Effective Doses of Neuromuscular Blockers During Electroconvulsive Therapy
We thank Drs Kopman and Naguib for their interest in our recently published article on neuromuscular blocking agents (NMBAs) for electroconvulsive therapy (ECT), particularly Dr Kopman who also served as 1 of our reviewers in the peer review process.1 They made a number of comments, most of which were also discussed and addressed during the review process.
In our study, we aimed to investigate the minimum effective doses (MEDs) of succinylcholine and rocuronium to provide adequate control of muscle activity during induced seizure activity with ECT based on defined clinical criteria. We applied creative use of the randomized crossover design combined with up and down dose adjustment, because the 2 NMBAs have short half-lives, much reducing the risk of carryover effects between each treatment. Needless to say, randomized controlled crossover experiments are especially important in health care given that adequate power can sometimes be achieved with a relatively small number of patients. Our randomized clinical trial was a repeated-measures design, in which the same measures were collected multiple times in each subject. Our crossover design helped to achieve proper “balance” with all subjects receiving a similar number of treatments with both NMBAs.
The Dixon’s Up and Down method that was used in our study estimates the median and standard error of the ED50 for a population and not for each subject. Dr Kopman’s comments are inconsistent with the use of Dixon’s method along with the fact that ED50 is a population measure.2 It is illogical to discuss the ED50 for an individual. In our study, an optimal dose for each individual was estimated, and these individual estimates from multiple subjects were then used to calculate the ED50 for the population. Although the number of measurements per individual was partly reduced because of the crossover design of the study, well-validated methods (bootstrap resampling and mixed modeling) were used to account for both intraindividual and interindividual variabilities in the analysis. In addition, through exploration of the existing data and those from our pilot studies of 10 subjects, we narrowed the starting dose of each NMBA (0.4 and 0.8 mg/kg for rocuronium and succinylcholine, respectively) to achieve ideal control of the induced motor activity with minimal titration required, hence reducing the required ECT sessions in each subject to identify the actual MED50 by approximately 30% to 40%.3
Dr Kopman also seems surprised that an “intubating dose” of rocuronium would be insufficient to provide optimal conditions for ECT in some patients. Would not the dose of rocuronium needed to provide total body relaxation intuitively be expected to exceed the dose needed to relax the laryngeal muscles? Rocuronium doses of up to 1.2 mg/kg intravenously are commonly used for intubation when shorter onset time and potentially increased probability of successful intubation might be desired (ie, rapid sequence induction).4,5 Furthermore, it is well known that anesthetics potentiate the effects of NMBAs, and the duration and dose of anesthetics used for intubation of a patient and for ECT are therefore not comparable.6 Moreover, ECT and the induced seizure can result in an excessive release of acetylcholine into the neuromuscular junction, which can potentially interfere with the neuromuscular effects of the administered NMBA (ie, reducing the effect and duration of rocuronium). In our study, the MED90 of rocuronium (0.57 mg/kg) is the 90th percentile of doses resulting in adequate seizure activity, demonstrating that only 10% of population might need a higher dose to achieve this endpoint. Our estimated MED99 (99th percentile) is, nevertheless, only slightly higher (0.6 mg/kg), meaning that almost all patients will achieve adequate muscle relaxation for ECT with a dose of 0.6 mg/kg rocuronium.
Dr Kopman’s comments on the recovery time after administration of rocuronium are similar to those on its effective ECT dose. The estimated recovery time to train of four (TOF) 0.9 in our study is simply the average of recovery times of subjects who had optimized induced seizure activity. First, comparing the average recovery time after 0.41 mg/kg (MED50) rocuronium in our study with 0.6 mg/kg in other studies is irrelevant. In addition, volatile anesthetics are used in many of the previously mentioned studies but not during ECT.6 Considering that the median of applied doses (0.4 mg/kg) might only provide a comparable estimate under similar conditions, whereas ECT and intubation are 2 different clinical conditions, the comparison of results is therefore not necessarily conclusive. Interestingly, the recovery times in our study are comparable with what was reported by Lederer et al7 and Turkkal et al8 but was longer than what was reported by Wright et al,9 as explained in the manuscript. Again, 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.10
With regard to Dr Kopman’s comments on the criteria for assessing the quality of induced seizures in our study, it is important to note that such assessment is by necessity clinical, because no alternative techniques exist. Are similar clinically subjective approaches not applied for the assessment of intubating conditions?11,12 Both psychiatrists involved in the study have >40 years combined experience in ECT practice and have used standard and well-defined criteria for the assessment of the ECT quality. We agree that future research that addresses the letter writers’ question of “what degree of neuromuscular block is required to prevent traumatic injury from an induced seizure” would be valuable. However, it is perhaps of greater clinical value to optimize the quality and adequacy of seizure and the efficacy of the ECT treatment. Accordingly, it is more prudent to define the MED of NMBAs under the optimum defined seizure quality.13,14
We would like to emphasize that, contrary to studies for intubation condition, few studies have systematically and objectively investigated different NMBAs during ECT. We not only believe that our results provide important clinical implications in this context, but also hope that they inspire other investigators to conduct relevant research within this important area of clinical practice.
Hooman Mirzakhani MD, MMSc, PhD
Edward Bittner, MD, PhD
Matthias Eikermann, MD, PhD
Ala Nozari, MD, PhD
Department of Anesthesia and Critical Care
Massachusetts General Hospital
Harvard Medical School
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