Phenobarbital Augments Hypothermic Neuroprotection

Abstract

Seizures are associated with adverse outcome in infants with hypoxic-ischemic encephalopathy. We hypothesized that early administration of the anticonvulsant phenobarbital after cerebral hypoxia ischemia could enhance the neuroprotective efficacy of delayed-onset hypothermia. We tested this hypothesis in a neonatal rodent model. Seven-d-old rats (n ϭ 104) underwent right carotid ligation, followed by 90 min 8% O 2 exposure; 15 min later, they received injections of phenobarbital (40 mg/kg) or saline. One or 3 h later, all were treated with hypothermia (30°C, 3 h). Function and neuropathology were evaluated after 7 d (early outcomes) or 1 mo (late outcomes). Early outcome assessment demonstrated better sensorimotor performance and less cortical damage in phenobarbital-treated groups; there were no differences between groups in which the hypothermia delay was shortened from 3 to 1 h. Late outcome assessment confirmed sustained benefits of phenobarbital ϩ hypothermia treatment; sensorimotor performance was better (persistent attenuation of contralateral forepaw placing deficits and absence of contralateral forepaw neglect); neuropathology scores were lower (median, phenobarbital 2 and saline 8.5, p Ͻ 0.05); and less ipsilateral cerebral hemisphere %Damage (mean Ϯ SD, 11 Ϯ 17 versus 28 Ϯ 22, p Ͻ 0.05). These results suggest that early posthypoxia-ischemia administration of phenobarbital may augment the neuroprotective efficacy of therapeutic hypothermia. T he results of four clinical trials support the safety and efficacy of hypothermia to decrease death and disability in infants with hypoxic-ischemic encephalopathy (HIE) (1-4). However, in these trials Ͼ40% of hypothermia-treated infants died or had poor neurologic outcomes. Thus, there is a need for strategies to improve the neuroprotective efficacy of hypothermia. One possible approach is to combine hypothermia with pharmacotherapy.In experimental models of neonatal hypoxic-ischemic brain injury, several agents enhance the neuroprotective efficacy of hypothermia; these include topiramate, an anticonvulsant (5); xenon, an anesthetic (6); and N-acetylcysteine, an antioxidant (7). There is minimal neonatal clinical experience with these drugs (8). Nevertheless, many neuroactive drugs are commonly administered to encephalopathic neonates, and an important question is whether any of these drugs could augment hypothermic neuroprotection.Anticonvulsants are an attractive group of drugs to study in combination with hypothermia. Many have neuroprotective properties in cerebral ischemia models, although it is uncertain whether these effects are attributable to seizure cessation (9). Seizures are common in encephalopathic neonates, in whom they may exacerbate hypoxic-ischemic brain injury (10,11). In one hypothermia trial, seizures were an independent predictor of adverse outcome (12). Phenobarbital is currently the anticonvulsant used most commonly to treat neonatal seizures (13). Moreover, in a small randomized trial, treatment of infants with HIE with phenobarb...

Nonadditive Neuroprotection With Early Glutamate Receptor Blockade and Delayed Hypothermia After Asphyxia in Preterm Fetal Sheep

“…3,4 In the present study, mild whole-body cooling in preterm fetal sheep, delayed by 5.5 hours and continued for 72 hours, was associated with partial neuroprotection. Although there was a striking improvement in neuronal survival in CA1/2, to near sham control values, CA3 and striatal nuclei were only partially protected.…”

“…10 The finding that early drug treatment did not augment protection with delayed hypothermia contrasts with previous findings that treatment with anticonvulsants such as topiramate and phenobarbital started 15 minutes after hypoxiaischemia in P7 rats synergistically increased neuroprotection with hypothermia started up to 3 hours later. 3,4 It is possible that the contrasting findings may reflect differences in species, insult, or receptor-specific effects. Furthermore, we used a longer interval of delayed hypothermia, consistent with clinical protocols, 7 which may have reduced the scope to demonstrate improvement with combined therapy.…”

“…2 Early anticonvulsant treatment in the P7 rat can extend the window of opportunity for delayed treatment with hypothermia. 3,4 However, these studies used relatively short, less effective intervals of hypothermia. Thus, in this study, we evaluated whether early treatment with dizocilpine could augment neuroprotection with a clinical protocol of delayed, but prolonged, whole-body hypothermia after severe asphyxia in preterm fetal sheep.…”

Mechanisms of Perinatal Arterial Ischemic Stroke

“…Hypothermia may also widen the window for repair but the beneficial effects of hypothermia alone seem insufficient, suggesting that outcomes may improve when hypothermia is used in conjunction with other therapies. [173][174][175][176][177] Considering that initial observations on a limited endogenous neural repair are not specially promising, as injury can adversely affect postnatal brain development and reprogram the neonatal brain after stroke, more recent studies have begun targeting repair as a way to improve long-term recovery after focal or global H-I injury during the newborn period. Growth factors may prove potent for perinatal stroke and HIE when given alone or as adjunctive therapies.…”

Post-hypoxic hypothermia is protective in human NT2-N neurons regardless of oxygen concentration during reoxygenation

“…Potentially dangerous haemodynamic side effects also limit the use of calcium channel antagonists in infants 214 . Although the anticonvulsant phenobarbital has been shown to augment the neuroprotective effect of therapeutic hypothermia in the neonatal rat 215 , a reduction in neurogenesis in the neonatal brain secondary to phenobarbital use was recently reported 216 .…”