk of hypoglycaemia in the starved state is mol1 (1%). They are frequently used in combination with many
low. other medications, such as metformin, sulphonylureas, and in-
The use of this class of drug has been severely limited over sulin. Both GLP-1 analogues and DPP-4 inhibitors are currently
the last few years owing to the development of potential com- contraindicated in renal failure. The gastric emptying rate may

a
plications including increased risk of cardiovascular death, be significantly prolonged, and has been reported to nearly dou-

tth
macular oedema, and bladder cancer.16–19 The use of this class ble. This may have important implications for the choice of an-

C s
aesthesia and preoperative fasting times.19
ad ote
of drug is reducing, with only pioglitazone now available in the

ha
UK.
hm N
Pioglitazone works very slowly and needs to be given for at
least 4–6 months for maximum benefit. It is most frequently
fo r P ale A am

used in combination with other agents, and the overall im- Glucagon-like peptide-1 (GLP)-1 analogues
provement in control is modest at 8–11 mmol mol1 (0.75–1%). Examples: dulaglutide, exenatide, liraglutide, lixisenatide.
ot o S an x

These drugs are peptides and thus must be administered by

N ot f or sh a E

the s.c. route to avoid degradation by intestinal peptidases.

The incretin pathway n These GLP-1 analogues are resistant to degradation by DPP-4,
N ot f ee esi

tio
Incretin hormones, such as glucagon-like peptide-1, are se- and thus have a longer half-life than endogenous GLP-1. The
creted from the gastrointestinal tract and cause a glucose-de- fact that exenatide can be given by weekly s.c. injection as an
N r. Z th

bu

pendent increase in the secretion of insulin from b-cells. GLP-1 extended release form has the potential to aid in patient
D es

tri
ed t
r R rin
An

is

GLP-1 analogues
e.g. exenatide

Supra-normal levels of GLP-1

resistant to DPP4

Stimulate insulin release in response to food

Reduce hepatic gluconoeogenesis
ACTIVE GLP-1 Decreased blood glucose
Reduce gastric emptying
Promote satiety

Increased active
GLP-1

DPP-IV
DPP4 inhibitors
(breaks down
e.g. sitagliptin
GLP)

Deactivated GLP-1

Fig 5 Pharmacological action of GLP-1 analogues and DPP-4 inhibitors (orange arrows/boxes) on endogenous incretin pathway (blue arrows/boxes).

206 BJA Education | Volume 17, Number 6, 2017

Diabetes medication pharmacology

compliance. Owing to their mechanism of action they can aid sa.nhs.uk/alerts/?entryid45¼74287 (accessed 28 December
with weight loss.20 2016)
7. National Institute for Clinical and Healthcare Excellence.
Type 2 diabetes in adults: management. NICE guideline
Dipeptidyl peptidase- 4 (DPP-4) inhibitors
NG28. 2015. Available from https://www.nice.org.uk/guid
Examples: alogliptin, linagliptin, saxagliptin, sitagliptin, ance/NG28 (accessed 28 December 2016)
vildagliptin. 8. Al-Tabakhah MM. Future prospect of insulin inhalation for
The incretin pathway can also be modified by inhibition of diabetic patients. The case of Afrezza versus Exubera. J Con
the enzyme DPP-4 by the DPP-4 inhibitors. Whilst these agents
Rel 2015; 215: 25–38
can improve glycaemic control, they do not have the weight
9. UK Hypoglycaemia Study Group. Risk of hypoglycaemia in
loss benefits of the GLP-1 analogues and they have been associ-
types 1 and 2 diabetes: effects of treatment modalities and
ated with pancreatitis and pancreatic cancer.21
their duration. Diabetologia 2007; 50: 1140–7
10. Inzucchi SE, Bergenstal RM, Buse JB et al. Management of
Conclusion hyperglycemia in type 2 diabetes, 2015: a patient-centered
The pharmacological management of diabetes has progressed approach: Update to a position statement of the American
exponentially in recent years, with multiple new formulations Diabetes Association and the European Association for the
of insulin and new non-insulin glucose lowering agents now Study of Diabetes. Diabetes Care 2015; 38: 140–9
available. A thorough understanding of the pharmacokinetic 11. Guardado-Mendoza R, Prioletta A, Jimenez-Ceja LM et al.
and pharmacodynamic properties of these drugs is vital for the “The role of nateglinide and repaglinide, derivatives of
anaesthetist to ensure safe perioperative care of the surgical pa- meglitinide, in the treatment of type 2 diabetes mellitus”.

a
tient on glucose-lowering medication. Arch Med Sci 2013; 9: 936–43

tth
12. Zinman B, Wanner C, Lachin JM et al. Empagliflozin, cardio-

C s
ad ote vascular outcomes, and mortality in type 2 diabetes. N Eng J

ha
Declaration of interest Med 2015; 373: 2117–28
hm N
None declared. 13. Peters AL, Buschur EO, Buse JB, Cohan P, Diner JC, Hirsch IB.
Euglycemic diabetic ketoacidosis: a potential complication
fo r P ale A am

of treatment with sodium-glucose cotransporter 2 inhib-

MCQs ition. Diabetes Care 2015; 38: 1687–93
ot o S an x

14. Eppenga WL, Lalmohamed A, Geerts AF et al. Risk

N ot f or sh a E

The associated MCQs (to support CME/CPD activity) can be

accessed at https://access.oxfordjournals.org by subscribers to of lactic acidosis or elevated lactate concentrations
in metformin users with renal impairment: a
BJA Education.
n
N ot f ee esi

tio
population-based cohort study. Diabetes Care 2014; 37:
2218–24
N r. Z th

bu

References 15. Summary of Product Characteristics: Metformin. Available

D es

1. National Audit Office (2015) The management of adult dia-

tri

from http://www.medicines.org.uk/emc/medicine/23244/
ed t
r R rin
An

betes services in the NHS: progress review. Available from SPC (accessed 28 December 2016)
is

https://www.nao.org.uk/wp-content/uploads/2015/10/The- 16. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of

management-of-adult-diabetes-services-in-the-NHS-prog myocardial infarction and death from cardiovascular
ress-review.pdf (accessed 28 December 2016) causes. N Eng J Med 2007; 356: 2457–71
2. Gale EAM, Anderson JV. Diabetes mellitus and other dis- 17. Consoli A, Formoso G. Do thiazolidinediones still have a role
orders of metabolism. In: Kumar P, Clark M, eds. Kumar and in treatment of type 2 diabetes?. Diabetes Obes Metab 2013;
Clark’s Clinical Medicine, 8th Edn. Saunders Ltd, 2012; 1001–46 15: 967–77
3. Rang HP, Ritter JM, Flower RJ, Henderson G. The control of 18. Nauck M, Stockmann F, Edert R, Creutzfeldt W. Reduced
blood glucose and drug treatment of diabetes mellitus. In: incretin effect in Type 2 (non-insulin-dependent) diabetes.
Rang and Dale’s Pharmacology, 8th Edn. Edinburgh: Elsevier Diabetologia 1986; 29: 46–52
Churchill Livingstone, 2015; 380–92 19. Linnebjerg H, Park S, Kothare PA et al. Effect of exenatide on
4. Barker P, Creasey PE, Dhatiraya K et al. “Perioperative gastric emptying and relationship to postprandial glycemia
Management of the surgical patient with Diabetes 2015” in type 2 diabetes. Regul Pept 2008; 151: 123–9
(Association of Anaesthetists of Great Britain and Ireland). 20. Thong KY, Jose B, Sukumar N et al. Safety, efficacy and
Anaesthesia 2015; 70: 1427–40 tolerability of exenatide in combination with insulin in the
5. Dhatariya K, Levy N, Flanagan D et al., for the Joint British Association of British Clinical Diabetologists nationwide
Diabetes Societies. Management of adults with diabetes exenatide audit. Diabetes Obes Metab 2011; 13: 703–10
undergoing surgery and elective procedures: Improving 21. Butler AE, Campbell-Thompson M, Gurlo T, Dawson DW,
standards, September 2015. Available from http://www.dia Atkinson M, Butler PC. Marked expansion of exocrine and
betologists-abcd.org.uk/JBDS/JBDS_IP_Surgical_Guideline_ endocrine pancreas with incretin therapy in humans with
2015_Full.pdf (accessed 28 December 2016) increased exocrine pancreas dysplasia and the potential for
6. National Patient Safety Agency. Safer Use of Insulin, Rapid glucagon-producing neuroendocrine tumors. Diabetes 2013;
Response Report, 2010. Available from http://www.nrls.np 62: 2595–604

BJA Education | Volume 17, Number 6, 2017 207

153
Chapter 26
Diabetic Emergencies

Diabetic Ketoacidosis
What is diabetic ketoacidosis?

Diabetic ketoacidosis (DKA) is a potentially life-threatening metabolic complica-

tion of diabetes defined by the biochemical triad of ketonaemia, hyperglycae-

a
mia and acidaemia.
tth
C s
ad ote
ha
hm N

What is the pathophysiology of DKA?

fo r P ale A am

Diabetic ketoacidosis usually occurs as the result of absolute or relative insulin

ot o S an x
N ot f or sh a E

deficiency which, when combined with increases in glucagon, catecholamines

n

and cortisol stimulates lipolysis, free fatty acid production and ketogenesis.
N ot f ee esi

tio

Accumulation of the ketoacids (3-β-hydroxybutyrate, acetone and acetoacetate)

N r. Z th

bu

then results in a metabolic acidosis. Hyperglycaemia results from increased

D es

tri
t
r R rin

hepatic gluconeogenesis and glycolysis in addition to reduced glucose uptake

An

is

peripherally due to insulin deficiency.

ed

The marked fluid depletion characteristic of DKA is the result of several processes:
1 Osmotic diuresis secondary to hyperglycaemia
2 Vomiting (commonly seen in DKA)
3 Reduced oral intake secondary to reduced consciousness

What are the causes of DKA?

Common precipitating factors include surgery, intercurrent infection, myocar-
dial infarction and non-compliance with drug therapy.

What are the clinical features of DKA?

The clinical features of DKA include thirst, polyuria, nausea, vomiting, abdom-
inal pain, dehydration, smell of ketones on the breath, Kussmaul breathing
(deep, laboured and gasping breathing pattern secondary to severe metabolic
acidosis), confusion and coma.
154 Chapter 26: Diabetic Emergencies

What are the diagnostic criteria for DKA?

As stated by the Joint British Diabetes Societies, all three of the following must
be present:
1 Capillary blood glucose >11 mmol/l
2 Ketonaemia >3 mmol/l or urine ketones >2+ on urine dipsticks
3 Venous bicarbonate <15 mmol/l and/or venous pH <7.3

What are the indications for consideration of admission to

HDU/ICU?

The presence of one or more of the following may indicate severe DKA, and
therefore a higher level of care should be considered:

a
1 Blood ketones >6 mmol/l
tth
C s
2 Bicarbonate <5 mmol/l
ad ote
ha
3 Venous/arterial pH <7.1
hm N

4 Hypokalaemia on admission <3.5 mmol/l

fo r P ale A am

5 GCS <12
6 SpO2 <92% (assuming normal baseline function)
ot o S an x
N ot f or sh a E

7 Systolic BP <90 mmHg

n

8 Heart rate <60 or >100 bpm

N ot f ee esi

tio

9 Anion gap >16

N r. Z th

bu
D es

tri
t
r R rin

Anion gap = (Na+ + K+ ) − (Cl − + HCO3− )

An

is
ed

What is the treatment of DKA?

Most hospitals have clear guidelines/protocols for the management of DKA.

The patient with DKA should be managed with an ABCDE approach, treating
abnormalities as they are found. Specific management focuses on the following
principles:
1 Fluid and electrolyte replacement
– Aims:
i Restore circulating volume
ii Clear ketones
iii Correct electrolyte imbalance
– Crystalloid fluid replacement should be used and 0.9% sodium chloride is
the fluid of choice (although debate over this persists)
– Initial hypotension (SBP <90 mmHg) should be treated with 500 ml boluses
of 0.9% sodium chloride
– Fluid replacement should be continued with 1 litre over the first hour,
a further litre over 2 hours, followed by another litre over 4 hours
– Modify rate and volume of fluid in young and elderly patients, and those
with renal and heart failure (increased risk of cerebral oedema)
Chapter 26: Diabetic Emergencies 155

– The potassium debt is typically 3–5 mmol/kg: Each bag of 0.9% sodium
chloride should be supplemented with potassium when the plasma potas-
sium is <5.5 mmol/l
2 Insulin therapy and metabolic treatment targets
Role of insulin: Suppression of ketogenesis, reduction of blood glucose,
correction of electrolyte disturbance
– A fixed rate insulin infusion should be commenced (0.1 units/kg/hour)
– Do not give an initial insulin bolus
– If the patient normally takes a long-acting insulin analogue this should be
continued
– Close monitoring of venous blood gases and urinary/blood ketones is essen-
tial to closely monitor treatment efficacy
– Overall targets for treatment:
i Decrease blood ketone level by 0.5 mmol/l per hour
ii Increase venous bicarbonate by 3 mmol/l per hour
iii Decrease capillary blood glucose by 3 mmol/l per hour

a
iv Maintain potassium 4.0–5.5 mmol/l
tth
C s
– If these targets are not achieved, then the fixed rate insulin infusion rate
ad ote
ha
should be increased
hm N

– 10% glucose infusion may be necessary to avoid hypoglycaemia and allow

fo r P ale A am

the continuation of the insulin infusion to suppress ketogenesis

ot o S an x

3 Treatment of the underlying cause

N ot f or sh a E

4 Other supportive treatments

n
N ot f ee esi

i Thromboprohylaxis (mechanical and pharmacological)

tio

ii Stress ulcer prophylaxis

N r. Z th

bu
D es

iii Consider enteral feeding as necessary

tri
t
r R rin
An

is
ed

What is the commonest cause of death in DKA?

Cerebral oedema (more so in children and young adults).

How does the management of DKA differ in children?

The markedly increased risk of cerebral oedema in the paediatric population
necessitates judicious use of fluid.
1 A 10 ml/kg bolus of 0.9% sodium chloride be given only if the child is shocked
(poor peripheral pulses, prolonged capillary refill with tachycardia and/or
hypotension)
2 Fluid requirement = deficit + maintenance – volume used in resuscitation
This volume of fluid is given over 48 hours in the paediatric population (rather
than 24 hours)

Fluid deficit (ml) = Body weight × % dehydration × 10

3 Maintenance fluid volumes are lower than standard and it is important not to
over-estimate fluid requirement
4 Insulin therapy is delayed for one hour
156 Chapter 26: Diabetic Emergencies

Hyperglycaemic Hyperosmolar State

What is hyperglycaemic hyperosmolar state?

The characteristic features of a hyperglycaemic hyperosmolar state (HHS) are

severe hyperglycaemia and fluid depletion with no or mild ketosis. It is usually
seen in elderly patients with uncontrolled type 2 DM and often other significant
comorbidity.

What is the mortality associated with HHS?

Hyperglycaemic hyperosmolar state is associated with significant morbidity and

a higher mortality than DKA (15–30%).

a
What are the clinical features of HHS? tth
C s
ad ote
ha
hm N

The characteristic features of HHS include:

fo r P ale A am

1 Hypovolaemia
ot o S an x

Significant fluid losses are evident, estimated to be between 100–220 ml/kg

N ot f or sh a E

2 Marked hyperglycaemia (>30 mmol/l)

n
N ot f ee esi

Without significant hyperketonaemia (<3 mmol/l)

tio

Without significant acidosis (pH >7.3, bicarbonate >15 mmol/l)

N r. Z th

bu
D es

3 Serum hyperosmolarity
tri
t
r R rin
An

Osmolality >320 mosmol/kg

is
ed

The presenting signs and symptoms are generally non-specific: anorexia, malaise
and weakness, which progresses to severe dehydration, renal impairment and coma.
Whilst DKA tends to present within hours of onset, HHS develops over many days
and consequently dehydration and metabolic disturbance may be very severe.

What are the goals of treatment of HHS?

A hyperglycaemic hyperosmolar state should be managed with an ABCDE

approach, treating abnormalities as they are found. Specific treatment involves:
1 Treatment of the underlying cause
2 Normalisation of osmolality
– It is very important to calculate osmolality regularly to monitor the response
to treatment

Osmolality ¼ (2Na+ + glucose + urea)

3 Replacement of fluid and electrolyte losses

– Debate persists around the speed and type of fluid required; however, the
Joint British Diabetes Societies suggests:
Chapter 26: Diabetic Emergencies 157

– 0.9% sodium chloride (+/- potassium as necessary) is generally advocated,

as the majority of losses are sodium, chloride and potassium
– 0.45% sodium chloride is only used if osmolality is no longer declining
despite adequate fluid resuscitation
– Replace potassium if <5.5 mmol/l
– Targets for treatment:
i K+ 4.0–5.5 mmol/l
ii Na+ reduction by ≤10 mmol/l in 24 hours
iii Glucose reduction by ≤5 mmol/l per hour
4 Normalisation of blood glucose
– Fluid replacement alone will result in a falling blood glucose (there is a risk
however of precipitously dropping the osmolality)
– Start a low dose insulin infusion (0.05 units/kg/hour) only once glucose
values are no longer decreasing with fluid resuscitation (unless ketonaemia
is identified)
5 Prevention of complications

a
– Thrombotic events (including myocardial infarction (MI) and ischaemic
tth
C s
stroke) are more common than in DKA
ad ote
ha
– Care of pressure areas is mandatory in this group of patients
hm N
fo r P ale A am

What are the indications for potential admission to HDU/

ot o S an x
N ot f or sh a E

ICU?
n
N ot f ee esi

tio

1 Osmolality >350 mosmol/kg

N r. Z th

bu
D es

2 Sodium >160 mmol/l

tri
t
r R rin
An

3 pH <7.1
is
ed

4 K+ <3.5 or >6 mmol/l

5 GCS <12
6 SpO2 <92% on room air
7 SBP <90 mmHg
8 Heart rate <60 and >100 bpm
9 Urine output <0.5 ml/kg/hour
10 Creatinine >200 μmol/l
11 Hypothermia
12 MI, stroke or other serious comorbidity

Further Reading
British Society for Paediatric Endocrinology and Diabetes, 2015. BSPED Recommended Guideline for
the Management of Children and Young People under the Age of 18 Years with Diabetic Ketoacidosis
[online]. Available at: www.bsped.org.uk/clinical/docs/DKAguideline.pdf (Accessed:
16 November 2016)
Joint British Diabetes Societies Inpatient Care Group, 2013. The Management of Diabetic Ketoacidosis
in Adults [online]. Available at: www.diabetologists-abcd.org.uk/jbds/JBDS_IP_DKA_Adults_Revised
.pdf (Accessed: 16 November 2016)
Joint British Diabetes Societies Inpatient Care Group, 2012. The management of the hyperosmolar
hyperglycaemic state (HHS) in adults with diabetes [online]. Available at: www.diabetologists-abcd
.org.uk/jbds/jbds_ip_hhs_adults.pdf (Accessed: 16 November 2016)
BJA Education, 16 (1): 8–14 (2016)

doi: 10.1093/bjaceaccp/mkv006
Advance Access Publication Date: 8 June 2015
Matrix reference
1A01, 2A03, 2A05, 2C01

Developments in the management of diabetic

ketoacidosis in adults: implications for anaesthetists
A Hallett MBChB FRCA, A Modi MBBS MD FRCA and
N Levy MBBS BSc FRCA FFICM*
Consultant Anaesthetist, West Suffolk Hospital, Hardwick Lane, Bury St Edmunds IP33 2QZ, UK

a
tth
C s
*To whom correspondence should be addressed. Tel: +44 01284 712819; Fax: +44 01284 713100; E-mail: [email protected]

ad ote
ha
hm N
and are associated with significant morbidity and mortality.
fo r P ale A am

Key points The majority of mortality and morbidity in DKA are attributable
to delays in presentation and initiation of treatment. Rapid recog-
• Diabetic ketoacidosis (DKA) is a medical emergency
ot o S an x

nition and treatment of DKA is critical.

and bedside capillary ketone testing allows timely
N ot f or sh a E

To overcome these concerns and to highlight current man-

diagnosis and identification of successful treatment. n agement strategies, the Joint British Diabetes Societies (JBDS)
N ot f ee esi

• 0.9% saline with premixed potassium chloride published guidelines in 2010. This was updated in consultation
tio
should be the main resuscitation fluid on the gen- with the Intensive Care Society in September 2013.1
N r. Z th

eral wards and in theatre; this is because it complies

bu

This article will review the pathophysiology of DKA and high-

with National Patient Safety Agency recommenda- light the modern management of DKA that is relevant for anaes-
D es

tri
ed t

tions on the administration of potassium chloride. thetists. A summary of the JBDS guidelines pertinent to intensivists
r R rin
An

has been published.2

is

• Weight-based fixed rate i.v. insulin infusion (FRIII)

is now recommended rather than a variable rate
i.v. insulin infusion (VRIII).
Epidemiology
• The blood glucose must be kept above 14 mmol In England in 2010, there were 14 375 admissions to acute NHS
litre−1 with the FRIII. trusts where DKA was the primary diagnosis. Subsequently, it
• Precipitating factor(s) needs to be identified and was estimated that 13% of these patients were admitted to Inten-
treated. Surgery and also critical care may be indi- sive Care Units (2% of all general ICU admissions).3 Furthermore,
cated to manage the patient presenting with DKA. the National Diabetes Inpatient Audit 2012 found that 0.5% of in-
patients with diabetes actually developed DKA as an inpatient
whilst in hospital.4
The mortality rate has decreased in some patient popula-
tions; however, in the elderly and in patients with comorbidities,
Diabetic ketoacidosis (DKA) is a medical emergency. The diag- it remains >5%.
nostic triad is:

(i) Ketonaemia ≥3.0 mmol litre−1 or significant ketonuria (more Pathophysiology

than 2+ on urine sticks)
(ii) Blood glucose >11.0 mmol litre−1 or known diabetes mellitus DKA results from a relative or absolute insulin deficiency with a
(iii) Bicarbonate <15.0 mmol litre−1, venous pH <7.3, or both. concomitant increase in counter regulatory hormones such
as glucagon, catecholamines, cortisol, and growth hormone.
DKA can occur in both type 1 and type 2 diabetes mellitus and, al- Hyperglycaemia ensues because of increased gluconeogenesis,
though preventable, it remains a frequent and life-threatening accelerated glycogenolysis, and impaired glucose utilization by
complication. Errors in the management of DKA are not uncommon peripheral tissues.

© The Author 2015. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved.
For Permissions, please email: [email protected]

8
Developments in the management of diabetic ketoacidosis in adults

This is magnified by transient insulin resistance because of

the hormone imbalance itself. The combination of insulin defi-
ciency and increased counter regulatory hormones leads to the
release of free fatty acids and their unrestrained oxidation in
the liver to ketones. These ketones include acetone, 3-beta-
hydroxybutyrate, and acetoacetate. The predominant ketone in
DKA is 3-β-hydroxybutyrate. Hydrogen ions produced by the dis-
sociation of the ketone bodies causes the metabolic acidosis.5
Hyperglycaemia causes osmotic fluid shifts from intracellular
to extracellular compartments. The glucose load in the glomeru-
lar tubules exceeds the renal threshold leading to glucosuria and
an obligatory osmotic diuresis. This diuresis causes a loss of so-
dium, potassium, and phosphate along with water and glucose.

Causes
The three most common causes are:

(i) An underlying infection

(ii) Missed insulin treatment
(iii) First presentation of diabetes mellitus.6

a
Inadequate insulin therapy is the recognized cause of hospital-

tth
C s
acquired DKA. This may be caused by inadequate prescription

ad ote
or administration of insulin, or insufficient monitoring of capil-

ha
lary blood glucose (CBG).
hm N
The cause may occasionally necessitate emergency surgical
treatment (e.g. appendicitis; infarcted bowel; incision and drain-
fo r P ale A am

age of abscess; ectopic pregnancy).

ot o S an x
N ot f or sh a E

Clinical presentation Fig 1 GlucoMen blood glucose meter

DKA occurs predominantly in patients with type 1 diabetes, but it

n
N ot f ee esi

can also develop in patients with ketone prone type 2 diabetes. Ketone meters
tio
There is a wide clinical spectrum in the presentation of DKA. In the past, diagnosis and successful treatment of DKA was
N r. Z th

bu

DKA is a recognized cause of the acute abdomen, and this in itself guided by CBG with the erroneous assumption that correction
D es

can actually result in unnecessary emergency surgery. Presenta- of hyperglycaemia would be a marker for suppression of ketogen-
tri
ed t

tion in type 2 diabetes is the same as in type 1 diabetes; however, esis and successful reversal of acidosis. However, CBG is both a
r R rin
An

is

some studies have found there to be a different biochemical pres- poor determinant of severity and a poor surrogate marker for suc-
entation with a less severe acidosis and a tendency for normal cessful treatment. Euglycaemic ketoacidosis is possible depend-
initial serum potassium levels.7 ing on the hepatic glycogen stores before the onset of DKA. This
demonstrates the necessity for ketone monitoring.
Ketone meters (Fig. 1) are now available for rapid testing for β-
Investigations hydroxybutyrate at the bedside. Handheld ketone meters are
Initial investigations fall into three categories: operated in an identical fashion to bedside CBG meters. Results
are available within 10 s allowing immediate differentiation
(i) Establish diagnosis of DKA
between simple hyperglycaemia and ketotic states.
(ii) Baseline investigations
Trials have found that the utilization of blood ketone testing is
(iii) Identify cause.
more effective than urine acetoacetate testing in improving diag-
Ongoing investigations are then required to monitor the effect of nosis and their use is associated with a reduced time to recovery
treatment, and to ensure successful and safe treatment. from DKA and shorter hospital stay.8

Blood gas
Investigations to establish diagnosis of DKA
To make the diagnosis, a blood gas is essential for the assessment
As DKA is the triad of: of the acidosis and serum bicarbonate levels. Recent evidence has
shown little difference between arterial and venous pH and bicar-
(i) Ketonaemia ≥ 3.0 mmol litre−1 or significant ketonuria (more
bonate.9 These small differences are inconsequential to the diag-
than 2+ on urine sticks)
nosis or management of DKA, and therefore the JBDS guidelines
(ii) Blood glucose >11.0 mmol litre−1 or known diabetes mellitus
recommend the use of venous blood gases if the patient is mana-
(iii) Bicarbonate <15.0 mmol litre−1, venous pH <7.3, or both.
ged on the ward, in order to prevent repeated arterial punctures.
The following investigations are mandatory.
Baseline investigations
(i) Capillary ketone levels/urinalysis for ketones
(ii) Blood sugar These include full blood count, urea, creatinine, potassium, so-
(iii) Blood gas for pH, bicarbonate, or both. dium, chloride, CRP, and liver function tests.

BJA Education | Volume 16, Number 1, 2016 9

Developments in the management of diabetic ketoacidosis in adults

Investigations to identify cause Table 1 Typical fluid replacement regimen for a previously well
70 kg adult on the general ward
It is imperative to discover the cause of the DKA and investigations
should be based on the clinical findings. Common investigations Fluid Fluid Rate
include ECG, blood cultures, amylase, and pregnancy test. number

Initial bag 1 litre 0.9% saline 1000 ml h−1

Ongoing investigations 2nd bag 1 litre 0.9% saline with premixed 500 ml h−1
To assure safe response to treatment, the following should occur potassium chloride
hourly till resolution of the ketosis: 3rd bag 1 litre 0.9% saline with premixed 500 ml h−1
potassium chloride
(i) CBG/arterial blood glucose (if arterial line sited) 4th bag 1 litre 0.9% saline with premixed 250 ml h−1
(ii) Capillary blood ketones. potassium chloride
5th bag 1 litre 0.9% saline with premixed 250 ml h−1
To assure metabolic stability, the following should occur at a potassium chloride
minimum of 2 hourly intervals until resolution of the ketosis: 6th bag 1 litre 0.9% saline with premixed 150 ml h−1
potassium chloride
(i) pH Further 1 litre 0.9% saline with premixed Clinical
(ii) bicarbonate fluid potassium chloride assessment
(iii) potassium. With regular re-assessment

Initial management

a
receive an initial bolus of 500 ml over <15 min, and further fluid
DKA is a life-threatening condition and resuscitation along with

tth
C s
boluses dependent on clinical re-assessment.
initial treatment must occur simultaneously with clinical assess-
ad ote
ha
ment. Appropriate history, examination, and investigations
should be undertaken to diagnose the condition, identify the
Insulin administration
hm N
severity, and identify the cause.
Initial management should focus on: Administration of i.v. human soluble insulin is mandatory. Clas-
fo r P ale A am

sically the insulin has been titrated against the surrogate marker
(i) Airway protection, if required of the blood glucose using a variable rate i.v. insulin infusion
ot o S an x

(ii) Fluid resuscitation (VRIII). The term ‘variable rate i.v. insulin infusion’ has now re-
N ot f or sh a E

(iii) Insulin administration placed the ambiguous and obsolete term ‘sliding scale’. It is
(iv) Assessment of severity now recognized that glucose levels are a poor surrogate marker
n
N ot f ee esi

(v) Identification of cause.

tio
for resolution of ketosis, and using the blood glucose as a marker
to guide insulin therapy may (and does) lead to the erroneous ac-
N r. Z th

bu

tion of reducing insulin whilst the patient is still highly ketotic. A

Resuscitation
D es

fixed rate administration of i.v. insulin whilst the patient remains

tri
ed t
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An airway, breathing, circulation, disability, exposure (ABCDE) ketotic avoids this risk. Thus, recent evidence and guidelines sug-
An

is

approach will provide structure to the initial resuscitation. Ap- gest that a weight-dependent fixed rate i.v. insulin infusion (FRIII)
propriate venous access must be obtained. should be administered, rather than the variable rate i.v. insulin
infusion (VRIII). Table 2 summarizes the advantages and disad-
Fluid resuscitation vantages of an FRIII.

The most important initial therapeutic invention in DKA is fluid

replacement followed by insulin administration. It is now univer- Preparation and administration of the fixed rate i.v. insulin infusion
sally agreed that crystalloids with a sodium concentration in the The FRIII is administered via an infusion pump. The FRIII is con-
range of 130–154 mmol litre−1 should be used as the resuscitation stituted by adding 50 units of human soluble insulin (Actrapid®,
fluid. In the UK, this is generally either 0.9% saline or Hartmann’s Humulin S®) to 0.9% sodium chloride to make a final volume of
solution. There is ongoing debate on which crystalloid is super- 50 ml (1 unit ml−1). Ideally this should be provided as a ready-
ior. There is evidence to suggest that the use of balanced crystal- made infusion. The FRIII is then administered at a fixed rate of
loid solutions are associated with a faster resolution of the 0.1 unit kg−1 h−1 (i.e. 7 ml h−1 if weight is 70 kg). Weight should
metabolic acidosis and less hyperchloraemic metabolic acid- be estimated if not available, and pregnant patients should
osis.10 11 However, balanced solutions such as Hartmann’s solu- have their current weight used.
tion contains insufficient potassium, and under NPSA rules, 3% Metabolic targets for the continuation of the current fixed rate
potassium chloride should not be stored/added to fluids on the insulin infusion are:
general wards.12 Therefore, the use of 0.9% saline with premixed
potassium chloride is advocated for ward and theatre use. Critic- (i) Reduction of blood ketone concentration by >0.5 mmol
al care can both administer concentrated potassium centrally, litre−1 h−1
and add potassium to Hartmann’s solution. Thus, critical care (ii) If blood ketone measurement is not available, the venous
may choose to use Hartmann’s solution as the primary fluid for bicarbonate should increase by 3.0 mmol litre−1 h−1
resuscitation. (iii) Reduction in CBG by 3.0 mmol litre−1 h−1.
Table 1 is an example of a typical fluid replacement regimen
for a previously well 70 kg adult. However, the exact rate of infu- If the above targets are not being achieved, it is necessary to
sion should be formulated after clinical assessment of the indi- reassess the patient and consider the causes of non-successful
vidual patient. If the patient is shocked, the patient should treatment. This may include:

10 BJA Education | Volume 16, Number 1, 2016

Developments in the management of diabetic ketoacidosis in adults

Table 2 Advantages and disadvantages of an FRIII

Advantages Disadvantages

(i) Faster resolution of DKA Risk of hypoglycaemia if CBG is not measured hourly and
(ii) No titration of the insulin against the false surrogate marker of capillary additional glucose containing solutions not administered
glucose once CBG <14 mmol litre−1
(iii) Complete resolution of DKA provided the FRIII is turned off once the ketone
levels are <0.6 mmol litre−1

(i) Non-administration of the insulin for any reason (e.g. tissued Critical care referral
cannula, pump not running, anti-syphon valve not used, etc.).
Patients should be considered for critical care referral if any of the
(ii) Ongoing co-morbidity that will need senior review
following criteria are present:
(iii) Insufficient insulin.

If it is deemed that unsuccessful treatment is secondary to insuf- (i) Glasgow Coma Score (GCS) <12 or abnormal AVPU (alert,
ficient insulin, the FRIII will need to be increased in increments of voice, pain, unresponsive) scale
1 unit h–1 until the targets are met. A maximum rate of 15 units (ii) Blood ketones >6 mmol litre−1
h−1 is recommended. (iii) Bicarbonate level <5 mmol litre−1
(iv) Venous/arterial pH <7.0
(v) Hypokalaemia on admission (<3.5 mmol litre−1)

a
Safe cessation of the FRIII

tth
The FRIII should be continued until resolution of the ketosis. (vi) Oxygen saturation <92% on air (assuming normal baseline

C s
respiratory function)
Resolution of DKA is defined as:
ad ote
ha
(vii) Systolic BP below 90 mmHg
(i) pH >7.3 (viii) Pulse over 100 or below 60 beats min
hm N
(ii) bicarbonate >15.0 mmol litre−1 (ix) Anion gap >16 [Anion gap = (Na+ + K+) – (Cl− + HCO3−) ].
fo r P ale A am

(iii) blood ketone level <0.6 mmol litre−1.

It is often necessary to admit emergency surgical patients to a
Before stopping the FRIII, it is necessary to administer insulin in level 2 or 3 facility, both pre- and post-surgery.
ot o S an x
N ot f or sh a E

another form; otherwise, the patient will re-develop ketosis. The

patient can either be recommenced on their usual regimen (if
n
they are eating and drinking) or converted to a variable rate i.v. in-
DKA complications
N ot f ee esi

tio
sulin infusion with concurrent administration of 5% dextrose in Mortality from DKA in the UK has fallen significantly in the last
0.45% saline with 0.15% potassium chloride. This transition 20 yr from 7.96 to 0.67%.1 Hypokalaemia, acute lung injury, and
N r. Z th

bu

should ideally be managed by the diabetes specialist team. co-morbid states such as pneumonia, sepsis, and myocardial
D es

infarction are associated with increased mortality. Cerebral

tri

To aid the transition from i.v. insulin to subcutaneous insu-

ed t
r R rin

oedema remains the most common cause of death in DKA in chil-

An

lins, it now advised that the long-acting analogue insulins are

is

continued. The long-acting analogue insulins are Levemir®, Lan- dren. The exact mechanism is uncertain; however, it is felt that
tus®, and Tresiba®. Some units are also beginning to experiment cerebral oedema may be related to cerebral hypoperfusion before
with the continuation of the long-acting human basal insulins treatment, with subsequent vasogenic oedema occurring during
such as Humulin I®, Insulatard®, and Insuman Basal®. Continu- DKA treatment as a result of reperfusion of previously ischaemic
ation of the long-acting insulins avoids rebound hyperglycaemia brain tissue (i.e. the osmotic fluctuations during DKA treatment
when the i.v. insulin is stopped and may subsequently reduce the do not play the primary causal role).14
length of stay.13 Table 3 summarizes the risk factors, signs and symptoms,
immediate treatment and also the different strategies that are
Management of blood glucose <14 mmol litre−1 utilized by paediatricians to reduce the risk of cerebral oedema.15

The FRIII should be continued until there is resolution of the

ketosis; however, it may cause hypoglycaemia before resolution Further management
of the ketosis. Therefore, it is mandatory to perform hourly Monitoring and replacement of electrolytes
CBGs and to be prepared to give additional glucose once the
CBG is <14 mmol litre−1. It is recommended that 10% glucose Initial serum potassium may be normal, raised or low in DKA.
at 125 ml h−1 should be administered. In theatre, 20% glucose However, there is a total body potassium deficit. Potassium loss
at 50 ml h−1 or 50% glucose may be administered. The rate of is caused by a shift from the intracellular to extracellular space
the primary resuscitation fluid may need to be altered to prevent in exchange for hydrogen ions which accumulate in acidosis.
fluid overload. The extracellular potassium is then lost through osmotic
diuresis.
The initial litre of fluid should not have potassium added. Pro-
Management of continuous subcutaneous insulin
vided the serum potassium is <5.5 mmol litre−1, and the patient is
infusion (CSII) pumps
not oliguric, subsequent fluids should have 40 mmol litre−1 of
Because of erratic and unpredictable insulin absorption, these potassium chloride.
devices should probably be stopped and disconnected during Adequate fluid, potassium and insulin therapy will resolve
an episode of DKA, and only reinstated with diabetes specialist the acidosis in DKA, but there may be disturbances of other
team input. electrolytes including bicarbonate, sodium, and phosphate.

BJA Education | Volume 16, Number 1, 2016 11

Developments in the management of diabetic ketoacidosis in adults

Table 4 Typical fluid and electrolyte deficits in adults with DKA

(iii) Gradual rather rapid restoration of normovolaemia

100 ml kg−1

(ii) Commencement of i.v. insulin after 1 h of fluid

(iv) Use of 0.9% saline initially (1st 4–6 h) and then

Water

Major differences in treatment of paediatric DKA to

7–10 mml kg−1

consideration of saline with tonicity >0.45%

according to serum sodium and osmolality.
Sodium
Chloride 3–5 mmol kg−1
Potassium 3–5 mmol kg−1

Generally, these electrolyte imbalances improve as the DKA is

minimize risk of cerebral oedema

treated effectively. Typical fluid and electrolyte deficits are sum-

(i) No i.v. boluses of insulin
Table 3 Summary of risk factors, signs and symptoms, initial treatment of cerebral oedema, and the strategies used to minimize the risk of cerebral oedema in children

marized in Table 4.

Nasogastric tube
Ketosis causes delayed gastric emptying; therefore, the use of
treatment

nasogastric tube may help protect the airway in those patients

(>48 h)

with an altered mental state, and those who require surgery

and anaesthesia.

Urinary catheter
(iv) CT to rule out other pathology
and avoidance of aggressive

A urinary catheter should be inserted in all patients with an al-

(i) Immediate i.v. mannitol or

(iii) Intubation and ventilation

tered mental state, those in a critical care setting or undergoing

a
Initial treatment of cerebral

anaesthesia for monitoring of urine output and fluid balance.

tth
hypertonic 3% saline

C s
(ii) Reduce fluids by 1/3

Oliguria is a sign of acute kidney injury.

ad ote
hyperventilation

ha
Venous thromboembolism risk assessment
hm N
and prophylaxis
fo r P ale A am

All patients should receive appropriate venous thrombo-

oedema

embolism (VTE) risk assessment and subsequent prophylaxis.

ot o S an x

Dehydrated patients with DKA are at high risk of VTE. Both chem-
N ot f or sh a E

ical (e.g. low-molecular-weight heparin) and physical (e.g. anti-

(iii) Change in neurological status

embolic stockings) thromboprophylaxis should be considered.

n
N ot f ee esi
(iv) Specific neurological signs

(v) Increase in blood pressure

(e.g. cranial nerve palsies)

tio
(restlessness, irritability,

(vi) Decreased O2 saturation

Antibiotics
increased drowsiness,

N r. Z th
(ii) Slowing of heart rate

bu
D es

If infection is suspected appropriate antibiotic therapy should be

Signs and symptoms

tri
ed t

commenced according to local policy.

incontinence)

r R rin
An

is
(i) Headache

Involvement of diabetes specialist teams

The diabetes specialist team must be involved in the care of those
with DKA as soon as possible in the acute phase. Their involve-
ment has been shown to reduce the length of stay and improve
patient safety.
Greater hypocapnia at presentation after adjusting for

An attenuated increase in measured serum sodium

Perioperative management of DKA

Administration of insulin in the first hour of fluid
Bicarbonate treatment for correction of acidosis
Increased serum urea nitrogen at presentation

Greater volumes of fluid given in the first 4 h

If a surgical cause is identified, senior multidisciplinary review to

discuss the optimal timing of surgery is required. It is also im-
portant to try and ensure that the clinical picture of an ‘acute
More severe acidosis at presentation

abdomen’ is not secondary to the DKA in order to prevent need-

less surgery. The Royal College of Surgeons (RCS) document
concentrations during therapy
Longer duration of symptoms

‘Emergency Surgery, Standards for unscheduled surgical care’

provides a useful framework that promotes timely surgery but al-
Risk factors for cerebral oedema

lows time for accurate diagnosis, initial treatment, and resuscita-

tion.16 The standards are summarized below.
New onset diabetes

degree of acidosis

Timeframe to theatre as suggested by Royal College

Younger age

of Surgeons
treatment

(i) Patients with ongoing haemorrhage require immediate

surgery.
(ii) Patients with septic shock who require immediate surgery
(x)
(i)

(iii)

(v)

(vii)

(ix)
(ii)

(iv)

(vi)

(viii)

are operated on within 3 h of the decision to operate as

delay increases mortality significantly.

12 BJA Education | Volume 16, Number 1, 2016

Developments in the management of diabetic ketoacidosis in adults

(iii) Patients with severe sepsis (with organ dysfunction) who re- Postoperative care
quire surgery are operated on within a maximum of 6 h to
After operation patients should receive nursing care in a level 2/3
minimize deterioration into septic shock.
environment until resolution of the DKA. The patient should re-
(iv) Patients with sepsis (but no organ dysfunction) who require
ceive their normal long-acting insulin analogue at the normal
surgery should have this within a maximum of 18 h.
time. The Diabetes specialist teams will be able to assist in the tran-
(v) Patients with no features to indicate systemic sepsis can be
sition from i.v. insulin to subcutaneous insulin and can provide fur-
managed with less urgency but in the absence of modern
ther education and reinforce the ‘sick day rules’ to the patient.
and structured systems of care, delay will result in unneces-
sary hospital stay, discomfort, illness, and cost.
Summary
Each patient must be managed individually, including the opti-
mal time to operate. Unless the patient requires immediate sur- (i) DKA is a life-threatening medical emergency characterized
gery, preoperative resuscitation should occur with correction of by the biochemical triad of ketonaemia, hyperglycaemia,
the hypovolaemia, the metabolic acidosis, and the electrolyte and acidaemia.
imbalances. (ii) Bedside monitoring of capillary ketones, glucose, blood
gases, and electrolytes should be used to make the initial
diagnosis and guide subsequent management.
Preoperative preparation (iii) Weight based fixed rate i.v. insulin infusion (FRIII) is now
recommended rather than a variable rate i.v. insulin infu-
Preoperative management should be focused on optimizing the
sion (VRIII), and the blood glucose must be kept >14
patient for surgery. Furthermore, the senior anaesthetist must
mmol litre−1 with the FRIII.
decide whether a VRIII or a FRIII will be used intra-operatively.

a
(iv) 0.9% Saline with premixed potassium chloride should be
If the anaesthetist decides to use the FRIII intraoperatively, as a

tth
the main resuscitation fluid on the general wards and in

C s
minimum, provision must be made to have sufficient vascular
theatre. This is because it complies with National Patient
access for the following:
ad ote
ha
Safety Agency recommendations on administration of
potassium chloride.
hm N
(i) Administration of the fixed rate i.v. insulin infusion via a
(v) Balanced electrolyte solutions are associated with a faster
pump
fo r P ale A am

resolution of acidosis, but contain insufficient potassium

(ii) Administration of the DKA resuscitation fluid (0.9% saline
to justify their safe use except in critical care.
with 0.3% premixed potassium chloride via a pump may be
ot o S an x

(vi) The cause of the DKA must be sought and surgery may be
the most appropriate) at the rate as guided by Table 1.
N ot f or sh a E

required.
(iii) Administration of the intra-operative resuscitation fluid
(vii) Critical care may be required.
(iv) Administration of anaesthetic bolus drugs
n
N ot f ee esi

(viii) Continuation of long acting insulins may reduce complica-

(v) Administration of 20% glucose at 50 ml h−1 if the CBG is
tio
tions during transition from i.v. to subcutaneous insulin.
<14 mmol litre−1.
N r. Z th

bu

(ix) Early involvement of diabetic specialist teams is mandatory.

(vi) Ability to check blood glucose, potassium, and pH at regular
D es

intervals (minimum hourly).

tri
ed t
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An

is

Central venous access should be obtained to guide fluid therapy

Declaration of interest
and to facilitate the administration of multiple drugs and fluids.
N.L. is a member of the writing group for JBDS DKA guidelines.

Conduct of anaesthesia
MCQs
Patients should be anaesthetized with full monitoring, with an
arterial line in situ, and in theatre to facilitate continuous blood The associated MCQs (to support CME/CPD activity) can be
pressure monitoring post induction. An arterial blood gas (ABG) accessed at https://access.oxfordjournals.org by subscribers to
should be obtained before induction to give an indication of the BJA Education.
degree of acidosis, and to ensure no hyperkalaemia, as succinyl-
choline is often used to facilitate intubation as part of a rapid se-
quence induction. Because of gastric stasis, the nasogastric tube
References
should be aspirated before induction of anaesthesia. 1. Joint British Diabetes Societies Inpatient Care Group. The
Patients should be intubated with a rapid sequence induction Management of Diabetic Ketoacidosis in Adults, 2nd Edn. 2013.
with cricoid pressure. In view of the hypovoalemic state and the Available from http://www.diabetes.org.uk/Documents/About
acidosis, anaesthesia must be induced with a combination of %20Us/What%20we%20say/Management-of-DKA-241013.pdf
drugs that promote cardiovascular stability. (accessed 30 September 2014)
Regular (minimum hourly) monitoring of ABGs and blood 2. Kohler K, Levy N. Management of diabetic ketoacidosis: a
glucose is mandatory. Patients should be ventilated to ensure summary of the 2013 Joint British Diabetes Societies guide-
no iatrogenic respiratory acidosis. Potassium needs to be kept lines. J Intensive Care Soc 2014; 15: 2–5
within the normal range, and replaced as indicated. Blood 3. Rudd B, Patel K, Levy N, Dhatariya K. A survey of implemen-
glucose needs to be kept >14 mmol litre−1 whilst the patient is tation of NHS diabetes guidelines for management of diabet-
being treated with the FRIII. ic ketoacidosis in the intensive care units of the East of
Consideration should be given to flow/cardiac output directed England. J Intensive Care Soc 2013; 14: 60–4
guided fluid therapy given the complex intra-operative fluid 4. Health and Social Care Information Centre. National Dia-
requirements of the surgical patient with DKA. betes Inpatient Audit 2012. Available from http://www.

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diabetes.org.uk/Documents/Reports/NaDIA-annual-report- 11. Chua H-R, Venkatesh B, Stachowski E et al. Plasma-Lyte

2012-0613.pdf (accessed 30 September 2014) 148 vs 0.9% saline for fluid resuscitation in diabetic ketoaci-
5. Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN. Hypergly- dosis. J Crit Care 2012; 27: 138–45
caemic crises in adult patients with diabetes. Diabetes Care 12. National Patient Safety Agency. Potassium solutions: risks to
2009; 32: 1335–43 patients from errors occurring during intravenous adminis-
6. Causes of DKA. NHS Choices. Available from http://www.nhs. tration. 2002. Available from http://www.nrls.npsa.nhs.uk/
uk/Conditions/diabetic-ketoacidosis/Pages/Causes.aspx (ac- resources/?entryid45=59882 (accessed 30 September 2014)
cessed 30 September 2014) 13. Hsia E, Seggelke S, Gibbs J et al. Subcutaneous administration of
7. Newton CA, Raskin P. Diabetic ketoacidosis in type 1 and type glargine to diabetic patients receiving insulin infusion prevents
2 diabetes mellitus: clinical and biochemical differences. rebound hyperglycemia. J Clin Endocrinol Metab 2012; 97: 3132–7
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8. Klocker AA, Phelan H, Twigg SM, Craig ME. Blood beta- of diabetic ketoacidosis be avoided? Pediatric Diabetes 2014;
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818–24 cidosis in children and adolescents with diabetes. Pediatric
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64–7 Standards for unscheduled surgical care. 2011. Available
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with balanced electrolyte solutions prevents hyperchlorae- surgery-standards-for-unscheduled-care/@@download/pdffile/

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ad ote
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fo r P ale A am
ot o S an x
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14 BJA Education | Volume 16, Number 1, 2016

DOI: 10.1111/tog.12344 2017;19:55–62
The Obstetrician & Gynaecologist
Review
http://onlinetog.org

Management of diabetic ketoacidosis in pregnancy

Manoj Mohan MBBS MRCOG,a,* Khaled Ahmed Mohamed Baagar MB BCh CABM MRCP,b Stephen Lindow MBChB
c
MMed (O&G) MD FRCOG FCOG(SA) FRCPI
a
Attending Physician, Department of Obstetrics and Gynaecology, Sidra Medical and Research Center, Doha, Qatar, PO Box 26999, and Assistant
Professor of Clinical Obstetrics and Gynaecology, Weill Cornell Medical College, Doha, Qatar
b
Specialist Diabetologist, Diabetic Obstetric Service, Hamad General Hospital, Doha, Qatar
c
Head of the Division of Obstetrics, Sidra Medical and Research Center, Doha, Qatar Professor of Obstetrics and Gynecology, Weill College Medical
College in Qatar
*Correspondence: Manoj Mohan. Email: [email protected]

Accepted on 31 May 2016

Key content Ethical issues

Diabetic ketoacidosis in pregnancy (DKP) is a serious Despite adequate knowledge and care of patients with diabetes, is
complication that poses several challenges with respect to DKA a major cause for concern?

a
diagnosis, management and prevention. To increase awareness, and reduce the perinatal morbidity and

tth
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This article covers the precipitating factors for DKP in pregnancy mortality associated with DKP.
as well as diagnosis, management and prevention of ad ote
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Keywords: diabetes / diagnosis / management / pregnancy /
the complication.
prevention
hm N

Learning objectives
Linked resource: Single best answer questions are available for this
fo r P ale A am

To manage the acute crisis of DKP.

article at https://stratog.rcog.org.uk/tutorial/tog-online-sba-resource
To increase awareness of DKP.
ot o S an x

To reduce the perinatal morbidity and mortality associated

N ot f or sh a E

with DKP. n
N ot f ee esi

tio
Please cite this paper as: Mohan M, Baagar KAM, Lindow S. Management of diabetic ketoacidosis in pregnancy. The Obstetrician & Gynaecologist 2017;19:
55–62.
N r. Z th

bu
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associated with physiological changes that can predispose a

r R rin

Introduction
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is

pregnant woman with diabetes to diabetic ketoacidosis.

