Discussion
epileptic, super-refractory
ADVERSE EVENTS, EPILEPTIC
In this multicentre, double-blind, randomised, controlled, and pragmatic trial, we found that the intravenous administration of VPA, in addition to first- and second-line ASMs, did not increase the proportion of patients discharged alive from hospital within the first 15 days. We also found that VPA did not increase the occurrence of adverse events and did not decrease incidence of refractory and super-refractory status epilepticus or 90-day mortality.The absence of impact of VPA on the patient status at day 15 could be a result of various factors. First, the observed median length of hospital stay (12 days) was close to what we had anticipated (15 days), whereas it was 21 days in the ICU-admitted GCSE population of the HYBERNATUS trial and 10 days in the pre-hospital GCSE population of the SAMUKeppra trial [Second, the low rate of mortality and refractoriness might suggest that our cohort is not representative of ICU-admitted GCSE patients. This is unlikely given that 16 general ICUs participated in our trial. Moreover, patients from this trial were appropriately referred to the ICU, as indicated not least by the fact that there was an 85% rate of invasive mechanical ventilation within the first 24 h. It is noteworthy that only a third and one half, respectively, of GCSE patients admitted to the ICU were intubated in the ESETT and RAMPART trials [The main explanation for the low rate of refractory and super-refractory GCSE is that the step-by-step anti-epileptic treatment had been closely followed and was effective. Of note is the rate of refractory GCSE at ICU admission, which was 9% in our trial but 25% in the HYBERNATUS study [We are not able to rule out that greater circulating levels of VPA would have allowed a better epileptic control and a greater neuroprotective effect, as evidenced in experiment models [Another limitation is related to the early termination of the trial. Although 99% (245/248) of the calculated sample size had been enrolled, which would have led to negligible loss of power, some participants did not receive the allocated treatment and a few outcomes were missing, so that the power of the trial may be slightly decreased. However, the confidence interval of the treatment difference on the primary outcome clearly ruled out the anticipated 20% risk reduction.
In conclusion, administration of VPA, when added to the recommended stepwise anti-epileptic regimen, is well tolerated but not associated with a significant impact on hospital discharge or evolution towards refractory or super-refractory status epilepticus in patients admitted to an ICU for GCSE. Altogether, our results indicate that most ICU-admitted GCSE patients were treated according to available guidelines and had good short-term outcomes.
