785CHAPTER 64 Status Epilepticus Drug Initial Dose Maximum Single Dose IV Administration Onset of Action Half Life Principal Adverse Effects in Short Term Use Lorazepam 0 05–0 1 mg/kg IV 4 mg 0 5 mg/m[.]
CHAPTER 64 Status Epilepticus 785 TABLE Drugs Used in the Treatment of Status Epilepticus 64.1 Maximum Single Dose IV Administration Onset of Action 0.05–0.1 mg/kg IV mg 0.5 mg/min bolus 1–3 Neonates: 40 h Children: 10 h Sedation, hypotension, bradycardia, respiratory depression, paradoxical hyperactivity Diazepam 0.05–0.3 mg/kg IV ,5 y: mg 5 y: 10 mg 0.1 mg/kg/min bolus 1–3 Neonates: 50–95 h Infants: 40–50 h Children: 15–20 h Sedation, hypotension, bradycardia, respiratory depression, paradoxical hyperactivity, thrombophlebitis Phenobarbital 15–20 mg/kg IV 1g mg/kg/min bolus to max 60 mg/min Neonates: 45–200 h Infants: 20–133 h Children: 37–73 h Hypotension, sedation, respiratory depression, paradoxical hyperactivity, immunosuppression Phenytoin 15–20 mg/kg IV 1g mg/kg/min bolus, to max 50 mg/min 7–42 h (first-order kinetics not apply) Dysarthria, ataxia, sedation, hypotension, cardiac arrhythmia, thrombophlebitis, extravasation causes purple glove syndrome Fosphenytoin 15–20 mg PE/kg IV g PE mg PE/kg/min bolus to max 150 mg PE/min 12–29 h (firstorder kinetics not apply) Dysarthria, ataxia, sedation, hypotension, bradycardia, tachycardia Valproic acid 10–30 mg/kg IV 30 mg/kg mg/kg/min bolus Children mo: 7–13 h Children 2–14 y: 3.5–20 h Hypotension, cardiac arrhythmia, hepatitis, pancreatitis Drug Initial Dose Lorazepam Half-Life Principal Adverse Effects in Short-Term Use IV, Intravenous; NA, not applicable; PE, phenytoin equivalents First-Line Benzodiazepines: Diazepam, Lorazepam, or Midazolam Diazepam and lorazepam were compared in a study funded by the National Institutes of Health and coordinated by the Pediatric Emergency Care Applied Research Network to determine which drug is safer and more effective.21,22 The results of the randomized clinical trial showed that lorazepam was not superior to diazepam for pediatric SE lasting at least minutes Both medications were effective in stopping SE in more than 70% of cases and had rates of severe respiratory depression of less than 20% Another randomized trial of adults and children, the Rapid Anticonvulsant Medication Prior to Arrival Trial (RAMPART), found that intramuscular midazolam initiated in the prehospital setting overall stopped more seizures at arrival to the ED than intravenous lorazepam However, a subgroup analysis showed similar results for the two medications There was also a similar intubation rate of 14% in each group.23 All three benzodiazepines have an onset of action of less than minutes and enhance inhibitory neurotransmission by binding to a specific benzodiazepine site on the GABAA receptor However, diazepam’s duration of antiseizure action appears to be less than hour, making it less attractive than lorazepam Often, patients may have received rectal diazepam before arrival to the hospital, which should be kept in mind when escalating therapy for SE Lorazepam has a slower onset of action than diazepam because it is less lipophilic, but its advantage is its prolonged antiseizure effect of greater than hours Currently, the US Food and Drug Administration (FDA) has approved diazepam for adults and children, whereas lorazepam is approved for adults but is being used off label for children Midazolam is a short-acting benzodiazepine used as a first-line agent in prehospital care It may also be used in the treatment of RSE and administered as a continuous infusion It may be given intravenously, intraosseously, intramuscularly, and per rectum Small pediatric series have also shown efficacy when given via the buccal or intranasal route as well The duration of effect is shorter than for lorazepam All of the benzodiazepines have the potential to cause respiratory depression and hypotension Benzodiazepines are less likely to halt seizure activity if multiple dosages are required; in these situations, additional anticonvulsant medications should be administered Furthermore, repeated doses of benzodiazepines will have additive sedating effects that may prolong a diminished level of consciousness and prevent adequate neurologic assessment Second-Line Fosphenytoin and Phenobarbital Fosphenytoin and phenytoin are preferred