Diabetic ketoacidosis in pregnancy (DKP) is a serious Some specific physiological reasons for DKP are
complication that poses several challenges with respect to as follows:2,3
diagnosis, management and prevention. It develops because Pregnancy is a state of respiratory alkalosis associated with
of relative or absolute insulin deficiency and the a compensatory drop in bicarbonate levels; this impairs the
simultaneous increase in counter-regulatory hormones buffering capacity and renders the pregnant woman more
(cortisol, catecholamines, glucagon and growth hormone). prone to develop diabetic ketoacidosis.
This causes significant changes in metabolism,1 such as Relative insulin resistance in pregnancy along with
lipolysis and proteolysis, which increase gluconeogenesis, and enhanced lipolysis and elevated free fatty acids form the
together with glycogenolysis, contribute to the development base for DKP.
of hyperglycaemia. This is accompanied by a decrease in Hormonal changes including increased levels of human
glucose uptake by peripheral tissues. Lipolysis provides excess placental lactogen, progesterone, and cortisol impair
free fatty acids to the liver, enhancing the process of maternal insulin sensitivity.
ketogenesis, with subsequent ketoacidosis.1
At present, most obstetric centres offer specialised care for DKP is more commonly observed along with type I
diabetes in pregnancy, which reduces the chance of DKP diabetes, but can also be observed with type II diabetes and
occurring. However, DKP does occur and can result in gestational diabetes. It is likely to be precipitated by specific
significant morbidity and mortality for both the mother and factors such as protracted vomiting, hyperemesis gravidarum,
the fetus. The rate of pregnancy associated with diabetes is starvation, infections, insulin non-compliance, medications
rising, especially with the rise in obesity. Pregnancy is also precipitating DKP (e.g. beta sympathomimetic agents),

ª 2017 Royal College of Obstetricians and Gynaecologists 55

Diabetic ketoacidosis in pregnancy

steroid prophylaxis/steroid treatment, insulin pump failure Blood glucose level more than 11.0 mmol/l or known
(as pumps deliver rapid-acting insulin, interruption for a few diabetes mellitus
hours completely deprives the patient of insulin) and Bicarbonate level less than 15.0 mmol/l and/or venous pH
conditions such as diabetic gastroparesis (Box 1).2 less than 7.3

Diagnosis of diabetic ketoacidosis in

Management of diabetic ketoacidosis in
pregnancy (DKP)
pregnancy (DKP) (Figure 1)
In pregnant women with any combination of the signs and
DKP is considered as an emergency that needs to be managed
symptoms specified in Box 2, DKP should be excluded;
in at least Level 2 critical care units,5 such as a high-dependency
occasionally, DKP may be the first presentation of diabetes
unit (HDU) or intensive care unit (ICU), by a team of
in pregnancy.2,3
professionals experienced in dealing with similar cases. This
When DKP is suspected, laboratory investigation is
team usually consists of an obstetrician, a diabetologist/
required to confirm the diagnosis, and to assess the severity
endocrinologist, an obstetric anaesthesiologist, and well-
of DKP and its possible cause (Box 3). The Joint British
trained nursing staff/midwives.2 It is important to stabilise a
Diabetes Societies Inpatient Care Group guidelines4 state the
patient with DKP and insert large intravenous accesses or
following diagnostic criteria for DKP:
central venous line and continuous maternal monitoring with
Blood ketone level more than or equal 3.0 mmol/l (or)
a cardiac monitor and pulse oximetry.6 The management
urine ketone level more than 2+

a
incorporates six main aspects (Box 4), which should be carried

tth
C s
out simultaneously. The six aspects are described below.
ad ote
ha
Box 1. Precipitating factors for diabetic ketoacidosis in pregnancy
Intravenous fluid therapy
hm N

Protracted vomiting Fluid replacement should be commenced by infusing isotonic

fo r P ale A am

Hyperemesis gravidarum
saline (0.9%), as most patients have a negative fluid balance
Infections
Insulin non-compliance of about 100 ml/kg of body weight.4 This represents a total
ot o S an x

fluid deficit of approximately 6–10 l. The intravenous (IV)

N ot f or sh a E

Medications precipitating diabetic ketoacidosis in pregnancy

Insulin pump failure infusion should be started at 10–15 ml/kg/h in the first hour,1
Conditions such as gastroparesis
n
after which the rate should be adjusted according to the
N ot f ee esi

tio

haemodynamic status of the patient, guided by monitoring of

N r. Z th

bu

Box 2. Signs and symptoms

blood pressure, urine output, and central venous pressure in
D es

selected cases.4 For example, in a healthy adult weighing

tri
ed t
r R rin

Nausea or vomiting 70 kg, IV fluid therapy should be performed as follows:

An

is

Abdominal pain If her systolic blood pressure (SBP) is less than 90 mmHg,
Polyuria or polydipsia
Blurred vision she should be resuscitated with 500 ml of normal saline
Muscle weakness infusion over 10 to 15 minutes and if the SBP does not
Drowsiness improve this can be repeated. Senior medical staff evaluation
Lethargy
should be undertaken to diagnose other causes of
Change in mental status
Hyperventilation (Kussmaul breathing)/pear drop odour hemodynamic instability such as sepsis.4 After stabilisation
Tachypnoea of the SBP above 90 mmHg the patient can be maintained
Hypotension with normal saline infusion of 1 l over 1 hour, then 500 ml/hr
Tachycardia
for 4 hours, followed by 250 ml/h for 8 hours, after which the
Coma
Shock infusion rate can be reduced to 150 ml/h.4 This fluid
Abnormal fetal heart tracing

Box 3. Investigation for diabetic ketoacidosis in pregnancy (DKP) Box 4. Management of diabetic ketoacidosis in pregnancy (DKP)

Positive serum/urine ketones Multidisciplinary approach

Lab glucose hyperglycaemia (≥ 11.0 mmol), but DKP can occur at lower 1. Intravenous fluid therapy
glucose levels 2. Intravenous insulin therapy
Low serum bicarbonate (<15 mEq/l) 3. Electrolyte correction
Arterial pH ≤7.30 4. Evaluation of the need for bicarbonate administration
Anion gap >12 5. Identification and treatment of any precipitating factors
Elevated base deficit ≥4 mEq/l 6. Monitoring of maternal and fetal responses
Potassium level may be falsely normal/elevated

56 ª 2017 Royal College of Obstetricians and Gynaecologists

Mohan et al.

a
tth
C s
ad ote
ha
hm N
fo r P ale A am
ot o S an x
N ot f or sh a E

n
N ot f ee esi

tio
N r. Z th

bu
D es

tri
ed t
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An

is

Figure 1. Algorithm. BUN = blood urea nitrogen; CBC = complete blood count; DKA = diabetic ketoacidosis; IV = intravenous; K = potassium;
q = every (Latin quaque)

maintenance regimen will be adequate for a patient who If the blood glucose level falls below 14 mmol/l (250 mg/dl),
presents with an SBP more than or equal to 90 mmHg. The 10% dextrose should be added to the ongoing normal saline IV
patient should be closely monitored by adjusting the IV fluid fluid therapy at a rate of 125 ml/h.4 Careful fluid management
therapy according to her response. is imperative in patients with impaired heart or
IV fluid therapy improves tissue perfusion, decreases stress kidney function.7
hormone levels, and causes haemodilution; this, in turn,
lowers the hyperglycaemia and increases the response to Insulin therapy
insulin therapy.2 Adequate perfusion should be ensured, The development of DKP could be attributed to absolute or
taking into account fluid losses, through close monitoring of relative insulin deficiency. Therefore, IV insulin therapy not
urine output. Urine output should be monitored using an only corrects the hyperglycaemia but also inhibits the ongoing
indwelling catheter, and it should be more than or equal to synthesis of keto acids. IV therapy with regular insulin should
0.5 ml/kg/h to ensure that the patient is well hydrated.4 be commenced promptly in patients with serum potassium

ª 2017 Royal College of Obstetricians and Gynaecologists 57

Diabetic ketoacidosis in pregnancy

level more than or equal to 3.3 mmol/l.1 However, insulin Patients with a good urine output (at least 0.5 ml/kg/h) and
administration should be postponed if serum potassium is low, serum potassium level less than 5.5 mmol/l should receive
until it is corrected to more than or equal to 3.3 mmol/l, potassium chloride in order to maintain their potassium level
because the insulin pushes the potassium into the intracellular in the range of 4–5 mmol/l, as the potassium starts to return
space, which aggravates the existing hypokalaemia and may to the cells with the ongoing IV fluids and insulin therapy.2
precipitate fatal cardiac arrhythmias.1 Regular insulin infusion Failure to replace potassium may result in hypokalaemia with
should be commenced at a fixed rate of 0.1 unit/kg/h, and it is life-threatening cardiac arrhythmias.
recommended not to initially exceed 15 units/h.4 Priming with If the serum potassium level at presentation4 is more than
an IV insulin bolus (0.1 unit/kg) is not required unless there is a 5.5 mmol/l potassium should not be added to the infused
delay in the preparation of the fixed rate IV insulin infusion.4 If fluid. However, if the level is 3.5–5.5 mmol/l, 40 mmol/l of
the metabolic targets (Box 5), primarily blood ketone levels, potassium chloride should be administered with IV normal
cannot be achieved by the current infusion rate, the insulin saline. The National Patients Safety Agency and Irish
infusion rate should be increased by 1 unit/h until ketones Medication Safety Network recommend not to infuse more
reach the desired level.4 than 20 mmol potassium per hour.9,10 If the serum
IV regular insulin has been compared with the new IV potassium is less than 3.3 mmol/l, review by a senior
rapid-acting insulin analogues (in men and non-pregnant medical staff is important, as the patient may require a
women), and both preparations have demonstrated the same higher-strength potassium infusion,4 which may require
efficacy, without any difference in treatment duration or the central venous access.
total number of insulin units administered.8 Therefore,

a
Phosphate replacement

tth
regular insulin is adopted as it is more cost effective. If the

C s
patient is already maintained on basal insulin e.g. detemir or
ad ote Although the whole body phosphate is decreased,

ha
glargine, then this should be prescribed and administered replacement is not recommended, unless the serum level is
concomitantly with the IV insulin infusion.4 This ensures the
hm N

less than 0.32 mmol/l (1 mg/dl) or the patient develops

presence of insulin in case of interruption in the insulin cardiac impairment or respiratory depression.2,4
fo r P ale A am

infusion and allows a smooth transition to the usual

Evaluation of the need for bicarbonate
ot o S an x

subcutaneous insulin regimen of the patient when he or

N ot f or sh a E

she is able to sufficiently eat and drink, and the period of administration
ketoacidosis has resolved. The use of bicarbonate is not recommended,4 as there is no
n
N ot f ee esi

The fixed-rate infusion can be discontinued after DKP evidence of a beneficial effect with it, and it may be harmful
tio

resolution4 and after 30–60 minutes from the first dose of to the patient and the fetus. Bicarbonate inhibits the
N r. Z th

bu

subcutaneous rapid acting insulin, administered with a meal, compensatory hyperventilation that washes out carbon
D es

tri

as a part of the subcutaneous insulin regimen. This is to dioxide (CO2), leading to an increment in CO2 partial
ed t
r R rin
An

is

avoid rebound hyperglycemia or recurrence of DKP. pressure (PCO2), which may, in turn, decrease fetal oxygen
When the DKP has resolved but still the patient cannot delivery.11 In addition, the patient may develop paradoxical
reliably eat or drink, a transition of variable-rate (commonly cerebral acidosis, because the CO2 diffuses through the blood
referred as sliding scale) IV insulin infusion4 with IV fluid brain barrier faster than the infused bicarbonate.12 Further,
can be used to control the blood glucose level until the bicarbonate administration delays the wash out of ketones13
patient tolerates an oral diet and subcutaneous rapid acting and can worsen hypokalaemia.
insulin can be given with discontinuation of the variable-rate
infusion 30–60 minutes later. Identification and treatment of precipitating factors
Recognition of the condition that precipitates DKP is
Electrolyte correction: potassium replacement essential for its management, as any delay in the correction
Although patients have a total potassium deficit of of the precipitating factor can worsen the prognosis and
3–5 mmol/kg4 the measured serum potassium is usually increase the risk of recurrence.2 A detailed history and
normal or even high and this is related to the increased physical examination are very important to direct the
osmolality and insulin deficiency, which cause trans-cellular investigations for the targeted treatment of precipitating
shift of potassium outside the cells.1 factors. Elevated total white blood cell count is commonly
observed; however, it does not always mean that the
Box 5. Metabolic targets to be achieved using initial intravenous patient has an infection, as it can be secondary to
insulin therapy
dehydration. Nevertheless, a thorough clinical assessment
Decrease in blood ketone levels by 0.5 mmol/l/h to exclude infection should be performed, and appropriate
Increase in venous bicarbonate levels by 3 mmol/l/h treatment should be started if infection is suspected
Decrease in capillary glucose levels by 3 mmol/l/h (54 mg/dl/h) or confirmed.3

58 ª 2017 Royal College of Obstetricians and Gynaecologists

Mohan et al.

Monitoring of maternal and fetal response DKP, the fetal brain is susceptible to increased maternal 3BHB
and lactate concentration, which lead to decreased glucose
Maternal response uptake by the fetal brain.20 These events may increase the
Capillary glucose should be monitored hourly during insulin chance of fetal brain injury and may have a long-term
infusion. Blood ketones4 should also be monitored hourly for developmental impact.20,21 Future research may assist in
the first 6 hours in order to ensure that ketone levels decrease at understanding the complete effect of DKP on the fetus.
the required rate of at least 0.5 mmol/l. Other biochemical
parameters such as pH, bicarbonate and serum potassium can Fetal monitoring and delivery in diabetic
be monitored using venous gas samples every 2 hours in the ketoacidosis in pregnancy (DKP)
first 6 hours,4 provided that a concomitant laboratory sample
The fetal effects in DKP involve a combination of severe
is taken at baseline to confirm the accuracy of serum potassium
maternal dehydration with acidosis, which may be caused by
levels. If a ketone meter is not available, the calculated anion
reduced uteroplacental perfusion in an acidotic environment.
gap (Box 6) helps in monitoring the patient response.1
In addition to this combined insult, severe maternal
Measurement of arterial pH is not required (unless the
electrolyte disturbances (particularly potassium) could
patient is hypoxic or has an impaired level of consciousness), as
result not only in maternal cardiac arrhythmias but also
it is only 0.03 units higher than the venous pH.14
fetal cardiac arrhythmias, which may lead to fetal death.22
The bicarbonate level can be reliably used to evaluate the
Fetal heart tracing performed in DKP may often demonstrate
treatment response in the first 6 hours of management, as,
fetal acidotic changes, representing the effect of maternal
subsequently, aggressive hydration using 0.9% sodium

a
metabolic acidosis on the fetus. This is often corrected with

tth
chloride could lead to the development of hyperchloraemic

C s
maternal hydration and correction of metabolic acidosis.
ad ote
acidosis associated with a normal anion gap, which tends to

ha
Normalisation of fetal heart tracing after correction of DKP
lower the bicarbonate level.4 Ketoacidosis and
may require 4–8 hours. Fetal biophysical profile and Doppler
hm N

hyperchloraemic acidosis are two different types of

studies may also reflect the fetal acidotic status. However, the
metabolic acidosis associated with low serum bicarbonate
fo r P ale A am

decision to deliver should be individualised and should be

levels. In ketoacidosis, the primary process is the increased
primarily based on evaluation of the maternal clinical status
ot o S an x

production of keto acids. The body uses bicarbonate to

to ensure a safe labour and delivery, fetal gestational age23,24
N ot f or sh a E

neutralise these keto acids; therefore, serum bicarbonate level

and the results of fetal investigations such as fetal heart
decreases and, subsequently, the anion gap increases.
n
tracing. All these factors should be considered together with a
N ot f ee esi

tio
Hyperchloraemic acidosis results from the administration
multidisciplinary approach while making a decision
of large volumes of normal saline with high chloride content
N r. Z th

bu

regarding delivery. However, in the majority of cases of

to the patient, which dilutes plasma bicarbonate, leading to
D es

DKP, the aim should be to monitor the fetus until the

tri
ed t

increased chloride with low bicarbonate, and, subsequently,

r R rin

maternal metabolic state is stabilised, without any immediate

An

metabolic acidosis associated with a normal anion gap.2,4,15

is

plans for delivery, and to continue the pregnancy with

Urinary ketones take time to clear, as the body excretes
complete resolution of DKP. There is no consensus on
ketones through metabolising the major ketone of DKP
further fetal monitoring after complete resolution of DKP,
(3-beta-hydroxybutyrate [3BHB]), which can be measured
especially when the fetus is preterm. The best practice,
on a bedside capillary sample, to acetoacetate, which is semi-
however, is aimed at educating the patient to avoid further
quantitatively measured in urine. Thus, ketonuria can persist
recurrence of DKP, and an increased surveillance to ensure
for a significant period after 3BHB has cleared and the
adequate diabetic control and compliance with treatment.
metabolic acidosis has resolved.16
The frequency of fetal monitoring is unknown and no
definite recommendations are currently available. Therefore,
Fetal response
individualised care with a multidisciplinary approach is
DKP may result in severe maternal complications such as acute
recommended as a best practice option.
renal failure, adult respiratory distress syndrome, cerebral
oedema, coma and even death.2,11,17 The fetal mortality
Resolution of diabetic ketoacidosis in
associated with DKP ranges between 9% and 36%;1,18,19
pregnancy (DKP)
however, considerably higher perinatal morbidity is observed
with DKP, including hypoxia-related complications, which are Recovery from DKP is defined by a blood ketone level less than
attributable to an increased rate of preterm delivery. During 0.6 mmol/l, a pH more than 7.3 and a serum bicarbonate more
than 15 mmol/l (however, after 6 hours, bicarbonate may not
Box 6. Anion gap calculation be a reliable indicator, as mentioned above).4 Moreover,
normalisation of the anion gap (less than or equal to 12 mEq/l)
Anion gap = (NA+ + K+) – (Cl + HCO3 )
helps to ensure that the patient has recovered from DKP

ª 2017 Royal College of Obstetricians and Gynaecologists 59

Diabetic ketoacidosis in pregnancy

(Box 6).1 Insulin infusion has no role in the management of she has hyperglycaemia or feels unwell. Patients should be
hyperchloraemic acidosis. This condition is usually corrected educated regarding sick day rules. Ideally, a woman with
by the kidney, and no intervention is required. diabetes should be in touch with her diabetes medical team
to check her prepregnancy HbA1c level and to keep it
below 6.5% (48 mmol/mol).30 Pregnancy should be
Euglycaemic diabetic ketoacidosis in avoided if HbA1c level is above 10% (86 mmol/mol).30
pregnancy (DKP) Prepregnancy counselling: A woman with diabetes should
receive counselling from her primary care physician or at
Euglycaemic (normoglycaemic) DKP is a rare situation where
her diabetes clinic. Effective contraception to avoid
the patient presents with normal or below normal, rather than
unplanned pregnancy should be discussed.
high, blood glucose levels with diabetic ketoacidosis.25 This can
affect patients with type I diabetes, type II diabetes or
gestational diabetes.2,26 The likely mechanisms are as follows:26 During pregnancy
the use of glucose by the fetoplacental unit, with decreased Team: During pregnancy, the diabetes specialist nurse/
maternal glycogenolysis and gluconeogenesis midwife, diabetes specialist dietician and/or joint
increased renal loss of glucose as the renal blood flow obstetric-diabetes consultations will form a group of
increases with increased glomerular filtration of glucose service providers for effective management.
without a corresponding increase in tubular Screening: Diabetes screening of the general obstetric
glucose reabsorption population should be offered to exclude diabetes in

a
increase in estrogen and progesterone in pregnancy pregnancy as per the local diabetic guidelines, if

tth
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accompanied by increased maternal usage of blood glucose available; otherwise, efforts should be made to formulate
ad ote
ha
dilutional effect on blood glucose because of the increased an effective diabetic local screening policy.
plasma volume during pregnancy Education: Women diagnosed with diabetes should be
hm N

educated in a structured and impartial manner and in

Moreover, starvation, which is associated with increased
fo r P ale A am

simple language about the precipitating factors and

ketone production, is also accompanied by depletion of
manifestations of DKP.
glycogen stores and normoglycaemic DKP.27
ot o S an x

Self-monitoring: Patients should continue to have a

N ot f or sh a E

It is notable that the management of euglycaemic DKP

glucose meter for self-monitoring, and those with type I
follows the same principles. However, IV fluid therapy should
n
diabetes should have a ketone meter to be used as
N ot f ee esi

involve the concomitant administration of 5% dextrose with

tio

previously described.30
IV saline via a separate line from the start of treatment to
N r. Z th

bu

Suspected DKP: Pregnant women with any type of diabetes

avoid hypoglycaemia caused by IV insulin administration,
D es

should be advised to seek prompt attention at a medical

which is necessary to stop the production of ketoacids.28,29
tri
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facility if their blood glucose level is persistently above

An

is

11.1 mmol/l (200 mg/dl), or if they have any signs of

Prevention of diabetic ketoacidosis in infection or any other problems, as outlined in Box 1.2
pregnancy (DKP) They should be assessed for hospital admission.
Corticosteroid treatment: If a woman with diabetes
Several strategies should be adopted during the
requires antenatal corticosteroid therapy for the fetus,
preconception period and during pregnancy to prevent DKP.
e.g. for fetal lung maturation in a suspected preterm birth,
her insulin dose should be gradually adjusted (usually,
Prepregnancy
insulin dose is increased by 25–40%).31
Education: As per National Institute for Health and Care
Tocolysis treatment: If tocolysis is required, it is preferable
Excellence (NICE) guidlines,30 a woman with diabetes
to avoid betamimetics (they increase susceptibility for
should plan her pregnancy with support from her team of
DKP) and use a different class of tocolytics. Tocolytics that
diabetes experts; she should receive structured education
are safer to use are the oxytocin receptor antagonist
with explanation of the facts regarding the risks associated
atosiban or a calcium channel blocker e.g. nifedipine.32
with uncontrolled blood glucose in pregnancy. This can
reduce complications such as DKP as well as the maternal To prevent the recurrence of DKP, prior to discharge, it is
and fetal risk associated with diabetes in pregnancy. necessary to:4
Self-monitoring: A woman with diabetes should be offered educate the patient about how to identify and rectify the
a glucose meter to check her blood glucose levels at home. precipitating factors;
Women with type I diabetes should be provided a capillary review the pre-admission diabetes control, injection
ketone meter to check for blood ketonaemia, (or) at least technique, injection sites, glucometer reliability, and
urine ketone test strips to check for urine ketonuria when storage of insulin with the patient; and

60 ª 2017 Royal College of Obstetricians and Gynaecologists

Mohan et al.

provide the patient with the contact information of the 4 Joint British Diabetes Societies Inpatient Care Group. The Management of
Diabetic Ketoacidosis in Adults. Sept 2013. [http://www.diabetologists-
diabetes team and a written plan of care. abcd.org.uk/JBDS/JBDS_IP_DKA_Adults_Revised.pdf].
5 Department of Health. Comprehensive Critical care: A Review of Adult
In addition, future fetal monitoring should also be planned Critical Care Services. UK: Department of Health; 2000 [http://webarchive.
prior to discharge and a follow-up should be organised to nationalarchives.gov.uk/20130107105354/http:/www.dh.gov.uk/prod_
review both maternal and fetal antenatal progress, and to consum_dh/groups/dh_digitalassets/@dh/@en/documents/digitalasset/dh_
4082872.pdf].
ensure continuation of care. 6 Wass J, Owen K. Diabetic hyperglycaemic emergencies. Oxford Handbook of
Endocrinology and Diabetes. 3rd ed. Oxford: Oxford University Press; 2014.
7 Barrett EJ, DeFronzo RA. Diabetic ketoacidosis: diagnosis and treatment.
Conclusion Hosp Pract (Off Ed) 1984;19(89–95):99–104.
8 Umpierrez GE, Jones S, Smiley D, Mulligan P, Keyler T, Temponi A, et al.
DKP is a life-threatening condition; therefore, prompt Insulin analogs versus human insulin in the treatment of patients with
diagnosis along with rapid initiation of acute care diabetic ketoacidosis: a randomized controlled trial. Diabetes Care
management involving an experienced multidisciplinary 2009;32:1164–9.
9 National Patient Safety Agency. Potassium Solutions: Risks to Patients from
team could help to reduce maternal and fetal mortality, Errors Occurring during Intravenous administration. London: National
and morbidity. Patient education will form the main Patient Safety Agency; 2002 [http://www.nrls.npsa.nhs.uk/resources/?
framework to reduce the risks associated with DKP. This entryid45=59882].
10 Irish Medication Safety Network. Best Practice Guidelines for the Safe Use
study intends to spread awareness regarding DKP among of Intravenous Potassium in Irish Hospitals. Dublin: Irish Medication Safety
caregivers and to improve the quality of care in pregnancy. Network; 2013 [http://www.imsn.ie/images/guidelines/imns-july-2013-
best-practice-guidance-for-iv-potassium-use.pdf].
11 Parker JA, Conway DL. Diabetic ketoacidosis in pregnancy. Obstet Gynecol

a
Disclosure of interests Clin North Am 2007;34:533–43, xii.

tth
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There are no conflicts of interest. 12 Morris LR, Murphy MB, Kitabchi AE. Bicarbonate therapy in severe diabetic
ad ote ketoacidosis. Ann Intern Med 1986;105:836–40.

ha
13 Okuda Y, Adrogue HJ, Field JB, Nohara H, Yamashita K. Counterproductive
Contribution to authorship effects of sodium bicarbonate in diabetic ketoacidosis. J Clin Endocrinol
hm N

MM instigated, designed, drafted, and critically revised the Metab 1996;81:314–20.

fo r P ale A am

14 Middleton P, Kelly AM, Brown J, Robertson M. Agreement between arterial

intellectual content of the manuscript, and contributed to the and central venous values for pH, bicarbonate, base excess, and lactate.
obstetric management of the study in the manuscript. KB Emerg Med J 2006;23:622–4.
ot o S an x

contributed to the medical management of the study, and 15 Yeung SJ, Agraharkar M, Sarlis NJ, Fahlen MT, Baweja K. Hyperchloremic
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Acidosis. Medscape; 2014 [http://emedicine.medscape.com/article/

assisted in drafting and revising the intellectual content of the 240809-overview#a5].
n
manuscript. SL contributed to drafting and revising the
N ot f ee esi

16 Laffel L. Ketone bodies: a review of physiology, pathophysiology and

tio

intellectual content of the manuscript. All authors approved application of monitoring to diabetes. Diabetes Metab Res Rev
N r. Z th

1999;15:412–26.
bu

the final version of the manuscript. 17 Kamalakannan D, Baskar V, Barton DM, Abdu TA. Diabetic ketoacidosis in
D es

pregnancy. Postgrad Med J 2003;79:454–7.

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a
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is

62 ª 2017 Royal College of Obstetricians and Gynaecologists

An
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Thyroid disease 157

Thyroid disease
May present for thyroidectomy (see E p. 574) or non-thyroid surgery.
General considerations for non-thyroid surgery
Hypothyroidism
• Commonly due to autoimmune thyroid destruction.
• CVS complications include decreased blood volume, cardiac output, and
HR, with a predisposition to hypotension and IHD. Pericardial effusions
also occur.
• Also associated with anaemia, hypoglycaemia, hyponatraemia, and
impaired hepatic drug metabolism.
• If clinical evidence of hypothyroidism, delay elective surgery to obtain a
euthyroid state. Liaise with the endocrinologist. Suggest levothyroxine
(T4) (starting dose 50 micrograms, increasing to 100–200 micrograms
PO over several weeks). The elderly are susceptible to angina and
heart failure, with increasing cardiac work caused by thyroxine, so start
with 25 micrograms, and increase by 25 micrograms at 3- to 4-weekly
intervals.
a

• If surgery is urgent, then liothyronine (T3) (10–50 micrograms slow IV

tth
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with ECG monitoring, or 5–20 micrograms in patients with known or

ha

suspected cardiac disease, followed by 10–25 micrograms 8-hourly) can

hm N
fo r P ale A am

be used, but this is more controversial.

• Be cautious in interpreting low serum thyroid hormones in sick
ot o S an x
N ot f or sh a E

or surgical patients, as it is important to distinguish between

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hypothyroidism and the ‘euthyroid sick syndrome’. There is no clear

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evidence to give thyroid hormone replacement in the latter.

N . Z th

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Hyperthyroidism (thyrotoxicosis)
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A

• Typically presents with weight loss, hypertension, sweating, and cardiac

r

arrhythmias (especially AF). Treatment is with carbimazole (30–45mg

PO daily for 6–8wk). This inhibits iodination of tyrosyl residues in
thyroglobulin. Occasionally, in severe cases with a large thyroid, Lugol’s
iodine is substituted 10d preoperatively to reduce gland vascularity.
• β-blockade (propranolol 30–60mg tds) is also started if there are signs
of tremor or palpitations. The non-cardioselective β-blockers, such as
propranolol, are more effective than the selective ones. β1-adrenergic
blockade treats the symptoms of tachycardia, but β2-adrenergic
blockade prevents the peripheral conversion of T4 to T3.
Preoperative assessment
• Thyroid function: check the patient is euthyroid (HR <80bpm, no
hand tremor)—delay surgery, if possible, until achieved. Patients with
subclinical hypothyroidism usually have no anaesthetic problems, and
elective surgery can proceed without special preparation.5
• Airway: look for tracheal deviation—a large goitre can cause respiratory
obstruction. This is a particular problem when the gland extends
retrosternally. Ask the patient about positional dyspnoea and dysphagia.
Look for evidence of tracheal compression with shortness of breath,
dysphagia, and stridor (occurs with 50% compression). Infiltrating
158 Chapter 8 Endocrine and metabolic disease

carcinoma may make any neck movement difficult and is an independent

predictor of difficult intubation.
• Superior vena cava (SVC) obstruction can occur. Look for distended
neck veins that do not change with respiration.
• Check for other autoimmune disorders.
Investigations
• FBC, U&Es, serum calcium, thyroid function tests.
• CXR/thoracic inlet views essential to assess tracheal compression.
• If tracheal compression present, perform CT or MRI scan to reveal the
site and length of narrowing and also the presence of any calcification.
• Refer to the ENT surgeon for indirect laryngoscopy to document any
preoperative vocal cord dysfunction.
Conduct of anaesthesia
Hypothyroid patients
• Give all drugs slowly. Susceptible to profound hypotension, which may
be relatively resistant to the effects of catecholamine therapy.
• Low metabolic rate predisposes to hypothermia, so actively warm.
a

• Controlled ventilation is recommended—tendency to hypoventilate.

tth
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• Drug metabolism can be slow. Monitor twitch response, and reduce the
ha

dose of relaxants and opioids.

hm N
fo r P ale A am

Hyperthyroid patients
ot o S an x

• Continue β-blockade perioperatively to reduce the possibility of a

N ot f or sh a E

thyroid storm.
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N ot f ee esi

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Special considerations
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Thyroid storm
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A

• A life-threatening exacerbation of the hyperthyroid state, with evidence

r

of decompensation in one or more organ systems—mortality 20–30%.

• Usually presents 6–24hr post-surgery with fever (>40°C), sweating,
sinus tachycardia (>140bpm), coma, nausea, vomiting, diarrhoea.
• Rehydrate with IV saline and glucose.
• Treat hyperthermia with tepid sponging and paracetamol. Do not give
NSAIDs or aspirin, as these displace thyroid hormone from serum
binding sites.
• Give propranolol (1mg increments, up to 10mg), with CVS monitoring,
to decrease the pulse rate to <90bpm. Alternatively, give esmolol
(loading dose 250–500 micrograms/kg, followed by 50–100
micrograms/kg/min).
• Give hydrocortisone (200mg IV qds) to treat adrenal insufficiency and
to decrease T4 release and conversion to T3 at very high levels.
• Give propylthiouracil (1g loading dose via NGT, followed by 200–300mg
qds). This inhibits thyroid hormone release and also decreases the
peripheral conversion of T4 to T3.
• After blockade by propylthiouracil, give sodium iodide (500mg tds IV),
potassium iodide (five drops qds via NGT), or Lugol’s iodine (5–10
drops qds via NGT).5
Thyroid disease 159

Hypothyroid coma
• A rare form of decompensated hypothyroidism—mortality 15–20%.
• Characterized by coma, hypoventilation, bradycardia, hypotension, and
a severe dilutional hyponatraemia.
• Precipitated by infection, trauma, cold, and CNS depressants.
• Rehydrate with IV glucose and saline.
• Stabilize cardiac and respiratory systems, as necessary. May require
ventilation.
• Sudden warming may lead to extreme peripheral vasodilatation, so use
cautious passive external warming.
• Give levothyroxine 200–400 micrograms IV bolus, followed by 100
micrograms the next day. Use smaller doses in patients with CVS
disease.
• Patients should first receive stress-dose steroids (e.g. hydrocortisone
100mg qds IV), in case they have concomitant 1° or 2° adrenal
insufficiency, a common result of hypothyroidism.
• Consider a combination of IV T3 and T4, particularly if urgent surgery
required.6 The conversion of T4 to T3 is suppressed in hypothyroid
coma, and T3 is more active than T4. For doses of IV T3, see E p. 157.
a
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• Transfer to ICU.
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References
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5 Bennett-Guerrero E, Kramer DC, Schwinn DA (1997). Effect of chronic and acute thyroid
hormone reduction on perioperative outcome. Anesth Analg, 85, 30–6.
ot o S an x
N ot f or sh a E

6 Mathes DM (1998). Treatment of myxedema coma for emergency surgery. Anesth Analg, 86,
445–51.
n
N ot f ee esi

tio

Further reading
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tri

Bahn RS, Burch HB, Cooper DS, et al. (2011). Hyperthyroidism and other causes of thyrotoxi-
ed t
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cosis: management guidelines of the American Thyroid Association and American Association of
A

Clinical Endocrinologists. Thyroid, 21, 593–646.

r

Farling PA (2000). Thyroid disease. Br J Anaesth, 85, 15–28.

Langley RW, Burch HB (2003). Perioperative management of the thyrotoxic patient. Endocrinol
Metab Clin North Am, 32, 519–34.
Manzullo EF, Ross DS (2014). Non-thyroid surgery in the patient with thyroid disease. M http://www.
uptodate.com/contents/nonthyroid-surgery-in-the-patient-with-thyroid-disease.
Stathalos N, Wartoskky L (2003). Perioperative management of patients with hypothyroidism.
Endocrinol Metab Clin North Am, 32, 503–18.
574 Chapter 23 Endocrine surgery

Thyroidectomy

Procedure Removal of all or part of the thyroid gland

Time 1–2hr, depending on complexity
Pain +/++
Position Bolster between shoulders with head ring.
Head-up tilt
Blood loss Usually minimal. Potentially major if retroster-
nal extension
Practical techniques IPPV + reinforced ETT

General considerations
(See also E p. 157.)
• Complexity can vary from removal of a thyroid nodule to removal of a
long-standing retrosternal goitre to relieve tracheal compression.
a
tth
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• Retrosternal goitre is usually excised through a standard incision, but

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occasionally a sternal split is required.

hm N

• Recurrent laryngeal nerves and parathyroid glands may be damaged or

fo r P ale A am

removed.
ot o S an x

• Straightforward unilateral surgery can be performed under superficial

N ot f or sh a E

and deep cervical plexus block, but GA is usual (see E p. 1106).

n
N ot f ee esi

tio
N . Z th

Preoperative
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• Ensure that the patient is as near euthyroid as possible (see E p. 157).

r R rin
is
A

• Check for complications associated with hyperthyroidism: AF,

r

tachycardia, proptosis.
• Acute preparation of thyrotoxic patients involves iodine and
corticosteroids—both inhibit the conversion of T4 to T3 and narrow the
window (7–10d) for surgery, necessitating joint management with the
surgeon and endocrinologist.
• Check biopsy histology for malignancy.
• Ask about duration of goitre. Long-standing compression of the trachea
may be associated with tracheomalacia.
• Ask about positional breathlessness. Assess the airway.
• Examine the neck. How big is the goitre? Consistency?—malignant
goitres are hard. Can you feel below the gland (retrosternal spread)? Is
there evidence of tracheal deviation (check the radiograph)?
• Look for signs of SVC obstruction—distended neck veins that do not
vary with the respiratory cycle.
• Listen for stridor.
• Check the range of neck movements preoperatively, and do not extend
them outside of their normal range during surgery.
• Preoperative paracetamol/NSAIDs (PO or PR) help post-operative pain
control.
Thyroidectomy 575

Investigations
• FBC, U&Es, Ca2+, and thyroid function tests are routine.
• Chest radiograph. Check for tracheal deviation and narrowing. Thoracic
inlet views may be necessary if retrosternal extension is suspected,
and to detect tracheal compression in the anterior–posterior plane
(retrosternal enlargement may be asymptomatic).
• CT scan accurately delineates the site and degree of airway
encroachment or intraluminal spread. Advisable if there are symptoms
of narrowing (e.g. stridor, positional breathlessness) or >50% narrowing
on the radiograph. Plain radiographs overestimate diameters, due to
magnification effects, and cannot be relied on when predicting ETT
diameter and length. Furthermore, a CT scan will help assess the degree
of retrosternal extension.
• ENT consultation to document cord function for medico-legal
purposes is not routine in all units, unless an abnormality is likely, e.g.
previous surgery and malignancy. Pre-existing cord dysfunction may be
asymptomatic. Fibreoptic examination also defines any possible laryngeal
displacement (useful in airway planning).
a

Airway planning
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• The majority of cases are straightforward, even when there is some

ha
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tracheal deviation or compression. A reinforced ETT will negotiate

fo r P ale A am

most distorted tracheas and permit optimal head positioning. Tracheal

compression by a benign goitre will often accommodate an ETT
ot o S an x
N ot f or sh a E

beyond the predicted size, as the gland is soft. Preoxygenation should

n
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be followed by IV induction and a neuromuscular-blocking drug (after

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checking that the lungs can be inflated manually).

bu
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• The following features should lead to a more considered approach and

tri
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may require discussion with the surgeon and radiologist:

A
r

• Malignancy. Cord palsies are likely. Distortion and rigidity of

surrounding structures. Possibility of intraluminal spread. The larynx
may be displaced. The tumour can produce obstruction anywhere
from the glottis to the carina
• Significant respiratory symptoms or >50% narrowing on chest
radiograph or lateral thoracic inlet view
• Coexisting predictors of difficult intubation.

Options to secure the airway for complicated

thyroid surgery
• Teamwork between the anaesthetist and surgeon is the key to successful
and safe airway management.
• Inhalational induction with sevoflurane or halothane in patients with
stridor and a suspected difficult upper airway. Stridor and decreased
minute ventilation delay the onset of sufficiently deep anaesthesia for
intubation. Topical LA may be useful.
• Fibreoptic intubation (see E p. 969). Attempts to pass a fibreoptic
bronchoscope in an awake patient with stridor are difficult, as the
narrowed airway may become obstructed by the instrument. May be
useful where there is marked displacement of the larynx or coexisting
difficulties with intubation, e.g. ankylosing spondylitis.
576 Chapter 23 Endocrine surgery

• LMA may be difficult to place in patients with laryngeal displacement.

• Tracheostomy under LA. This will only be possible if the tracheostomy
can be easily performed below the level of obstruction.
• Ventilation through a rigid bronchoscope is a backup option when
attempts to pass an ETT fail. The surgeon and necessary equipment
should be immediately available for complex cases, particularly those
involving significant mid- to lower tracheal narrowing.
• ‘Plan C’ of the difficult airway algorithm (perform a cricothyroid
puncture) may not be an option.
Perioperative
• Eye padding, lubrication, and tape are important, especially if the patient
has exophthalmos.
• Full relaxation is required to accommodate tube movements. LA spray
on the ETT reduces the stimulation produced by tracheal manipulation
during surgery.
• Electrophysiological monitoring of the recurrent laryngeal nerves is now
possible intraoperatively, using specialized reinforced ETTs.
• Securely fix the ETT with tape, avoiding ties around the neck. Access to
a

check the tube is difficult during the procedure.

tth
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• Head and neck extension with slight head-up tilt.

ha

• Consider a superficial cervical plexus block for post-operative analgesia.

hm N

Some surgeons infiltrate SC with LA and adrenaline before starting. LA

fo r P ale A am

at the end can produce spurious nerve palsies (see E p. 1106).

ot o S an x
N ot f or sh a E

• Arms to sides, IV extension.

n
N ot f ee esi

• Communicate with the surgeon if there are excessive airway pressures

tio

during manipulation of the trachea. Obstruction may be due to airway

N . Z th

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manipulation distal to the tube or the bevel of the tube abutting on the
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trachea.
A
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• Monitor muscle relaxation on the leg.

• In cases of long-standing goitre, some surgeons like to feel the
trachea before closing to assess tracheomalacia. They may ask for
partial withdrawal of the ETT, so that the tip is just proximal to the
operative site.
• At the end of surgery, reverse the muscle relaxant, and extubate with
the patient sitting up to reduce venous compression. Use an extubation
technique that minimizes coughing to reduce early 2° haemorrhage.
Any respiratory difficulty should lead to immediate reintubation. The
traditional practice of inspecting the cords immediately following
extubation is difficult and unreliable. Possible cord dysfunction and
post-operative tracheomalacia are better assessed with the patient
awake and sitting up in the recovery room.
Post-operative
• Intermittent opioids with oral/rectal paracetamol and NSAIDs.
• The opioid requirement is reduced with SC infiltration and superficial
cervical plexus blocks.
• Use fibreoptic nasendoscopy if there is doubt about recurrent laryngeal
nerve injury.
Thyroidectomy 577

Post-operative stridor
• Haemorrhage with tense swelling of the neck. Remove clips from the
skin, and sutures from the platysma/strap muscles to remove the clot. In
extremis, this should be done at the bedside. Otherwise return to theatre
without delay. A haematoma will affect lymphatic and venous drainage of
the upper airway, causing laryngeal and pharyngeal oedema. Removing
the haematoma will not always restore airway patency immediately.
• Tracheomalacia. Long-standing large goitres may cause tracheal collapse.
This is a very rare complication. Immediate reintubation, followed by
tracheostomy, may be necessary.
• Bilateral recurrent laryngeal nerve palsies. This may present with
respiratory difficulty immediately post-operatively or after a variable
period. Stridor may only occur when the patient becomes agitated.
Assess by fibreoptic nasendoscopy. May require tracheostomy.
Other post-operative complications
Hypocalcaemia
• Hypocalcaemia from parathyroid removal is rare. Serum Ca2+ should be
checked at 24hr, and again daily if low.
a
tth

• Presentation—may present with signs of neuromuscular excitability,

C s
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tingling around the mouth, or tetany. May progress to fits or ventricular

hm N

arrhythmias.
fo r P ale A am

• Diagnosis—carpopedal spasm (flexed wrists, fingers drawn together)

ot o S an x

may be precipitated by cuff inflation (Trousseau’s sign). Tapping over the

N ot f or sh a E

facial nerve at the parotid may cause facial twitching (Chvostek’s sign).
n
N ot f ee esi

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Prolonged QT interval on ECG.

N . Z th

bu

• Treatment: serum Ca2+ below 2mmol/L should be treated urgently with

D nes

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10mL of 10% calcium gluconate over 3min plus alfacalcidol 1–5g orally
r R rin
is
A

(calcium gluconate is preferable, as calcium chloride will cause tissue

r

necrosis if extravasation occurs). Check the level after 4hr, and consider
Ca2+ infusion if still low. If hypocalcaemic, but level above 2mmol/L,
treat with oral Ca2+ supplements (see also E p. 161).
Thyroid crisis
• This is rare, as hyperthyroidism is usually controlled beforehand with
antithyroid drugs and β-blockers. May be triggered in uncontrolled or
undiagnosed cases by surgery or infection.
• Diagnosis: increasing HR and temperature. May be difficult to
distinguish from MH. Higher mixed venous PvCO2 and higher creatinine
phosphokinase in MH.
• Treatment: see E p. 158.
Pneumothorax
Pneumothorax is possible if there has been retrosternal dissection.
Further reading
Cook TM, Morgan PJ, Hersch PE (2011). Equal and opposite expert opinion. Airway obstruction
caused by a retrosternal thyroid mass: management and prospective international expert opinion.
Anaesthesia, 66, 828–36.
Dempsey GA, Snell JA, Coathup R, Jones TM (2013). Anaesthesia for massive retrosternal thyroid-
ectomy in a tertiary referral centre. Br J Anaesth, 111, 594–9.
Farling PA (2000). Thyroid disease. Br J Anaesth, 85, 15–28.
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Structured oral
examination 4
Long case 4

Information for the candidate

Clinical Anaesthesia
History

a
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A 38-year-old Afro-Caribbean female patient is scheduled for an elective
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subtotal thyroidectomy. She gives a history of intolerance to heat,
hm N

palpitations, lethargy and weight loss. She had failed radio-iodine therapy
fo r P ale A am

3 years ago. She has a sickle cell trait. She had an uneventful pregnancy
ot o S an x
N ot f or sh a E

5 years ago. Her current medications are carbimazole 20mg o.d., the oral
n
N ot f ee esi

contraceptive pill and methylcellulose eye drops.

tio

Clinical examination
N r. Z th

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She is breathless, sweaty and clammy. She has a large diffuse goitre.

Table 4.1 Clinical examination.

Weight 56kg
Height 170cm
Heart rate 120 bpm
Blood pressure 110/75mmHg
Temperature 36.7°C
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Investigations

Table 4.2 Biochemistry.

Normal values
Sodium 142mmol/L 135-145mmol/L
Potassium 4.1mmol/L 3.5-5.0mmol/L
Urea 3.5mmol/L 2.2-8.3mmol/L
Creatinine 63mmol/L 44-80mmol/L
Blood glucose 5.5mmol/L 3.0-6.0mmol/L

Table 4.3 Haematology.

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Normal values
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Hb 10.2g/dL 11-16g/dL
fo r P ale A am

Haematocrit 0.34 0.4-0.5 males, 0.37-0.47 females

ot o S an x
N ot f or sh a E

RBC 3.7 x 1012/L 3.8-4.8 x 1012/L

WBC 3.2 x 109/L 4-11 x 109/L
n
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Platelets 95 x 109/L 150-450 x 109/L

N r. Z th

bu

INR 1.0 0.9-1.2

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PT 12.5 seconds 11-15 seconds

is
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APTT ratio 1 0.8-1.2

Table 4.4 Thyroid function tests.

T4 30.7pmol/L 10-22pmol/L
Free T3 10.5pmol/L 2.8-7.1pmol/L
TSH 0.1mU/L 0.3-4.6mU/L
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Structured Oral Examination 4

a
Figure 4.1 ECG.
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ot o S an x

Examiner’s questions
N ot f or sh a E

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N ot f ee esi

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Please summarise the case

N r. Z th

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A

This is a 38-year-old lady with thyrotoxicosis and anaemia who is known to

have a sickle cell trait. She is listed for an elective thyroid operation. She
is clearly hyperthyroid despite her antithyroid medications.

Prior to surgery, thyrotoxicosis should be controlled by optimising drug

therapy. She needs further airway assessment and further investigations
such as nasoendoscopy, a thoracic inlet X-ray and a CT scan as indicated
from clinical history and examination. The full blood count shows
pancytopenia which may be related to carbimazole.

What could be the cause for this patient’s hyperthyroid state?

Since this lady is on methylcellulose eye drops (artificial tear drops), she
most probably has eye signs. Therefore, this is most likely to be Graves’
disease.
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What are the causes of hyperthyroidism?

The causes of hyperthyroidism can be classified as follows.

Common causes

w Graves’ disease (autoimmune).

w Toxic multinodular goitre.
w Solitary toxic nodule/adenoma.

Uncommon causes

w Acute thyroiditis: viral, autoimmune and post-irradiation.

w

a
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Neonatal thyrotoxicosis (maternal thyroid antibodies).
w
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Exogenous iodine.
w
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Drugs (e.g. amiodarone).

fo r P ale A am

What are the abnormal findings in the investigations provided?

ot o S an x
N ot f or sh a E

n
N ot f ee esi

tio

The full blood count shows a low haemoglobin, a low white cell count and
N r. Z th

bu
D nes

low platelets suggesting pancytopenia. Carbimazole can cause bone

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ed t
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is

marrow suppression and pancytopenia.

A

A low haemoglobin level can also be caused by bone marrow suppression

as a result of aplastic crises which usually follow infection with parvovirus
B19 and may also cause pancytopenia. A haemoglobin concentration
above 8g/dL is an adequate level during the pre-operative period, so this
patient does not require pre-operative transfusion.

A marked increase in haemoglobin may increase blood viscosity and

precipitate a vaso-occlusive crisis. If the patient has received multiple
blood transfusions in the past, there is a possibility of developing red cell
antibodies.

Her thyroid function tests show a very low thyroid stimulating hormone
(TSH) and elevated free T3 and T4 suggesting that her thyrotoxicosis is
not controlled.
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Structured Oral Examination 4

The ECG shows narrow complex regular tachycardia with a rate of 150
bpm, most likely to be atrial flutter. There is ST segment depression in V4-
V6 and T-wave inversion in leads II, II and aVF.

Can you explain the synthesis of thyroid hormones?

The thyroid hormones, thyroxine (T4) and tri-iodothyronine (T3), are

synthesized in the follicular cells. The synthesis of thyroid hormones
involves the following steps:

w Iodide trapping. Iodide from dietary sources is actively absorbed from

the bloodstream and concentrated in the thyroid follicles.
w Oxidation. Iodide is rapidly oxidised to iodine.
w Iodination. Iodination of tyrosine to form mono-iodotyrosine (MIT) and

a
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di-iodotyrosine (DIT). The enzyme, thyroid peroxidase, catalyses the
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oxidation of iodide and iodination of tyrosine. Tyrosine residues are
hm N

part of the thyroglobulin molecule (glycoprotein) in the colloid.

fo r P ale A am

Thyroglobulin is synthesised in the thyroid cells and secreted into the

ot o S an x

colloid by exocytosis.
N ot f or sh a E

w Combination. T3 is formed by combining one MIT and one DIT

n
N ot f ee esi

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molecule. T4 is formed by combining two DIT molecules. T4 is stored

N r. Z th

bu

in the colloid bound to the thyroglobulin molecule. Proteases digest

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iodinated thyroglobulin, releasing the hormones, T4 and T3, the

is
A

biologically active agents central to metabolic regulation.

The production of T4 and T3 is regulated by TSH, released by the anterior

pituitary, which in turn is controlled by thyrotropin releasing hormone
released by the hypothalamus. When the T4 levels are high, TSH
production is suppressed forming a negative feedback loop.

In the blood, T3 and T4 are partially bound to thyroxine binding globulin

and albumin and only a small fraction of the circulating hormone is free
(unbound). The free fraction of the hormone is active. The half-life of T4 is
5-7 days; the half-life of T3 is only 24 hours. T3 is four times more active
than the more abundant T4.

What are the drugs used in the management of hyperthyroidism?

The two main group of drugs used in the treatment of hyperthyroidism are
antithyroid drugs and beta-blockers.
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Antithyroid drugs

w Carbimazole. This prevents the synthesis of T3 and T4 by inhibiting

oxidation of iodide to iodine, thereby preventing the iodination of
tyrosyl residues in thyroglobulin. It can cause bone marrow
suppression causing pancytopenia and agranulocytosis. Carbimazole
is a prodrug, well absorbed from the gastrointestinal tract and
converted to methimazole (active component) in the liver. It usually
takes 4-8 weeks for the patient to become euthyroid; the dose is then
gradually reduced and continued for 12-18 months. The side effects
include rashes, arthralgia and pruritis. Agranulocytosis is a rare side
effect.
w Propylthiouracil. This inhibits the iodination of tyrosyl residues in
thyroglobulin and prevents the peripheral conversion of T4 to T3. It is

a
tth
C s
used if patients are sensitive to carbimazole. It can also cause bone
ad ote
ha
marrow suppression. A euthyroid state is usually achieved after 4-8
hm N

weeks of treatment. It has a slightly higher incidence of

fo r P ale A am

agranulocytosis compared with carbimazole.

w
ot o S an x
N ot f or sh a E

Lugol’s iodine. Traditionally this has been used as an adjunct to

n

antithyroid drugs for 10-14 days before a partial thyroidectomy to

N ot f ee esi

tio

reduce the vascularity of the gland.

N r. Z th

bu
D nes

Beta-blockers
tri
ed t
r R rin
is
A

These are used to control the symptoms of thyrotoxicosis. Propranolol is

most commonly used. It controls the cardiovascular effects and prevents
the peripheral conversion of T4 to T3. It is also used in a thyrotoxic crisis
to control the sympathetic effects. Propranolol is a non-selective beta-
blocker and is relatively contraindicated in patients with cardiac failure and
chronic obstructive airway disease.

What are the anaesthetic implications in this patient?

w Anaesthetic implications due to the effects of thyrotoxicosis. As she is

hyperthyroid at present, she is more prone to cardiovascular
complications such as arrhythmias, an exaggerated cardiovascular
response to laryngoscopy and surgical stimulation, and peri-operative
ischaemic events. There may be precipitation of a thyroid storm in the
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Structured Oral Examination 4

peri-operative period. This patient most probably has eye signs (she
uses methylcellulose drops) and may be more prone to corneal
abrasions and pressure injury because of the proptosis.
w Anaesthetic implications due to the effects of goitre. With regard to
the airway, a large goitre may cause tracheal deviation or obstruction.
It may be worse in the supine position and usually eases in the lateral
position. Postoperatively, after the removal of the thyroid gland,
tracheomalacia can lead to airway obstruction. There may be
involvement of the recurrent laryngeal nerve causing a hoarse voice
(unilateral) or stridor (bilateral).
w Anaesthetic implications due to the effect of the sickle cell trait. A
sickle crisis may occur in the peri-operative period due to hypoxia,
acidosis, and hypothermia.

a
What investigations would you do to assess her airway?
tth
C s
ad ote
ha
hm N

w Thoracic inlet X-ray with an anteroposterior view to check for tracheal

fo r P ale A am
ot o S an x

deviation and narrowing. A lateral thoracic inlet view is needed to

N ot f or sh a E

assess the degree of tracheal compression. The thoracic inlet X-ray

n
N ot f ee esi

tio

may also reveal retrosternal extension of the goitre.

w
N r. Z th

bu

A CT scan of the neck and thoracic inlet is useful in assessing the site
D nes

tri
ed t
r R rin

and extent of tracheal obstruction. The diameter of the airway at the

is
A

narrowest point can be measured which will aid in estimating the size
of the ETT.
w An indirect laryngoscopy or fibreoptic nasoendoscopy should be
performed to view and document the pre-operative function of the
vocal cords.

