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Minimum Effective Doses of Succinylcholine and Rocuronium During Electroconvulsive Therapy: A Prospective, Randomized, Crossover Trial

Mirzakhani, Hooman MD, PhD, MMSc; Guchelaar, Henk-Jan PharmD, PhD; Welch, Charles A. MD; Cusin, Cristina MD; Doran, Mary E. NP; MacDonald, Teresa O. RN; Bittner, Edward A. MD, PhD; Eikermann, Matthias MD, PhD; Nozari, Ala MD, PhD

doi: 10.1213/ANE.0000000000001218
Ambulatory Anesthesiology and Perioperative Management: Original Clinical Research Report

BACKGROUND: Neuromuscular blockade is required to control excessive muscle contractions during electroconvulsive therapy (ECT). In a crossover, assessor-blinded, prospective randomized study, we studied the minimum effective dose (MED) of succinylcholine and rocuronium for ECT. The MED was the lowest dose to provide a predefined qualitative measure of acceptable control of muscle strength during induced convulsions.

METHODS: Succinylcholine (0.8 mg kg−1) or rocuronium (0.4 mg kg−1) was randomly administered in 227 ECT sessions to 45 patients. The dose was incrementally increased or decreased by 10% based on 2 psychiatrists’ (blinded to treatment) assessment of “acceptable” or “not acceptable” control of evoked muscle contractions (sufficient versus insufficient or excessive paralysis). The neuromuscular transmission was monitored quantitatively until full recovery.

RESULTS: In our study, the MEDs of succinylcholine and rocuronium to produce acceptable ECT conditions in 50% of patients (MED50ECT) were 0.85 mg kg−1 (95% confidence interval [CI], 0.77–0.94) and 0.41 mg kg−1 (95% CI, 0.36–0.46) and in 90% of patients (MED90ECT) were 1.06 mg kg−1 (95% CI, 1.0–1.27) and 0.57 mg kg−1 (95% CI, 0.5–0.6), respectively. Nadir twitch height for acceptable muscle activity was 0% (0–4) and 4% (0–30; P < 0.001), respectively, and the time to recovery of the neuromuscular transmission was 9.7 ± 3.5 and 19.5 ± 5.7 minutes, respectively.

CONCLUSIONS: A twitch suppression of >90% is needed for control of motor contractions during ECT. The initial ECT dose of succinylcholine should be selected based on each patient’s preprocedural condition, ranging between 0.77 and 1.27 mg kg−1 to produce acceptable muscle blockade in 50% to 90% of patients. Rocuronium–neostigmine combination is a safe alternative if appropriately dosed (0.36–0.6 mg kg−1) and monitored.

Supplemental Digital Content is available in the text.Published ahead of print March 10, 2016

From the *Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Broad Institute of MIT and Harvard, Cambridge, Massachusetts; Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts; §Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden University, Leiden, The Netherlands; Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Patient Care Services/Special Care Nursery, Massachusetts General Hospital, Boston, Massachusetts; and #Clinic for Anesthesiology and Intensive Care, Essen University Hospital, Essen, Germany.

Accepted for publication December 18, 2015.

Published ahead of print March 10, 2016

Funding: Departmental.

Conflict of Interest: See Disclosures at the end of the article.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website.

This report was previously presented, in part, at the IARS 2012 meeting, Boston, Massachusetts.

Reprints will not be available from the authors.

Address correspondence to Hooman Mirzakhani, MD, PhD, MMSc, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, 55 Fruit St, Boston, MA 02114. Address e-mail to hoomi@post.harvard.edu.

Electroconvulsive therapy (ECT) is a treatment in which generalized seizures are induced by transcutaneous electrical stimuli to the brain to treat specific psychiatric conditions such as major depressive or cyclothymic disorders.1,2 The quality and duration of the induced seizure by ECT have been associated with the efficacy of the procedure. Anesthetic drugs and neuromuscular blocking agents (NMBAs) are administered to ensure patient comfort and safety but need also be titrated to provide optimal conditions for the induced seizure activity during the treatment while allowing a rapid recovery on its completion.3 Because of its rapid onset and short duration of action, succinylcholine is considered the NMBA of choice for ECT; however, a nondepolarizing NMBA needs to be considered in some patients with metabolic, neuromuscular, or neurologic comorbidities or other contraindications to succinylcholine (eg, immobilization or pseudocholinesterase deficiency).4 Despite the importance of NMBAs to provide favorable conditions for ECT, the NMBA dose to achieve acceptable level of muscle contracture via the use of neuromuscular blockade without excessive or untoward effects has not been identified in a prospective randomized fashion and via the use of objective monitoring techniques.5 The aim of this study is, therefore, to identify the minimum effective starting NMBA doses of 2 commonly used neuromuscular blocking drugs (succinylcholine and rocuronium), defined as the lowest dose to provide optimized muscle strength modulation during ECT.

