This study demonstrates that temperature influences early EEG bursting after resuscitation from CA. In normothermic rats, EEG burst frequency in the first hour after resuscitation was strongly associated with 72-hour NDS, which reaffirms previous observations in animals 14
. Because hyperthermia is known to increase brain injury after CA, we hypothesized that early burst frequency – a marker of neurological outcome – would be lower in the hyperthermia group. Surprisingly, we found that burst frequency was increased during this period by both hypothermia and hyperthermia, despite the predicted opposite effects on outcome. Additionally, burst frequency was not predictive of outcome in either hypothermic or hyperthermic rats. As predicted, hypothermic rats had increased burst frequency, earlier restitution of continuous EEG activity, and better neurological outcomes. With hyperthermia, however, we found a paradoxical increase in burst frequency during the first hour but later restitution of continuous EEG activity and an increase in mortality and poor neurological outcomes. Use of early burst frequency as a marker of neurological recovery outside the normal physiological range may, therefore, lead to inaccurate outcome prediction.
Burst-suppression is a highly stereotyped pattern of EEG activity that is characterized by spontaneous alternation of periodic high amplitude, low frequency bursts followed by intervals of generalized EEG suppression27
. This pattern of activity is frequently seen among comatose survivors of CA28, 29
. The presence of persistent burst-suppression >24 hours after resuscitation from CA has high specificity for poor neurological outcomes (death or persistent vegetative state)30, 31
, as was recently highlighted by an American Academy of Neurology consensus statement on prognostication after CA6
. Despite its prognostic infamy, burst-suppression is part of the natural evolution of EEG activity after CA, representing an intermediate stage between generalized suppression and continuous activity32, 33
. This finding has been demonstrated in humans32
as well as in dog34
, and pig25
models of CA.
We have previously demonstrated that a shorter duration of EEG burst-suppression and higher burst frequency soon after ROSC is strongly associated with good neurological recovery in normothermic rats14, 15, 20
. The human translation of this finding is implicit in the conclusion that the presence of burst-suppression has excellent specificity for poor outcome after 24 hours but lower accuracy at earlier timepoints6, 37, 38
Over the past decade, an increasing amount of clinical and basic research has focused on manipulation of temperature to improve or worsen neurological outcomes and neuronal injury after global ischemia. This body of literature has consistently shown worsening neuronal injury with spontaneous or induced hyperthermia9
and a neuroprotective effect of mild hypothermia11, 12
. The interaction between temperature and neuronal activity is complex and non-linear. Brain slice and in vivo
preparations have consistently shown a transient increase in neuronal firing within the range of mild hypothermia (30–34°C) and a relatively linear decrease in activity below this range39–41
. Similarly, mild hyperthermia transiently increases evoked and spontaneous neuronal spikes39, 41
The current experiment was designed to explore the effects of different temperature ranges on the evolution of EEG bursting after CA. Based on the correlation between outcome and burst frequency in this setting and the known protective effect of hypothermia and injurious effect of hyperthermia, we anticipated that early burst frequency would decrease with increasing temperature. As described above, however, a non-linear relationship between temperature and burst frequency was demonstrated with higher frequency in both the hyperthermia and hypothermia groups compared to the normothermic animals. The reason for this nonlinear relationship is not known, but these results closely parallel the relationship between temperature and spontaneous neuronal activity described above. Increased burst frequency in the hyperthermia group may reflect an overall increase in the spontaneous neuronal depolarization rate, lower threshold for depolarization, and higher basal metabolic rate associated with increased temperature. On the other hand, early burst frequency may be an inaccurate measure of outcome because the detrimental effects of hyperthermia on neuronal injury are delayed beyond this period which presumably due to overheightened metabolic rate7–9
As previously demonstrated in normothermic rats after CA14, 15, 20
, earlier EEG recovery was associated with significant improvement in NDS. Burst frequency in the first 90 minutes after resuscitation was strongly associated with neurological outcome. This strong linear relationship between early burst frequency and 72-hour NDS, however, was not present in the hypothermic and hyperthermic groups. The reason for this finding most likely relates to confounding influences of temperature on burst frequency. These findings may invalidate use of early burst frequency as an outcome predictor among CA survivors treated with induced hypothermia and in those with spontaneous hyperthemia. Simple burst counting methods, however, may not account for alterations in burst complexity caused by temperature manipulation and quantitative EEG methods may be required to capture the discriminative information contained within EEG signal outside the normal physiological temperature range.
Limitations of this study include a small number of animals. This limitation was especially evident in the hyperthermia group, in which 3/7 animals did not survive to the conclusion of the 72-hour experiment. The small number of animals and the assignment of an NDS score of 0 for non-survivors may have influenced the predictive accuracy of burst counting in the hyperthermia group. In addition, the major limitation of burst counting is that it does not account for the burst-suppression ratio and burst duration or complexity, which may contain discriminative information.