By Kimberly Pargeon, MD

Assistant Professor of Clinical Neurology, Weill Cornell Medical College

Dr. Pargeon reports no financial relationships relevant to this study.

SYNOPSIS: In a multicenter trial in France, patients admitted to the ICU from 2011-2015 for convulsive status epilepticus were randomly assigned to receive standard therapy (control group) or hypothermia plus standard therapy (treatment group). The primary outcome measure was an absence of functional impairment at 90 days after seizure onset, as measured by the Glasgow Outcome Scale (score of 5). There was no significant difference in outcomes between the two groups.

SOURCE: Legriel S, Lemiale V, Schenck M, et al. Hypothermia for neuroprotection in convulsive status epilepticus. N Engl J Med 2016;375:2457-2467.

Convulsive status epilepticus (CSE) is considered a neurological emergency, and even when treatment with antiepileptic drugs is initiated early, in-hospital mortality can be as high as 20% and as high as 40% when it remains medically refractory.1 In addition, a prospective study by the same lead author showed that about half of survivors had “severe” residual functional impairment 90 days after symptom onset.2 As such, the authors proposed combining therapeutic hypothermia to standard treatment for CSE to see if this had added neuroprotective and antiepileptic benefits, leading to an absence of later functional impairment.

This study was a multicenter, randomized, controlled trial conducted in 11 French ICUs from March 2011 to January 2015. All patients were adults admitted to an ICU for less than eight hours since onset of CSE and were mechanically ventilated. CSE was defined as five minutes or more of continuous clinical seizure activity or more than two clinical seizures without return to baseline in between. Patients (n = 268) were randomized to receive either standard medical therapy alone (control group, n = 130) or hypothermia plus standard therapy (treatment group, n = 138). In the hypothermia group, the goal was to lower core body temperature, as measured by an esophageal probe, to 32-34°C and to maintain this for 24 hours. This was achieved through cold IV fluids, and maintained with ice packs at the groin and neck and with a cold air tunnel around the body. Patients in this group were sedated with propofol and neuromuscular blockade, and patients in the control group requiring sedation also were given propofol using a similar protocol. Continuous EEG monitoring was also initiated for both groups within two hours after randomization and maintained for at least 48 hours or until the hypothermia group was normothermic. A 30-minute segment of the initial two hours of EEG was read at a central site to determine the presence of ongoing seizure activity (i.e., whether a patient was refractory) and used to decide the need for a burst-suppression pattern.

The groups were similar in terms of demographics and clinical characteristics. The median age was 57 years and 65% were men. Nearly half (49%) had a history of epilepsy, with most episodes of CSE starting outside of the hospital (65%). Median time from seizure onset to initiation of drug therapy was 40 minutes, and it required a median of two medications before seizures were controlled. The median time to control electrical seizure activity was 80 minutes, although SE was refractory in 25% at the time of randomization. In the hypothermia group, cooling was initiated a median of 5.8 hours after seizure onset and the target temperature was reached in 98% of patients within a median of 5.2 hours.

The primary outcome was an absence of functional impairment at 90 days as measured by a score of 5 on the Glasgow Outcome Scale (GOS), indicating little to no impairment. They found that 49% of patients in the hypothermia group vs. 43% of those in the control group achieved a score of 5, which was not significantly different. However, it was noted that the odds ratio for recovery was significantly higher in patients who were 65 years of age when comparing the treatment vs. control groups (1.75) as compared to older patients (0.49). In terms of secondary outcomes, there were no significant differences in mortality rates between the groups, although significantly more patients in the control group were found to progress to electrographic SE (29 vs. 15). Lastly, more adverse events were noted in the hypothermia (85%) vs. control group (77%), with the majority of these being aspiration pneumonia in both groups.

COMMENTARY

The findings of this trial do not support the addition of therapeutic hypothermia to standard medical treatment for CSE in critically ill patients. However, there were several limitations with this study. First, the median time for electrographic seizure control was 80 minutes, yet the hypothermia protocol was not initiated until a median of 5.8 hours after seizure onset and the goal temperature was achieved a median time of an additional 5.2 hours later. This protocol may have been better used in patients who were refractory; it may not have been necessary in patients whose seizures resolved with medical treatment alone. In addition, the delay in initiating hypothermia may make this a less practical choice for SE, as prolonged seizures can lead to failure of intrinsic inhibitory mechanisms3 and may result in refractory CSE. However, the authors did note that more patients in the control group had refractory or super-refractory SE, although this was not significant and did not seem to affect overall outcome. Given the differences in age, future directions could focus on use of therapeutic hypothermia in younger patients (< 65 years of age), initiated earlier after seizure onset, and with more refractory cases.

REFERENCES

  1. Legriel S, Lemiale V, Schenck M, et al. Hypothermia for neuroprotection in convulsive status epilepticus. N Engl J Med 2016;375:2457-2467.
  2. Legriel S, Azoulay E, Resche-Rigon M, et al. Functional outcome after convulsive status epilepticus. Critical Care Med 2010;38:2295-2303.
  3. Huff JS, Fountain NB. Pathophysiology and definitions of seizures and status epilepticus. Emerg Med Clin N Am 2011;29:1-13.