second-line, longeracting ASMs for the treatment of SE Both drugs exert their effect by stabilizing the neuronal membrane Each drug takes ≈20 minutes to achieve a therapeutic effect Fosphenytoin, a water-soluble disodium phosphate ester of phenytoin, is converted to phenytoin in plasma Fosphenytoin is compatible with most intravenous solutions, is devoid of propylene glycol and, although it has a safer hemodynamic profile than phenytoin, administration must be rate limited Fosphenytoin does not have the deleterious effects on tissue that occur with phenytoin in the event of extravasation, nor does it cause respiratory depression or sedation In most centers, fosphenytoin is ordered in phenytoin equivalent dosages The higher cost of fosphenytoin and the lack of definitive evidence for superior efficacy, however, may limit its widespread use despite the suggestion by pharmacoeconomic analysis that fosphenytoin is cost-effective Although phenytoin is the second-line agent indicated for the treatment of most 786 S E C T I O N V I Pediatric Critical Care: Neurologic causes of seizures, it is usually not efficacious in the management of drug-induced seizures Phenobarbital has a long-proven history as an effective drug in epilepsy It is used commonly to treat neonatal seizures and SE It may be given intravenously, intraosseously, or intramuscularly Potential side effects include respiratory depression, hypotension, bradycardia, and prolonged sedation Prolonged sedation can impair neurologic assessment and is a significant disadvantage of phenobarbital when compared with fosphenytoin or phenytoin Additionally, the combination of a benzodiazepine and phenobarbital often necessitates tracheal intubation because of respiratory depression Other Therapies Propofol is a nonbarbiturate anesthetic agent (GABA agonist) initially approved for rapid induction and maintenance of anesthesia Its efficacy has been detailed in case reports and small case series It has been associated with the cessation of seizure activity or burst suppression within seconds of administration However, in the United States and some other countries, propofol is not approved for use in prolonged continuous infusion for pediatric patients Adverse effects include bradycardia, apnea, hypotension, and the propofol infusion syndrome, which includes potentially fatal metabolic acidosis, rhabdomyolysis, and cardiovascular collapse Valproic acid (VPA) is a common drug used in epilepsy as well as in SE and RSE Possible mechanisms of action include an increase in CNS GABA levels by increased synthesis and decreased catabolism, blockade of T-type calcium (Ca21) currents, and enhancement of sodium (Na1) channel inactivation The FDA has not yet approved intravenous VPA for treating SE However, some reports describe effective seizure treatment, with a VPA protocol as follows: loading dosing is 20 to 40 mg/kg, diluted 1:1 with normal saline or 5% dextrose, infused over to minutes; followed by an infusion of mg/kg per hour; then, after a 12-hour seizure-free period, the infusion can be decreased by mg/kg every hours.24,25 In general, this protocol does not cause changes in heart rate or rhythm, blood pressure, or liver enzymes Transient tremor has been reported after the infusion Serum ammonia concentration should be followed while using this protocol, and treatment reduced or discontinued if the ammonia concentration rises Levetiracetam has no effect on voltage-gated Na1 channels or GABAergic transmission and no affinity for either GABAergic or glutamatergic receptors Some have proposed that it binds to a presynaptic vesicle glycoprotein (sv2A) to act as a transporter for presynaptic P/Q type voltage-dependent calcium channels It has been considered a potentially useful agent for SE because, in comparison with other intravenous ASMs, it has few known side effects, including a low risk of sedation, cardiorespiratory depression, or coagulopathy Thus it is potentially useful in critically ill children.26–28 Clearance is dependent on renal function and completely avoids hepatic metabolism Lacosamide is a functionalized amino acid that selectively enhances slow inactivation of voltage-gated Na1 channels, increasing the proportion of Na1 channels unavailable for depolarization This stabilizes neuronal membranes and inhibits sustained repetitive neuronal firing