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METHODS

This crossover, randomized controlled, assessor-blinded clinical trial was conducted in the postanesthesia care unit at Massachusetts General Hospital in Boston, Massachusetts. The IRB approved the study protocol, and written informed consent was obtained from all participating patients. The study was registered before patient enrollment. Registry Url: http://clinicaltrials.gov/ct2/show/NCT01441960. Identifier: NCT01441960.

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Patients

Two hundred twenty-seven ECT sessions were conducted in 45 hospitalized patients aged 24 to 80 years with ASA physical status I to III admitted for a series of ECT treatments at a frequency of 3 times per week. The indication for ECT in all enrolled patients was major depressive disorder or bipolar disorder, and all patients were taking psychotropic medications, including antidepressants and antipsychotics, as indicated by their psychiatric condition. Only patients within 20% of the ideal body weight were included. Exclusion criteria included age <18 years, patients with illness or medications known to influence neuromuscular transmission, significant renal or liver dysfunction, electrolyte abnormalities, and pregnant women.

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Protocol

The flow of patients through the study is depicted in Figure 1. After screening by the psychiatrist and anesthesiologist responsible for the clinical treatment of each patient, informed consent was obtained and patients were enrolled. After preoxygenation with 100% oxygen for 3 minutes through a facemask, anesthesia was induced with propofol (1.2 mg kg−1 IV over 5 seconds). Continuous neuromuscular transmission monitoring was applied after stabilization and baseline calibration to establish a control twitch response before NMBA injection (see the Neuromuscular Transmission Monitoring section). Succinylcholine (Quelicin®, Hospira Inc., Lake Forest, IL) 0.8 (2.67 × ED95) mg kg−1 or rocuronium-bromide (Zemuron®, Organon USA Inc., a subsidiary of Merck & Co. Inc., Roseland, NJ) 0.4 mg kg−1 (1.33 × ED95) was then administered IV over 5 seconds through an IV catheter in the arm contralateral to the side of neuromuscular transmission monitoring, which was then flushed with a 10-mL bolus of normal saline. These initial doses were selected as the median of applied succinylcholine and rocuronium doses to achieve acceptable ECT-induced motor activity in a pilot study of 10 patients. Ventilation was assisted until recovery of normal spontaneous ventilation through a facemask and an Ambu-bag with supplemental 100% oxygen.

Figure 1

Figure 1

After the peak effect of neuromuscular transmission blockade was established, an electrical stimulus at approximately 6× seizure threshold was delivered with right unilateral application of electrodes with a MECTA Model SR II apparatus (MECTA Corp., Portland, OR). The treating psychiatrists, blinded to the type and dose of the NMBA (see Discussion), determined the stimulus parameters for the applied ECT (level, dynamic, energy, intensity, and duration of stimulus) and the subsequent duration of seizure (Table 1). The duration of seizure was monitored by electroencephalogram (EEG) and recorded from EEG activity.

Table 1

Table 1

Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were recorded every 3 minutes, and the heart rate (HR) and oxygen saturation (SpO2) were monitored and recorded continuously throughout the procedure and until the patient’s full recovery. Temperature was monitored and maintained at ≥35°C. Labetalol (10–50 mg IV) or esmolol (40–80 mg IV) was administered to treat hypertension and tachycardia, when necessary.