What could precipitate a sickle cell crisis?

The following factors can precipitate a sickle cell crisis:

w Infection.
w Dehydration.
w Acidosis.
w Hypothermia.
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w Inadequate analgesia.
w Vascular stasis (tourniquets).
w Alcohol.
w Stress.

What are the types of sickle cell crises you know of?

w Vaso-occlusive crisis. This is the most common of all the crises. It is

caused by sickling and subsequent obstruction of small vessels. It may
present as an acute abdomen, priapism or acute pain in the hands and
feet (dactylitis).
w Aplastic crisis. This usually follows infection with parvovirus B19,
which causes temporary shutdown of the bone marrow.
w

a
Sequestration crisis. This occurs mainly in children. There is splenic

tth
C s
ad ote
pooling of red cells causing painful splenomegaly which may lead to
ha
hypovolaemia and circulatory collapse.
hm N

w
fo r P ale A am

Haemolytic crisis. This presents as a fall in haemoglobin and a rise in

reticulocytes and bilirubin.
ot o S an x
N ot f or sh a E

What precautions would you take to prevent sickle cell crises in

n
N ot f ee esi

this patient?
tio
N r. Z th

bu
D nes

tri
ed t
r R rin
is

The aim is to avoid dehydration, hypoxia, acidosis and hypothermia during

A

the peri-operative period.

An intravenous fluid infusion should be started pre-operatively to avoid

dehydration whilst the patient is starved. Administration of oxygen along
with sedative premedication avoids hypoxia during the pre-operative
period. Pre-oxygenation at induction and meticulous care during
positioning to avoid venous stagnation should be taken. The temperature
of the patient should be monitored and active warming should be used to
prevent hypothermia. During the postoperative period, hydration, adequate
analgesia and supplemental oxygen should be continued.

Would you anaesthetise this patient?

This patient should not be anaesthetised for an elective thyroidectomy as

she is not in a euthyroid state.
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Structured Oral Examination 4

If this patient was clinically euthyroid and had no airway

problems anticipated how would you anaesthetise her?

Pre-operatively

Benzodiazepine premedication may be beneficial in reducing anxiety.

Intra-operatively

Monitoring during anaesthesia includes peripheral oxygen saturation using

pulse oximetry, continuous ECG and non-invasive blood pressure
measurement.

Induction and maintenance of anaesthesia

a
tth
C s
ad ote
ha
The cardiovascular response to laryngoscopy can be minimised by using
hm N

opioids at induction. Local anaesthetic spray to the vocal cords and

fo r P ale A am

trachea reduces the pressor response to tracheal manipulation during

ot o S an x
N ot f or sh a E

surgery.
n
N ot f ee esi

tio

As there are no anticipated airway problems, pre-oxygenation and

N r. Z th

bu
D nes

intravenous induction can be used. Prior to administration of the muscle

tri
ed t
r R rin
is

relaxant the ability to ventilate the lungs should be checked with gentle
A

ventilation through a face mask. An armoured ETT is usually chosen to

secure the airway. The eyes should be taped and padded to protect the
exophthalmic eye.

If intubation and/or ventilation should prove difficult, manually lifting

forward a large goitre may relieve airway obstruction.

The MAC of volatile anaesthetics in patients with thyrotoxicosis may be

increased.

The patient should be positioned in the head-up tilt position, with neck
extension achieved with a sand bag or a one litre fluid bag placed between
the shoulders. Care should be taken to prevent venous obstruction and
venous engorgement.
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During the intra-operative period factors triggering sickling of red blood

cells (RBCs) such as hypothermia, hypovolaemia, hypercarbia and
hypoxia should be avoided.

At the end of the procedure the surgeon may request for a Valsalva
manoeuvre to be performed to check haemostasis.

Recovery and postoperative period

The trachea should be extubated once the patient is fully awake. While the
patient is still ‘deep’ the ETT can be replaced by an LMA. This enables
visualisation of the vocal cord movement via the LMA using a fibreoptic
scope, after which the patient is allowed to wake up.

a
tth
C s
The patient should be monitored in the immediate postoperative period for
ad ote
ha
airway obstruction, thyroid storm, sickle cell crisis and hypocalcaemia.
hm N

Postoperative analgesia should be provided with regular paracetamol and

fo r P ale A am

NSAIDs such as ibuprofen or diclofenac sodium. Opioids such as codeine

ot o S an x

phosphate and morphine can be administered to manage breakthrough

N ot f or sh a E

pain when required.

n
N ot f ee esi

tio
N r. Z th

bu

Supplementary oxygen and intravenous fluids should be continued in the

D nes

tri
ed t

postoperative period to prevent dehydration and hypoxia. Sitting the

r R rin
is
A

patient up reduces oedema and venous engorgement.

What are the possible postoperative complications that can

occur following thyroidectomy?

Postoperative haemorrhage

This may cause swelling of the neck and airway obstruction. If airway
obstruction due to a haematoma is suspected, the immediate management
involves removal of skin clips or sutures to evacuate the haematoma. Clip
removers or stitch cutters should be available at the patient’s bed side.

Laryngeal oedema

This may be due to traumatic intubation or extensive neck surgery.

Dexamethasone 8mg administered intra-operatively may reduce oedema.
It can also be treated with humidified oxygen and nebulised steroids.
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Structured Oral Examination 4

Recurrent laryngeal nerve palsy

A bilateral partial injury of the recurrent laryngeal nerves may cause

complete airway obstruction. Unilateral injury causes hoarseness of the
voice. Intra-operative electrophysiological monitoring of the recurrent
laryngeal nerve has been used to reduce injury to the nerve. This
technique uses a special ETT with integrated electromyographic (EMG)
electrode wires to detect the EMG signs from the laryngeal muscles (vocal
cord movement). While placing the ETT in the trachea, care should be
taken to ensure that the distal ends of the electrodes are in contact with
the vocal cords.

Tracheomalacia

a
tth
C s
ad ote
This is a rare but possible complication following thyroidectomy in
ha
longstanding or retrosternal goitre. At the end of surgery the surgeon may
hm N
fo r P ale A am

want to examine the trachea under direct vision for erosion of the tracheal
rings. Prior to extubation there should be an air leak around the tracheal
ot o S an x
N ot f or sh a E

tube after deflating the cuff. Airway obstruction due to tracheomalacia may
n
N ot f ee esi

need immediate reintubation and a subsequent tracheostomy.

tio
N r. Z th

bu

Hypocalcaemia
D nes

tri
ed t
r R rin
is
A

Hypocalcaemia may occur due to accidental removal or injury or oedema

of the parathyroid glands. This usually occurs 24-36 hours following
surgery. The serum calcium should be checked after 24 hours.

Pneumothorax

May occur following surgery for a retrosternal goitre.

Thyroid crisis

A thyroid crisis is rare if hyperthyroidism is controlled pre-operatively.

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10 hours postoperatively the patient starts to become agitated

and complains of nausea. She is febrile (temperature 39.2°C) and
tachycardic. What do you think is the most likely diagnosis and
what would you do?

As this patient had a subtotal thyroidectomy 10 hours ago, this is most

likely to be a thyroid crisis, also known as thyroid storm. This is a medical
emergency and needs urgent treatment as it can be fatal.

Supportive measures

w Ensure and establish an adequate airway, breathing, circulation and

administer 100% oxygen.
w Secure venous access and administer cold intravenous fluids (a litre

a
tth
C s
of crystalloid infused rapidly and further IV fluids should be given as
ad ote
ha
required).
w
hm N

Paracetamol 1g IV or orally should be given 6-hourly to control the

fo r P ale A am

temperature.
ot o S an x
N ot f or sh a E

Specific drug therapy

n
N ot f ee esi

tio

w Propylthiouracil 600-1200mg given orally or via a nasogastric tube.

N r. Z th

bu

w Lugol’s iodine (potassium iodide) given orally, or sodium iodide 0.25g

D nes

tri
ed t
r R rin
is
A

IV. It should not be given until an hour after the administration of

antithyroid drugs. It acts immediately and prevents the further release
of thyroid hormones.
w Esmolol 0.5mg/kg as a bolus dose over one minute, followed by 50-
200mg/kg/minute as an infusion, or propranolol 1-5mg IV up to 10mg
should be used to control the sympathetic effects.
w Hydrocortisone 100mg IV should be administered every 6-hourly.
w Plasma exchange may be needed.
w Dantrolene has been used with variable success.
w Ionotropes and vasopressors may rarely be required.

A thyrotoxic crisis occurring during the intra-operative period has often

been misdiagnosed as malignant hyperthermia and successfully treated
with dantrolene.
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Structured Oral Examination 4

The clinical features of hyperthyroidism

The classical features of thyrotoxicosis include hyperactivity, weight loss

and tremor. The important cardiovascular effects are tachycardia, atrial
fibrillation (AF) and congestive cardiac failure.

Table 4.5 Clinical features of hyperthyroidism.

Symptoms Signs
Weight loss Goitre
Increased appetite Tachycardia
Diarrhoea/vomiting Atrial fibrillation

a
tth
C s
ad ote
Palpitation Exophthalmos
ha
hm N

Heat intolerance Lid lag

fo r P ale A am

Menstrual disturbance Conjunctivitis

ot o S an x
N ot f or sh a E

n
N ot f ee esi

Pretibial myxoedema
tio
N r. Z th

bu
D nes

Retrosternal goitre
tri
ed t
r R rin
is
A

Retrosternal goitre occurs when the thyroid extends underneath the

sternal wall. Retrosternal goitres can cause compression of mediastinal
structures leading to dyspnoea and dysphagia. The pressure effect on the
superior vena cava impairs the venous drainage from the head and neck
region and may cause airway oedema and oedema of the face. The
engorgement of the nasal mucosa may result in bleeding during nasal
fibreoptic intubation. Small retrosternal goitres may cause more problems
than huge visible goitres. The problems associated with very large and
retrosternal goitres include difficult intubation, excessive blood loss,
prolonged operating time and postoperative tracheomalacia.

Anaesthesia for retrosternal goitre can be challenging, particularly with

regard to the airway. The incidence of complications can be greatly
reduced by adequate pre-operative assessment and planning. The
presence of noisy breathing, dyspnoea and position-related breathing
difficulty indicates airway obstruction.
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a
tth
C s
ad ote
ha
hm N
fo r P ale A am
ot o S an x
N ot f or sh a E

Figure 4.2 Thoracic inlet X-ray showing

n

tracheal deviation.
N ot f ee esi

tio
N r. Z th

bu
D nes

tri
ed t
r R rin
is
A

Figure 4.3 CT scan showing tracheal

compression and deviation.
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Structured Oral Examination 4

The following options for airway management are available when a

difficulty is anticipated:

w Inhalational induction with sevoflurane. The aim is to maintain

spontaneous ventilation until the airway is secured. Premedication with
an anti-sialogogue should be considered to dry the secretions in
patients with a non-toxic goitre. A nasopharyngeal or oral airway
should be immediately available to overcome the airway obstruction at
the level of the oropharynx or nasopharynx. In the presence of airway
obstruction, inhalation induction may be prolonged. Airway collapse
leading to complete airway obstruction may occur as the patient is
induced.
w Awake fibreoptic intubation. This is the technique of choice when the

a
airway anatomy is distorted. If the patient is in stridor, due to narrowing

tth
C s
ad ote
of the airway, however, passage of the fibreoptic scope may result in
ha
complete airway obstruction.
hm N
fo r P ale A am

Sickle cell disease

ot o S an x
N ot f or sh a E

n
N ot f ee esi

In normal adults the haemoglobin molecule (HbA) consists of four

tio
N r. Z th

bu

polypeptide chains: two alpha chains and two beta chains. Each alpha
D nes

tri

chain consists of 141 amino acid residues and each beta chain of 146
ed t
r R rin
is
A

amino acid residues. When valine (amino acid) replaces the glutamine
(amino acid) at the 6th position of the beta chain of the haemoglobin
molecule, abnormal haemoglobin is formed, known as haemoglobin S
(HbS).

There are two genes responsible for haemoglobin synthesis. In the

heterozygous state (sickle cell trait) there is a mixture of normal gene
(HbA) and abnormal gene (HbS). This haemoglobin is known as HbAS. In
the homozygous state (sickle cell disease or sickle cell anaemia) both
genes are abnormal. This haemoglobin is known as HbSS.

Sickle cell trait

Individuals with a sickle cell trait have no symptoms unless they are
exposed to severe hypoxia. Typically they have about 60% HbA and 40%
HbS. A sickle cell trait protects against plasmodium falciparum, which
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causes malaria. The diagnosis of a sickle cell trait is made by a positive

sickle cell test and by haemoglobin electrophoresis.

Sickle cell anaemia

Individuals with sickle cell anaemia have 85-95% HbS, the remainder
being HbF (foetal haemoglobin). The deoxygenated HbS is 50 times less
soluble in blood than deoxygenated HbA. The deoxygenated Hb forms
long crystals called tactoids which distort the red blood cell membrane
causing the red cell to assume a sickle shape. The sickle cells are
susceptible to premature destruction, which causes chronic haemolytic
anaemia. Sickled cells result in increased blood viscosity, cause damage
to the endothelium and result in vascular injury.

a
tth
C s
The Sickledex test is a rapid screening tool. It detects the presence of
ad ote
ha
HbS but does not differentiate a sickle cell trait from sickle cell anaemia.
hm N

Haemoglobin electrophoresis is useful in distinguishing sickle cell anaemia

fo r P ale A am

from the trait.

ot o S an x
N ot f or sh a E

Patients with sickle cell anaemia may require pre-operative blood

N ot f ee esi

tio

transfusion prior to major surgery. A conservative transfusion to achieve an

N r. Z th

bu
D nes

Hb around 10g/dL is as effective as aggressive exchange transfusion to

tri
ed t
r R rin
is

reduce HbS below 30%. The optimal transfusion requirement should

A

always be discussed with a haematologist.

Key points

w For elective thyroid surgery the patient should be euthyroid.

w In a large goitre careful airway evaluation should be performed to rule
out potential airway obstruction.
w A retrosternal goitre can cause compression of the mediastinal
structures.
w In a patient with sickle cell disease, hypoxia, dehydration, hypercarbia
and acidosis should be avoided.
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Structured Oral Examination 4

Further reading

a
tth
C s
ad ote
ha
1. Farling PA. Thyroid disease. British Journal of Anaesthesia 2000; 85:

hm N
fo r P ale A am
15-28.

ot o S an x
N ot f for sh ia E

n
2. Vijay V, Cavenagh JD, Yate P. The anaesthetist’s role in acute sickle

N ot ee es

tio
N r. Z sth

bu
cell crisis. British Journal of Anaesthesia 1998; 80: 820-8.

tri
D ne

ed t
r R rin
is
A
3. Malhotra S, Sodhi V. Anaesthesia for thyroid and parathyroid surgery.
British Journal of Anaesthesia CEACCP 2007; 7: 55- 8.
4. Howlett TA. Endocrine disease. In: Clinical medicine, 6th ed. Kumar P,
Clark M, Eds. Philadelphia, USA: Elsevier Saunders, 2005; Chapter
18: 1073-80.

Short case 4.1: Latex allergy

A 25-year-old theatre nurse has presented for elective laparoscopy on a

gynaecology list. She is usually fit and well but for the past 6 months has
developed an itchy rash on her hands 10-15 minutes after wearing normal
theatre gloves.

What do you think is the most likely cause of the rash?

As this patient is a health care professional who gets a rash after wearing
gloves, she is most likely to be having a latex allergy.

Who is more prone to develop a latex allergy?

The condition usually occurs in persons who are repeatedly exposed to

latex:

w Health care workers; the prevalence may be as high as 17%.

w Rubber industry workers.
w Patients with spina bifida (prevalence may be as high as 60%).
w Patients exposed to repeated bladder catheterisation and multiple
operations.
w History of anaphylaxis of uncertain aetiology, especially if associated
with previous surgery and hospitalisation.
w Patients who have a fruit allergy to banana, grapes, avocado, tomato,
kiwi fruit and chestnuts (they have a cross reactivity with latex).
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ANAESTHESIA FOR THYROID SURGERY

ANAESTHESIA TUTORIAL OF THE WEEK 162

30TH NOVEMBER 2009

Lucy Adams, Specialty Registrar

Sarah Davies, Locum Consultant

Department of Anaesthesia, Leeds General Infirmary,

Leeds, UK
Correspondence to [email protected]

QUESTIONS

Before reading the tutorial try answering the following questions. Answers can be found at the end of
the text.

a
tth
1. Hyperthyroidism C s
ad ote
a. Can be identified by high levels T3/T4 and Thyroid Stimulating Hormone (TSH)
ha
b. Is most commonly caused by Graves disease
hm N

c. Patients are prone to exaggerated hypotensive response during induction of anaesthesia

d. Increases Minimum Alveolar Concentration (MAC) values
fo r P ale A am

e. Thyroid surgery is usually first line treatment

ot o S an x
N ot f or sh a E

2. Regarding superficial cervical plexus block

a. C1-5 anterior primary rami form the cervical plexus
n
N ot f ee esi

b. Block can be achieved with infiltration along the posterior border of Sternocleidomastoid
tio

c. Phrenic nerve palsy is a common complication

N r. Z th

bu

d. Could be used as a sole anaesthetic technique in a patient with a retrosternal goitre

D es

e. Can reduce postoperative morphine requirements.

tri
ed t
r R rin
An

is

3. Hypocalcaemia
a. Should be diagnosed by total body calcium levels
b. Can cause paraesthesiae
c. Is indicated by Trousseau’s sign
d. Can potentiate the negative inotropic effects of volatile anaesthetics
e. Reliably prolongs non-depolarising neuromuscular blocking agents

INTRODUCTION

Thyroid surgery can range from simple removal of a thyroid nodule to highly complex surgery. The
presence of longstanding or large goitres can pose difficult airway management decisions whilst
endocrine imbalance can have can have profound systemic manifestations that need to be considered
and controlled perioperatively.

This tutorial presents some of the more common thyroid pathologies that may be encountered, reviews
the anaesthetic management of thyroid surgery plus looks at some of the common postoperative
complications.

ATOTW 162 – Anaesthesia for thyroid surgery, date 30/11/2009 Page 1 of 9

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THYROID PATHOLOGY AND INDICATIONS FOR SURGERY

There are many indications for thyroid surgery, including: thyroid malignancy, goitres that produce
obstructive symptoms and/or are retrosternal; hyperthyroidism resistant to medical management;
cosmetic and anxiety related reasons. Patients with hypothyroidism usually respond to thyroxine
therapy and surgery is rarely indicated.

Hyperthyroidism

Hyperthyroidism results from excess circulating T3 and T4. The vast majority of cases are caused by
intrinsic thyroid disease. Indications for surgery include:

1. Grave’s disease: An autoimmune condition associated with diffuse enlargement and increased
vascularity of the gland caused by IgG antibodies mimicking Thyroid Stimulating Hormone (TSH). It
is the only cause of hyperthyroidism associated with eye signs and pretibial myxoedema. It can be
associated with other autoimmune conditions.
2. Thyroid secreting adenomas often presenting as a solitary nodule.
3. Toxic Multinodular Goitre. More common in women; a goitre develops one or two nodules with
hypersecretory activity.
4. Other causes that may or may not be associated with goitre include: Exogenous iodine, Amiodarone,
Post irradiation thyroiditis. In this group, medical management has proved unsatisfactory and

a
tth
radioiodine is not suitable. C s
ad ote
Hypothyroidism
ha
hm N

May be from intrinsic thyroid disease or failure of the hypothalamo-pituitary axis. Those associated
fo r P ale A am

with goitre include:

ot o S an x
N ot f or sh a E

1. Hashimoto’s thyroiditis. This is the commonest cause of hypothyroidism and although initially may
cause gland enlargement will later lead to thyroid atrophy due to autoantibody destruction of the
n
N ot f ee esi

follicles.
tio

2. Iodine deficiency. A lack of iodine leads to thyroid hormone depletion, Thyroid Stimulating
N r. Z th

bu

Hormone (TSH) stimulation and gland hypertrophy. Dietary iodine deficiency can be found in
D es

mountainous areas.
tri
ed t
r R rin
An

is

Malignancy

These will most commonly present as thyroid nodules and are usually minimally active hormonally
(patient is euthyroid). The most common types are Papillary and Follicular carcinomas arising from the
epithelium that confer a good prognosis if confined to the gland. Medullary carcinomas arising from
calcitonin producing cells are associated with Multiple Endocrine Neoplasia II (MEN), which may be
linked with phaeochromocytoma and primary hyperparathyroidism. Lymphomas cause diffuse swelling
of the gland and carry a very poor prognosis.

ANAESTHETIC CONSIDERATIONS

It is fundamental to ensure that patients are clinically and chemically euthyroid prior to embarking on
elective thyroid surgery. Although the majority of cases may be straightforward the possibility of both
expected and unexpected challenging airway situations should be anticipated.

Preoperative Assessment

History

This should be focused on establishing if the patient is clinically euthyroid and assessing for airway
compromise. The symptoms of hyper and hypothyroidism can occur insidiously and a collateral history
from family may be useful.

ATOTW 162 – Anaesthesia for thyroid surgery, date 30/11/2009 Page 2 of 9

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It is important to establish the pathological nature, position and size of the goitre to appreciate the
complexity and potential complications that may occur. A large goitre that has been present for some
time may be associated with tracheomalacia postoperatively. Symptoms of dysphagia, positional
breathlessness with a difficulty lying flat, change in voice or stridor may alert the anaesthetist to
possible difficulties with airway compromise on induction. Evidence of other systemic disease,
cardiorespiratory compromise and associated endocrine or automimmue disorders should also be
sought. For example, medullary thyroid cancer associated with phaeochromocytoma.

Examination

The patient should be assessed for signs of hyperthyroidism or hypothyroidism (Table 1).

An examination of the goitre or nodule should be performed to assess size and extent of the lesion. A
fixed hard nodule suggests malignancy with possible tethering to surrounding structures and limited
movement. An inability to feel the bottom of the goitre may indicate retrosternal spread. The trachea
should be examined to check for any deviation or compression. Retrosternal or large goitres can
compress surrounding structures and may elicit signs of superior vena cava (SVC) obstruction,
Horner’s Syndrome, pericardial or pleural effusions. A mandatory detailed airway examination would
also include assessment of atlantoaxial flexion and extension, thyromental distance, Mallampatti,
mandibular protrusion and incisor distance.

a
tth
C s
Table 1. Clinical features Hypothyroidism / Hyperthyroidism
ad ote
ha
HYPERTHYROIDISM HYPOTHYROIDISM
hm N

General Weight loss, Malaise, Malaise, Cold intolerance,

fo r P ale A am

Muscle weakness, Heat intolerance, Myalgia, Arthralgia,

ot o S an x

Cachexia, Palmar erythma, Dry, coarse skin.

N ot f or sh a E

Proximal muscle wasting, ‘Peaches & Cream complexion’,

Pretibial myxoedema (Graves Loss of eyebrows, Hypothermia,
n
N ot f ee esi

disease) Carpal tunnel syndrome, Myotonia

tio
N r. Z th

bu

Central nervous Irritability, Anxiety, Poor memory, Depression, Psychosis,

D es

system Hyperkinesis, Tremor Mental slowness, Dementia,

tri
ed t
r R rin
An

Poverty of movement, Ataxia,

is

Slow relaxing reflexes

Deafness

Cardiovascular Palpitations, Angina, Breathlessness, Hypertension, Bradycardia,

Hypertension, Cardiac failure, Heart failure, Oedema
Tachycardia, Tachyarrhythmias, Pericardial & pleural effusions,
Atrial fibrillation, Vasodilatation Anaemia, Cool peripheries

Gastrointestinal Increased appetite, Constipation,

Vomiting, Diarrhoea Obesity

Genitourinary Oligomenorrhoea, Menorrhagia,

Loss of libido Loss of libido

Eye (Graves Blurred / double vision,

disease only) Exophthalmos, Lid lag,
Conjunctival oedema

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Investigations

1. Routine blood tests include Full Blood Count (FBC), electrolytes, thyroid function and corrected
calcium levels. It is imperative to ensure the patient is euthyroid prior to surgery to avoid complications
of a thyroid storm or myxoedema coma in the perioperative period. FBC is essential due to the
potential for blood loss during the procedure plus to detect any serious adverse haematological effects
of concurrent antithyroid medications. (Table 2)

2. A CXR may be useful to assess the size of goitre and detect any tracheal compression or deviation.
Lateral thoracic inlet views may also help to assess retrosternal extension and the tracheal
anteroposterior diameter.
3. If there are any concerns regarding airway compromise, a CT scan is performed to determine the
extent and location of tracheal narrowing or detect tracheal invasion.

4. Nasendoscopy is often performed preoperatively by ENT to document vocal cord function. This is
an invaluable tool for the anaesthetist to assess the laryngeal inlet and any deviation from normal
anatomy.

5. Respiratory flow volume loops may show fixed upper airway obstruction but performed routinely
are rarely useful

a
Table 2. Anti-thyroid drugs

tth
C s
ad ote
DRUG DOSE
ha
MECHANISM OF ACTION SIDE EFFECTS
Carbimazole Initial:15-40mg Prodrug rapidly converted to Rashes, arthralgia,
hm N

daily methimazole. pruritis, myopathy.

fo r P ale A am

Maintenance: 5- Prevents synthesis of T3 and T4 Bone marrow suppression

15mg daily by blocking oxidation of iodide Agranulocytosis (0.1%)
ot o S an x
N ot f or sh a E

to iodine and inhibiting thyroid Crosses placenta: foetal

Takes 6-8 weeks peroxidase hypothyroidism
n
N ot f ee esi

to work
tio

Propylthiouracil Initial:200- Blocks iodination of tyrosine Thrombocytopenia,

N r. Z th

bu

400mg daily residues present in Aplastic anaemia,

D es

Maintenance: 50- thyroglobulin. Agranulocytosis

tri
ed t
r R rin

150mg daily Inhibits conversion of T4 – T3 Hepatitis, nephritis,

An

is

Crosses placenta: foetal

Takes 6-8 weeks hypothyroidism

Iodide/Iodine Lugol’s solution: Large doses of Iodide inhibit Antithyroid effects

5g Iodine hormone production. diminish with time.
solution in 10g Reduced the effect of TSH. Hypersensitivity
Potassium iodide: Marked reduction in thyroid reactions.
0.1-0.3ml TDS vascularity over 10-14days Crosses placenta: foetal
hypothyroidism

Propanolol Oral: 40-80mg Controls sympathetic effects of Negative inotropy &

TDS (May need thyrotoxic crisis. chronotropy.
higher dose as Blocks peripheral conversion of Bronchospasm
metabolism T4 to T3 Poor peripheral
increased) circulation.
IV: 0.5mg titrated CNS effects
to effect

Optimisation

Elective work should be postponed until the patient is euthyroid. On the day of surgery, usual
antithyroid medications should be administered except for Carbimazole as it increases the vascularity
of the gland. Benzodiazepines may be administered for anxiolysis but should be avoided if there is any

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airway concern. Anticholinergics may be helpful to dry secretions if an inhalational or fibreoptic

technique is planned.

In emergency surgery, it may not be possible to render those patients with uncontrolled thyroid disease
euthyroid. In these circumstances, hyperthyroid patients should have immediate control of symptoms
with beta blockade (e.g. propanolol, esmolol), intravenous hydration and active cooling if necessary.
Severely hypothyroid patients are at risk of perioperative myxoedema coma and should be treated with
intravenous T3 and T4.

Intraoperative Management

Historically thyroid surgery was performed under local anaesthesia. General anaesthesia is now the
preferred technique but regional anaesthesia can still have a place either as a sole technique with or
without sedation or alongside general anaesthesia to enhance analgesia.

Regional Anaesthesia

Regional anaesthesia for thyroid surgery is seldom used in the UK but has been successfully employed

a
tth
as the sole anaesthetic technique particularly in areas with limited resources. To achieve the most
C s
ad ote
successful results a multidisciplinary team approach needs to be employed with appropriate patient
ha
selection, excellent patient education and modification of surgical technique.
hm N

A commonly used technique is bilateral C2-C4 superficial cervical plexus block performed under full
fo r P ale A am

monitoring with or without sedation. Conscious sedation can be achieved via increments of Midazolam
or a Target Controlled Infusion (TCI) of Propofol. Bilateral deep cervical plexus blocks have a higher
ot o S an x
N ot f or sh a E

incidence of complications including vertebral artery and subdural injection, and notably bilateral
phrenic nerve palsy, which may not be tolerated in some patients.
n
N ot f ee esi

tio

The nerves supplying the anterolateral part of the neck emerge from the posterior border of
N r. Z th

bu

sternocleidomastoid (SCM) as the anterior rami of C2-C4, which divide into greater auricular,
D es

transverse cervical, lesser occipital and supraclaviclar nerves (Figure 1).

tri
ed t
r R rin
An

is

Figure 1: Superficial Cervical Plexus Block

To perform the superficial cervical plexus block, the patient should be positioned with their head
extended to the opposite side, the midpoint of the posterior border of SCM visualised. 15-20mls of

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local anaesthetic (e.g. lidocaine and/or bupivacaine with adrenaline) is injected in a superficial wheal
deep to the first fascial layer in caudad and cephalad directions along the posterior border of SCM
(Figure 1). For thyroidectomy, bilateral blocks should be performed. A midline field block can be
achieved by a subcutaneous injection from the thyroid cartilage to the suprasternal notch. This is a
useful addition to prevent the pain from surgical retractors on the medial aspect of the neck.

Regional anaesthesia avoids the risks of a general anaesthetic, allows intraoperative voice monitoring
and provides excellent postoperative analgesia. The technique may be suited to medically
compromised patients (including complicating thyrotoxicosis), or those with obstructive symptoms
secondary to large goitres to avoid the risks of a general anaesthetic. However, these techniques do
have a number of complications including local anaesthetic toxicity, haematoma, pneumothorax, and
require excellent patient cooperation.

General Anaesthesia

A variety of techniques can be employed for general anaesthesia. In most cases, the patient can be
given an intravenous induction and intubated with a reinforced tube. It is advisable to demonstrate
manual ventilation prior to giving a non-depolarising muscle relaxant. Care should be taken to avoid
overinflating the tube cuff (or use a cuff manometer) to minimise anaesthesia related cord/tracheal
damage. In our institution, we spray the vocal cords with lidocaine prior to intubation, which may help
reduce coughing on emergence.

a
tth
C s
If there are any concerns regarding airway patency or distorted anatomy alternative options should be
ad ote
ha
considered. Further information on managing predicted and unpredicted difficult airways can be found
on the Difficult Airway Society website.
hm N
fo r P ale A am

1. Inhalational induction. The technique includes good preoxygenation and gradual induction with
Sevoflurane. Airway adjuncts and difficult airway equipment should be immediately available if the
ot o S an x

airway is lost during induction.

N ot f or sh a E

2. If there is concern regarding distorted anatomy or that the airway may be lost altogether on
N ot f ee esi

tio

induction, an awake fibreoptic intubation may be used. This technique should be avoided in those
N r. Z th

bu

patients with marked symptoms of airway obstruction as complete obstruction may be provoked.
D es

tri
ed t

3. If either of these options are not suitable, a tracheostomy under local anaesthetic by the surgeons
r R rin
An

is

may be appropriate.

4. Ventilation through a rigid bronchoscope can be used if attempts at passing an endotracheal tube fail
or if there is subglottic tracheal compression.

5. The Laryngeal Mask Airway (LMA) can be used for thyroid surgery but should be avoided in those
with airway compromise or distorted anatomy. The use of an LMA has the advantage of allowing the
assessment of the vocal cords intraoperatively via a fibreoptic scope with stimulation of the recurrent
laryngeal nerve. It does not provide a definitive airway, and relies on close cooperation between the
surgeon and anaesthetist to avoid displacement during surgery.

Intravenous or inhalation agents can be used for maintenance of anaesthesia. Good muscle relaxation is
paramount and neuromuscular function should be monitored. Remifentanil infusion is commonly used
as it reduces the need for muscle relaxation allowing for intraoperative electrophysiological testing of
the recurrent laryngeal nerve in complicated cases. It can also be titrated against the blood pressure to
assist in producing a bloodless surgical field during dissection, yet allow return to normal
(supranormal) pressures prior to closure to check haemostasis. This may also require the use of a
vasopressor such as phenylephrine boluses.

Positioning

For optimal surgical access the head is fully extended and rested on a padded ring with a sandbag
between the scapulae. The eyes should be adequately padded and particular attention paid to those
with exophthalmos. Access to the airway will be limited during the procedure so the endotracheal tube
should be taped securely. Neck ties should be avoided. A head up tilt is preferable to allow venous

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drainage although care must be taken to ensure arterial pressure is not compromised. As the arms are
extended by the patient’s side, long extension leads on the drips are useful.

Retrosternal goitres can usually be removed via the cervical route. However, a few may require a
sternotomy.

Analgesia

The surgeon will usually infiltrate local anaesthetic and adrenaline subcutaneously prior to incision that
confers some analgesic effect into the postoperative period. Regular paracetamol, non-steriodal
antinflammatories (NSAIDs) plus weak opioids are usually adequate to ensure the patient is
comfortable but morphine maybe required. Bilateral superficial cervical plexus blocks can significantly
reduce pain and morphine requirements in the postoperative period. Administration of antiemetics is
important as these patients are at high risk of postoperative nausea and vomiting. We use a
combination of ondansetron and/or cyclizine with dexamethasone, which may also help reduce
postoperative airway oedema.

Emergence

At the end of the procedure the surgeon may request a Valsalva manoeuvre to check for haemostasis. If
there have been any concerns regarding the integrity of the recurrent laryngeal nerve, then the vocal

a
cords are visualised with either a laryngoscope, or a fibreoptic scope via an LMA (if in place or sited

tth
post deep extubation).
C s
ad ote
ha
Neuromuscular blockade should be fully reversed, the patient sat up and endotracheal tube cuff
hm N

deflated to ensure a leak prior to extubation. In our institution, we extubate our patients awake. It is
fo r P ale A am

important to minimise airway manipulation and head and neck movement during emergence, to prevent
coughing and straining. If the vocal cords have been sprayed with lidocaine at intubation, this may also
ot o S an x
N ot f or sh a E

help to achieve a smooth emergence. Alternative techniques include extubation at a deep level of
anaesthesia or intravenous lidocaine (1.5mg/kg). Steroids (e.g. dexamethasone 8mg) may help to
n

reduce airway oedema if the procedure has been long or difficult.

N ot f ee esi

tio
N r. Z th

bu

Postoperative Considerations
D es

tri
ed t
r R rin

Haemorrhage
An

is

Postoperative bleeding can cause compression and rapid airway obstruction. Signs of swelling or
haematoma formation that is compromising the patient’s airway should be immediately decompressed
by removal of surgical clips. Clip removers should be kept by the patient’s bedside. If there is time to
return to theatre, reintubation should be performed early.

Laryngeal oedema
This is an uncommon cause of postoperative respiratory obstruction. It can occur as a result of
traumatic tracheal intubation or in those who develop a haematoma that can cause obstruction to
venous drainage. It can usually be managed with steroids and humidified oxygen

Recurrent Laryngeal Nerve (RLN) Palsy

Trauma to the recurrent laryngeal nerve can be caused by ischaemia, traction, entrapment or transection
of the nerve during surgery and may be unilateral or bilateral. Unilateral vocal cord palsy will present
with respiratory difficulty, hoarse voice or difficulty in phonation whilst bilateral palsy will result in
complete adduction of the cords and stridor. Bilateral RLN palsy requires immediate reintubation and
the patient may subsequently need a tracheostomy.

Hypocalcaemia
Unintended trauma to the parathyroid glands may result in temporary hypocalcaemia. Permanent
hypocalcaemia is rare. Signs of hypocalcaemia may include confusion, twitching and tetany. This can
be elicited in Trousseau’s (carpopedal spasm precipitated by cuff inflation) or Chvostek’s sign (facial
twitch on tapping parotid gland) Calcium replacement should be instituted immediately as
hypocalcaemia can precipitate layngospasm, cardiac irritability, QT prolongation and subsequent
arrhythmias

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Tracheomalacia
The possibility of tracheomalacia should be considered in those patients who have had sustained
tracheal compression by large goitres or tumours. A cuff leak test just prior to extubation is reassuring
but equipment should be available for immediate reintubation if it occurs.

Thyroid Storm
Characterised by hyperpyrexia, tachycardia, altered consciousness and hypotension this is a medical
emergency. Although less commonly seen now as patients are rendered euthyroid prior to surgery it
can still occur in patients with hyperthyroidism when they sustain a stress response such as surgery or
infection. Management is supportive with active cooling, hydration, beta blockers and antithyroid
drugs. Dantrolene 1mg/kg has also been successfully used in the treatment of thyroid storm.

SUMMARY
• Patients should be clinically and chemically euthyroid prior to thyroid surgery
• Perioperative airway complications are common and the expected or
unexpected difficult airway should be anticipated.
• Postoperative complications of haematoma formation, recurrent laryngeal

a
nerve palsy, hypocalcaemia and tracheomalacia can all cause airway

tth
C s
compromise and must be acted upon quickly.
ad ote
ha
• Thyroid storm although less common than it used to be, is a medical
hm N

emergency
fo r P ale A am

ANSWERS TO QUESTIONS
ot o S an x
N ot f or sh a E

1. FTTFF
n

Thyroid function tests classically reveal high levels of T3 and T4 but low levels of TSH suppressed by
N ot f ee esi

tio

the negative feedback on the pituitary. The commonest cause is Grave’s disease. These patients can be
N r. Z th

chronically hypovolaemic and vasodilated and therefore do show exaggerated response to induction.
bu
D es

Hyperthyroidism does not increase anaesthetic requirements. Thyroid surgery is considered after
tri
ed t

medical or radioiodine treatment.

r R rin
An

is

2. FTFFT
Cervical plexus is formed from C1-C4. Phrenic nerve palsy is a common complication of deep cervical
plexus block. A sole regional technique would not be appropriate in a patient with retrosternal goitre

3. FTTTF
Hypocalcaemia should only be diagnosed on the basis of plasma ionised calcium concentration, i.e.
corrected for plasma albumin concentration. Paraesthesiae and Trousseau’s sign can occur. Decreased
cardiac contractility will occur and potentiaton of negative inotropes should be expected. The response
of NMBA is inconsistent.

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REFERENCES

1. Kumar P, Clark M. Clinical medicine 4th ed. W. B Saunders 1999. 932-941

2. Farling P.A. Thyroid disease. British Journal of Anaesthesia 2000; 85(1):15-28
3. Malhotra S, Sodhi V. Anaesthesia for thyroid and parathyroid surgery. Continuing Education
in Anaesthesia Critical Care and Pain 2007; 7(2): 55-58
4. Spanknebel K, Chabot JA, DiGeorgi M, Cheung K, Lee S, Allendorf J, LoGerfo P.
Thyroidectomy Using Local Anaesthesia: A Report of 1,025 Cases over 16 Years. Journal of
American College of Surgeons 2005;201(3): 375-385
5. www.NYSORA.com
6. Dieudonne N, Gomola A, Bonnichon P, Ozier Y. Prevention of Postoperative Pain After
Thyroid Surgery: A Double-Blind Randomised Study of Bilateral Superficial Cervical Plexus
Blocks. Anesth Analg 2001;92:1538-42
7. www.DAS.uk.com

a
tth
C s
ad ote
ha
hm N
fo r P ale A am
ot o S an x
N ot f or sh a E

n
N ot f ee esi

tio
N r. Z th

bu
D es

tri
ed t
r R rin
An

is

ATOTW 162 – Anaesthesia for thyroid surgery, date 30/11/2009 Page 9 of 9

442
Chapter 82
Thyroid Emergencies

Thyroid Storm
What is a thyroid storm?

A thyroid storm is a rare life-threatening disorder occurring in approximately

1% of patients with hyperthyroidism.

a
tth
Describe the pathophysiology of a thyroid crisis
C s
ad ote
ha
hm N

The most common underlying mechanism is primary overproduction of thyroid

fo r P ale A am

hormone. Additional causes include damage to the gland precipitating release

of thyroid hormone and excessive iodine intake which may cause thyrotoxicosis.
ot o S an x
N ot f or sh a E

There are causes and precipitants of a thyroid storm. Please

N ot f ee esi

tio

can you give examples of each?

N r. Z th

bu
D es

tri
t
r R rin
An

Causes
is
ed

1 Grave’s disease (most common) – due to autoimmune process involving thyr-

oid-stimulating antibodies
2 Toxic multinodular goitre
3 Thyroid adenoma
4 Trauma
5 Excessive exogenous thyroid hormone
Precipitants
1 Sepsis
2 Trauma
3 Surgery
4 MI
5 Administration of iodinated contrast load in previous 6 weeks
6 Poorly-controlled DM
7 The puerperium
8 Drugs (anticholinergic, adrenergic, NSAIDs)

How does it present?

Patients typically present with features reflecting a hypermetabolic state. It may

Chapter 82: Thyroid Emergencies 443

Cardiovascular
– Tachycardia, tachyarrhythmias (especially AF)
– Flushing, sweating
– High output cardiac failure

Neuropsychiatric
– Agitation, confusion, psychosis and coma

Metabolic
– Hyperpyrexia
– Rhabdomyolysis
– Dehydration
– Electrolyte disturbance (hypernatraemia and hypokalaemia)

Gastrointestinal

a
tth
C s
ad ote

– Abdominal pain, nausea and vomiting

ha
hm N

Signs of underlying hyperthyroidism

fo r P ale A am

– Eye signs: lid retraction, proptosis, exophthalmos

ot o S an x
N ot f or sh a E

– Hot, moist skin

– Hair loss
n
N ot f ee esi

tio
N r. Z th

bu
D es

tri

What investigations would you request if you suspected

t
r R rin
An

is

a thyroid storm?
ed

1 Blood tests
– FBC, CRP and cultures looking for infection
– U+Es (prerenal AKI, hypokalaemia)
– LFTs
– Clotting screen
– TFTs (↑T3, ↑T4, ↓thyroid stimulating hormone (TSH))
– CK
– Cortisol, ACTH
– Glucose (usually high due to sympathetic activity)
– ABG (metabolic or mixed acidosis)
2 Urinalysis
– MC+S
– Myoglobin
– Catecholamines (phaeochromocytoma is a differential)
3 CXR looking for pulmonary oedema; lower respiratory tract infection (LRTI) is
a potential precipitant
4 ECG looking for arrhythmias and evidence of myocardial ischaemia (may be
causative or secondary to hyperthyroid state)
5 Echo to assess LV function and look for RWMAs (MI is a potential precipitant)
444 Chapter 82: Thyroid Emergencies

How would you manage a patient with a thyroid storm?

A patient presenting with a thyroid crisis should be managed with an ABCDE
approach, and abnormalities treated as they are found. Treatment is both
supportive and directed at correcting the underlying endocrine abnormality,
precipitant or cause.
1 Supportive management
i Supplemental oxygen should be given as the underlying metabolic rate is high
ii Sedation and mechanical ventilation may be required to reduce metabolic
rate – be aware of difficulty in intubation in patients with goitre (usually
causes either difficult direct laryngoscopy or difficulty passing the ETT due
to external compression causing subglottic narrowing)
iii Fluid resuscitation
iv Treat life-threatening arrhythmias
v Provide cardiovascular support

a
vi Electrolyte replacement
tth
C s
ad ote

vii Cool patient

ha
– Passive: remove clothing, cool cloths
hm N

– Active: cold IV infusions, bladder irrigation, intravascular devices, extra-

fo r P ale A am

corporeal circuits
ot o S an x

– Antipyretics (aspirin is best avoided as it competes with thyroxine for

N ot f or sh a E

thyroid-binding globulin (TBG))

n
N ot f ee esi

2 Treat precipitating cause

tio
N r. Z th

3 Treat endocrine abnormality

bu
D es

i Betablockade – propranolol IV
tri
t
r R rin

– Sympatholysis for symptomatic control

An

is
ed

– Reduced peripheral conversion of T4 to T3

ii Thionamides (anti-thyroid medication)
– Propylthiouracil enterally
– Blocks iodination of tyrosine and peripheral conversion of T4 to T3
– Carbimazole (slower onset but longer acting than propylthiouracil)
enterally
– Blocks thyroid hormone production
– Often associated with short-lived leucopenia
iii Steroids (reduce peripheral conversion of T4 to T3)
– This is a glucocorticoid-deficient state and correction of thyrotoxicosis
may precipitate an Addisonian crisis
– Dexamethasone or hydrocortisone can be given
4 Additional measures
i Digoxin and amiodarone (after giving propylthiouracil, as may exacerbate
crisis) can be used
ii Vitamin B complex
– Vitamin B1 (thiamine) requirements are increased in thyrotoxicosis
– There is a risk of precipitating Wernicke’s when thyrotoxicosis is treated
if vitamin B complex is not given
iii Dantrolene has been used in case reports of significant muscle hyperactivity
iv Plasma exchange may be needed in rare cases
Chapter 82: Thyroid Emergencies 445

What Is the prognosis of a thyroid storm?

Mortality approaches 30%.

Myxoedema Coma
What is myxoedema coma?

Myxoedema coma is a rare, potentially fatal clinical syndrome caused by defi-

ciency of thyroid hormone.

What are the causes of a hypothyroid crisis?

Myxoedema coma most commonly occurs in patients with undiagnosed or

a
undertreated hypothyroidism. The causes of hypothyroidism are:
tth
C s
ad ote
ha
1 Iodine deficiency (most common cause worldwide)
hm N

2 Hashimoto’s thyroiditis (autoimmune condition caused by anti-thyroid

fo r P ale A am

antibodies)
3 Previous treatment with radioactive iodine or thyroid surgery
ot o S an x
N ot f or sh a E

4 Thyroid or pituitary injury

n

5 Medications including amiodarone

N ot f ee esi

tio
N r. Z th

The common precipitants include:

bu
D es

tri
t

1 Sepsis
r R rin
An

is

2 Trauma
ed

3 Surgery
4 Drugs, including sedatives
5 Hypothermia
6 (Over)treatment of hyperthyroidism

How does myxoedema coma present?

Respiratory
– Hypoventilation, hypoxaemia

Cardiovascular
– Bradycardia, long QTc, T wave flattening / inversion
– Pericardial effusion

Neuropsychiatric
– Seizures
– Stupor, obtunded, coma
446 Chapter 82: Thyroid Emergencies

Metabolic
– Hypothermia
– Electrolyte disturbance (hyponatraemia, hyperphosphataemia)
– Hypoglycaemia

Signs of underlying hypothyroidism

– Coarse, dry skin
– Peripheral and periorbital oedema, macroglossia
– Slow-relaxing reflexes

How is myxoedema coma managed?

A patient presenting with a hypothyroid crisis should be managed with an

ABCDE approach, and abnormalities treated as they are found. Treatment is

a
both supportive and directed at correcting any underlying endocrine abnorm-
tth
C s
ality, precipitant or cause.
ad ote
ha
1 Supportive management
hm N

i Airway control may be necessary due to reduced GCS

fo r P ale A am

ii Fluid resuscitation using normal saline (these patients have a dilutional

ot o S an x
N ot f or sh a E

hyponatraemia with high total body water but intravascular hypovolaemia)

iii Provide cardiovascular support with inotropes
n
N ot f ee esi

tio

iv Correction of hypoglycaemia and electrolyte abnormalities

N r. Z th

bu

v Warming (avoid rewarming too rapidly as vasodilatation in an under-

D es

resuscitated circulation will produce cardiovascular collapse)

tri
t
r R rin
An

is

2 Treat the precipitating cause

ed

3 Treat endocrine abnormality using small incremental doses of thyroxine

(there is no evidence of any prognostic benefit of using parenteral over
enteral thyroid hormone). Use cautiously in the elderly or those with IHD to
avoid precipitating myocardial ischaemia.
i Liothyronine IV (quicker onset)
ii Levothyroxine enterally or IV (gastric absorption may be impaired)
– Blocks iodination of tyrosine and peripheral conversion of T4 to T3
iii Corticosteroids
– Adrenal function is impaired in hypothyroidism
– Give steroid before thyroxine to avoid precipitating an Addisonian crisis

What is the prognosis of myxoedema coma?

The mortality is between 30–50%.

Further Reading
Eledrisi M S, 2016. Myxedema coma or crisis [online]. Qatar: Medscape. Available at: http://emedicine
.medscape.com/article/123577 (Accessed 18 December 2016)
Schraga E D, 2016. Hyperthyroidism, thyroid storm, and Grave’s disease treatment & management
[online]. California: Medscape. Available at: http://emedicine.medscape.com/article/767130
(Accessed: 18 December 2016)
T Thyroidectomy 245

Magnesium may also be used to control spasms.

Intensive care may be indicated with paralysis and ventilation.
Ventilation is likely to be prolonged if required and early tracheostomy
should be considered.
Autonomic dysfunction often occurs after the onset of respiratory
symptoms. Treatment with ␤-blockers is controversial since their use has
been associated with sudden cardiac arrest and unresponsive hypotension.
Esmolol, because it is short acting, may be the most suitable drug in this
class.
Other general ICU measures include nutritional support and
thromboprophylaxis.
Mortality, even with supportive intensive care, is around 11%
Patients die from aspiration, hypoxia, respiratory failure and cardiac arrest.

Bibliography
Cook TM, Protheroe RT, Handel JM. (2001). Tetanus: a review of the literature. British Journal of
Anaesthesia, 87(3), 477–87.
Thwaites CL. (2005). Tetanus. Current Anaesthesia in Critical Care, 16, 50–7.

Thyroidectomy
What are the anaesthetic problems of a patient who is thyrotoxic with a
large goitre presenting for thyroidectomy?
These may be divided into the effects of thyrotoxicosis and those of the goitre
on the airway and surrounding structures.
a

Thyrotoxicosis
tth
C s
ad ote

Cardiovascular Tachycardia
ha

Arrhythmias (esp. AF)

hm N
fo r P ale A am

Congestive cardiac failure

Ischaemic heart disease
ot o S an x
N ot f or sh a E

May be chronically hypovolaemic and vasodilated

n
N ot f ee esi

causing hypotension on induction

tio

Exaggerated response to laryngoscopy and surgical

N r. Z th

bu
D nes

stimulation with tachycardia, hypertension and

tri
ed t
r R rin
is

ventricular arrhythmias
A

Thyroid storm See below

Eyes Lid retraction, exophthalmos, conjunctivitis
Other Proximal myopathy
Anaemia
Thrombocytopaenia
Hypercalcaemia
Abnormal glucose tolerance
Associated auto-immune disease, e.g. diabetes,
myasthenia
246 Thyroidectomy T

Effects of goitre
Compression
Airway May be worse in supine position, eased on side or
prone
Tracheomalacia (especially post-operatively)
SVC Retrosternal extension
Oedematous face and airway
Engorgement of nasopharyngeal veins (epistaxis with
fibre-optic intubation)
Poor venous return therefore place i.v. line in lower
extremity (IVC territory)
Recurrent laryngeal 1% have involvement pre-operatively. This causes cord
nerve adduction leading to a hoarse voice.
Bilateral nerve involvement causes stridor.
Tumour invasion of local tissues

How would you assess her thyroid status?

a
tth
C s

Symptoms Weight loss, diarrhoea, vomiting

ad ote
ha

Restlessness, tremor
hm N

Palpitations
fo r P ale A am

Heat intolerance
ot o S an x

Eye complications (Graves’ disease)

N ot f or sh a E

Signs Tachycardia
n
N ot f ee esi

tio

Atrial fibrillation
N r. Z sth

bu

Cardiac failure
Warm, vasodilated peripheries
tri
D e

ed t
r R rin
An

is

Goitre with bruit

Hyperkinesis
Investigations TSH ↓
T3 ↑
T4 ↑
Free T4 ↑
Thyroid scan (131 I) – ‘hot’ or ‘cold’ spots

Which drugs are used to manage thyrotoxicosis?

