LEARNING OBJECTIVES

Introduction

Status epilepticus (SE) is a common neurologic emergency associated with high morbidity and risk of mortality. Changes in neurotransmitter receptors during ongoing seizures may contribute to increased resistance to benzodiazepines (BZDs) and other gamma-amino butyric acid (GABA_A) positive allosteric modulators as well as the tendency of prolonged seizures to self-perpetuate. Early and effective treatment may halt the evolution of SE. Once the patient is in refractory or super-refractory SE, treatment efficacy is based on limited data, side effects are potentially severe, and outcomes are markedly worse. Nonconvulsive SE is a frequent occurrence among critically ill children in the intensive care unit (ICU). The main outcome predictor of convulsive and nonconvulsive SE epilepticus is the underlying etiology. However, SE duration is also a predictive factor and may be amenable to modification with timely and effective treatment, which may, in turn, improve outcomes.

Population Impact of Status Epilepticus

Convulsive SE is a medical emergency that affects approximately 17–23/100,000 children in the United States and Europe each year (Figure 5.1 and Table 5.1).^1–3 There is wide variability in the reported prevalence of convulsive and nonconvulsive SE in critically ill children in the ICU, partly because the detection of electrographic-only SE depends on whether patients are evaluated with continuous EEG (cEEG) monitoring.⁴ Convulsive SE is associated with a mortality of approximately 0% to 3% in children,^1,2,5–7 with a much higher mortality, approximately 5% to 8%,^8–11 among children admitted to the pediatric ICU (Figure 5.2). Survivors of SE often have cognitive and other neurologic sequelae.¹² In addition, SE imposes a major economic burden on societies with the cost of each hospital admission for pediatric convulsive SE in the United States estimated to be approximately $8,000, with much higher costs for refractory and super-refractory SE than for nonrefractory SE.¹³

Pathophysiology

Neurotransmitter Receptor Changes and Pharmacoresistance in Status Epilepticus

Neurotransmitter receptor trafficking to and from the synapse during SE contributes to seizures that, over time, become more resistant to GABA_A receptor positive allosteric modulators like benzodiazepines and more sensitive to N-methyl-D-aspartate (NMDA) receptor antagonists like ketamine (Figure 5.3). Prolonged seizure activity leads to internalization of GABA_A 164receptors, decreasing their synaptic concentration and thereby decreasing GABA-mediated synaptic inhibition.^14,15 In contrast, GluN1 subunit-containing NMDA receptors and GluA2-deficient alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors tend to accumulate in the synapse during prolonged seizures.^16,17 These changes may contribute to the progressive resistance to GABA_A receptor allosteric modulators and progressive pharmacosensitivity to NMDA antagonists that is seen in animal models of status epilepticus.^18–20 Further, inhibitory GABA_A-mediated currents may become excitatory as a result of changes in extracellular chloride concentration that occur during SE.²¹

In the lithium-pilocarpine animal model of convulsive SE in rats, the ability of diazepam to stop seizures progressively decreased from 100% (6/6) when diazepam was administered early (mean of 7.3 minutes after seizure onset) to 17% (1/6) when diazepam was administered late (mean of 36.7 minutes after seizure onset).²⁰ In a similar study, diazepam terminated seizures in all (3/3) subjects when administered 10 minutes after seizure onset but did not terminate seizures (0/3) when administered 45 minutes after seizure onset.¹⁹ In keeping with this, the dose required to achieve seizure control in half of a cohort of subjects with status epilepticus was 10 times higher when diazepam was administered 45 minutes after seizure onset compared to when it was administered 10 minutes after seizure onset.¹⁸ In contrast, in an animal model of electrically induced SE, blocking the NMDA receptor with MK-801 or ketamine rapidly aborted convulsive SE.²²

Similar findings are reported in the clinical literature. In a series of 120 adults, treatment was effective in 80% of patients who received first-line therapy within 30 minutes of seizure onset, but effectiveness progressively declined to less than 40% for patients who received first-line therapy 2 or more hours after seizure onset.²³ Similarly, in a study of 157 children with convulsive SE, administering the first anti-seizure medication (ASM) more than 30 minutes after seizure onset was independently associated with a poor response to treatment.²⁴

Homeostatic Imbalances

Prolonged convulsive seizures and convulsive SE are medical emergencies associated with changes in blood pressure, heart rate, respiratory function, body temperature, and electrolyte and glucose concentrations. These pathophysiologic disturbances, when prolonged, may cause or exacerbate underlying brain injury.

