790 SECTION VI Pediatric Critical Care Neurologic once an infusion is stopped will be prolonged and the drug effect will potentially last for days, even with short infusion periods of 12 to 24 hours T[.]
790 S E C T I O N V I Pediatric Critical Care: Neurologic once an infusion is stopped will be prolonged and the drug effect will potentially last for days, even with short infusion periods of 12 to 24 hours These phenomena should guide how the medication is escalated and the approach to weaning Much of what is known about the PICU treatment protocol for pentobarbital in RSE comes from a systematic review of four studies (1993–2011) including 95 children and a recent pSERG PICU experience of using pentobarbital for RSE after midazolam has failed.43,44 These reports show that typical loading doses are to mg/kg (IQR 0.6–5.2 mg/kg) with initial and highest infusion rates of 1.0 (IQR 1.0–2.0 mg/kg per hour) and 3.0 (IQR 1.5–4.0 mg/kg per hour), respectively Maximum infusion rates needed to achieve burst suppression on cEEG are in the range of 10 mg/kg per hour Breakthrough seizures occur in up to 67% of cases, and recurrent seizures occur in 22% Of note, hypotension and need for vasopressors was seen in 93% of cases Taken together, this information has implications on how clinicians should use pentobarbital The treatment goals are seizure control and induced burst suppression on cEEG (see later discussion) However, the overall aim is to provide the minimum infusion rate necessary to achieve these end points to limit hemodynamic compromise Such a strategy requires attention to and supervision of the following: • Bolus dosing: Repeated bolus dosing quickly achieves steadystate drug concentrations to achieve burst suppression Alternatively, if escalating the infusion rate in increments of mg/ kg per hour every 15 to 30 minutes were done, it would take several hours for the blood concentration to achieve the same steady state For example, consider that the infusion rate is at mg/kg per hour, burst suppression is not present on cEEG, and the infusion is increased to mg/kg per hour In this scenario, 12 to 24 hours would be required to achieve a new steady state Bolus pentobarbital (5 mg/kg) will bring the blood level up more quickly—ideally, near steady state—prevent overescalating the continuous infusion rate every 15 to 30 minutes to achieve burst suppression It is never rational to make an infusion rate increase after only 15 to 30 minutes without a preceding bolus Breakthrough seizures should be treated with additional boluses of to mg/kg • Infusion dosing: The continuous infusion rate most commonly used is between and mg/kg per hour When patients receive prolonged treatment with pentobarbital, they will develop tolerance to the sedative effect but not to the anticonvulsant effect, which explains why tachyphylaxis is less common with pentobarbital than with midazolam infusions It is important to give the minimum dosing necessary to achieve the desired end point, which may mean decreasing the infusion rate in order to avoid drug accumulation cEEG Monitoring Not all centers use cEEG and, in those that do, burst suppression is not necessarily the end point.43,44 However, the majority of practitioners use burst suppression, but there is debate about the recommended “interburst interval” (i.e., length of period of EEG suppression between bursts in activity) and how long the burstsuppression pattern should be maintained There is also debate about whether an isoelectric EEG pattern should be the target However, these discussions need to be balanced by patient safety and risk of hemodynamic and other complications (see later discussion) In the pSERG experience, the duration of pentobarbital therapy for RSE lasted a median of 30 (IQR 4–120) hours.43 A systematic review reported a median duration of 17.5 days, which likely reflects a disproportionate number of FIRES cases.44 As a general observation, pediatric practitioners often use pentobarbital after midazolam has failed to control RSE Therefore, it is used for 24 to 48 hours initially, with an attempt to wean the infusion rate over the next 24 hours Abrupt weaning may lead to breakthrough seizures; thus, the rate of weaning should be thoughtfully planned If seizures recur when pentobarbital is tapered, then therapy can be reescalated to achieve burst suppression and attempts at weaning delayed for to days.43,44 Complications of Pentobarbital Hypotension should be anticipated in all patients receiving pentobarbital infusions.43,44 It is caused by a dose-dependent reduction in systemic vascular resistance and, to a lesser extent, myocardial depression (more prominent in adults than children) One major advantage of cEEG monitoring in these patients is to enable the use of the minimum infusion rate of pentobarbital necessary to induce burst