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bioRxiv · 10.1101/2022.08.04.502847

Probability Ramp Control reduces the number of sessions required to find an acceptable dose of succinylcholine during Electroconvulsive Therapy - an in silico analysis.

Mandel, J. E.
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Abstract

IntroductionElectroconvulsive Therapy may be utilized in as many as 76,000 cases annually in the US, with the majority of cases employing succinylcholine. The reported dose spans the range of 0.29 - 2.1 mg/kg, and while motor seizures only last 36 {+/-} 6 seconds, the duration of paralysis extends to 310 {+/-} 38 seconds. While a model of succinylcholine pharmacokinetics/pharmacodynamics exists, this has not been employed to facilitate dose selection in clinical practice. Probability ramp control was investigated for this purpose. MethodsTwo approaches to dose finding were implemented. The first was an optimized Up-Down Method (UDM) that utilized an initial bolus, an adjustment dose, and a decrement to decrease the adjustment when crossing the target of 95% twitch depression. The second utilized probability ramp control (PRC) comprised of an infusion sequence that stopped when 95% twitch depression was obtained, a model that mapped the times for onset and offset of blockade to a subsequent bolus, and an adjustment dose to refine this dose when needed. Two populations of 10000 randomly parameterized models were developed from published data to train and evaluate the performance. Performance was assessed with a fuzzy classifier that segmented outcomes into three sets - LOW, HIGH, and SUCCESS. A loss function was developed that determined the number of sessions required to bring all models to SUCCESS. The probability distributions were compared using the Kolmogorov-Smirnov 2 sample test, with P<0.001 considered significant. ResultsOptimal values for the UDM parameters BOLUS, ADJUSTMENT, and DECREMENT were 0.7834 mg/kg, 0.3334 mg/kg, and 0.4056. Optimal values for the PRC SEQUENCE were 0.2663 mg/kg/min for 3 minutes followed by 0.7028 mg/kg/min. A fourth order polynomial MODEL produced estimates of the bolus that brought 99% of models to SUCCESS on the second session, while UDM required 6 sessions to achieve 99% SUCCESS. The probability distributions were distinct with P<<0.001. DiscussionPRC was able to correctly produce SUCCESS in significantly fewer sessions than UDM. Additionally, PRC is easy to implement and allows pooling of results from multiple clinicians. The performance of PRC in clinical use for ECT will require further study. Key Points QuestionCan probability ramp control reduce the number of ECT sessions with suboptimal succinylcholine dosing? FindingsProbability ramp control found the correct dose in two sessions in 99% of simulations, compared to six sessions for the Up-Down Method. MeaningProbability ramp control is a more efficient method for finding the appropriate dose of succinylcholine for repeated sessions of ECT.

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Mandel, J. E.. 2022-08-05. Probability Ramp Control reduces the number of sessions required to find an acceptable dose of succinylcholine during Electroconvulsive Therapy - an in silico analysis.. https://doi.org/10.1101/2022.08.04.502847

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