In randomized controlled trials in adults, it demonstrated significant benefit in treating refractory seizures, with 30% to 40% of patients achieving a more than 50% reduction in seizures at doses of 400 to 600 mg/day Pediatric studies describe similar results in children and young adults with refractory epilepsy.29 It is generally well tolerated, and the most frequent reactions are dizziness, headache, diplopia, and nausea These adverse effects are usually dose related and reversible on dose reduction or discontinuance Pyridoxine (vitamin B6) is a cofactor for both glutamic acid decarboxylase and GABA transaminase, the enzymes required for the synthesis and metabolism of GABA in the brain Pyridoxine dependency and pyridoxine deficiency are rare disorders (with a prevalence of ,1 in 300,000 in the United Kingdom) that usually present in the neonatal or infantile period but may present as late as age 2.5 years Patients with these disorders have intractable seizures that are refractory to conventional anticonvulsant medications but respond promptly to pyridoxine Therefore, a trial of pyridoxine should be considered in any child who is seen before years of age with recurrent seizures or SE, particularly if the seizures are refractory to conventional ASMs Isoniazid poisoning is another clinical scenario in which pyridoxine may be the only effective therapy Medications for Established Status Epilepticus There are no controlled, randomized, blinded clinical trials to compare the efficacy and tolerability of currently available treatments for established SE (ESE), defined as seizures that continue despite the administration of a benzodiazepine An ongoing study, the Established Status Epilepticus Treatment Trial,30 is attempting to determine the most effective or least effective treatment of benzodiazepine-refractory SE among patients older than years Three active treatment arms are being compared: fosphenytoin, levetiracetam, and valproic acid Other objectives include comparing the three drugs for secondary outcomes and describing effectiveness, safety, and rate of adverse reactions to these drugs in children Management of Refractory Status Epilepticus and Other Forms of TreatmentResistant Status Epilepticus SE that persists beyond hour despite ASM therapy is one definition of RSE Another definition—as used by the pSERG group— is failure to respond to two different classes of ASMs, since some 30% of SE cases may prove resistant to standard treatment with one of the benzodiazepines and phenytoin This subgroup of patients has a higher risk of complications and longer hospital length of stay and mortality Most have some structural cerebral damage, metabolic disorders, and/or cerebral hypoxia (Box 64.2) Other risk factors include delay in receiving treatment and encephalitis Conventional ASMs have low efficacy in RSE and, although drugs such as topiramate, levetiracetam, and carbamazepine should be continued during the episode, higher doses or higherpotency agents are often required to stop RSE Therapeutic options include using high-dose benzodiazepines, short-acting barbiturates, VPA, ketamine, lidocaine, and inhalational anesthetic agents It is unknown what to use and in what order, and whether administering anesthetic agents with the aim of drug-induced coma versus merely to control seizure activity is best It is also unknown whether outcome differs if anesthetic agents are avoided Here, clinicians have the problem of trying to separate patient outcome related to the underlying diagnosis/pathology from outcome related to aggressive treatment There is no doubt that CHAPTER 64 Status Epilepticus • BOX 64.2 Diagnostic Considerations in Patients Presenting on the Spectrum of RSE-FIRES Clinical Evaluation • General assessment for acute cause not previously considered: meningoencephalitis, sepsis, FIRES, demyelinating disease, toxicology • Detailed neurologic assessment for nonacute cause, such as cortical malformation, neurocutaneous syndromes, autoimmune disorder, monogenic epileptic encephalopathies, chromosomal abnormalities, metabolic disease • Ophthalmic evaluation Laboratory Testing Not Previously Evaluated • Inflammatory markers: C-reactive protein, erythrocyte sedimentation rate, von Willebrand factor antigen • Infectious work-up: bacteria, fungal and viral cultures, and serology • Testing for