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J Thorac Cardiovasc Surg 2003;126:631-633
© 2003 The American Association for Thoracic Surgery
Editorial |
a From the Department of Anesthesiology and Perioperative Medicine, University Hospital Campus—London Health Sciences Center, University of Western Ontario, London, Ontario, Canada
Received for publication February 10, 2003; accepted for publication March 4, 2003.
* Address for reprints: John M. Murkin, MD, FRCPC, Department of Anesthesiology and Perioperative Medicine, University Hospital Campus—London Health Sciences Center, University of Western Ontario, London, Ontario, N6A 5A5, Canada
jmurkin{at}uwo.ca
| See related article on page 638.
|
In this issue of the Journal, Harrington and colleagues1 have taken an important clinical step in assessing cerebroprotective strategies for patients undergoing hypothermic circulatory arrest (HCA). Prospective randomization of patients into groups to undergo either HCA or HCA with retrograde cerebral perfusion (RCP) and inferior vena caval occlusion (IVCO) by using changes in serial performance on a standardized and sensitive preoperative and postoperative cognitive test battery as the primary outcome measure was unable to show any superiority of RCP for cerebral protection. In fact, their results indicated that there might be some incremental disadvantage to RCP. At 6 weeks, patients undergoing RCP had significantly lower scores on 2 separate cognitive tests, whereas at 12 weeks, their overall standardized cognitive test scores (z scores) were lower than those of patients treated with HCA alone, suggesting greater overall cognitive dysfunction.
Although there are significant limitations to the current study as acknowledged by the authors, including the sample size of only 38 patients, the relatively short 30-minute duration of HCA, and the approximately 15% and 20% drop-out rates of apparently well patients at the follow-up testing intervals, several important messages can be identified. First, the incidence of cognitive dysfunction after HCA is not improved and might be marginally worsened by RCP. This is in accordance with the results of several other clinical trials, however. In a nonrandomized study Reich and coworkers2 performed preoperative and postoperative cognitive testing on 56 patients undergoing HCA, of whom 12 patients underwent RCP. Memory dysfunction and the overall incidence of cognitive dysfunction had strong associations with RCP, even when controlling separately for age and cerebral ischemia time, suggesting worsened outcome with RCP. Okita and colleagues3 separately evaluated 60 patients who were nonrandomized but were sequentially stratified to receive either RCP or selective antegrade cerebral perfusion (ACP) using serial brain imaging, brain isoenzyme measurement, and limited cognitive testing. They also demonstrated that the prevalence of clinically defined transient brain dysfunction was significantly higher in patients undergoing RCP. Svensson and coworkers4 used cognitive testing in a subset of 30 of 139 patients undergoing HCA and prospectively randomized into 3 groups to receive either HCA alone, HCA and RCP, or HCA and selective ACP. Consistent with the current study, comparison of postoperative mean cognitive test scores showed that the group undergoing HCA alone did significantly better than either the RCP or ACP groups.
Given these directionally similar results by several different groups showing marginally worsened central nervous system (CNS) outcomes with RCP, it is unlikely that the results of a larger study would differ substantially. In none of these studies were stroke rate, mortality, or other measures of morbidity influenced by treatment mode, although all were underpowered to detect such outcomes. Conceptually, this is not different from the conclusions of Hagl and associates,5 who retrospectively analyzed outcomes in 717 survivors of ascending aortic and aortic arch surgery. They determined that the method of cerebral protection did not influence the occurrence of stroke but that ACP did result in a significant reduction in the incidence of temporary neurologic dysfunction, again a result not seen after RCP.
Given the conclusions of several clinically relevant experimental studies, these results are not entirely unexpected. Despite its conceptual attractiveness, RCP has not been demonstrated to result in clinically significant cerebral blood flow, even under conditions of hypothermia-induced lowered cerebral metabolism. In a primate study comparing HCA alone with HCA combined with RCP, Boeckxstaens and Flameng6 demonstrated that less than 1% of the RCP inflow returned to the aortic arch and that on histologic analysis slightly more glial edema was found in the RCP group. Similarly, during HCA in 14 swine, use of RCP or RCP with IVCO also resulted in negligible cerebral blood flows, and it was similarly observed that less than 13% of retrograde superior vena caval inflow blood returned to the aortic arch with either technique.7
Although it had been postulated that even if cerebral perfusion was minimal with RCP, perhaps enhanced brain cooling could be effected, there is minimal clinical evidence for this. In a study of 42 patients undergoing HCA and randomized to RCP or control therapy, Bonser and colleagues8 observed that postarrest nasopharyngeal temperature was similar between groups and that RCP did not affect postarrest oxygen extraction, glucose extraction, or jugular bulb oxygenation.