Carbimazole Inhibits hormone synthesis.
Takes 4–8 weeks to work.
Major side effect is depression of the white cell count.
Agranulocytosis in 1/1000 after 3 months.
Propylthiouracil Inhibits hormone synthesis.
Also inhibits peripheral conversion of T4 to more active
T3.
Given if sensitive to carbimazole.
Takes 4–8 weeks to work.
Side effects include leucopaenia, aplastic anaemia,
lupus-like syndrome.
T Thyroidectomy 247

Iodine (Lugol’s solution) Traditionally given for 10 days prior

to surgery to reduce the vascularity of the gland. This
practice is now less common because the thyroid gland
is dissected without transection.
β-blocker Propranolol controls cardiovascular effects and
decreases peripheral conversion of T4 to more active T3
Heart rate of less than 85 has been recommended
Atenolol or nadolol (both longer acting) may achieve
better control of symptoms.

How would you assess the airway?

Symptoms Positional dyspnoea (esp supine with retrosternal goitre).
Dysphagia
Signs Stridor
Routine assessment of expected difficulty with intubation.
Investigations Indirect laryngoscopy or fibre-optic nasendoscopy by ENT
surgeon will give clues as to whether the larynx is likely to
a
tth
C s

be easily visualized at direct laryngoscopy.

ad ote
ha

Chest X-ray/lateral thoracic inlet – tracheal

hm N

compression/deviation.
fo r P ale A am

CT scan – extension of retrosternal goitre and site/degree

ot o S an x

of tracheal compression. Diameter of airway at narrowest

N ot f or sh a E

point can also be measured.

n
N ot f ee esi

tio
N r. Z sth

This patient was euthyroid with no clinical or radiological evidence of

bu
tri

obstruction. How would you anaesthetise them?

D e

ed t
r R rin
An

is

Pre-medication Benzodiazepine
␤-blocker continued
Standard i.v. induction and muscle relaxation is acceptable.
Care to obtund pressor responses.
Armoured tube – well secured
Attention to eye protection
Sandbag between shoulder blades
Head-up (reduces bleeding) and extended
Arms by the side therefore long drip extensions
Check cords at the end when breathing spontaneously – bilateral recurrent
laryngeal nerve damage will cause bilateral cord adduction and stridor.
Extubate ‘awake’.
Post-operative care to include attention to oxygenation, fluid balance,
analgesia, airway monitoring for signs of obstruction – clip remover
immediately available.
Check serum calcium and have i.v. calcium by the bedside.
Continue ␤-blocker.
248 Trauma T

What is thyroid storm and how is it managed?

This is a life-threatening syndrome seen in hyperthyroid patients typically
6–24 hours post-operatively, although it may occur intra-operatively. It is
characterized by hyperpyrexia, tachycardia, hypotension and altered
consciousness. It may initially mimic malignant hyperthermia, but is not
associated with muscle rigidity or a rise in CK. Other factors such as labour or
severe infection may also precipitate the syndrome.
Treatment consists of:

a
Antithyroid drugs Propylthiouracil – orally or N/G

tth
C s
Iodide – inhibits release of hormone from gland

ad ote
ha
Dexamethasone – inhibits synthesis, release and

hm N
peripheral conversion
fo r P ale A am
β-blocker Propranolol – combined β1 and β2 preferable
ot o S an x

β1 Cardiovascular effects
N ot f or sh a E

β2 Suppresses metabolic effects

n
N ot f ee esi

tio
Reduces muscle blood flow and therefore heat
N r. Z sth

production bu
tri
Active cooling
D e

ed t
r R rin
An

is

i.v. fluids
Paracetamol
Invasive monitoring and inotropic/vasopressor therapy as indicated

Bibliography
Craft T, Upton P. (1995). Key Topics in Anaesthesia. Bios Scientific Publishers.
Deakin CD. (1998). Clinical Notes for the FRCA. Churchill Livingstone.
Farling PA. (2000). Thyroid disease. British Journal of Anaesthesia, 85(1), 15–28.
Goldstone J, Pollard B. (1996). Handbook of Clinical Anaesthesia. Churchill Livingstone.
Hagberg CA. (2000). Handbook of Difficult Airway Management. Churchill Livingstone.
Kumar P, Clark M. (2002). Clinical Medicine, 5th edition. WB Saunders.
Malhotra S, Sodhi V. (2007). Anaesthesia for thyroid and parathyroid surgery. CEACCP, 7, 55–8.
Marshall P. (2002). Oxford Handbook of Anaesthesia. Oxford, UK: Oxford University Press.
Morgan GE, Mikhail MS. (1996). Clinical Anaesthesiology, 2nd edition. Appleton and Lange.

Trauma
You are called to casualty to assess a 25-year-old male pedestrian who
has been hit by a car at unknown speed. He was unconscious at the
scene and has an obvious compound fracture of his right tibia and fibula.
His foot is cool and dusky. He is agitated and his GCS is now 14. The
orthopaedic surgeons want to fix his leg as soon as possible.
How would you assess this patient?
This is a major trauma case and he should be assessed and resuscitated
according to the ATLS guidelines. From the history he may have sustained
295

Long Case 5
‘The one about the young, thyrotoxic woman listed for a
thyroidectomy’

A 31-year-old woman presents for a thyroidectomy. Three years

ago she presented with tachycardia, heat intolerance and
exophthalmos. She was diagnosed as having Graves’ disease that
proved to be unresponsive to radioactive iodine. She was
therefore treated with carbimazole.

O/E HR 120 regular

BP 138/84 mmHg
HS normal
Chest clear

Investigations Hb 13 g/dl

a
WCC 15 × 109 /l
tth
C s

Plt 170 × 109 /l

ad ote
ha
hm N

Urea and electrolytes normal

fo r P ale A am

Albumin 37 g/l
ot o S an x

Calcium 2.23 mmol/L (corrected)

N ot f or sh a E

TSH 0.17 mU/l (0.3 – 3.5 mU/l)

n
N ot f ee esi

tio

Free T4 64 pmol/l (13 – 30 pmol/l)

N r. Z sth

bu

Thyroid scintogram – nodular thyroid

tri
D e

ed t
r R rin
An

is
296 Young, thyrotoxic woman for thyroidectomy

Questions

1. Tell me about the case.

This is a young woman presenting for elective thyroidectomy after failed
medical treatment. There are two major issues that need addressing in the
preoperative assessment.
She has been treated for Graves’ disease but remains thyrotoxic. The
operation must be postponed until she is euthyroid to minimise the risk of
developing thyroid storm peri-operatively. In addition, there is no comment in
the history regarding the presence of a goitre and there has been no imaging
of the thyroid to assess the airway such as a CT scan, chest X-ray or lateral
thoracic inlet views.

2. Do you want any other investigations?

She should have the airway imaged as above. A plain chest X-ray will show
lateral tracheal deviation or compression. Lateral thoracic inlet views will show

a
compression in the AP plane. A CT scan will show both of the above and give
tth
C s

additional information concerning the exact level at which the compression is

ad ote
ha

occurring and should be performed where >50% compression is seen on plain

hm N

X-ray. It is especially useful with retrosternal extension of a goitre. Magnetic

fo r P ale A am

resonance imaging can give views in the saggital and coronal planes if
ot o S an x

required. A nasendoscopy should be performed routinely by the ENT surgeon

N ot f or sh a E

pre-operatively. It will give information on the quality of laryngeal view likely

n
N ot f ee esi

tio

to be obtained at direct laryngoscopy and whether there is any evidence of

N r. Z sth

bu

recurrent laryngeal nerve palsy. Unilateral palsy results in ipsilateral cord

tri

adduction. This is associated with glottic incompetence, hoarseness, poor

D e

ed t
r R rin
An

is

cough and aspiration.

Respiratory function tests (flow-volume loops) are of debatable value.

3. What are the symptoms and signs of Graves’ disease?

Signs of thyrotoxicosis have been described in the short case on

thyroidectomy.

The signs of particular importance to the anaesthetist are atrial fibrillation,

cardiac failure and cardiac ischaemia.
Signs unique to Graves’ disease include the eye signs, pre-tibial myxoedema
and thyroid acropachy.
The eye signs of Graves’ disease are due to specific antibodies causing
retro-orbital inflammation. The extra ocular muscles are affected leading to a
reduction in the range of movement. There may be exophthalmos, lid lag, lid
retraction, conjunctival oedema and corneal scarring. These signs may be
present even if the patient is euthyroid.
Pre-tibial myxoedema is a skin infiltration over the shins and thyroid
acropachy consists of clubbing, swollen fingers and periosteal new bone
formation.
Young, thyrotoxic woman for thyroidectomy 297

4. How do thyroid hormones exert their effects?

The thyroid hormones T3 and T4 are transported in the blood mainly bound to
plasma proteins. Their mechanism of action is thought to involve specific
receptors bound to the plasma membrane, mitochondria and nucleus. The
hormones enter the cell by a carrier mechanism, after which most of the T4 is
converted to T3 . Binding of T3 to specific receptors results in alterations in DNA
transcription and thus protein synthesis and energy metabolism.

5. What do you think of the white cell count?

The white cell count is high. The differential count would help to distinguish
the many causes. It would be important to exclude acute infection, the source
of which should be found and treated before surgery.

Causes of a neutrophil leukocytosis:

Bacterial infection
a
tth
C s
ad ote

Inflammation/tissue necrosis
ha

Metabolic disorders
hm N

Neoplasms
fo r P ale A am

Haemorrhage/haemolysis
ot o S an x
N ot f or sh a E

Myeloproliferative disorders
Drugs, e.g. steroids
n
N ot f ee esi

tio
N r. Z sth

bu
tri
D e

ed t
r R rin
An

6. How does carbimazole work? What are the side effects?

is

Carbimazole is the pro-drug, the active compound is methimazole. It acts by

inhibiting iodine incorporation and the coupling of iodotyrosines, it also has
immunosuppressive properties. It may take up to 8 weeks to render the
patient euthyroid, after which it is continued at a reduced dose for about 18
months. Side effects include rashes, pruritis, headache, nausea and arthralgia.
The most serious side effect is agranulocytosis (1/1000 after 3 months).

7. Would the surgeon be happy if the carbimazole had been continued

up until the day of surgery?
No. Carbimazole increases the vascularity of the gland making surgical
conditions more difficult.

8. Would you anaesthetise this lady today?

No. She should be rendered euthyroid before surgery and the rest of her
investigations need addressing. She should also have the raised white cell
count investigated and any infection treated.
298 Young, thyrotoxic woman for thyroidectomy

9. What could be done to improve her pre-operative state?

She could be changed to propylthiouracil for several weeks to see if she
responds. In any case, she should be commenced on a beta-blocker to control
the cardiovascular symptoms and signs. Corticosteroids inhibit the conversion
of T4 to T3 and are sometimes used short term to prepare patients for surgery.

10. Which beta-blocker would you use and why?

Propranolol is the traditional beta-blocker used to control the symptoms of
thyrotoxicosis. It controls the cardiovascular complications and also reduces
the peripheral conversion of T4 to T3 . A heart rate of less than 85 has been
recommended. Atenolol or nadolol are other suitable beta-blockers.

11. She returns in 1 month well controlled. How would you

anaesthetise her?
She should continue her beta-blocker on the day of surgery and an anxiolytic
a
tth
such as a benzodiazepine would also be reasonable.
C s
ad ote
ha

The technique for securing the airway would be determined by the clinical
hm N

findings and the results of the investigations of her airway. If a difficult

fo r P ale A am

intubation is expected, then either gas induction or awake fibre-optic

intubation is appropriate (intubation is difficult in 6% of cases of
ot o S an x
N ot f or sh a E

thyroidectomy). If there is serious concern that the airway may be lost after
n

induction, then awake fibre-optic intubation is the method of choice, though

N ot f ee esi

tio

care should be taken as complete obstruction by the fibre-optic scope can

N r. Z sth

bu

occur if severe stenosis. If complete obstruction occurs after induction of

tri
D e

ed t
r R rin

anaesthesia and attempts to pass an endotracheal tube fail, ventilation via a

An

is

rigid bronchoscope may be necessary. An awake surgical tracheostomy may be

considered, but could be technically difficult.

The general principles of anaesthesia for thyroidectomy have been

described in the short question on thyroidectomy.

12. She is on the femodene OCP. Would you stop it?

When a patient who is taking a combined oral contraceptive stops it, there is a
period of hypercoagulability before a return to baseline. It should ideally be
stopped 4 weeks before surgery.

13. What else could you do to reduce the risk of thromboembolism?

The use of heparin and graduated compression stockings is recommended in
the British National Formulary for women still taking the combined OCP and
undergoing major elective surgery (and all surgery to the legs). In addition,
pneumatic calf compressors should be used in theatre.
Young, thyrotoxic woman for thyroidectomy 299

Bibliography
Bent G. (2008). Graves’ disease. New England Journal of Medicine, 358(24), 2594–605.
Farling PA. (2000). Thyroid disease. British Journal of Anaesthesia, 85(1), 15–28.
Hagberg CA. (2000). Handbook of Difficult Airway Management. Edinburgh, UK: Churchill
Livingstone.
Malholta S, Sodhi V. (2007). Anaesthesia for thyroid and parathyroid surgery. BJA CEACCP, 7, 55 – 8.
Morgan GE, Mikhail MS. (1996). Clinical Anaesthesiology, 2nd edition. Appleton and Lange

a
tth
C s
ad ote
ha
hm N
fo r P ale A am
ot o S an x
N ot f or sh a E

n
N ot f ee esi

tio
N r. Z sth

bu
tri
D e

ed t
r R rin
An

is
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PHAEOCHROMOCYTOMA: PERIOPERATIVE
MANAGEMENT

ANAESTHESIA TUTORIAL OF THE WEEK 151

14TH SEPTEMBER 2009

Prabodh Sasidharan, SpR, Aberdeen Royal Infirmary
Ian Johnston, Consultant, Raigmore Hospital, Inverness

Correspondence to [email protected]

SELF ASSESSMENT
1. Regarding adrenal glands

a
tth
a. The medulla secretes adrenaline , noradrenaline and dopamine
C s
ad ote
b. The rate limiting enzyme of catecholamine synthetic pathway is tyrosine hydroxylase
ha
c. The adrenaline:noradrenaline ratio in a normal adrenal gland is 15:85
hm N

d. α 2 receptors mediate the presynaptic feed back inhibition of NA release

fo r P ale A am

2. Regarding phaeochromocytomas
ot o S an x
N ot f or sh a E

a. Phaeochromocytomas account for 1% of all cases of hypertension in adults

n
N ot f ee esi

tio

b. MEN 2a constitutes medullary carcinoma of thyroid, hyperparathyroidism and phaeochromocytoma

c. The right adrenal gland is more involved that the left
N r. Z th

bu

d. The most common sites of extra adrenal phaeochromocytomas are the neck and thorax
D es

tri
ed t
r R rin
An

is

3. With regards to phaeochromocytoma

a. Hypertension is the most common sign

b. The most common symptom is sweating
c. It is more common in males
d. The perioperative mortality of elective phaeochromocytoma is around 2%

4. With regards to the diagnosis of phaeochromocytoma

a. A total catecholamine plasma concentration greater than 2000pg/ml is diagnostic

b. MIGB scintigraphy is used for locating extra adrenal tumours
c. Plasma free metanephrines are the most sensitive test
d. Adrenaline secreting tumours are the most common

5. With regards to the management of phaeochromocytoma

a. The use of ephedrine is contraindicated

b. Suxamethonium induced fasciculation can set off a hypertensive crises
c. Tachycardia is a side effect of prazosin
d. Phenoxybenzamine is a non selective irreversible α blocker

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6. Regarding phaeochromocytoma

a. Hormone secretion is under neurogenic control

b. Familial phaeochromocytoma is inherited in an autosomal recessive manner
c. Persistent hypotension after tumour removal can be due to persistent α blockade and down regulation
of α receptors
d. The perioperative mortality of untreated phaeochromocytoma can be as much as 50%

INTRODUCTION

Phaeochromocytomas are catecholamine secreting neuroendocrine tumours that arise from the chromaffin cells
of the sympathoadrenal system. They are usually found in the adrenal gland but extra-adrenal
phaeochromocytomas, though less common, are tumours that originate in the ganglia of the sympathetic nervous
system. It is a rare tumour, being responsible for less than 0.1% of all cases of hypertension. These tumours
although rare are important as they present a great challenge to the anaesthetist. The condition is potentially life
threatening unless diagnosed and treated. The morbidity and mortality in an unexpected emergency situation is
quoted to be 50% but less than 2% in planned surgery. Clear understanding of the pathophysiology is important

a
to manage the condition safely.

tth
C s
ad ote
ha
hm N

PATHOLOGY
fo r P ale A am

The word phaeochromocytoma in Greek means “dusky coloured tumour” referring to the colour it acquires
ot o S an x
N ot f or sh a E

when stained with chromium salts. Phaeochromocytoma is often referred to as the ‘10% tumour’ because 10%
are extra adrenal, 10 % are malignant, 10% are inherited as an autosomal dominant trait and 10% present
n
N ot f ee esi

bilaterally. Though usually found in the adrenal medulla these tumours can be found anywhere in association
tio

with the sympathetic ganglia. The organ of Zuckerkandl near the aortic bifurcation is the most common extra
N r. Z th

bu

adrenal site. Phaechromocytomas are usually solid highly vascular tumours. Malignant spread can occur in 10%
D es

tri
ed t

cases, with a predisposition for the liver.

r R rin
An

is

Ten percent of phaeochromocytomas are inherited as an autosomal dominant trait. Familial

phaeochromocytomas can be part of the multiple endocrine neoplastic syndromes (MEN) and can also occur in
association with neuroectodermal dysplasia. Patients with MEN2a (Sipples’s syndrome) have
phaeochromocytoma, medullary carcinoma of the thyroid and hyperparathyroidism. Almost 100% of patients
with MEN2a have or will develop phaeochromocytoma and they are frequently bilateral. MEN2b is
characterised by medullary carcinoma thyroid, phaeochromocytoma and a specific phenotype consisting of a
marfanoid body habitus, mucosal neuromas and intestinal ganglioneuromas. The neuroectodermal dysplasias
associated with phaeochromocytomas are Von Hippel-Lindau Syndrome and Von Recklinghausen’s Disease.

Phaeochromocytomas are highly active tumours secreting adrenaline, noradrenaline and rarely dopamine. Most
tumours predominantly secrete noradrenaline. (Normal adrenal secretion is 85% adrenaline). Familial
phaeochromocytomas are an exception because they secrete large amounts of adrenaline. Phaeochromocytomas
are not under neurogenic control but the trigger for catecholamine release is not clear although postulated
mechanisms include changes in pressure or tumour blood flow. On rare occasions chromaffinomas can secrete
intestinal peptides such as VIP and somatostatins.

The incidence is equal in both males and females, being most prevalent between the third and fifth decades of
life.

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CLINICAL FEATURES

The classical symptom complex of recurring attacks of headaches, sweating with hypertension strongly
suggests a diagnosis of phaeochromocytoma. In fact the occurrence of these combined symptoms is probably a
more sensitive and specific indicator than any one biochemical test. Hypertension is the commonest sign and
headache the commonest symptom. Hypertension is usually sustained but can less commonly be truly
paroxysmal.

The overall clinical picture depends on the relative proportions of noradrenaline or adrenaline. The paroxysms
of headache, palpitation and sweating are sometimes accompanied by facial pallor, anxiety and a feeling of
impending doom, especially when the predominant catecholamine is adrenaline. Nausea and vomiting are
features seen in dopamine secreting tumours.

The headache, anxiety and sweating accompanied by hypertension can be triggered by physiological factors
such as changes in position, increased abdominal pressure (defecation, sneezing, voiding of urine and labour).
Iatrogenic factors precipitating an attack include induction of anaesthesia, certain opioids (eg. pethidine),
dopamine antagonists, cold medications, radiographic contrast media and drugs which inhibit catecholamine
reuptake, such as tricyclic antidepressants and cocaine.

a
Cardiovascular system

tth
C s
ad ote
Cardiovascular symptoms include palpitations secondary to a tachyarrhythmia. With excess secretion of
ha
noradrenaline, α adrenergic effects predominate and patients have systolic and diastolic hypertension and a
hm N

reflex bradycardia. With adrenaline secreting tumours β effects predominate and patients have systolic
fo r P ale A am

hypertension and diastolic hypotension with a tachycardia. Acute presentation can be with ventricular
dysarrythmias, heart failure or myocardial infarction.
ot o S an x
N ot f or sh a E

Untreated cases can present with pulmonary oedema or cardiomyopathy secondary to a chronic increase in
n
N ot f ee esi

vascular systemic resistance High catecholamine levels can cause coronary vasoconstriction by their effect on α
tio

receptors leading to myocardial ischaemia. Prolonged exposure of the circulation to noradrenaline leads to
N r. Z th

bu

constriction of arteriolar and venous circulation with a marked decrease in circulatory blood volume. This
D es

tri
ed t

explains the raised haematocrit and apparent polycythemia. (Treatment often reveals an underlying anaemia.)
r R rin
An

is

There exists a discrepancy between the degree of hypertension and blood catecholamine concentrations in
patients with phaeochromocytoma. Despite a 10 fold increase in circulating catecholamines, the degree of
hypertension is not substantially different from patients with essential hypertension. This is explained by the fact
that long term exposure to catecholamines leads to desensitisation of the vascular system, a down regulation of
adrenergic receptors or changes in the receptor –effector coupling.

Central nervous system

Central nervous system manifestations include anxiety, psychosis, nervousness and tremors. Patients can present
with cerebrovascular accidents either as a cerebral haemorrhage from uncontrolled hypertension or an embolic
episode from a mural thrombus associated with a dilated cardiomyopathy. Uncontrolled hypertension can lead to
hypertensive encephalopathy, which is characterized by an altered mental status, focal neurologic signs and
symptoms, or seizures.

Metabolic disturbances

Glucose control is impaired because of the excessive glycogenolysis induced by the catecholamines, combined
with an impaired release of insulin. Excessive adrenaline secretion can cause a state of hypermetabolism
associated with weight loss.

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Rare presentations

Bladder phaeochromocytomas can present with crisis symptoms precipitated by the voiding of urine.
Phaeochromocytoma can present during pregnancy mimicking preeclampsia.

Phaeochromocytoma is an extremely rare tumour in children, but may be suspected in episodic hypertension
especially in association with a family history of medullary carcinoma of the thyroid gland or
phaeochromocytoma or both.

DIAGNOSIS: CLINICAL, BIOCHEMICAL, RADIOLOGICAL LOCALISATION

Clinical: symptoms and signs (as above)

Biochemical tests

Once a clinical diagnosis is made, an excessive catecholamine secretion must be demonstrated.

No single test is perfect as the measurement of plasma catecholamines reflects only that single moment when

a
the blood sample is collected. Catecholamines are metabolised into free metanephrines within the tumour cells

tth
C s
and are continuously released into the circulation. Tests are usually carried out to estimate either the 24 hr
ad ote
ha
catecholamine level in urine and random blood concentrations, or urine metanephrines.
hm N

• Free catecholamine level in a 24 hr urine sample: best confirmatory test. High performance liquid
fo r P ale A am

chromatography allows accurate measurement of free adrenaline, noradrenaline and dopamine in body
fluids.
ot o S an x
N ot f or sh a E

• Plasma or urine catecholamine metabolites such as metanephrines (free urine catecholamine estimation has
superseded this investigation)
n
N ot f ee esi

tio

• Plasma free metanephrines: a sensitive test for high risk patients e.g.: familial phaeochromocytoma.
Urine metanephrine levels: the single best urine screening test
N r. Z th

•
bu

Urinary vanillylmandellic acid (VMA) levels: the oldest and least expensive test, but nonspecific.
D es

•
tri
ed t
r R rin

• Clonidine suppression test: clonidine lowers plasma catecholamines in patients without

An

is

phaeochromocytoma whilst having no effect on patients with the tumour.

• Provocative testings with histamine and tyramine are not used anymore due to concerns over precipitating
hypertensive crises.

Localisation

MRI and CT both provide accurate and consistent identification of the majority of phaeochromocytomas.

MIBG scan. Meta-iodobenzyl guanidine is a radiopharmaceutical agent which is an analogue of guanethedine,

similar in structure to noradrenaline and hence taken up by adrenergic neurons and concentrated in
catecholamine secreting tumours. MIGB is detected by scintigraphy. and such scans can help to localise
recurrent tumours, metastases and tumours in unusual sites.

Other useful tests include positron emission scans and selective venous catheterisation and catecholamine
sampling.

Preoperative investigations

A clinical evaluation of the cardiac status of the patient, especially if a catecholamine induced cardiomyopathy
is suspected

FBC, and serial haematocrit values: normalisation of the haematocrit is indicative of the adequacy of α blockade
as the intravascular volume is corrected. Occult anaemia might be revealed on correction of the vascular tone.

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Hyperglycaemia is common.

ECG: ST and T changes secondary to myocardial ischemia, ventricular hypertrophy, arrhythmias. Most changes
are reversible on treatment.

2D Echo: to estimate myocardial function if cardiomyopathy is suspected.

PREOPERATIVE MANAGEMENT

Early multidisciplinary involvement is recommended in order to optimise the outcome. The occasional
management of phaeochromocytoma is now deemed to be inappropriate and patients should be referred to an
experienced team.

Perioperative optimisation includes the use of adrenergic receptor blocking drugs. The value of preoperative α
blockade has not been subject to any randomised studies, but the mortality of patients undergoing surgery has
dropped from 50% to less than 6% since α receptor blockade was introduced.

Preoperative adrenergic blockade achieves the following objectives:

a
tth
• Lowers blood pressure, C s
ad ote
• Increases intravascular volume,
ha
Reduces the chance of hypertensive crises during induction and tumour manipulation,
hm N

•
• Allows resensitisation of adrenergic receptors
fo r P ale A am

• Reduces myocardial dysfunction in the perioperative period.

ot o S an x
N ot f or sh a E

Criteria for optimal control include:

n
N ot f ee esi

• Blood pressure readings consistently less than 160/90

tio

• Presence of orthostatic hypotension (not less than 80/45)

N r. Z th

bu

• ECG should be free of ST-T changes

D es

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ed t

• No more than one premature ventricular contraction every 5 minutes

r R rin
An

is

• Nasal congestion

Nonselective α blockers

Traditionally phenoxybenzamine has been used for achieving adrenergic blockade. Phenoxybenzamine is an
irreversible non selective α blocker which alkylates α receptors permanently. This confers a degree of protection
against blood pressure surges during tumour manipulation when catecholamine levels can rise by a factor of
several hundred. (A competitive reversible blockade would be overwhelmed by this catecholamine surge!) The
long half life of phenoxybenzamine confers the advantage of twice daily dosage. Disadvantages, however,
include an undesirable α 2 receptor blockade which causes inhibition of presynaptic NA reuptake and therefore
causes a tachycardia, and the persistent α blockade which can be responsible for resistant hypotension after
tumour removal. For these reasons many clinicians choose to stop phenoxybenzamine administration 48 hrs
prior to surgery. Phenoxybenzamine is started at least 14 days (sometimes even months) before surgery to
increase the intravascular volume and restore myocardial dysfunction. The usual starting dose is 10 mg twice
daily slowly increased up to 60 -250mg/day.

Selective α 1 blockers

Selective α1 blockers, in comparison to phenoxybenzamine, do not block the α2 receptors and therefore do not
induce a tachycardia as a side effect. Because they are competitive blockers they are not as efficient as
phenoxybenzamine in preventing surges in blood pressure during tumour manipulation when a massive release
of catecholamines displaces the drug from the receptors.

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Doxazosin has been successfully used instead of phenoxybenzamine and the long duration of action of
doxazosin means daily dosing is sufficient. Oral dosing starts at 1 mg and is titrated up to 16 mg if required.

Prazosin, another selective α 1 blocker, is favoured by some clinicians because of its shorter half life and ease
of titration to the desired end point. However this may also render it relatively ineffective in the intraoperative
control of blood pressure especially if the last dose was given on the night before surgery. Profound first dose
hypotension may be seen with this drug.

Beta blockers

The role of β blockers is to control the tachycardia. Tachycardia can be secondary to α 2 receptor blockade from
phenoxybenzamine or it could be due to secretion of adrenaline or dopamine from the tumour. Most tumours,
however, are predominantly noradrenaline secreting and β blockers are added to counteract the side effects of
non selective α blockade. In a pure noradrenaline secreting tumour controlled by a selective α1 blocker such as
doxazosin, β blockers are not necessary.

The choice and timing of β blockade is important. A non selective β blocker should not be prescribed before α
blockade is achieved as blockade of β 2 vasodilatory receptors leads to unopposed stimulation and worsening of
hypertension. The removal of β1 stimulation following β blockade means the heart has to cope with an increased
after load with less ability to contract and this can precipitate heart failure in patients with myocardial

a
tth
dysfunction. This is another reason why β blockade should only be started after appropriate arteriolar dilatation
C s
ad ote
has been achieved with α blockers. Selective β1 blockers, including atenolol and bisoprolol, are useful in
ha
patients with reactive airway disease or peripheral vascular disease. Popularly used non selective β blockers
hm N

include propranolol, with most patients requiring 80-120 mg/day and pure adrenaline secreting tumours may
fo r P ale A am

require up to 480mg/day. β blockers with additional α blocking properties are synergistic with α blockers in
reducing blood pressure. Examples include labetalol (100-400mg/day) and carvedilol (12.5-50mg/day).
ot o S an x
N ot f or sh a E

Other drugs
n
N ot f ee esi

tio

α- methylparatyrosine (Metyrosine) is an inhibitor of tyrosine hydroxylase enzyme. It can reduce catecholamine

N r. Z th

bu

production by 50 – 80% but, unfortunately, its side effects have limited the use of this drug except in malignant
D es

tri

and inoperable tumours

ed t
r R rin
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is

Calcium channel blockers and ACE inhibitors have been used in the preoperative control of blood pressure but
clear evidence to support their use as primary agents is lacking.

INTRAOPERATIVE MANAGEMENT

Most anaesthetic drugs and techniques have been tried with success and any technique based on sound
pharmacological principles and clear understanding of the pathophysiology of the condition should lead to a
favourable outcome. Close communication amongst team members is important to anticipate and treat periods
of instability.

The choice of surgery can be either an open (retroperitoneal or transperitoneal) approach or laparoscopic.
Hospital stay is reduced and postoperative pain control is better with the latter although the incidence of
catecholamine surges would appear to be the same with both procedures. Unfortunately gas insufflation during
laparoscopy can produce a hypertensive crisis due to the increased intra-abdominal pressure.

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The intraoperative goals are to:

• Avoid drugs or manoeuvres which produce a catecholamine surge

• Maintain cardiovascular stability with short acting drugs
• Maintain normovolaemia and haemodynamics after tumour resection

Periods of instability include:

• Induction and intubation

• Surgical incision
• Pneumoperitoneum during laparoscopic approach
• Abdominal exploration and tumour manipulation
• Ligation of venous drainage

Monitoring and vascular access

• ECG (CM5)
• Pulse oximeter
• EtCO2
• Temperature probe

a
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• Invasive blood pressure – Arterial line(inserted prior to induction of anaesthesia) and CVP monitoring
C s
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• Cardiac output monitoring in patients with cardiomyopathy (Pulmonary artery catheter, TOE)
ha
• Large bore peripheral venous access
hm N

• Urinary catheter
fo r P ale A am
ot o S an x

ANAESTHETIC TECHNIQUE
N ot f or sh a E

Technique: General ± epidural anaesthesia have been successfully used. A low thoracic epidural blocks sensory
N ot f ee esi

tio

and sympathetic discharge in the area of the surgical field, but it cannot prevent the effect of the catecholamines
N r. Z th

bu

released during surgical manipulation of the tumour.

D es

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ed t
r R rin
An

Factors which release catecholamines should be avoided: stress, anxiety, pain, hypoxia, hypercarbia. Consider
is

premedication (e.g.Temazepam 20mg). Endotracheal intubation should be attempted having achieved a

satisfactory depth of anaesthetia as catecholamines released from stored nerve terminals often produce an
exaggerated pressor response.

Choice of agents: Avoid medications that can stimulate the sympathetic nervous system. Caution should be
exercised when using histamine releasing drugs (Atracurium, Morphine). Suxamethonium can produce a
catecholamine surge by virtue of muscle fasciculation and drugs such as metoclopramide, ephedrine, and
chlorpromazine can also produce hypertensive responses

Drugs considered safe include: Propofol, Etomidate, Fentanyl, Alfentanil, Remifentanil, Benzodiazepines,
Vecuronium, Rocuronium, Isoflurane, Sevoflurane.

Blood glucose should be closely monitored (hypoglycaemia is common after tumour removal)

Normothermia should be maintained with the use of forced air warming devices.

Pharmacological options for intraoperative haemodyanamic control

Despite preoperative α blockade almost all patients demonstrate haemodynamic disturbances during tumour
manipulation. This can be a predominant hypertensive response in noradrenaline secreting tumours or a
tachycardia in adrenaline secreting tumours. Vasoactive medications must be drawn up and ready to be used to
control these surges. Tumour manipulation can result in blood levels of catecholamines up to 200,000 to
1,000,000pg/ml. (the pressor response to intubation in a normal patient can produce an increase to 200 to

ATOTW 151 Phaeochromocytoma: Perioperative management, 14/09/2009 Page 7 of 10

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2000pg/ml). The response to this huge surge should be anticipated and treated to avoid myocardial dysfunction.
The pharmacological options are discussed below

• Phentolamine: A competitive α blocker and direct vasodilator, given as boluses of 1-5 mg for controlling
surges in blood pressure. Tachyphylaxis and tachycardia are common. Phentolamine can be used on its own
or in combination with labetalol.
• Sodium nitroprusside: A direct potent, vasodilator with an immediate onset and short duration of action
make it a favourite of many clinicians. The toxicity of SNP is not seen at normal clinical doses.
• Glyceryl TriNitrate: A venodilator. Larger doses are generally required and the reflex tachycardia may
present a problem
• Magnesium sulphate: Direct vasodilator, inhibits catecholamines from the adrenal medulla and nerve
terminals, reduces sensitivity of α receptors and is a useful antiarrythmic. A loading dose of 40-60mg/kg
followed by 1-2g/hr has been described.
• Volatile anaesthetics: Increasing the depth of anaesthesia using volatile agents works at a cost of a
persisting hypotension after tumour removal.
• Calcium channel blockers: Calcium ion transfer is needed for the release of catecholamines from the
adrenal medulla. Nicardipine is the drug of choice from this group..
• β blockers: the selective, short acting β blocker, esmolol is useful for isolated tachyarrythmias and
tachycardia without hypertension. The rapid onset and offset of esmolol makes it the drug of choice in such

a
situations. Labetalol: predominantly a β blocker with some α blocking effect, it is used to control blood

tth
C s
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pressure as well as tachycardias in adrenaline secreting tumours. When administered with phentolamine, the
ha
effects are synergistic.
hm N

• Antiarrhythmics: Lidocaine is useful for ventricular arrhythmias with amiodarone is an alternative.

fo r P ale A am

Catecholamine withdrawal following venous ligation

ot o S an x
N ot f or sh a E

A combination of factors is responsible for the refractory hypotension following ligation of the venous drainage
of the tumour. A sudden drop in the catecholamine concentration, the residual α blockade from
n
N ot f ee esi

tio

phenoxybenzamine, down regulation of adrenoceptors, suppression of the normal contralateral adrenal gland
N r. Z th

bu

from excessive catecholamines, catecholamine induced myocardial dysfunction and hypovolaemia from blood
D es

and fluid loss are all causative factors.

tri
ed t
r R rin
An

is

A preventative measure involves volume loading before tumour ligation and fluid boluses should be tried before
initiating vasoactive medications. When this is ineffective, treatment options include adrenaline, noradrenaline
and phenylephrine. Vasopressin is also effective in refractory cases (0.04U/min increasing as required). One
should consider glucocorticoids if hypoadrenalism is suspected or if bilateral adrenalectomy is performed.

Patients are usually extubated at the end of the procedure after ensuring haemodynamic stability. Morphine may
be used for post operative analgesia in the absence of a working epidural.

POST OPERATIVE MANAGEMENT

These patients, ideally, are managed post operatively in an ITU/HDU. Anticipated problems include refractory
hypotension (which might require large volumes of fluid and vasopressor therapy),and hypoglycaemia due to
excess insulin release and inadequate glycogenolysis.

Consider steroid supplementation if bilateral adrenalectomy is carried out or if hypoadrenalism is suspected.

Post operative pain control depends on the type of incision. Epidural analgesia provides good post operative
pain relief and may be supplemented by regular oral medications.

The majority of patients are restored to normotension although plasma catecholamine levels may still be
elevated due to their slow release from the nerve terminals. Sustained hypertension after surgery could be due to
residual tumour, renal ischemia or underlying essential hypertension.

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Special circumstances

Pregnancy

The mortality from phaeochromocytoma in pregnancy is high. Undiagnosed cases can mimic preeclampsia.
Labour can also precipitate crises and hence an elective Caesarean Section should be planned if the condition is
diagnosed late in pregnancy. If diagnosed early, resection of the tumour can be considered before the second
trimester with the risk of miscarriage. Phenoxybenzamine can be safely used during pregnancy.

Unexpected phaeochromocytoma

There is, unfortunately, no quick test to diagnose the condition in an acute situation. Patients can present with
severe hypertension or tachyarrhythmia or even refractory hypotension following induction. Attempts to resect
the tumour without prior optimisation can increase the mortality and hence the procedure should be abandoned
pending investigation and adrenergic blockade. In an acute situation arteriolar dilatation is the main stay of
management. Patients presenting with heart failure secondary to excess vasoconstriction present a diagnostic
dilemma as vasoactive mediations worsen the situation. The mortality in untreated cases undergoing anaesthesia
is quoted to be around 50%.

CONCLUSION

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C s
ad ote
The perioperative mortality associated with phaeochromocytoma is around 2%. A thorough grasp of the
ha
pathophysiology and pharmacology will enable one to develop an anaesthetic plan tailored to suit each patient.
hm N

Good preoperative preparation and the judicial use of a combination of vasodilatory and vasoactive medications
fo r P ale A am

help in reducing the mortality and morbidity associated with surgery. Good communication between the
surgeon, endocrinologist and anaesthetist is crucial for the safe management of these patients. Patients with this
ot o S an x

condition are best managed by a team experienced in dealing with such cases.
N ot f or sh a E

ANSWERS TO SELF ASSESSMENT

N ot f ee esi

tio
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bu

1. TTFT 2.FTTF 3.TFFT 4.TTTF 5.TTFT 6.FFTT

D es

tri
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An

Explanation for select questions

is

1b True: Tyrosine hydroxylase is inhibited by Metyrosine which is used very rarely because of the side
effect profile. It is used in malignant and inoperable tumours
1c False: In the normal gland the ratio is 85:15, the reverse is true for tumours where the predominant
catecholamine is noradrenaline
1d True: α 2 receptors are blocked by phenoxybenzamine resulting in tachycardia sue to catecholamine
release at cardiac nerve endings
2a False: Phaeochromocytoma accounts for less than 0.1% of all cases of hypertension.
2d False: Only 2% of extraadrenal phaeochromocytomas occur in the neck and thorax. The most
common site of extra adrenal phaeochromocytoma is the organ of Zuckerkandl near the aortic
bifurcation
3a True: 80% of patients with phaeochromocytoma are hypertensive
3b False: Headache is the most common symptom
3c False: It has an equal incidence in both sexes
4a True: 500-2000pg/ml is equivocal and <500pg/ml rules out the diagnosis
4d False: Noradrenaline secreting tumours are the commonest and dopamine secreting tumours are the
rarest
5a True: Ephedrine can release stored catecholamines from nerve endings leading to a hypertensive
crisis
5c False: Prazosin does not block α 2 receptors so there is no tachycardia

ATOTW 151 Phaeochromocytoma: Perioperative management, 14/09/2009 Page 9 of 10

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6a False: Secretion is autonomous, there are physical and iatrogenic triggers which can release
catecholamines
6b False: Familial phaeochromocytoma is inherited as autosomal dominant
6c True: Hypovolaemia, myocardial dysfunction and suppressed function of normal adrenals contribute
to the cause

REFERENCES AND WEBLINKS

1. Phaeochromocytoma- recent progress in its management C.Prys-Roberts. British Journal of

Anaesthesia 85(1):44-57(2000)
2. Phaeochromocytoma: Nick Pace, Michael Buttigieg. British Journal of Anaesthesia CEPD
Reviews/Volume 3Number/ 20-23(2003)
3. Russell T Wall. Stoelting’s Anesthesia and Co-existing disease, fifth edition, Churchill
Livingstone, Philadelphia, 2008; 388-393.
4. Anna Batchelor. Oxford Handbook of Anaesthesia. Oxford University Press, UK, 2006; 560-563.
5. Michael F. Roizen and Lee A. Fleisher. Anesthetic implications of concurrent diseases. Chapter
35; Miller’s Anesthesia, Seventh Edition Churchill Livingstone, Philadelphia; 1084-1085.

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Useful link: C s
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http://emedicine.medscape.com/article/124059-overview
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ATOTW 151 Phaeochromocytoma: Perioperative management, 14/09/2009 Page 10 of 10

BJA Education, 16 (5): 153–158 (2016)

doi: 10.1093/bjaed/mkv033
Advance Access Publication Date: 9 September 2015
Matrix reference
2A03, 2A07, 3A03

Perioperative care of phaeochromocytoma

David Connor BMedSci BMBS FRCA1 and Stephen Boumphrey MBBS FRCA2,*

Downloaded from http://bjaed.oxfordjournals.org/ by Syed Zeeshan Javaid Hashmi on December 17, 2016
1
Anaesthetics and ICM Trainee ST6, Department of Anaesthesia, Derriford Hospital, Level 9, Terence Lewis
Building, Plymouth PL6 8DH, UK, and 2Consultant Anaesthetist, Anaesthetics Department, Derriford Hospital,
Level 9, Terence Lewis Building, Plymouth PL6 8DH, UK
*To whom correspondence should be addressed. Tel: + 44 1752 439205; E-mail: [email protected]

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Incidence
hm N
Key points
The annual European incidence rate of phaeochromocytomas is
• Initial diagnosis is achieved via analysis of meta-
fo r P ale A am

around 0.2 per 100 000 people.

nephrine levels followed by CT or MRI. The traditional ‘Rule of 10s’ states that 10% of phaeochromo-
cytomas are ‘extra-adrenal’, 10% are malignant, 10% are bilateral,
ot o S an x

• Half of phaeochromocytomas are diagnosed inci-

N ot f or sh a E

10% are found in normotensive patients, and 10% are familial.

dentally on abdominal imaging.
n However, this statement probably no longer holds true as there
• A greater proportion of phaeochromocytomas are appears to be a significantly higher proportion of tumours that
N ot f ee esi

tio
malignant, extra-adrenal, and/or familial than pre- are malignant (29%),1 extra-adrenal (24%),2 and/or familial (32%).3
viously suspected.
N r. Z th

bu

• Associated
D es

cardiomyopathies occur relatively

tri
ed t

frequently. Symptoms
r R rin
An

is

• Vasopressin is effective in treating catecholamine- Phaeochromocytomas may present with a classic symptom triad
resistant hypotension after tumour resection. of headache, palpitations, and sweating. Hypertension is present
in around 90% of cases, although it is paroxysmal in 35–50% of
these.
Other non-specific presentations include anxiety, lethargy,
nausea, weight loss, hyperglycaemia, and tremor. Abdominal
pain may result from bowel ischaemia due to excessive vasocon-
Classification striction. Visual disturbance may develop from papilloedema in-
duced by malignant hypertension. Half of phaeochromocytomas
Phaeochromocytomas are catecholamine-secreting tumours of
are diagnosed incidentally on abdominal imaging for an unre-
the adrenal medulla, while paragangliomas are closely related
lated indication.
neuroendocrine tumours arising from extra-adrenal paraganglia,
some of which produce catecholamines. In this article, their peri-
operative management will be considered together.
Biochemical tests
Phaeochromocytomas produce a variable mixture of norepin-
Aetiology ephrine, epinephrine, or, more rarely, dopamine. Traditional bio-
The majority develop sporadically, although around one-third of chemical diagnosis of phaeochromocytomas relied upon 24 h
cases have specific gene mutations which are usually inherited in collections of urinary catecholamines and vanillylmandelic
an autosomal-dominant fashion. These may be associated with acid (24 h due to diurnal variation in levels), and also blood sam-
other tumours, for example, multiple endocrine neoplasia 2A pling for plasma catecholamines. The short half-life of plasma
and 2B, Von Hippel–Lindau disease, succinate dehydrogenase catecholamines makes it difficult to differentiate pathological
enzyme mutations, and neurofibromatosis. over-production from a transient stress response to venesection.

© The Author 2015. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved.
For Permissions, please email: [email protected]

153
Perioperative care of phaeochromocytoma

Modern techniques measure levels of metanephrine and nor- Imaging

metanephrine which are breakdown products of epinephrine
After positive biochemical tests, the first-line investigation for lo-
and norepinephrine, respectively (Fig. 1). Sampling of these can
calizing the tumour is either CT or MRI of the abdomen. They
be performed from either urine or plasma and there is no agree-
have comparable sensitivities, but MRI is superior in identifying
ment over which is superior. Plasma tests are slightly more
paragangliomas and its specificity is higher than that for CT.
sensitive and more convenient to collect, while urine tests have
Further functional imaging (e.g. scintigraphy) is probably
a greater specificity. Consensus opinion from the first sympo-
not necessary in patients with a low probability of metastatic
sium on phaeochromocytoma recognized the superior diagnos-
or multi-focal disease. This comprises patients aged over
tic ability of metanephrine analysis over traditional methods,
40 yr, with no family history, negative genetic testing, and a
irrespective of whether the sample was derived from urine or
small phaeochromocytoma secreting predominantly metane-
plasma. Dopamine-secreting tumours can be identified by meas-
phrines. However, functional imaging is of crucial importance
uring plasma or urinary dopamine and homovanillic acid levels.
for preoperative staging in those patients with extra-adrenal
Both modern and traditional methods have numerous poten-
paragangliomas.
tial causes of false-positive results, including recent exercise,
Scintigraphy is an imaging technique where a radiopharma-
venous sampling in the sitting position, dietary factors, renal im-
ceutical is administered to the patient and the resultant emis-
pairment, and many common medications. Examples of these

Downloaded from http://bjaed.oxfordjournals.org/ by Syed Zeeshan Javaid Hashmi on December 17, 2016
sions are captured on a two-dimensional gamma camera to
medications include:
form an image. Meta-iodobenzylguanidine (MIBG-123) is a radio-
• norepinephrine re-uptake inhibitors (amitriptyline, olanza- active analogue of norepinephrine and is thus concentrated in
pine, venlafaxine), adrenergic tissue after ingestion. It can be used to identify both
• adrenergic receptor blockers (atenolol, phenoxybenzamine), phaeochromocytomas and paragangliomas, although it is less
• monoamine oxidase inhibitors (moclobemide, phenelzine), sensitive for dopamine-secreting tumours. Since normal adrenal

a
• recreational drugs (cocaine, amphetamine, caffeine), glands absorb MIBG-123, the findings must be correlated with

tth
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• sympathomimetics (salbutamol, terbutaline), other cross-sectional imaging.
ad ote
ha
• others ( paracetamol).
hm N
fo r P ale A am
ot o S an x
N ot f or sh a E

n
N ot f ee esi

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N r. Z th

bu
D es

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is

Fig 1 Catecholamine metabolism. COMT, catechol-O-methyltransferase; DOPAC, 3,4-dihydroxyphenylacetic acid; AD, aldehyde dehydrogenase; AR, aldehyde reductase;
MAO, monoamine oxidase; DHPG, dihydroxyphenol-glycol; DHMA 3,4-dihydroxymandelic acid.

154 BJA Education | Volume 16, Number 5, 2016

Perioperative care of phaeochromocytoma

Preoperative preparation could occur after antagonism of β2-mediated vasodilatation,

which may precipitate a hypertensive crisis (while the negative
The objectives of preoperative care include:
inotropic effect of β-blockade further compromises myocardial
function).
• arterial pressure control,
• reversal of chronic circulating volume depletion,
• heart rate and arrhythmia control, Assessment and optimization of myocardial function
• assessment and optimization of myocardial function, An ECG may reveal ventricular hypertrophy, tachyarrhythmias,
• reversal of glucose and electrolyte disturbances. or myocardial ischaemia.
A degree of diastolic dysfunction appears to occur in the
Arterial pressure control and volume expansion majority of patients, while left ventricular systolic dysfunction
occurs in around 10%. Echocardiography is therefore considered
Early phaeochromocytoma surgery saw mortality rates of
mandatory.
up to 45%, with severe intraoperative hypertension, strokes, ar-
Various forms of cardiomyopathy have been described, with
rhythmias, myocardial ischaemia, left ventricular failure, and
hypertrophic cardiomyopathy, as a result of chronic hyperten-
refractory hypotension after tumour resection.
sion, being the most frequent. There are also many case reports
Although the evidence base has recently been questioned,4

Downloaded from http://bjaed.oxfordjournals.org/ by Syed Zeeshan Javaid Hashmi on December 17, 2016
of inverted (atypical) Takotsubo cardiomyopathy.
preoperative α-block is standard practice and aims to provide pre-
The impaired cardiac function associated with phaeochromo-
operative arterial pressure control with subsequent restoration of
cytoma may improve once catecholamine levels return to
blood volume (which may be titrated using serial haematocrits).
normal.
Commonly used α-blockers include phenoxybenzamine and
doxazosin.

a
Reversal of glucose and electrolyte disturbances

tth
C s
Phenoxybenzamine Hyperglycaemia can occur due to increased glycogenolysis (α1
ad ote
Phenoxybenzamine is a non-selective, non-competitive, long-

ha
receptors), impaired insulin release (α2 receptors), lipolysis (β1
acting α-blocker. Its non-competitive antagonism may reduce receptors), and increased glucagon release coupled with periph-
hm N
the effects of catecholamine surges, but may be implicated in eral insulin resistance (β2 receptors) and is treated with standard
postoperative refractory (catecholamine-resistant) hypotension. therapies.
fo r P ale A am

It should therefore be stopped 24–48 h before surgery due to its Electrolyte measurements will identify catecholamine-
long half-life. Its non-specific nature also allows pre-synaptic induced renal impairment. Hypercalcaemia occurs when a neu-
ot o S an x

α2-blockade which interferes with the norepinephrine negative

N ot f or sh a E

roendocrine tumour is associated with a parathyroid adenoma

feedback loop that regulates norepinephrine release. The result- (e.g. as occurs in MEN 2A).
ing uninhibited release of norepinephrine from cardiac sympa-
n
N ot f ee esi

thetic neurones causes a reflex tachycardia via β1 stimulation.

tio
Assessment of adequate optimization
Central α2-blockade also results in somnolence, headache, and
N r. Z th

bu

nasal congestion. α-Blockade is commenced at least 7–14 days before surgery, al-
D es

though a longer course of treatment may be required for patients

tri
ed t
r R rin

Doxazosin with cardiomyopathy or refractory hypertension. The aim is to

An

is

Doxazosin is a competitive, selective α1-blocker. It does not cause achieve arterial pressure control with spontaneous restoration
tachycardia or sedation and some studies suggest a reduced inci- of circulating volume. Until recently, the 1982 Roizen criteria for
dence of postoperative hypotension, making it a good alternative optimal preoperative control have been cited:
to phenoxybenzamine. Its efficacy is currently being investigated
by the PRESCRIPT trial,5 which randomizes patients to receive • arterial pressure readings consistently <160/90,
either phenoxybenzamine or doxazosin. • the presence of orthostatic hypotension with a decrease in
systolic arterial pressure of at least 15% but not <80 mm Hg,
Calcium channel blockers • an ECG which is free of ST or T wave changes for 2 weeks.
Calcium channel blockers inhibit norepinephrine-induced
calcium influx and have been utilized for haemodynamic control These should now be questioned. Although there is no consen-
before surgery, mainly as an additional drug class to further sus, contemporary arterial pressure targets are tighter (seated ar-
improve control in those already α-blocked. They are not re- terial pressure of <130/80 mm Hg) and orthostatic hypotension is
commended for monotherapy unless patients have very mild not a necessity. ST or T wave changes may reflect inverted Takot-
hypertension or develop severe orthostatic hypotension with subo cardiomyopathy rather than ischaemia.
α-blockers.6 Sustained-release nicardipine 30 mg twice daily is
a commonly used preparation. Intraoperative management
In addition to pharmacological control, a high sodium diet
and fluid intake are also recommended to help restore blood The available data do not support one intraoperative approach
volume. over another. Surgery is increasingly laparoscopic, reducing post-
operative recovery times, but not haemodynamic instability.
Open surgery is likely to be required for large or invasive adrenal
Heart rate and arrhythmia control
masses and most paragangliomas.
Tachyarrhythmias may result from epinephrine/dopamine- Laparoscopic surgery may be performed via a transabdominal
secreting tumours or be secondary to α-blockade. Selective β1 or retroperitoneal approach. Both are performed in the lateral
antagonists (such as atenolol or metoprolol) are preferred to position, with the retroperitoneal approach also requiring signifi-
manage these and must be started after complete α-blockade. cant table break to improve access and allow triangulation of the
This avoids the unopposed α-mediated vasoconstriction that laparoscopic ports in a relatively confined space. The

BJA Education | Volume 16, Number 5, 2016 155

Perioperative care of phaeochromocytoma

transabdominal approach is now increasingly favoured due to Dexmedetomidine

more familiarity with the anatomy and quicker access to the ad- Dexmedetomidine is a centrally acting selective α2-receptor
renal vein. While this approach does not require the significant agonist with sedative and analgesic properties. Its use as part
table break, it may still be requested ( probably as a historical of a general anaesthetic technique is well described outside the
hangover). UK. It has a slow onset and is usually loaded at a dose of around
Risk factors for intraoperative haemodynamic instability 1 μg kg−1 (over 10 min) and then infused at around 0.5 μg kg−1 h−1
include high pre-induction plasma norepinephrine levels, large as an adjuvant to volatile or propofol anaesthesia. In addition to
tumour size, profound postural drop after commencement of its sedative and analgesic properties, its central sympatholytic
α-blockade, and a pre-induction mean arterial pressure (MAP) effects result in substantial reductions in plasma norepinephrine
above 100 mm Hg.7 The chosen anaesthetic technique should: levels, making it a potentially very attractive agent for phaeo-
chromocytoma surgery. However, the relatively few case reports
• avoid drug-induced catecholamine release, describing its use in this setting have still required additional va-
• avoid catecholamine release induced by anaesthetic or surgi- sodilators, particularly during tumour handling.
cal manoeuvres,
• minimize haemodynamic responses to tumour handling, Minimizing haemodynamic responses to tumour
• treat episodes of hypotension, particularly after tumour

Downloaded from http://bjaed.oxfordjournals.org/ by Syed Zeeshan Javaid Hashmi on December 17, 2016
handling
devascularization.
Catecholamine surges during manipulation of the tumour can re-
sult in profound hypertension, bradycardia (with norepineph-
rine), and tachyarrhythmias (with epinephrine). Although early
Avoiding drug-induced catecholamine release surgical ligation of the adrenal vein was traditionally recom-

a
mended to attenuate intraoperative haemodynamic instability,
A number of commonly used drugs may increase catecholamine

tth
increases in catecholamine levels may still occur and the ap-

C s
levels by promoting their pre-synaptic release, inhibiting their re-

ad ote
uptake or via raised catecholamine levels accompanying hista-
proach carries a higher risk of damaging surrounding structures,

ha
particularly for larger tumours. A recent randomized control trial
mine release. Drugs to consider avoiding on this basis include
found no difference in plasma catecholamine levels or episodes
hm N
desflurane, ketamine, morphine, pethidine, atracurium, pancur-
of haemodynamic instability between the early or late adrenal
onium, ephedrine, droperidol, metoclopramide, and cocaine. In
fo r P ale A am

vein ligation groups.

addition to stimulating sympathetic ganglia, succinylcholine
Hypertensive crises are generally managed with a vasodilator,
may theoretically provoke tumour catecholamine release via
ot o S an x

while tachyarrhythmias, including the reflex tachycardia seen

raised abdominal pressure from muscle fasciculation, although
N ot f or sh a E

with the use of many vasodilators, are controlled with β-blockers.

its use has been described without complications.
n β-Blockers also minimizes the excessive inotropy seen with
N ot f ee esi

epinephrine-secreting tumours.
tio
Avoiding catecholamine release induced by anaesthetic Although there is little evidence on which to base drug selec-
or surgical manoeuvres
N r. Z th

bu

tion, agents that have been used successfully are described below.
D es

Although tumour handling induces by far the most significant

tri
ed t

haemodynamic responses, catecholamine release is also pro- Phentolamine

r R rin
An

is

voked by tracheal intubation and the raised intra-abdominal Phentolamine is a reversible non-selective α-receptor antagonist,
pressure associated with capnoperitoneum or coughing. Capno- which primarily results in vasodilatation and can lead to reflex
peritoneal pressures of up to 28 mm Hg have been advocated to tachycardia. It is usually administered as a bolus of 1–2 mg, has
both improve surgical access and reduce venous bleeding with- a short duration of action, but may demonstrate tachyphylaxis.
out any apparent increase in cardiovascular instability, although It can be used as the sole vasodilator, but is particularly useful
the supporting evidence is sparse.8 The arterial pressure re- to control surges in arterial pressure while establishing desired
sponse to pain is also likely to be exaggerated. infusion rates of other drugs.