suppression, thereby avoiding overtreatment and the additive hemodynamic risks It is also advisable to make sure that the patient has adequate preload and that vasopressors such as norepinephrine are used to prevent and/or treat hypotension Pentobarbital also causes leukocyte dysfunction and is associated with immunosuppression Thus, particular vigilance for nosocomial infections and pneumonia is needed Also, doserelated nephrogenic diabetes insipidus with electrolyte abnormalities can be seen in patients receiving prolonged pentobarbital infusions Last, of particular note, is the collection of problems that will impair the ability to establish a ketogenic diet and enteral feedings in general Patients on pentobarbital invariably will develop some degree of ileus; thus, nasogastric ketogenic feeds are typically not tolerated Also, the excipient for intravenous pentobarbital (and phenobarbital) is propylene glycol, which stimulates gluconeogenesis and prevents the development of ketosis In order to establish ketosis with a ketogenic diet, patients will need to be off pentobarbital infusions Concurrent Antiseizure Medications With Pentobarbital In parallel with high-dose pentobarbital, other conventional ASMs (i.e., topiramate, levetiracetam, and carbamazepine) titrated to high therapeutic levels assist in stopping RSE and providing continued anticonvulsant coverage after tapering the infusion Another strategy described in the literature combines the veryhigh-dose phenobarbital approach with the dosing of pentobarbital described earlier Here, phenobarbital is given in incremental boluses of 10 mg/kg, without reference to a predetermined maximum level or dose, until seizures are suppressed There appears to be no maximum dose beyond which further doses are ineffective, and serum levels of up to 344 mg/mL (1490 mmol/L) have been reported.54 Among the barbiturates, phenobarbital probably carries the lowest risk of hypotension and respiratory depression For example, in the literature, there is one example of an 18-year-old with a flu-like prodrome and SRSE who had the pentobarbitalphenobarbital combination for over weeks while other AEDs were tried.55 Inhalational Anesthetics for (Super) Refractory Status Epilepticus Several reports describe the efficacy of inhalational anesthetics for RSE that is refractory to high-dose benzodiazepines and barbiturates.56,57 Inhalational anesthetics have the advantage of being CHAPTER 64 Status Epilepticus easily titratable but must be supervised by anesthesia staff in most institutions Unlike other anesthetics for RSE, inhaled anesthetics provide immediate control of seizure activity regardless of seizure duration or type The mechanism by which inhaled anesthetics control seizure activity likely involves multiple receptors, including GABA, nicotinic, and glycine receptors, and potassium-gated ion channels It is difficult to determine what role the volatile anesthetics should have in the treatment of RSE and SRSE Many protocols mention the use of these agents as a last resort, at a time when permanent neurologic damage is likely to have already occurred; advocates argue that initiation sooner would yield better outcomes Overall, the inhalational anesthetics are a reliable method for controlling seizures and inducing burst suppression These goals are achieved within minutes, and hypotension is not dose-limiting The inhalational anesthetics are easier to titrate than pentobarbital, and the pattern of emergence from anesthesia is more predictable In PICU practice, this means that long-term seizure medications can be started and blood levels optimized while the patient is in burst suppression However, each PICU should decide whether appropriate personnel and equipment are available to safely initiate, supervise, and monitor inhalational anesthetic therapy Isoflurane is the most commonly available agent and is given via an anesthetic machine with end-tidal monitoring of isoflurane concentration Initially, the concentration of the anesthetic is increased until adequate suppression of the seizure and background EEG activity has occurred, and this dose is maintained Then, at regular intervals, the minimum dose of anesthetic needed to achieve burst suppression should be determined The total anesthetic exposure is calculated using the minimum alveolar concentration (MAC) units per hour of treatment, that is, the hourly end-tidal percentage concentration of isoflurane divided by 1.15 is summed for each hour of treatment (The MAC is defined as the concentration of vapor in the lungs at one atmosphere that prevents the reaction to a standard surgical stimulus in 50% of individuals.) The anesthetic agents cause a nonlinear decrease in CMRO2, and once burst suppression occurs, there is no further decrease in cerebral metabolism Hence, there is little value in