Hypothermia: No Outcome Improvement in Status Epilepticus

Pauline Anderson

December 22, 2016

Hypothermia did not improve the rate of good functional outcomes at 90 days over standard antiepileptic therapy in patients with convulsive status epilepticus receiving mechanical ventilation, a new randomized trial shows.

The study did, however, indicate that hypothermia may provide an anticonvulsant effect.

"Hypothermia does not add a significant neuroprotective effect in patients with convulsive status epilepticus, but may be an interesting adjuvant anticonvulsant treatment in particularly refractory cases," said lead author, Stephane Legriel, MD, Medical-Surgical Intensive Care Unit, Versailles Hospital, France.

Dr Stephane Legriel

The study was published online December 22 in the New England Journal of Medicine.

Status epilepticus, in which a patient has unremitting seizures, is a neurologic emergency. One in five patients who need hospital treatment for status epilepticus will die, and that rate is twice as high for patients who don't respond to initial treatment.

Convulsive status epilepticus is also associated with an almost 60% functional impairment, so it's important to look for improved treatment interventions, said Dr Legriel.

The HYBERNATUS (Hypothermia for Brain Enhancement Recovery by Neuroprotective and Anticonvulsant Action After Convulsive Status Epilepticus) trial was conducted in 11 French intensive care units (ICUs).

It included 268 adult patients with convulsive status epilepticus, defined as 5 or more minutes of continuous clinical seizure activity, or more than two seizures without a return to baseline in the interval.

Mechanical Ventilation

Study patients had to have been admitted to the ICU less than 8 hours after the onset of seizures. They also had to be ill enough to require mechanical ventilation.

Patients were randomly assigned to receive standard care (control group) or standard care plus therapeutic hypothermia, defined as lowering body temperature using ice-cold intravenous fluids to 32 to 34℃C (about 90℃F) for 24 hours. In the control group, if the physician determined that sedation was needed, a propofol regimen the same as that in the therapeutic hypothermia group was used.

In both groups, continuous electroencephalography (EEG) monitoring was started within 2 hours after randomization and was maintained for 48 hours, or until body temperature was normalized in the hypothermia group.

The median age of study participants was 57 years, and 65% of patients were male. Almost half (49%) had a history of epilepsy.

The median time from seizure onset to initiation of an antiepileptic drug was 40 minutes. A median of two drugs were administered before the ongoing seizures were controlled.

The median time to control of electrical seizure activity was 80 minutes. At randomization, status epilepticus was refractory in 25% of patients. The median time to first EEG interpretation was 6.6 hours.

The primary outcome was the absence of functional impairment at 90 days, as defined by a score of 5 on the Glasgow Outcome Scale (GOS). The GOS ranges from 1 to 5, with 1 representing death and 5 representing no or minimal neurologic deficit.

In the intention-to-treat analysis, a GOS score of 5 occurred in 49% of the hypothermia group and 43% of the control group (odds ratio [OR], 1.22; 95% confidence interval [CI], 0.75 - 1.99; P = .43).

As for secondary outcomes, the analysis found that mortality in the ICU, in-hospital mortality, and 90-day mortality did not differ significantly between the two groups.

However, hypothermia patients had somewhat better brain wave patterns as measured by EEG. Significantly fewer of them than control group patients had progression to EEG-confirmed electrographic status epilepticus (15 vs 29; OR, 0.40; 95% CI, 0.20 - 0.79; P = .009).

One or more adverse events of any severity occurred in 85% of the hypothermia group and in 77% of the control group. Pneumonia attributed to aspiration occurred in 51% of the hyperthermia group and 45% of the control group.

"Hypothermia has physiologic effects, such as bradycardia and vasoconstriction, but also hypoventilation and an increase in renal output," said Dr Legriel, adding that infections have also been reported in patients receiving hypothermia.

"Given the inherent risk of aspiration pneumonia in patients with coma, the prevalence of this complication was higher in the hypothermia group."

There were no significant between-group differences in the number of deaths in the hospital or during the subsequent 90 days.

Although the study wasn't powered to detect significant effects according to age, an exploratory analysis found that the OR of a GOS score of 5 in patients treated with hypothermia compared with controls was 1.75 (95% CI, 0.98 - 3.16) among patients 65 years and younger but 0.49 (95% CI, 0.19 - 1.25) among older patients.

"The poorer prognosis in patients older than 65 years may be related to comorbidities, but also to pharmacokinetic and pharmacodynamic properties of anticonvulsants, and with interactions with medications regularly used in these patients," said Dr Legriel.

A limitation of the study may be the timing of the cooling. "We can't exclude the possibility that earlier implementation of hypothermia may have changed the study results," said Dr Legriel.

"Fascinating" Study

Asked to comment, Zachary Grinspan, MD, Komansky Center for Children's Health, New York-Presbyterian/Weill Cornell Medical College, said he found the article "fascinating" and the results "important."

"Status epilepticus is a bad disease — the more data we have to guide treatment, the better we'll be able to care for these critically ill individuals," he said.

Although the study's results were largely negative, Dr Grinspan said he doesn't think it closes the door on therapeutic hypothermia for status epilepticus.

"The authors used very low temperatures as their target — 90℃F is really cold, and we know it puts people at risk for multiple complications during an ICU stay, including pneumonia," he said. "So it's possible that less aggressive therapeutic hypothermia — maybe to 93 to 95℃F — might avoid some of the complications seen in this trial while retaining some of the potential beneficial effects."

As a pediatric epilepsy doctor, Dr Grinspan said he was "very intrigued" to see that age played a potential role in the response. "I would love to see a trial that focused only on young adults, or ideally on children, to see if there is a protective effect in those populations."

Dr Grinspan pointed out that cooling the brain by a few degrees can be helpful in other conditions. "For example, in individuals who have a cardiac arrest, no blood flow for several minutes, and who are then resuscitated, cooling the brain for 24 hours gives a better chance of having a good outcome. Therapeutic hypothermia is also used in newborns who don't get enough oxygen during the birthing process. Keeping their brains cool for 72 hours after birth improves survival without increasing the risk for developmental disability."

Experts have tried therapeutic hypothermia for other brain injuries, such as stroke or trauma, but the results have not been as good, he said.

The study was supported by a research grant from the French Ministry of Health. Dr Legriel has disclosed no relevant financial relationships.

N Engl J Med. Published online December 22, 2016. Abstract

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