Animal models of convulsive SE have shown that during the first 20 to 40 minutes of convulsive status epilepticus, homeostatic mechanisms are able to compensate for the extreme metabolic demands of the brain and muscles.^25,26 Peripheral vasoconstriction allows for the routing of blood and oxygen to the most metabolically active organs, namely the brain and muscles,^25,26 while tachycardia, systemic hypertension, and dilation of the cerebral blood vessels work in concert to maintain adequate cerebral perfusion.²⁵ An initial increase in glucose concentration helps meet energy demands; however, increasing anaerobic metabolism leads to rising lactate levels and acidosis.²⁵ In nonmechanically ventilated primate models of convulsive SE, compensatory mechanisms begin to fail after approximately 20 to 40 minutes of convulsive seizure activity.²⁵ Progressive hypoventilation, hypoxia, and pulmonary edema lead to respiratory acidosis that worsens the already existing lactic acidosis.²⁵ There is a progressive inability to maintain an adequate blood pressure and, therefore, cerebral perfusion and oxygenation become suboptimal.²⁵ Repetitive muscular contraction contributes to hypoglycemia, rhabdomyolysis with electrolyte imbalances, and hyperthermia.²⁵ In previously healthy primates with a normal cardiorespiratory reserve, this failure of compensatory mechanisms leads to arrhythmias and cardiovascular collapse starting approximately 30 minutes after seizure onset.²⁵

Studies in humans show a similar chain of events, with marked elevations of epinephrine and norepinephrine,²⁷ and initial tachycardia, hypertension, and increased cerebral blood flow²⁸ followed by acidosis and hyperthermia.²⁹ There are no studies on the timeline to homeostatic decompensation in humans; however, this is assumed to happen, as in primates, approximately 30 minutes after seizure onset.

Homeostatic decompensation is a major contributor to brain damage in convulsive SE.³⁰ Hypotension, hypoglycemia, and acidosis from prolonged convulsive seizures contribute to a pattern of brain damage similar to that seen after circulatory arrest, systemic hypotension, or hypoglycemia with lesions in the cortex, cerebellum, and hippocampus.³⁰ There is an association of prolonged convulsive SE with hippocampal sclerosis, although whether this association is causal, consequential, or both is a matter of debate.³¹ Although homeostatic decompensation is a major contributor to brain damage, epileptiform activity by itself also causes brain damage. In a model of SE induced in paralyzed and artificially ventilated primates, nonconvulsive SE led to neuronal injury and neuronal death, mainly through the hyperactivation of glutamate receptors and subsequent Ca²⁺ influx into neurons.^32,33

In humans, although there is no definitive proof that electrographic seizures cause brain damage, electrographic seizures and electrographic SE are independently associated with outcome, including poor neurodevelopmental outcome, in neonates,^34–37 children,^{35,36,38–42} and adults.^43,44 Further, serum neuron-specific enolase, a marker of neuronal damage, is elevated in convulsive as well as nonconvulsive SE.^45–47 In summary, prolonged seizures are thought to cause neuronal injury, which is more prominent when convulsive activity disrupts physiologic homeostasis.

165Pre-ICU Management of Status Epilepticus

The focus of this chapter is SE in critically ill children. However, most episodes of convulsive SE begin out of the hospital and most of the initial treatment occurs prior to arrival to the ICU.⁴⁸ Additionally, the initial treatment of convulsive SE and its timeliness affects the duration of SE, the choice of treatments, the response to interventions in the ICU, and the eventual outcome.^49–51

Time to Treatment and Definitions of Status Epilepticus

Convulsive SE is a medical emergency. The importance of timely treatment is based on two lines of evidence: (1) basic science research suggesting that the longer seizures last, the more there are changes in neurotransmitter receptor composition and trafficking at the synapse that promote self-sustaining seizures,^14–17 and (2) clinical studies showing that the later the treatment, the poorer the response and the worse the outcome after SE.^49–51 The importance of time in the treatment of convulsive SE has become increasingly recognized over the past few decades. In the 1981 “Proposal for revised clinical and electroencephalographic classification of epileptic seizures,” the International League Against Epilepsy (ILAE) defined SE as when “a seizure persists for a sufficient length of time or is repeated frequently enough that recovery between attacks does not occur,”⁵² without mention of a specific time frame. Initial definitions required seizures to last for at least 60 minutes to be considered SE.⁵³ Subsequent consideration of evidence from animal models showing irreversible neuronal damage after approximately 30 minutes of seizure activity prompted the Epilepsy Foundation of America to recommend defining SE as a seizure lasting 30 minutes or more.⁵³ When clinical research showed that most seizures stop spontaneously within 5 minutes of onset^54,55 and that, when they last more than 5 minutes, they tend to continue and evolve into SE,^50,54,55 the concept of “impending” SE was developed, to emphasize the importance of early treatment.⁵⁶ The current ILAE definition of SE emphasizes two relevant time points: the time beyond which self-resolution of a seizure is unlikely, and the time beyond which neuronal damage from ongoing seizure activity is likely. The ILAE defines status epilepticus as “a condition resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms that lead to abnormally prolonged seizures (after time point t1). It is a condition that can have long-term consequences (after time point t2), including neuronal death, neuronal injury, and alteration of neuronal networks, depending on the type and duration of seizures.”⁵⁷ In this definition, t1 (5 minutes for convulsive generalized tonic-clonic seizures) emphasizes the time point after which seizures are considered continuous, and t2 (30 minutes for convulsive generalized tonic-clonic seizures) emphasizes the time point after which irreversible neuronal damage is likely to occur.⁵⁷ The electroclinical characteristics and risk factors for pediatric convulsive SE are similar when SE is defined with a cutoff duration of 5 or 30 minutes.^58,59

