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

• [article] Hypothermia for Neuroprotection in Convulsive Status Epilepticus
• [FOAMed] St. Emlyn’s. Hypothermia in status epilepticus
• [FOAMed] CC Nerd-The Case of the Uncertain Surrogate CC Nerd-The Case of the Uncertain Surrogate

Metadata

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