After termination of seizure and when appropriate, as determined by the practicing anesthesiologist, the rocuronium-induced neuromuscular blockade was reversed with 50 μg kg−1 neostigmine in conjunction with 10 μg kg−1 glycopyrrolate.6 After return of normal spontaneous breathing, patients were placed in a lateral decubitus position. Neuromuscular monitoring was continued until full recovery of the neuromuscular blockade was recorded (T1 = 100% or train-of-four [TOF] ratio of >0.9 for succinylcholine and rocuronium, respectively).7

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Neuromuscular Transmission Monitoring

Neuromuscular transmission was monitored using acceleromyography, and a TOF-Watch SX® monitor (Organon) was connected to a laptop computer. Before induction of anesthesia, the subject’s arm was taped in a stable and comfortable position, skin was cleansed, and surface electrodes were placed (3–5 cm apart) over the ulnar nerve at the wrist. A hand adaptor (Organon) was used to fix the thumb position to minimize the potential variability in evoked muscle contraction. The TOF-Watch was calibrated by use of the standard calibration with default supramaximal stimulation (CAL1: 10-second stimulation current of 50 mA), and ulnar nerve stimulation was resumed with single twitch stimulation at 0.1 Hz and continued till observation of <5% variation of twitch heights for 2 to 3 minutes, after which a bolus dose of the NMBA was injected.8 The same mode of stimulation was continued until the peak effect of neuromuscular transmission blockade was established (first of 3 consecutive twitches with the same/increasing value or ≥95% depression of twitch).8

After completion of the ECT-induced seizure, twitch stimulation was continued in patients who had received succinylcholine until a twitch height of 100% of control (baseline) with response variation <5% for 2 minutes was recorded.8 For rocuronium-treated patients, the mode of stimulation was changed to TOF stimulation with square wave pulses of 0.2-milliseconds duration delivered at 2 Hz every 15 seconds and continued until 3 consecutive responses with a TOF ratio ≥0.9 were recorded. All twitch height values during the recovery phase were normalized to final twitch value and were expressed as percentages of control values.8

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NMBA Randomization and Crossover

Patients were assigned randomly to receive either succinylcholine or rocuronium at a standard initial dose, as listed previously, during their first ECT. During each subsequent ECT treatment (2 days apart), patients received a 10% higher (if insufficient paralysis) or lower (if sufficient or excessive paralysis) dose of the same NMBA until the minimum effective dose (MED) that resulted in acceptable neuromuscular blockade (MEDECT) was identified. When the MEDECT dose of the first NMBA was identified, each patient received the second NMBA (ie, succinylcholine if rocuronium had been administered, and vice versa) for his or her subsequent ECT treatments, and the dose was increased or decreased in 10% increments according to the same protocol until the MEDECT dose for the second NMBA was established (Supplemental Digital Content 1, Supplemental Figure 1, study design, http://links.lww.com/AA/B372).

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Quality Assessment of Neuromuscular Blockade

Table 2

Table 2

The quality of neuromuscular blockade during seizure was independently assessed by the use of a dichotomous scale of “acceptable” or “not acceptable” by 2 psychiatrists blinded to the dose and type of NMBA. A grading system was used to score the 2 psychiatrists’ evaluation. Each psychiatrist provided a single score based on the defined criteria for “acceptable” or “not acceptable” ECT conditions (Table 2). A summed score of ≥2 was considered as acceptable level of induced muscle relaxation. Any summed score of <2 was considered as a not acceptable level of induced neuromuscular blockade. Consequently, NMBA trials were continued until the lowest dose that provided acceptable neuromuscular blockade during induced seizure was identified.

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Outcome Variables

The primary clinical outcome of the study was to define the MEDECT of succinylcholine and rocuronium for each subject to achieve our definition of an acceptable level of neuromuscular blockade. MED50ECT was, hence, defined as the smallest dose of succinylcholine or rocuronium that resulted in adequate muscle relaxation and safe application of ECT in 50% of the cases. We also provide the NMBA dose that resulted in adequate relaxation in 90% and 95% of the population (MED90ECT and MED95ECT, respectively) and the nonparametric bootstrap confidence intervals (CIs) for the upper tail distribution of the optimal doses. The measured MED50ECT of succinylcholine and rocuronium and the corresponding T1 suppression for acceptable motor activity during ECT were compared with their ED95s (median dose corresponding to >95% adductor pollicis twitch depression9), ie, m × ED95 under the conditions studied (ECT). As a coprimary outcome, the estimated CIs for each MEDECT are calculated to identify the range of MEDs for each applied NMBA for ECT.

