505427

research-article2013

AOPXXX10.1177/1060028013505427Annals of PharmacotherapyEsaian et al

Case Report

Ketamine Continuous Infusion for Refractory Status Epilepticus in a Patient With Anticonvulsant Hypersensitivity Syndrome

Annals of Pharmacotherapy 47(11) 1569­–1576 © The Author(s) 2013 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028013505427 aop.sagepub.com

Diana Esaian, PharmD, BCPS1, Danielle Joset, PharmD1, Candace Lazarovits, ACNP-BC1, Patricia C. Dugan, MD2, and David Fridman, MD1

Abstract Objective: Refractory status epilepticus (RSE) requires aggressive management with multiple antiepileptic drugs (AEDs) often requiring the initiation of continuous infusions of propofol, midazolam, or pentobarbital to achieve adequate control in addition to intermittent agents. Ketamine has been implicated in several case reports as a successful agent for treating RSE given that it blocks the N-methyl-D-aspartate receptor, which is overexpressed in prolonged status epilepticus. Case Summary: We describe a previously healthy 27-year-old woman who presented with prolonged RSE requiring the initiation of multiple AEDs, including high-dose propofol and midazolam continuous infusions. As a result of hypotension from propofol and inadequate seizure control with midazolam, the patient was successfully transitioned to a pentobarbital infusion in combination with multiple AEDs. Although the patient achieved control of her RSE, her course was complicated by the development of an anticonvulsant hypersensitivity syndrome (AHS) with transaminitis. Limited with the options of AED that could have been used, it was decided to initiate the patient on a continuous ketamine infusion plus midazolam and slowly wean the patient off pentobarbital as well as to avoid further use of phenytoin and phenobarbital. Discussion: The patient was successfully transitioned off pentobarbital to a ketamine infusion plus midazolam with complete seizure control after several dose escalations. Her AHS and transaminitis resolved on a ketamine infusion for a total of 12 days, and she was successfully discharged from the hospital after 60 days in the ICU. Conclusion: This is the first case report to describe a successful transition to a ketamine infusion in a patient with AHS and transaminitis. Keywords ketamine, refractory status epilepticus, anticonvulsant hypersensitivity reaction, pentobarbital

Background Status epilepticus, commonly defined in clinical practice as seizure activity lasting more than 5 minutes or 2 or more seizures occurring without return to baseline consciousness, is a major medical emergency associated with significant morbidity and mortality.1,2 Refractory status epilepticus (RSE) has been defined as status epilepticus unresponsive to first-line antiepileptic medications and occurs in a quarter to one-third of patients presenting with status epilepticus.1,3 Initial standard treatment of status epilepticus includes a parenteral benzodiazepine followed by the initiation of an antiepileptic drug (AED).4 In critically ill adults, if seizure activity does not respond after 60 minutes of initial therapy, RSE should be managed with the addition of a continuous infusion of midazolam, propofol, or pentobarbital.4 Although barbiturates have been shown to have high

success rates in terminating RSE, they are associated with significant adverse effects such as hypotension, respiratory depression, ileus, and infection.4 Several case reports have implicated ketamine as a successful agent for treating RSE based on the fact that it is an N-methyl-D-aspartate (NMDA) receptor blocker, and these receptors have been shown to be upregulated over time in RSE.5-9 We describe the case of a previously healthy 27-year-old woman with prolonged RSE 1

New York University Langone Medical Center, New York, NY, USA New York University Langone Medical Center Comprehensive Epilepsy Center, New York, NY, USA 2

Corresponding Author: Diana Esaian, PharmD, BCPS, Department of Pharmacy, New York University Langone Medical Center, 550 First Avenue, GBH-SC2-097 New York, NY 10016, USA. Email: [email protected]

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who, after responding to barbiturate therapy, was unable to be weaned from pentobarbital utilizing supratherapeutic doses of concomitant AEDs and also experienced anticonvulsant hypersensitivity syndrome (AHS). A continuous ketamine infusion plus midazolam was utilized to successfully transition off pentobarbital while controlling her refractory seizures.