Current guidelines and protocols recommend a timely stepwise administration of a rescue ASM every 5 to 10 minutes until seizures are controlled.^60,61 However, delays in treatment continue to be the norm rather than the exception in the “real world” treatment of convulsive SE.^62,63 An initial series of 81 patients from the Pediatric Status Epilepticus Research Group (pSERG) showed marked delays to treatment of refractory status epilepticus.⁴⁸ The first, second, and third ASM were administered at a median (p₂₅–p₇₅) of 28 (6–67) minutes, 40 (20–85) minutes, and 59 (30–120) minutes after SE onset.⁴⁸ The time to administration of the first and second dose of a non-BZD ASM was also prolonged at 69 (40–120) minutes and 120 (75–296) minutes after seizure onset, respectively.⁴⁸ Further, in 64 patients with out-of-hospital SE onset, 40 (62.5%) patients did not receive an ASM before hospital arrival.⁴⁸ These findings have been confirmed in larger series,^64,65 and similarly prolonged delays have been found in almost all studies that have evaluated the time to treatment of convulsive SE.^62,63 Of note, additional analyses of 189 children with refractory SE showed that delays to administration of the first BZD were similar in patients with and without a prior diagnosis of epilepsy (15 [5–60] versus 16.5 [5–42.75] minutes, p = .858) and that children with a prior diagnosis of epilepsy received their first non-BZD ASM later than children without a prior diagnosis of epilepsy (93 [46–190] versus 50.5 [28–116] minutes, p = .002).⁶⁵ This series also showed that children with a prior episode of SE received their first BZD earlier than children without a prior episode of SE (8 [3.5–22.3] versus 20 [5–60] minutes, p = .0073), although they had a similar time to treatment with their first non-BZD ASM (76.5 [45.3–124] versus 65 [32.5–156] minutes, p = .749).⁶⁵ Therefore, delays to treatment occurred even in patients with a prior diagnosis of epilepsy, who, in theory, should be more prepared to treat prolonged convulsive seizures.⁶⁵ In contrast, having had a prior episode of SE led to less delay in the administration of an initial BZD.⁶⁵ Further analysis of 219 children with refractory SE showed that the factors independently associated with delays to administration of the first BZD and the first non-BZD ASM were status epilepticus manifesting as intermittent seizures without return to baseline, as opposed to a continuous single seizure, and out-of-hospital onset, identifying potential targets for intervention to improve time to treatment.⁶⁴

The association between treatment delay and outcome is a matter of debate.⁶³ In a study of 226 patients (91 children and 135 adults) with prolonged seizures, mortality was higher among those with seizures lasting 30 or more minutes (19% versus 2.6%), although this may reflect the presence of more severe co-occurring conditions in this group.⁵⁰ In a study of 151 adults with SE, initial treatment after 30 minutes was associated with increased 166mortality (odds ratio [OR]: 2.06; confidence interval [CI], 1.01–4.17; p = .046), an association that remained after adjusting for SE duration and the presence of nonconvulsive seizures, but was no longer present after adjusting for acute symptomatic etiology.⁶⁶ In a series of 218 children, administration of the first BZD 10 or more minutes after seizure onset was independently associated with in-hospital mortality (OR: 11.0; 95% CI, 1.43 to ∞; p = .02), odds of requiring a continuous infusion for SE (OR: 1.8; 95% CI, 1.01–3.36; p = .047), convulsive seizure duration (OR: 2.6; 95% CI, 1.38–4.88; p = .003), and presence of hypotension (OR: 2.3; 95% CI, 1.16–4.63; p = .02).⁵¹ Another study of 206 children followed for 8 years after their index episode of SE showed that their mortality was 46 times higher than expected.⁶⁷ Seven children died during the index SE episode, three with bacterial meningitis and four with a progressive neurologic disorder.⁶⁷ In the long term, increased mortality was largely secondary to an underlying neurologic condition, and children without prior neurologic impairment who survived their acute SE episode did not have increased mortality.⁶⁷ This study emphasizes that mortality in pediatric convulsive SE is largely secondary to the underlying etiology.⁶⁷

Preintensive Care Unit Treatment Choices in Status Epilepticus

The treatment of SE typically follows a stepwise approach with ASMs given sequentially for persistent seizures. In the following sections, we discuss evidence regarding choices for convulsive SE treatment and evaluate gaps between available data and implementation in clinical practice (Table 5.2).