oligoclonal banding • Testing for antibodies, including neuronal and ion-channel antibodies Brain Imaging • Brain magnetic resonance imaging with gadolinium, fluid attenuation inversion recovery sequences, diffusion-weighted imaging, and magnetic resonance angiography • Conventional angiogram for microvasculitis CSF Analysis • CSF cell count and differential, protein, and glucose • Bacterial, fungal, and viral cultures and serology (or metagenomic sequencing, see text) • Testing for oligoclonal bands • Testing for neuronal and ion-channel antibodies Brain Biopsy • Consider, if normal angiogram, as diagnostic of microvascular vasculitis CSF, Cerebrospinal fluid; FIRES, febrile infection-related epilepsy syndrome; RSE, refractory status epilepticus escalating to drug-induced coma can exacerbate cardiorespiratory insufficiency and metabolic derangements in these already vulnerable patients Hence, at this point in a child’s management, care must include a multidisciplinary approach The pediatric neurologist brings expertise regarding diagnosis—which could be anything from CNS vasculitis, to autoimmune disease, to NMDA-receptor encephalitis, to difficult-to-control epileptic encephalopathy— and the complex use of a range of drug categories with potential toxicities and interactions The pediatric intensivist brings expertise regarding life support at extremes, management of metabolic derangement and multiple-organ system interventions, and supervision of safe induction of coma and anesthetic states Given these roles, the team should discuss at a very early stage, after admission to the PICU, the likely pathway for the child and goal of further seizure treatment The remainder of this perspective on RSE will now focus on our suggested approach to seizure control for children managed with chemical coma: what to be aware of, what to expect, and what strategies are being used in the PICU First, there are some labels or clinical syndromes that appear in the literature that need to be defined Super-Refractory Status Epilepticus Super-refractory SE (SRSE) is a new descriptive term first appearing in 2011 in the summary of the Third London-Innsbruck 787 Colloquium on SE.31 Of course, SRSE is not a new entity, but giving it a name helps to clarify an approach to therapy in this difficult clinical situation SRSE can be considered as a stage of RSE characterized by unresponsiveness to initial anesthetic therapy and is defined as SE that continues or recurs 24 hours or more after the onset of general anesthesia, including those cases in which SE recurs on the reduction or withdrawal of anesthesia The pediatric literature suggests a more liberal definition of SRSE, namely, a patient still requiring anesthesia at 24 hours, or a more stringent definition, a patient having seizure recurrence at 48 hours when weaning is commenced In adults, SRSE is generally seen in two distinctive clinical situations: in patients with severe acute brain injury and in previously healthy patients who have no apparent cause for SE, so-called new-onset RSE (NORSE).32 The pattern of presentation is similar in children but with focus on specific age of occurrence and fever as an apparent triggering factor Fever may precede the onset of neurologic symptoms and no longer be present at the time of presentation In the pediatric literature, two conditions have been described in younger-age groups: in school-aged children, febrile infection-related epilepsy syndrome (FIRES)33 and, in infancy, idiopathic hemiconvulsionhemiplegia syndrome (IHHS).34 Whether the diagnoses of NORSE, FIRES, and IHHS represent distinct pathophysiologies or a spectrum of acute encephalopathy with inflammationand immunology-mediated SE is, at present, unknown.35,36 FIRES is now considered a subset of NORSE, which is a subset of SRSE Fever-Induced Refractory Epileptic Encephalopathy and Febrile Infection-Related Epilepsy Syndrome This group of conditions has multiple labels in the literature, including FIRES, fever-induced refractory epileptic encephalopathy in school-aged children, IHHS, acute encephalopathy with inflammation-mediated status epilepticus (AEIMSE), acute encephalitis with refractory repetitive partial seizures (AERRPS), NORSE, and devastating epilepsy in school-aged children (DESC).32–36 From the non-drug management perspective, it is critical to