going beyond burst suppression and inducing electrocerebral silence cEEG monitoring is required to determine that minimum dosing is used The anesthetic agents also decrease cerebrovascular resistance, thereby causing an increase in CBF and, potentially, ICP This complication is seen with isoflurane and, to a lesser degree, with desflurane Increased ICP is typically mild, transient, and only of major significance in patients with evidence of preexisting intracranial hypertension Regarding toxicities, both isoflurane and desflurane produce a dose-dependent fall in arterial blood pressure via lowering of systemic vascular resistance and, to a much lesser degree, negative inotropy As a consequence, a compensatory increase in heart rate is frequently seen when starting these agents There are some concerns that the volatile anesthetics may be neurotoxic when used for prolonged periods in RSE For example, pediatric case series have shown that after prolonged administration, adverse timelimited neurotoxicity may develop, with extreme agitation, nonpurposeful movements, and psychomotor disturbances It is unclear whether these symptoms are the result of withdrawal or a direct neurologic insult; however, typically, symptoms self-resolve A case series from 1989 with five pediatric patients with RSE—four of whom had failed treatment with pentobarbital— described the use of isoflurane (end-tidal concentrations of 791 0.5%–2.25%) after a median duration of RSE of days before treatment.58 Overall, this therapy is now rarely used but is available as an option with the right support personnel Hypothermia for (Super) Refractory Status Epilepticus Therapeutic hypothermia has been used to treat RSE and SRSE for many years In 1984, Orlowski et al.51 reported three children with SE successfully treated with a combination of therapeutic hypothermia (30°–31°C) and thiopental Guilliams et al.53 described using therapeutic hypothermia in five children with RSE; the authors also reviewed seven other children reported in the literature Nine of these 12 children had failed to respond to midazolam, four had also failed to respond to pentobarbital, and one had not responded to ketamine In all cases, whole-body cooling to 30.0°C to 35.3°C achieved acute seizure control Taking these studies together, therapeutic hypothermia may help with acute control of RSE and even have a barbiturate-sparing effect However, like inducing anesthesia (see earlier discussion), this is a temporizing strategy for seizure control while other ASMs are considered To date, there is one prospective randomized study of therapeutic hypothermia in CSE (HYBERNATUS) in adults.59 The inclusion criteria included age greater than 18 years, CSE of minutes or longer, mechanical ventilation, and trial recruitment within hours of seizure onset Out of 268 patients at randomization, 25% were classified as having RSE, and 9% had seizure duration longer than hour Induced hypothermia (32°C–34°C) added to standard care versus temperature control at 37°C was not associated with significantly better 90-day outcomes than standard care alone Regarding ICU management, SRSE occurred in 17% of hypothermia patients and 23% of normothermia patients (odds ratio, 0.64; 95% confidence interval [CI], 0.34–1.19; P 16) Hence, the use of “prophylactic” therapeutic hypothermia within the first hours of RSE did not prevent subsequent SRSE However, application of hypothermia as an adjuvant with the aim of barbiturate and/or other ASM sparing may be considered in patients with RSE Ketogenic Diet for (Super) Refractory Status Epilepticus The ketogenic diet is a high-fat, low carbohydrate, and adequate protein diet used widely to treat refractory epilepsies in children It has also been used in a number of series of children with RSE and SRSE.56,57 The ketogenic diet is given through a gastric tube Most studies use a 4:1 or 3:1 ketogenic ratio (grams of fat to protein and carbohydrate combined) with total avoidance of glucose initially The diet is started after screening to exclude underlying biochemical, metabolic, or mitochondrial disease, including betaoxidation deficiencies, and 24 hours of fasting The short-term side effects include acidosis, hypoglycemia, weight loss, and gastroesophageal reflux, which can obviously complicate the care of a critically ill patient In the initiation phase, blood glucose should be measured at least every hours for the first days and then, if appropriate, every hours thereafter Glucose is given if blood sugar is less than 45 mg/dL Once ketosis is achieved, urinary ketones and serum b-hydroxybutyrate should be measured daily Later, the frequency of serum testing can be changed to weekly During the ketogenic diet, glucose needs to be severely 792 S E C T I O N V I Pediatric Critical Care: Neurologic restricted and total fluid intake should