Magnesium sulphate Sodium nitroprusside and glyceryl trinitrate

Magnesium sulphate inhibits adrenal catecholamine release and Sodium nitroprusside (SNP) and glyceryl trinitrate (GTN) are both
reduces α-adrenergic receptor sensitivity to catecholamines. It nitric oxide donors, which cause venular and arteriolar vasodila-
also dilates predominantly arteriolar vessels, reducing left ven- tation. SNP causes predominantly arteriolar dilatation while GTN
tricular afterload while maintaining preload and exerts anti- is principally a venodilator. Although both have rapid onset and
arrhythmic effects via antagonism of L-type calcium channels. offset of action, the decrease in arterial pressure seen with SNP is
In a case series by James,9 3–5 μg kg−1 fentanyl combined with more rapid which probably explains its preferential use as the
40–60 mg kg−1 of magnesium sulphate before intubation followed first-line vasodilator for phaeochromocytoma surgery. GTN
by an infusion of 1–2 g h−1 (with further boluses if required) pro- may have a greater role in patients with ischaemic heart disease
vided good control of systolic arterial pressure before tumour since it increases coronary blood flow by dilating collateral ves-
handling. sels and suppressing coronary vasospasm; conversely, SNP may
reduce coronary perfusion through its greater effect on diastolic
Remifentanil arterial pressure and theoretical potential to induce intracoron-
Remifentanil is a popular alternative to fentanyl as its pharmaco- ary steal. Reports on the effect of SNP and GTN on cardiac output
kinetic profile facilitates rapid titration to effect. It is very effect- are contradictory—probably as a result of differences in pre-
ive in blunting haemodynamic responses to intubation or pain, operative circulatory volume. SNP infusions should be started
although it is inadequate in preventing hypertension associated at 0.5–1.5 μg kg−1 min −1 and increased up to 4 μg kg −1 min −1
with tumour manipulation when used as a single agent. If remi- as required. At this dose, the risk of cyanide toxicity is very
fentanil is used, alternative postoperative analgesics are required. low for intraoperative infusions of <12 h in patients with

156 BJA Education | Volume 16, Number 5, 2016

Perioperative care of phaeochromocytoma

normal renal and hepatic function.10 GTN infusions are usually Monitoring
adjusted according to response within the range of 10–200 μg
Invasive arterial monitoring should be obtained before induction
min−1. Tachyphylaxis commonly becomes an issue after a con-
of anaesthesia. Central venous access is necessary, if only for
tinuous infusion lasting over 24 h.
drug infusions, and can usually be inserted after induction.
There is no evidence base to support the use of cardiac output
Nicardipine monitoring in phaeochromocytoma surgery. Nevertheless, as-
Nicardipine, a dihydropyridine calcium channel antagonist, is a sessment of circulatory volume can be particularly challenging
potent arterial vasodilator and can be administered by infusion in the context of cardiomyopathy and cardiac output monitoring
intraoperatively. It is initiated at a rate of 3–5 mg h−1 for 15 min may be invaluable in this subgroup.
and adjusted by increments of 0.5 or 1 mg h−1 every 15 min. Traditionally, pulmonary artery catheters were the preferred
Once the target pressure is achieved, the infusion should be grad- cardiac output monitor,12 but there are well-documented risks
ually reduced to 2–4 mg h−1. Hypertensive crises can be treated of insertion. Case reports describe the use of intraoperative trans-
with boluses of 1–2 mg. Cardiac output is maintained without oesophageal echocardiography to guide fluid management and
the tachycardia seen with SNP and GTN, making it the preferred titration of vasodilators.13
choice of some authors. However, clinical experience is still lim- Oesophageal Doppler has been used in the paediatric popula-

Downloaded from http://bjaed.oxfordjournals.org/ by Syed Zeeshan Javaid Hashmi on December 17, 2016
ited and its elimination half-life of 40–60 min can result in per- tion14 and a prospective study investigating its efficacy in phaeo-
sistent hypotension. Clevidipine is a novel alternative of the chromocytoma patients is currently being undertaken in Austria
same class which achieves a shorter half-life via plasma and tis- (http://clinicaltrials.gov/show/NCT01425710).
sue esterase hydrolysis and has been successfully used in phaeo- Devices relying on arterial pulse contour analysis may be ei-
chromocytoma surgery.11 ther calibrated by lithium or thermodilution (LiDCO and PiCCO,
respectively) or by an algorithm (LiDCO Rapid & Flotrac-Vigileo).

a
Neither have been formally evaluated in phaeochromocytoma

tth
Esmolol

C s
Esmolol is a selective β1 antagonist with a rapid action and short surgery.
ad ote
ha
duration. These properties make it the ideal β-blocker for these There has been some interest in the Δdown parameter (the dif-
cases. The initial loading dose is 500 μg kg−1 over 1 min, followed ference between the minimum systolic arterial pressure during the
hm N
by a 4 min maintenance infusion of 50 μg kg−1 min−1, which is respiratory cycle in a mechanically ventilated patient and the sys-
fo r P ale A am

subsequently titrated to clinical effect. tolic arterial pressure during an end-expiratory pause) with a small
Canadian study reporting a Δdown of <2 mm Hg as predictive of ad-
equate intra-vascular volume during phaeochromocytoma sur-
ot o S an x

Treating hypotension after tumour devascularization

N ot f or sh a E

gery.15 There are also several case reports describing the use of a
Periods of hypotension during surgery are relatively common
n variety of these monitors in this patient cohort, some suggesting
they are beneficial while others describe them as misleading.
N ot f ee esi

and may result from anaesthetic drugs ( particularly if circulating

tio
volume is reduced) or from the treatment of a hypertensive epi- This is not surprising. Concerns have previously been raised
that cardiac output readings from algorithm-calibrated systems
N r. Z th

sode outlasting a transient catecholamine surge. These periods

bu

can be managed with a combination of fluid boluses, titration in particular display poor accuracy in conditions of haemo-
D es

dynamic instability and significantly fluctuating vascular

tri

of vasodilators, and administration of direct α-receptor agonists.

ed t
r R rin

tone.16 As it is precisely these conditions that are observed in

An

Of more significance is the hypotension seen after devascu-

is

larization of the tumour which is relatively common and may phaeochromocytoma surgery, the potential benefit of such de-
be both profound and catecholamine-resistant. vices should be questioned. Thus, although they have obvious
The underlying mechanisms of this hypotension are still de- appeal, it is hard to recommend devices relying on pulse contour
bated. One common explanation is residual α-blockade, particu- analysis for phaeochromocytoma surgery.
larly after the preoperative use of phenoxybenzamine. Abrupt
catecholamine deficiency after tumour resection in combination
with catecholamine receptor down-regulation caused by chronic Postoperative care
elevation of catecholamine levels may also be implicated. If the procedure is surgically uncomplicated, most patients should
In the first instance, hypotensive agents should be stopped be suitable for extubation at the end of surgery. All patients should
and fluid balance optimized taking into account the possibility receive invasive arterial pressure monitoring in a high depend-
of ongoing postoperative haemorrhage, myocardial dysfunction, ency environment for at least 24 h after the procedure. Hyperten-
or both. Norepinephrine can initially be used to increase periph- sion is most commonly the result of pain, co-existing essential
eral vascular resistance and vasopressin should be considered if hypertension, urinary retention, or fluid overload. Inadvertent
hypotension is refractory. ligation of the renal artery precipitates hyper-reninism, which
may lead to delayed hypertension. Persistent hypertension her-
Vasopressin alds more sinister causes such as incomplete tumour resection
Vasopressin causes systemic vasoconstriction and pulmonary or metastatic disease. Even in those patients without recurrence,
vasodilatation by acting on V1 receptors. It also increases circula- hypertension is present in 26% at 5 yr and 55% at 10 yr after
tory volume by acting on V2 receptors in the distal convoluting surgery. All patients should therefore receive both clinical and
tubule and collecting ducts of the kidney, thereby increasing biochemical outpatient follow-up at 6 weeks and 6 months
water reabsorption. followed by an annual review for at least 10 yr.
There have been several case reports of the successful use The mechanisms and management of postoperative hypo-
of vasopressin after phaeochromocytoma resection, although tension have been discussed previously.
dosing practices varied widely. Bolus doses of 0.4–20 units were Lifelong steroid replacement is indicated if a bilateral adrena-
administered and subsequently followed by an infusion of 1–3 lectomy has been performed, but steroid supplementation is
mU kg−1 min−1. rarely required otherwise. One common regimen is initiated

BJA Education | Volume 16, Number 5, 2016 157

Perioperative care of phaeochromocytoma

before operation with 100 mg of hydrocortisone administered References

every 8 h. In the first postoperative 72 h, the hydrocortisone dos-
1. Proye C, Vix M, Goropoulos A, Kerlo P, Lecomte-Houcke M.
age is weaned to 25 mg twice daily before being converted to oral
High incidence of malignant pheochromocytoma in a surgi-
prednisolone.
cal unit. 26 cases out of 100 patients operated from 1971 to
Hypoglycaemia due to rebound hyper-insulinism can occur
1991. J Endocrinol Invest 1992; 15: 651–63
when the inhibitory effect of norepinephrine on insulin produ-
2. Goldstein RE, O’Neill JA, Holcomb GW, et al. Clinical experi-
cing cells is eliminated and its presentation may be masked by
ence over 48 years with pheochromocytoma. Ann Surg 1999;
concurrent β-receptor blockade. Regular blood glucose monitor-
229: 755–66
ing and appropriate titration of dextrose infusions is therefore
3. Mannelli M, Castellano M, Schiavi F, et al. Clinically guided
recommended.
genetic screening in a large cohort of Italian patients with
pheochromocytomas and/or functional or nonfunctional
paragangliomas. J Clin Endocrinol Metab 2009; 94: 1541–7
Incidental presentation during surgery
4. Lentschener C, Gaujoux S, Tesniere A, Dousset B. Point of
Phaeochromocytoma may first present during incidental sur- controversy: perioperative care of patients undergoing
gery. Although historically associated with mortality rates of up phaeochromocytoma removal—time for a reappraisal? Eur J

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to 40%, a recent review of 62 cases between 1988 and 2010 showed Endocrinol 2011; 165: 365–73
a perioperative mortality of 8%17 with the majority of deaths 5. Phenoxybenzamine Versus Doxazosin in PCC Patients
occurring after operation. (PRESCRIPT). Available from http://clinicaltrials.gov/show/
Presenting features include hypertension (by far the most NCT01379898
common presentation during incidental surgery), tachyarrhyth- 6. Lenders JW, Duh QY, Eisenhofer G, et al. Pheochromocytoma
mias, and cardiac failure associated with hypotension and pul- and paraganglioma: an endocrine society clinical practice

a
monary oedema. This makes the differential diagnosis wide guideline. J Clin Endocrinol Metab 2014; 99: 1915–42

tth
C s
and in the aforementioned review, only 26% of cases were sus- 7. Bruynzeel H, Feelders RA, Groenland THN, et al. Risk factors
ad ote
ha
pected as a phaeochromocytoma intraoperatively. for hemodynamic instability during surgery for phaeochro-
If phaeochromocytoma is suspected, intraoperative manage- mocytoma. J Clin Endocrinol Metab 2010; 95: 678–85
hm N
ment follows the same principles as in elective cases. Factors 8. Walz MK, Alesina PF, Wenger FA, et al. Posterior retroperito-
fo r P ale A am

triggering release of catecholamines should be eliminated, in- neoscopic adrenalectomy—results of 560 procedures in 520
cluding tumour manipulation, and invasive arterial monitoring patients. Surgery 2006; 140: 943–8
should be instigated urgently. Hypertension may be controlled 9. James MF. Use of magnesium sulphate in the anaesthetic
ot o S an x
N ot f or sh a E

by the use of an α-blocker, such as phentolamine, or nitrates. management of phaeochromocytoma: a review of 17 anaes-
Unopposed β-blockade may precipitate myocardial dysfunction
n thetics. Br J Anaesth 1989; 62: 616–23
via the mechanisms previously discussed, thus any severe tachy- 10. Lockwood A, Patka J, Rabinovich M, Wyatt K, Abraham P.
N ot f ee esi

tio
cardia would be best controlled with esmolol due to its β1 select- Sodium nitroprusside-associated cyanide toxicity in adult
ivity and short duration of action. patients—fact or fiction? A critical review of the evidence
N r. Z th

bu

Surgery should be terminated as soon as is feasible and thus, and clinical relevance. Open Access J Clin Trials 2010; 2: 133–48
D es

tri

unlike planned phaeochromocytoma surgery, continued cat- 11. Kline JP. Use of clevidipine for intraoperative hypertension
ed t
r R rin
An

echolamine surges may persist after operation. Excessive intra- caused by an undiagnosed pheochromocytoma: a case
is

and postoperative vascular spasm may result in myocardial or report. AANA J 2010; 78: 288–90
cerebral infarction, acute kidney injury, and/or mesenteric 12. Pinaud M, Desjars P, Cozian A, Nicolas F. Fluid loading in the
ischaemia. surgical care of pheochromocytoma. Hemodynamic study.
Postoperative management should be provided on a high Ann Fr Anesth Reanim 1982; 1: 53–8
dependency unit until haemodynamic control is achieved with 13. Matsuura T, Kashimoto S, Okuyama K, Oguchi T, Kumazawa T.
definitive surgery generally waiting until optimal adrenergic Anesthesia with transesophageal echocardiography for re-
blockade. In a very small minority of cases, definitive surgery moval of pheochromocytoma. Masui 1995; 44: 1388–90
may be expedited if multi-organ failure ensues, despite maximal 14. Hack H. Use of the esophageal Doppler machine to help
medical therapy. guide the intraoperative management of two children with
phaeochromocytoma. Paediatr Anaesth 2006; 16: 867–76
15. Mallat J, Pironkov A, Destandau M-S, Tavernier B. Systolic
Declaration of interest pressure variation (Δdown) can guide fluid therapy during
pheochromocytoma surgery. Can J Anaesth 2003; 50: 998–1003
None declared.
16. Camporota L, Beale R. Pitfalls in haemodynamic monitoring
based on the arterial pressure waveform. Crit Care 2010;
14: 124
MCQs 17. Hariskov S, Schumann R. Intraoperative management of
The associated MCQs (to support CME/CPD activity) can be patients with incidental catecholamine producing tumors:
accessed at https://access.oxfordjournals.org by subscribers to a literature review and analysis. J Anaesthesiol Clin Pharmacol
BJA Education. 2013; 29: 41–6

158 BJA Education | Volume 16, Number 5, 2016

189

Phaeochromocytoma – peri-operative
management
You are asked to anaesthetise a patient for resection of a
phaeochromocytoma. What is a phaeochromocytoma?
A phaeochromocytoma is a functionally active, catecholamine-secreting
tumour of the neuroendocrine chromaffin cells found in the sympathetic
nervous system. They account for about 0.1% of cases of hypertension. They
are usually benign and localised to an adrenal gland. These tumours are
important to the anaesthetist because they can present unexpectedly
peri-operatively and the mortality is high.

They may secrete any combination of

r Noradrenaline
r Adrenaline
r Dopamine
r Occasionally vasoactive intestinal peptide (VIP) or ACTH.
a
tth
C s
ad ote
ha
hm N

How does it present?

fo r P ale A am

The commonest presentation is sustained hypertension.

ot o S an x
N ot f or sh a E

The classic presentation is of paroxysms of sympathetic crises (in 35% of

cases).
n

r Severe hypertension
N ot f ee esi

tio

r Flushing
N r. Z sth

bu

r Sweating
tri
D e

ed t
r R rin

r Palpitations
An

is

r Headache
r Anxiety
r Weakness
r Lethargy
Paroxysms may be precipitated by multiple factors:
r Simple activities such as exercise
r Manoeuvres that increase intra-abdominal pressure such as sneezing,
voiding and defaecating.
r Histamine releasing drugs and succinylcholine
r Anaesthetic procedures (particularly intubation)
If undiagnosed, it may present with end-organ damage:
r Heart failure
r Pulmonary oedema
r Myocardial ischaemia
r Cerebro-vascular events
Presentation may be determined by the dominant catecholamine secreted:
r Mainly noradrenaline Hypertension, headaches,
Slow, thudding palpitations
190 Phaeochromocytoma – peri-operative management P

r Mainly adrenaline Tachycardias

Anxiety attacks
r Mainly dopamine Nausea and vomiting

Effects of adrenoreceptors
α1 Vasoconstriction
Sweating
↓ insulin and glucagon release
α2 Inhibition of noradrenaline release
β1 Chronotropy
Inotropy
Renin secretion
β2 Smooth muscle relaxation -bronchi
-vascular wall
-uterus
↑ insulin and glucagon release

a
tth
C s
ad ote
ha

How is the diagnosis confirmed?

hm N
fo r P ale A am

Clinical suspicion on the basis of history or hypertension.

ot o S an x
N ot f or sh a E

Traditionally by measuring urinary catecholamines or their metabolites

(vanillylmandelic acid [VMA] and metanephrine).
n
N ot f ee esi

tio

Clonidine Suppression Test – lack of suppression suggests

N r. Z sth

bu

phaeochromocytoma (prevents noradrenaline reuptake).

tri
D e

ed t

Genetic testing may identify familial cases.

r R rin
An

is

CT can localise adrenal tumours with 93%–100% sensitivity.

MRI scan of the abdomen has a slightly higher sensitivity for extra-adrenal
tumours.
An isotope scan may help to localise an extra-adrenal tumour. A
radio-labelled iodine isotope, 123 I-metaiodobenzylguanidine (MIBG), is
taken up by the chromaffin cells.
Selective vena caval sampling.

What is the 10% rule?

10% are extra-adrenal and can be anywhere along the sympathetic chain
from skull base to pelvis.
10% are bilateral.
10% are malignant.
10% occur in children.

Are there any associations with other conditions?

Multiple endocrine neoplasia (MEN) Syndrome Type 2
r Type 2A – medullary thyroid carcinomas and parathyroid adenomas
r Type 2B – medullary thyroid carcinomas and Marfanoid features.
P Phaeochromocytoma – peri-operative management 191

Von Hippel–Lindau disease (Phaeochromocytomas, cerebellar

haemangioblastomas, and renal cell carcinoma).
Neurofibromatosis Type I (von Recklinghausen disease) – 1% incidence of
phaeochromocytoma.
Familial carotid body tumours.

If you saw this person 10 weeks pre-operatively, what investigations and

treatment would you institute?
The aim of pre-operative management is to:
r Determine the site of the tumour and what it secretes.
r Normalize the blood pressure.
r Allow the resolution of catecholamine cardiomyopathy.
r Correct hypovolaemia (contracted intravascular volume).
An echocardiogram is useful to assess left ventricular function and to
exclude cardiomyopathy.
ECG
a
tth
␣ and ␤-adrenoceptor blockade
C s

r Controls the symptoms and hypertensive swings

ad ote
ha

r Reduces the hypertensive surges associated with tumour handling.

hm N
fo r P ale A am

␣-adrenoceptor blockade should be instituted prior to ␤-blockade.

ot o S an x
N ot f or sh a E

Regarding ␤-blockers
n
N ot f ee esi

tio

Theoretically unopposed ␤-blockade should be avoided. This can block

N r. Z sth

bu

compensatory ␤2 vasodilatation and precipitate a hypertensive crisis.

tri
D e

ed t
r R rin
An

Cardiac failure may also occur due to the reduced contractility in the
is

presence of a high afterload.

Selective ␤1 -blockade is used in adrenaline secreting tumours.
NB It is not uncommon for patients to have been commenced on a
␤-blocker for treatment of their hypertension, usually without adverse
effects.

Does it matter which alpha blocker you use?

Phenoxybenzamine is a non-selective ␣1 and ␣2 blocking drug
r It binds covalently and irreversibly to the receptors.
r It has a long duration of action and may contribute to post-operative
hypotension.
r ␣2 blocking can inhibit pre-synaptic noradrenaline re-uptake
r Usually necessitates the use of ␤-blockade to treat secondary tachycardia
Prazosin and doxasosin are shorter acting competitive ␣1 selective blocking
drugs
r Less tachycardia
r May not require adjuvant ␤-blockade unless the tumour is secreting
adrenaline.
192 Phaeochromocytoma – peri-operative management P

Do you need a cardioselective ␤-blocker?

In theory, avoiding ␤2 blockade will allow ␤2 -mediated vasodilatation to
continue but in practice a selective ␤1 -blocker is not necessary. ␤-blockers are
usually added to control tachycardia secondary to ␣-blockade. Selective ␤1 -
blockers may be used for adrenaline secreting tumours or to treat the
tachycardia associated with the use of phenoxybenzamine.

Assuming that this patient has been adequately treated

pre-operatively, how would you anaesthetise them for laparoscopic
tumour removal?
Sedative pre-medication
Invasive arterial and central venous monitoring is essential.
Large bore i.v. access
r The patient may be intravascularly depleted after prolonged sympathetic
over-stimulation.
r Large fluid shifts are possible.
a
tth
C s

Cardiac output monitoring is useful in those with cardiomyopathy

ad ote
ha

Induction with remifentanil and propofol. Remifentanil may be useful in

hm N

this instance as it has short-acting sympatholytic properties.

fo r P ale A am

Vecuronium to paralyse the patient to avoid the potential histamine (and

ot o S an x

therefore catecholamine) release associated with other agents.

N ot f or sh a E

Intubate the patient and maintain anaesthesia with a mixture of oxygen,

n
N ot f ee esi

tio

air, sevoflurane and remifentanil.

N r. Z sth

bu

Opioid-based analgesia is reasonable for a laparoscopic technique.

tri

Thoracic epidural for an open procedure.

D e

ed t
r R rin
An

is

What drugs would you have drawn up or immediately available?

Blood pressure swings can be dramatic but transient and so the available
drugs must be potent and short-acting.

Phentolamine (a non-selective ␣-antagonist) may be given as an infusion or

a bolus (1–2 mg increments). It acts within one circulation time.
The heart rate should be kept below 100 bpm. Short-acting ␤-blockers such
as Esmolol or Metoprolol may be useful for this.
Magnesium blocks catecholamine release and the adrenoceptor response to
noradrenaline. It also has anti-arrhythmic activity.
Labetalol is a combined ␣ and ␤ blocker (∼1:10 ␣: ␤ activity). Onset in 5
minutes but effect may last hours.
There can be hypotension during these procedures too, particularly once
the tumour has been removed.
There may be profound hypovolaemia necessitating several litres of fluid.
Vasopressors such as epinephrine and metaraminol should also be
immediately available.
P Phaeochromocytoma – peri-operative management 193

Surgical technique
Open lateral retroperitoneal approach
r Quicker
r Fewer catecholamine surges
r More painful
Laparoscopic approach
r Long operation
r Shorter recovery time
r Greater surgical manipulation – more instability.

How would you treat post-operative hypotension?

Post-operative hypotension is a common problem as the source of
catecholamines has been removed but the adrenergic blockade remains.

a
tth
C s
ad ote

Assessment of pre-load/volume status, cardiac function, inotropy and the

ha

peripheral vascular resistance should guide treatment.

hm N

Catecholamine infusions in ‘normal’ doses may be ineffective, therefore

fo r P ale A am

fluid and posture may need to be the mainstays of treatment.

ot o S an x

Early extubation helps by negating the need for sedation.

N ot f or sh a E

Adrenaline can be useful if there is evidence of left ventricular failure.

n
N ot f ee esi

tio

Noradrenaline or Vasopressin may be useful in refractory vasodilatation.

N r. Z sth

bu

When both adrenals have been removed, hydrocortisone is required

tri
D e

ed t

immediately.
r R rin
An

is

What other specific problems may occur post-op?

Hypoglycaemia: Hyperglycaemia is often associated with the catecholamine
surges and following tumour removal the patients may become
hypoglycaemic.
The symptoms of this may be masked by ␤-blockade so the glucose should
be measured regularly.
Glucocorticoid and mineralocorticoid deficiency requiring supplementation
with hydrocortisone and fludrocortisone.
Electrolyte and fluid imbalance

Bibliography
Allman K, Wilson I. (2002). Oxford Handbook of Anaesthesia (Oxford Handbooks) 2nd edition.
Oxford, UK: Oxford University Press. ISBN: 0192632736.
McIndoe AK. (2002). Recognition and management of phaeochromocytoma. Anaesthesia and
Intensive Care Medicine, 3(9), 319–24.
Prys-Roberts C. (2000). Phaeochromocytoma – recent progress in its management. British Journal of
Anaesthesia, 85, 44–57.
performance indicator and is closely monitored by various “quality
management” agencies. Although studies regarding the perioperative
administration of β-blockers have yielded conflicting results as to benefit versus
harm, maintenance of β-blockers in patients already being treated with them is
essential, unless contraindicated by other clinical concerns. Initial small trials did
not demonstrate adverse outcomes from initiation of perioperative β-blocker
therapy. Subsequent studies either demonstrated no benefit or actual harm (eg,
stroke) when β blockade was begun perioperatively. Consequently, guidelines
continue to be revised as new evidence is evaluated.
The 2014 American College of Cardiology/American Heart Association
(ACC/AHA) guidelines recommend continuation of β-blocker therapy during the
perioperative period in patients who are receiving them chronically (class I
benefit >>> risk). β-Blocker therapy postoperatively should be guided by clinical
circumstances (class IIa benefit >> risk). Irrespective of when β-blocker therapy
was started, therapy may need to be temporarily discontinued (eg, bleeding,
hypotension, bradycardia). The ACC/AHA guidelines suggest that it may be is
reasonable to begin perioperative β-blockers in patients at intermediate or high
risk for myocardial ischemia (class IIb benefit ≥ risk). Other conditions such as
risk of stroke or uncompensated heart failure should be considered in discerning
if β-blockade should be initiated perioperatively. Additionally, in patients with
three or more Revised Cardiac Risk Index risk factors (see Chapter 21), it may
be reasonable to begin β-blocker therapy before surgery (class IIb). Lacking
these risk factors, it is unclear whether preoperative β-blocker therapy is
effective or safe. Should it be decided to begin β-blocker therapy, the ACC/AHA
guidelines suggest that it is reasonable to start therapy sufficiently in advance of
the surgical procedure to assess safety and tolerability of treatment (class IIb).
Lastly, β-blockers should not be initiated in β-blocker naïve patients on the day
of surgery (class III: harm).
Abrupt discontinuation of β-blocker therapy for 24 to 48 h may trigger a
withdrawal syndrome characterized by rebound hypertension, tachycardia, and
angina pectoris. This effect seems to be caused by an increase in the number of
β-adrenergic receptors (upregulation).

CASE DISCUSSION
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N ot f for sh ia E

Pheochromocytoma
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A 45-year-old man with a history of paroxysmal attacks of headache,
hypertension, sweating, and palpitations is scheduled for resection of
an abdominal pheochromocytoma.
What is a pheochromocytoma?
A pheochromocytoma is a vascular tumor of chromaffin tissue (most
commonly the adrenal medulla) that produces and secretes norepinephrine
and epinephrine. The diagnosis and management of pheochromocytoma are
based on the effects of abnormally high circulating levels of these
endogenous adrenergic agonists.
How is the diagnosis of pheochromocytoma made in the
laboratory?

a
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Urinary excretion of vanillylmandelic acid (an end product of
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catecholamine metabolism), norepinephrine, and epinephrine is often
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markedly increased. Elevated levels of urinary catecholamines and
fo r P ale A am

metanephrines (Figure 14–3) provide a highly accurate diagnosis.

Fractionated plasma-free metanephrine levels may be superior to urinary
ot o S an x
N ot f or sh a E

studies in making the diagnosis. The location of the tumor can be

n
determined by magnetic resonance imaging or computed tomographic scan
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with or without contrast.

N r. Z th

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What pathophysiology is associated with chronic elevations of

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norepinephrine and epinephrine?

α1 Stimulation increases peripheral vascular resistance and arterial blood
pressure. Hypertension can lead to intravascular volume depletion
(increasing hematocrit), renal failure, and cerebral hemorrhage. Elevated
peripheral vascular resistance also increases myocardial work, which
predisposes patients to myocardial ischemia, ventricular hypertrophy, and
congestive heart failure. Prolonged exposure to epinephrine and
norepinephrine may lead to a catecholamine-induced cardiomyopathy.
Hyperglycemia results from decreased insulin secretion in the face of
increased glycogenolysis and gluconeogenesis. β1 Stimulation increases
automaticity and ventricular ectopy.
Which adrenergic antagonists might be helpful in controlling
the effects of norepinephrine and epinephrine hypersecretion?
Phenoxybenzamine, an α1-antagonist, effectively reverses the
vasoconstriction, resulting in a drop in arterial blood pressure and an
increase in intravascular volume (hematocrit drops). Glucose intolerance is
often corrected. Phenoxybenzamine can be administered orally and is
longer acting than phentolamine, another α1-antagonist. For these reasons,
phenoxybenzamine is often administered preoperatively to control
symptoms.
Intravenous phentolamine has been used intraoperatively to control
hypertensive episodes. Compared with some other hypotensive agents,
however, phentolamine has a slow onset and long duration of action;
furthermore, the agent no longer is widely available. Other vasodilators can
be used in this circumstance.
β1 Blockade is recommended after initiation of α blockade for patients

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with tachycardia or ventricular arrhythmias.
ad ote
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Why should α1-receptors be blocked with phenoxybenzamine
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fo r P ale A am

before administration of a β-antagonist?

ot o S an x
N ot f or sh a E

If β-receptors are blocked first, norepinephrine and epinephrine will

produce unopposed α stimulation. β2-Mediated vasodilation will not be able
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to offset α1 vasoconstriction, and peripheral vascular resistance would

N r. Z th

bu

increase. This may explain the paradoxical hypertension that has been
D es

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reported in a few patients with pheochromocytoma treated only with

An

is

labetalol. Finally, the myocardium might not be able to handle its already
elevated workload without the inotropic effects of β1 stimulation.

Which anesthetic agents should be specifically avoided?

Ketamine is a sympathomimetic and might exacerbate the effects of
adrenergic agonists. Halothane sensitizes the myocardium to the
arrhythmogenic effects of epinephrine. Vagolytic drugs (eg, anticholinergics
and pancuronium) may contribute to tachycardia. Because histamine
provokes catecholamine secretion by the tumor, drugs associated with
histamine release (eg, atracurium) are best avoided. Vecuronium and
rocuronium are probably the neuromuscular blocking agents of choice.
Would an epidural or spinal technique effectively block
sympathetic hyperactivity?
A major regional block—such as an epidural or spinal anesthetic—could
block sensory (afferent) nerves and sympathetic (efferent) discharge in the
area of the surgical field. However, the catecholamines released from a
pheochromocytoma during surgical manipulation would still be able to bind
and activate adrenergic receptors throughout the body.

GUIDELINES
Fleisher LA, Fleischmann KE, Auerbach AD, et al. 2014 ACC/AHA guideline
on perioperative cardiovascular evaluation and management of patients
undergoing noncardiac surgery: Executive summary: A report of the
American College of Cardiology/American Heart Association Task Force on

a
Practice Guidelines. Circulation. 2014;130:2215.

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SUGGESTED READINGS
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Brunton L, Knollman B, Hilal-Dandan R, eds. Goodman and Gilman’s The

ot o S an x

Pharmacological Basis of Therapeutics. 13th ed. New York, NY: McGraw-

N ot f or sh a E

Hill Education; 2018. n

N ot f ee esi

Gu YW, Poste J, Kunal M, Schwarcz M, Weiss I. Cardiovascular manifestations

tio
N r. Z th

of pheochromocytoma. Cardiol Rev. 2017;25:215.

bu
D es

Katzung BG, Trevor AJ, eds. Basic and Clinical Pharmacology, 13th ed. New
tri
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York, NY: McGraw-Hill Education; 2015.

Lother A, Hein L. Pharmacology of heart failure: From basic science to novel
therapies. Pharmacol Ther. 2016;166:136.
Nguyen V, Tiemann D, Park E, Salehi A. Alpha-2 agonists. Anesthesiol Clin.
2017;35:233.
An
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Chapter 8 147

Endocrine and metabolic

disease

Hannah Blanshard
Diabetes mellitus 148
Acromegaly 156
Thyroid disease 157
Parathyroid disorders 160
Adrenocortical insufficiency 162
The patient on steroids 165
Cushing’s syndrome 167
Conn’s syndrome 168
Apudomas 170
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Hypokalaemia 174
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Hyperkalaemia 176
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Hyponatraemia 178
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Hypernatraemia 180
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See also:
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Preoperative 578
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Hypocalcaemia 577
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148 Chapter 8 Endocrine and metabolic disease

Diabetes mellitus
Insulin is necessary, even when fasting, to maintain glucose homeostasis and
balance stress hormones (e.g. adrenaline). It has two classes of action:
• Excitatory—stimulating glucose uptake and lipid synthesis
• Inhibitory (physiologically more important)—inhibits lipolysis,
proteolysis, glycogenolysis, gluconeogenesis, and ketogenesis.
Lack of insulin is associated with hyperglycaemia, osmotic diuresis, dehy-
dration, hyperosmolarity, hyperviscosity predisposing to thrombosis, and
increased rates of wound infection. Sustained hyperglycaemia is associated
with increased mortality, hospital stay, and complication rates.
Diabetes mellitus is present in 5% of the population.
• Type 1 diabetes (20%): immune-mediated and leads to absolute
insulin deficiency. Patients cannot tolerate prolonged periods without
exogenous insulin. Glycogenolysis and gluconeogenesis occur, resulting
in hyperglycaemia and ketosis. Treatment is with insulin.
• Type 2 diabetes (80%): a disease of adult onset, associated with insulin
resistance. Patients produce some endogenous insulin, and their
metabolic state often improves with fasting. The treatment may be diet
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control, oral hypoglycaemics, and/or insulin.

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General considerations
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Many diabetic patients are well informed about their condition and have
ot o S an x

undergone previous surgery. Discuss management with them. Hospital

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diabetic teams can be useful for advice. The overall aims of perioperative
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diabetic management are to maintain physiological glucose levels (above

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hypoglycaemic levels, but below those at which deleterious effects of

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hyperglycaemia become evident) and prevent hypokalaemia, hypomagnes-

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aemia, and hypophosphataemia.

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Preoperative assessment
• CVS: the diabetic is prone to hypertension, IHD (may be ‘silent’),
cerebrovascular disease, MI, and cardiomyopathy. Autonomic
neuropathy can lead to tachy- or bradycardia and postural hypotension.
• Renal: 40% of diabetics develop microalbuminuria, which is associated
with hypertension, IHD, and retinopathy. This may be reduced by
treatment with ACE inhibitors.
• Respiratory: diabetics are prone to perioperative chest infections,
especially if they are obese and smokers.
• Airway: thickening of soft tissues (glycosylation) occurs, especially in
ligaments around joints, leading to limited joint mobility syndrome.
Intubation may be difficult if the neck is affected or there is insufficient
mouth opening.
• GI: 50% of patients have delayed gastric emptying and are prone to
reflux.
• Diabetics are prone to infections.
Diabetes mellitus 149

Investigations
• Ensure that diabetic control is optimized prior to surgery.
• Measure glycosylated Hb (HbA1c), a measure of recent glycaemic
control (normal 20–48mmol/mol, 4–6.5%). If HbA1c is >69mmol/mol
(8.5%), refer to the team who manages their diabetes for optimization.
Surgery may then proceed with caution. A value >85mmol/mol (10%)
suggests inadequate control. Refer to the diabetic team, and only
proceed if surgery is urgent.
• Patients with hypoglycaemic unawareness should be referred to the
diabetes specialist team, irrespective of HbA1c.
Preoperative management
• Make an individualized diabetes management plan, agreed with the
patient, for the pre-admission and perioperative period.
• Ensure that co-morbidities are recognized and optimized prior to
admission.
• Place the patient first on the operating list, if possible.
• Individuals with type 1 diabetes should NEVER go without insulin, as
they are at risk of diabetic ketoacidosis.
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• The Enhanced Recovery Partnership Programme recommends

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high-carbohydrate drinks prior to surgery. This may compromise blood

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sugar control and is not recommended for people with insulin-treated

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diabetes.
• Avoid overnight preoperative admission to hospital wherever possible.
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• Patients with a planned short starvation period (no more than one
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missed meal in total) should be managed by modification of their usual

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diabetes regime, avoiding a variable-rate IV insulin infusion (VRIII)

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wherever possible.
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• Patients expected to miss >1 meal should have a VRIII.

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• For suggested perioperative management of insulin, see Table 8.1. For

suggested perioperative management of non-insulin diabetic medication,
see Table 8.2.
Perioperative management
• Monitor blood glucose on admission, and hourly during the day of
surgery. Aim for blood glucose level of 6–10mmol/L; 4–12mmol/L is
acceptable.
• If blood glucose is >12mmol/L either pre- or post-surgery, check
capillary blood ketones or urinary ketones. If capillary blood ketones
are >3mmol/L or urinary ketones > +++, cancel surgery.
• Consider an RSI if gastric stasis is suspected.
• Regional techniques may be useful for extremity surgery and to reduce
the risk of undetected hypoglycaemia. Document any existing nerve
damage.
• Autonomic dysfunction may exacerbate the hypotensive effect of
spinals and epidurals.
150 Chapter 8 Endocrine and metabolic disease

Table 8.1 Perioperative management of insulin therapy

Day of surgery
Patient for a.m. surgery Patient for p.m. surgery
Once daily (evening) No dose change
Once daily (morning) No dose change
Twice daily Halve the usual morning dose
Leave the evening meal dose unchanged
Twice daily—separate Calculate the total dose of both morning insulins,
injections of short-acting and give half as intermediate-acting only in
and intermediate-acting the morning
Leave the evening meal dose unchanged
3–5 injections daily Basal bolus regimens: Take usual morning
Omit the morning and insulin dose(s)
lunchtime short-acting Omit lunchtime
insulins. Keep the basal dose
unchanged, unless patient
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grazes all day when consider

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reducing by a third
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Premixed a.m. insulin

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Halve morning dose, and

omit lunchtime dose
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Reproduced from Dhatariya, K. et al., NHS Diabetes perioperative management guideline,

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Appendix 2, Diabetic Medicine © Crown Copyright 2012.

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Perioperative adjustment of insulin (short starvation

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period—no more than ONE missed meal)

Insulin should be taken as usual on the day before surgery.
Check blood glucose on admission.
Perioperative adjustment of non-insulin medication (short
starvation period—no more than ONE missed meal)
For well-controlled patients (HbA1c<69mmol/mol) undergoing surgery
with a short starvation period (one missed meal) and preoperative hyper-
glycaemia (blood glucose >12mmol/L):
• Type 1 diabetes: give SC rapid-acting insulin analogue. Assume that 1U
will drop blood glucose by 3mmol/L, but take advice from the patient
wherever possible. Recheck blood glucose hourly. If surgery cannot be
delayed, commence VRIII.
• Type 2 diabetes: give 0.1U/kg of SC rapid-acting insulin analogue, and
recheck blood glucose 1hr later to ensure it is falling. If surgery cannot
be delayed or the response is inadequate, commence VRIII.
Diabetes mellitus 151

Table 8.2 Perioperative management of oral diabetic medication

Day of surgery
Patient for a.m. surgery Patient for p.m. surgery
Acarbose Omit morning dose Give morning dose
if NBM if eating
Meglitinide Omit morning dose Give morning dose if
(repaglinide or nateglinide) if NBM eating
Metformin Take as normal Take as normal
(if procedure not requiring
use of contrast media*)
Sulfonylurea Once daily a.m. omit Once daily a.m. omit
(e.g. glibenclamide, Twice daily, omit a.m. Twice daily, omit a.m.
gliclazide, glipizide, etc.) and p.m.
Pioglitazone Take as normal Take as normal
DDP-4 inhibitor Omit on day of surgery Omit on day of surgery
(e.g. sitagliptin, vildagliptin,
saxagliptin)
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GLP-1 analogue Omit on day of Omit on day of

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(e.g. exenatide, surgery surgery

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liraglutide)
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* If contrast medium is to be used and estimated GFR <50mL.min/1.732, metformin should be

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omitted on the day of surgery and for the following 48hr.

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a.m., morning; DDP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; NBM, nil by
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mouth; p.m., afternoon.

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Reproduced from Dhatariya, K. et al., NHS Diabetes perioperative management guideline,

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Appendix 3, Diabetic Medicine © Crown Copyright 2012.

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Patients undergoing surgery with a long starvation period

(i.e. two or more missed meals)
• Commence VRIII on admission.
• If patient is already on a long-acting insulin analogue, these should be
continued, even if planning to use a VRIII through the perioperative
period.
• Glucose/insulin infusions should be administered through the same
cannula to prevent accidental administration of insulin without glucose.
Both infusions should be regulated by volumetric pumps, with an
anti-reflux valve on the IV glucose line.
• Hartmann’s solution should be used in preference to 0.9% saline in
those patients not requiring a VRIII.
152 Chapter 8 Endocrine and metabolic disease

Hypoglycaemia
• Blood glucose <4mmol/L is the main danger to diabetics
perioperatively. Fasting, recent alcohol consumption, liver failure, and
septicaemia commonly exacerbate this.
• Characteristic signs are tachycardia, light-headedness, sweating, and
pallor. This may progress to confusion, restlessness, incomprehensible
speech, double vision, convulsions, and coma. If untreated, permanent
brain damage will occur, made worse by hypotension and hypoxia.
• Anaesthetized patients may not show any of these signs. Monitor blood
sugar regularly, and suspect hypoglycaemia with unexplained changes in
the patient’s condition.
• If hypoglycaemia occurs, give 75mL of 20% glucose over 15min or
150mL of 10% glucose, and repeat the blood glucose after 15min.
Alternatively, give 1mg of glucagon (IM or IV); 10–20g (2–4 teaspoons)
of sugar by mouth or an NGT is an alternative.
Variable-rate intravenous insulin infusion
• The recommended 1st-choice solution for VRIII is 0.45% NaCl with
5% glucose, and either 0.15% potassium chloride (KCl) or 0.3% KCl;
a

however, this is not always available.

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• 4% glucose and 0.18% NaCl, 10% glucose, or 5% glucose are

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acceptable. Whenever giving hypotonic parenteral fluids, beware of

fo r P ale A am

hyponatraemia. Preferably give 10% glucose at 60mL/hr, rather than

5% glucose at 120mL/hr (prevents water overload, particularly in the
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elderly).
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• If K+ <4.5mmol/L, add 10mmol KCl to each 500mL bag of glucose.

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• Start VRIII using a syringe pump. Adjust according to the sliding scale
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in Table 8.3. Test blood glucose hourly initially. Patients on >100U of

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insulin/day will need higher doses of insulin by infusion.

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Transferring from a variable-rate intravenous insulin

infusion to subcutaneous insulin or oral treatment
Restarting oral hypoglycaemic medication
• Recommence oral hypoglycaemic agents once the patient is ready to eat
and drink.
• Be prepared to withhold or reduce sulphonylureas if the food intake is
likely to be reduced.
• Metformin should only be recommenced if the estimated GFR (eGFR)
>50mL/min/1.732.
Restarting subcutaneous insulin for patients already established on insulin
• Conversion to SC insulin should be delayed until the patient is able to
eat and drink without nausea and vomiting.
• It should take place when the next meal-related SC insulin dose is due,
e.g. with breakfast or lunch.
Diabetes mellitus 153

Table 8.3 VRIII sliding scale

Blood glucose Initial rate of insulin infusion Insulin infusion rate if blood
(mmol/L) (U/hr) glucose not maintained
<10mmol/L (U/hr)
<4.0 0.5 0.5
(0.0 if a long-acting (0.0 if a long-acting
background insulin has been background insulin has been
continued), and treat as for continued), and treat as for
hypoglycaemia hypoglycaemia
4.1–7.0 1.0 2.0
7.1–9.0 2.0 3.0
9.1–11.0 3.0 4.0
11.1–14.0 4.0 5.0
14.1–17.0 5.0 6.0
17.1–20.0 6.0 8.0
>20 Check infusion running, Check infusion running, and
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and seek diabetes team or seek diabetes team or medical

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medical advice) advice

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ot o S an x

• Restart the normal pre-surgical regime. Be aware that insulin

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requirement may change due to post-operative stress, infection, or

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altered food intake.

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• Consult the diabetes team if blood sugar is outside the acceptable range
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(4–12mmol/L) or if a change in diabetic management is needed.

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• Ensure overlap between the VRIII and the 1st injection of the fast-acting
r

insulin. The fast-acting insulin should be injected SC with the meal, and
the VRIII discontinued 30–60min later.
For patients on basal bolus insulin
• If the patient was previously on a long-acting insulin analogue, such as
Lantus® or Levemir®, this should have been continued, and so the patient
only needs to restart their normal short-acting insulin at the next meal.
For patients on a twice-daily fixed-mix regimen
• The insulin should be only reintroduced before breakfast or before the
evening meal.
For patients on continuous subcutaneous insulin
• Commence the SC insulin infusion at their normal basal rate as long as
not at bedtime.
• VRIII should be continued until the next meal bolus has been given.
154 Chapter 8 Endocrine and metabolic disease

Intensive care unit admissions

• Manage patients admitted to ICU post-operatively to ensure blood
glucose between 5 and 10mmol/L. Previous evidence from Van den
Berghe et al.1 for tighter glucose control (4.4–6.1mmol/L), leading to
improved mortality and morbidity, has not been borne out by recent
evidence from the Glucontrol study2 and the VISEP study.3 These
showed no difference in outcomes, but significantly more hypoglycaemia
and the need for more nursing input to achieve this level of glycaemic
control safely.
Glucose–potassium–insulin regime (GKI or Alberti)
This is an alternative, simpler regime which does not require infusion
pumps, but may provide less accurate control of blood sugar. The original
regime, as described by Alberti,4 consists of:
• 500mL of 10% glucose
• Add 10–15U of soluble insulin, plus 10mmol of KCl per 500mL bag
• Infuse at 100mL/hr
• Provides insulin 2–3U/hr, K+ 2mmol/hr, and glucose 10g/hr.
Glucose 10% is not always available, so the following regime with 5% glu-
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cose can be used—infuse 5% glucose (500mL bags) at the calculated rate

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for the patient’s fluid maintenance requirements. Insulin and K+ should be

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added to each bag, as per Table 8.4. The bag may be changed according to
fo r P ale A am

2-hourly blood glucose measurements.

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Table 8.4 GKI infusions based on 5% glucose solution

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Blood glucose Soluble insulin Blood K+ (mmol/L) KCl (mmol) to

(mmol/L) (U) to be added to be added to each
each 500mL bag of 500mL bag of 5%
5% glucose glucose
<4 5 <3 20
4–6 10 3–5 10
6.1–10 15 >5 None
10.1–20 20
>20 Review If potassium level not
available, add 10mmol
KCl to each bag
Diabetes mellitus 155

References
1 Van den Berghe G, Wouters P, Weekers F, et al. (2001). Intensive insulin therapy in critically ill
patients. N Engl J Med, 345, 1359–67.
2 Preiser JC, Devos P, Ruiz-Santana S, et al. (2009). A prospective randomized multi-centre con-
trolled trial on tight glucose control by intensive insulin therapy in adult intensive care units: the
Glucontrol study. Intensive Care Med, 35, 1738–48.
3 Brunkhorst FM, Engel C, Bloos F, et al. (2008). Intensive insulin therapy and pentastarch resuscita-
tion in severe sepsis. N Engl J Med, 358, 125–39.
4 Alberti KGMM (1991). Diabetes and surgery. Anesthesiology, 74, 209–11.