establish whether the condition is consistent with autoimmune disease (e.g., glutamate-receptor subunit R3 antibodies, NMDA-receptor antibodies, voltage-gated potassium channel antibodies) since early plasmapheresis and immunomodulation may have a role There is little literature on each of these entities; thus, our PICU approach is to deal with them as one, bearing in mind that there may be specific diagnostic tests used in each instance Therapeutic Strategies in the RSE-SRSE-NORSEFIRES Spectrum The overall goal of PICU treatment for pediatric patients in the clinical spectrum of RSE n SRSE n NORSE n FIRES is to achieve clinical and electrographic seizure control As such, four parallel therapeutic strategies need to be addressed—to a greater or lesser extent depending on the history—in each patient: Are immunotherapies indicated? What is the hierarchy in escalating ASMs via intravenous infusion or anesthetic agents? Should a ketogenic diet be initiated? Is this patient a candidate for surgical intervention? 788 S E C T I O N V I Pediatric Critical Care: Neurologic Immunotherapies Immunotherapies that have been used in these severe forms of SE include high-dose steroids, IVIG, PLEX, and anakinra (a recombinant version of human interleukin-1 [IL-1] receptor antagonist) There have been five recent reports on the use of anakinra in FIRES since 2016, four in 2019.37–41 Therefore, the case-based discussion should involve various specialties, including immunology, rheumatology, infectious diseases, neurology, and critical care Often, decisions involve the following issues: • Steroids: These are considered for antiinflammatory purposes However, safety and whether CNS infection has definitely been excluded are concerns The state-of-the-art investigation now is metagenomic next-generation sequencing of CSF to identify all causes of meningitis and encephalitis in a single test.42 Another concern is whether steroids can be discontinued at the time of trying to induce ketosis (see later discussion) • IVIG and PLEX: If PLEX is going to be used, it should occur before administering IVIG Otherwise, the latter will simply be removed with the first exchange Infusions and Anesthesia for Seizure Control Once a child is in the PICU, the most commonly used sequence of ASMs via continuous infusion is midazolam followed by a choice between ketamine and/or pentobarbital if midazolam fails to control seizures Some advocate starting with pentobarbital, which is the most common practice in adult patients with RSE Midazolam This imidazobenzodiazepine has a short elimination half-life of 1.5 to 3.5 hours and little accumulation These favorable pharmacokinetics allow for repeat bolus dosing, aggressive titration of an infusion, and relatively fast recovery time Midazolam shares anxiolytic, muscle-relaxant, hypnotic, and anticonvulsant actions with other benzodiazepines Yet, given these similarities, an obvious question is this: Why should it be effective when other GABA agonists have failed to control the seizure episode? A recent pSERG PICU experience of using midazolam for RSE shows that in a series of 45 pediatric patients, typical loading doses (interquartile range [IQR] 0.10–0.20 mg/kg) and highest infusion rates (IQR 0.05–1.50 mg/kg per hour)43 were similar to those described in a systematic review of studies (1993–2011), including 521 children (loading dose IQR 0.15–0.50 mg/kg; highest infusion rates IQR 0.07–1.44 mg/kg per hour),44 with highest maximum infusion rate safely administered being 1.92 mg/kg per hour (i.e., with negligible hemodynamic compromise).45 Breakthrough seizures occur in up to 52% of cases and recurrent seizures occur in 12% even when using infusion rates up to 1.44 mg/kg per hour Of note, vasopressors were needed in fewer than 3% of patients in whom very high doses of midazolam were used The exact clinical or electrographic target or end point when using midazolam is unknown Not all centers in the pSERG group43 or all of the pediatric studies previously reported44 use cEEG-guided therapy, but most Of note, time to seizure control and duration of midazolam infusion is longer when cEEG is used Also, at EEG, burst suppression is rarely achieved with the doses described earlier, and it should not be the therapeutic goal when using midazolam Rather, the target is a seizure-free period for 12 