Fast rewarming after deep hypothermic circulatory arrest in rats impairs histologic outcome and increases NFκB expression in the brain.

OBJECTIVE: Deep hypothermia is used as a neuroprotectant during cardiac surgery utilizing deep hypothermic circulatory arrest (DHCA), although the ideal rewarming strategy is not known yet. Some of the neuroprotective properties of hypothermia seem to be mediated by Nuclear Factor Kappa B (NFκB) as an important transcription factor. The current study was designed to investigate the effect of the rewarming rate on histologic outcome and cerebral NFκB expression one day following DHCA in rats. METHODS: With IRB approval, 20 rats were cannulated for cardiopulmonary bypass (CPB), cooled to a rectal temperature of 15-18°C, subjected to 45min of DHCA and randomly assigned to either a slow (40 min) or a fast (20 min) rewarming protocol. At 24 hours post DHCA, the number of eosinophilic neurons was analyzed with hematoxylin and eosin (HE) staining, and NFκB expression immunohistochemically. The two experimental groups were compared with untreated control rats. RESULTS: HE staining showed more eosinophilic neurons in the motor cortex following fast rewarming (60 [15-388]) compared to slow rewarming (15 [10-21]) (p<0.05). Neuronal expression of NFκB was increased in the fast rewarming group in both brain areas, the motor cortex (fast: 258 [135-393]; slow: 165 [80-212]; control: 73 [44-111]) as well as the hippocampus (fast: 243 [209-314]; slow: 202 [187-239]; control: 86 [68-108]) (p<0.05). Hyperthermic episodes were strictly avoided. CONCLUSIONS: Fast rewarming with strict avoidance of hyperthermia after DHCA in rats was accompanied by pronounced histologic damage and accentuated cerebral NFκB expression.

Long-term assessment of NFkappaB expression in the brain and neurologic outcome following deep hypothermic circulatory arrest in rats.

OBJECTIVES: Inflammatory response is discussed as a contributor to neurologic deficits following cardiac surgery using deep hypothermic circulatory arrest (DHCA). Nuclear Factor Kappa B (NFkappaB) presents a central transcription factor whose expression pattern and subsequent role very much depend on the type and manner of cerebral injury. This study was designed to assess the time course of cerebral NFkappaB expression in relation to neurologic performance over 28 days following 45min of DHCA in rats. METHODS: With Institutional Review Board approval, 30 rats were subjected to cardiopulmonary bypass (CPB) with 45min of DHCA (rectal temperature 15-18 degrees Celsius) and randomly assigned to 1, 3, 7, 14 and 28 days of postoperative survival. Untreated animals served as control (n=6). Cerebral NFkappaB expression was analyzed immunohistochemically, cyclooxygenase-2 (COX-2) and inhibitor of kappa B-alpha (IkappaBalpha) using Western Blot and the number of eosinophilic neurons with hematoxylin and eosin (HE) staining. Neurologic outcome was assessed pre- and postoperatively. RESULTS: Neuronal expression of NFkappaB in the hippocampus peaked at day one, remaining elevated in the motor cortex until day 28. Rats showed neurologic deficits on postoperative day one. Cerebral COX-2 was increased during the first postoperative week and IkappaBalpha peaked on day 14. Histologic damage in the motor cortex and hippocampus persisted until day 28. No systemic inflammation was detectable postoperatively. CONCLUSIONS: Postoperative day one presents with the highest NFkappaB-expression in the ischemia-sensitive hippocampus, accompanied by neurologic dysfunction and histologic damage following 45min of DHCA in rats.

Xenon impairs neurocognitive and histologic outcome after cardiopulmonary bypass combined with cerebral air embolism in rats.

BACKGROUND: The neuroprotective properties of xenon may improve cerebral outcome after cardiac surgery using cardiopulmonary bypass (CPB). However, its disposition to expand gaseous bubbles that during CPB present as cerebral air emboli (CAE) could abolish any beneficial effect or even worsen cerebral outcome. Therefore, the authors studied the impact of xenon on neurologic, cognitive, and histologic outcome after CPB combined with CAE in rats. METHODS: With institutional review board approval, 40 rats were assigned to four groups (n = 10). In two CPB-CAE groups, rats were subjected to 90 min of normothermic CPB with 10 repetitively administered CAEs (0.3 microl/bolus). Rats in two sham groups were not exposed to CPB and CAE. Groups were further subdivided into xenon (56%; 20 min before, during, and 30 min after CPB) and nitrogen groups. Neurologic and cognitive function was tested until postoperative day 14, when cerebral infarct volumes were determined. RESULTS: Animals of the CPB-CAE groups showed transient deficits in gross neurologic function. Further, rats of the CPB-CAE-xenon group demonstrated impaired fine motor and cognitive performance persisting until postoperative day 14. Consistently, infarct volumes were larger in the CPB-CAE-xenon group compared with the CPB-CAE-nitrogen group (P = 0.03). CONCLUSIONS: This is the first demonstration in which the neurologic effects of CAE have been examined in a rat model of CPB. Xenon exposure aggravated the neurologic dysfunction that is produced by CAE during CPB; potential neuroprotective effects of xenon may have been masked by the effects of xenon on CAE.