Further reading
Dhatariya K, Levy N, Kilvert A, et al. (2011). NHS Diabetes guideline for the peri-operative manage-
ment of the adult patient with diabetes. Diabet Med, 29, 420–33.
Lobo DN, et al. (2012). The peri-operative management of the adult patient with diabetes.
M http://www.asgbi.org.uk.
Rehman HU, Mohammed K (2003). Peri-operative management of diabetic patients. Curr Surg, 60,
607–11.
Simpson AK, Levy N, Hall GM (2008). Perioperative IV fluids in diabetic patients—don’t forget the
salt. Anaesthesia, 63, 1043–5.
Sonksen P, Sonksen J (2000). Insulin: understanding its action in health and disease. Br J Anaesth,
85, 69–79.
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156 Chapter 8 Endocrine and metabolic disease

Acromegaly
A rare clinical syndrome caused by overproduction of growth hormone
from the anterior pituitary. Patients may present for pituitary surgery (see
E p. 399) or require surgery unrelated to their pituitary pathology.
Preoperative assessment
• CVS: cardiac assessment for hypertension (30%), IHD, cardiomyopathy,
heart failure, conduction defects, and valvular disease.
• Airway: difficult airway management/intubation may occur—check for
large jaw, head, tongue, lips, and general hypertrophy of the larynx and
trachea. Also vocal cord thickening or strictures and chondrocalcinosis
of the larynx. Consider direct/indirect laryngoscopy preoperatively if
vocal cord or laryngeal pathology is suspected. Snoring and daytime
somnolence may indicate sleep apnoea. Look for enlargement of the
thyroid (25%) which may compress the trachea.
• Drugs: somatostatin analogues (octreotide, lanreotide) may cause
vomiting and diarrhoea. Bromocriptine, a long-acting dopamine agonist,
is often used to lower growth hormone levels. It can cause severe
a

postural hypotension.
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• Neurological: symptoms and signs of raised ICP.

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Investigations
fo r P ale A am

• ECG as routine. Echocardiogram if patient symptomatic or has

ot o S an x
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murmurs.
• CXR if cardiorespiratory problems.
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• Blood glucose—25% of cases are diabetic.

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Conduct of anaesthesia
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• Large face masks and long-bladed laryngoscopes may make airway

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management and intubation easier. Awake fibreoptic intubation

(AFOI) is the technique of choice for patients with anticipated difficult
intubation but is seldom required (see E p. 969). Elective tracheostomy
should be considered in those with severe respiratory obstruction.
• Positioning may be difficult. A long table may be required.
• Nerve compression syndromes are common, so take care to protect
vulnerable areas (ulnar nerve at the elbow, median nerve at the wrist,
and common peroneal nerve below the knee).
• Experience shows more problems with extubation than intubation.
• If evidence of sleep apnoea, extubate the patient awake and sitting up.
Post-operative care
If major surgery, consider ventilating the patient with sleep apnoea for a few
hours in ICU, until they are stable to wean from the ventilator.
Further reading
Nemergut EC, Dumont AS, Barry UJ, Lawes ER (2005). Perioperative management of patients
undergoing transphenoidal pituitary surgery. Anesth Analg, 101, 1170–81.
Seidman PA, Kofke WA, Policare R, Young M (2000). Anaesthetic complications of acromegaly.
Br J Anaesth, 84, 179–82.
Thyroid disease 157

Thyroid disease
May present for thyroidectomy (see E p. 574) or non-thyroid surgery.
General considerations for non-thyroid surgery
Hypothyroidism
• Commonly due to autoimmune thyroid destruction.
• CVS complications include decreased blood volume, cardiac output, and
HR, with a predisposition to hypotension and IHD. Pericardial effusions
also occur.
• Also associated with anaemia, hypoglycaemia, hyponatraemia, and
impaired hepatic drug metabolism.
• If clinical evidence of hypothyroidism, delay elective surgery to obtain a
euthyroid state. Liaise with the endocrinologist. Suggest levothyroxine
(T4) (starting dose 50 micrograms, increasing to 100–200 micrograms
PO over several weeks). The elderly are susceptible to angina and
heart failure, with increasing cardiac work caused by thyroxine, so start
with 25 micrograms, and increase by 25 micrograms at 3- to 4-weekly
intervals.
a

• If surgery is urgent, then liothyronine (T3) (10–50 micrograms slow IV

tth
C s
ad ote

with ECG monitoring, or 5–20 micrograms in patients with known or

ha

suspected cardiac disease, followed by 10–25 micrograms 8-hourly) can

hm N
fo r P ale A am

be used, but this is more controversial.

• Be cautious in interpreting low serum thyroid hormones in sick
ot o S an x
N ot f or sh a E

or surgical patients, as it is important to distinguish between

n
N ot f ee esi

hypothyroidism and the ‘euthyroid sick syndrome’. There is no clear

tio

evidence to give thyroid hormone replacement in the latter.

N . Z th

bu
D nes

tri
ed t

Hyperthyroidism (thyrotoxicosis)
r R rin
is
A

• Typically presents with weight loss, hypertension, sweating, and cardiac

r

arrhythmias (especially AF). Treatment is with carbimazole (30–45mg

PO daily for 6–8wk). This inhibits iodination of tyrosyl residues in
thyroglobulin. Occasionally, in severe cases with a large thyroid, Lugol’s
iodine is substituted 10d preoperatively to reduce gland vascularity.
• β-blockade (propranolol 30–60mg tds) is also started if there are signs
of tremor or palpitations. The non-cardioselective β-blockers, such as
propranolol, are more effective than the selective ones. β1-adrenergic
blockade treats the symptoms of tachycardia, but β2-adrenergic
blockade prevents the peripheral conversion of T4 to T3.
Preoperative assessment
• Thyroid function: check the patient is euthyroid (HR <80bpm, no
hand tremor)—delay surgery, if possible, until achieved. Patients with
subclinical hypothyroidism usually have no anaesthetic problems, and
elective surgery can proceed without special preparation.5
• Airway: look for tracheal deviation—a large goitre can cause respiratory
obstruction. This is a particular problem when the gland extends
retrosternally. Ask the patient about positional dyspnoea and dysphagia.
Look for evidence of tracheal compression with shortness of breath,
dysphagia, and stridor (occurs with 50% compression). Infiltrating
158 Chapter 8 Endocrine and metabolic disease

carcinoma may make any neck movement difficult and is an independent

predictor of difficult intubation.
• Superior vena cava (SVC) obstruction can occur. Look for distended
neck veins that do not change with respiration.
• Check for other autoimmune disorders.
Investigations
• FBC, U&Es, serum calcium, thyroid function tests.
• CXR/thoracic inlet views essential to assess tracheal compression.
• If tracheal compression present, perform CT or MRI scan to reveal the
site and length of narrowing and also the presence of any calcification.
• Refer to the ENT surgeon for indirect laryngoscopy to document any
preoperative vocal cord dysfunction.
Conduct of anaesthesia
Hypothyroid patients
• Give all drugs slowly. Susceptible to profound hypotension, which may
be relatively resistant to the effects of catecholamine therapy.
• Low metabolic rate predisposes to hypothermia, so actively warm.
a

• Controlled ventilation is recommended—tendency to hypoventilate.

tth
C s
ad ote

• Drug metabolism can be slow. Monitor twitch response, and reduce the
ha

dose of relaxants and opioids.

hm N
fo r P ale A am

Hyperthyroid patients
ot o S an x

• Continue β-blockade perioperatively to reduce the possibility of a

N ot f or sh a E

thyroid storm.
n
N ot f ee esi

tio

Special considerations
N . Z th

bu
D nes

tri
ed t

Thyroid storm
r R rin
is
A

• A life-threatening exacerbation of the hyperthyroid state, with evidence

r

of decompensation in one or more organ systems—mortality 20–30%.

• Usually presents 6–24hr post-surgery with fever (>40°C), sweating,
sinus tachycardia (>140bpm), coma, nausea, vomiting, diarrhoea.
• Rehydrate with IV saline and glucose.
• Treat hyperthermia with tepid sponging and paracetamol. Do not give
NSAIDs or aspirin, as these displace thyroid hormone from serum
binding sites.
• Give propranolol (1mg increments, up to 10mg), with CVS monitoring,
to decrease the pulse rate to <90bpm. Alternatively, give esmolol
(loading dose 250–500 micrograms/kg, followed by 50–100
micrograms/kg/min).
• Give hydrocortisone (200mg IV qds) to treat adrenal insufficiency and
to decrease T4 release and conversion to T3 at very high levels.
• Give propylthiouracil (1g loading dose via NGT, followed by 200–300mg
qds). This inhibits thyroid hormone release and also decreases the
peripheral conversion of T4 to T3.
• After blockade by propylthiouracil, give sodium iodide (500mg tds IV),
potassium iodide (five drops qds via NGT), or Lugol’s iodine (5–10
drops qds via NGT).5
Thyroid disease 159

Hypothyroid coma
• A rare form of decompensated hypothyroidism—mortality 15–20%.
• Characterized by coma, hypoventilation, bradycardia, hypotension, and
a severe dilutional hyponatraemia.
• Precipitated by infection, trauma, cold, and CNS depressants.
• Rehydrate with IV glucose and saline.
• Stabilize cardiac and respiratory systems, as necessary. May require
ventilation.
• Sudden warming may lead to extreme peripheral vasodilatation, so use
cautious passive external warming.
• Give levothyroxine 200–400 micrograms IV bolus, followed by 100
micrograms the next day. Use smaller doses in patients with CVS
disease.
• Patients should first receive stress-dose steroids (e.g. hydrocortisone
100mg qds IV), in case they have concomitant 1° or 2° adrenal
insufficiency, a common result of hypothyroidism.
• Consider a combination of IV T3 and T4, particularly if urgent surgery
required.6 The conversion of T4 to T3 is suppressed in hypothyroid
coma, and T3 is more active than T4. For doses of IV T3, see E p. 157.
a
tth

• Transfer to ICU.
C s
ad ote
ha

References
hm N
fo r P ale A am

5 Bennett-Guerrero E, Kramer DC, Schwinn DA (1997). Effect of chronic and acute thyroid
hormone reduction on perioperative outcome. Anesth Analg, 85, 30–6.
ot o S an x
N ot f or sh a E

6 Mathes DM (1998). Treatment of myxedema coma for emergency surgery. Anesth Analg, 86,
445–51.
n
N ot f ee esi

tio

Further reading
N . Z th

bu
D nes

tri

Bahn RS, Burch HB, Cooper DS, et al. (2011). Hyperthyroidism and other causes of thyrotoxi-
ed t
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is

cosis: management guidelines of the American Thyroid Association and American Association of
A

Clinical Endocrinologists. Thyroid, 21, 593–646.

r

Farling PA (2000). Thyroid disease. Br J Anaesth, 85, 15–28.

Langley RW, Burch HB (2003). Perioperative management of the thyrotoxic patient. Endocrinol
Metab Clin North Am, 32, 519–34.
Manzullo EF, Ross DS (2014). Non-thyroid surgery in the patient with thyroid disease. M http://www.
uptodate.com/contents/nonthyroid-surgery-in-the-patient-with-thyroid-disease.
Stathalos N, Wartoskky L (2003). Perioperative management of patients with hypothyroidism.
Endocrinol Metab Clin North Am, 32, 503–18.
160 Chapter 8 Endocrine and metabolic disease

Parathyroid disorders
General considerations
The parathyroid glands secrete parathyroid hormone (PTH), which acts on
the bones and kidneys to increase serum calcium and decrease serum phos-
phate. It stimulates osteoclasts to release calcium and phosphate into the
extracellular fluid (ECF) and simultaneously increases phosphate excretion
and calcium reabsorption in the kidney. Patients may present for parathy-
roidectomy (see E p. 578) and non-parathyroid-related surgery.
Hyperparathyroidism
• 1° hyperthyroidism: usually an adenoma causing a high PTH, high
calcium, and low phosphate. Associated with familial multiple endocrine
neoplasia (MEN) type 1. Tumours rarely palpable and are located at
surgery. Methylthioninium chloride (methylene blue) up to 1mg/kg is
often given preoperatively to localize the parathyroid gland.
• Presentation—50% of cases are asymptomatic, and presentation is
often subtle. May present with anorexia, dyspepsia, nausea, vomiting
and constipation, hypertension, shortened QT interval, polydipsia,
a
tth

polyuria, renal calculi, depression, poor memory, and drowsiness.

C s
ad ote
ha

Hypercalcaemic crisis
hm N
fo r P ale A am

• Occurs most commonly in the elderly with undiagnosed

ot o S an x

hyperparathyroidism and with malignant disease. Dehydration results

N ot f or sh a E

in anorexia and nausea/vomiting which exacerbates the cycle. Also

n
N ot f ee esi

tio

characterized by weakness, lethargy, mental changes, and coma.

N . Z th

bu

• Serum calcium >4.5mmol/L is life-threatening and can be rapidly, but

D nes

tri
ed t

transiently, lowered with phosphate (500mL of 0.1M neutral solution

r R rin
is
A

over 6–8hr).
r

• Rehydrate (4–6L of fluid often required).

• Pamidronate (60mg in 500mL of saline over 4hr) is the 1st-line
treatment. Bisphosphonates are potent inhibitors of osteoclastic bone
resorption. Effect is rapid and long-lasting.
• Calcitonin (3–4U/kg IV, then 4U/kg SC bd). Causes a rapid, but
temporary, decrease in skeletal release of calcium and phosphate.
• 2nd-line treatment, once volume repletion has been achieved, is with
forced saline diuresis with furosemide (40mg IV every 4hr). Loop
diuretics decrease the proximal tubular resorption of calcium. Consider
central pressure monitoring in the elderly at risk of LV failure.
• Hydrocortisone (200–400mg IV daily) in patients with malignancy.
• Dialysis is reserved for patients with renal failure.
Secondary hyperparathyroidism
• Results from compensatory parathyroid hypertrophy due to chronic
low calcium. Complicates CRF.
• Parathyroid hyperplasia causes a high PTH, normal or low calcium level,
and a high phosphate level.
• Usually presents as excessive bone resorption (seen earliest in the radial
aspect of the middle phalanx of the 2nd digit) or soft tissue calcification
of the vascular and soft tissues, including kidneys, heart, lungs, and skin.
Parathyroid disorders 161

• Treat medically with dietary phosphate restriction, calcium, and vitamin

D supplements. Medical therapy fails in 5–10% of patients on long-term
dialysis, and surgery becomes necessary.
• Risks of surgery are bleeding, recurrent hyperparathyroidism,
hypoparathyroidism, and injury to the recurrent laryngeal nerves.
Patients should undergo dialysis within 1d of surgery and then 48hr
post-operatively or as required.
• Watch for post-operative hypocalcaemia and hypomagnesaemia.
Tertiary hyperparathyroidism
• Parathyroid hyperplasia progresses to autonomous secretion, behaving
like an adenoma. Excessive secretion of PTH continues, despite
correction of renal failure. Only a few cases require operation.
Perioperative plan
• Restore intravascular volume with 0.9% NaCl. If the patient has normal
CVS and renal systems, a normal ECG, and a total serum calcium
<3mmol/L, then proceed with the operation. If the serum calcium
is >3mmol/L, the ECG is abnormal, or the patient has CVS or renal
a

impairment, the operation should be postponed until after treatment.

tth
C s

• Careful monitoring of NMB should be undertaken if NDMRs are used.

ad ote
ha
hm N

Hypoparathyroidism
fo r P ale A am

• Usually caused by parathyroidectomy, but post-radiotherapy and

ot o S an x

idiopathic cases also occur. Patients with a history of extensive neck

N ot f or sh a E

dissection in the past should have serum calcium measured before

n
N ot f ee esi

tio

further surgery.
N . Z th

bu

• Results in hypocalcaemia—ionized calcium <0.9mmol/L, total calcium

D nes

tri
ed t
r R rin

(corrected for albumin) <2.2mmol/L. Trough level usually occurs at

is
A

20hr following parathyroidectomy and typically normalizes by days 2–3.

r

• The presenting features are due to low calcium levels and manifest as
carpopedal spasm, tetany, dysrhythmia, hypotension, and prolonged
P–R interval on ECG.
• Treat with calcium (calcium gluconate 10mL 10% IV over 10min,
followed by 40mL in 1L of saline over 8hr).
• Low serum magnesium is also common and can be treated with
magnesium sulfate (1–5mmol IV slowly).

To adjust calcium concentration for albumin level:

Add 0.1mmol/L to calcium for each 5g/L that albumin is below 40g/L.

Further reading
Mihai R, Farndon JR (2000). Parathyroid disease and calcium metabolism. Br J Anaesth, 85, 29–43.
Sasidharan P, Johnston IG (2009). Parathyroid physiology and anaesthesia. Anaesthesia tutorial of the
week. M http://www.anaesthesiauk.com.
162 Chapter 8 Endocrine and metabolic disease

Adrenocortical insufficiency
Primary (Addison’s disease)
• Destruction of adrenal cortex by autoimmune disease (75%), infection
(TB), septicaemia, acquired immune deficiency syndrome (AIDS),
haemorrhage, metastases, surgery. Associated with glucocorticoid and
mineralocorticoid deficiency.
Secondary
• Insufficient adrenocorticotrophic hormone (ACTH) to stimulate the
adrenal cortex due to pituitary suppression by exogenous steroids
or generalized hypopituitarism usually from pituitary or hypothalamic
tumours. Associated with glucocorticoid deficiency only.
Acute adrenal crisis
• Due to stress in patients with chronic adrenal insufficiency without
adequate steroid replacement, acute adrenal haemorrhage, or pituitary
apoplexy (apoplexy is defined as a sudden neurologic impairment,
usually due to a vascular process, i.e. infarction or haemorrhage).
a
tth
C s

Clinical features of chronic adrenal insufficiency

ad ote
ha

• Weakness, fatigue (100%), skin hyperpigmentation (90%—1° only),

hm N
fo r P ale A am

postural hypotension (90%—pronounced in 1°), nausea, vomiting,

diarrhoea, weight loss (60%), myalgia, joint pain, salt craving (1° only),
ot o S an x
N ot f or sh a E

pale skin (2° only).

n
N ot f ee esi

tio

Investigations
N . Z th

bu
D nes

• Low serum glucose, low Na+ (90%), raised K+ (70%), raised urea and
tri
ed t
r R rin
is

creatinine (1° only), raised Ca2+ (1° only) (Table 8.5).

A
r

Table 8.5 Biochemical diagnosis of adrenal insufficiency

Test Normal range Definite adrenal insufficiency
1° 2°
Early morning 165–680nmol/L Cortisol <165nmol/L and Cortisol
cortisol ACTH >22.0pmol/L <100nmol/L
Early morning 1.1–11.0pmol/L Not
ACTH diagnostic
Standard short Peak cortisol Peak cortisol <500nmol/L Peak cortisol
Synacthen® test1 >500nmol/L <500nmol/L
Insulin tolerance Peak cortisol Peak cortisol
test2 >500nmol/L <500nmol/L
1
Serum cortisol at 0 and 30min after 250 micrograms of Synacthen® IV.
2
Serum glucose and cortisol 0, 15, 30, 45, 60, and 90min after insulin (0.1–0.15U/kg IV).
Test only valid if symptomatic hypoglycaemia (serum glucose <2.2mmol/L) is achieved. Gold
standard test—close supervision mandatory.
Adrenocortical insufficiency 163

Treatment
• Hydrocortisone (20mg in the morning and 10mg at night PO).
• Fludrocortisone (0.1mg PO) to replace aldosterone (1° deficiency only)
Perioperative management of patients with long-standing
Addison’s disease (according to M http://www.Addisons.org.uk)
• Give all medication on the morning of surgery.
• For any nil-by-mouth regime, give IV saline to prevent dehydration, and
maintain mineralocorticoid stability, e.g. 100mL every 8hr if >50kg.
• IM hydrocortisone is preferable to IV administration, as it gives more
sustained stable cover. It may alternatively be given by an infusion pump,
e.g. hydrocortisone 25mg bolus, then 5mg/hr in glucose 5%.
• Give hydrocortisone 100mg IM just before anaesthesia, and continue
every 6hr until the patient is eating and drinking normally. Then double
the oral dose for 48hr if major surgery, and 24hr if minor surgery. Then
return to normal dose.
• If any post-operative complications arise, e.g. fever, delay the return to
normal dose.
• Four-hourly blood glucose and daily electrolytes.
a

• Joint care with an endocrinologist is advisable.

tth
C s
ad ote
ha

• With respect to mineralocorticoid potency, 20mg hydrocortisone is

hm N

equivalent to 0.05mg fludrocortisone, so, with hydrocortisone doses of

fo r P ale A am

50mg or more, mineralocorticoid replacement in 1° adrenal insufficiency

ot o S an x

can be reduced.
N ot f or sh a E

Adrenal crisis (Addisonian crisis)

N ot f ee esi

tio

Classically presents as hypotension, hyponatraemia, hyperkalaemia, and

N . Z th

bu
D nes

hypoglycaemia with abdominal pain. Characteristically resembles hypo-

tri
ed t
r R rin
is

volaemic shock but can also mimic septic shock with fever, peripheral
A
r

vasodilatation, and a high cardiac output. In patients with type 1 diabetes,

deterioration of glycaemic control with recurrent hypoglycaemia can be the
presenting sign of adrenal insufficiency.
• 100% O2 and ventilatory support if necessary. Refer to ICU/HDU.
• IV fluids. Colloid to restore blood volume, saline to replace Na+ deficit
initially at 1000mL/hr, and glucose for hypoglycaemia.
• Hydrocortisone 200mg stat, followed by 100mg qds. If hydrocortisone
is given IV, please administer over a minimum of 10min to prevent
vascular damage. Baseline cortisol and ACTH prior to administration
of hydrocortisone. Dexamethasone (4mg IV) can be used if the
diagnosis has not been confirmed, since this does not interfere with the
measurement of cortisol and ACTH stimulation testing.
• Inotropes/vasopressors, as required. May be resistant in the absence of
cortisol replacement.
• Ascertain and treat the precipitating cause.
164 Chapter 8 Endocrine and metabolic disease

Relative adrenal insufficiency in the critically ill

• Relative hypoadrenalism in ICU patients occurs in ~30–50%
of septic patients. Consider in patients who are increasingly
vasopressor-dependent or require prolonged mechanical ventilation.
Treat if suspected—200mg hydrocortisone IV.
• Abnormal response to a short Synacthen® test is a poor prognostic
indicator.
Further reading
Annane D, Bellissant E, Bollaert PE, Briegel J, Keh D, Kupfer Y (2004). Corticosteroids for severe
sepsis and septic shock: a systematic review and meta-analysis. BMJ, 329, 480–4.
Arit W, Allolio B (2003). Adrenal insufficiency. Lancet, 361, 1881–93.
Wass J, Howlett T, Arlt W, Pearce S (2014). Glucocorticoid medication requirements for surgery and
dentistry. M http://www.addisons.org.uk/comms/publications/surgicalguidelines-colour.pdf.

a
tth
C s
ad ote
ha
hm N
fo r P ale A am
ot o S an x
N ot f or sh a E

n
N ot f ee esi

tio
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tri
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is
A
r
The patient on steroids 165

The patient on steroids

Steroids are used as replacement therapy in adrenocortical insufficiency
or to suppress inflammatory and immunological responses. Patients on
steroids requiring surgery may develop complications from their under-
lying disease or from a potentially impaired stress response due to
hypothalamic–pituitary–adrenal (HPA) suppression. Classically, these
patients were given additional large doses of steroids perioperatively; how-
ever, recent research suggests that smaller physiological replacement doses
are more than adequate (Table 8.6).

Table 8.6 Perioperative steroid replacement therapy

<10mg prednisolone/ Assume normal No additional steroid cover required
day HPA axis
>10mg prednisolone/ Minor surgery, Routine preoperative steroid or
day e.g. hernia hydrocortisone 25mg IV at induction
Intermediate Routine preoperative steroid plus
surgery, e.g. hydrocortisone 25mg IV at induction,
a
tth

hysterectomy and then 6-hourly for 24hr

C s
ad ote
ha

Major surgery, Routine preoperative steroid plus

hm N

e.g. cardiac hydrocortisone 25mg IV at induction,

fo r P ale A am

then 6-hourly for 48–72hr

ot o S an x
N ot f or sh a E

High-dose Should continue usual immunosuppressive dose

immunosuppression until able to revert to normal oral intake, e.g. 60mg
n
N ot f ee esi

tio

prednisolone/24hr = 240mg hydrocortisone/24hr

N . Z th

bu
D nes

Patient formerly <3 months since stopped steroids—treat as if on

tri
ed t
r R rin

taking regular steroids steroids

is
A

>3 months since stopped steroids—no perioperative

r

steroids necessary

Hypothalamic–pituitary–adrenal suppression
• Endogenous cortisol (hydrocortisone) production is of the order of
25–30mg/24hr (following a circadian pattern). During stress induced
by major surgery, it rises to 75–100mg/d and can remain elevated for a
variable period of time (up to 72hr following cardiac surgery).
• Prednisolone is a synthetic glucocorticoid with the general properties
of the corticosteroids. Prednisolone exceeds hydrocortisone in
glucocorticoid and anti-inflammatory activity, being ~3–4 times
more potent on a weight basis than the parent hormone, but is
considerably less active than hydrocortisone in mineralocorticoid
activity. Therefore, it is often given for chronic conditions to limit water
retention and is found only as an oral preparation. In contrast, the
relatively high mineralocorticoid activity of hydrocortisone and the
resulting fluid retention make it unsuitable for disease suppression on
a long-term basis; however, hydrocortisone can be given as an oral or
IV preparation, which is why it is often used perioperatively, instead of
prednisolone.
166 Chapter 8 Endocrine and metabolic disease

• Low-dose steroid treatment (<10mg prednisolone per day) usually

carries little danger of HPA suppression. Treatment with >10mg
prednisolone (or equivalent) risks HPA suppression. This may occur
after treatment via the oral, topical, parenteral, nebulized, and inhaled
routes. These patients must be assumed to be suffering from an inability
to mount a normal endogenous steroid response to stress and be
supplemented accordingly.
• HPA suppression can be measured using various methods. In practice,
the short Synacthen® test (corticotropin test) is reliable, cheap, and safe.
Patients are given Synacthen® (synthetic corticotropin) (250 micrograms
IV), and serum cortisol is measured at 0, 30, and 60min. Normal peak
cortisol levels range from 420 to 700nmol/L and indicate the ability
of the patient to mount a stress response. If the result is equivocal, an
insulin tolerance test can be performed under the supervision of an
endocrinologist.
For beclometasone and adrenal suppression, see E p. 99.
Prednisolone 5mg is equivalent to:
• Hydrocortisone 20mg
• Methylprednisolone 4mg
a
tth
C s

• Betamethasone 750 micrograms

ad ote
ha

• Dexamethasone 750 micrograms

hm N

• Cortisone acetate 25mg

fo r P ale A am

• Deflazacort 6mg
ot o S an x

• Triamcinolone 4mg.
N ot f or sh a E

n
N ot f ee esi

Fludrocortisone is available only in the oral preparation. It may be with-

tio

held on the day of surgery and while the patient is receiving stress doses
N . Z th

bu
D nes

of hydrocortisone (20mg hydrocortisone has equivalent mineralocorticoid

tri
ed t
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is

potency of 0.05mg fludrocortisone).

A
r

Further reading
Nicholson G, Burrin JM, Hall GM (1998). Peri-operative steroid replacement. Anaesthesia, 53,
1091–104.
Cushing’s syndrome 167

Cushing’s syndrome
A syndrome due to excess plasma cortisol caused by iatrogenic steroid
administration (commonest), pituitary adenoma (Cushing’s disease—80%
of remainder), ectopic ACTH (15% of remainder—e.g. oat cell carcinoma
of lung), adrenal adenoma (4% of remainder), adrenal carcinoma (rare).
Clinical features
• Moon face, truncal obesity, proximal myopathy, and osteoporosis.
• Easy bruising and fragile skin, impaired glucose tolerance, diabetes.
• Hypertension, LV hypertrophy, sleep apnoea.
• High Na+, bicarbonate (HCO3−), and glucose; low K+ and Ca2+.
• GI reflux.
Diagnosis
• High plasma cortisol and loss of diurnal variation (normal range
~165–680nmol/L; trough level at ~ midnight, peak level at ~6.00 a.m.).
• Increased urinary 17-(OH)-steroids.
• Loss of suppression with dexamethasone 2mg.
• ACTH level:
a
tth
C s

• Normal/high—pituitary
ad ote
ha

• Low—adrenal, ectopic cortisol administration

hm N

• Very high—ectopic ACTH.

fo r P ale A am
ot o S an x

Preoperative assessment
N ot f or sh a E

• Many patients have ECG abnormalities (high-voltage QRS and inverted

n
N ot f ee esi

tio

T waves) which may make IHD difficult to exclude, but they will revert
N . Z th

bu

to normal after curative surgery. These ECG changes seem to be related

D nes

tri
ed t
r R rin

to the Cushing’s disease itself.

is
A

• Eighty-five per cent of patients are hypertensive and are often poorly
r

controlled.
• Sleep apnoea and gastro-oesophageal reflux are common.
• Sixty per cent of patients have diabetes or impaired glucose tolerance,
and a sliding scale should be started before major surgery if glucose is
>10mmol/L.
• Patients are often obese with difficult veins!
• Patients are at risk of peptic ulcer disease, so give prophylactic antacid
medication.
Conduct of anaesthesia
• Position the patient carefully intraoperatively due to increased risk of
pressure sores and fractures secondary to fragile skin and osteoporosis.
Further reading
Sheeran P, O’Leary E (1997). Adrenocortical disorders. Int Anesthesiol Clin, 35, 85–98.
Smith M, Hirsch NP (2000). Pituitary disease and anaesthesia. Br J Anaesth, 85, 3–14.
168 Chapter 8 Endocrine and metabolic disease

Conn’s syndrome
Excess of aldosterone produced from either an adenoma (60%), benign
hyperplasia of the adrenal gland (35–40%), or adrenal carcinoma (rare).
General considerations
Aldosterone promotes active reabsorption of Na+ and excretion of
K+ through the renal tubules. Water is retained with Na+, resulting in an
increase in extracellular fluid (ECF) volume. To a lesser extent, there is also
tubular secretion of hydrogen (H+) ions and Mg2+, resulting in a metabolic
alkalosis.
Clinical features
• Refractory hypertension, hypervolaemia, metabolic alkalosis.
• Spontaneous hypokalaemia (K+ <3.5mmol/L); moderately severe
hypokalaemia (K+ <3.0mmol/L) during diuretic therapy despite oral K+.
• Muscle weakness or paralysis, especially in ethnic Chinese (2° to
hypokalaemia).
• Nephrogenic diabetes insipidus 2° to renal tubular damage (polyuria).
• Impaired glucose tolerance in ~50% of patients.
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Preoperative assessment for adrenalectomy

hm N

• Spironolactone (competitively inhibits aldosterone production) is usually

fo r P ale A am

given to reverse the metabolic and electrolyte effects. It also allows the
ot o S an x

patient to restore normovolaemia. Doses of up to 400mg/d may be

N ot f or sh a E

required.
n
N ot f ee esi

tio

• The patient should have normal serum K+ and HCO3−, but this may be
N . Z th

bu

difficult to achieve.
D nes

tri
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• Hypertension is usually mild and well controlled on spironolactone, but

is
A

features of end-organ damage, e.g. LV hypertrophy, should be excluded.

r

• Calcium channel blockers, such as nifedipine, are effective

antihypertensive agents with aldosterone-secreting adenomas. This is a
specific action.
Investigations
• Aldosterone (pg/mL) to renin (ng/mL/hr) ratio >400.
• 2° hyperaldosteronism has a raised serum aldosterone with a
normal ratio.
• Important to distinguish between adenoma and hyperplasia, as adenoma
is usually treated surgically and hyperplasia medically.
• Adrenal vein sampling, radiolabelling tests, CT, and MRI are all used.
Conduct of anaesthesia for adrenalectomy
Unilateral adrenalectomy can be done laparoscopically or via laparotomy,
and an appropriate method of analgesia should be discussed. Handling of
the adrenal gland during surgery can cause CVS instability but is not as
severe as with a phaeochromocytoma (see E p. 580).
• A short-acting α-blocker should be available (phentolamine 1mg
boluses IV).
• Check blood glucose perioperatively.
Conn’s syndrome 169

• Chronic hypokalaemia has an antagonistic action upon insulin secretion/

release and may result in abnormal glucose tolerance with the stress of
surgery.
Post-operative care
• Give hydrocortisone IV post-operatively until the patient can tolerate
oral hydrocortisone and fludrocortisone.
• Hypertension may persist after removal of the adenoma, due
presumably to permanent changes in vascular resistance.
Management of patients with Conn’s syndrome
for non-adrenal surgery
Such patients usually have bilateral hyperplasia of the zona glomerulosa.
Hypertension is usually more severe and may require additional therapy
(ACE inhibitors are useful). Try to restore K+ to normal value preopera-
tively. Perform CVS assessment as for any hypertensive patient.
Further reading
Winship SM, Winstanley JH, Hunter JM (1999). Anaesthesia for Conn’s syndrome. Anaesthesia, 54,
564–74.
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170 Chapter 8 Endocrine and metabolic disease

Apudomas
Tumours of amine precursor uptake and decarboxylation (APUD) cells
which are present in the anterior pituitary gland, thyroid, adrenal medulla,
GI tract, pancreatic islet, carotid bodies, and lungs. Apudomas include
phaeochromocytoma, carcinoid tumour, gastrinoma, VIPomas, and insu-
linoma and may occur as part of the MEN syndrome.
Phaeochromocytoma
See E p. 580.
Carcinoid tumours
• Carcinoid tumours are derived from argentaffin cells and produce
peptides and amines. Most occur in the GI tract (75%), bronchus,
pancreas, and gonads. Tumours are mainly benign, and, of those that are
malignant, only about a quarter release vasoactive substances into the
systemic circulation, leading to the carcinoid syndrome.
• Mediators are metabolized in the liver; therefore, only tumours with
hepatic metastases or a 1° tumour with non-portal venous drainage lead
to the carcinoid syndrome.
a
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• Vasoactive substances include serotonin, bradykinin, histamine,

ad ote
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substance P, prostaglandins, and vasoactive intestinal peptide (VIP).

hm N

• Patients with an asymptomatic carcinoid tumour have simple carcinoid

fo r P ale A am

disease and do not present particular anaesthetic difficulties.

ot o S an x
N ot f or sh a E

Patients with carcinoid syndrome can be extremely difficult to manage

perioperatively.
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N ot f ee esi

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N . Z th

Carcinoid syndrome
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Affects about 10% of patients with carcinoid tumours.

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Patients may have symptoms related to:

r

• The 1° tumour, causing intestinal obstruction or pulmonary symptoms,

e.g. haemoptysis and respiratory compromise
• Vasoactive peptides, resulting in intermittent flushing (90%), especially
of the head, neck, and torso, or diarrhoea (78%), which may lead to
dehydration and electrolyte disturbances. Other symptoms include
bronchospasm (20%), hypotension, hypertension, tachycardia,
hyperglycaemia, and right heart failure 2° to endocardial fibrosis
affecting the pulmonary and tricuspid valves (mediators are metabolized
in the lung before reaching the left heart).
Preoperative assessment
• Treat symptomatically—antidiarrhoeals, bronchodilators, correction of
dehydration/electrolyte imbalance, treatment of heart failure.
• Prevent the release of mediators—octreotide (100 micrograms SC tds)
for 2wk prior to surgery, and octreotide (100 micrograms IV, slowly
diluted to 10 micrograms/mL) at induction.
• Avoid factors that may trigger carcinoid crises—catecholamines, anxiety,
and drugs that release histamine, e.g. morphine.
Apudomas 171

Investigations
• Check FBC, electrolytes (may show the effects of chronic diarrhoea),
LFTs, and clotting if metastases present.
• Ensure rapid cross-matchable blood is available.
• ECG (may show RV hypertrophy).
• Echocardiography to exclude right-sided cardiac disease.
• CXR and lung function tests, if indicated.
Conduct of anaesthesia
This is best managed by centres familiar with the difficulties. Major compli-
cations anticipated in the perioperative period include severe hypotension,
severe hypertension, fluid and electrolyte shift, and bronchospasm.
• Premedication: anxiolytic (benzodiazepine) and octreotide (100
micrograms (50–500 micrograms) SC 1hr preoperatively), if not already
treated; otherwise continue with preoperative regime.
• Monitoring should include invasive BP pre-induction (both induction
and surgical manipulation of the tumour can cause large swings), CVP,
regular blood glucose, and blood gases. Cardiac output monitoring will
guide fluid therapy and help in managing hormone-induced preload and
a

afterload variations, particularly if cardiac complications present.

tth
C s

• Consider an epidural. Benefits include a reduced risk of a carcinoid

ad ote
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crisis with decreased stress response 2° to good analgesia; however,

hm N

low doses of LA should be used (avoiding hypotension, as this may elicit

fo r P ale A am

bradykinergic crisis).
ot o S an x
N ot f or sh a E

• Induction: prevent pressor response to intubation. Suxamethonium

has been used safely for RSI, although fasciculations may theoretically
n
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stimulate hormone release by increasing the intra-abdominal pressure.

N . Z th

bu

• Maintenance: both total IV anaesthesia (TIVA) and inhalation techniques

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have been used successfully.

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• Octreotide (10–20 micrograms boluses IV) to treat severe hypotension.

r

• Avoid all histamine-releasing drugs (atracurium, morphine) and

catecholamines (release serotonin and kallikrein, which activate
bradykinins).
• Labetalol, esmolol, or ketanserin (5-HT2 receptor blocker) can be used
for hypertension.
Post-operative
• ICU or HDU is required.
• Patients may waken very slowly (thought to be due to serotonin).
• Avoid morphine, and use either PCA with fentanyl or pethidine, or an
epidural.
• Hypotensive episodes may occur, as surgery may have reduced, rather
than eliminated, the tumour, thus requiring further IV boluses of
octreotide (10–20 micrograms).
• Wean octreotide over 7–10d following tumour resection.
Gastrinoma
Excess production of gastrin by benign adenoma, malignancy, or hyperpla-
sia of the D cells of the pancreatic islets. Gastrin stimulates acid produc-
tion from gastric parietal cells. Leads to Zollinger–Ellison syndrome, severe
peptic ulceration, and diarrhoea. May also have GI bleeds, perforation,
172 Chapter 8 Endocrine and metabolic disease

electrolyte disturbance, and volume depletion. Treatment includes PPIs

(e.g. omeprazole), H2 receptor antagonists, and octreotide. May present
for surgery related to gastrinoma, e.g. perforation, or pancreatic resection
of the tumour, or a totally unrelated pathology.
• FBC to look for anaemia from bleeding gastric ulceration.
• Check clotting screen and LFTs, since alterations in fat absorption may
influence clotting factors, and hepatic function may be affected by liver
metastases.
• Antacid prophylaxis preoperatively and RSI.
• Invasive pressure monitoring for major surgery.
• Continue omeprazole post-operatively, as the gastric mucosa may have
become hypertrophied, producing excess acid.
VIPoma
Rare tumour secreting VIP which leads to Verner–Morrison syndrome.
Characterized by profuse watery diarrhoea, intestinal ileus, abdominal dis-
tension, confusion, drowsiness, hypokalaemia, achlorhydria, hypomagnes-
aemia, hyperglycaemia, metabolic alkalosis, and tetany.
• VIP inhibits gastrin release; therefore, give H2 receptor-blocking drugs
a

preoperatively to prevent rebound gastric acid hypersecretion.

tth
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ad ote

• Replace fluids and electrolytes.

ha

• Treat medically with somatostatin analogues (octreotide). If this fails, try

hm N

steroids (such as methylprednisolone) and indometacin (a prostaglandin

fo r P ale A am

inhibitor).
ot o S an x
N ot f or sh a E

• Sixty per cent become malignant with liver metastases, so all warrant
n

resection.
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• Use invasive pressure monitoring for major surgery.

N . Z th

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D nes

• Frequent measurement of ABGs to check the acid–base status and

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electrolytes.
A
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Insulinoma
Rare tumour of β cells of the pancreas which secrete insulin—diagnosis
made by the Whipple’s triad—symptoms of hypoglycaemia, low plasma
glucose, and relief of symptoms when glucose is given.
• Diagnosis also made by a fasting blood glucose <2.2mmol/L, increased
insulin, increased C-peptide, and absence of sulphonylurea in the
plasma.
• Medical treatment is used to reduce symptoms. Diazoxide (a
non-diuretic benzothiazide which inhibits the release of insulin and
stimulates glycogenolysis) has been used where surgery has failed but
has unpredictable efficacy. Octreotide is also used. It binds with the
somatostatin receptors on insulinomas and decreases insulin secretion in
40–60% of patients.
• Tumours are usually non-malignant, but, if malignant, hepatic resection
may be required.
• Start 10% glucose and K+ infusion preoperatively, and monitor blood
glucose closely perioperatively, particularly at the time of tumour
manipulation.
Apudomas 173

Glucagonoma
Tumour of the α cells of the pancreas. Glucagon stimulates hepatic gly-
cogenolysis and gluconeogenesis, resulting in increased blood glucose
and diabetes mellitus. Ketoacidosis is rare, since insulin is also increased.
Characterized by a rash (necrotizing migratory erythema which presents in
the groin/perineum and migrates to the distal extremities).
• Associated with weight loss, glossitis, stomatitis, anaemia, and diarrhoea.
• Patients usually have liver metastases at presentation.
• Treatment consists of surgical debulking and somatostatin analogues.
• Increased incidence of venous thrombosis, so give prophylactic
antithrombotic therapy.
Further reading
Holdcraft A (2000). Hormones and the gut. Br J Anaesth, 85, 58–68.
Mancuso K, Kaye AD, Boudreaux JP, et al. (2011). Carcinoid syndrome and perioperative anesthetic
considerations. J Clin Anesth, 23, 329–41.
Powell B, Al Mukhtar A, Mills GH (2011). Carcinoid: the disease and its implications for anaesthesia.
Contin Educ Anaesth Crit Care Pain, 11, 9–13.
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174 Chapter 8 Endocrine and metabolic disease

Hypokalaemia
Defined as plasma K+ <3.5mmol/L.

• Mild 3.0–3.5mmol/L
• Moderate 2.5–3.0mmol/L
• Severe <2.5mmol/L

Causes
• Decreased intake.
• Increased K+ loss—vomiting or nasogastric suctioning, diarrhoea, pyloric
stenosis, diuretics, renal tubular acidosis, hyperaldosteronism, Mg2+
depletion, leukaemia.
• Intercompartmental shift—insulin, alkalosis (0.1 increase in pH
decreases K+ by 0.6mmol/L), β2-agonists, and steroids.
Clinical manifestations
a

• ECG changes—T wave flattening and inversion, prominent U wave,

tth
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ST-segment depression, prolonged P–R interval.

ha

• Dysrhythmias, decreased cardiac contractility.

hm N
fo r P ale A am

• Skeletal muscle weakness, tetany, ileus, polyuria, impaired renal

concentrating ability, decreased insulin secretion, growth hormone
ot o S an x
N ot f or sh a E

secretion, aldosterone secretion, negative nitrogen balance.

n
N ot f ee esi

• Encephalopathy in patients with liver disease.

tio
N . Z th

bu

Management
D nes

tri
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is

• Check U&Es, creatinine, Ca2+, phosphate, Mg2+, HCO3−, and glucose

A

if other electrolyte disturbances suspected. Hypokalaemia resistant to

r

treatment may be due to concurrent hypomagnesaemia.

• Exclude Cushing’s and Conn’s syndromes.
• Oral replacement is safest, up to 200mmol/d, e.g. KCl (Sando-K®) two
tablets qds = 96mmol K+.
• IV replacement—essential for patients with cardiac manifestations,
skeletal muscle weakness, or where oral replacement not appropriate.
• Aim to increase K+ to 4.0mmol/L if treating cardiac manifestations.
• Maximum concentration for peripheral administration is 40mmol/L
(greater concentrations than this can lead to venous necrosis);
40mmol KCl can be given in 100mL of 0.9% NaCl over 1hr, but only
via an infusion device, with ECG monitoring, in HDU/ICU/theatre
environment, and via a central vein. Plasma K+ should be measured at
least hourly during rapid replacement. K+ depletion sufficient to cause
0.3mmol/L drop in serum K+ requires a loss of ~100mmol of K+ from
total body store.
Hypokalaemia 175

Anaesthetic considerations
The principal problem is the risk of arrhythmia. The rate of onset is
important—chronic, mild hypokalaemia is less significant than that of
rapid onset.
Patients must be viewed individually, and the decision to proceed should
be based on the chronicity and level of hypokalaemia, the type of surgery,
and any other associated pathologies. The ratio of intracellular to extracel-
lular K+ is of more importance than isolated plasma levels.
• Classically, K+ <3.0mmol has led to postponement of elective
procedures (some controversy exists about this in the fit, non-digitalized
patient who may well tolerate chronically lower K+ levels, e.g.
2.5mmol/L, without adverse events).
• For emergency surgery, if possible, replace K+ in the 24hr prior to
surgery. Aim for levels of 3.5–4.0mmol/L. If this is not possible, use an
IV replacement regime, as documented earlier, intra-/perioperatively.
• If HCO3− is raised, then the loss is probably long-standing with low
intracellular K+, and will take days to replace.
• May increase sensitivity to NMB; therefore, need to monitor.
• Increased risk of digoxin toxicity at low K+ levels. Aim for K+ of
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4.0mmol/L in a digitalized patient.

C s
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Further reading
hm N
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Freshwater-Turner D (2006). Sodium, potassium and the anaesthetist. M http://www.frca.co.uk/

article.aspx?articleid=100676.
ot o S an x
N ot f or sh a E

Gennari FJ (2002). Disorders of potassium homeostasis. Hypokalaemia and hyperkalaemia. Crit Care
Clin, 18, 273–88.
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176 Chapter 8 Endocrine and metabolic disease

Hyperkalaemia
Defined as plasma K+ >5.5mmol/L.

• Mild 5.5–6.0mmol/L
• Moderate 6.1–7.0mmol/L
• Severe >7.0mmol/L

Causes
• Increased intake—IV administration, rapid blood transfusion.
• Decreased urinary excretion—renal failure (acute or chronic),
adrenocortical insufficiency, drugs (K+-sparing diuretics, ACE inhibitors,
ciclosporin, etc.).
• Intercompartmental shift of K+—acidosis (H+ is taken into the cell, in
exchange for K+), rhabdomyolysis, trauma, malignant hyperthermia
(MH), suxamethonium (especially with burns or denervation injuries),
familial periodic paralysis.
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• Pseudohyperkalaemia—due to in vitro haemolysis

C s
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Clinical manifestations
hm N
fo r P ale A am

• ECG changes, progressing through peaked T waves, widened QRS,

prolonged P–R interval, loss of P wave, loss of R wave amplitude, ST
ot o S an x
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depression, VF, asystole. ECG changes potentiated by low Ca2+, low

n
N ot f ee esi

Na+, and acidosis.

tio

• Muscle weakness at K+ >8.0mmol/L.

N . Z th

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• Nausea, vomiting, diarrhoea.

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Management
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Treatment should be initiated if K+ >6.5mmol/L or ECG changes present.

Unlike hypokalaemia, the incidence of serious cardiac compromise is high,
and therefore intervention is important. Treat the cause, if possible. Ensure
IV access and cardiac monitor.
• Insulin (10U in 50mL of 50% glucose IV over 30–60min). This has the
fastest onset of action and is very effective in reducing serum K+ by
shifting the K+ into the cells. Beware rebound occurs within 2hr.
• β2-agonist—salbutamol (5–10mg nebulized—beware tachycardia).
Should see a response at 30min and has a longer duration of action than
insulin.
• Ca2+ (5–10mL of 10% calcium gluconate or 3–5mL of 10% calcium
chloride). Ca2+ stabilizes the myocardium by increasing the threshold
potential. Rapid onset, short-lived.
• If acidotic, give HCO3− (50mmol IV).
• Ion exchange resin—calcium resonium (15g PO or 30g per rectum (PR)
8-hourly). This binds K+ in the gut.
• If initial management fails, consider dialysis or haemofiltration.
Hyperkalaemia 177

Anaesthetic considerations
Do not consider elective surgery. If life-threatening surgery, treat
hyperkalaemia first.
Avoid Hartmann’s solution and suxamethonium, if possible. If there
is a compelling case for rapid intubation conditions without long-term
paralysis, suxamethonium has been used safely with a preoperative K+ of
>5.5mmol/L.7 However, rocuronium, followed by its reversal agent sugam-
madex, is an excellent alternative and widely available now. Monitor NMB,
since effects may be accentuated.
• Avoid hypothermia and acidosis.
• Control ventilation to prevent respiratory acidosis.
• Monitor K+ regularly.
Reference
7 Schow AJ, Lubarsky DA, Olson RP, Gan TJ (2002). Can succinylcholine be used safely in hyper-
kalaemic patients? Anesth Analg, 95, 119–22.

Further reading
Elliot MJ, Ronksley PE, Clase CM, Ahmed SB, Hemmelgarn BR (2010). Management of patients with
acure hyperkalaemia. CMAJ, 182, 1631–5.
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Nyirenda MJ, Tang JI, Padfield PL, Seckl JR (2009). Hyperkalaemia. BMJ, 339, 1019–24.
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178 Chapter 8 Endocrine and metabolic disease

Hyponatraemia
Defined as serum Na+ <135mmol/L.

• Mild 125–134mmol/L
• Moderate 120–124mmol/L
• Severe <120mmol/L

ECF volume is directly proportional to total body Na+ content. Renal Na+
excretion ultimately controls the ECF volume and total body Na+ content.
To identify the causes of abnormalities of Na+ homeostasis, it is important
to assess plasma and urinary Na+ levels, along with the patient’s state of
hydration (hypo-/eu-/hypervolaemic).
Causes
Hypovolaemic hyponatraemia
Urinary Na+ <30mmol/L suggests an extrarenal cause, i.e. diarrhoea, vom-
iting, burns, pancreatitis, trauma.
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Urinary Na+ >30mmol/L suggests a 1° renal problem, i.e. diuretic excess,

ad ote
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osmotic diuresis, mineralocorticoid deficiency, salt-wasting nephropathy,

hm N

proximal renal tubular acidosis.

fo r P ale A am

Euvolaemic hyponatraemia
ot o S an x
N ot f or sh a E

Hypotonic fluid replacement post-surgery, hypothyroidism, glucocorticoid

n
N ot f ee esi

deficiency, syndrome of inappropriate antidiuretic hormone secretion

tio

(SIADH), psychogenic polydipsia.

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Hypervolaemic hyponatraemia
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ARF or CRF, CCF, cirrhosis, nephrotic syndrome, transurethral resection of

r

the prostate (TURP) syndrome.

Presentation
• Important to differentiate between acute and chronic hyponatraemia.
Speed of onset is much more important for the manifestation of
symptoms than the absolute Na+ level. Rare to get clinical signs if Na+
>125mmol/L.
• Na+ 125–130mmol/L causes mostly GI symptoms, i.e. nausea/vomiting.
• Na+ <125mmol/L—neuropsychiatric symptoms, nausea/vomiting,
muscular weakness, headache, lethargy, psychosis‚ raised intracranial
pressure, seizures, coma, and respiratory depression. Mortality high, if
untreated.
Treatment of symptomatic hyponatraemia
• Acute symptomatic hyponatraemia (develops in <48hr), e.g. TURP
syndrome, hysteroscopy-induced hyponatraemia, SIADH. Aim to
raise serum Na+ by 2mmol/L/hr until symptoms resolve. Complete
correction is unnecessary, although not unsafe. Infuse hypertonic saline
(3% NaCl) at a rate of 1.2–2.4mL/kg/hr through a large vein. Measure
Na+ levels hourly. In cases of fluid excess, give furosemide (20mg IV) to
Hyponatraemia 179

promote diuresis. If there are severe neurological symptoms (seizures,

coma) 3% NaCl may be infused at 4–6mL/kg/hr. Electrolytes should be
carefully monitored (see also E p. 593).
• Chronic symptomatic hyponatraemia (present for >48hr or duration
unknown). Aim to correct serum Na+ by 5–10mmol/d. Rapid
correction (serum Na+ rise of >0.5mmol/L/hr) can lead to central
pontine myelinolysis, subdural haemorrhage, and cardiac failure. If
hypovolaemia is present, correct with 0.9% NaCl. This removes the
antidiuretic hormone (ADH) response that accentuates the Na+/
water imbalance. If hypervolaemic, treat with fluid restriction and
furosemide. Monitor electrolytes and urine output every 12hr. For
SIADH—fluid-restrict, and give demeclocycline (300–600mg daily).
• Consult with an endocrinologist.
• Watch for resolution of symptoms.
• Treat the cause.
Asymptomatic hyponatraemia (often chronic)
• Fluid-restrict to 1L/d.
• Treat the cause.
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Anaesthetic implications
ad ote
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• No elective surgery if Na+ <120mmol/L or symptomatic

hm N

hyponatraemia.
fo r P ale A am

• Emergency surgery: consider risk to benefits. Consult an

ot o S an x
N ot f or sh a E

endocrinologist.
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180 Chapter 8 Endocrine and metabolic disease

Hypernatraemia
Defined as serum Na+ >145mmol/L.