The secondary outcome was the duration of the neuromuscular transmission blockade defined as the time to complete recovery from neuromuscular blockade after a single bolus dose of the MED50ECT, ie, return of the twitch height to its baseline if succinylcholine had been administered or TOF ratio ≥0.9 if rocuronium was used. All patients were monitored until full recovery from neuromuscular blockade (twitch height of 100% or TOF ratio ≥0.9 for succinylcholine and rocuronium, respectively).

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Statistical Analysis

Data are presented as mean ± SD or (range) unless otherwise specified. On the basis of results from previous NMBA dose−response studies, we considered a minimum sample size of 24 to be adequate for the estimation of MED50ECT with 80% power and with a reasonable degree of assurance.10,11 We also used resampling and bootstrap method for estimation of MED50ECT CIs to investigate the adequacy of sample size on the estimated confidence limits (Supplemental Digital Content 2, http://links.lww.com/AA/B373). In addition, we conducted a power analysis to determine the sample size needed for our secondary outcome parameters, ie, the duration of block and time to recovery. In our pilot data from10 patients, a 3-minute difference in recovery end points (100% twitch height recovery or TOF ≥0.9 for succinylcholine and rocuronium, respectively) with a SD of 5 minutes was observed. Assuming a normal distribution of the data, we calculated a sample size of 31 to achieve 90% power to detect a mean of paired differences of 3.0, with a known SD of differences of 5.0 and with a significance level (α) of 0.05 using a 2-sided Wilcoxon test. Accordingly, we concluded that a sample size of 31 would provide adequate power for both of our clinical outcome parameters.

All the calculations were performed using SPSS Statistics for Windows, version 19.0 (IBM Corp., Armonk, NY, 2010), PASS 11 (NCSS, LLC., Kaysville, UT), and SigmaPlot 11 (Systat Software, San Jose, CA).

Normality assumption of the measured variables was assessed using the Lilliefors test (all P > 0.12 and N = 31). The Welch t test was conducted to compare the measured variables (eg, recovery time, duration of seizure, and hemodynamic variables) obtained under succinylcholine and rocuronium conditions (P > 0.01).12,13 Cohen κ for interrater reliability was used to assess interrater reliability between the 2 assessors of motor seizure activity during ECT. The MED of NMBA was defined as the lowest dose that provided completion of ECT under our definition of acceptable conditions (MEDECT). The minimum acceptable doses obtained from the study patients (31 minimum doses for either of crossed-over groups, succinylcholine or rocuronium) were resampled 10,000 times using the nonparametric bootstrap method.14 The 25th, 50th (median), 75th, 90th, and 95th percentiles of these samples (MED25ECT, MED50ECT, MED75ECT, MED90ECT, MED95ECT, and MED99ECT, respectively) and the corresponding 95% and 99% CIs were then calculated.

Covariates included were age, ASA physical status, anesthetic dose, and the ECT parameters. A P value <0.05 (unless otherwise specified) was considered statistically significant and reported for a 2-tailed test.

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RESULTS

Two hundred twenty-seven ECT treatments in 45 enrolled subjects were recorded. Thirty-one subjects completed their series of treatment, generating a total of 187 qualified ECTs for data analysis (Figure 1). To identify the optimal dose of each NMBA, a range of 2 to 4 observations was needed, yielding a total of 187 qualified ECTs for data analysis. The mean age and body weight of the subjects were 50 ± 8 years (range, 24–80 years, female/male: 15/16) and 80 ± 20 kg (range, 49–109 kg), respectively. Median of ASA physical status was II. There were no significant differences between the 2 groups (treated patients with succinylcholine or rocuronium) in baseline values of SpO2, HR, SBP, and DBP. The dose of propofol used to induce anesthesia was not different in the succinylcholine and rocuronium groups (100 ± 28 mg vs 105 ± 29 mg, P > 0.05). No significant difference was observed between the groups in the dose of any medications administered during ECT (eg, esmolol and labetalol).

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Primary Clinical Outcome: Minimum Effective Dose of NMBA and Onset Time

MED50ECT of succinylcholine and rocuronium were 0.85 mg kg−1 (95% CI, 0.77–0.94) and 0.41 mg kg−1 (95% CI, 0.36–0.46), respectively. The MED90ECT and MED95ECT doses (the MEDs that provided optimal ECT conditions in 90% and 95% of patients, respectively) were 1.06 mg kg−1 (95% CI, 1.02–1.27) and 1.16 mg kg−1 (95% CI, 1.08–1.5) for succinylcholine and 0.57 mg kg−1 (95% CI, 0.51–0.61) and 0.59 mg kg−1 (95% CI, 0.56–0.63) for rocuronium, respectively. The range of applied MEDECT for succinylcholine and rocuronium were 0.46 to 1.22 mg kg−1 and 0.26–0.59 mg kg−1, respectively. Table 3 demonstrates 95% and 99% CI of the MED percentiles.

