Date: November 27th, 2017

Reference: Legriel et al. Hypothermia for Neuroprotection in Convulsive Status Epilepticus. NEJM Dec 2016

Guest Skeptic: Dr. Neal Little is an Emergency Physician who works at Chelsea Hospital in Chelsea, Michigan. He is also a Faculty member of the Emergency Medicine and Acute Care Series 1986 to present.

Case: Johnny is a 22-year-old male patient who presents to the emergency department via EMS with a seizure. He is known to have poorly controlled epilepsy. It was a witnessed clonic-tonic seizure that stopped but he did not wake up. The paramedics report another seizure on route to the hospital. He arrives with normal vital signs, normal finger stick blood glucose and a Glasgow Coma Scale of 3. He then has another seizure in the department. You quickly assess him in the resuscitation room, the team attempts intravenous (IV) access and collects labs while you give 10mg of midazolam intramuscularly and the seizures seem to stop. His oxygen saturation begins to drop and you decide to intubate and mechanically ventilate. He is now stabilized, fosphenytoin is being infused, you are getting ready to ship him to the neuro-ICU and wonder if cooling him down would help.

Background: We have covered hypothermia a number of times on the SGEM. This has been for out-of-hospital cardiac arrests (OHCA). Therapeutic hypothermia has not been demonstrated to have benefit in the pre-hospital setting (SGEM#54 and SGEM#183)

The TTM trial provided evidence that it was not necessary to drive the temperature down to 32C. There was no statistical difference in the primary outcome between 33C vs. 36C (SGEM#82).

Status epilepticus used to be defined as a seizure lasting 30 minutes or more. This definition has been changed to a single seizure lasting more than five minutes or two or more seizures within a five-minute period without the person returning to normal between them (Al-Mufti and Claassen Neurocritical Care Oct 2014).

The American Epilepsy Society has guidelines on the acute management of convulsive status epilepticus (Glauser et al Epilepsy Currents 2016). They recommend in adults without IV access to use midazolam IM. There is no significant difference in effectiveness between IV lorazepam and IV diazepam in adults. See the proposed treatment algorithm for status epilepticus from the guidelines for details.

Status protocol

The hypothesis would be that cooling down the seizing brain could protect it from further injury. However, there is not good evidence that therapeutic hypothermia is neuroprotective in ischemic or hemorrhagic stroke, IHCA or traumatic brain injury.

Clinical Question: Does induced therapeutic hypothermia improve neurologic outcomes in patients with convulsive status epilepticus?

Reference: Legriel et al. Hypothermia for Neuroprotection in Convulsive Status Epilepticus. NEJM Dec 2016

  • Population: Critically ill adult (> 18 years of age) with convulsive status epilepticus who were receiving mechanical ventilation
    • Convulsive Status Epilepticus: Defined as seizing for five minutes or more continuously or more than two seizures without a return to baseline.
    • Excluded: Full recovery, need for emergency surgery, postanoxic status epilepticus, imminent death and do-not-resuscitate orders (Bacterial meningitis was added later)
  • Intervention: Therapeutic hypothermia (32-34C) via IV fluids (4C), ice packs and cold-air tunnel for 24 hours.
  • Comparison: Standard care
  • Outcome:
    • Primary: Good neurologic outcome at 90 days defined as a Glascow Outcome Scale (GOS) of 5 (Range 1-5 with 1 = death, 5=minimal or no neurological deficit)
    • Secondary: Mortality at 90 days, progression to EEG confirmed status epilepticus, refractory status epilepticus on day one, “super-refractory” status epilepticus (resistant to general anesthesia), and functional sequelae on day 90.


Authors’ Conclusions: “In this trial, induced hypothermia added to standard care was not associated with significantly better 90-day outcomes than standard care alone in patients with convulsive status epilepticus.”

checklistQuality Checklist for Randomized Clinical Trials:

  1. The study population included or focused on those in the ED. No. These were patients recruited from the intensive care unit.
  2. The patients were adequately randomized. Yes. 1:1 ratio, computer generated stratified by location, age (<=65 or >65) and seizure duration <= 60 min or > 60 min)
  3. The randomization process was concealed. Yes
  4. The patients were analyzed in the groups to which they were randomized. Yes
  5. The study patients were recruited consecutively (i.e. no selection bias). Yes
  6. The patients in both groups were similar with respect to prognostic factors. Yes
  7. All participants (patients, clinicians, outcome assessors) were unaware of group allocation. No. Treaters would know temperature, but physicians assessing outcomes, trial administrators and statisticians were not aware of group allocation.
  8. All groups were treated equally except for the intervention. No. Some hypothermia patients required neuromuscular blockade.
  9. Follow-up was complete (i.e. at least 80% for both groups). Yes
  10. All patient-important outcomes were considered. Unsure
  11. The treatment effect was large enough and precise enough to be clinically significant. No

Key Results: The study included 268 patients with 138 in the hypothermia group and 130 in the control group. The median age was 57 years with about 2/3 being male.