• Mild 145–150mmol/L
• Moderate 151–160mmol/L
• Severe >160mmol/L

Caused by excessive salt intake or, more frequently, inadequate water

intake. Important to assess the volume status.
Causes
Hypovolaemic
• Renal—loop/osmotic diuretics, intrinsic renal disease, post-obstruction
• Extrarenal—diarrhoea/vomiting, burns, excessive sweating, fistulae.
Euvolaemic
• Diabetes insipidus, insensible losses.
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Hypervolaemic
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• Na+ ingestion/administration of hypertonic saline, Conn’s syndrome,

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Cushing’s syndrome.
fo r P ale A am

Presentation
ot o S an x
N ot f or sh a E

CNS symptoms likely if serum Na+ >155mmol/L due to hyperosmolar

n
N ot f ee esi

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state and cellular dehydration, e.g. thirst, confusion, seizures, and coma.
N . Z th

bu

Features depend on the cause, e.g. water deficiency will present with hypo-
D nes

tri
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tension, tachycardia, and decreased skin turgor.

r R rin
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Management
Correct over at least 48hr to prevent occurrence of cerebral oedema and
convulsions. Treat the underlying cause. Give oral fluids (water), if possible.
• Hypovolaemic (Na+ deficiency): 0.9% NaCl until hypovolaemia
corrected, then consider 0.45% saline.
• Euvolaemia (water depletion): estimate the total body water (TBW)
deficit; treat with 5% glucose.
• Hypervolaemic (Na+ excess): diuretics, e.g. furosemide (20mg IV) and
5% glucose; dialysis if required.
• Diabetes insipidus—replace urinary losses, and give desmopressin (1–4
micrograms daily SC/IM/IV).
Anaesthetic implications
• No elective surgery if Na+ >155mmol/L or hypovolaemic.
• Urgent surgery—use CVP monitoring if the volume status is uncertain
or may change rapidly intraoperatively, and be aware of dangers of
rapid normalization of electrolytes.
Hypernatraemia 181

Further reading
Bagshaw SM, Townsend DR, McDermid RC (2009). Disorders of sodium and water balance in hos-
pitalized patients. Can J Anaesth, 56, 151–67.
Kaye AD, Kucera IJ (2005). Sodium physiology (in Chapter 46, Intravascular fluid and electrolyte
physiology). In: Miller RD, ed. Anesthesia, 6th edn. Philadelphia: Churchill Livingstone, pp. 1764–8.

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tio tth
n a
A
D nes
r
Pete Ford
N . Z th
N ot f ee esi
Thyroidectomy 574
Chapter 23

N ot f or sh a E
Parathyroidectomy 578
ot o S an x
Phaeochromocytoma 580
fo r P ale A am
r R rin hm N
ed t ad ote
is C s
tri ha
bu
tio tth
n a
Endocrine surgery
573
574 Chapter 23 Endocrine surgery

Thyroidectomy

Procedure Removal of all or part of the thyroid gland

Time 1–2hr, depending on complexity
Pain +/++
Position Bolster between shoulders with head ring.
Head-up tilt
Blood loss Usually minimal. Potentially major if retroster-
nal extension
Practical techniques IPPV + reinforced ETT

General considerations
(See also E p. 157.)
• Complexity can vary from removal of a thyroid nodule to removal of a
long-standing retrosternal goitre to relieve tracheal compression.
a
tth
C s

• Retrosternal goitre is usually excised through a standard incision, but

ad ote
ha

occasionally a sternal split is required.

hm N

• Recurrent laryngeal nerves and parathyroid glands may be damaged or

fo r P ale A am

removed.
ot o S an x

• Straightforward unilateral surgery can be performed under superficial

N ot f or sh a E

and deep cervical plexus block, but GA is usual (see E p. 1106).

n
N ot f ee esi

tio
N . Z th

Preoperative
bu
D nes

tri
ed t

• Ensure that the patient is as near euthyroid as possible (see E p. 157).

r R rin
is
A

• Check for complications associated with hyperthyroidism: AF,

r

tachycardia, proptosis.
• Acute preparation of thyrotoxic patients involves iodine and
corticosteroids—both inhibit the conversion of T4 to T3 and narrow the
window (7–10d) for surgery, necessitating joint management with the
surgeon and endocrinologist.
• Check biopsy histology for malignancy.
• Ask about duration of goitre. Long-standing compression of the trachea
may be associated with tracheomalacia.
• Ask about positional breathlessness. Assess the airway.
• Examine the neck. How big is the goitre? Consistency?—malignant
goitres are hard. Can you feel below the gland (retrosternal spread)? Is
there evidence of tracheal deviation (check the radiograph)?
• Look for signs of SVC obstruction—distended neck veins that do not
vary with the respiratory cycle.
• Listen for stridor.
• Check the range of neck movements preoperatively, and do not extend
them outside of their normal range during surgery.
• Preoperative paracetamol/NSAIDs (PO or PR) help post-operative pain
control.
Thyroidectomy 575

Investigations
• FBC, U&Es, Ca2+, and thyroid function tests are routine.
• Chest radiograph. Check for tracheal deviation and narrowing. Thoracic
inlet views may be necessary if retrosternal extension is suspected,
and to detect tracheal compression in the anterior–posterior plane
(retrosternal enlargement may be asymptomatic).
• CT scan accurately delineates the site and degree of airway
encroachment or intraluminal spread. Advisable if there are symptoms
of narrowing (e.g. stridor, positional breathlessness) or >50% narrowing
on the radiograph. Plain radiographs overestimate diameters, due to
magnification effects, and cannot be relied on when predicting ETT
diameter and length. Furthermore, a CT scan will help assess the degree
of retrosternal extension.
• ENT consultation to document cord function for medico-legal
purposes is not routine in all units, unless an abnormality is likely, e.g.
previous surgery and malignancy. Pre-existing cord dysfunction may be
asymptomatic. Fibreoptic examination also defines any possible laryngeal
displacement (useful in airway planning).
a

Airway planning
tth
C s
ad ote

• The majority of cases are straightforward, even when there is some

ha
hm N

tracheal deviation or compression. A reinforced ETT will negotiate

fo r P ale A am

most distorted tracheas and permit optimal head positioning. Tracheal

compression by a benign goitre will often accommodate an ETT
ot o S an x
N ot f or sh a E

beyond the predicted size, as the gland is soft. Preoxygenation should

n
N ot f ee esi

be followed by IV induction and a neuromuscular-blocking drug (after

tio
N . Z th

checking that the lungs can be inflated manually).

bu
D nes

• The following features should lead to a more considered approach and

tri
ed t
r R rin
is

may require discussion with the surgeon and radiologist:

A
r

• Malignancy. Cord palsies are likely. Distortion and rigidity of

surrounding structures. Possibility of intraluminal spread. The larynx
may be displaced. The tumour can produce obstruction anywhere
from the glottis to the carina
• Significant respiratory symptoms or >50% narrowing on chest
radiograph or lateral thoracic inlet view
• Coexisting predictors of difficult intubation.

Options to secure the airway for complicated

thyroid surgery
• Teamwork between the anaesthetist and surgeon is the key to successful
and safe airway management.
• Inhalational induction with sevoflurane or halothane in patients with
stridor and a suspected difficult upper airway. Stridor and decreased
minute ventilation delay the onset of sufficiently deep anaesthesia for
intubation. Topical LA may be useful.
• Fibreoptic intubation (see E p. 969). Attempts to pass a fibreoptic
bronchoscope in an awake patient with stridor are difficult, as the
narrowed airway may become obstructed by the instrument. May be
useful where there is marked displacement of the larynx or coexisting
difficulties with intubation, e.g. ankylosing spondylitis.
576 Chapter 23 Endocrine surgery

• LMA may be difficult to place in patients with laryngeal displacement.

• Tracheostomy under LA. This will only be possible if the tracheostomy
can be easily performed below the level of obstruction.
• Ventilation through a rigid bronchoscope is a backup option when
attempts to pass an ETT fail. The surgeon and necessary equipment
should be immediately available for complex cases, particularly those
involving significant mid- to lower tracheal narrowing.
• ‘Plan C’ of the difficult airway algorithm (perform a cricothyroid
puncture) may not be an option.
Perioperative
• Eye padding, lubrication, and tape are important, especially if the patient
has exophthalmos.
• Full relaxation is required to accommodate tube movements. LA spray
on the ETT reduces the stimulation produced by tracheal manipulation
during surgery.
• Electrophysiological monitoring of the recurrent laryngeal nerves is now
possible intraoperatively, using specialized reinforced ETTs.
• Securely fix the ETT with tape, avoiding ties around the neck. Access to
a

check the tube is difficult during the procedure.

tth
C s
ad ote

• Head and neck extension with slight head-up tilt.

ha

• Consider a superficial cervical plexus block for post-operative analgesia.

hm N

Some surgeons infiltrate SC with LA and adrenaline before starting. LA

fo r P ale A am

at the end can produce spurious nerve palsies (see E p. 1106).

ot o S an x
N ot f or sh a E

• Arms to sides, IV extension.

n
N ot f ee esi

• Communicate with the surgeon if there are excessive airway pressures

tio

during manipulation of the trachea. Obstruction may be due to airway

N . Z th

bu
D nes

manipulation distal to the tube or the bevel of the tube abutting on the
tri
ed t
r R rin
is

trachea.
A
r

• Monitor muscle relaxation on the leg.

• In cases of long-standing goitre, some surgeons like to feel the
trachea before closing to assess tracheomalacia. They may ask for
partial withdrawal of the ETT, so that the tip is just proximal to the
operative site.
• At the end of surgery, reverse the muscle relaxant, and extubate with
the patient sitting up to reduce venous compression. Use an extubation
technique that minimizes coughing to reduce early 2° haemorrhage.
Any respiratory difficulty should lead to immediate reintubation. The
traditional practice of inspecting the cords immediately following
extubation is difficult and unreliable. Possible cord dysfunction and
post-operative tracheomalacia are better assessed with the patient
awake and sitting up in the recovery room.
Post-operative
• Intermittent opioids with oral/rectal paracetamol and NSAIDs.
• The opioid requirement is reduced with SC infiltration and superficial
cervical plexus blocks.
• Use fibreoptic nasendoscopy if there is doubt about recurrent laryngeal
nerve injury.
Thyroidectomy 577

Post-operative stridor
• Haemorrhage with tense swelling of the neck. Remove clips from the
skin, and sutures from the platysma/strap muscles to remove the clot. In
extremis, this should be done at the bedside. Otherwise return to theatre
without delay. A haematoma will affect lymphatic and venous drainage of
the upper airway, causing laryngeal and pharyngeal oedema. Removing
the haematoma will not always restore airway patency immediately.
• Tracheomalacia. Long-standing large goitres may cause tracheal collapse.
This is a very rare complication. Immediate reintubation, followed by
tracheostomy, may be necessary.
• Bilateral recurrent laryngeal nerve palsies. This may present with
respiratory difficulty immediately post-operatively or after a variable
period. Stridor may only occur when the patient becomes agitated.
Assess by fibreoptic nasendoscopy. May require tracheostomy.
Other post-operative complications
Hypocalcaemia
• Hypocalcaemia from parathyroid removal is rare. Serum Ca2+ should be
checked at 24hr, and again daily if low.
a
tth

• Presentation—may present with signs of neuromuscular excitability,

C s
ad ote
ha

tingling around the mouth, or tetany. May progress to fits or ventricular

hm N

arrhythmias.
fo r P ale A am

• Diagnosis—carpopedal spasm (flexed wrists, fingers drawn together)

ot o S an x

may be precipitated by cuff inflation (Trousseau’s sign). Tapping over the

N ot f or sh a E

facial nerve at the parotid may cause facial twitching (Chvostek’s sign).
n
N ot f ee esi

tio

Prolonged QT interval on ECG.

N . Z th

bu

• Treatment: serum Ca2+ below 2mmol/L should be treated urgently with

D nes

tri
ed t

10mL of 10% calcium gluconate over 3min plus alfacalcidol 1–5g orally
r R rin
is
A

(calcium gluconate is preferable, as calcium chloride will cause tissue

r

necrosis if extravasation occurs). Check the level after 4hr, and consider
Ca2+ infusion if still low. If hypocalcaemic, but level above 2mmol/L,
treat with oral Ca2+ supplements (see also E p. 161).
Thyroid crisis
• This is rare, as hyperthyroidism is usually controlled beforehand with
antithyroid drugs and β-blockers. May be triggered in uncontrolled or
undiagnosed cases by surgery or infection.
• Diagnosis: increasing HR and temperature. May be difficult to
distinguish from MH. Higher mixed venous PvCO2 and higher creatinine
phosphokinase in MH.
• Treatment: see E p. 158.
Pneumothorax
Pneumothorax is possible if there has been retrosternal dissection.
Further reading
Cook TM, Morgan PJ, Hersch PE (2011). Equal and opposite expert opinion. Airway obstruction
caused by a retrosternal thyroid mass: management and prospective international expert opinion.
Anaesthesia, 66, 828–36.
Dempsey GA, Snell JA, Coathup R, Jones TM (2013). Anaesthesia for massive retrosternal thyroid-
ectomy in a tertiary referral centre. Br J Anaesth, 111, 594–9.
Farling PA (2000). Thyroid disease. Br J Anaesth, 85, 15–28.
578 Chapter 23 Endocrine surgery

Parathyroidectomy
Procedure Removal of solitary adenoma or four glands
for hyperplasia
Time 1–3hr
Pain +/++
Position Bolster between shoulders with head ring.
Head-up tilt
Blood loss Usually minimal
Practical techniques IPPV + ETT

General considerations
(See also E p. 160.)
• Usual indication for operation is 1° hyperparathyroidism from
parathyroid adenoma.
a
tth
C s

• With preoperative localization, removal of simple adenoma has been

ad ote
ha

described using sedation and LA. GA is more usual.

hm N

• Carcinoma may require en bloc dissection.

fo r P ale A am

• Total parathyroidectomy may also be performed in 2°

ot o S an x

hyperparathyroidism associated with CRF.

N ot f or sh a E

• Hypercalcaemia may produce significant debility, particularly in the

n
N ot f ee esi

tio

elderly.
N . Z th

bu
D nes

tri

Preoperative
ed t
r R rin
is
A

Hypercalcaemia is usual. With moderate elevation, ensure adequate hydra-

r

tion with 0.9% NaCl. Levels over 3mmol/L should be corrected before
surgery, as follows:
• Urinary catheter.
• One litre of 0.9% NaCl in the 1st hour, then 4–6L over 24hr.
• Pamidronate 60mg in 500mL of saline over 4hr.
• Watch for fluid overload. CVP measurement may be necessary in some
patients. Monitor electrolytes, including Mg2+, phosphate, and K+.
Severe hypercalcaemia may occasionally necessitate emergency surgery. It
may cause arrhythmias and may antagonize the effects of NDMRs.
• Preoperative imaging using ultrasound and technetium-99m sestamibi
scanning may be used to localize parathyroid adenomas, allowing a
minimal access or targeted approach with a 2cm incision over the
suspected gland.
• 2° hyperparathyroidism occurs 2° to low serum Ca2+ in CRF. In this
situation:
• Total parathyroidectomy may be required. Control afterwards is
easier if no functioning parathyroid tissue is left
• Dialysis will be required preoperatively
• The risk of bleeding is increased
• Alfacalcidol is usually started preoperatively
Parathyroidectomy 579

• 1° hyperparathyroidism has been associated with an increased risk of

death from CVS disease, hypertension, LV hypertrophy, valvular and
myocardial calcifications, impaired vascular reactivity, alterations in
cardiac conduction, impaired glucose metabolism, and dyslipidaemia.
PTH has serious consequences on cardiac function in renal failure
• A less utilized technique these days is to use methylthioninium chloride
(methylene blue) to highlight the parathyroid glands. Most useful in
four-gland hyperplasia; parathyroids are highly vascular and take up
the dye faster than surrounding tissues. If given too early, however, the
effect is lost, as the surrounding tissue colours. The usual dose is 5mg/
kg, diluted in 500mL, given over 1hr prior to surgery. Complications of
methylthioninium chloride (methylene blue) use include restlessness,
paraesthesiae, burning sensation, chest pain, dizziness, headache, and
mental confusion. Pulse oximetry will not be accurate if the infusion is
too fast.
Perioperative
• Similar anaesthetic considerations as for thyroid surgery, using either a
reinforced ETT or LMA.
a

• Airway encroachment is not usually a problem.

tth
C s
ad ote

• Operation times may be unpredictable, especially if frozen section or

ha

parathyroid assays are performed.

hm N

• Consider active heat conservation.

fo r P ale A am

• Point-of-care PTH assays are available, making intraoperative

ot o S an x
N ot f or sh a E

measurement of PTH possible in minimally invasive or targeted surgery,

n
N ot f ee esi

thereby allowing a rapid assessment of success intraoperatively.

tio

• Extubation requires a cough-free technique, reducing the incidence of

N . Z th

bu
D nes

early 2° haemorrhage.
tri
ed t
r R rin
is
A

Post-operative
r

• Serum Ca2+ checked at 6hr and 24hr. Hypocalcaemia may occur (for
diagnosis and treatment, see Thyroidectomy, E p. 574 and also
E p. 577). Continuation of alfacalcidol in 2° hyperparathyroidism
lessens the chance of hypocalcaemia post-operatively.
• Perform fibreoptic nasendoscopy if recurrent laryngeal nerve damage is
suspected.
• Pain not usually severe, especially with LA infiltration or superficial
cervical plexus blocks. Rectal paracetamol is useful. Avoid NSAIDs in
patients with poor renal function.
Further reading
Mihai R, Farndon JR (2000). Parathyroid disease and calcium metabolism. Br J Anaesth, 85, 29–43.
580 Chapter 23 Endocrine surgery

Phaeochromocytoma
Procedure Removal of one or two adrenals or
extra-adrenal tumour
Time 1–2hr open, possibly longer if laparoscopic
Pain +/++ (depending if open or laparoscopic)
Position Lateral or supine for open, lateral for
laparoscopic
Blood loss Variable
Practical techniques IPPV + ETT, art and CVP lines, ± cardiac
output monitor

• Tumours of chromaffin cells secreting noradrenaline (commonest),

adrenaline, or dopamine (least common). May secrete >1 amine.
• May secrete other substances, e.g. VIP, ACTH.
a

• Ninety-nine per cent occur in adrenals; 10% bilateral; may be anywhere

tth
C s
ad ote

along the sympathetic chain from the base of the skull to the pelvis.
ha

• Most are benign; a few are malignant.

hm N
fo r P ale A am

• Occur in all age groups, less commonly in children.

• Can occur in association with MEN2A (medullary thyroid carcinoma,
ot o S an x
N ot f or sh a E

parathyroid adenomas) and MEN2B (medullary thyroid carcinoma and

n
N ot f ee esi

marfanoid features). Both have abnormalities of the RET oncogene on

tio

chromosome 10 (see E p. 577).

N . Z th

bu
D nes

• Also found in patients with neurofibromatosis and von Hippel–Lindau

tri
ed t
r R rin
is

syndrome (see E p. 308).

A
r

Presentation
• Hypertension can be constant, intermittent, or insignificant.
• Association of palpitations, sweating, and headache with hypertension
has a high predictive value.
• Anxiety, nausea and vomiting, weakness, and lethargy are also common
features.
• Acute presentations include pulmonary oedema, MI, and
cerebrovascular episodes.
• Can present perioperatively. Unless the diagnosis is considered and
appropriate treatment instituted, the mortality rate is high—up to 50%.
Diagnosis
• Clinical suspicion.
• With increased genetic testing of families, more patients are being
diagnosed before they become symptomatic.
• Urinary catecholamines or their metabolites (metadrenaline and
normetadrenaline) measured either over 24hr or overnight.
• CT radiocontrast may provoke phaeo crises, and its use must be
avoided in unblocked patients. Modern contrast agents may be used.
Phaeochromocytoma 581

• MIBG (meta-iodobenzylguanidine) scan—a radiolabelled isotope of

iodine taken up by chromaffin tissue.
• MRI.
• Search in the abdomen first, and widen the search if tumour not
located. MIBG is particularly helpful in revealing unusual sites.
Investigations relevant to anaesthesia
• Echocardiography—patients with a history of ischaemia or signs of
heart failure require a cardiac echocardiography. Rarely, patients can
present with a catecholamine cardiomyopathy.
• Blood glucose—excess catecholamines result in glycogenolysis and
insulin resistance; some patients become frankly diabetic.
Preoperative
• Refer the patient to an experienced team. It is not acceptable to manage
on an occasional basis.
• Usual management is sympathetic blockade with first α- and then
β-blocker, if required, for tachycardia (phenoxybenzamine—a
non-competitive, non-selective α-blocker and then atenolol/
a

propranolol/metoprolol).
tth
C s

• Phenoxybenzamine causes postural hypotension, lethargy, and nasal

ad ote
ha

congestion.
hm N

• Whereas α-blockade is generally considered a necessity, the use of

fo r P ale A am

β-blockade is more controversial, and some anaesthetists will actively

ot o S an x
N ot f or sh a E

avoid them at the time of surgery.

n

• Preoperative blockade:
N ot f ee esi

tio

• Allows safe anaesthesia for the removal of the tumour

N . Z th

bu

• Prevents hypertensive response to induction of anaesthesia

D nes

tri
ed t
r R rin

• Limits surges in BP seen during tumour handling.

is
A

• Avoid unopposed β-blockade—theoretical risk of increasing

r

vasoconstriction and precipitating a crisis. Although this has been

reported, many patients will already have received β-blockers for
hypertension before presentation, without adverse effects.
• Prazosin and doxazosin have been used. These are competitive,
selective α1-blockers. They do not inhibit presynaptic noradrenaline
reuptake and thus avoid the tachycardia seen with non-selective
α-blockade. The literature contains reports both in favour and against
the use of selective blockade.
• Calcium channel blockers (particularly nicardipine) have been used. This
inhibits noradrenaline-mediated Ca2+ influx into smooth muscle but
does not affect catecholamine secretion by the tumour.
• Metirosine is an inhibitor of catecholamine synthesis. It is toxic and not
widely used.
• There are no absolute criteria for fitness for surgery.
Assessment of sympathetic blockade
• Patients will often be admitted a few days prior to surgery to observe
BP control and/or have had outpatient 24hr ambulatory BP monitoring.
• Aim for BP <140/90, with HR <100bpm.
582 Chapter 23 Endocrine surgery

• Erect and supine BP and HR. Should exhibit a marked postural drop
>20mmHg, with a compensatory tachycardia.
• The duration of blockade is determined by the practicalities of tumour
localization and scheduling of surgery.
• Blockade is started to treat symptoms, as well as to prepare for surgery.
Perioperative
• Laparoscopic or open adrenalectomy through a midline, transverse, or
flank incision (introduction of gas for laparoscopic resection can result in
hypertension in normal subjects, and this may be exaggerated in patients
with phaeochromocytomas).
• Premedication, as required (e.g. temazepam 20–30mg).
• Monitoring to include direct BP and CVP (triple lumen to allow drug
infusions). Consider cardiac output monitoring in patients with CVS
disease and catecholamine cardiomyopathy.
• Large-bore IV access.
• Monitor and maintain temperature, particularly during laparoscopic
resection which can be prolonged.
• Induction: avoid agents that release histamine, and thus catecholamines
a

(use propofol, alfentanil or remifentanil, and vecuronium or

tth
C s
ad ote

rocuronium).
ha

• Hypotension is unlikely at induction and can be treated with either

hm N

ephedrine, metaraminol, or phenylephrine. Due to preoperative

fo r P ale A am

α-blockade, doses will likely need to be increased. Rarely, dilute

ot o S an x
N ot f or sh a E

adrenaline may be required.

n
N ot f ee esi

• Maintenance: use isoflurane or sevoflurane. Desflurane should be

tio

avoided, as it can cause sympathetic nervous system activation.

N . Z th

bu
D nes

• Consider epidural with opioid and LA for open procedures (sympathetic

tri
ed t
r R rin
is

blockade will not prevent catecholamine-induced vasoconstriction);

A
r

otherwise fentanyl/alfentanil/remifentanil until tumour removal, when

morphine (10–20mg) can be substituted.
• Nicardipine and Mg2+ are also useful (block catecholamine release,
block receptors, provide direct vasodilator, and possibly myocardial
protection).
• Mg2+ is started prior to induction, given as a bolus of 2–4g, and then
continued at a rate of 1–2g/hr. It is normal for the patient to feel
nauseated with the Mg2+ bolus.
• Surges in BP can occur at induction, formation of the
pneumoperitoneum, and with tumour handling. The fluctuations in
BP tend to be transient, and medication needs to respond in a similar
fashion. Hypertension can be treated in a number of ways: intermittent
2g boluses of Mg2+, boluses of remifentanil, phentolamine, sodium
nitroprusside, or labetalol (if associated with a tachycardia).
• Control HR at <100bpm with the β-blocker of choice.
• Once the tumour is resected, BP takes several minutes to decline.
Prevent hypotension by ensuring an adequate preload. Maintain a high
CVP of 10–15mmHg. Several litres of a crystalloid may be needed.
• Hypotension following resection can be due to low cardiac output or
a low SVR. Treat the former with low-dose adrenaline, and the latter
with metaraminol or phenylephrine. Vasopressin has been used in
Phaeochromocytoma 583

resistant hypotension. Terlipressin 1mg bolus, followed, if required, by

vasopressin, starting at 0.04U/min, then titrated to effect.
• It is unusual to require inotropic support by the time the patient is ready
to leave theatre, unless there are coexisting medical problems.
Post-operative
• Patient should be nursed in ICU/HDU for 12hr.
• Monitor blood glucose. The withdrawal of catecholamine excess can
lead to severe hypoglycaemia.
• If both adrenals are resected, the patient will require steroid support
immediately. Hydrocortisone 100mg bolus in theatre, decreasing to
maintenance dose after surgical stress. Fludrocortisone 0.1mg daily may
be commenced with oral intake.
• Even when only one adrenal is removed, patients may occasionally be
relatively hypoadrenal and require support. If this is suspected (e.g.
unexpectedly low BP), a small dose of hydrocortisone (50mg) will do
no harm, while the result of cortisol estimation is awaited.
Special considerations
a

Pregnancy
tth
C s
ad ote

• There are many reports of the combination of a newly diagnosed

ha

phaeochromocytoma and pregnancy. Overall mortality is up to 17%.

hm N

• Phenoxybenzamine and metoprolol are safe.

fo r P ale A am

• If phaeochromocytoma is diagnosed before mid trimester, it should be

ot o S an x
N ot f or sh a E

resected at this stage.

n

• There is a high mortality associated with normal delivery; consider

N ot f ee esi

tio

lower-segment Caesarean section (LSCS), with or without resection of

N . Z th

bu
D nes

the phaeochromocytoma, at the same procedure.

tri
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is
A

Management of an unexpected phaeochromocytoma

r

• Any patient who has unexplained pulmonary oedema, hypertension,

or severe unexpected hypotension should prompt consideration of the
diagnosis; however, it can be very difficult. There is no quick available
test to support the diagnosis in the acute situation.
• Once the diagnosis has been considered, if possible, surgery should be
discontinued to allow acute treatment, investigation, and blockade prior
to definitive surgery. Attempts to remove the tumour during a crisis may
result in significant morbidity, or even mortality.
• Treatment acutely should consist of vasodilators and IV fluid; this
may be counterintuitive in a patient with severe pulmonary oedema.
The circulating volume in patients with phaeochromocytoma may be
markedly reduced, and vasodilatation will result in a profound drop in
BP. GTN can usually be successfully titrated in this situation.
• Patients who present with hypotension have an acutely failing heart due
to profound vasoconstriction. These are the most difficult patients in
whom to make the diagnosis and to treat. Additional catecholamines in
this situation merely fuel the fire but are difficult to resist. The mortality
rate is very high.
584 Chapter 23 Endocrine surgery

Further reading
James MFM (2010). Adrenal medulla: the anaesthetic management of phaeochromocytoma.
In: James MFM, ed. Anaesthesia for patients with endocrine disease. Oxford: Oxford University
Press, pp. 149–69.
O’Riordan JA (1997). Pheochromocytomas and anesthesia. Int Anesthesiol Clin, 35, 99–127.
Prys-Roberts C (2000). Phaeochromocytoma—recent progress in its management. Br J Anaesth,
85, 44–57.
Subramaniam R (2011). Phaeochromocytomas—current concepts in diagnosis and management.
Trends Anaesth Crit Care, 1, 104–10.

a
tth
C s
ad ote
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fo r P ale A am
ot o S an x
N ot f or sh a E

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N ot f ee esi

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N . Z th

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THE ADRENAL GLANDS

ANAESTHESIA TUTORIAL OF THE WEEK 216
7th MARCH 2011
Dr Christopher Haley
Salford Royal NHS Foundation Trust
Dr Carl Gwinnutt
Salford Royal NHS Foundation Trust
Correspondence: [email protected]

QUESTIONS
Before reading the tutorial answer the following true/false questions:

Q1.

a
a. The adrenal glands consist of an inner medulla and outer cortex.

tth
b. The medulla produces mainly catecholamines. C s
ad ote
c. The cortex produces mainly catecholamines. ha
d. The zona glomerulosa produces aldosterone.
hm N

e. The zona fasciculata produces androgens.

fo r P ale A am

Q2.
ot o S an x
N ot f or sh a E

a. Tyrosine is the precursor for catecholamines.

b. Epinephrine is the precursor of norepinephrine.
n
N ot f ee esi

tio

c. Aldosterone causes sodium and water retention.

d.
N r. Z th

Cortisol inhibits gluconeogenesis.

bu
D es

e. The zona reticularis produces sex hormones.

tri
ed t
r R rin
An

is

Q3. Phaeochromocytoma:
a. Arises from the adrenal medulla.
b. Is bilateral in 10% of patients.
c. Causes paroxysms of hypotension.
d. May present initially with symptoms of myocardial ischemia.
e. Can be diagnosed by measuring plasma norepinephrine.
Q4. Cushing‟s disease:
a. Is caused by an adrenal adenoma.
b. Causes progressive weight loss.
c. May cause amenorrhea.
d. May present with symptoms of diabetes mellitus.
e. Is diagnosed using a dexamethasone suppression test.
Q5. Addison‟s disease:
a. Is due to failure of the adrenal medulla.
b. Is associated with increased pigmentation.
c. Causes progressive weight loss.
d. Causes low plasma ACTH levels.
e. Will require treatment with increased steroids peri-operatively.

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INTRODUCTION
Homeostasis or maintenance of the body‟s internal environment is a complex process of interconnected
pathways and feedback loops. One of the major links in a number of these pathways is the adrenal
gland. The adrenals compared to the body as a whole are small but they produce some major hormones
and as such, medical conditions arising from them often have profound effects on the body.
Knowledge of these conditions, an understanding of their role and subsequent pathology is vital to the
treatment of patients undergoing surgery.

ANATOMY OF THE ADRENAL GLANDS

Relations
The adrenal glands (figure 1) are an important organ but often
overlooked as a single entity due, most likely, to their size and position
in the body. They are located behind the abdominal cavity and
peritoneum in the retroperitoneal space, one on the superior pole of each
kidney hence they are often referred to as the “suprarenal glands”. They
are surrounded by renal fascia and adipose tissue and are obedient
factories producing essential hormones for the body.

a
tth
Blood Supply C s
ad ote
The arterial blood supply to each adrenal gland is via three adrenal
ha
arteries:
hm N

The superior suprarenal artery, a branch of the inferior phrenic artery

The middle suprarenal artery, a branch of the aorta
fo r P ale A am

The inferior suprarenal artery, a branch of the renal artery.

Figure 1. The Adrenal gland
ot o S an x
N ot f or sh a E

The venous drainage of the adrenal glands is via the suprarenal veins (Reproduced with permission
which drain into different main veins on each side: from the Internet Encyclopedia
n
N ot f ee esi

the right into the inferior vena cava of Science)

tio

the left into either the left renal or left inferior phrenic vein.
N r. Z th

bu
D es

tri

Nerve supply
ed t
r R rin
An

As an organ of hormone production the adrenals have a rich nerve supply. Branches from the coeliac
is

plexus and the thoracic splanchnic nerves supply the chromaffin cells of the medulla (see below).

Functional anatomy
The adrenal gland can be divided into two very distinct zones, each of which produces specific
hormones:
The inner part of the adrenal or medulla produces and secretes amine hormones, adrenaline
(epinephrine) and noradrenaline (norepinephrine). The medulla is essentially a sympathetic
ganglion where the postganglionic cells have become secretory cells named chromaffin cells (also
called phaeochromocytes – see below).
The outer part of the adrenal gland or cortex makes up the majority of the gland. Three main types
of hormones are secreted; mineralocorticoids, glucocorticoids, and androgens. Each is produced in
a different part of the cortex
the outer zona glomerulosa producing mainly the mineralocorticoid aldosterone
the middle zona faciculata producing glucocorticoids eg cortisol
the innermost layer the zona reticulosa producing androgens.
These zones are remembered as G.F.R. and as they sit on top of the kidneys, this is a handy aide
memoire.

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BIOCHEMISTRY AND PHYSIOLOGY OF THE ADRENAL HORMONES

Medullary hormones
Amines : adrenaline (epinephrine), noradrenaline (norepinephrine), dopamine
Others: acetylcholine, metenkephalin, chromogranin A
The amines are produced from phenylalanine or tyrosine and are often referred to as “catecholamines”
which reflects their structure; they contain a catechol (a benzene ring with hydroxyl groups at positions
1 and 2, or 1,2 dihydroxybenzene and an amine side chain). The synthesis of these hormones is shown
in figure 2.

a
tth
C s
ad ote
ha
hm N
fo r P ale A am
ot o S an x
N ot f or sh a E

Figure 2: Catecholamine synthesis

n
N ot f ee esi

tio

Both adrenaline and noradrenaline have different degrees of action on adrenergic receptors (termed
alpha and beta adrenoreceptors), both essentially part of the bodies primeval „fight or flight‟ stress
N r. Z th

bu

response with actions mainly on the cardiovascular and respiratory system; increased alertness,
D es

tri
ed t

dilatation of the bronchioles, increased heart rate and contractility and changes in metabolism to favour
r R rin
An

is

release of energy.

Alpha(α) adrenoreceptors
These are subdivided into:
α 1 - responsible for vascular smooth muscle contraction, i.e. control of the degree of vasoconstriction
in the skin, gut and kidneys. Stimulated glycogenolysis and gluconeogenesis. Relaxes the pregnant
uterus.
α 2 - responsible for platelet activation (increased adhesiveness) and synaptic transmission. Inhibits
insulin release, stimulates glucagon release.

Beta(β) adrenoreceptors
These are subdivided into:
β 1 - increases the rate (positively chronotropic) and force of contraction (positively inotropic) of the
heart. Increases renin secretion.
β 2 – smooth muscle relaxation i.e. dilatation of bronchioles and blood vessels in skeletal muscle.
Stimulated glycogenolysis and gluconeogenesis. Increases insulin secretion from beta cells of the
pancreas. Increases renin secretion.

Dopamine is mainly a neurotransmitter and does not cross the blood brain barrier. As such it is
produced and has its effects locally. Exogenous dopamine is, however, used in clinical practice as it is
an agonist to peripheral dopamine (D), β and α receptors. The effects are dose related; initially only
dopamine receptors are stimulated followed by action upon β and then α adrenoreceptors. Dopamine
receptors are located in renal arterioles and their stimulation causes renal vasodilatation. It has been
used in low dose infusions to maintain renal perfusion if compromised in clinical states although its
efficacy is questionable.

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Cortical hormones

All the adrenal cortical hormones are produced from the common precursor cholesterol.

Zona glomerulosa
This region of the adrenal cortex produces aldosterone, a mineralocorticoid. Its release is the end point
of the renin-angiotensin-aldosterone system. This system plays an important role in regulating blood
volume and systemic vascular resistance, which together influence cardiac output and blood pressure.
The main action of aldosterone is to retain sodium in the kidneys (in exchange for potassium) which in
turn causes fluid retention. Aldosterone can be released by the renin-angiotensin system, but also by
ACTH, following physiological stress or trauma, hyperkalemia and directly by hyponatraemia.

Zona faciculata
This region of the cortex produces cortisol. Its main action is
on gluconeogenesis and as such, it is termed a glucocorticoid.
However, mineralocorticoid activity may be seen in
conditions associated with excess secretion (see below).
Cortisol has a major function in response to stress and
suppressing the immune system. It also maintains levels of
glucose in the blood by stimulating gluconeogenesis and

a
regulates the metabolism of proteins, carbohydrates, and fats.

tth
C s
Its release is under the control of the hypothalamic-pituitary
ad ote
ha
axis in response to the production of adrenal corticotrophic
hormone (ACTH). Cortisol has a diurnal variation with the
hm N

peak at 8am, is essential for life and has a multitude of

fo r P ale A am

actions.
Figure 3: Regulation of
ot o S an x

cortisol production
N ot f or sh a E

The synthetic production of cortisol and other corticosteroids is one of the major advancements in
N ot f ee esi

tio

medical science and had allowed us to suppress immunological and inflammatory processes. Steroids
N r. Z th

bu

are used to treat a plethora of ailments from asthma, dermatological conditions to allowing transplanted
D es

organs to survive.
tri
ed t
r R rin
An

is

Zona reticulosa
This region of the adrenal cortex and is named due to the reticular or net like appearance it has
microscopically and it produces dehydroepiandrosterone (DHEA), and androstenedione. These are
weak androgenic (sex) hormones but are converted into the more potent testosterone and oestrogens in
the testes and ovaries respectively. The release of these hormones is controlled by ACTH and they are
responsible for protein anabolism and growth.

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MEDICAL CONDITIONS ASSOCIATED WITH ABNORMALITIES OF THE

ADRENAL GLAND

Hormone Syndrome Features

Catecholamines phaeochromocytoma Hypertension, Flushing, abdominal cramps,
palpitations headaches.

Glucocorticoid Cushing’s syndrome Buffalo hump, Moon face, truncal obesity,

excess abdominal striae, muscle weakness and wasting,
hypertension, diabetes mellitus, hypokalaemia and
metabolic alkalosis.
+
Adrenocortical Addison’s disease Skin pigmentation, Na depletion, fatigue, lethargy
insufficiency muscle weakness, low mood (mild depression) or
irritability, loss of appetite and unintentional weight
loss, hypotension.
+ +
Mineralocorticoid Conn’s syndrome K depletion, Na retention, polyuria and
excess hypokalaemic alkalosis, hypertension, tetany and
weakness.

a
tth
Adrenal adrenogenital In female: hirsutism, acne, oligomenorrhea &
C s
ad ote
androgen syndrome virilisation.
ha
excess adrenal
hm N

congenital In male: precocious puberty

hyperplasia
fo r P ale A am
ot o S an x
N ot f or sh a E

Adrenal medulla - phaeochromocytoma

A phaeochromocytoma is a tumour that arises in the adrenal medulla and secretes catecholamines. In
n
N ot f ee esi

tio

1912 the German pathologist Pick coined the term "phaeochromocytoma" from the Greek 'phaios'
(dusky) and 'chromo' (colour). It is known as “the 10% tumour” because:
N r. Z th

bu

10% are bilateral

D es

tri
ed t

10% arise outside the adrenals

r R rin
An

is

10% are malignant

10% are familial

It has a wide range of symptoms depending on the catecholamine secretion:

Hypertension, often paroxysmal. Complications of this may be the first signs e.g. stroke,
myocardial infarction
Attacks of:
o Palpitations
o Pallor, flushing and sweating
o Tremor
o Headaches
o Anxiety
Abdominal pain, nausea and/or vomiting
Weight loss
Constipation or diarrhoea
Glucose intolerance

Diagnosis
24 hour urinary collection. Measuring the excretion of metanephrines (breakdown product) or free
catecholamines. Occasionally plasma norepinephrine (noradrenaline) is measured. Localisation is
usually by CT scanning.

Anaesthesia
Specialist anaesthetic considerations have to be observed in surgical removal of phaeochromocytomas
as handling these tumours can cause a surge of catecholamaine release, severe hypertension and end

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organ damage. Preoperatively patients are given a non-selective alpha antagonist (alpha 1 and 2)
traditionally phentolamine. Once alpha blockade is achieved then beta blockade is started to counter the
increase in cardiac output due to the alpha 2 blockade. A more selective approach using doxazosin
(alpha 1 blockade) has the benefit of not requiring the beta blockade. However, there is always the risk
that a large release of catecholamines from the tumour during surgery may overcome the block causing
increased instability. More details can be found at ANAESTHESIA TUTORIAL OF THE WEEK 151.

Adrenal cortex. Zona glomerulosa - primary hyperaldosteronism (Conn’s syndrome)

Primary hyperaldosteronism was first described by Conn in 1955. An overproduction of aldosterone
causes sodium retention which in turn leads to:
hypertension
headaches
muscle cramps, due to the low potassium (may be exacerbated by the treatment of the
“hypertension” with thiazide diuretics)
metabolic alkalosis, due to increased secretion of H+ ions by the kidney
The high pH of the blood makes calcium less available to the tissues and causes symptoms of
hypocalcaemia.

o Paraesthesia (usually fingers, toes and around mouth)

o Tetany
o

a
Carpopedal spasm (wrist flexion)

tth
o Muscle cramps C s
ad ote
ha
Note: liquorice (glycyrrhizin) ingestion can mimic the symptoms!
hm N
fo r P ale A am

Diagnosis
Persistent hypernatraemia, hypokalaemia and metabolic alkalosis in the absence of the use of diuretics
ot o S an x

therapy is very suggestive. Confirmation in many cases may be made by measuring plasma or urinary
N ot f or sh a E

aldosterone and renin levels and the ratio of these two hormones.
n
N ot f ee esi

tio

Adrenal cortex. Zona faciculata- Hypercortisolism (Cushing’s syndrome)

N r. Z th

Cushing‟s syndrome, first described by Harvey Cushing in 1932, is a collection of signs and symptoms
bu

associated with prolonged, raised levels of glucocorticoid in the blood. The cause may be endogenous
D es

tri
ed t

e.g. adrenal cortical adenoma or exogenous e.g. therapeutic use of prednisolone (non-ACTH
r R rin
An

is

dependent). Cushing‟s disease refers specifically to a state of high cortisol caused by an adenoma in the
pituitary gland which releases an excess of ACTH (80% cases) and more rarely an ACTH secreting
tumour e.g. small cell carcinoma of the bronchus (ACTH-dependent). The signs of the syndrome are
not unfamiliar to anyone who has seen patients on long-term steroids and
gives rise to the characteristic features: fat pads on the upper back (buffalo
hump) and face (moon face), weight gain centrally (centripetal obesity),
striae on the trunk, thin legs, and excess facial hair. Patients are often
described as a “lemon on matchsticks”. In addition long term cortisol
causes:

change of appearance
depression, psychosis
insomnia
amenorrhoea/oligomenorrhoea
poor libido
thin skin/easy bruising
hair growth/acne
muscular weakness
growth arrest in children
back pain
polyuria/polydipsia. Figure 4: Features of Cushing’s
syndrome.

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These signs can also be remembered by the mnemonic:

C - Central obesity, Cervical fat pads, Collagen fibre weakness, Comedones (acne)
U - Urinary free cortisol and glucose increase
S - Striae, Suppressed immunity
H - Hypercortisolism, Hypertension, Hyperglycaemia, Hirsutism
I - Iatrogenic (Increased administration of corticosteroids)
N – Non-iatrogenic (Neoplasms)
G - Glucose intolerance, Growth retardation

Diagnosis
Low-dose dexamethasone suppression test. Following the collection of baseline urine samples to
measure cortisol levels, dexamethasone 0.5mg is taken orally every six hours (precisely) for two days.
24-hour urine collections are performed on the second day of medication and the day after stopping
(day 3). Alternatively, plasma cortisol levels can be measured before and after treatment. In normal
patients, low-dose dexamethasone stops cortisol being produced and urine and plasma levels fall. In
Cushing‟s syndrome, production of cortisol is maintained and levels remain high confirming the
diagnosis.

Primary hypocortisolism (Addison's disease)

Thomas Addison first identified the disease in 1855. It is caused by a failure of the adrenal cortex due

a
to an autoimmune process, infection or surgery. Addison‟s disease is not usually apparent until over

tth
C s
90% of the adrenal cortex has been destroyed, so that very little adrenal capacity is left.
ad ote
Symptoms are those of:
ha
hm N

fatigue /lethargy
fo r P ale A am

muscle weakness
low mood (mild depression) or irritability
ot o S an x
N ot f or sh a E

loss of appetite and unintentional weight loss

hypotension
n
N ot f ee esi

polyuria
tio

increased thirst
N r. Z th

bu

craving for salty foods

D es

tri

hypoglycaemia
ed t
r R rin
An

is

All of these symptoms may occur in a rather insidious nature and as such make it difficult to diagnose.
It usually intercurrent trauma or infection requiring an increase in steroid production that unmasks the
problem. The lack of cortisol fails to feedback to the pituitary and so there is continual production of
ACTH to attempt to stimulate cortisol production. Consequently ACTH levels are high. Melanocyte
stimulating hormone (MST) is also released in conjunction and leads to the characteristic pigmentation
of the skin and buccal mucosa seen in Addisonian patients.

Diagnosis
A Synacthen Stimulation Test is often used to aid diagnosis. Synacthen is the trade name for
tetracosactide, a synthetic ACTH analogue. When synacthen is given, the adrenal glands normally
respond in the same way as they would to ACTH and increase plasma cortisol and aldosterone levels.
However, if the ACTH level is high, but the cortisol and aldosterone levels are low, it is usually
confirmation of Addison‟s disease.

Addisonian crisis and anaesthesia

Adrenal crisis is a life-threatening condition which can be induced by stress during surgery in patients
with adrenal insufficiency. Exogenous replacement should be considered in such cases, this includes all
patients on long term steroids as they will also display iatrogenic adrenal suppression.

Secondary hypocortisolism (pituitary tumour, Sheehan's syndrome)

This is caused by reduced levels of ACTH production following damage to the anterior pituitary. In
this situation there is a deficiency in both mineralocorticoids and glucocorticoids. Mineralocorticoid
deficiency leads to loss of sodium and water causing dehydration and hypotension, while
glucocorticoid deficiency leads to weight loss, muscle weakness, hyopglycemia and eventual collapse.

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Sheehan‟s syndrome is an eponymous name for post-partum necrosis of the pituitary gland. In
pregnancy the anterior pituitary enlarges which compromises its blood supply from the low pressure
portal veins. Any sudden cause of hypotension e.g. haemorrhage causing shock, further compromises
the anterior pituitary and results in loss of function. Early symptoms include failure of lactation and
amenorrhoea (lack of LH), or alternatively women experience gradual onset of the symptoms of
secondary adrenal insufficiency.

Zona reticulosa

Tumours can arise in this layer but it would seem only in women and even these are very rare. Signs
and symptoms in women:

hirsutism
acne
oligomenorrhea
virilisation

REFERENCES AND WEBLINKS

a
tth
C s
Yentis S, Hirsch N, and Smith G. (editors). Anaesthesia and Intensive Care A–Z. An Encyclopaedia of
ad ote
Principles and Practice, 4th edition, 2009 ha
hm N

Pinnock C, Lin T, Smith T, Jones R (Editors). Fundamentals of Anaesthesia. 2nd edition, 2002
fo r P ale A am

Ganong WF. Review of Medical Physiology. 23rd edition, 2009

ot o S an x
N ot f or sh a E

Guyton AC, Hall JE. Textbook of Medical Physiology. 10th edition, 2000
n
N ot f ee esi

tio

Yong SL, Marik P, Esposito M, Coulthard P. Supplemental perioperative steroids for surgical patients
N r. Z th

bu

with adrenal insufficiency. Cochrane Database of Systematic Reviews 2009, Issue 4.

D es

tri
ed t
r R rin

http://update.anaesthesiologists.org/wp-content/uploads/2008/12/Endocrine-Physiology.pdf
An

is

http://totw.anaesthesiologists.org/wp-content/uploads/2010/07/186-The-hypothalamic-pituitary-axis-
part-1-anatomy-physiology.pdf

http://totw.anaesthesiologists.org/2009/09/14/phaeochromocytoma-perioperative-management-151/

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ANSWERS TO QUESTIONS:
1.TTFTF 2.TFTFT 3.TTFTT 4.FFTTT 5.FTTFT

Q1.
a. T
b. T
c. F The cortex produces aldosterone, cortisol and androgens.
d. T
e. F The zona reticularis produces androgens.

Q2.
a. T
b. F Norepinephrine is the precursor epinephrine.
c. T
d. F Cortisol stimulates gluconeogenesis.
e. T

Q3.
a. T
b. T

a
tth
c. F Phaeochromocytoma causes episodes of hypertension.
C s
d. T
ad ote
e. T
ha
hm N

Q4.
fo r P ale A am

a. F Cushing‟s disease is caused by a pituitary adenoma. Cushing‟s syndrome may be caused by an

adrenal tumour.
ot o S an x
N ot f or sh a E

b. F Causes weight gain.

c. T
n
N ot f ee esi

d. T
tio

e. T
N r. Z th

bu
D es

Q5.
tri
ed t
r R rin

a. F Addison‟s disease is due to failure of the adrenal cortex.

An

is

b. T
c. T
d. F There is a rise in ACTH due to failure to suppress the pituitary gland.
e. T

ATOTW 216 – The Adrenal Glands 07/03/11 Page 9 of 9

An
D es
N r. Z th
N ot f ee esi
N ot f or sh a E
ot o S an x
fo r P ale A am
r R rin hm N
ed t ad ote
is C s
tri ha
bu
tio tth
n a
11

Acromegaly
An acromegalic patient presents for surgery to a pituitary tumour.
What are the common surgical approaches?
There are two main approaches to surgery:

(1) Over 90% of pituitary adenomas will be treated by the trans-sphenoidal

approach. This approach, in which an incision is made in the nasal septum,
is well tolerated and gives good cosmetic results. Complications are
uncommon but include:

Haemorrhage
Visual loss
Persistent CSF leak
Panhypopituitarism
Stroke

(2) The other surgical option is a frontal craniotomy.

a
tth
C s
ad ote
ha
hm N

How can pituitary tumours present?

fo r P ale A am

Most pituitary tumours are benign and arise from the anterior pituitary. They
ot o S an x
N ot f or sh a E

can be secreting (around 70%) or non-secreting and may present in a number

of ways:
n
N ot f ee esi

tio

Mass effect of the tumour: Headache

N r. Z sth

bu

Nausea and vomiting

tri
D e

ed t
r R rin
An

Visual field defects

is

Cranial nerve palsies

Papilloedema
Raised ICP (rare, but more common with
non-functioning macroadenomas)
Effects from the secretion of one or more hormones
Non-specific – headache, infertility, epilepsy
Incidental, e.g. during imaging (‘incidentalomas’)

Classification of pituitary tumours:

1. Non-functioning (25%) Commonly null-cell adenomas,
craniopharyngiomas and meningiomas
2. Functioning (75%) Prolactin 30%
Prolactin + GH 10–12%
GH 20%
ACTH 12–15%
FSH/LH 1–2%
TSH 1%
12 Acromegaly A

What are the features of acromegaly?

There is hypersecretion of growth hormone with resultant soft tissue
overgrowth.
Clinical features include:
Face Increased skull size
Prominent supraorbital ridge
Prognathism
Headaches
Mouth Macroglossia
Soft tissue overgrowth in larynx/pharynx
Obstructive sleep apnoea
Skeleton Large hands and feet
Thick skin
Osteoporosis
Kyphosis
Neuromuscular RLN palsy

a
Peripheral neuropathy tth
C s

Proximal myopathy
ad ote
ha

Cardiovascular Hypertension
hm N

Heart failure
fo r P ale A am

Endocrine Diabetes
ot o S an x
N ot f or sh a E

Diagnostic tests for acromegaly:

n
N ot f ee esi

tio

Random serum growth hormone > 10 mU/l – can give false-positives

N r. Z sth

bu

due to its short half-life and pulsatile pattern of release.

tri
D e

ed t
r R rin
An

is

Failure of growth hormone suppression following a glucose load.

Elevated IGF-1 – growth hormone exerts many of its effects through
insulin-like growth factor-1 (IGF-1) which also has a longer half-life
than growth hormone.

Which features are of concern to the anaesthetist?