FIRST-LINE TREATMENT

Conventional initial treatment for impending SE consists of BZDs. Parenteral BZDs most commonly recommended in SE guidelines are intravenous lorazepam, intravenous diazepam, and intramuscular midazolam,^60,61 with little evidence to support the superiority of one choice versus another.^68,69 In contrast, there is extensive literature comparing the effectiveness of nonintravenous rescue medications for impending SE. A network meta-analysis of 16 studies, 15 of which included only pediatric patients, showed that the most efficacious initial BZDs for impending SE were intramuscular midazolam (the most efficacious in terms of time to administration, time from administration to seizure termination, and time to seizure cessation after arrival at the hospital) and intranasal midazolam (the most efficacious in terms of seizure cessation within 10 minutes of administration).⁷⁰ Rectal diazepam was inferior to intramuscular midazolam and intranasal midazolam and led to seizure cessation within 10 minutes of administration in approximately 70% of patients (approximately 20 percentage points lower than intranasal midazolam), with sustained seizure cessation for more than one hour in approximately 55% of patients.⁷⁰ In a systematic review, meta-analysis, and cost-effectiveness study, in which 23 of the 24 reviewed studies included pediatric patients, the most effective rescue medications were intranasal midazolam and intramuscular midazolam, with a probability of stopping seizures within 5 to 10 minutes of seizure onset of 89% (95% CI: 81%–94%) and 88% (95% CI: 73%–95%), respectively.⁷¹ Rectal diazepam was one of the least efficacious alternatives, with a probability of stopping seizures within 5 to 10 minutes of administration of 75% (95% CI: 60%–86%).⁷¹ In addition, based on prices in the United States, rectal diazepam was markedly less cost-effective.⁷¹ In addition to being more efficacious and cost-effective than rectal diazepam, intranasal midazolam is better tolerated by caregivers and school personnel.^72–74

In terms of outcomes, a retrospective review of a claims database from a large academic medical center in the United States showed that pediatric patients with a prescription for intranasal midazolam (N = 1,114), when compared with patients with a prescription for rectal diazepam (N = 3,120), had fewer urgent care and emergency department visits and lower use of ambulance services.⁷⁵ Because of the nature of the study, adjustment for potential confounders was not possible,⁷⁵ but these results are consistent with the hypothesis that using a more efficacious,^70,71 cost-effective,⁷¹ and better tolerated^72–74 nonintravenous rescue medication than rectal diazepam may lead to better outcomes, improved patient satisfaction, and lower health care costs.⁷⁵ There continues to be a gap between existing evidence and SE treatment protocols, which typically emphasize the use of rectal diazepam when the parenteral route is not available,⁶¹ and bridging this gap may result in reduced morbidity, mortality, and cost.

SECOND-LINE TREATMENT

If one or two doses of BZDs have failed to control SE, a non-BZD ASM is recommended as the next treatment step.^60,61 Fosphenytoin, phenobarbital, valproate, and levetiracetam are among the most commonly recommended non-BZD ASMs (Figure 5.4)^60,61 with fosphenytoin typically used as the initial second-line agent in children. Recent guidelines acknowledge that there is insufficient evidence from individual studies to recommend a preferred non-BZD ASM for SE.^60,76 The American Epilepsy Society Evidence-Based Guideline for the treatment of CSE recommends the use of IV fosphenytoin, levetiracetam, or valproic acid for status epilepticus not responsive to an intravenous or intramuscular benzodiazepine; it is recommended that phenobarbital be used if none of the other three medications are available.⁷⁶ A meta-analysis including 22 studies with 727 SE episodes showed that, among non-BZD ASMs for SE, effectiveness of stopping SE was highest for valproate: 76% (95% CI: 64%–85%), followed by phenobarbital: 74% (95% CI: 58%–85%), levetiracetam: 69% (95% CI: 56%–79%), and fosphenytoin/phenytoin: 50% (95% CI: 34%–66%).⁷⁷ This meta-analysis included patients in whom non-BZD ASMs were given as second-line treatment after failure of BZDs to control SE, but also patients in whom non-BZD ASMs were given as first line before BZDs and patients in whom non-BZD ASMs were given after failure of other non-BZD ASMs.⁷⁷ In light of the gap between existing evidence and SE treatment protocols,⁶¹ the Established Status Epilepticus Treatment Trial (ESETT), a randomized, blinded, adaptive, multicenter trial, compared both the efficacy and safety of IV levetiracetam, fosphenytoin, and valproic acid in children and adults with CSE unresponsive to an appropriately dosed benzodiazepine.⁷⁸ Children aged 2 to 17 comprised 39% (n = 156) of the cohort. The dose of each medication was levetiracetam 60 mg/kg (maximum dose 4,500 mg), fosphenytoin 20 mg phenytoin equivalents (mgPE)/kg (maximum dose 1,500 mgPE), and valproate 40 mg/kg (maximum dose 3,000 mg). The primary outcome measure was cessation of status epilepticus and improvement in mental status 60 minutes after the start of the trial drug infusion. There was no difference in efficacy or adverse events when comparing these three medications. Of note, this study was performed in the emergency department, and its generalizability to critically ill patients in the ICU remains to be determined.