No difference in Glasgow Outcome Scale at 90 days

  • Primary Outcome: GOS of 5 at 90 days
    • 67/138 (49%) hypothermia vs. 56/130 (43%) control
    • Odds Ratio, 1.22; 95% CI: 0.75 to 1.99; P=0.43
  • Secondary Outcomes:
    • Mortality at 90 Days – No Difference
    • Refractory Status Epilepticus on Day 1 – No Difference
    • Super Refractory Status Epilepticus – No Difference
    • Progression of EEG to Confirmed Status Epilepticus – 11% vs. 22% (odds ratio, 0.40; 95% CI, 0.20 to 0.79; P=0.009)
    • Functional Sequelae on Day 90 – No Difference
    • Adverse Events – 85% hypothermia vs. 77% control (pneumonia 51% vs. 45%)

Screen Shot 2015-04-25 at 3.11.12 PM

  1. Blinding: This was an open label trial. The treating physician knew the group allocation, while outcome assessors, administrators and statisticians did not. The hypothesis was that therapeutic hypothermia has a neuroprotective effect. Therefore, you would think any bias from lack of blinding would have been in favour of the intervention. The lack of significant difference between the two groups despite being an open label trial strengthens our confidence in the results.
  2. Patients: These were patients from the intensive care unit and not emergency department patients. We have good evidence from the OHCA literature that cooling in the pre-hospital setting does not make a difference. We do not know if cooling started in the emergency department for patients with status epilepticus would make a difference. However, until we have evidence of benefit we must accept the null hypothesis of no benefit to cooling.
  3. Power: They powered the study to find a 20% difference (NNT of 5). This might have been setting the bar too high. There was an observed difference of 6% in favour of the hypothermia group but it was not statistically significant. A larger sample would be needed to confirm if this was a true difference.
  4. Outcome: The primary outcome was a GOS of 5 (good recovery). If you considered GOS 4 or 5 as a positive outcome the absolute difference was 9.1% better with therapeutic hypothermia (65.3% vs. 56.2%). This would give a NNT of 11. This result could be a significant patient oriented outcome if it was demonstrated to be statistically significant with a larger sample size. In addition, the GOS scale may also have not been granular enough to pick up important clinical differences. There is an extended version of the GOS that subdivides each of the three conscious levels into an upper and lower level of disability. This increases the total number of categories to eight. It is possible that therapeutic hypothermia could improve outcomes at 90 days on the extended GOS.Screen Shot 2017-11-26 at 8.31.50 PM
  5. ClinicalTrials.Gov: We had to include looking at the website to see if any of the outcomes were changed. The primary outcome did not change but they did add a number of new secondary outcomes from what was originally posted.
  • Original Secondary Outcomes:
    • mortality [ Time Frame: hospital discharge ]
    • incidence of functional sequelae [ Time Frame: 3 months ]
      • judged on the frequency of seizures, the recurrence of status epilepticus after hospitalization, the number of anti-epileptic drug, MMS score.
    • length of icu stay [ Time Frame: 3 months ]
    • length of hospital stay [ Time Frame: 3 months ]
  • Current Secondary Outcomes:
    • mortality [ Time Frame: hospital discharge ]
    • mortality [ Time Frame: ICU discharge ]
    • mortality [ Time Frame: 90 days ]
    • Incidence of functional sequelae [ Time Frame: 3 months ]
      • Judged on the frequency of seizures, the recurrence of epileptic status after hospitalization, the number of anti-epileptic drug, mini mental score (MMS).
    • length of icu stay [ Time Frame: 3 months ]
    • length of hospital stay [ Time Frame: 3 months ]
    • Percentages of convulsive and non-convulsive seizure recurrences [ Time Frame: 6 to 12 hours ]
      • Progression to status epilepticus
    • Seizure duration in minutes [ Time Frame: 3 days ]
    • Percentage of refractory status epilepticus cases [ Time Frame: 3 days ]
      • Judged on the frequency of seizures within 24 hours after status epilepticus onset (refractory status epilepticus on day 1) and on the frequency of seizures within 48 hours after anesthetic treatment withdrawal (super refractory status epilepticus)

Comment on Authors’ Conclusion Compared to SGEM Conclusion: We agree with the authors’ conclusions.

SGEM Bottom Line: Therapeutic hypothermia does not appear to have benefit for adult patients admitted to the ICU with convulsive status epilepticus.

Case Resolution: The patient is intubated, sedated and has been stabilized. Your works is done and the patient is transferred to the Neuro-ICU for further management.


Dr. Neal Little

Clinical Application: This is another study failing to demonstrate a patient important benefit with therapeutic hypothermia. 

What Do I Tell My Patient? You can’t talk to these patients because they are intubated. I would however, tell the family that Johnny had a bad seizure and needed to be sedated and intubated. Cooling down the body has been tried to help protect the brain from more damage. Unfortunately, it has not shown to help. Johnny is going to be transferred to the Neuro-ICU where they will take good care of him.

Keener Kontest: Last weeks’ winner was Matthew Corey a PA from Phoenix, Arizona. He knew Calvin Stevens at the Park Davis Laboratories is credited with being the first person to synthesize ketamine.

Listen to the podcast on iTunes for this weeks’ keener question. If you think you know the answer then send an email to TheSGEM@gmail.com with “keener” in the subject line. The first correct answer will receive a cool skeptical prize.

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Remember to be skeptical of anything you learn, even if you heard it on the Skeptics’ Guide to Emergency Medicine.

EMAC 2018