hours and then a trial of weaning the infusion Table 64.2 can be used as a guide, but readers are encouraged to refer to local PICU policies and procedures Other issues regarding midazolam drug dosing are detailed in the next section Midazolam Infusions for Refractory Status Epilepticus The very high doses of midazolam that some have reported (i.e., 1.92 mg/kg per hour)45 may be too high Midazolam is soluble at pH less than 4.5, and the hydrochloric acid diluent/excipient in the infusion when using a rate of 1.5 mg/kg per hour (i.e., 25 mg/kg per minute) is roughly equivalent to administering continuous whole-body hydrogen ion Thus, at higher rates, caution is in order in the presence of unexplained metabolic acidosis, especially with impaired renal or hepatic function, with consideration of transition to other infusion options Clinicians should consider using a lower midazolam infusion failure dose to signify failure of midazolam rather than the 1.92 mg/kg per hour (36 mg/kg per minute) dose presented in Table 64.2.45 For example, the ketamine in RSE in children open-label trial (KETASER01)46 uses a new definition of midazolam failure as an infusion rate greater than 0.36 mg/kg per hour (i.e., mg/kg per minute) This dosing is close to the median infusion rates used in other studies.43–45 So, although it may be reasonable to push midazolam dosing to 1.50 to 1.92 mg/kg per hour (i.e., 25 to 36 mg/ kg per minute), with close metabolic/biochemical observation, perhaps other infusions should be considered earlier The exact place of ketamine in this sequence—that is, before or after shortacting barbiturates—is unknown (see next section) Ketamine Ketamine is a unique NMDA antagonist reported to have both anticonvulsant and neuroprotective properties Because of its unique mechanism of action, it is an option for RSE that has failed to respond to high-dose benzodiazepines At present, there is no consensus as to when ketamine should be used For example, it is used in combination with midazolam in the KETASER01 study,46 in which it is administered at 0.12 to 0.24 mg/kg per hour (2–4 mg/kg per minute) Ketamine Infusions for Refractory Status Epilepticus For patients treated with continuous infusion of midazolam for fewer than days, the dosage is reduced from the midazolam failure dose of 0.36 to 0.12 mg/kg per hour to prevent anesthetic emergence reactions In patients treated with midazolam for or more days, it is reduced from 0.36 to 0.24 mg/kg per hour to avoid seizure occurrence secondary to abrupt benzodiazepine withdrawal and prevent emergence reactions Ketamine has also been used in combination with pentobarbital as a barbituratesparing agent47 or, as has recently been described in US pediatric hospitals, after a trial of pentobarbital infusion.48 A word of caution about this off-label use of ketamine: two recent systematic reviews49,50 of dosing and consequences of ketamine infusion in RSE in adults and children describe heterogeneity in dosing and concerns about metabolic acidosis, hemodynamic instability, sepsis, and pneumonia with prolonged use Ketamine is a sympathomimetic in the short term, but prolonged infusion may deplete catecholamines In the KETASER01 study,46 ketamine is given as an initial bolus of to mg/kg, followed by a continuous infusion rate starting at 10 mg/kg per minute The infusion rate is increased by to 10 mg/kg per minute every 10 minutes, up to a maximum CHAPTER 64 Status Epilepticus 789 TABLE 64.2 Strategy for High-Dose Intravenous Midazolam in Refractory Status Epilepticus Timing From Start of This Strategy Midazolam Dosing Steps min: Initial bolus Give 0.5 mg/kg A min: Start continuous infusion Start at mg/kg/min (0.12 mg/kg/h) B min: If seizure persists after bolus (step A) Repeat 0.5 mg/kg bolus Increase infusion to mg/kg/min (0.24 mg/kg/h) C 10 min: If seizure persists or recurs after step C Give 0.1 mg/kg Increase infusion by mg/kg/min (0.24 mg/kg/h) D 15 min: If seizure persists or recurs after step D Repeat step D E 20–45 min: If seizure persists or recurs after step E, continue to repeat step D every until a maximum infusion rate is achieved Maximum infusion rate of 36 mg/kg/min (1.92 mg/kg/h) F (5 cycles of D to E may be needed) 45 min: By the completion of step F, an EEG should be available to confirm seizure control or otherwise If seizure is not controlled, then