Case Report A 27-year-old Chinese woman born in Taiwan with no past medical history, known allergies, or medications prior to admission was brought into the emergency department (ED) after experiencing a seizure at home, which was witnessed by her boyfriend. He reported that the patient was in her usual state of health approximately 5 days prior to admission, when she developed fevers up to 101.8°F and a productive cough with yellow sputum. She was prescribed a course of oral amoxicillin, which was completed 1 day prior to admission. On the day of her admission she developed a headache without photophobia or phonophobia and then later developed acute neck stiffness followed by generalized shaking, eye rolling, and foaming of the mouth; this seizure lasted approximately 2 minutes. Vital signs on presentation were: blood pressure of 146/89 mm Hg, heart rate of 106 bpm, temperature of 99.0°F, 95% oxygen saturation on 100% nonrebreather, and glucose finger stick of 125 mg/ dL. Labs on admission were notable for sodium 151 mEq/L, potassium 4.8 mEq/L, white blood cells 9.8 × 103/µL, platelets 134 × 103/µL, lymphocytes 56%, monocytes 22%, segmented cells 8%, and venous blood gas with pH 7.22, pCO2 43 mm Hg, pO2 51 mm Hg, bicarbonate 17.6 mmol/L, and base deficit 9.8 mmol/L. While in the ED, the patient experienced another seizure, which ceased with administration of 2 mg intravenous (IV) lorazepam. At this time, she was also started on levetiracetam 1000 mg IV every 12 hours as well as empirical treatment for meningitis with stat doses of vancomycin 1000 mg, ceftriaxone 2 g, and acyclovir 500 mg. A noncontrast head computerized tomography scan was obtained and showed normal results, and a lumbar puncture was performed but demonstrated no abnormalities. The neurology service was consulted, and the patient was admitted to the medical intensive care unit with continuous 21-channel video electroencephalography (vEEG) recording. The next morning the patient underwent a magnetic resonance image of her brain, which was normal. Later on, she developed a fever and experienced 2 more generalized tonic-clonic seizures, which ceased with 5 mg IV midazolam pushes. The patient was subsequently intubated, given a 750-mg IV loading dose of phenytoin followed by 100 mg IV every 8 hours, and initiated on a continuous propofol infusion at 50 µg/kg/min. The patient remained in status epilepticus overnight on vEEG, and levetiracetam was

increased to 1500 mg IV every 12 hours with the addition of lacosamide 200 mg IV every 12 hours. Because of significant hypotension (blood pressure to a low of 95/43 mm Hg and mean arterial pressure in the low 50s), she was converted from the propofol infusion to a continuous midazolam infusion, which still required low-dose norepinephrine to maintain a normal blood pressure. For the next few days, the patient remained persistently febrile resulting in several changes to her antibiotics. The patient was continued on ampicillin 2 g every 8 hours and acyclovir 10 mg/kg IV every 8 hours for suspected viral or listeria meningitis; in addition, treatment for ventilator-associated pneumonia was initiated with several days of piperacillin/ tazobactam prolonged infusion, and then, she was transitioned to cefepime 2 g every 8 hours after the cultures were positive for Pseudomonas aeruginosa and Acinetobacter baumannii. By day 7 of admission, the vEEG continued to show seizure activity, despite the patient being restarted briefly on propofol and having the midazolam titrated up to a maximum of 100 mg/h. A repeat lumbar puncture was consistent with a viral encephalitis or meningitis; therefore, 3 daily doses of methylprednisolone 1 g were administered. Her last phenytoin level was therapeutic at 21.7 µg/mL (adjusted for albumin), and topiramate 100 mg every 12 hours was added on to the patient’s AED regimen. On day 9, she received an additional phenytoin bolus of 750 mg IV in response to an adjusted level of 14.3 µg/mL in addition to 1000 mg IV phenobarbital. Later that evening, it was decided to initiate a pentobarbital infusion to control her RSE. Over the course of the next few days, no electrographic seizures were recorded while in a pentobarbital-induced coma (maximum dose of 8 mg/kg/h), and the midazolam was successfully titrated down and discontinued. During this time on day 11, the patient was found to have Stenotrophomonas maltophilia ventilator-associated pneumonia and was started on sulfamethoxazole/trimethoprim IV 15 mg/kg/daily for a total of 12 days. On day 13 of her admission, the patient developed diabetes insipidus necessitating vasopressin therapy as well as a diffuse maculopapular rash on her torso and back concerning for AED-induced hypersensitivity reaction versus allergic reaction to antibiotics. At the time the rash appeared, the patient was febrile to 102°F and had leukocytosis with a white blood cell count of 21.5 × 103/µL. Her serum creatinine, eosinophils, and platelets were within normal limits, and she did not have any lymphadenopathy, facial swelling, or glossitis. Her hepatic panel also revealed steadily increasing transaminase levels, which were closely monitored. The pentobarbital infusion was subsequently weaned down by 1 mg/kg every 12 hours until it was turned off for approximately 10 hours on day 16 of admission, at which point the patient developed generalized periodic epileptic discharges but was still without clinical seizures. On the same day, phenytoin was

