Nottingham City Hospital, Critical Care Journal Club Hypothermia for Neuroprotection in Convulsive Status Epilepticus Dr S Legirel et Al for the HYBERNATUS Study Group Nottingham 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 Convulsive status epilepticus defined as 5 minutes of continuous clinical seizure activity or more than two seizures without return to baseline in the interval Admitted less than 8 hours after the onset of seizures Receiving mechanical ventilation Full recovery from seizure (defined as a return to the baseline state of consciousness) A need for emergency surgery that would preclude therapeutic hypothermia 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 burst- suppression 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.