We identified three patients who received continuous ketamine infusion for RSE or SRSE during our study period. The average age at admission was 47 days and two patients (67%) were female. The underlying etiology of refractory seizures included abusive head trauma, ischemic stroke, and ischemic injury status post cardiac arrest. Patients included were refractory to an average of six anti-seizure medications prior to initiation of continuous ketamine infusion. Each patient received several boluses ranging from 1 to 1.5 mg/kg/dose prior to initiation of a continuous ketamine infusion. Each patient was initiated on a rate of 1 mg/kg/hr with one patient requiring titration to a maximum of 6 mg/kg/hr. The average duration of infusion was 5 days. Patients were maintained on an average of 3 concomitant anti-seizure medications during continuous ketamine infusion. In one case, the concomitant use of continuous ketamine allowed for a reduction in benzodiazepine continuous infusion rate. In all cases, ketamine was well tolerated especially in the setting of hemodynamic instability. The following review describes in detail the use of continuous ketamine infusion in three infants with RSE or SRSE identified during our study period.
Patient Case 1
A 29-day-old patient born at 36 weeks gestation with no significant past medical history presented to the emergency department with low temperature, fussiness, and vomiting. On imaging, the patient was found to have bilateral subdural hemorrhages consistent with abusive head trauma. When the clinical presentation progressed to include non-suppressible rhythmic movements concerning for seizure, the patient was given lorazepam and a single dose of phenobarbital. Several hours later, fosphenytoin was given followed by three additional doses of phenobarbital and a continuous midazolam continuous infusion was initiated with no resolution of seizures. Continuous electroencephalography (EEG) was initiated on hospital day 1 that demonstrated evidence of focal seizures. Over the next three days, seizures persisted that were refractory to levetiracetam, continuous midazolam, two pentobarbital-induced burst suppressions, and maintenance therapy with phenobarbital and levetiracetam, as outlined in the Table.
Due to failure of multiple therapies and subsequent hemodynamic instability requiring vasoactive support with epinephrine, a continuous ketamine infusion was initiated on hospital day 7. Following two ketamine boluses (2 mg/kg IV), an infusion was initiated at 1 mg/kg/hr and titrated to a maximum rate of 4.5 mg/kg/hr over two days (Figure). Lacosamide was started as an additional adjunctive agent. Following 5 days of ketamine infusion without successful capture of subclinical seizures, the decision was made to stop continuous EEG and monitor for clinical seizures. Ketamine was weaned off over the next 24 hours. The patient was maintained on lacosamide, levetiracetam, topiramate, and phenobarbital and an EEG on day 14 of hospitalization showed resolution of seizures (Table). The patient experienced significant hypoglycemia throughout the clinical course requiring infusion with dextrose 25%. The hypoglycemia was initially thought to be secondary to acute illness and ketamine, however, further workup attributed it to adrenal insufficiency secondary to traumatic brain injury. No other significant adverse events were reported.
Patient Case 2
A 52-day-old patient born at 33 weeks with a vein of Galen malformation developed status epilepticus. The patient’s course prior to seizure onset included vein of Galen embolization and a subsequent postoperative complication of ischemic stroke. At approximately day of life 50, the patient began to demonstrate frequent, repetitive hemiclonic seizures and a decline in clinical stability. Further imaging showed new areas of ischemia, consistent with a new stroke. Several doses of lorazepam, phenobarbital, fosphenytoin, and levetiracetam were given before the patient was started on a midazolam continuous infusion that was quickly titrated to 0.5 mg/kg/hr for both hemiclonic and subclinical seizures (Table). To optimize cerebral blood flow and control refractory seizures, a ketamine 1 mg/kg IV bolus was given, followed by initiation of a ketamine continuous infusion at 1 mg/kg/hr (Figure). Seizures ceased within one hour of initiation of ketamine in conjunction with midazolam. The midazolam infusion rate was slowly decreased from 0.5 mg/kg/hr to 0.1 mg/kg/hr within 60 hours of initiation of continuous ketamine.
