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Neurologic injury as a consequence of cerebral embolism of either air or atherosclerotic debris during cardiac or aortic surgery is still a major cause of postoperative morbidity and mortality. While exploring various means of improving cerebral protection during complex cardiothoracic procedures, we have developed a chronic porcine model to study retrograde cerebral perfusion. We have previously demonstrated that retrograde perfusion results in a small amount of nutritive flow and provides cerebral protection that appears to be superior to simple prolonged hypothermic circulatory arrest. The current study was designed to evaluate the efficacy of retrograde cerebral perfusion in mitigating the effects of particulate cerebral embolism occurring during cardiac surgery. Four groups of pigs (19 to 28 kg) underwent cardiopulmonary bypass with deep hypothermia at an esophageal temperature of 20^oC: an antegrade control group (AC, n = 5), an antegrade embolism group (AE, n = 10), a retrograde control group (RC, n = 5), and a retrograde embolism group (RE, n = 10). In addition, because of extreme heterogeneity in outcome in the initial RE group, an additional group of 10 animals underwent embolism and retrograde perfusion at a later time. Embolization was accomplished by injection of 200 mg of polystyrene microspheres (250 to 750 @mg in diameter) via the aortic cannula into an isolated aortic arch preparation in the AE and RE groups; the control groups received injections of 10 ml of saline solution. After infusion of the microspheres or saline solution, conventional perfusion, with the aortic arch pressure maintained at 50 mm Hg, was continued for a total of 30 minutes in the antegrade groups; in the retrograde groups, retrograde flow was initiated via a cannula positioned in the superior vena cava, and was continued for 25 minutes. Superior vena caval flow was regulated to maintain a sagittal sinus pressure of approximately 30 mm Hg in the retrograde groups, and blood returning to the isolated aortic arch was collected and measured. All animals were allowed to recover and were evaluated daily according to a quantitative behavioral score in which 9 indicates apparently complete normalcy, with lower numbers indicating various degrees of cerebral injury. At the time of planned death on day 6, half of the brain was used for recovery of embolized microspheres after digestion with 10N sodium hydroxide. The other half was submitted for histologic study. Neurologic recovery in both the antegrade and retrograde control groups appeared to be complete, although mild evidence of histologic damage was present in some animals in the retrograde control group. After embolization, unequivocal neurologic injury occurred in both groups, accompanied by significant cerebral histopathologic abnormalities. Although neurologic outcome was not significantly better in the initial RE group as a whole than in the AE group, it was noted that several of the RE animals recovered almost completely after retrograde cerebral perfusion (behavioral scores >7). The animals with good behavioral recovery were noted to have been perfused with markedly lower superior vena caval pressures than those used in animals that sustained severe neurologic injury. An additional 10 animals were therefore subjected to embolization and retrograde perfusion to clarify the impact on outcome of different superior vena caval pressures during retrograde perfusion. When these additional animals are included in the analysis, the behavioral and neuropathologic evidence suggests that use of retrograde cerebral perfusion may attenuate the severity of cerebral injury resulting from particulate emboli when adequate retrograde perfusion can be maintained at low superior vena caval pressures (<40 mm Hg). This observation merits further study. (J THORAC CARDIOVASC SURG 1995;110:1470-85)

Thirty-two inbred weanling puppies were divided into four groups to study the effect on cerebral blood flow and metabolism of different hypothermic strategies for cerebral protection similar to those used during cardiac operations in infancy. All animals were cooled to 18 ^o C. The animals in the hypothermic control group were immediately rewarmed. One group underwent 30 minutes of hypothermic circulatory arrest at 18 ^o C; another group had 90 minutes of hypothermic circulatory arrest at 18 ^o C, and the final group had low-flow cardiopulmonary bypass (25 ml/kg per minute) at 18 ^o C for 90 minutes. All animals had preoperative and postoperative neurologic and behavioral evaluation and extensive intraoperative monitoring of cerebral blood flow, cerebral vascular resistance, and oxygen and glucose