The main results of this single-center prospective study can be summarized as follows: (1) absent EEG background reactivity observed during the maintenance phase of TH appeared to be strongly associated with poor outcome in patients with coma after CA; (2) all patients in whom cEEG showed background reactivity to painful stimuli survived, and the large majority (74%) awoke and had a favorable outcome; (3) persistent discontinuous background and the presence of seizures or epileptiform discharges on cEEG were also strong risk factors for poor outcome; (4) nonreactive cEEG background yielded a significantly better prognostic value than SSEPs, mostly because of a higher negative predictive value; (5) EEG reactivity to painful stimulation did not seem to be affected by TH, because all patients with absent background reactivity during TH had similar findings on the EEG performed in normothermic conditions, and it was not influenced by sedation-analgesia.
To our knowledge, this is the first clinical study showing that nonreactive EEG background activity during TH is an early predictor of poor outcome in patients with postanoxic coma. Before TH became a widely used treatment of hypoxic/ischemic encephalopathy, diffuse EEG background suppression below 20 μV, burst-suppression with generalized epileptiform activity, or generalized periodic complexes on a flat background have been associated with poor outcome [
16,
17]. This was recently confirmed by our group in patients treated with TH, in whom standard EEG was performed at the end of treatment in normothermic conditions [
6]. Moreover, prolonged epileptiform EEG features are independently correlated with mortality after postanoxic coma [
13], in patients assessed both after [
6] and during [
10,
13] TH. However, none of these studies formally addressed the predictive value of any of the EEG findings during TH or compared the value of EEG with that of neurologic examination or SSEPs, the latter being regarded as reliable predictors of poor prognosis [
5]. We have recently shown that background reactivity performed after TH in normothermic conditions is a strong outcome predictor of postanoxic coma [
6], and thus undertook this study to examine the prognostic value of EEG background performed during TH in the early phase after CA. Our present findings confirm our previous study and indeed seem to suggest that reactive background on cEEG has a strong prognostic predictive value, even when monitoring is performed during TH. They also suggest that background reactivity is not significantly influenced by core temperature or by sedation. After earlier reports on favorable outcome for patients showing continuous amplitude-integrated EEG after TH [
18], a recent study on 30 patients showed that quantitative EEG features during TH (burst-suppression ratio, response entropy, state entropy) were significantly associated with long-term functional outcome [
19]. Although our results are in line with these findings, we add important concomitant clinical information and describe a much easier approach for EEG interpretation, without the need for more-complicated and not easily available software analysis.
Although our study was not primarily focused on the epidemiology of postanoxic seizures, this issue deserves further discussion. Previous studies reported a variable prevalence of postanoxic seizures from 10% [
11] to 47% [
10]. We observed a 21% prevalence (seven of 34 patients) of epileptiform abnormalities during TH, of whom five patients (15% of the entire cohort) had sustained EEG seizures. Because mild hypothermia and sedation (midazolam in our study) have antiepileptic action, the occurrence of electrical seizures during TH may reflect more-severe and diffuse brain injury. This might explain why none of the seven patients with seizures during TH survived, in line with previous observations [
11]. In contrast, it appears that seizures occurring only at the end of TH, after rewarming and off sedation, carry a better prognosis, possibly because brain injury is less severe (thus they are effectively treated with induced hypothermia and sedatives). Indeed, one patient in our cohort, treated for status epilepticus that developed after TH, survived. Altogether, these data underline the value of early cEEG for the treatment of comatose CA patients treated with TH.
Study limitations
This study has several limitations. First, the sample size is limited; thus our results are to be considered preliminary and will need further confirmation by other groups and larger studies. However, for this reason, we applied conservative statistical corrections for multiple comparisons (Bonferroni). Second, it was a single-center study, thus data cannot be generalized. Some subjectivity may also be related to the scoring of EEG reactivity; however, we used the same method described in our recent report, which included more than 100 patients. Time from CA to initiation of cEEG did not differ significantly between survivors and nonsurvivors (Table
2); thus it is unlikely that timing of cEEG affected the predictive value of the test. Finally, because the cEEG was interpreted before knowing final patient prognosis, it is unlikely that it influenced outcome. Furthermore, although clinicians were aware of cEEG results, EEG findings (both during TH and at normothermia) were not used to guide therapy or decisions for withdrawal of care; thus we believe that this contributed to minimize the so-called "self-fulfilling prophecy" phenomenon [
6].