Variability in pharmacologically-induced coma for treatment of refractory status epilepticus.

Jingzhi An,Emery N Brown,M Brandon Westover,Patrick L Purdon,Durga Jonnalagadda,Valdery Moura,Cecil D Hahn

doi:10.1371/journal.pone.0205789

Jingzhi An, Emery N Brown + Show 5 more

Open Access

https://doi.org/10.1371/journal.pone.0205789

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Journal: PloS one	Publication Date: Oct 31, 2018
Citations: 18	License type: CC BY 4.0

Affiliation: Massachusetts General Hospital, Harvard University

Abstract

ObjectiveTo characterize the amount of EEG suppression achieved in refractory status epilepticus (RSE) patients treated with pharmacologically-induced coma (PIC).MethodsWe analyzed EEG recordings from 35 RSE patients between 21–84 years-old who received PIC that target burst suppression and quantified the amount of EEG suppression using the burst suppression probability (BSP). Then we measured the variability of BSPs with respect to a reference level of BSP 0.8 ± 0.15. Finally, we also measured the variability of BSPs with respect to the amount of intravenous anesthetic drugs (IVADs) received by the patients.ResultsPatients remained in the reference BSP range for only 8% (median, interquartile range IQR [0, 29] %) of the total time under treatment. The median time with BSP below the reference range was 84% (IQR [37, 100] %). BSPs in some patients drifted significantly over time despite constant infusion rates of IVADs. Similar weight-normalized infusion rates of IVADs in different patients nearly always resulted in distinct BSPs (probability 0.93 (IQR [0.82, 1.0]).ConclusionThis study quantitatively identified high variability in the amount of EEG suppression achieved in clinical practice when treating RSE patients. While some of this variability may arise from clinicians purposefully deviating from clinical practice guidelines, our results show that the high variability also arises in part from significant inter- and intra- individual pharmacokinetic/pharmacodynamic variation. Our results indicate that the delicate balance between maintaining sufficient EEG suppression in RSE patients and minimizing IVAD exposure in clinical practice is challenging to achieve. This may affect patient outcomes and confound studies seeking to determine an optimal amount of EEG suppression for treatment of RSE. Therefore, our analysis points to the need for developing an alternative paradigm, such as vigilant anesthetic management as happens in operating rooms, or closed-loop anesthesia delivery, for investigating and providing induced-coma therapy to RSE patients.

Highlights

Refractory status epilepticus (RSE) is a life threatening condition with a mortality rate of up to 40%. [1, 2] It is defined by generalized or focal continuous seizures that fail to respond to first and second line pharmacological treatment. [3] International guidelines advocate treating RSE with pharmacologically-induced coma achieved with a continuous infusion of intravenous anesthetic drugs (IVADs), such as midazolam, propofol, and/or barbiturates
This study quantitatively identified high variability in the amount of EEG suppression achieved in clinical practice when treating RSE patients
While some of this variability may arise from clinicians purposefully deviating from clinical practice guidelines, our results show that the high variability arises in part from significant inter- and intra- individual pharmacokinetic/pharmacodynamic variation

Summary

Introduction

Refractory status epilepticus (RSE) is a life threatening condition with a mortality rate of up to 40%. [1, 2] It is defined by generalized or focal continuous seizures that fail to respond to first and second line pharmacological treatment. [3] International guidelines advocate treating RSE with pharmacologically-induced coma achieved with a continuous infusion of intravenous anesthetic drugs (IVADs), such as midazolam, propofol, and/or barbiturates. [3] International guidelines advocate treating RSE with pharmacologically-induced coma achieved with a continuous infusion of intravenous anesthetic drugs (IVADs), such as midazolam, propofol, and/or barbiturates. This treatment aims to suppress brain activity in order for normal physiology to resume and abort seizures. Delivering PIC therapy for RSE patients is challenging because it requires frequent patient monitoring, subjective interpretation of the EEG, and manual titration of IVADs by busy intensive care staff for prolonged periods often lasting 24–48 hours. [10,11] In this investigation, we examined the challenges associated with the delivery of PIC in RSE patients by providing a quantitative assessment of the amount of EEG suppression achieved under current practice Many have questioned the quality of inducedcoma provided to RSE patients and have searched for ways to improve the therapy. [10,11]

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