uptake and metabolism: quantitative electroencephalography was also monitored before, during, and after operation, but those results are reported separately. Two animals in the 90-minute arrest group died, and all the survivors showed evidence of clinical, neurologic, and behavioral impairment on postoperative day 1, with residual abnormalities in all but one animal on day 6. In contrast, the survivors in all the other groups showed no significant clinical or behavioral sequelae. Cerebral metabolism was reduced only to 32% to 40% of baseline values at 18 ^o C in all groups, although systemic metabolism was only 16% of normal. Cerebral metabolism returned promptly to baseline in all groups during rewarming and remained at baseline levels throughout the 8 hours of follow-up. Cerebral blood flow showed marked hyperemia in the hypothermic arrest groups during rewarming but then significant reductions below baseline values in all groups except the controls at 2 and 4 hours after the operation, lasting as late as 8 hours after the operation in the 90-minute arrest group. Cerebral vascular resistance showed increases in all groups at 2 and 4 hours after the operation, which persisted in the 90-minute arrest group at 8 hours. Cerebral metabolism was maintained at baseline levels despite postoperative decreases in cerebral blood flow and increases in cerebral vascular resistance by increases in oxygen and glucose extraction. The result was very low sagittal sinus oxygen saturations in all groups, most marked in the 90-minute arrest groups, which had a saturation of only 24% 8 hours after the operation. Our data show a severe, prolonged disturbance in cerebral blood flow and cerebral vascular resistance after 90 minutes of hypothermic circulatory arrest at 18 ^o C, which correlates with clinical evidence of cerebral injury. The presence of similar but milder inappropriate hemodynamic responses in animals after 30 minutes of arrest at 18 ^o C, and even after prolonged low-flow cardiopulmonary bypass at 18 ^o C, suggest that strategies to improve cerebral protection during hypothermia--including use of colder temperatures--need to be explored. ( J THORAC CARDIOVASC SURG 1995; 109: 959-75)

Although hypothermic circulatory arrest and low-flow cardiopulmonary bypass are routinely used for surgical correction of congenital cardiac anomalies, use of long durations of arrest, often required for more complex repairs, raises serious concerns about cerebral safety. Searching for an intraoperative assessment that can reliably predict cerebral injury, we have found an excellent correlation between changes in quantitative electroencephalography intraoperatively and immediately postoperatively after prolonged hypothermic arrest, and neurologic and behavioral evidence of cerebral injury. After epidural placement of four recording electroencephalographic electrodes and baseline neurologic/behavioral and electroencephalographic assessment, 32 puppies were randomly assigned to one of four groups: hypothermic controls in which cooling to 18^o C was followed immediately by rewarming, 30 minutes of hypothermic circulatory arrest at 18^o C, 90 minutes of arrest at 18^o C, and 90 minutes of low-flow cardiopulmonary bypass at 25 ml/kg per minute at 18^o C. An electroencephalogram was recorded at baseline, after cooling, during rewarming, and at 2, 4, and 8 hours after the start of rewarming, as well as before the operation and 1 week after the operation. Postoperative neurologic and behavioral outcome was assessed 24 hours after cardiopulmonary bypass and daily for 1 week by means of a graded scale in which 0 is normal and 12 and 13 indicate severe neurologic injury (coma and death). Thirty animals survived the experimental protocol: two animals in the 90-minute hypothermic arrest group died before neurologic evaluation could be completed, and the remainder exhibited various degrees of neurologic and behavioral impairment, more severe on day 1 than on day 6. No animal in the remaining groups had a significant neurologic deficit. Quantitative electroencephalographic analysis shows marked differences between the 90-minute arrest group and the controls in the percent electroencephalographic silence during rewarming and at 2 hours, and in the percent recovery of baseline power at 2, 4, and 8 hours. At 2 hours after the start of rewarming, a correlation between electroencephalographic amplitude and neurologic/behavioral score on day 1 was carried out, which predicts with great certainty ( p < 0.00001) that if electroencephalographic power at this time is less than 500 @mV^2 , overt neurologic injury will subsequently become apparent. In addition, a significant shift from higher to lower frequency in the