It does appear as though modified RCP might be effective in flushing emboli from the cerebral circulation, although at the cost of some mild cerebral ischemic damage. Juvonen and coworkers9 studied the effect on histologic and behavioral outcome of an interval of RCP with and without IVCO versus ACP control after cerebral arterial embolization in a chronic porcine model. Microsphere recovery from the brain revealed significantly fewer emboli after RCP with IVCO but demonstrated that significant mild ischemic damage occurred after RCP with IVCO, even in nonembolized animals, but not in the other groups. Behavioral scores by day 7 were considerably lower in all groups after embolization, with no significant differences between groups. Given the absence of improved behavioral scores and evidence of a greater prevalence of mild ischemic cerebral damage, it is thus unlikely that RCP with IVCO represents any clinically significant advantage for routine application during HCA, which is consistent with the current results.
What other factors might be at play? It has become clear that in addition to ischemia, reperfusion and gaseous and atheromatous cerebral emboli also have a variable and significant influence on CNS outcomes after HCA. The milieu in which HCA is conducted might well also have an important effect, but this has not yet been systematically investigated in adult patients. Although clinical studies and experimental evidence point to a benefit of pH-stat management in infants and children undergoing HCA, it should be noted that neither the clinical studies in pediatric patients10 nor the experimental models using nonatheromatous animals are necessarily relevant to the adult patient, who invariably has substantial atheromatous disease within the ascending aorta, often with concomitant extracranial and intracranial involvement. For adults at least undergoing moderate hypothermic cardiopulmonary bypass, the weight of evidence from CNS outcomes of at least 3 separate prospective randomized clinical trials supports alpha-stat pH management over pH-stat.11-13 In this context alpha-stat has also been associated with decreased cerebral embolization14 and preservation of cerebral autoregulation,12,13,15 factors likely of paramount importance in perioperative CNS injury in adult patients undergoing HCA.
It is unlikely that pH management will substantially change the results noted above, however, because the current study used alpha-stat management,1 whereas that of Reich and associates2 used pH-stat management, both with similar directional results relatively unfavorable to RCP. Whether pH management will influence the overall incidence of CNS dysfunction after HCA is unknown, however, so that until randomized prospective clinical trials assessing pH management during HCA in adults are conducted and reported, each team must use their own best-guess pH-management strategy on the basis of limited evidence and their own experience.
It should be noted that the use of ACP combined with HCA might offer some significant advantages, especially if the duration of HCA is to be prolonged. Although there have only been limited and equivocal prospective studies,4 there is suggestive evidence of benefit from Di Eusanio and colleagues16 on the basis of a retrospective review of 413 patients undergoing HCA with selective ACP. They demonstrated that even cerebral perfusion times of longer than 90 minutes were not associated with an increased risk of hospital mortality or poorer neurologic outcome, which is similar to the conclusions of Hagl and coworkers5 in patients undergoing HCA with selective ACP with total cerebral protection times of between 40 and 80 minutes. Again there is a need for prospective randomized studies to more rigorously evaluate HCA with ACP in the setting of prolonged HCA of greater than 40 minutes' duration. Perhaps the real message is that for shorter ischemic periods, there is no benefit and possibly some detriment to using RCP or even ACP during HCA. For cases in which more prolonged episodes are anticipated, however, use of selective ACP should be strongly considered.
As in the current report, meticulous clinical management with systemic hypothermia combined with topical cooling of the head, avoidance of cerebral hyperthermia during rewarming and in the immediate postoperative interval, maintenance of normal or even low normal perioperative blood glucose concentrations, and careful deairing of grafts and arteries, ideally with carbon dioxide flushing before reperfusion, all coupled with an expeditious surgical repair designed to minimize the duration of HCA should be the minimum acceptable standard of care. Further refinements, including clinical assessments of the role of hyperoxia, pH management, optimal hematocrit concentration, putative pharmacologic cerebroprotectants, and various anti-inflammatory and leukocyte suppression strategies are all awaited.
There is another benefit of the current study by Harrington and colleagues.1 They have demonstrated that it is eminently possible to perform a rigorous, well-conducted, and clinically relevant study in this challenging and high-risk patient group and that by using sensitive measures of CNS outcome, this does not require an inordinately large sample size. Furthermore, they have greatly facilitated subsequent studies by enabling the performance of a much more robust power analysis on the basis of their cognitive outcomes results to ensure an adequate sample size, an excellent contribution toward further optimizing clinical management for this complex patient group.
References
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