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Esaian et al increased to 100 mg IV every 6 hours (last trough 8.7 µg/ mL) and the pentobarbital infusion restarted. On day 20, another attempt at weaning the pentobarbital drip off was made with the addition of valproic acid 15 mg/kg loading dose followed by 500 mg IV every 12 hours maintenance, increase in levetiracetam to 2000 mg IV every 12 hours, and increase in topiramate to 200 mg every 12 hours. Phenytoin was discontinued the same day because of the concern that it could be the cause of her rash, which was worsening and spreading to her face. Her aspartate aminotransferase (AST) and alanine aminotransferase (ALT) continued to trend upward, now at 112 and 107 U/L, respectively. At this time, it was decided to proceed with a trial of phenobarbital in lieu of the pentobarbital. On day 22, the patient was loaded with 20 mg/kg IV and started on a maintenance dose of 60 mg IV every 8 hours in hopes of titrating pentobarbital off, once therapeutic. Valproic acid was simultaneously increased to 750 mg 3 times daily because of subtherapeutic levels (70 mm Hg while on propofol

Abbreviations: AED, antiepileptic drug; SE, status epilepticus; SDH, subdural hematoma; CP, cerebral palsy; MAP, mean arterial pressure.

should be carefully avoided during status epilepticus because seizures can alter cerebral blood flow and may precipitate ischemia or metabolic crisis.36 Higher or prolonged doses of ketamine can be neurotoxic because of indiscriminate blockade of both intrasynaptic and extrasynaptic

NMDA receptors.38 Only 1 study to date reported neurotoxicity and sustained cognitive dysfunction attributed to ketamine therapy, and this was with the highest reported dose of 7.5 mg/kg/h.32 Other side effects secondary to the sympathomimetic activity of ketamine include hypertension

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Esaian et al (observed often with loading doses), tachycardia, and increased intracranial pressure.33,38 The reasons for our decision to initiate ketamine on day 30 were multifactorial. The patient required discontinuation of propofol early on in her RSE course because of significant hypotension (requiring norepinephrine to maintain adequate blood pressure) with the transition to high-dose midazolam infusion. Although the patient was initially without electrographic or clinical evidence of seizures while maintained on a pentobarbital infusion, persistent elevation in LFTs attributed to the continuous infusion required dose decrease, which coincided with increased seizure activity. Because of evidence of a hypersensitivity syndrome, we lost the ability to use phenytoin and phenobarbital as adjunctive anticonvulsant to help facilitate the pentobarbital wean. Furthermore, ileus attributed to pentobarbital resulted in reduced absorption of topiramate and subtherapeutic levels. We initiated ketamine with a 1.5 mg/kg bolus and started the continuous infusion at 1.2 mg/kg/h, which was similar to starting doses reported in previously discussed cases. The patient’s refractory subclinical and clinical seizure activity subsided at a maximum dose of 3.75 mg/ kg/h. We successfully weaned her from the pentobarbital infusion using the combination of ketamine and midazolam with transition to oral therapy, and her rash and LFTs resolved during this time. The duration of ketamine was 12 days, which was at the longer end of previously reported durations (Table 2). However, no evidence of long-term cognitive impairment or severe patient debilitation was observed.

Conclusion RSE is a challenging condition that requires aggressive management to prevent detrimental outcomes. Management consists of multiple AEDs that have a high risk of some serious toxicities; specifically, in rare instances, the aromatic anticonvulsants can cause AHS. To our knowledge, this is the first case report of a patient with RSE who developed AHS as well as possible worsening hepatotoxicity on pentobarbital who was successfully transitioned to continuous IV ketamine plus low-dose midazolam. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.

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Ketamine continuous infusion for refractory status epilepticus in a patient with anticonvulsant hypersensitivity syndrome.

Refractory status epilepticus (RSE) requires aggressive management with multiple antiepileptic drugs (AEDs) often requiring the initiation of continuo...
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