HYBERNATUS

Hypothermia for Neuroprotection in Convulsive Status Epilepticus

Legriel S et al. N Engl J Med 2016;375:2457-67. DOI: 10.1056/NEJMoa1608193

 

Clinical Question

  • In patients with convulsive status epilepticus, does the addition of therapeutic hypothermia to standard care improve neurological outcomes?

Design

  • Randomised controlled trial
    • Consecutive recruitment
    • Computer-generated permuted blocks
  • Multi-centre
  • Open-labelled
  • Parallel arm standard care
  • Power calculation: 135 patients per group to demonstrate 20% difference in Glasgow Outcome Score (GOS) of 5 at 90 days (90% power)
    • Assumed 40% in standard care group vs 60% in intervention group
    • Intention to treat analysis

Setting

  • 11 French ICUs
  • Data collected: March 2011 – January 2015

Population

  • Inclusion criteria:
    • ≥18 years old
    • Convulsive status epilepticus admitted to ICU defined as 5 minutes or more of continuous clinical seizure activity or more than two seizures without a return to baseline in the interval
    • Admitted less than 8 hours after the onset of seizures
    • Receiving mechanical ventilation
  • Exclusion criteria:
    • Full recovery from seizure (defined as a return to the baseline state of consciousness)
    • Emergency surgery that would preclude therapeutic hypothermia
    • Postanoxic status epilepticus
    • Imminent death
    • Do-not-resuscitate orders
    • Bacterial meningitis was added in January 2013
  • Participant numbers
    • 270 patients enrolled. 2 withdrew consent
    • 138 assigned to intervention group and 130 to control group
  • Baseline characteristics:
    • Median age 57
    • 65% male
    • 49% known history of epilepsy

Intervention

  • Target core temperature of 32 to 34°C as rapidly as possible post randomisation
  • Target temperature maintained for 24 hours
  • Hypothermia induced with ice-cold IV fluids at 4°C, maintained with ice packs at the groin and neck and a cold-air tunnel around the patient’s body

Control

  • No target temperature set

For both intervention and control group

  • Propofol as sedative agent
  • Continuous EEG monitoring within 2 hours of randomisation
    • Continued for at least 48 hours or normothermia in the intervention group
  • Standard EEG extracted and intepreted by neurophysiologists
  • If EEG-proven seizure activity seen, propofol administered to achieve burst-suppression pattern for 24 hours
  • Continuous core temperature monitoring by oesophageal probe

Outcome

  • Primary outcome: GOS score of 5 (indicating survival with no or minimal neurological deficit)
    • No significant difference: 49% in intervention vs 43% in control (CI 0.75 – 1.99, p=0.43)
  • Secondary outcomes: comparing intervention vs. control group
    • No significant difference in:
      • ICU mortality: 9% vs 12%, odds ratio 0.83 (CI 0.38 – 1.82, p=0.64)
      • Hospital mortality: 12% vs 15%, odds ratio 0.81 (CI 0.40 – 1.64, p=0.55)
      • Mortality at 90 days post discharge: 13% vs 15%, odds ratio 0.86 (CI 0.43 – 1.72, p=0.67)
      • Total seizure duration: Median 75min vs 90min, p=0.26)
      • Refractory status epilepticus on day 1: 31% vs 50%, odds ratio 0.68 (CI 0.40 – 1.15, p=0.15)
      • Super-refractory status epilepticus, defined as ongoing or recurrent status epilepticus between 24 and 48 hours after the initiation of anaesthetic treatment: 17% vs 23%, odds ratio 0.64 (CI 0.34 – 1.159, p=0.16)
      • Length of stay in ICU: Median 8 days vs 7 days, p=0.44
      • Length of stay in hospital: Median 21 days vs 19 days, p=0.89
      • Incidents of 1 or more adverse events: 85% vs 77%
    • Significant difference in progression in EEG-confirmed status epilepticus: 11% vs 22%, odds ratio 0.4 (CI 0.20 – 0.79, p=0.009)

Authors’ Conclusions

  • In critically ill patients with convulsive status epilepticus receiving mechanical ventilation, the addition of therapeutic hypothermia to standard antiepileptic therapy showed no significant benefit with respect to good functional outcome

Strengths

  • RCT
  • Incidence of primary outcome in control group in line with power calculations
  • Standardised initial treatment with anti-epileptic drugs similar in both groups
  • Standardised sedation protocol
  • Separation of temperature between intervention and control group achieved
  • Hypothermia target achieved in 98% of patients randomised to intervention group

Weaknesses

  • Only 25% of patients were in status epilepticus as defined at the time of randomisation
  • Early utilisation of hypothermia not standard practice

The Bottom Line

  • This study only looked at patients with status epilepticus requiring mechanical ventilation. Despite the early use of induced hypothermia, the lack of clear functional benefit means that I would continue not to use it in my current practice.

External Links

Metadata

Summary author: @avkwong
Summary date: 4th January 2017
Peer-review editor: @stevemathieu75

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