Table 3

Table 3

Acceptable ECT-induced seizure contracture after applying MEDECTs was achieved after 1.4 ± 0.5 minutes and 3.7 ± 1 minutes in the succinylcholine and rocuronium groups, respectively (P < 0.001). Nadir twitch suppression to achieve an acceptable controlled seizure quality (muscle activity) was 0% ± 2% (0–10, frequency of 0: 92.5%) for succinylcholine and 4% ± 6% (0–30, frequency of 0: 40%) for rocuronium. An adductor pollicis twitch suppression of 0% to 10% resulted in 100% acceptable neuromuscular blockade after succinylcholine (97.5%: 0%–4%; 2.5%: 5%–10%). When rocuronium was used, a T1 twitch value of 0% to 10% of baseline resulted in acceptable level of neuromuscular blockade in 95% of cases (60% of these patients had a T1 value of 0%–4% baseline, and 35% had T1 of 5%–10% baseline).

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Secondary Clinical Outcome: Time to Recovery from Neuromuscular Blockade

Figure 2

Figure 2

The time to 90% twitch recovery after succinylcholine was 9.37 ± 3.2 minutes, whereas 100% twitch recovery was obtained after 9.7 ± 3.5 (3–20) minutes (Figure 2). The time to TOF recovery >0.9 was 19.5 ± 5.7 minutes after rocuronium (Table 1).

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ECT Parameters, Hemodynamic Variables, and Ancillary Data

No clinically significant differences were identified in the recorded EEG parameters or seizure quality when adequate neuromuscular blockade was obtained with rocuronium instead of succinylcholine. ECT parameters including pulse width, energy, frequency, and duration were similar in both groups (Table 1). No differences in HR, SBP, and DBP data were observed between or within the succinylcholine and rocuronium groups. Nadir SpO2, defined as the lowest recorded periprocedural oxygen saturation, was 94% ± 3% (85–100) and 92% ± 4% (79–99) for rocuronium and succinylcholine, respectively (P > 0.05).

The interrater reliability for the raters was found to be κ = 0.862 (P < 0.001; 95% CI, 0.801–0.923). Duration of motor seizure activity after succinylcholine and rocuronium amounted to 27 ± 14 and 31 ± 11 seconds, respectively (P < 0.001, Table 1).

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DISCUSSION

The findings reported herein indicate that near-complete twitch suppression is required for optimal neuromuscular blockade during ECT. The MED50ECT for succinylcholine and rocuronium was 0.85 mg kg−1 (95% CI, 0.77–0.94) and 0.41 mg kg−1 (95% CI, 0.36–0.46), respectively. The time to achieve acceptable neuromuscular blockade was increased by approximately 2.3 minutes with rocuronium compared with succinylcholine, resulting in a total of approximately 12 minutes increased procedure time.

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Minimum Effective Dose of Succinylcholine and Time to Onset of Maximal Effect

Although a single best dose of succinylcholine for ECT has not been identified in the literature, doses between 0.5 and 6 mg kg−1, 0.8 and 1 mg kg−1, and even up to 1.4 mg kg−1 have been recommended on the basis of the anecdotal reports, previous experience of anesthesia providers, or limited clinical studies.5,15–19 The methodologic differences of these observations, interindividual and intraindividual variability, and particularly the lack of objective assessment in most occasions could explain the wide range of the recommended effective doses of succinylcholine for ECT.

The optimal dose of an NMBA is determined not only by its pharmacodynamics but also by its clinical use and the individual patient’s preexisting medical conditions. As an example, the recommended intubating dose for rocuronium is 2 × its adductor pollicis ED95, whereas for rapid sequence intubation, a significantly greater dose of 4 × ED95 is used. Similarly, for an elderly patient with severe osteoporosis, a clinician may choose to start the ECT treatments using a greater dose of NMBA (eg, MED90ECT) to minimize the risk of insufficient neuromuscular blockade, excessive muscle contractions, and potentially bone fractures, whereas in a younger and healthier patient, MED50ECT may be more desirable because of the lower risk for complications from a “suboptimal” muscle relaxation and the benefits of a more rapid recovery from anesthesia and the procedure. The applied initial dose in both examples can then be adjusted in subsequent ECT treatments based on the initial response.