The patient continued midazolam and ketamine continuous infusions until 36 hours without evidence of seizures. During this time, the patient experienced periods of hypotension thought to be secondary to midazolam. Thus, midazolam infusion was weaned prior to ketamine and hypotension improved. Levetiracetam maintenance therapy was initiated after discontinuation of midazolam and ketamine continuous infusions. The following day, the patient demonstrated signs of clinical seizures and ketamine continuous infusion was reinitiated at 1 mg/kg/hr. The infusion was titrated to a rate of 1.5 mg/kg/hr before resolution of seizures and subsequent discontinuation the following day. Intracranial pressure measurements were 5 to 12 millimeters of mercury throughout the infusion measured via external ventricular drain. Levetiracetam maintenance therapy was increased, and additional seizures were managed with topiramate and ketamine boluses (Table). The patient was discharged on hospital day 75.
Four days later, the patient was readmitted after parents noted right sided leg shaking, left eye deviation, and lip smacking that was unresolved despite a dose of levetiracetam at home. The patient was brought into the emergency department and received two doses of intranasal midazolam followed by fosphenytoin for persistent lip smacking. The patient was subsequently transferred to the neonatal intensive care unit (NICU) for intubation and management of refractory seizures. The patient received additional IV midazolam, oral topiramate, and IV phenobarbital upon arrival to the NICU for persistent clinical seizures. On hospital day 2, continuous EEG was placed, and the patient received an additional dose of IV phenobarbital and 1 mg/kg of IV ketamine followed by a continuous ketamine infusion at 1 mg/kg/hr with resolution of clinical seizures, but persistent subclinical seizures on continuous EEG. On hospital day 3, the continuous ketamine was titrated to 3 mg/kg/hr without resolution of subclinical seizures and a midazolam 0.1 mg/kg IV bolus was given followed by a continuous infusion at 0.1 mg/kg/hr. On hospital day 4, lacosamide was given until initiation of clobazam maintenance on hospital day 10.
The patient was maintained on continuous ketamine (maximum rate 6 mg/kg/hr on hospital day 8) and midazolam (maximum rate 0.9 mg/kg/hr on hospital day 9) through hospital day 14. Complete dose titration details of continuous ketamine can be found in the Figure. The patient continued to receive intermittent boluses of midazolam, ketamine, phenobarbital, and fosphenytoin for subclinical seizures. Phenobarbital was added on hospital day 14 as well. Subclinical seizure activity significantly decreased on hospital day 14 and continuous EEG was discontinued. The patient was extubated on hospital day 18 and repeat magnetic resonance imaging demonstrated no new cerebral infarct. Repeat EEG on hospital day 25 showed no evidence of seizures and the patient was discharged home on phenobarbital, topiramate, and clobazam maintenance therapy. Each continuous ketamine infusion was well-tolerated with no additional adverse effects noted.
Patient Case 3
A 60-day-old patient born at term with no past medical history presented to the emergency department with respiratory distress and was found to have severe cardiomegaly on chest x-ray. Further diagnostics revealed anomalous left coronary artery from the pulmonary artery which required surgical intervention on day 2 of hospitalization. On day 4 of hospitalization, the patient became hypotensive and bradycardic, requiring chest compressions and cannulation to veno-arterial extracorporeal membrane oxygenation. Neuroprotective measures including therapeutic hypothermia and targeted normotension were implemented post-arrest and imaging was reassuring against significant multiorgan damage, including a normal head ultrasound.
Multifocal seizures were identified on via continuous EEG on day 5 of hospitalization and were initially treated with IV lorazepam, levetiracetam and fosphenytoin. Maintenance levetiracetam was then initiated. The patient’s seizures continued and were refractory to additional doses of fosphenytoin and phenobarbital until initiation of midazolam and pentobarbital continuous infusions. On day 7 of hospitalization, the patient developed severe lactic acidosis and worsening kidney function thought to be secondary to propylene glycol toxicity from pentobarbital (Table). The patient was transitioned to continuous renal replacement therapy (CRRT) and pentobarbital was discontinued. Due to continued seizures and initiation of CRRT, the decision was made to initiate a continuous ketamine infusion. A bolus dose of ketamine 1 mg/kg IV was given followed by a continuous infusion at 1 mg/kg/hr (Figure). The infusion was titrated to 2 mg/kg/hr over the next 24 hours. No adverse effects were noted throughout the course of the infusion. The family chose to limit life sustaining therapy on day 8 and the patient died shortly thereafter.