be monitored closely As steroids may inhibit the development of ketosis, they should be avoided if possible Also, drug sources of alcohol and propylene glycol (e.g., intravenous phenobarbital and pentobarbital) should be stopped One reason for considering the ketogenic diet in children in SRSE is that in a literature review of cases, seizure control was reported in as many as 33 of 43 children (proportion, 77%; 95% CI, 61%–88%).57 Effectiveness appears to be most evident in the FIRES population, and there are more FIRES/SRSE case series demonstrating a similar degree of response.60–63 In adults with SRSE, there is one prospective, multicenter phase I/II feasibility study.64 Cervenka et al recruited 24 adult patients older than 18 years in SRSE (defined as medically induced coma for 24 hours with persistent SE or return after attempt to wean one or more anesthetics) and found that 14 patients completed ketogenic diet treatment SRSE resolved in 11 of the patients, there were five deaths, and side effects included metabolic acidosis, hyperlipidemia, constipation, hypoglycemia, hyponatremia, and weight loss Taken together, the ketogenic diet is certainly possible— albeit with the limitations described (off pentobarbital and tolerating enteral diet)—but it seems unlikely that there will be evidence from a large randomized trial in children Therefore, some researchers are focusing on prospective “comparative effectiveness” approaches.61,64 Surgical Options When SE is refractory to multiple medical treatments, including high-dose barbiturates and benzodiazepines, surgical intervention can be considered by centers with experience in pediatric epilepsy surgery This approach is most feasible in, but not limited to, children with an identified cortical malformation Focal cortical resections may be indicated if a focal structural abnormality can be identified on neuroimaging However, the presence of a lesion on magnetic resonance imaging (MRI) is not sufficient to ensure that seizures are arising from that region Furthermore, in children with prolonged RSE, secondary epileptogenic foci may develop Typically, multiple investigations will be undertaken to ensure that seizures are arising from the area of potential surgical resection At a minimum, there should be concordance between the structural lesion and the location of ictal and interictal EEG discharges If the patient is medically stable, fluorodeoxyglucose positron emission tomography may be used to demonstrate interictal hypometabolism or ictal hypermetabolism of the epileptogenic focus, and magnetoencephalography may be used to support the identification of the epileptogenic focus Magnetoencephalography is a relatively new functional imaging modality that delineates the epileptogenic zone by detecting magnetic fields produced by interictal epileptiform activity Implantation of subdural electrodes allows for the most precise localization of the epileptogenic focus; however, this procedure usually is not feasible in the setting of RSE The evidence for such surgical approaches is limited to case reports and small series Specific groups that may benefit from surgical intervention include those with cortical dysplasia, tuberous sclerosis complex, polymicrogyria, hypothalamic hamartoma, hemispheric syndromes, Sturge-Weber syndrome, Rasmussen syndrome, and Landau-Kleffner syndrome These patients should be referred to a center with expertise in pediatric epilepsy surgery Surgical procedures may include placement of a vagal nerve stimulator, resection of a cortical lesion, temporal lobectomy, hemispherectomy, corpus callosotomy, or multiple subpial transection Changing Goals of Therapy in Prolonged SRSE/FIRES Cases of SRSE/FIRES are infrequent; children should be managed as individuals with their families using the best expertise available This approach is multidisciplinary; invariably, pediatric neurology and PICU services are central When using anesthetic agents, there is no limit to duration of anesthesia or to the number of cycles of general anesthesia Rather, the limit comes down to setting of goals and deciding at what point the therapeutic target should change from total seizure control to accepting a particular seizure frequency/duration in a patient In our practice, making decisions about choice of ASMs, duration of drug-induced coma and setting realistic therapeutic targets requires recurrent team and family meetings Prognostication is always difficult However, there is some evidence from pediatric FIRES/SRSE series65,66 that the development of MRI evidence of brain atrophy is associated with poor outcomes Serial alternateweek MRI studies along with other updated information can inform such discussions Key References Chin RF, Neville BG, Peckham C, et al Treatment of community-onset childhood convulsive status epilepticus: a