Consistent with the reports from the study by Murali et al.20 and Bryson et al.,21 our data suggest that succinylcholine doses close to 1 mg kg−1 (MED90ECT in this study) may provide acceptable ECT conditions in most patients and also highlight the importance of avoiding early application of ECT after the administration of succinylcholine (<1.4 minutes, time to onset of acceptable neuromuscular blockade), even in the absence of a twitch response to nerve stimulation. This observation also is consistent with the previous finding by Beale et al.22 that the muscle response to ulnar nerve stimulation can be extinguished long before cessation of muscle fasciculation and suggests that the time to onset of adequate relaxation for ECT is longer than the traditional 60 seconds used for rapid sequence intubation (1 mg kg−1of succinylcholine, 3.5 × its adductor pollicis ED95).23–25 This difference in time to obtain acceptable ECT conditions compared with that for endotracheal intubation may be attributed to a difference in sensitivity to succinylcholine in different muscle groups (eg, oropharynx versus extremities) but also can indicate that a deeper neuromuscular blockade is needed for acceptable ECT conditions compared with endotracheal intubation. Kopman et al.26 showed that the onset speed of succinylcholine might be dependent on the rapid plasma clearance such that, in patients with normal plasma cholinesterase activity, after an ED95 dose of succinylcholine, time to peak effect (95% twitch depression) occurs in <2 minutes (109 ± 15 seconds).

The MED90ECT of 1.06 mg kg−1 succinylcholine (≈3.5 × its adductor pollicis ED95) in our study and an induced twitch height suppression of 0% to 4% for acceptable motor seizure modification are in line with the findings by Murali et al.20, who recommended a dose of 1.0 mg kg−1 and twitch suppression to 0% to 5% of baseline. The MED95ECT (1.16 mg kg−1) has also been used in other clinical trials (1.2 mg kg−1).27–30

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Duration of Paralysis and Time to Recovery After Succinylcholine

The time required for 90% twitch recovery (9.4 minutes) after succinylcholine in each subject is comparable with the reported recovery time by others after a single dose of 1 mg kg−1 (9.3 minutes).31,32 Similarly, the time required for 100% twitch recovery (9.7 minutes) in our study is similar to that in previously published pharmacokinetic studies of this NMBA (10 minutes after applying the dose of 1.0 mg kg−1).33,34 Accordingly, our data suggest that the seizure-induced release of acetylcholine into the neuromuscular junction does not significantly alter the duration of succinylcholine-induced neuromuscular blockade.

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Rocuronium as an Alternative to Succinylcholine During ECT

Rocuronium is used increasingly as an alternative to succinylcholine for neuromuscular blockade during ECT, primarily in the elderly and in patients with cardiovascular and neurologic comorbidities. Immobilized patients and elderly or those who have suffered a stroke are particularly susceptible to succinylcholine-induced hyperkalemia because of depolarization of upregulated nicotinic (neuronal) α-7 acetylcholine receptors.5 Conversely, ECT is highly effective and is increasingly applied in the elderly and those with increased incidence of prolonged immobilization and higher risk of hyperkalemia.5 Nondepolarizing NMBAs do not cause hyperkalemia and can be given to these patients and those with susceptibility to malignant hyperthermia or with contraindications to succinylcholine.

Currently, rocuronium is given as a single bolus of 0.3 to 0.6 mg kg−1 before ECT treatment.5 Our result is consistent with the previous applied doses and provides the estimation of recommended initial doses in the range of 0.36 to 0.6 mg kg−1 (MED50ECT−MED99ECT). Our study also confirms that, in patients with contraindications to the use of succinylcholine,3 the rocuronium–neostigmine combination can provide a safe and relatively time-effective alternative to succinylcholine if appropriately dosed and monitored.