167

168INTENSIVE CARE UNIT MANAGEMENT

Although there is no single definition of refractory SE, when convulsive SE has not been controlled with BZDs and second-line non-BZD ASMs, a patient is generally considered to be in refractory SE (Table 5.1).^{23,60,79–86} Estimating the proportion of SE that becomes refractory is challenging due to differing definitions; however, in a series of 240 pediatric convulsive SE episodes, 44 (18%) required continuous infusion for seizure termination,⁴⁹ suggesting that refractory SE is relatively frequent. Refractory convulsive SE is primarily treated in the ICU, and the main objectives of treatment are to stabilize the patient and to terminate seizure activity.

Stabilization

A major objective of SE treatment is to stabilize the patient’s airway, breathing, and circulation.⁶⁰ The stabilization of the patient in SE begins at the time of seizure onset and persists throughout the duration of SE. Although airway protection and breathing might be facilitated initially by noninvasive methods such as head positioning and supplemental oxygen, intubation may be necessary in the case of respiratory depression, and this may be caused or exacerbated by treatment with ASMs such as benzodiazepines or phenobarbital.⁶⁰ Peripheral intravenous access should be established as soon as possible to administer rescue ASMs.⁶⁰ Intravenous access also facilitates correction of electrolyte imbalances, administration of glucose, and correction of hypotension.⁶⁰ Active detection and treatment of acute causes of SE such as hypoglycemia, hypocalcemia, meningitis, encephalitis, or increased intracranial pressure may greatly improve outcomes.

Continuous Infusions for Status Epilepticus

When convulsive SE becomes refractory, many guidelines recommend treatment with continuous infusions of medications such as midazolam, pentobarbital, and propofol.^60,61,81 There is some data to suggest that continuous infusions for refractory SE may be associated with increased mortality; however, confounding by indication and the likely greater use of continuous infusions in patients with more severe SE limits these claims. A study of 171 adults with convulsive SE found that patients treated with continuous infusions (n = 63) had a higher mortality than patients not treated with continuous infusions (n = 108) (relative risk: 2.88, 95% CI: 1.45–5.73).⁸⁷ A similar study of 406 adults also found that patients treated with continuous infusions (p = 139) had higher mortality than patients not treated with continuous infusions (n = 267) (OR: 3.29, 95% CI: 1.35–8.05).⁸⁸ Comparable results were also seen in a study of 144 SE episodes (convulsive SE in 132 episodes) in 126 patients, with SE episodes treated with continuous infusions (n = 47) associated with a higher mortality than those not treated with continuous infusions (n = 97) (OR: 12.1, 95% CI: 2.3–63.4).⁸⁹ In contrast, in a study of 362 adults in 4 tertiary care centers in the USA and Switzerland, the use of continuous infusion was not associated with increased mortality.⁹⁰

Treatment of refractory SE does not aim to control seizures at all costs, but to find a balance between stopping seizures and avoiding or minimizing the effects of prolonged coma, respiratory depression, and hypotension that can occur with continuous infusions of anesthetic agents.⁸⁵ The most commonly used continuous infusions are midazolam, pentobarbital, and propofol, with limited evidence to recommend any of them over the others.^91–95

MIDAZOLAM

One of the most frequently used continuous infusions for the treatment of refractory SE in pediatric patients is midazolam (Figure 5.5), which is a positive allosteric modulator of the GABA_A receptor.⁹⁶ Midazolam is typically administered as a 0.2 mg/kg loading dose followed by a 0.2–2 mg/kg/hour infusion^83,95,97,98 with a goal of seizure suppression. Midazolam infusion is relatively safe, causes less frequent hypotension than pentobarbital infusion, and is often used as the initial continuous infusion in pediatric patients.^83,95 169Tachyphylaxis develops within 24–48 hours of treatment initiation, so the infusion rate typically needs to be adjusted to maintain a constant pharmacologic action.⁹⁵ In a study of 51 children with SE (13 with established SE and 38 with refractory SE), midazolam infusion controlled seizures in all patients except one.⁹⁹ In a series of 111 patients with refractory SE, 42 received midazolam as the initial continuous infusion, which controlled SE in 30 (71%).⁹⁵ In this study, the patients who responded to midazolam had a maximum median infusion rate of 0.1 (interquartile range [IQR] 0.06 to 0.5) mg/kg/hour.⁹⁶ There is substantial variability in infusion rate and duration, as these depend on response to treatment, adverse effects, and goals of treatment.^95,99

