Hypothermia for Neuroprotection in
Convulsive Status Epilepticus
Dr S Legirel et Al for the HYBERNATUS Study Group
NOT TINGHAM CITY HOSPITAL, CRITICAL CARE JOURNAL CLUB
Method
Multicenter, open-label, parallel-group, randomised control trial
Conducted in 11 Intensive Care Units in France
From March 2011 to January 2015
Ethically approved and a steering committee provided guidance
throughout the trial
Independent data and safety monitoring group reviewed the data
and performed scheduled blinded interim analysis.
INCLUSION CRITERIA
EXCLUSION CRITERIA
Older than 18 years
Full recovery from seizure (defined as a
return to the baseline state of
Convulsive status epilepticus defined as 5 consciousness)
minutes of continuous clinical seizure
activity or more than two seizures without A need for emergency surgery that would
return to baseline in the interval
preclude therapeutic hypothermia
Admitted less than 8 hours after the
onset of seizures
Receiving mechanical ventilation
Postanoxic Status Epilepticus
Imminent death
Do not resuscitate orders
An exclusion for bacterial meningitis was
added in January 2013
Trial intervention
Hypothermia group:
 Aim was to reduce core body temperature to 32 to 34C as rapidly as possible
after randomisation and to maintain this for 24h.
Sedation was implemented with propofol and neuromuscular blockade
Control group:
If the physician determined that sedation was needed, a propofol regimen
that was the same as that in the therapeutic hypothermia group was used.
In both groups, continuous EEG monitoring was started within 2h and was
maintained for 48h or until body temperature was normalised in the
hypothermia group.
Trial intervention
A 30 min extract from the 2h recording was interpreted at a central site by a
neurophysiologist within 2h after initiation of the continuous EEG
In both groups, if results showed ongoing seizures, repeated propofol boluses
were administered followed by a maintenance infusion to maintain a burstsuppression EEG pattern for 24h
Core body temperature was monitored continuously during the first 48h
Patients were screened for propofol infusion syndrome every 8h during this
time
Primary Outcomes
Absence of functional impairment 90 days after Status epilepticus
Defined by a score of 5 on the Glasgow Outcome Scale (GOS) indicating survival
with good function
GOS score ranges from 1 to 5, with 1 representing death and 5 representing no
or minimal neurological deficit
The score was determined during a structured interview at 90 +/- 7 days
60 of the 270 patients agreed to an additional evaluation by a neurologist who
was unaware of the trial group assignments; evaluation included an interview
and calculation of GOS score and MMSE. Before this visit, patients underwent
MRI brain and conventional EEG at their local hospital.
Secondary Outcomes
The rates of death in the ICU, in the hospital and by day 90
Progression to EEG-confirmed status epilepticus, defined as coma with or without subtle
convulsive movements but with generalised or lateralised ictal discharges on EEG between 6 and
12h after randomisation
Refractory status epilepticus on day 1, defined as continuous or intermittent clinical seizures,
EEG-confirmed seizures, or both despite two types of AEDs within 24h after onset of status
 Super-refractory status epilepticus, defined as ongoing or recurrent status epilepticus between
24 and 48h after the initiation of anaesthetic treatment
Total seizure duration
Length of stay in the ICU and in the hospital
In a subset of patients, impairments on day 90 (determined by new seizures, recurrent status
epilepticus after discharge, number of AEDs being used, and the score on MMSE
Trial Patients
270 patients were enrolled, 2 of whom withdrew consent
Of the 268 patients who were included, 138 were assigned to the hypothermia
group and 130 to the control group.
One patient in each group had a second episode of status epilepticus and each
was enrolled twice.
Demographics and baseline clinical characteristics were similar in both groups
Median age was 57 years
173 patients (65%) were male
130 (49%) had history of epilepsy
Clinical Characteristics
Most episodes of status epilepticus started outside hospital (n=173; 65%)
Median time from seizure onset to initiation of AED was 40 mins (interquartile
range, 10 to 75)
Median of two drugs (interquartile range 1 to 3) were administered before
seizures were controlled.
Median time to control of electrical seizure activity was 80 minutes
At time of randomisation, status epilepticus was refractory in 67 patients (25%)
Median time to first EEG interpretation was 6.6h
Body temperature during the
intervention period
Oesophageal core temperature at
randomisation:
37C (interquartile range, 36.4 to 37.7) in the
hypothermia group
37C (interquartile range 36.1 to 37.7) in the
control group
Cooling was initiated at median 5.8h
(interquartile range 3.5 to 8.0)
Target temperature (32 to 34C) was reached
in 135 of 138 patients (98%), within a median
of 5.2h (interquartile range 3.5 to 7.1)
Results: Primary Outcomes
Intention-to-treat analysis:
GOS score of 5 occurred in 67 of 138 patients (49%) in the hypothermia group
GOS score of 5 occurred in 56 of 130 patients (43%) in the control group
Odds ratio, 1.22; 95% CI, 0.75 to 1.99; P=0.43
Results: Secondary Outcome
Results: Secondary Outcome
Subgroup Analysis
Adverse Events
One or more adverse Events of any grade of severity occurred in:
117 of 138 patients (85%) in hypothermia group
100 of 130 patients (77%) in control group

Pneumonia attributed attributed to aspiration occurred in 51% patients in the
hypothermia group and in 45% of patients in the control group
Of 261 patients who received propofol, 1 patient (in the hypothermia group) had
propofol infusion syndrome
There was no significant difference between the groups in the number of deaths in the
hospital or during the subsequent 90 days
Discussion
Results from this trial do not support a beneficial effect of therapeutic
hypothermia as compared with standard care alone (AEDs and sedation)
Percentage of patients with GOS score of 5 at 90 days was similar in the two
groups
Finding that 43% of patients in control group had GOS score of 5 was consistent
with working hypothesis that Outcomes after status epilepticus are
unsatisfactory. This finding is consistent with results from previous studies.
The number of adverse events was higher in the treatment group mainly
because of higher rates of hypothermia and other minor adverse events.
Aspiration has been reported in patients receiving hypothermia for treatment in
other conditions. Pneumonia was not associated with increased incidence of
septic shock.
 The lack of benefit in older patients may have been related to the poorer outcome of
status epilepticus that was previously reported in this population.
 Antiepileptic drugs are challenging to use in older patients owing to alteration in
pharmacokinetics/pharmacodynamics in this population as well as interactions with
medications used on long term basis.
 Further assessment of therapeutic hypothermia may be warranted in young patients.
 Refractory status epilepticus on day 1 and progression to EEG-confirmed status were
less common in the hypothermia group which resulted in shorter total seizure
duration
 Incidence of super refractory status was also less common in the hypothermia group,
however this did not reach statistical significance.
 These findings are consistent with experimental and clinical data but apparently had
no effect on ensuring a good clinical outcome in our trial
Limitations
Applicability of our findings to all patients with convulsive status is uncertain
Patients must be receiving mechanical ventilation before therapeutic hypothermia can be
initiated, therefore all spontaneously breathing patients were excluded, who account for
approximately one third of patients with convulsive status epilepticus.
External cooling devices were used, there is a possibility that results may have been different if
hypothermia had been implemented earlier with the use of intravascular devices
A good outcome was limited to a GOS score of 5
The choice of propofol as a sedative and antiepileptic anaesthetic agent could conceivably have
been harmful and may have negated the effect of hypothermia. However there is no strong
evidence supporting the choice of a particular initial anaesthetic agent and therefore propofol
was chosen to ensure early patient awakening.