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Minimum Effective Dose of Rocuronium and Time to Onset of Maximal Effect

The MED90ECT in our study (0.57 mg kg−1 ≈ 2 × ED95) is comparable with the dose that has been reported to induce >95% block in 98% of subjects.35,36 The time needed to achieve acceptable conditions for ECT is also consistent with previous studies, with a twitch suppression to 10% baseline after 2.9 ± 1.0 minutes and 0% after 3.7 ± 1.0 minutes. The time from NMBA injection to acceptable ECT conditions is hence approximately 2.3 minutes longer with rocuronium compared with succinylcholine. As anesthetics affect the duration of the ECT-induced convulsions, clinicians should consider this difference in time from anesthesia induction to ECT application with rocuronium versus succinylcholine and adjust the dose and timing of their hypnotic agents accordingly.

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Duration of Paralysis and Time to Recovery After Rocuronium

Bevan et al.37 reported the time to 90% recovery of the first twitch (T1 90) to be >10 minutes. Consistent with their data, our study showed that a twitch value of 90% was obtained 12 minutes after rocuronium was administered; however, in the former study, the TOF ratio of 0.9 (indicating the average recovery time for induced acceptable neuromuscular blockade) was achieved 28 minutes after rocuronium-induced paralysis (0.45 mg kg−1), whereas it was recorded after only 19.5 minutes in this study. This time is also shorter than the recovery time reported by Wierda et al.38 (0.4 mg kg−1 rocuronium), but it is comparable with a recovery time of 19.4 ± 5.1 minutes reported by Lederer et al.,39 who applied 0.05 mg kg−1 neostigmine 5 minutes after injection of 0.4 mg kg−1 rocuronium.

Similarly, the observed recovery times after 0.5 to 0.6 mg kg−1 rocuronium for some subjects to achieve acceptable induced seizure activity in our study were shorter than what has been reported after a comparable dose in procedures other than ECT.40,41 This observed difference may imply that during induced convulsions, the release of acetylcholine into the neuromuscular junction may reduce the duration of the induced neuromuscular blockade from rocuronium.

In line with our findings, in an ECT study by Turkkal et al.,42 the reported recovery time for the tongue depressor test was 15 ± 2 minutes after a single dose of 0.3 mg kg−1 rocuronium and after reversal with 20 μg kg−1 of neostigmine. Of note, the tongue depressor test is considered a sensitive and practical bedside test to assess the recovery from neuromuscular blockade, and it is reported to correspond with a TOF ratio recovery to 0.8.43 These observations may indicate that the recovery time is dependent not only on the applied dose and the time at which reversal agent is given but also dependent possibly on the quality and vigor of the induced seizures. Regardless of these observations, it is prudent to use standard neuromuscular reversal criteria and monitoring before allowing the patient to emerge from anesthesia.

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ECT Quality and Seizure Duration After Rocuronium Versus Succinylcholine

By using subjective tools to assess the recovery from neuromuscular blockade and as stated earlier, Turkkal et al.42 reported that motor seizure duration was greater after 0.3 mg kg−1 rocuronium compared with 1 mg kg−1 succinylcholine (33 and 24 seconds, respectively). Similarly, Hoshi et al.44 reported longer duration of seizure with rocuronium compared with succinylcholine. Our data are consistent with these previously published studies confirming a small difference in seizure duration, which may be attributed to a decline in propofol-induced EEG suppression45 after rocuronium associated with the 2-minute delay in achieving appropriate muscle relaxation. Because there is an association between clinical effectiveness of ECT and the duration of induced seizure,46 the American Psychiatric Association task force advocates seizure lengths >20 seconds for effective ECT outcome.47 This recommendation underscores the importance of titrating the dose of the NMBA to achieve an adequate neuromuscular blockade. EEG monitoring is also recommended for induced seizure monitoring,48 particularly in patients who might need greater doses of an NMBA to achieve acceptable modified seizure. Further studies are needed to assess the therapeutic effects of the cumulative seizure time in a series of ECTs using optimal doses of these NMBAs.