PENTOBARBITAL

Another commonly used agent for the treatment of pediatric refractory SE is pentobarbital, either as the first continuous infusion or after failure of midazolam infusion (Figure 5.6).⁹⁵ Pentobarbital acts through positive allosteric modulation of GABA_A receptors, as well as through antagonism of NMDA receptors.⁹⁶ Pentobarbital is typically administered with a loading dose of 5 to 10 mg/kg followed by a 1 to 5 mg/kg/hour infusion^83,95 with a goal of seizure suppression or burst suppression. The long half-life of pentobarbital makes it challenging to adjust medication levels in patients with rapidly changing needs.⁸³ Further, hypotension is more common with pentobarbital than with midazolam.⁹⁵ In a study of 30 children with refractory SE, 10 patients (33%) achieved burst-suppression without relapse of SE during therapy; among the 20 patients who relapsed, 12 (60%) reachieved burst-suppression.¹⁰⁰ The rate of adverse effects among these 30 patients was high, with hypotension requiring inotropic support in 93%, infection in 67%, metabolic acidosis in 10%, and pancreatitis in 10%, despite dosing being within recommended ranges in most patients.¹⁰⁰ In a series of 111 patients with refractory SE, 2 received pentobarbital as the initial infusion, and 11 of 12 patients who failed to respond to midazolam ultimately received pentobarbital (9 as the second continuous infusion and 2 as the third continuous infusion).⁹⁵ The response to pentobarbital in this series was difficult to measure as it varied based on the endpoint used (seizure termination or induction of burst-suppression).⁹⁵ As with midazolam, there is substantial variability in infusion rate and duration, as these similarly depend on response to treatment, adverse effects, and goals of treatment.^95,100

PROPOFOL

Propofol is also a positive allosteric modulator of the GABA_A receptor⁹⁶ and is used in the treatment of refractory status epilepticus, although much more commonly in adults than in children. Propofol is typically administered with a loading dose of 2 mg/kg followed by a 2 to 5 mg/kg/hour infusion.⁸³ Its short half-life makes it amenable to rapid adjustment as dictated by clinical demands.⁸³ Its main disadvantage is propofol infusion syndrome, a potentially fatal adverse effect of propofol administration.⁸³ This is caused by an imbalance between energy demand and utilization secondary to propofol-mediated impairment of free fatty acid utilization and mitochondrial activity.¹⁰¹ This energy imbalance may present with circulatory collapse, lactic acidosis, hypertriglyceridemia, and rhabdomyolysis and may lead to cardiac and peripheral muscle necrosis.¹⁰¹ This syndrome is more common in young children, therefore propofol infusion with rates 4 mg/kg/hour or higher are not recommended for more than 48 hours in pediatric patients.¹⁰¹ In a study of pediatric refractory SE, propofol infusion controlled 14 of 22 episodes (64%), but the infusion had to be stopped in 4 patients for rhabdomyolysis (n = 1) or hypertriglyceridemia (n = 3), which normalized after stopping propofol.¹⁰²

Super-Refractory Status Epilepticus and Other Treatments

When seizures have not responded to BZDs, non-BZD ASMs, and continuous infusions, SE is considered super-refractory (Table 5.1).⁸⁵ Although there is not a single definition of super-refractory SE, it is commonly considered when SE continues or recurs 24 hours or more after the onset of anesthetic therapy (continuous infusions), including those cases that recur upon reduction or withdrawal of anesthesia.⁸⁵ Although super-refractory SE is a relatively rare occurrence, a study in adults estimates that approximately 15% of patients with SE requiring hospital admission will go on to develop super-refractory SE,⁸⁵ and in a series of 602 children with convulsive SE, approximately 7% became super-refractory.¹⁰³ Super-refractory SE is a life-threatening condition for which evidence regarding the best treatments is limited.^96,104 Even more so than in refractory SE, in super-refractory SE, the objective of treatment is often not to stop seizures at all costs, but to find a balance between suppressing seizures and avoiding iatrogenic damage secondary to anesthetic treatment and prolonged ICU admission, including prolonged respiratory failure, hepatic and renal failure, coagulopathy, rhabdomyolysis, ileus and other gastrointestinal disturbances, infection, and critical illness myopathy/neuropathy.⁸⁵

Once SE has become super-refractory, treatment is based on limited evidence, mostly case series and case reports, with limited potential to adjust for the multiple confounding factors that may influence outcomes. One approach to treatment of super-refractory SE is to try different types and doses of continuous infusions of anesthetics, individually or in combination with other continuous infusions or with the other options briefly described below.