Upper airway This may result from a large mandible, tongue and
obstruction epiglottis together with generalised mucosal hypertrophy.
Laryngeal narrowing may cause difficulty with tracheal
intubation and post-operative respiratory obstruction can
occur. A history of stridor, hoarseness, dyspnoea or
obstructive sleep apnoea should be specifically asked for.
Cardiac Hypertension and congestive cardiac failure requiring
pre-operative investigation and treatment.
Endocrine Commonly glucose intolerance and diabetes mellitus. Other
associations include thyroid and adrenal abnormalities that
may necessitate thyroxine and steroid replacement.
A Acute asthma 13

What post-operative management problems may you encounter?

Surgical complications
such as: Haemorrhage
Stroke
Visual loss
Cerebral oedema leading to impaired consciousness
Hormonal
supplementation
Steroids Surgery may reduce the function of the pituitary
gland and hydrocortisone is often prescribed in the

a
immediate peri-operative phase.

tth
C s
ad ote
Thyroxine Prescribed with caution due to the risk of cardiac

ha
ischaemia.
hm N
Insulin Titrated to the required serum glucose
fo r P ale A am

concentration.
ot o S an x

Diabetes insipidus This occurs in 40% of patients and is transient,

N ot f or sh a E

typically occurring in the first 12–24 hours due to

n
N ot f ee esi

tio
oedema around the surgical site. It presents as
N r. Z sth

bu
polyuria with a low urine osmolality despite
tri
D e

ed t

normal/high serum osmolality. Treatment is by

r R rin
An

is

estimating and replacing the fluid deficit (which is

hypo-osmolar) and the administration of
desmopressin (DDAVP), a synthetic ADH analogue.
CSF rhinorrhoea Generally, no treatment is required, although the
risk of infection is probably increased. CSF drainage
(e.g. lumbar drain) may reduce the pressure
sufficiently to allow the leak to seal.
Post-operative pain
Hypertension on May contribute to post-operative bleeding but is
emergence often short-lived. Ensure adequate analgesia. May
require short-acting agents to control such as
labetalol.
Bibliography
Nemergut E, Dumont A, Barry U, Laws E. (2005). Perioperative management of patients undergoing
trans-sphenoidal pituitary surgery. Anesthesia and Analgesia, 101, 1170–81.
Smith M, Hirsch NP. (2000). Pituitary disease and anaesthesia. British Journal of Anaesthesia, 85(1),
3–14.

Acute asthma
You are called to the accident and emergency department to see a
31-year-old lady, known to have asthma, who has been admitted with
acute shortness of breath.
An
D es
r
N . Z th
o
N t f e si e e
o
N t f or sh a E
ot o S an x
fo r P ale A am
r R rin hm N
ed t ad ote
is C s
tri ha
bu
tio tth
n a
Carcinoid: the disease and its implications
for anaesthesia
Matrix reference 3I00
Bruce Powell MRCP FRCA
Ahmed Al Mukhtar FRCS
Gary H Mills PhD UKDICM FRCA

This article describes the features of carcinoid inhibit synthesis, prevent release, and antagonize
Key points
tumours and the challenges involved in the receptors has been given by Veall.3
Carcinoid surgery carries a anaesthetic management and post-operative care The classification of carcinoid tumours is
significant morbidity/
of patients undergoing surgery for carcinoid. hence based on the site of origin and the histo-
mortality.
Carcinoid tumours were first described in logical characteristics, with tumours being
Thorough pre-operative

a
1888 by Lubarsch who found multiple tumours broadly described as either well-differentiated or

tth
assessment may at times

C s
in the distal ileum of two patients at autopsy. poorly differentiated neuroendocrine tumours.
require cardiology input.
ad ote
Ransom then published the first detailed Recent epidemiology4 suggests that carci-

ha
Physiological changes are description of the classic symptoms of carci- noid tumours may be increasing in frequency
hm N
unpredictable and noid1 and Oberndorfer introduced the name with the highest incidence in some racial
hazardous.
fo r P ale A am

when he used the term ‘karzinoide tumoren’ in groups (4.5 per 100 000 in African males),
Octreotide plays a vital role 1907 because of the tumour’s similarity to car- suggesting a genetic role associated with their
ot o S an x

in tumour control and cinomas despite their apparently benign nature. development. The sites of highest incidence are
N ot f or sh a E

should commence before Gosset and Masson realized in 1914 that carci- the gastrointestinal tract (67.5%) and the
operation. noid tumours were related to endocrine tissue.2
n broncho-pulmonary system (25.3%). Within the
N ot f ee esi

tio
Post-operative care should It is the endocrine-like nature of these tumours gastrointestinal tract, approximately 40% of
be provided in a that lead to their unusual effects, which can be tumours occur in the small intestine, with a
N r. Z th

bu

high-dependency area. a major challenge to anaesthetists. further 27% in the rectum and 10% in the
D es

tri
ed t

stomach. In nearly all carcinoid tumours, irre-

r R rin
An

is

spective of site of origin, staging of the tumour

Epidemiology and aetiology of correlates with survival. The presence of
carcinoid tumours regional or distant metastases significantly
Bruce Powell MRCP FRCA
Specialist Registrar in Anaesthesia Carcinoid tumours are derived from enterochro- reduces the 5-yr survival from 71% of patients
Department of Anaesthesia maffin or Kulchitsky cells and arise from the who have no metastases to approximately 38%
C Floor Outpatients Block
Royal Hallamshire Hospital different embryonic divisions of the gut. They for patients with metastases.
Sheffield Teaching Hospitals depend for their frequency of occurrence on the
Glossop Road site density of neuroendocrine cells. Hence,
Sheffield S10 2JF, UK
foregut tumours arise in the lungs, bronchi, or
The clinical features of
Ahmed Al Mukhtar FRCS stomach; midgut carcinoid tumours occur in the
carcinoid syndrome
Consultant in Hepatobiliary Surgery small intestine, appendix, and proximal large Many carcinoid tumours are found coinciden-
Department of Hepatobiliary Surgery
Ward K1, Royal Hallamshire Hospital
bowel; hindgut carcinoid tumours arise in the tally during surgery for other conditions.
Sheffield Teaching Hospitals distal colon or rectum. As a group, carcinoid Patients may describe vague upper or lower GI
Glossop Road tumours represent a wide spectrum of neuroendo- symptoms, with the average time from
Sheffield S10 2JF, UK
crine cell types. Under electron microscopy, they symptom onset to diagnosis being 9 yr.5
Gary H Mills PhD UKDICM FRCA typically contain numerous membrane-bound Carcinoid syndrome is relatively uncom-
Consultant in Anaesthesia neurosecretory granules composed of hormones mon, affecting approximately 10% of patients
Department of Anaesthesia and biogenic amines. The most familiar of these with carcinoid tumours. Vasoactive substances
C Floor Outpatients Block
Royal Hallamshire Hospital is serotonin, which is metabolized from its pre- secreted by tumours arising in the gut must
Sheffield Teaching Hospitals cursor, 5-hydroxytryptophan by a decarboxylase pass through the liver via the hepatic portal
Glossop Road enzyme, but they are also known to secrete corti- vein before circulating more extensively.
Sheffield S10 2JF, UK
Tel: þ44 0114 2712381 cotrophin, histamine, dopamine, substance P, Consequently, these vasoactive hormones are
E-mail [email protected] neurotensin, prostaglandins, and kallikrein. A metabolized before they can exert widespread
(for correspondence) broad description of drugs used traditionally to systemic effects. However, tumours either
doi:10.1093/bjaceaccp/mkq045 Advance Access publication 16 December, 2010
9 Continuing Education in Anaesthesia, Critical Care & Pain | Volume 11 Number 1 2011
& The Author [2010]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia.
All rights reserved. For Permissions, please email: [email protected]
Carcinoid: the disease and its implications for anaesthesia

a
tth
C s
ad ote
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Fig 1 Carcinoid heart. The carcinoid syndrome has resulted in fibrosis of the right-sided valve cusps of both pulmonary and tricuspid valves. They show a
hm N
white coating (arrowed), which represents carcinoid plaque on their ventricular surfaces. Picture kindly provided by Dr Tim Stephenson, Consultant
fo r P ale A am

Pathologist, Royal Hallamshire Hospital.

originating or more commonly metastasizing to the liver may tumours. They are usually perihilar and present with recurrent
ot o S an x
N ot f or sh a E

bypass this metabolism and thereby exert more widespread sys- pneumonia, cough, haemoptysis and, very occasionally, chest pain.
temic effects. n Rarely, cushingoid or acromegalic features may occur and meta-
N ot f ee esi

The release of serotonin and other vasoactive substances such as stases occur in 15–50% of tumours dependent on its differen-
tio
histamine is responsible for the unpredictable, but classically tiation. They may be treated with lung lobectomy or where this is
N r. Z th

bu

described, ‘carcinoid syndrome’. This is typically intermittent and not feasible (such as in cases of multiple intraluminal bronchial
D es

is characterized by flushing, sometimes associated with exercise, or polypoid tumours), they have been treated with laser/argon plasma
tri
ed t
r R rin

the ingestion of alcohol or high tyramine content foods such as blue coagulation. Survival of 92% at 10 yr has been reported.
An

is

cheeses and chocolate. Diarrhoea, lacrymation, rhinorrhoea and ulti- Gastric carcinoid tumours account for ,1% of gastric neo-
mately right-sided valvular heart disease may also occur. Carcinoid plasms and they may be associated with the Zollinger–Ellison syn-
heart disease (Fig. 1) classically affects the right side of the heart drome or chronic atrophic gastritis and can be invasive, multiple,
with fibrous thickening of the endocardium causing retraction and or be associated with carcinoid syndrome. Patients with small-
fixation of the tricuspid valve leaflets and is related to the duration bowel carcinoids tend to present in the fifth and sixth decades,
of exposure to high concentration of 5-hydroxytryptamine. most often with mass effects from the tumour (e.g. abdominal pain
Consequently, mixed tricuspid and pulmonary valvular disease are or obstruction). The majority of small-bowel carcinoids have
well recognized.6 Such heart disease occurs in two-thirds of those metastases at presentation and approximately 5% have the carci-
with carcinoid syndrome and is associated with a statistically signifi- noid syndrome.
cant increase in peri-operative complications.7 Left-sided heart Carcinoid tumours are the commonest tumour of the appendix,
disease is uncommon and generally associated with bronchial carci- with peak incidence in the fourth or fifth decade, more commonly
noid or right to left intracardiac shunting. in women. Fewer than 10% produce obstructive symptoms because
‘Carcinoid crises’ are an exaggerated form of the syndrome of the tumour’s predilection to affect the distal third of the appen-
characterized by profound flushing, bronchospasm, tachycardia, and dix. Metastases at the time of presentation are unusual and the size
widely fluctuating blood pressure, including hypo- and hyperten- of the tumour is a good predictor of survival. Carcinoid syndrome
sion. The most common cause of such dramatic crises is anaesthetic, may occur in those with liver metastases and thereby reduce the
radiological, or surgical interventions and such crises are potentially 5-yr survival of appendicular carcinoid from .90 to ,35%. Liver
fatal. Carcinoid tumours may also present with bleeding. metastases can be removed at surgery. If total removal is not feas-
ible (which is often the case), surgical debulking and radiofre-
quency ablation will reduce the systemic effects of carcinoid and
Tumour location and presentation
may postpone end-stage hepatic disease. Large-bowel carcinoid
Pulmonary carcinoids (Fig. 2) account for only 2% of all primary generally presents later in life, and prognosis is associated with
lung tumours and often present in a similar way to other lung tumour size and the presence of metastases.

10 Continuing Education in Anaesthesia, Critical Care & Pain j Volume 11 Number 1 2011
Carcinoid: the disease and its implications for anaesthesia

a peri-operative 30-day mortality of 6%.9 Patients may also present

for surgery for removal of tumours from other sites or may present
for correction of severe valvular dysfunction produced by carcinoid.
For anaesthetic purposes, patients with carcinoid tumours
should be regarded as suffering from a multi-system disease and so
require thorough pre-planning followed by post-operative manage-
ment in a high dependency environment by clinicians who are well
versed in the complications associated with carcinoid.

Pre-operative assessment
History and examination
Complications such as obstruction, malnutrition, dehydration,
anaemia, and electrolyte imbalance will be as common as other
obstructing or metastatic lesions. In addition, there may be symptoms
or signs suggestive of ongoing uncontrolled excessive hormonal

a
tth
activity such as diarrhoea or less commonly the carcinoid syndrome.

C s
ad ote There are two specific areas of concern for planning anaesthetic

ha
management. First, a cardiovascular history is essential as right or
Fig 2 Intra-bronchial arcinoid tumour. Bronchial segment occluded by
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invasive carcinoid tumour (arrowed). Picture kindly provided by Dr Kim
biventricular heart failure may complicate chronic, excessive
hormone release, pulmonary stenosis, or all may also be present.
fo r P ale A am

Suvarna, Consultant Pathologist, Northern General Hospital, Sheffield.

Reduced exercise tolerance, orthopnoea, paroxysmal dyspnoea, and
ot o S an x

peripheral oedema may all be signs of carcinoid heart disease.

Diagnosis
N ot f or sh a E

Occasionally, coronary artery spasm may occur during flushing

Serology n episodes associated with carcinoid.
N ot f ee esi

Secondly, there is the potential for unpredictable, uncontrolled

tio
The presence of carcinoid-like symptoms such as flushing and hormone release precipitated by haemodynamic variation, anaesthetic,
N r. Z th

bu

wheezing may indicate the need to measure urinary 5-HIAA and or surgical stimulus. This may result in hypo- or hypertensive crises
D es

serum chromagraffin A. The serotonin metabolite 5-HIAA, and haemodynamic collapse which is unresponsive to conventional
tri
ed t
r R rin

measured in a 24 h urine collection, may be used both diagnosti-

An

inotrope and pressor therapy. Even if patients lack symptoms or have

is

cally and as an aid to monitoring tumour activity. A positive result symptomatic control, peri-operative use of preventative drugs is essen-
for 5-HIAA has a 73% sensitivity and a 100% specificity for carci- tial, because the stimulus to release vasoactive hormones once anaes-
noid tumour.4 Serum chromagraffin A is a glycoprotein secreted thesia and surgery commence will be much higher than in day-to-day
with other hormones by neuroendocrine tumours and is 95% life. Therefore, it is paramount that tumour activity is minimized
specific and almost 80% sensitive for carcinoid tumours.8 before the day of surgery using octreotide. Octreotide acetate exerts
pharmacological actions similar to the natural hormone, somatostatin,
Imaging but it is an even more potent inhibitor of growth hormone, glucagon,
and insulin. Similar to somatostatin, it also suppresses luteinising
Metastatic disease is most commonly diagnosed using abdominal hormone (LH) response to gonadotrophin releasing hormone
CT and contrast; deposits appearing as isodense, hypervascular (GnRH), decreases splanchnic blood flow, and inhibits release of sero-
lesions. Somatostatin receptor scintigraphy using indium-111- tonin, gastrin, vasoactive intestinal peptide, secretin, motilin, and pan-
labelled octreotide is also useful.9 creatic polypeptide. Octreotide has widespread effects, important
among these are QT prolongation, bradycardia, conduction defects,
Principles of anaesthetic management for abdominal cramps, nausea, and vomiting. Octreotide infusion
carcinoid 50 mg h21 for at least 12 h immediately before surgery9 should
reduce tumour hormonal activity, but ongoing symptoms or signs sug-
Patients may have limited disease, including the primary tumour, gestive of excessive secretion should be treated aggressively with
with or without affected lymph nodes (usually in the distal third of further octreotide before any anaesthetic or surgical intervention.
the appendix) or have liver metastases. The disease may be resect-
able or the patients may undergo surgery to decrease tumour load
Investigations
and symptoms. Primary tumour and hepatic resection for single
lobe metastases is curative in approximately 10% of cases. The 5-yr Basic pre-operative investigations are as required for major surgi-
survival for multi-lobar metastases after resection is up to 87% with cal procedures. These normally include the following as a

Continuing Education in Anaesthesia, Critical Care & Pain j Volume 11 Number 1 2011 11
Carcinoid: the disease and its implications for anaesthesia

minimum: a chest X-ray (which may show carcinoid lesions or local preference, with both total intravenous anaesthesia (TIVA)
rarely miliary shadowing of carcinoid lung), ECG (which may and inhalation techniques being used successfully.
show right ventricular hypertrophy), electrolytes (which may show Morphine and atracurium have most potential for unwelcome
the effects of chronic diarrhoea), liver function tests (very rarely histamine release and could feasibly be avoided even though the
liver failure presents when the liver is completely infiltrated by evidence for adverse effects is case based. Suxamethonium has
carcinoid lesions), full blood count (may reveal signs of diffuse been implicated in the release of peptides from the liver as a con-
marrow spread), clotting studies and a cross match sample. A sequence of depolarization-induced fasciculations.3 Remifentanil
macrocytosis may suggest vitamin B12 and folate deficiency which (0.05 –0.2 mg kg21 min1) may have a role in optimizing intubating
may lead to anaemia. In carcinoid, high serotonin formation may conditions, provision of titratable analgesia and intra-operative
lead to tryptophan depletion and niacin deficiency, which is associ- blood pressure control.10 The benefits of its short context-sensitive
ated with dermatitis, diarrhoea, and dementia and has rarely led to half-life and titratability are attractive but must be balanced by the
reversible encephalitis. risk of hypotension and bradycardia.
A thorough cardiovascular pre-operative work-up, including
echocardiography to exclude right-sided carcinoid cardiac disease
Monitoring
and possibly exercise testing for those with ischaemic heart
disease, is appropriate, given the likely cardiovascular stress Given the potential for haemodynamic instability because of vaso-

a
associated with surgery. High right-sided heart pressures in the active hormone release and the potential for large blood loss, inva-

tth
C s
face of pulmonary stenosis secondary to carcinoid may lead to tri- sive monitoring is vital. The exact nature of that monitoring will
ad ote
ha
cuspid regurgitation, hepatomegaly, and a pulsatile liver. This may depend upon local resources and the nature of any cardiac involve-
make hepatic resection impossible without excessive blood loss ment, but a system such as a pulmonary artery flotation catheter,
hm N

because of high central venous pressure and hence hepatic vein LiDCO, or oesophageal Doppler in addition to arterial and central
fo r P ale A am

pressure. In these situations, serious consideration should be given venous pressure monitoring will be useful to guide fluid therapy
to pulmonary valve surgery before hepatic resection. and aid in the management of hormone-induced pre- and afterload
ot o S an x
N ot f or sh a E

variations.

Anaesthetic techniques
n
N ot f ee esi

Vasoconstrictors
tio
Regional anaesthesia
N r. Z th

bu

A significant proportion of the surgery related to carcinoid will be

D es

Thoracic epidural insertion before induction of general anaesthesia for the removal of metastases by hepatic resection. Here, the need
tri
ed t

is a reasonable technique for any patient undergoing an elective

r R rin

to try to maintain a relatively low CVP, during clamping of the

An

is

laparotomy, especially involving the upper abdomen to help hepatic artery and portal vein to avoid backflow into the liver and
achieve good pain relief and reduce post-operative atelectasis. In venous bleeding, will further exacerbate the risk of hypotension.
the context of carcinoid surgery, epidurals have benefits, but, The response to inotropic and vasopressor agents is unpredictable
however, are associated with some drawbacks. Excellent analgesia and, in general, drugs such as norepinephrine and epinephrine can
and the avoidance of stressors such as pain will reduce the risk of be hazardous in carcinoid patients. Norepinephrine has been shown
a carcinoid crisis; however, the potential hypotension produced by to activate kallikrein in the tumour and can even lead to the syn-
an epidural may then require vasoconstrictors that may lead to an thesis and release of bradykinin resulting paradoxically in further
exaggerated response. The balance of risks would seem to favour vasodilatation and worsening hypotension, although exaggerated
the use of epidurals with drug volumes and concentrations cau- hypertensive responses may be seen. Indeed, any pharmacological
tiously titrated to blood pressure response. stimulation of the autonomic nervous system has the potential to
provoke further problems with vasoactive hormone release. In
practice, cautious administration of small doses of phenylephrine
General anaesthesia
has been found helpful in some patients.
The primary objective in anaesthesia for carcinoid surgery is to Vasoactive hormone release intra-operatively is best treated
provide stable, controlled conditions, avoiding significant stimu- with intravenous boluses of 20 –50 mg of octreotide, titrated to
latory factors such as blood pressure variation and inadequate haemodynamic response. Vasopressin as an alternative vasocon-
analgesia. Reliable large bore access in case of rapid volume loss strictor that may be useful if prolonged vasoconstriction is
and the availability of fluid warmers and the use of a rapid infu- required; however, the evidence base is small.
sion system are sensible standards. It must be borne in mind that concomitant fluid losses,
Stable induction, adequate depth of anaesthesia before intuba- especially bleeding, may be responsible for intra-operative instabil-
tion and maintenance of anaesthesia and analgesia peri-operatively ity rather than hormone excess and that fluid resuscitation may be
are key to preventing instability. The choice of technique and the answer rather than further octreotide therapy. Monitoring of
anaesthetic agents is probably most dependent on familiarity and fluid losses, especially bleeding, is very important in these patients.

12 Continuing Education in Anaesthesia, Critical Care & Pain j Volume 11 Number 1 2011
Carcinoid: the disease and its implications for anaesthesia

Portal hypertension and tumour involving the portal veins may responses to variations in blood pressure and be in a position to
contribute to rapid, large volume blood losses requiring rapid recognize the cause of any change. Most importantly, the potential
replacement, which may be exacerbated by clotting abnormalities. for intra-operative release of vasoactive compounds must not be
Hourly blood gas monitoring will track acid –base balance and underestimated even in patients who are currently asymptomatic
glucose which may become problematical if surgery is prolonged, and peri-operative treatment with octreotide is vital.
resection extensive, or bleeding excessive.
For prolonged hypertension, labetalol infusions have been used,
as has alpha blockade. However, changes in blood pressure, Conflict of interest
although sometimes extreme, may be brief and it is possible for
the effects of treatment and vasoactive substance release to None declared.
become confused with one another.

Post-operative high-dependency care References

1. Ransom W. A case of primary carcinoma of the ileum. Lancet 1890; 2:
As with the intra-operative management, post-operative care will 1020– 23
focus on the provision of stable cardio-respiratory conditions and 2. Gosset A, Masson P. Tumeurs endocrines de l’appendice. Presse Med

a
adequate analgesia. High-dependency care is recommended. 1914; 25: 237 –9

tth
C s
Ongoing hormonal control of the tumour is important as post- 3. Veall GR, Peacock JE, Bax ND et al. Review of the anaesthetic manage-
ad ote ment of 21 patients undergoing laparotomy for carcinoid syndrome. Br J

ha
operative crises are possible and surgery may have been aimed at
Anaesth 1994; 72: 335–41
reducing the bulk of carcinoid tumour present, rather than eliminat-
hm N
ing it. Intravenous and then subcutaneous octreotide follow-up will 4. Modlin IM, Lye KD, Kidd M. A 5-decade analysis of 13,715 carcinoid
tumors. Cancer 2003; 97: 934– 59
fo r P ale A am

help control any further hormone release and there may well be
5. Horton KM, Kamel I, Hofmann L et al. Carcinoid tumors of the small
residual, hormonally active tumour remaining. Forty-eight hours of bowel: a multitechnique imaging approach. Am J Roentgenol 2004; 182:
ot o S an x

invasive monitoring, analgesia and fluid management may be 559–67

N ot f or sh a E

required to ensure safe recovery from the surgery.9 n 6. Lundin L, Norheim I, Landelius J et al. Carcinoid heart disease: relation-
ship of circulating vasoactive substances to ultrasound-detectable cardiac
N ot f ee esi

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abnormalities. Circulation 1988; 77: 264–9
Conclusion
7. Kinney MA, Warner ME, Nagorney DM et al. Perianaesthetic risks and
N r. Z th

bu

Combining new diagnostic and treatment modalities in metastatic outcomes of abdominal surgery for metastatic carcinoid tumours. Br J
D es

Anaesth 2001; 87: 447–52

tri

carcinoid patients may result in better quality of life and longer

ed t
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An

survival times. Patients should be aware of the limitations of 8. Feldman JM, O’Dorisio TM. Role of neuropeptides and serotonin in the
is

diagnosis of carcinoid tumors. Am J Med 1986; 81: 41– 8

surgery, which will often debulk tumours, reducing the amount of
9. Ramage JK, Davies AH, Ardill J et al. Guidelines for the management of
vasoactive compound release to a point where medical manage- gastroenteropancreatic neuroendocrine (including carcinoid) tumours.
ment of symptoms is effective. Provision of anaesthesia for these Gut 2005; 54(Suppl 4): iv1–iv16
patients, especially for the resection of hepatic metastases, carries 10. Farling PA, Durairaju AK. Remifentanil and anaesthesia for carcinoid
significant risk and requires thorough pre-operative preparation and syndrome. Br J Anaesth 2004; 92: 893– 5
optimized medical control. Invasive monitoring will be required
combined with the use of octreotide. Anaesthetists should preplan Please see multiple choice questions 8– 11.

Continuing Education in Anaesthesia, Critical Care & Pain j Volume 11 Number 1 2011 13
An
D es
r
N . Z th
o
N t f e si e e
o
N t f or sh a E
ot o S an x
fo r P ale A am
r R rin hm N
ed t ad ote
is C s
tri ha
bu
tio tth
n a
An
D es
N r. Z th
N ot f ee esi
N ot f or sh a E
ot o S an x
fo r P ale A am
r R rin hm N
ed t ad ote
is C s
tri ha
bu
tio tth
n a
vasoactive tumor products.

TABLE 35–9 Principal mediators of carcinoid syndrome and their clinical

manifestations.

Anesthetic Considerations
The key to perioperative management of patients with carcinoid syndrome is
to avoid anesthetic and surgical techniques or agents that could cause the tumor
to release vasoactive substances. Regional anesthesia may limit release of stress
hormones perioperatively. Large bolus doses of histamine-releasing drugs (eg,
morphine and atracurium) should be avoided. Surgical manipulation of the tumor
can cause a massive release of hormones. Monitoring likely will include an
arterial line. If there are concerns about hemodynamic instability or intrinsic
heart disease caused by carcinoid syndrome, transesophageal echocardiography
may be helpful. Alterations in carbohydrate metabolism may lead to unsuspected
hypoglycemia or hyperglycemia. Consultation with an endocrinologist may help
clarify the role of antihistamine, antiserotonin drugs (eg, methysergide),
octreotide (a long-acting somatostatin analogue), or antikallikrein drugs (eg,
corticosteroids) in specific patients.

CASE DISCUSSION
a
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C s

Multiple Endocrine Neoplasia

ad ote
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fo r P ale A am

An isolated thyroid nodule is discovered during physical examination

ot o S an x
N t f or sh a E

of a 36-year-old woman complaining of diarrhea and headaches.

N ot f ee esi

tio
N . Z th

bu
D nes

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Workup of the tumor reveals hypercalcemia and an elevated calcitonin

ed t
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is
A
r

level, which leads to the diagnosis of medullary cancer of the thyroid

o
and primary hyperparathyroidism. During induction of general
anesthesia for total thyroidectomy, the patient’s blood pressure rises to
240/140 mm Hg and her heart rate approaches 140 beats/min, with
frequent premature ventricular contractions. The operation is
canceled, an arterial line is inserted, and the patient is treated with
intravenous esmolol and nicardipine.
What could be the cause of this patient’s hypertensive crisis
during induction of general anesthesia?
Multiple endocrine neoplasia (MEN) is characterized by tumors in
several endocrine organs. MEN type 1 consists of pancreatic (gastrinomas,
insulinomas), pituitary, and parathyroid tumors. MEN type 2 consists of
medullary thyroid carcinoma, pheochromocytoma, and

a
tth
hyperparathyroidism (type 2a) or multiple mucosal neuromas (type 2b or

C s
ad ote
ha
type 3). The hypertensive episode in this case may be due to a previously
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undiagnosed pheochromocytoma. The pheochromocytoma in MEN may
fo r P ale A am

consist of small multiple tumors. These patients are typically young adults
with strong family histories of MEN. If multiple surgeries are planned,
ot o S an x
N ot f or sh a E

pheochromocytoma resection will usually be scheduled first.

n
N ot f ee esi

tio
What is calcitonin, and why is it associated with medullary
N r. Z th

bu

cancer?
D es

tri
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An

Calcitonin is a polypeptide manufactured by the parafollicular cells (C

is

cells) in the thyroid gland. It is secreted in response to increases in plasma

ionic calcium and tends to lower calcium levels by affecting kidney and
bone function. Therefore, it acts as an antagonist of parathyroid hormone
(see Table 35–6).
Why is this patient hypercalcemic if calcitonin lowers serum
calcium?
An excess or deficiency of calcitonin has minor effects in humans
compared with the effects of parathyroid disorders. This patient’s
hypercalcemia is most likely due to coexisting primary
hyperparathyroidism (MEN type 2a).
Are headache and diarrhea consistent with the diagnosis of
MEN?
The history of headaches suggests the possibility of pheochromocytoma,
whereas diarrhea may be due to calcitonin or one of the other peptides often
produced by medullary thyroid carcinoma (eg, ACTH, somatostatin, β-
endorphin).
What follow-up is required for this patient?
Because of the life-threatening hemodynamic changes associated with
pheochromocytoma, this entity must be medically controlled before any
surgery can be considered (see Case Discussion, Chapter 14). Because
MEN syndromes are hereditary, family members should be screened for
early signs of pheochromocytoma, thyroid cancer, and
hyperparathyroidism.

a
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GUIDELINES
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Practice guidelines for the perioperative management of patients with

fo r P ale A am

obstructive sleep apnea: An updated report by the American Society of

ot o S an x

Anesthesiologists Task Force on Perioperative Management of patients with

N ot f or sh a E

obstructive sleep apnea. Anesthesiology. 2014;120:268.

n
N ot f ee esi

tio
Society for Ambulatory Anesthesia Consensus Statement on Selection of
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Patients With Obstructive Sleep Apnea Undergoing Ambulatory Surgery.

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http://www.sambahq.org/main/clinical-practice-guidelines/
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SUGGESTED READINGS
Agus MS, Wypij D, Hirshberg EL, et al; HALF-PINT Study Investigators and
the PALISI Network. Tight glycemic control in critically ill children. N Engl
J Med. 2017;376:729.
Arlt W, Allolio B. Adrenal insufficiency. Lancet. 2003;361:1881.
Azim S, Kashyap SR. Bariatric surgery: Pathophysiology and outcomes.
Endocrinol Metab Clin North Am. 2016;45:905.
Blau JE, Collins MT. The PTH-vitamin D-FGF23 axis. Rev Endocr Metab
Disord. 2015;16:165.
El-Menyar A, Mekkodathil A, Al-Thani H. Traumatic injuries in patients with
diabetes mellitus. J Emerg Trauma Shock. 2016;9:64.
Jones GC, Macklin JP, Alexander WD. Contraindications to the use of
metformin. Evidence suggests that it is time to amend the list. BMJ.
Clinical Guideline for the Perioperative Steroid
Replacement
1. Aim/Purpose of this Guideline
1.1. This document provides guidelines for the safe management, within the
theatre environment, of patients in the perioperative period who have been
prescribed steroid medications.

2. The Guidance

Assume normal Additional steroid

< 10mg day-1
HPA response cover not required.

25 mg
Minor Surgery hydrocortisone @

a
tth
C s induction
ad ote
ha
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Usual pre-operative
fo r P ale A am

steroids
+25 mg
ot o S an x
N ot f or sh a E

Patients currently Moderate Surgery hydrocortisone @

induction
n
N ot f ee esi

taking steroids
tio

>10 mg day-1 +100 mg day-1 for

N r. Z th

bu

24 h
D es

tri
ed t
r R rin
An

is

Usual pre-operative
steroids
+25 mg
Major Surgery hydrocortisone @
induction
+100 mg day-1 for
48 – 72h

High-dose immunosuppression Give usual immunosuppressive doses

during peri-operative period
For example, a patient who is taking 60mg prednisolone 24 h-1 requires 250mg
hydrocortisone infusion 24 h-1

<3 months Treat as if on steroids

Patients stopped taking
steroids No peri-operative steroids
>3 months
necessary

Clinical Guideline for Perioperative Steroid Replacement

Page 1 of 5
ENDOCRINE
Dr. Fahad Rafiq Butt

Compiled by Dr. Zeeshan Ahmad Chattha

Diabetes:

Normal sugar kevel NICE guidelines: 6-10 mmol/L or 110-180 mg/dl

ADA criteria for Dx of Diabetes:
1. BSR more than 200mg/dl on 2 different occasions
2. HbA1c more than 6.5
3. BSF more than 126 mg/dl
4. OGTT Blood glucose level more than 200 mg/dl

a
tth
Oral Hypoglycemics:

C s
ad ote
ha
Short surgery: No oral hypoglycemic to be stopped
hm N

Side Effects:
fo r P ale A am

Metformin:
ot o S an x

If large fluid shifts expected, stop 24 hours before surgery

N ot f or sh a E

n
N ot f ee esi

tio
Which of following decreases glucose absorption from intestine?
N r. Z th

Metformin
bu
D es

tri
ed t
r R rin
An

Which one causes Metabolic acidosis?

is

Metformin

Sitagliptin:
Which of following causes: decreased immune function, more prone to infection, causes pancreatitis
and joint pains?
Sitagliptin
Regular
INSULINS:

Short Acting:
Rapid acting:
Lispro, Aspart
An
D es
N r. Z th
N ot f ee esi
N ot f or sh a E
ot o S an x
fo r P ale A am
r R rin hm N
ed t ad ote
is C s
tri ha
bu
tio tth
n a
Intermediate Acting:
NPH, Zinc Insulin

Long Acting:
Ultra Lente (Lantus), Glargine

What to do about Insulin in Renal failure patients?

They will need decreased dose of insulin because of decreased excretion. So they will need reduced
doses.

Pre-op Assessment concerns on Diabetics:

a
Diabetic Autonomic Neuropathy:

tth
C s
HR resting is more than 100/min
ad ote
ha
HR variability: When a patient prolonged inspiration or valsalva maneuvera, Intrathoracic pressure
hm N

increases venous return decreases Hypotension HR should increase, and as soon as valsalva is
fo r P ale A am

relieved… HR comes to normal…

In diabetics, the HR variability is less than 5 beats/min (because of blunted baroreceptor reflex)
ot o S an x
N ot f or sh a E

Normal HR variability is 15 beats/min

This HR variability is monitored in autonomic neuropathy…
n
N ot f ee esi

tio
N r. Z th

bu

Due to Autonomic neuropathy, there is gastroparesis. Medication recommended Metoclopramide

D es

tri
ed t
r R rin
An

is

Diabetics are more prone/sensitive to hypotension via inhalational, i.v anesthetics and Epidural
Anesthesia.

If diabetic patient, induction done… hypotension?

Autonomic neuropathy

Patient proned during surgery from supine position after induction  develops hypotension, reason?
Aorto caval compression

There is glycosylation of soft tissues and joints… leads to difficult intubation.

Checked by prayer sign
Namastey position of hands… if not possible to join hands… sign is positive.

Renal abnormality:
More protein is passed in Urine.

Drug of Choice for HTN in diabetics: ACE Inhibitors

Controlled diabetic… Epidural sited… hypotension, reason?
Normal epidural side effect of pooling of blood in lower limbs.. not due to diabetes
Diabetic Autonomic neuropathy hypotension will only develop in G.A

If patient not responding to vasopressors… it could be due to diabetic autonomic neuropathy

Patient for Day case. HbA1c is 9… what to do?

Postpone surgery and consult endocrinologist.
6.5-8.5… you may proceed for elective surgery.

If HbA1c more than 8.5… came for emergency surgery…?

Proceed with VRIII(Variable Rate Intravenous Insulin Infusion) protocol
More than 200mg/dl sugar give N.S 1000ml with KCl 20mEq @ 100ml/hr.

a
If less than 200mg/dl give 1/2Dex Saline 5% with KCl @ 100ml/hr. insulin units per hour is defined by

tth
C s
local guidelines.
ad ote
ha
Protocol of Shaukat Khanum:
hm N
fo r P ale A am
ot o S an x
N ot f or sh a E

n
N ot f ee esi

tio
N r. Z th

bu
D es

tri
ed t
r R rin
An

is
a
tth
C s
ad ote
ha
hm N
fo r P ale A am
ot o S an x
N ot f or sh a E

n
N ot f ee esi

tio
N r. Z th

bu
D es

tri
ed t
r R rin
An

is

Insulin Stop before surgery?

Short acting… do not stop
If patient is on single dose of Intermediate acting or long acting… continue as such.
If 2 doses per day… then morning dose to be halved and evening dose as usual to be continued.
If on 3 doses per day of Intermediate or long acting… then morning dose skip… midday is skipped due to
surgery and night/evening dose to be given as usual.
This protocol is for those patients who will be able to eat and drink within 24 hours.
a
tth
C s
ad ote
ha
hm N
fo r P ale A am
ot o S an x
N ot f or sh a E

If there is surgery in which more than 24 hours NPO is needed If HbA1c is less than 8.5 sliding scale,
if HbA1c more than 8.5 VRIII protocol.
n
N ot f ee esi

tio
N r. Z th

bu

DKA… Fluid of choice in DKA is Normal Saline

D es

Electrolyte abnormality in DKA?

tri
ed t
r R rin
An

is

Ans: Hyperkalemia (as acidosis always results in Hyperkalemia)

When Insulin given it will cause Hypokalemia because of intracellular shift with glucose.

When sugar levels decrease, potassium will also move intracellular, so always replace potassium

Insulin started at 0.1 unit/kg/hr

Insulin is then titrated up or down depending on following 3 things:
• Target is to increase HCO3 by 3mEq/hr
• Blood sugar level should come down by 3mmol/L/hr (54mg/dl/hr)
• Ketones decrease by 0.5/hr

You stop the insulin infusion when:

• pH is more than 7.3
• HCO3 is more than 18
• No ketones in the urine
Thyroid:
What is most common reason for surgery in hyperthyroidism?
Graves Disease

Patient with A.Fib for last 12 yrs. He is taking some meds which have caused hypothyroidism?
Amiodarone

Patient with Chronic A.Fib on Amiodarone. Before surgery which test would you advise?
PFTs (because it causes interstitial lung disease/lung fibrosis).

What is most common reason for surgery in patient who is hypothyroid?

Hashimoto thyroiditis

Patient tells he is on thyroid meds. Which test shows he is euthyroid?

a
TSH

tth
C s
ad ote
ha
Which is biologically active thyroid hormone?
hm N

T3
fo r P ale A am
ot o S an x

Thyroid hormone is bound with most?

N ot f or sh a E

Thyroid Binding Globulin 70% bound n

N ot f ee esi

tio

Superior thyroid artery is ligated close to the gland during surgery, and inferior thyroid artery is ligated
N r. Z th

bu

away from the gland, why?

D es

tri
ed t
r R rin

Superior Laryngeal nerve is away from the gland, so artery is ligated close to the gland to avoid damage
An

is

to nerve.
Recurrent Laryngeal nerve is close to the gland so inferior artery is ligated away from gland to protect
the nerve.

If unilateral superior Laryngeal Nerve is resected during surgery, what sign will be seen?
Hoarseness

If B/L Superior laryngeal nerve is tied/transected?

Hoarseness (because it supplies cricothyroid muscle which tenses the cord)

If unilateral recurrent laryngeal nerve injury?

Hoarseness

If B/L recurrent laryngeal nerve injury?

Stridor
Which of following lymph nodes will get spread of papillary thyroid carcinoma?
Paratracheal/Deep cervical lymph nodes

Patient says he gets difficulty breathing on lying supine. Which of following is recommended to see
extent of tracheal deviation or extent of compression?
CT Scan

Patient with MNG, Xray shows tracheal deviation and compression. How to see how much is the extent
of obstruction to air flow?
Ans: Flow Volume loops (tell us extent of obstruction)

Which of following electrolyte abnormality will be anticipated in patient with thyroid disease?
Calcium

a
Anti thyroid medications:

tth
C s
Carbimazole:
ad ote
ha
Side Effects:
hm N

• Joint pains (Arthralgias)

fo r P ale A am

• Bone Marrow suppression

• Agranulocytosis
ot o S an x
N ot f or sh a E

n
Propylthiouracil (PTU)
N ot f ee esi

tio

Side Effects:
N r. Z th

bu

• Liver and Kidney damage

D es

tri
ed t

• Aplastic Anemia
r R rin
An

is

• Thrombocytopenia

There is marked reduction in vascularity and size of tumor with which medicine?
Lugol’s Iodine

Which of blocks the conversion of T4 to T3 in periphery?

Propranolol

Which is drug of choice for hyperthyroid and pregnant?

PTU

Patient with Asthma, which medication to avoid?

Propranolol

Asthmatic Patient with SVT, which med to avoid?

Adenosine
Difference in Thyroid storm and Thyrotoxicosis?
If patient is clinically hyperthyroid and showing signs of hyperthyroidism… it is Thyrotoxicosis.
Management with PTU, Propranolol etc…

Thyroid Storm: Thyroid storm can also present with hypotension…

Main modality of treatment: Hydration and managing electrolyte imbalance.
• Saline, correct electrolyte and cold blanket.
• PTU given via NGT 200-400mg
• Methimazole 5-20mg via NGT
• Propranolol 40mg i.v stat
• Potassium Iodide 5-6 drops q6H
• Hydrocortisone 40-100mg stat and repeat q6H

a
To reduce tumor size: Lugol’s Iodine

tth
C s
ad ote
ha
Regional Anesthesia for Thyroid Surgery: Superficial Cervical Plexus Block
hm N

4 nerves in this block:

fo r P ale A am

1. Greater Auricular Nerve

ot o S an x

2. Lesser Occipital Nerve

N ot f or sh a E

3. Supraclavicular Nerve n
N ot f ee esi

4. Transverse Cervical
tio
N r. Z th

bu

What is the method of Anesthetizing a patient with a larger goiter… and has signs of compression on
D es

tri
ed t

lying supine?
r R rin
An

is

Awake Fiber optic (best option)

Inhalational Induction (Second option) with check laryngoscopy

Tracheostomy cannot be done in a Thyroid Patient

Patient with Hoarseness of voice and has vocal cord tumor, came for cord biopsy…
MLT (Micolaryngeal tube) to be used

Patient with Laryngeal Tumor. Came for Laryngectomy, and has stridor… what to do?
Ans: Tracheostomy under L/A
Always tracheostomy in laryngeal tumor or when there is Stridor

Which instrument do you need to have in an airway that can collapse?

Rigid Bronchoscopy
Post-op After Thyroid Surgery:
As soon as after extubation, patient is unable to breathe?
B/L Recurrent Laryngeal nerve transection

Large Thyroid post op?

Tracheomalacia… patient will go into resp obstruction immediately after extubation.

After thyroid surgery, surgeon shown the vocal cords… later patient becomes hypoxic and pink frothy
sputum…
Laryngospasm because of deep extubation causing Negative pressure pulmonary edema

Patient in recovery after thyroid… unable to breathe…?

Hematoma… Tx: Open the sutures.
If need to re-explore… Inhalational Induction.

a
If NPO broken… RSI

tth
C s
ad ote
ha
Patient in recovery, carpopedal spasm on BP cuff inflation?
hm N

Hypocalcemia
fo r P ale A am

Hyperthyroid patient, agent of choice for induction?

ot o S an x
N ot f or sh a E

Thiopentone (has some antithyroid action) n

N ot f ee esi

tio

Adrenal:
N r. Z th

bu

Addison Disease: Primary adrenal insufficiency

D es

tri
ed t
r R rin

Deficiency of mineralocorticoids and glucocorticoids

An

is

Pickup point: Hyperpigmentation (due to high ACTH)

Most common cause: Autoimmune

Secondary Adrenal Insufficiency:

ACTH decreased… there will be no pigmentation, and all rest signs of adrenal insufficiency will be
present.
Symptoms: Weakness, Fatigue, Weight loss.

Signs of Cushing’s disease:

• Hypertension
• Moon facies
• Truncal Obesity
• Muscular Weakness
• Striae on belly
• Osteoporosis in limbs

Conn’s Disease:
Increased Mineralocorticoids:
Hypokalemic metabolic alkalosis

Most common presentation of pituitary adenoma:

Prolactinoma

Major cause of mortality and morbidity in cushing syndrome/disease:

Ischemic heart disease due to hypertension

What is the best method to excise a pituitary adenoma?

Transsphenoidal Hypophysectomy

a
tth
C s
What is the advantage of Transsphenoidal approach?
ad ote
ha
Ans:
hm N

• Minimal post op pain

fo r P ale A am

• Decreased incidence of nasal perforation and trauma to dentures

ot o S an x
N ot f or sh a E

Disadvantages: n
• Inc incidene of CSF leak
N ot f ee esi

tio

• Hemorrhage control difficult

N r. Z th

bu
D es

tri
ed t

What is recommended for intra-op hemodynamic stability for transsphenoidal surgery?

r R rin
An

is

Propofol with Remifentanyl

What is target PaCO2 for patient with hypophysectomy?

Ans: Selective hypercapnia (40-45mmHg) so that ICP is a bit higher so that it pushes tumor down

Most risk with beach chair position?

VAE (venous air embolism)

Which maneuveur has best chance to decrease risk of venous air embolism?
Head tilt of less than 40o

Patient of transsphenoidal surgery NGT not to be placed for how many days?
14 days
Hyper and Hyponatremia:

Patient producing lot of urine after hypophysectomy?

Diabetes insipidus
Diabetes Insipidus after Transsphenoidal hypophysectomy… treatment?
Its usually self limiting
First treatment is Fluids
If urine out put is more than fluid intake for more than 6 hours… Desmopressin

Diabetes Insipidus:
Patient with TBI… polyuria
First thing to do is Plasma and urine osmolalities
Serum Sodium level

a
If ADH is low… its central D.I.

tth
C s
If ADH not able to act: Renal D.I (Peripheral DI)
ad ote
ha
Presentation:
hm N

Urine osmolality will be low due to dilute urine

fo r P ale A am

Serum osmolality will be high

Serum sodium will be increased
ot o S an x
N ot f or sh a E

If a patient has:
n
N ot f ee esi

tio

Urine output less

N r. Z th

bu

Serum osmolality high

D es

tri
ed t

Serum Sodium raised

r R rin
An

is

Urine osmolality high

This is dehydration.

Hypernatremia with High Urine output Low Urine output

DI Dehydration

Which one of following causes Iatrogenic D.I?

Lithium

Which is used in treatment of Iatrogenic D.I?

Carbamazepine

Differentiate between central and nephrogenic D.I?

Desmopressin Suppression test

Patient hypernatremia with high urine output?

Give desmopressin… if it improves… Its central D.I
SIADH/CSWS:
Hyponatremia with High urine output Low urine output
CSWS SIADH

Patient has hyponatremia and urine output low with good hydration status?
SIADH

Patient has hyponatremia and urine output high with dehydration?

CSWS

Osmolarities:
Hyponatremia, low urine output good volume status… urine osmolarity will be (SIADH)?
Urine Osmolarity will be High

a
Urine osmolarity should be higher than plasma osmolarity for diagnosis of SIADH.

tth
C s
ad ote
ha
CSWS:
hm N
Body unable to reabsorb Sodium
fo r P ale A am

CSWS in early phase… body has adequate sodium and adequate water… so when sodium is excreted it
ot o S an x
N ot f or sh a E

will take water with it, so urine osmolarity will be normal or decreased in early phase, but serum
osmolarity will be higher.
n
N ot f ee esi

tio
Later in disease… sodium is excreted but there is not adequate water left in body to be excreted along
N r. Z th

bu

with sodium… so urine osmolarity will be higher or normal later in disease.

D es

tri
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r R rin
An

is

Hyponatremia:
Patient Sodium less than 120mEq … treatment will be 3% hypertonic saline
Patient Sodium more than 120mEq with low urine output and good volume status of patient… initial
treatment will be fluid restriction.
Definitive management: Drug of choice… Demeclocyclin
Ferusemide can also be given.

CSWS patient, Sodium 125, high urine output, dehydrated patient… initial management?
Normal Saline infusion.
An
D es
N r. Z th
N ot f ee esi
N ot f or sh a E
ot o S an x
fo r P ale A am
r R rin hm N
ed t ad ote
is C s
tri ha
bu
tio tth
n a
Pheochromocytoma:
30 yr male with headache, sweating and palpitations with high BP….
Pheochromocytoma

Pehochromocytoma: Tumor of Enterochromaffin cells of adrenal medulla…

MEN IIA:
Tumors of:
Pheochromocytoma
Medullary Thyroid CA
Parathyroid

MEN IIB:
Tumors of

a
Pheochromocytoma

tth
C s
Medullary Thyroid CA ad ote
ha
Neurofibromatosis
hm N
fo r P ale A am

MEN I:
ot o S an x

Pituitary adenoma
N ot f or sh a E

Parathyroid tumors n
Pancreatic tumors
N ot f ee esi

tio
N r. Z th

bu
D es

tri
ed t
r R rin
An

is
An
D es
N r. Z th
N ot f ee esi

Rule of 10 regarding Pheochromocytoma:

N ot f or sh a E
ot o S an x
fo r P ale A am
r R rin hm N
ed t ad ote
is C s
tri ha
bu
tio tth
n a
Which one of following is the most sensitive test to detect pheochromocytoma?
Serum Free Metanephrine

Which is most specific test for pheochromocytoma?

Urinary VMA

Less than 2 cm adrenal tumor. Which test to diagnose it?

MRI

If tumor in extra adrenal tissues?

MIBG scan

Pre-op assessment/preparation…
First: Alpha blocker – Phenoxybenzamine – irreversible alpha blocker

a
Stop 24-72 hours before surgery. It has a half life of 24 hours and lasts for 72 hours. So we stop it 24-72

tth
C s
hours before to avoid intra-op hypotension.
ad ote
ha
Phentolamine half life is 20 minutes. (reversible alpha blocker)
hm N

These are both non selective alpha blockers

fo r P ale A am

When alpha blockade adequate… heart rate less than 100 and BP controlled… there is no need for Beta
ot o S an x
N ot f or sh a E

blocker. If H.R more than 100 only then Beta blockade is required.
Beta blockade to be done with Selective beta blocker… Atenolol or Metoprolol
n
N ot f ee esi

tio

Non selective not used so than B2 supply is not blocked.

N r. Z th

bu
D es

tri
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Alpha blockade done before beta blockade:

r R rin
An

is

To decrease the risk of unopposed alpha action that can cause hypertensive crisis and severe
bradycardia and risk of ischemic heart disease.

Assessment of Alpha Blockade:

5 criteria to be fulfilled:
1. BP is less than 160/90mmHg 24 hour before admission on 2 different occasions
2. Postural hypotension of more than 20mmHg
3. ECG free of all ST-T wave changes
4. No PVCs in 5 minutes
5. Nasal congestion

Patient elective surgery for pheochromocytoma… adequate alpha blockade achieved… how to blunt
laryngoscopy response?
Esmolol 0.5mg/kg
Remifentanyl 0.5mg/kg
Fentanyl 1-2 mcg/kg
Lignocaine 1.5mg/kg
Laparotomy for adrenalectomy… best pain management plan?
Epidural

Relaxant of choice in pheochromocytoma?

Vecuronium
Because Rocuronium and Pancuronium have vagolytic action, so these can cause tachycardia.
Atracurium to be avoided because histamine release which can cause tachycardia.

Vecuronium also indicated in hyperthyroid.

Hyperthyroid patient… induction agent of choice… Thiopentone
Thiopentone also agent of choice in Epilepsy

Which inhalational agent to avoid in pheochromocytoma?

a
Desflurane (To avoid sympathetic stimulation)

tth
C s
ad ote
ha
If there is high BP surge intra-op… which agent of choice?
hm N

Phentolamine
fo r P ale A am

Sodium Nitroprusside
(the one from Cyprian is to be followed)
ot o S an x
N ot f or sh a E

n
N ot f ee esi

tio

Patient being given sodium nitroprusside… BP rises again and acidosis on ABGs..?
N r. Z th

bu

Cyanide toxicity
D es

tri
ed t
r R rin
An

is

After removal of pheochromocytoma… in recovery BP is 90/50,.. initial management?

Fluids

After adequate fluids given… MAP is 56… what next?

Give more fluid…

Now BP not rising with ore fluids… then?

Noradrenaline
Also Noradrenaline with low dose Dopamine can be used.
Have to maintain peripheral perfusion

Patient with B/L adrenalectomy… post op hypotension with fever?

Adrenal crisis (cortisol deficiency)

Post op hypertension in a resected pheochromocytoma?

Pain
Rare cause… unresected tumor