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CLINICAL IMPLICATIONS

In a single-dose approach, an initial MED50ECT dose of each NMBA can be considered if a 50% risk of providing suboptimal relaxation as defined in this study (Table 2) is clinically acceptable. If there are clinical concerns that our definition of adequate neuromuscular blockade is insufficient for a specific patient (eg, in an elderly patient with severe osteoporosis), clinicians should instead consider an initial greater dose of each NMBA, such as an MED90ECT dose of succinylcholine at 1 mg kg−1, or rocuronium at 0.57 mg kg−1 to provide controlled seizure activity during ECT. Subsequent adjustments may be needed to further optimize the ECT response with the minimal dose of either NMBA. Accordingly, the presented data suggest that an initial succinylcholine dose of 0.85 mg kg−1 is reasonable for the first ECT session in most patients, with dose adjustments in 0.1 to 0.2 mg kg−1 increments or decrements, based on the quality of the observed motor seizure activity for each individual during subsequent treatments. As an alternative, and if clinically indicated, we suggest a 0.4 mg kg−1 bolus of rocuronium as the initial dose of the applied NMBA in healthier patients without osteoporosis. ECT should be applied after a twitch suppression of >90% is documented or, if twitch monitoring is not available, after sufficient time has been provided to ensure >90% peak effect from the administered rocuronium (ie, 3 minutes).

If excessive or insufficient neuromuscular blockade is noticed during the induced seizure, dose adjustment with 0.05 to 0.1 mg kg−1 decrements or increments is advisable. After the treatment, the rocuronium-induced neuromuscular blockade should be reversed in the regular fashion with neostigmine (50 μg kg−1). Quantitative neuromuscular transmission (NMT) monitoring should be used to evaluate adequate suppression of neuromuscular blockade, and to ensure sufficient recovery of the induced neuromuscular blockade, to minimize the risk for adverse respiratory events.5,49 Clinicians should ensure that all patients remain under close observation by appropriately trained personnel and should continue to monitor the neuromuscular function until complete recovery of the neuromuscular transmission has been verified (eg, tongue depressor test).43

A limitation of this study was our inability to completely blind the seizure quality assessors to the type of NMBA, because we could not mask the fasciculations (if significant) after succinylcholine. Moreover, this study does not systematically explore a single optimal dose for each NMBA that requires several further treatment sessions of each subject and a notably larger sample size to apply the identified MED for capturing the intrasubject variability of response to neuromuscular blockers. In general, using >1 crossover could be a better approach for defining the optimal doses of NMBAs for each patient and for determining its variability for any given patient or population.

In summary, the presented data show that a twitch suppression of >90% is required for acceptable neuromuscular blockade during ECT. The time to achieve acceptable neuromuscular blockade is increased by approximately 2.3 minutes when rocuronium is used instead of succinylcholine, resulting in an average of 12 minutes increased procedure time. When appropriately dosed and monitored, rocuronium can be a safe alternative NMBA for ECT in patients with contraindications to succinylcholine.

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DISCLOSURES

Name: Hooman Mirzakhani, MD, PhD, MMSc.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Conflicts of Interest: This author has no conflicts of interest.

Name: Henk-Jan Guchelaar, PharmD, PhD.

Contribution: This author helped write the manuscript.

Conflicts of Interest: This author has no conflicts of interest.

Name: Charles A. Welch, MD.

Contribution: This author helped conduct the study.

Conflicts of Interest: This author has no conflicts of interest.

Name: Cristina Cusin, MD.

Contribution: This author helped conduct the study and write the manuscript.

Conflicts of Interest: This author has no conflicts of interest.

Name: Mary E. Doran, NP.

Contribution: This author helped conduct the study.

Conflicts of Interest: This author has no conflicts of interest.

Name: Teresa O. MacDonald, RN.

Contribution: This author helped conduct the study.

Conflicts of Interest: This author has no conflicts of interest.

Name: Edward A. Bittner, MD, PhD.

Contribution: This author helped analyze the data.

Conflicts of Interest: This author has no conflicts of interest.

Name: Matthias Eikermann, MD, PhD.

Contribution: This author helped design the study, conduct the study, and write the manuscript.

Conflicts of Interest: Matthias Eikermann holds equity shares of Calabash Bioscience Inc., and received funding for research from MERCK.

Name: Ala Nozari, MD, PhD.

Contribution: This author helped design the study, conduct the study, and write the manuscript.

Conflicts of Interest: This author has no conflicts of interest.

This manuscript was handled by: Peter Glass, MB ChB, FFA(SA).

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ACKNOWLEDGMENTS

The authors thank all patients who participated in this study as well as Drs. Robert J. Glynn, Edward George, William J. Benedetto, Jonathan Charnin, and Sadeq Quraishi and all the postanesthesia care unit staff of the Massachusetts General Hospital for their valuable assistance and contribution during the study.

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