day 6 postoperative electroencephalogram compared with baseline occurs only in the 90-minute arrest group. Although clinical neurologic injury was not apparent in any but the 90-minute arrest group, further quantitative electroencephalographic comparisons of postoperative with baseline power show a much more rapid return of electroencephalographic power in the control than in either the 30-minute hypothermic arrest or the low-flow cardiopulmonary bypass group Between-group comparisons show significant differences between the 90-minute arrest and low-flow cardiopulmonary bypass groups at several time points, and fewer and less marked differences between 90-minute and 30-minute arrest groups. These results demonstrate that quantitative electroencephalographic logic injury after 90 minutes of hypothermic circulatory arrest at 18 ^o C. The presence of milder but significant differences from control quantitative electroencephalographic values after 30 minutes of arrest at 18 ^o C suggest that there may be subtle cerebral injury undetected by neurologic/behavioral evaluation in this group, although this interval is clinically accepted as safe. In contrast, no quantitative electroencephalographic evidence of cerebral dysfunction was apparent after 90 minutes of low-flow cardiopulmonary bypass at 18 ^o C. The study as a whole suggests that quantitative electroencephalographic is a sensitive indicator of cerebral injury and may prove extremely valuable in future studies of strategies for cerebral protection during cardiac surgery. (J THORAC CARDIOVASC SURG 1995;109:925-34)

Objective: We assessed the impact on histologic and behavioral outcome of an interval of retrograde cerebral perfusion after arterial embolization, comparing retrograde cerebral perfusion with and without inferior vena caval occlusion with continued antegrade perfusion. Methods: Sixty Yorkshire pigs (27 to 30 kg) were randomly assigned to the following groups: antegrade cerebral perfusion control; antegrade cerebral perfusion after embolization; retrograde cerebral perfusion control; retrograde cerebral perfusion after embolization; retrograde cerebral perfusion with inferior vena cava occlusion, retrograde cerebral perfusion with inferior vena cava occlusion control, and retrograde cerebral perfusion with inferior vena cava occlusion after embolization. After cooling to 20^o C, a bolus of 200 mg of polystyrene microspheres 250 to 750 (@mm diameter (or saline solution) was injected into the isolated aortic arch. After 5 minutes of antegrade cerebral perfusion, 25 minutes of antegrade cerebral perfusion, retrograde cerebral perfusion, or retrograde cerebral perfusion with inferior vena cava occlusion was instituted. After the operation, all animals underwent daily assessment of neurologic status until the time of death on day 7. Results: Aortic arch return, cerebral vascular resistance, and oxygen extraction data during retrograde cerebral perfusion showed differences, suggesting that more effective flow occurs during retrograde cerebral perfusion with inferior vena cava occlusion, which also resulted in more pronounced fluid sequestration. Microsphere recovery from the brain revealed significantly fewer emboli after retrograde cerebral perfusion with inferior vena cava occlusion. Behavioral scores showed full recovery in all but one control animal (after retrograde cerebral perfusion with inferior vena cava occlusion) by day 7 but were considerably lower after embolization, with no significant differences between groups. The extent of histopathologic injury was not significantly different among embolized groups. Although no histopathologic lesions were present in either the antegrade cerebral perfusion control group or the retrograde cerebral perfusion control group, mild significant ischemic damage occurred after retrograde cerebral perfusion with inferior vena cava occlusion even in control animals. Conclusions: Although effective washout of particulate emboli from the brain can be achieved with retrograde cerebral perfusion with inferior vena cava occlusion, no advantage of retrograde cerebral perfusion with inferior vena cava occlusion after embolization is seen from behavioral scores, electro- encephalographic recovery, or histopathologic examination; retrograde cerebral perfusion with inferior vena cava occlusion results in greater fluid sequestration and mild histopathologic injury even in control animals. Retrograde cerebral perfusion with inferior vena cava occlusion shows clear promise in the management of embolization, but further refinements must be sought to address its still worrisome potential for harm.(J Thorac Cardiovasc Surg 1998;115:1142-59) J Thorac Cardiovasc Surg 1998;115:1142-59