Hypothermia for 24 Hours After Asphyxic Cardiac Arrest in Piglets Provides Striatal Neuroprotection That Is Sustained 10 Days After Rewarming

Abstract

The neuroprotective effect of hypothermia instituted after resuscitation from asphyxic cardiac arrest has not been studied in immature brain, particularly in a large animal model with recovery periods greater than 4 d. Moreover, protection from severe hypoxia seen with 3 h of hypothermia was reported to be lost when hypothermic duration was extended to 24 h in unsedated piglets, in contrast to the neuroprotection reported by 72 h of intrauterine head cooling in fetal sheep. Piglets (5-7 postnatal days) were subjected to asphyxic cardiac arrest followed by 24 h of either hypothermia (34°C) or normothermia (38.5-39°C). Comparisons were made with normothermic and hypothermic surgical sham animals without asphyxia. All of these groups were sedated, paralyzed, and mechanically ventilated for the first 24 h to prevent shivering and possible depletion of glucose stores. Hypothermia per se did not cause remarkable structural abnormalities. Ischemic damage was evaluated in putamen at 1 d of recovery without rewarming and at 11 d (10 d Ϯ SD after rewarming). Ischemic cytopathology affected 60 Ϯ 12% of neurons in putamen of normothermic animals compared with 9 Ϯ 6% in hypothermic animals at 1 d of recovery without rewarming. At 11 d of recovery from hypoxia-ischemia, the density of viable neurons (neuron profiles/mm 2 ) in putamen was markedly reduced in normothermic animals (81 Ϯ 40) compared with hypothermic animals (287 Ϯ 22), which was the same as in sham normothermic (271 Ϯ 21), sham hypothermic (288 Ϯ 46) and naïve animals (307 Ϯ 51). These data demonstrate that 24 h of hypothermia at 34°C with sedation and muscle relaxation after asphyxic cardiac arrest prevents necrotic striatal neuronal cell death in immature brain before rewarming, and that the effect is sustained at 11 d after injury without deleterious side effects. Transient cerebral hypoxia-ischemia (HI) in newborns often results from difficulties during delivery or cardiorespiratory arrest. Perinatal HI in its most severe form may cause permanent neurodevelopmental impairment, which typically includes spastic quadriparesis, severe cognitive deficiency and epilepsy (1). Advances in obstetric and neonatal care have not significantly altered the outcome of HI encephalopathy (2). Treatment for newborns with HI remains supportive despite the efforts of a variety of investigators to evaluate neuroprotective interventions (3). In adults resuscitated from cardiac arrest, mild hypothermia lasting 12-24 h is one of the few interventions found to benefit neurologic outcome (4,5). In term newborns, selective head cooling is the subject of an on-going multicenter trial, where results to date have been encouraging (6). Preliminary data support the safety of mild hypothermia in sick newborns (7).

Neurobehavioral functional deficits following closed head injury in the neonatal pig

“…Previous survival studies of acute brain injury in piglets have utilized limited and relatively unsophisticated neurobehavioral assessments (Agnew 2003,Priestley 2001). Priestley et al utilized a simple neurologic performance scale and a functional disability score that evaluated piglets' ability to feed, ambulate, and explore their environment.…”

“…Typically a series of 4 or 5 categories of neurological function are used (e.g. mental status, cranial nerves, sensorimotor function, feeding), each of which is assigned a graded score of 1-4 representing the degree of abnormality, yielding a final score ranging from a possible total of 9 for the simplest grading scheme (Midulla 1994), to 150 for a more complicated neurological deficit score (Agnew 2003). These grading systems have shown only limited correlation with histopathologic abnormalities (Priestley 2001), but their sensitivity for assessment of complex behavior or cortical functions is poor, and none have been well validated with long-term survival studies.…”

Experimental model of pediatric asphyxial cardiopulmonary arrest in rats

“…The development of a piglet model of asphyxial cardiac arrest has led to progress in this regard, particularly in relation to studies determining the effectiveness of cardiopulmonary resuscitation (27). In addition, Agnew and colleagues have recently reported that 24 h of hypothermia reduces striatal damage in PND 5-7 day old piglets after 30 min of hypoxia followed by 7 min of asphyxia (12). Mechanistic information can also be extrapolated from models of temporary global ischemia such as the four-vessel occlusion model (28) or cardiac arrest initiated by ventricular fibrillation (29).…”

“…To date, there is no contemporary age-appropriate pediatric model of HIE for the evaluation of prolonged neurodegeneration and long-term neurologic outcome. Some insight into developmental aspects of HIE can be extrapolated from the well-established model of carotid artery ligation followed by hypoxemia in immature rodents (10), or asphyxial arrest in piglets (11,12); however, these models either do not model global and systemic hypoxemia/ischemia or are impractical in terms of long-term outcome assessment, respectively. To address these limitations, we have developed a model of pediatric asphyxial cardiac arrest in post-natal day (PND) 17 rats that has the capacity for 1) invasive physiologic monitoring and acute resuscitation that closely mimics guidelines used in humans; 2) acute and long-term biochemical and cellular assessment utilizing currently available molecular tools tested in rodents; 3) acute and long-term functional outcome assessment utilizing standardized behavioral tools developed for use in rodents with the potential for application of rehabilitation strategies; and 4) testing of potential clinically relevant therapies and their related mechanisms.…”

Anoxic Injury-Associated Cerebral Hyperperfusion Identified with Arterial Spin-Labeled MR Imaging

“…Recent animal models and clinical studies of global ischemia have shown promising neuroprotective effects of mild-to-moderate therapeutic hypothermia. [46][47][48][49] Future potential studies with ASL may examine the effects of hypothermia and other treatment strategies on cerebral perfusion in the anoxic patient.…”