KETAMINE

Ketamine is a noncompetitive antagonist of the NMDA receptor.⁹⁶ In contrast to medications for refractory SE that target GABA_A receptors, the mechanism 170of action of ketamine better addresses the changes that occur at the synapse with ongoing seizure activity, namely upregulation of NMDA receptors.⁸⁵ Ketamine is typically administered with a loading dose of 0.5 to 3 mg/kg and an infusion rate of 1 to 10 mg/kg/hour.⁹⁶ As opposed to most other anesthetics, ketamine is not a cardiac depressant and does not cause hypotension; in contrast, ketamine administration can result in tachycardia and hypertension.⁸⁵ While it was initially thought that ketamine should be used with caution in patients with traumatic brain injury or intracranial masses due to concerns about possible increases in intracranial pressure,⁹⁶ a systematic review of 101 adult and 55 pediatric patients with traumatic brain injury showed that ICP did not increase with ketamine infusion.¹⁰⁵ In a retrospective multicenter study that included 60 refractory SE episodes from 46 adults and 12 children, ketamine was likely responsible for control of SE in 7 patients (12%) and possibly responsible in 12 patients (20%).¹⁰⁶ Further, likely response was not observed with infusion rates lower than 0.9 mg/kg/hour, when ketamine was introduced 8 days or more after SE onset, or after failure of 7 or more medications.¹⁰⁶ In contrast, when ketamine was introduced as the fourth-line medication, it likely controlled SE in 4 of 10 cases (40%) and possibly controlled SE in 2 of 10 cases (20%).¹⁰⁶ These results suggest that ketamine might be more effective early in the treatment of refractory or super-refractory SE, rather than as a last resort medication. A meta-analysis of ketamine for the treatment of refractory SE also showed that ketamine resulted in EEG seizure control in 57% of 110 adult patients and 64% of 52 pediatric patients.¹⁰⁷ Because ketamine has a relatively safe cardiorespiratory profile when compared with other anesthetics and because its NMDA antagonism may help reduce excitotoxic neuronal damage, it is a promising treatment for refractory and super-refractory SE⁸⁵ (Figure 5.7).

KETOGENIC DIET

This high-fat and low-carbohydrate diet likely has a multifactorial mechanism of action, although its exact mechanism of action is largely unknown. In a retrospective study of 10 pediatric patients with super-refractory SE, the KD controlled SE in 9 of 10 patients (90%) a median of 7 days after KD initiation.¹⁰⁸ In a cohort of 14 pediatric patients with refractory SE treated with the KD, 10 of 14 patients (71%) showed EEG seizure resolution within 7 days of starting a KD.¹⁰⁹ The authors argued that the KD was likely underutilized as these 14 patients were collected from a cohort of 239 patients with refractory SE and there was a median delay of 13 days between SE onset and the initiation of the KD.¹⁰⁹ The KD acts on multiple levels of the epileptic cascade and may help reduce excitotoxic neuronal damage.¹⁰⁴ Although the KD is a promising treatment for SE, a potential shortcoming is the delay to onset of its effects, which can take at least 1 to 2 weeks.¹⁰⁴

THERAPEUTIC HYPOTHERMIA

While therapeutic hypothermia has been proposed as a potential treatment for super-refractory SE, there is little to no evidence to support its efficacy. A randomized controlled trial of therapeutic hypothermia for SE in 270 adults found no improvement in 90-day outcomes for those treated with hypothermia.¹¹⁰ Although the main outcome of this trial (proportion of patients with an absence of functional impairment 90 days after SE) may not have captured all of the potential benefits of treatment, it showed that therapeutic hypothermia does not lead to major outcome improvements, at least in adults.¹¹⁰ In a series of 5 children with super-refractory SE, therapeutic hypothermia reduced seizure burden during and after treatment in all cases, although it is unclear whether outcome was improved.¹¹¹ Although hypothermia might theoretically disrupt inflammatory cascades in SE,¹¹² it has not been shown to be of benefit,^110,111 and the risk of coagulopathy, immunosuppression, and electrolyte abnormalities makes therapeutic hypothermia a rarely used option for super-refractory SE.¹⁰⁴

EPILEPSY SURGERY

In patients with an epileptogenic focus likely to be responsible for SE, surgical resection may lead to SE control or even seizure freedom.¹⁰⁴ As in other instances of epilepsy surgery, the presence of an anatomical lesion improves the chances of success.¹⁰⁴ Although highly effective in selected cases, epilepsy surgery is only feasible for a small proportion of patients with super-refractory SE. Surgical planning and work-up is limited due to time constraints and limitations inherent to a critically ill patient in the ICU.¹⁰⁴

SPECIFIC INDICATIONS

Pyridoxine may be trialed in patients, especially neonates and infants, with suspected pyridoxine-dependent epilepsy or in areas with a high incidence of tuberculosis where treatment with isoniazid may have caused a secondary pyridoxine deficiency.¹⁰⁴ If the patient is not already ventilated, cardio-respiratory function should be closely monitored and supported because pyridoxine may cause respiratory depression and hypotonia.¹⁰⁴ Although less relevant in pediatrics, magnesium may be tried for super-refractory SE in the context of eclampsia.¹⁰⁴ Hypermagnesemia in these patients must be avoided because it may lead to cardiovascular instability.¹⁰⁴

