Epileptiform Activity During Rewarming from Moderate Cerebral Hypothermia in the Near-Term Fetal Sheep

Abstract

Moderate hypothermia is consistently neuroprotective after hypoxic-ischemic insults and is the subject of ongoing clinical trials. In pilot studies, we observed rebound seizure activity in one infant during rewarming from a 72-h period of hypothermia. We therefore quantified the development of EEG-defined seizures during rewarming in an experimental paradigm of delayed cooling for cerebral ischemia. Moderate cerebral hypothermia (n ϭ 9) or sham cooling (n ϭ 13) was initiated 5.5 h after reperfusion from a 30-min period of bilateral carotid occlusion in near-term fetal sheep and continued for 72 h after the insult. During spontaneous rewarming, fetal extradural temperature rose from 32.5 Ϯ 0.6°C to control levels (39.4 Ϯ 0.1°C) in 47 Ϯ 6 min. Carotid blood flow and mean arterial blood pressure increased transiently during rewarming. The cooling group showed a significant increase in electrical seizure events 2, 3, and 5 h after rewarming, maximal at 2 h (2.9 Ϯ 1.2 versus 0.5 Ϯ 0.5 events/h; p Ͻ 0.05). From 6 h after rewarming, there was no significant difference between the groups. Individual seizures were typically short (28.8 Ϯ 5.8 s versus 29.0 Ϯ 6.8 s in sham cooled; NS), and of modest amplitude (35.9 Ϯ 2.8 versus 38.8 Ϯ 3.4 V; NS). Neuronal loss in the parasagittal cortex was significantly reduced in the cooled group (51 Ϯ 9% versus 91 Ϯ 5%; p Ͻ 0.002) and was not correlated with rebound epileptiform activity. In conclusion, rapid rewarming after a prolonged interval of therapeutic hypothermia can be associated with a transient increase in epileptiform events but does not seem to have significant adverse implications for neural outcome. There is now consistent experimental evidence that a sufficient interval of moderate cerebral hypothermia started shortly after severe perinatal hypoxia-ischemia can reduce secondary neuronal injury and improve functional outcomes (1). Although only pilot data are available in newborn infants (2), early induction of moderate hypothermia in adult patients after cardiac arrest improves neurologic recovery (3,4). Rewarming after cooling treatment for severe hypoxic-ischemic encephalopathy (HIE), however, is potentially a more complex process than the original induction of cooling: first because it might lead to destabilizing cardiovascular changes such as a loss of peripheral tone with an increased requirement for cardiac work (5) and second because damaging processes such as release of excitatory amino acid neurotransmitters that have been suppressed by hypothermia could become active again (6,7).In view of such considerations, clinical studies of therapeutic hypothermia typically have rewarmed infants at no more than 0.5°C/h (8 -10); however, there are few systematic data. During our early pilot studies of head-cooling with mild systemic hypothermia for neonatal HIE, we observed a case of an infant who exhibited transient clinical seizures during rewarming. To examine the hypothesis that rewarming from prolonged moderate hypothermia may be associated with rebound seizure activ...

Hypothermic neuroprotection

“…Cooling was continued for 3 days in the fetal sheep studies because pilot studies demonstrated intense rebound seizure activity and increased cell loss if cooling was stopped after less than 24 to 48 h. In contrast, even very rapid spontaneous rewarming after 3 days of cooling was associated with only minor, transient epileptiform activity. 81 These results are consistent with the report from Colbourne and colleagues in the adult gerbil that when the delay after cerebral ischemia before initiating a 24 hour period of cooling was increased from 1 to 4 hours, neuroprotection in the CA1 region of the hippocampus after six months recovery fell from 70 to 12%. 82 This chronic loss could be prevented by extending the duration of moderate (32 to 34°C ) hypothermia to 48 hours or more, even when the start of cooling was delayed until 6 hours after reperfusion.…”

“…However, it is unclear whether cooling for 72 h is 'better' than 48 h. Equally, there are experimental and clinical data reporting rebound seizure activity after rewarming from 72 h of cooling, 81,155 and thus it remains possible that cooling for 4 or 5 days might provide further benefit.…”

Recooling for Rebound Seizures After Rewarming in Neonatal Encephalopathy

“…3,9 In the current report, this occurred despite extremely slow rewarming. Recooling of the infant to 33.5°C resulted in complete cessation of seizures within 30 minutes, and these did not recur on rewarming after an additional 24 hours of therapeutic hypothermia.…”

A Comparison of Cooling Methods Used in Therapeutic Hypothermia for Perinatal Asphyxia

“…Furthermore, it has been observed that cerebral metabolic rate for oxygen is increased and cerebral fractional oxygen extraction is decreased during rapid rewarming after cardiopulmonary bypass, 24,25 and seizures have been observed during rewarming both clinically and in experimental models. 14,26 Certainly posthypoxic hyperthermia is associated with adverse outcome in noncooled infants. 18,19 The results presented are from a retrospective analysis of infants who were sequentially recruited to studies, consequently, the treatment groups are not randomized.…”