High-sensitivity Cardiac Troponin Elevation after Electroconvulsive Therapy (ECT)

Study Design and Oversight

We conducted a prospective cohort study in 100 evaluable patients who underwent ECT at Barnes-Jewish Hospital, St. Louis, MO. The study was approved by the Institutional Review Board (IRB) of Washington University, St. Louis, MO, and written informed consent was obtained from each patient.

Patients and Treatment

Adult patients scheduled to undergo ECT were eligible for recruitment. Patients with baseline cognitive impairment were excluded. ECT and anesthesia were provided according to departmental standards. For anesthesia, etomidate (0.1–0.2 mg/kg body weight) and succinylcholine (0.5–1 mg/kg body weight) were administered intravenously and patients were ventilated with 100% oxygen. No beta-blockers or other antihypertensive drugs were administered per institutional practice. Typically, patients received either right unilateral, bifrontal or bitemporal ECT treatment according to a standard institutional ECT regimen using a Thymatron System IV Electroconvulsive Therapy Unit (Somatics, LLC, Venice, FL), and trains of 0.3 ms pulses at 6.0 times the seizure threshold for right unilateral (d’Elia position) and 1.0 ms pulses at 2.0 times the threshold for bitemporal and bitemporal treatments. Seizure thresholds were estimated at the initial treatment for all patients using a method of limits approach.

Assessment and Outcomes

The goal of this study was to quantify the incidence and magnitude of new cardiac troponin elevation after each ECT visit for a series of up to three treatments in each patient. Patient demographics, cardiovascular risks, and home medications were assessed at enrollment. For each treatment, high-sensitivity cardiac troponin I (hscTnI) and a 12-lead ECG were obtained within two hours before and within 15–30 minutes after ECT in all patients. After study initiation, the study protocol was amended to allow the acquisition of an additional hscTnI sample two hours after ECT to determine if hscTnI kinetics may reveal delayed troponin changes that were not present shortly after ECT. ECGs were analyzed for signs of ischemia (such as new ST-segment depression or elevation; T-wave inversion; presence of new Q-waves or left bundle branch block) by a blinded expert. Periprocedural heart rate, blood pressure, and pulse oximetry were recorded in 2- to 5-minute intervals, and clinical signs of myocardial ischemia were monitored and until two hours after ECT.

Primary outcome was the incidence of new hscTnI elevation after ECT, defined as an hscTnI increase >100% combined with at least one value above the limit of quantification (LOQ; 10 ng/L). In addition, we determined new hscTnI elevations above the sex-specific 99^th percentile upper reference limit (URL).¹⁷ We investigated up to three ECT treatments per patient to determine the variability of hscTnI elevation after each ECT visit. Additional outcomes included MI defined as an hscTnI increase above the LOQ plus clinical or ECG signs of myocardial ischemia according to the Third Universal definition of MI¹⁸, hypertensive episode defined as periprocedural peak systolic blood pressure >160 or >200 mmHg, and tachycardia defined as a peak heart rate >100 or >150 beats per minute.

Laboratory Analyses

Samples were collected in lithium heparin tubes, immediately put on ice and centrifuged within 30 minutes of collection. Plasma was transferred into cryogenic tubes and stored at −70°C. Biomarker measurements were performed in batches and by study personnel unaware of clinical outcomes. Grossly hemolyzed samples were excluded from analysis. hs-cTnI (reported as ng/L) was measured on an Abbott Architect STAT©, Abbott Laboratories, Abbott Park, IL, platform (limit of blank 0.7 – 1.3 ng/L; limit of detection 1.1 – 1.9 ng/L; LOQ: 10.0 ng/L; 99^th percentile URL female: 15.6 ng/L; male: 34.2 ng/L).¹⁹ Imprecision of the assay at the 99^th percentile concentrations is <6% coefficient of variation.¹⁵

Statistical Analysis

Only ECT treatment visits with available before-and-after hscTnI levels were included for analysis. The cumulative incidence of new hscTnI elevation, as well as hypertensive episodes and tachycardia after ECT was calculated per patient and per whole cohort. Sample size was not based on a formal sample size calculation, but chosen based on our previous experience with using hscTn and its ability to reliably detect even small hscTn changes.²⁰ HscTnI values are presented as median and interquartile range. Friedman’s ANOVA for paired hscTnI data was used to test for statistically significant changes in hscTnI levels over three treatments for all patients as well as in the subgroup with an additional hscTnI sample available two hours after ECT. Linear correlation was analyzed by calculation of Spearman’s correlation coefficient. All p-values are two-sided and a p<0.05 was considered statistically significant (IBM® SPSS® version 22, IBM, Armonk, NY; JMP Pro 12.2, SAS Institute, Cary, NC). Plots were produced using GraphPad Prism® version 6.07 (GraphPad Software Inc, La Jolla, CA) and JMP 12.2. (SAS Institute, Cary, NC).