IMMUNOLOGIC TREATMENTS

Treatments like steroids, intravenous immunoglobulins, or plasmapheresis show variable efficacy, which may reflect the different underlying etiologies 171and different stages of SE during which they are administered.⁹⁶ Immune modulatory agents are used most commonly in refractory and super-refractory status epilepticus with a possible or presumed autoimmune or inflammatory etiology, including cryptogenic new-onset refractory status epilepticus (NORSE)/febrile infection-related epilepsy syndrome (FIRES) (Figure 5.8).¹¹³ A recent consensus statement defines NORSE as a clinical presentation, rather than a specific diagnosis, in a patient without active epilepsy or other pre-existing relevant neurological disorder with new onset of refractory SE without a clear acute or active structural, toxic, or metabolic cause.¹¹³ FIRES is a subcategory of NORSE that requires a prior febrile infection, with fever starting between 2 weeks and 24 hours prior to onset of refractory SE, with or without fever at onset of SE.¹¹³ Antibodies against neuronal receptors are thought to trigger refractory seizures in autoimmune status epilepticus, while aberrant activation of pro-inflammatory signaling cascades are thought to contribute to the development of refractory seizures in status epilepticus with a presumed inflammatory etiology, including cryptogenic NORSE/FIRES.¹¹⁴ Nonetheless, despite potentially targeting the underlying pathophysiologic mechanisms, the efficacy of such treatments remains unclear. For example, a retrospective multicenter review of the pathogenesis, treatment, and outcome of 77 children with FIRES showed limited benefit of immune modulatory agents.¹¹⁵ Thirty patients were treated with IVIG and 29 patients were treated with steroids, primarily pulse-dose methylprednisolone. A possible benefit of IVIG was seen in only two patients, both of whom showed a >75% reduction in seizure burden following treatment with IVIG (also reported¹¹⁶). More recently, Husari et al. retrospectively reviewed the etiologies, treatment, and outcomes of 40 children with new-onset refractory status epilepticus at a single center.¹¹⁷ This included patients with refractory status epilepticus and super-refractory status epilepticus. Of the patients with super-refractory status epilepticus, 90% received immunotherapy, including corticosteroids, IVIG, plasmapheresis, and/or cyclophosphamide. There was no difference in outcome between patients who received immunotherapy as compared to those who did not nor did shorter time to treatment with immune modulating therapy show significant benefit. More recently, targeted treatments with agents that inhibit the action of specific pro-inflammatory cytokines have shown possible benefit in NORSE/FIRES. For example, Kenney-Jung et al. described the use of anakinra in the successful treatment of a pediatric patient with FIRES.¹¹⁸ Anakinra is a recombinant version of the human IL-1 receptor antagonist and inhibits the actions of IL-1β, which has been implicated in a variety of neuroinflammatory disorders, including various seizure models.^119,120 Similarly, Jun et al. described the treatment of seven adult patients with new-onset refractory status epilepticus with tocilizumab, an interleukin-6 receptor inhibitor.¹²¹ Status epilepticus was terminated after 1 to 2 doses of tocilizumab in all but one patient with a median interval of 3 days between the initiation of tocilizumab and seizure remission. Further studies analyzing inflammatory changes during RSE and SRSE in large heterogenous cohorts may enhance our ability to treat in a targeted fashion according to the patient’s inflammatory profile.

Etiologic Evaluation

Etiology is the strongest predictor of outcome in SE.^67,122 Although etiology is often not modifiable, potentially treatable etiologies should be rapidly identified. Etiologies of SE potentially amenable to treatment include electrolyte imbalances, bacterial meningitis, autoimmune encephalitis, and mitochondrial diseases, with early treatment potentially resulting in improved outcome.¹²³ Inflammatory and autoimmune disorders are increasingly recognized as causes of or contributors to refractory status epilepticus, and these disorders are potentially amenable to targeted treatment as detailed above. When an infectious, inflammatory, and/or autoimmune etiology is suspected, the diagnostic evaluation detailed in Table 5.3 or similar should be considered.

TABLE 5.3 POSSIBLE ETIOLOGIC WORK-UP FOR PATIENTS WITH REFRACTORY AND SUPER-REFRACTORY SE OF UNKNOWN ETIOLOGY^143,144

Only gold members can continue reading. Log In or Register to continue

Share this:

• Click to share on Twitter (Opens in new window)
• Click to share on Facebook (Opens in new window)

Related

Related posts:

Templates and Treatment Algorithms Cases Basics of EEG Monitoring in Pediatric Critical Care Questions and Answers by Chapter Encephalopathy, Coma Patterns, and Other Abnormalities of the EEG Background in Critically Ill Children Seizures in Critically Ill Children

Stay updated, free articles. Join our Telegram channel

Join