Neurologic outcome after cardiopulmonary bypass with deep hypothermic circulatory arrest in rats: description of a new model.

OBJECTIVE Neurodevelopmental impairments after repair of congenital heart disease with cardiopulmonary bypass and deep hypothermic circulatory arrest continue to affect the lives of children. To date, the preclinical investigation of cerebral injury mechanisms related to deep hypothermic circulatory arrest has been restricted to expensive, personnel-demanding, and cumbersome large-animal models without validated neuropsychologic assessment. We aimed to establish a rodent recovery model of deep hypothermic circulatory arrest to overcome these disadvantages. METHODS Male rats (n = 34) were cannulated for cardiopulmonary bypass, cooled to a rectal temperature of 16 degrees C to 18 degrees C within 30 minutes, and assigned to deep hypothermic circulatory arrest durations of 0, 45, 60, 75, 90 (n = 6, respectively), or 105 (n = 4) minutes. After rewarming within 40 minutes, animals were weaned from cardiopulmonary bypass at 35.5 degrees C. Neurologic and cognitive performance was assessed with the modified hole board test until postoperative day 14. Thereafter, brains were perfusion fixed and histologically analyzed. RESULTS Logistic regression analyses identified dose-dependent associations between survival, neurologic or cognitive function, and duration of deep hypothermic circulatory arrest. Functional and histologic deficits were detectable after clinically relevant deep hypothermic circulatory arrest durations. The overall neurologic function did not correlate with histologic outcome (r = 0.51, P > .05). CONCLUSIONS The current study presents a novel recovery model of cardiopulmonary bypass with deep hypothermic circulatory arrest in the rat. In contrast to studies in large animals, even clinically relevant deep hypothermic circulatory arrest durations up to 60 minutes resulted in detectable deficits. Consequently, this experimental model appears to be suitable to further elucidate the mechanisms associated with adverse cerebral outcome after cardiac surgery and deep hypothermic circulatory arrest and to investigate potential neuroprotective strategies.

[1]  D. Wypij,et al.  The effect of duration of deep hypothermic circulatory arrest in infant heart surgery on late neurodevelopment: the Boston Circulatory Arrest Trial. , 2003, The Journal of thoracic and cardiovascular surgery.

[2]  Gregory L. Holmes,et al.  Developmental and neurologic status of children after heart surgery with hypothermic circulatory arrest or low-flow cardiopulmonary bypass. , 1995, The New England journal of medicine.

[3]  Mark F. Newman,et al.  Cardiopulmonary Bypass Induces Neurologic and Neurocognitive Dysfunction in the Rat , 2001, Anesthesiology.

[4]  Hirofumi Nakatomi,et al.  Regeneration of Hippocampal Pyramidal Neurons after Ischemic Brain Injury by Recruitment of Endogenous Neural Progenitors , 2002, Cell.

[5]  R. Landgraf,et al.  Dimensions of emotionality in a rat model of innate anxiety. , 2001, Behavioral neuroscience.

[6]  F. Holsboer,et al.  Differential analysis of behavior and diazepam-induced alterations in C57BL/6N and BALB/c mice using the modified hole board test. , 2001, Journal of psychiatric research.

[7]  A. Tamas,et al.  Examination of sensorimotor performance following middle cerebral artery occlusion in rats , 2003, Brain Research Bulletin.

[8]  M. Priestley,et al.  Regional patterns of neuronal death after deep hypothermic circulatory arrest in newborn pigs. , 1999, The Journal of thoracic and cardiovascular surgery.

[9]  R. Felling,et al.  Enhanced neurogenesis following stroke , 2003, Journal of neuroscience research.

[10]  G. von Bernuth,et al.  Cognitive and motor development in preschool and school-aged children after neonatal arterial switch operation. , 1997, The Journal of thoracic and cardiovascular surgery.

[11]  F. Kirkham,et al.  Pathophysiology of the cerebral circulation during cardiac surgery , 2000, Critical Care.

[12]  J. Ware,et al.  A comparison of the perioperative neurologic effects of hypothermic circulatory arrest versus low-flow cardiopulmonary bypass in infant heart surgery. , 1993, The New England journal of medicine.

[13]  J. Simpson,et al.  The relationship between intelligence and duration of circulatory arrest with deep hypothermia. , 1995, The Journal of thoracic and cardiovascular surgery.

[14]  H. Naritomi,et al.  Neurological function after deep hypothermic circulatory arrest in the rat. , 1998, Circulation.

[15]  Catherine Limperopoulos,et al.  Predictors of developmental disabilities after open heart surgery in young children with congenital heart defects. , 2002, The Journal of pediatrics.

[16]  L. D'alecy,et al.  Motor performance in rats exposed to severe forebrain ischemia: effect of fasting and 1,3-butanediol. , 1987, Stroke.

[17]  F. Holsboer,et al.  Cognitive performance in rats differing in their inborn anxiety. , 2002, Behavioral neuroscience.

[18]  M. Marshall.  HIBERNATION AND HYPOTHERMIA, PERSPECTIVES AND CHALLENGES , 1972 .

[19]  F. Holsboer,et al.  The modified hole board as a differential screen for behavior in rodents , 2001, Behavior research methods, instruments, & computers : a journal of the Psychonomic Society, Inc.

[20]  A. Gelb,et al.  Propofol Neuroprotection in Cerebral Ischemia and Its Effects on Low-molecular-weight Antioxidants and Skilled Motor Tasks , 2004, Anesthesiology.

[21]  D. Randall,et al.  Roles of cardiac output and peripheral resistance in mediating blood pressure response to stress in rats. , 1998, The American journal of physiology.

[22]  J. Bucerius,et al.  Oxygenation strategy and neurologic damage after deep hypothermic circulatory arrest. II. hypoxic versus free radical injury. , 1999, The Journal of thoracic and cardiovascular surgery.

[23]  B. Hindman,et al.  Improving neurologic outcome after cardiac surgery. , 1999, Anesthesiology.

[24]  Gil Wernovsky,et al.  Periventricular leukomalacia is common after neonatal cardiac surgery. , 2004, The Journal of thoracic and cardiovascular surgery.

[25]  H. Reulen,et al.  Neurological impairment in rats after transient middle cerebral artery occlusion: a comparative study under various treatment paradigms , 2000, Brain Research.