Patients

Between June 2011 and September 2012 115 patients were recruited into the study. After withdrawal of 15 patients the final study population was 100 patients (Figure 1), of which 58 patients had three ECT visits, 29 patients had two ECT visits, and 13 patients had one ECT visit analyzed. In total, complete before-and-after hscTnI data were available for 245 ECT treatment visits (58×3+29×2+13×1=245). In the final 14 of 100 (14%) patients (35 of 245 ECT treatments) an additional hscTnI level was obtained 2 hours after ECT. Table 1 presents patient characteristics. The majority of patients received ECT for major depressive disorder or bipolar disorder. Table 2 provides details about the ECT treatments. In 38% (n=38), the first study ECT visit coincided with the first ECT treatment the patient received during which initial seizure threshold determination was made.

Study Outcomes

Figure 2 shows the absolute and relative changes in hscTnI after ECT. HscTnI levels did not change significantly after ECT treatments both immediately after ECT (n=72; P=0.4), as well as in the subgroup with an additional hscTnI sample available two hours after ECT (n=10; P=0.6) (Figure 3). Most patients did not experience an increase in hscTnI after ECT, but a subset had a marked increase (maximum hscTnI: 731.6 ng/L). Patients who developed new hscTnI elevation after ECT tended to be older and had more cardiovascular risk factors

Eight patients (8/100, 8%) experienced new hscTnI elevation after ECT with a cumulative incidence of 3.7% (9/245 treatments; one patient experienced two hscTnI elevations after separate ECT visits) (Table 3, Figure 4). A detailed description of the eight patients who developed a new hscTnI increase is provided in Table 3. Two patients (patients A and C in Table 3 and Figure 4) met definitive criteria for non-ST-elevation myocardial infarction (NSTEMI) (incidence 2/245, 0.8%). In a total of ten ECT visits (10/245, 4.1%) of six patients (6/100, 6%) hscTnI was already elevated >99th percentile URL prior to ECT, and they did not experience a subsequent new hscTnI elevation.

Table 3.

Patients with post-ECT hscTnI elevation >100%

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Patients who had their initial ECT treatment with seizure threshold determination did not experience significantly different absolute or relative hscTnI changes after ECT compared to patients who had subsequent ECT treatments (absolute difference: −0.1 ng/L [−0.9, 0.8] median [IQR], vs. −0.1 [−1.1, 0.9], p=0.74; relative difference: −1.8% [−16.9, 9.8], median [IQR], vs. −2.4% [−16.9, 14.4], p=0.95]. Four patients with initial ECT and seizure threshold determination experienced an hscTnI increase >100% (4/37, 10.8%) compared to four patients undergoing subsequent ECT treatments (4/62, 6.5%); this corresponded to a non-significant unadjusted odds ratio of 1.68 (95% CI 0.40 – 7.11, p=0.48). Neither central seizure duration nor convulsion duration were correlated with absolute hscTnI change after ECT (r=−0.10 and −0.13, respectively). Among the eight patients with hscTnI elevation, seven received right unilateral and one bifrontal ECT treatment.

In approximately two thirds of ECT visits tachycardia (HR >100/min) and/or elevated systolic blood pressure (>160 mmHg) after ECT developed (Table 4). In approximately 17% of ECT visits, peak systolic blood pressure was elevated > 200 mmHg with maxima reaching up to 250 mmHg. Neither peak heart rate (r = −0.06) nor systolic blood pressure (r = 0.19) were correlated with absolute hscTnI change.

