Mr. H, a 28-year-old otherwise healthy male, is admitted to your neurological critical care unit. He had presented to the emergency department with new-onset generalized tonic-clonic seizure activity. He was intubated for airway control, and despite exhausting the armamentarium of benzodiazepines, anti-epileptics, and sedatives, his EEG continues to demonstrate seizure activity. What treatment options remain?
Therapeutic hypothermia has been investigated as a potential neuroprotective intervention for post-cardiac arrest, refractory intracranial hypertension, ischemic stroke, and intracerebral hemorrhage, but the evidence for each is inconclusive. Hypothermia in patients with traumatic brain injury remains controversial and has been shown to be harmful in patients with severe bacterial meningitis. Current evidence is limited to support therapeutic hypothermia in status epilepticus or “super-refractory” status epilepticus (defined as ongoing or recurrent status epilepticus 24 to 48 hours after initiation of anesthetic treatment). In this week’s issue of NEJM, Legriel and colleagues report on the effects of induced hypothermia on neurologic outcomes in patients with convulsive status epilepticus.
The HYBERNATUS trial is an open-label, parallel-group, randomized-controlled trial conducted in 270 critically ill status epilepticus patients in 11 ICUs in France. Patients were randomized to receive hypothermia plus standard treatment or standard treatment alone. Hypothermia was instituted as early as possible, with cooling initiated at a median of 5.8 hours after seizure onset and taking 5.2 hours to reach target core temperatures (32–34°C).
The primary outcome was good functional outcome at 90 days, defined as a Glasgow Outcome Score (GOS) of 5 (range 1 to 5, with 1= death and 5= normal/minimal neurological deficit). This outcome was achieved in 67 of 138 patients (48.6%) in the intervention group and in 56 of 130 patients (43.1%) in the control group (a nonsignificant difference; P=0.43, OR 0.4; 95%CI, 0.20 to 0.79), and is consistent with results of prior studies documenting poor outcomes after status epilepticus (in up to 80%).
Of the secondary endpoints, progression to electroencephalographic status epilepticus was less common with hypothermia (OR, 0.40; 95%CI, 0.20 to 0.79; P=0.009). Unfortunately, the trial failed to demonstrate statistically significant differences between the two groups in total seizure duration, refractory status epilepticus on day 1 to 3, length of ICU stay, length of hospital stay, ICU deaths or functional sequelae, or seizure recurrences within 90 days. Subgroup analysis revealed heterogeneity in the intervention effect with a significant quantitative interaction with age and benefit in patients younger than 65 years (P=0.02), although the study was not powered to support this outcome.
More patients in the intervention group than in the control group (85% vs. 77%) had adverse effects of any severity, but the difference was not statistically significant. In the absence of successfully achieving the primary end-point, the adverse effects with hypothermia are concerning.
Given that only critically ill patients (intubation was an inclusion criterion) were included, this study does not entirely refute the biological plausibility of the premise that hypothermic neuroprotection has a therapeutic role in status epilepticus in less-ill patients. Also, the use of propofol could have been harmful and negated the effect of hypothermia.
NEJM Deputy Editor Dr. Allan Ropper comments that, ‘’There was biological plausibility so it was important to clinically test. (On the other hand, hypothermia keeps failing!). This was a solidly done study with good adherence to protocol, it was comprehensive in that they logged all status patients and missed very few during the period of the trial, and the study was difficult to carry out. I think this may close studies for status epilepticus, but we will see.’’
Our patient, Mr. H, continued to demonstrate epileptiform activity, still seizing 72 hours after ICU admission. Therapeutic hypothermia was initialed and at 96 hours, with continued anti-epileptic and sedative medications, epileptiform activity abated. However, at 6 months after discharge his GOS score was 4. He continued to demonstrate delayed responsiveness and inability to perform daily cognitive tasks to allow him to return to work.
NEJM Executive Editor Dr. Edward Campion remarks, ‘’We’ve been thinking and hoping that hypothermia would help in difficult situations like this. With the results of this large, difficult-to-perform trial, we now know that hypothermia is providing little, if any, benefit for the outcome that counts the most — the functional outcome for the patient.’’
The results of the HYBERNATUS trial are unlikely to go into hibernation but instead should stimulate more research to try to find better treatment options for status epilepticus.
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Bhavna Seth is a Resident in Internal Medicine at Boston University Medical Center.