prospective, populationbased study Lancet Neurol 2008;7:696-703 Pujar S, Scott RC Long-term outcomes after childhood convulsive status epilepticus Curr Opin Pediatr 2019;31(6):763-768 Rosati A, De Masi S, Guerrini R Ketamine for refractory status epilepticus: a systematic review CNS Drugs 2018;32:997-1009 Rosati A, Ilvento L, L’Erario M, et al Efficacy of ketamine in refractory convulsive status epilepticus in children: a protocol for a sequential design, multicenter, randomized, controlled, open-label, non-profit trial (KETASER01) BMJ Open 2016;6:e011565 Trinka E, Hofler J, Leitinger M, Brigo F Pharmacotherapy for status epilepticus Drugs 2015;75:1499-1521 Tasker RC, Goodkin HP, Sanchez-Fernandez I, et al Refractory status epilepticus in children: intention to treat with continuous infusions of midazolam and pentobarbital Pediatr Crit Care Med 2016;17:968-975 Wilkes R, Tasker RC Intensive care treatment of uncontrolled status epilepticus in children: systematic literature search of midazolam and anesthetic therapies Pediatr Crit Care Med 2014;15:632-639 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diagnosis of meningitis and encephalitis N Engl J Med 2019;380:2327-2340 43 Tasker RC, Goodkin HP, Sanchez-Fernandez I, et al Refractory status epilepticus in children: intention to treat with continuous infusions of midazolam and pentobarbital Pediatr Crit Care Med 2016;17:968-975 44 Wilkes R, Tasker RC Intensive care treatment of uncontrolled status epilepticus in children: systematic literature search of midazolam and anesthetic therapies Pediatr Crit Care Med 2014;15:632-639 45 Morrison G, Gibbons E, Whitehouse WP High-dose midazolam therapy for refractory status epilepticus in children Intensive Care Med 2006;32:2070-2076 46 Rosati A, Ilvento L, L’Erario M, et al Efficacy of ketamine in refractory convulsive status epilepticus in children: a protocol for a sequential e2 design, multicenter, randomized, controlled, open-label, non-profit trial (KETASER01) BMJ Open 2016;6:e011565 47 McGinn KA, Bishop L, Sarwal A Use of ketamine in barbiturate coma for status epilepticus Clin 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2013;54:1586-1594 54 Crawford TO, Mitchell WG, Fishman LS, Snodgrass SR Very-highdose phenobarbital for refractory status epilepticus in children Neurology 1988;38:1035-1040 55 Mirski M, Williams M, Hanley DF Prolonged pentobarbital and phenobarbital coma for refractory generalized status epilepticus Crit Care Med 1995;23:400-404 56 Wilkes R, Tasker RC Pediatric intensive care treatment of uncontrolled status epilepticus Crit Care Clin 2013;29:239-257 57 Tasker R, Vitali S Continuous infusion, general anesthesia and other intensive care treatment for uncontrolled status epilepticus Curr Opin Pediatr 2014;26:682-689 58 Kofke WA, Snider MT, Young RS, et al Prolonged low flow isoflurane anesthesia for status epilepticus Anesthesiology 1989;71:653659 59 Legriel S, Lemiale V, Schenck M, et al Hypothermia for neuroprotection in convulsive status epilepticus N Engl J Med 2016;375: 2457-2467 60 Farias-Moeller R, Bartolini L, Pasupuleti A, et al A practical approach to ketogenic diet in the pediatric intensive care unit for super-refractory status epilepticus Neurocrit Care 2017;26:267-272 61 Arya R, Peariso K, Gainza-Lein M, et al Efficacy and safety of ketogenic diet for treatment of pediatric convulsive refractory status epilepticus Epilepsy Res 2018;144:1-6 62 Park EG, Lee J, Lee J The ketogenic diet for super-refractory status epilepticus patients in intensive care units Brain Dev 2019;41:420-427 63 Peng P, Peng J, Yin F, et al Ketogenic diet as a treatment for superrefractory status epilepticus in febrile infection-related epilepsy syndrome Front Neurol 2019;10:423 64 Cervenka MC, Hocker S, Koenig M, et al Phase I/II multicenter ketogenic diet study for adult superrefractory status epilepticus Neurology 88:938-943, 2017 65 Kramer U, Chi CS, Lin KL, et al Febrile infection-related epilepsy syndrome (FIRES): pathogenesis, treatment, and outcome: a multicenter study on 77 children 52:1956-1965, 2011 66 Kramer U, Chi CS, Lin KL, et al Febrile infection-related epilepsy syndrome (FIRES): does duration of anesthesia affect outcome? Epilepsia 52 (S8):28-30, 2011 ... reliable method for controlling seizures and inducing burst suppression These goals are achieved within minutes, and hypotension is not dose-limiting The inhalational anesthetics are easier to titrate... pentobarbital, and the pattern of emergence from anesthesia is more predictable In PICU practice, this means that long-term seizure medications can be started and blood levels optimized while the... increased until adequate suppression of the seizure and background EEG activity has occurred, and this dose is maintained Then, at regular intervals, the minimum dose of anesthetic needed to achieve