New cardiac troponin elevation

Cardiac troponin, a myocardial protein, is a very sensitive and specific cardiac and standard biomarker for the diagnosis of MI.¹⁸ Cardiac troponin is released when myocardial cells are injured and the magnitude of cardiac troponin elevation correlates with the damaged or necrotic myocardial cell mass. The newly developed high-sensitivity cardiac troponin assays (not available in the U.S. at present) measure the same cardiac troponin molecule, but have significantly increased analytic sensitivity that allows detection of circulating cardiac troponin in >50% of healthy subjects.¹⁵

Cardiac troponin elevations in the absence of clinical symptoms, such as chest pain or ischemic ECG changes, have recently been referred to as “myocardial injury” or “myocardial damage”.^21,22 However, there are currently no accepted guidelines as to which absolute or relative cardiac troponin elevations and changes constitute myocardial injury.²¹ Short-term within individual biologic variability of cardiac troponin concentrations in healthy subjects has been reported to be 4–14% and when combined with analytic variability the positive reference change value for hscTnI is 45–52%.^23–25 The biologic and analytic variability of hscTnI levels may therefore result in intra-individual increases and decreases of up to 52%. The RCV is the change that exceeds normal biologic variability and analytic variability and represents a physiologic change. Thus, in the rapid rule in/rule out diagnosis of MI in patients with chest pain, a relative increase of >50% is often interpreted as a positive test.¹⁵ Little evidence is available for clinical scenarios in which a “true” baseline can be obtained, such as patients undergoing ECT or cardiac stress test. Taking into account the uncertainty around “significant” cardiac troponin elevations and analytical and biological variability, we opted for a conservative cutoff of a >100% hscTnI increase compared to the pre-ECT sample to identify patients with a new significant cardiac troponin elevation after ECT in order to decrease the likelihood of false positives.^{17,24,26–28}

Clinical relevance

New cardiac troponin elevations without definitive signs of myocardial ischemia have recently been referred to in the cardiology literature as “myocardial injury” or “myocardial damage”.²² Although the criteria for defining and diagnosing myocardial injury or damage are lacking, there is evidence that even small cardiac troponin elevations after major stress may have prognostic significance for subsequent cardiovascular morbidity and mortality.²⁹ The cause for the observed new hscTnI elevations in our patient population is unclear: in some patients, particularly those with pre-existing coronary artery disease, the cause may be stress-induced myocardial ischemia via supply-and-demand mismatch. In other patients, stress-induced catecholamine release may directly cause myocardial cell damage. The latter mechanism is possibly related to stress-induced cardiomyopathy (Takotsubo), which has been described in patients undergoing ECT. ^9–12 Investigations focused on electro- and echocardiographic evidence for ECT-induced myocardial ischemia found incidence rates of new regional wall motion abnormalities (indicative of ischemic myocardium in the distribution of a coronary artery) in 4 – 45% of patients.^4,30 The largest population-based study of mortality after ECT found 78 deaths within 30 days after ECT among 99,728 ECT treatments in the Danish National Patient Register (mortality rate: 0.08%). Six of these deaths occurred on the day of ECT treatment. The most prevalent attributed cause of deaths was cardiopulmonary.³¹

Using contemporary cardiac troponin assays, Martinez and coauthors found an 11.5% incidence rate of new abnormal cardiac troponin elevations after ECT.^13,32 Integrating case report series, cardiac biomarker studies, and echocardiographic evidence it appears that a small subset of patients – probably those with chronic heart and/or lung disease – are at higher risk of developing adverse cardiac events after ECT. It is beyond the scope of this article, but efforts have been made to use preventive strategies to mitigate the cardiac risk associated with ECT in high-risk patients, such as improved identification¹⁴ or therapeutic strategies, such as beta-blockers.^33,34 It should be pointed out that patients who did not develop new hscTnI elevation after ECT, but had already elevated baseline hscTnI values, may be at increased long-term cardiovascular risk even if they did not experience myocardial injury during ECT.

Strengths and Weaknesses

The use of a novel high-sensitivity cardiac troponin assay is a strength of the study for two main reasons. First, these novel assays have increased the sensitivity for detection of cardiac troponin by an order of magnitude over traditional cardiac troponin assays. The increased sensitivity allows for the detection of small cardiac troponin concentration differences with a high degree of precision. Second, the use of these hscTn assays allows for the detection of circulating cardiac troponin at “baseline” and in absence of an acute cardiac event. Thus, they allow before-and-after measurements and thereby a rigorous quantification of delta or change values which correspond to the amount of injured myocardium. However, there is overwhelming evidence in other populations that increased cardiac troponin predict future cardiovascular risk.^15,16

The fact that this study did not follow patients for long-term cardiovascular outcomes precludes the determination if observed cardiac troponin elevations had any long-term clinical relevance. Second, we were unable to obtain pre- and post ECT hscTnI values for all patients and all three planned ECT treatment measurements, which limited the power of the study. Third, the study was not designed to obtain robust incidence rates for hard clinical outcomes, such as NSTEMI. Thus the observed incidence rate of NSTEMI (2%) may substantially under- or overestimate the true incidence.