consider this episode as treatment failure and move to step H Maintain dose of continuous infusion that achieves clinical and EEG seizure control and 12 h later move to step I G 45 to 60 min: treatment failure Decrease midazolam infusion and start general anesthesia with ketamine and/or pentobarbital H 12 h: If patient is free of clinical and EEG seizures, start to wean the infusion Reduce infusion by mg/kg/min every 30 minutes I 12 h: Continue EEG monitoring to observe for breakthrough seizures Plan to discontinue infusion after optimizing other AEDs If seizures recur, then consider step K for weaning failure Alternatively, this episode may be in the category of SRSE J Weaning failure Consider re-bolus of 0.1 mg/kg and increase infusion by mg/ kg/min and/or Consider alternative ASMs K AEDs, Antiepileptic drugs; ASMs, antiseizure medications; EEG, electroencephalography; SRSE, super-refractory status epilepticus infusion dose of 100 mg/kg per minute, with each increment being preceded by a bolus of to mg/kg If the seizures resolve, the effective infusion rate is continued for 48 hours up to a maximum of days If there is no response (i.e., continued RSE at 100 mg/kg per minute) or adverse events, ketamine is discontinued and considered a failure When ketamine is weaned, the infusion rate is reduced by 25% every 12 hours if the starting rate was 50 to 100 mg/kg per minute Withdrawal may be more rapid (25% of the starting dose every hours) for infusions less than 50 mg/kg per minute or infusion durations of 48 hours or longer In regard to cEEG monitoring during ketamine dissociative anesthesia for RSE—again, like midazolam, burst suppression is rarely achieved with the doses described here, and it should not be the therapeutic goal Rather, the target is a seizure-free period for at least 48 hours High-Dose Barbiturates Barbiturates—including pentobarbital, thiopental, and phenobarbital—are widely used medications for RSE This discussion will mainly focus on pentobarbital in the RSE n FIRES spectrum of cases, which in US PICU practice is most often used as monotherapy following midazolam failure (see earlier discussion) However, practitioners should be aware that there are reports of combining pentobarbital-induced anesthesia with other strategies in order to limit the dose of pentobarbital needed for seizure control and induction of cEEG burst suppression For example, ketamine can be used before or with pentobarbital (see earlier discussion) Also, there are reports of using induced hypothermia with pentobarbital (see later discussion).51–53 Pentobarbital penetrates the CNS rapidly, allowing for rapid titration to EEG burst suppression It has multiple actions, including at a neuronal-level activation of the GABA receptor in a way that is different from the benzodiazepines, that is, increasing duration versus frequency of GABA channel opening Physiologically, pentobarbital causes a reduction in cerebral metabolic rate for oxygen (CMRO2) and, to a lesser degree, a matched fall in CBF A consequence of the fall in CBF may include a reduction in ICP, which would be an advantage in patients with cerebral swelling Theoretically, pentobarbital may also be neuroprotective because of its inhibition of neuronal excitation and reduction in CMRO2 These favorable mechanisms of action explain the drug’s potential effectiveness in RSE that is resistant to benzodiazepine therapy, or as the first-line ASM for RSE Treatment and Dosing Strategy With Pentobarbital When using pentobarbital as a prolonged infusion, drug elimination will change from first-order kinetics seen with bolus doses to unpredictable zero-order kinetics and a prolonged elimination half-life because of distribution into lipid Hence, recovery time ... patients Hence, at this point in a child’s management, care must include a multidisciplinary approach The pediatric neurologist brings expertise regarding diagnosis—which could be anything from CNS... in the summary of the Third London-Innsbruck 787 Colloquium on SE.31 Of course, SRSE is not a new entity, but giving it a name helps to clarify an approach to therapy in this difficult clinical... hours High-Dose Barbiturates Barbiturates—including pentobarbital, thiopental, and phenobarbital—are widely used medications for RSE This discussion will mainly focus on pentobarbital in the RSE n