- Email: [email protected]
Is Retrograde Cerebral Perfusion an Effective Means of Neural Support During Deep Hypothermic Circulatory Arrest?
Is Retrograde Cerebral Perfusion an Effective Means of Neural Support During Deep Hypothermic Circulatory Arrest? Randall B. Griepp, MD, Tatu Juvonen, MD, PhD, Eva B. Griepp, MD, Jock N. McCollough, MD, and M. Arisan Ergin, MD, PhD Department of Cardiothoracic Surgery, Mount Sinai School of Medicine, New York, New York
A
s surgical mortality and morbidity from cardiac and aortic operations have steadily improved over the past decade, interest has increasingly been directed toward the cerebral sequelae of these operations. In adults, it has become apparent that focal embolic events are the most frequent cause of serious permanent neurologic morbidity and subsequent mortality, but that at least transient diffuse cerebral dysfunction occurs in a large proportion of patients [1, 2]. In children with congenital heart disease, in whom operation is now carried out most frequently in the neonatal period and often requires prolonged hypothermic circulatory arrest (HCA), disturbing evidence is accumulating that later intellectual function may be compromised [3]. The recognition that cerebral function after cardiac or aortic operations is frequently impaired at least transiently has led to reevaluation of techniques for cerebral protection, especially when the operation requires interruption of antegrade flow. A consensus has emerged that prolonged durations of HCA are a frequent risk factor for later cerebral dysfunction [3, 4], fueling a search for alternatives to HCA and for adjuncts that would increase its safety. Among these, retrograde cerebral perfusion (RCP) has become very popular and has been adopted for clinical use, especially in aortic surgery, despite the fact that very little convincing evidence exists to document either its efficacy or safety. Enthusiasm for RCP stems from its appeal as a possible way of reducing embolic injury in addition to its potential usefulness in improving cerebral protection during HCA. Although a number of clinical studies extol the virtues of RCP, many suffer from serious shortcomings: the typical report includes fewer than 50 patients, the majority of whom had RCP for short intervals, which should have resulted in a good outcome with HCA alone [5–10]. Although ostensibly evaluating cerebral protection, none of these studies involve formal psychometric evaluation, and most make no distinction between permanent and temporary neurologic dysfunction or between focal and diffuse cerebral injury: they simply cite the incidence of permanent neurologic damage and perhaps compare this with unmatched historical controls. But because most permanent neurologic injury after aortic operations is
Address reprint requests to Dr Randall B. Griepp, Department of Cardiothoracic Surgery, Mount Sinai Medical Center, One Gustave Levy Pl, New York, NY 10029.
© 1997 by The Society of Thoracic Surgeons Published by Elsevier Science Inc
focal in nature, and therefore is likely to be embolic in origin [1, 2], its occurrence is probably only marginally related to the adequacy of cerebral protection. This is in contrast with the relatively more frequent syndrome of prolonged postoperative obtundation and confusion, which rarely results in obvious permanent sequelae but is clearly more prevalent with longer durations of HCA [1, 2] and is therefore a much more sensitive and appropriate indicator of the extent of cerebral protection. The theoretical appeal of RCP and the failure of clinical studies to answer vital questions about its possible benefits and risks prompted us to undertake a series of laboratory investigations [11–13]. These studies have convinced us that although RCP has promise for improving cerebral outcome after HCA, there is also potential for harm associated with its use.
The Experimental Model One of the factors that has made it difficult to synthesize a clear picture of the physiology of RCP has been that the dog, traditionally the animal of choice for cardiac surgical studies, is not an ideal candidate for RCP: venous valves in the head and neck often preclude effective retrograde flow via the traditional superior vena caval (SVC) route. Some investigators have overcome this difficulty by using stratagems, such as maxillary vein cannulation, whose clinical relevance has been called into question [14 –21]; we, like several other groups, have elected to do our studies in the pig [11–13, 22–25], and still other investigations have been carried out in sheep [26], primates [27], and even humans [28, 29]. Unfortunately, like HCA, RCP may depend to a considerable extent for its success on exactly how it is implemented, and this makes it difficult to compare studies in different species using different routes of perfusion, different perfusion pressures, different types of perfusates, different temperatures, and different durations, to name but a few of the relevant factors. Another obstacle in making a unified whole from the results of disparate studies has been the use of different end points to judge whether or not retrograde perfusion has provided effective cerebral protection: the correlation among different process variables, such as levels of high-energy phosphates, cerebral oxygen content, and degree of cerebral edema, is uncertain, and their relationship to the preservation of neuronal integrity and Ann Thorac Surg 1997;64:913– 6 • 0003-4975/97/$17.00 PII S0003-4975(97)00745-5
914
OUTCOMES ’97 GRIEPP ET AL IS RCP EFFECTIVE DURING DHCA?
functional recovery is tenuous at best. In our studies [11–13], proof of efficacy has been based on several direct measures of outcome: behavioral and neurologic recovery over a period of 7 days postoperatively, electrophysiologic studies, and postmortem histology. We have also monitored physiologic variables such as temperature, flow, vascular resistance, oxygen consumption, and lactate production to help us understand the physiology of RCP, but have not relied on these metabolic data to establish its overall worth.
Ann Thorac Surg 1997;64:913– 6
Similarly, a neuropathologic study in dogs by Imamaki and associates [14] evaluated 120 minutes of HCA versus the same interval of RCP at 15°C and at 20°C. Cerebral histologic damage was more severe in the HCA group than with RCP at 15°C, but no worse than with RCP at 20°C: the temperature in the HCA group had drifted from 15°C to 20°C during the interval of interrupted antegrade flow. These results make clear that the small amount of metabolic support that can be provided by RCP is only meaningful at very low temperatures, when only minimal levels of metabolic activity are required.
Retrograde Cerebral Perfusion and Cerebral Protection
Retrograde Cerebral Perfusion and Embolism
In our initial study [12], we compared the outcome of 90 minutes of HCA in 4 groups of 6 pigs at 20°C: RCP was compared with selective antegrade perfusion, HCA, and HCA with the head packed in ice. Behavioral outcome was best in the group with continued antegrade perfusion and worst in the group that underwent HCA without the head packed in ice, but was equally good whether the animals underwent RCP or HCA with the head packed in ice. Histologic examination, however, showed a clear superiority of RCP over HCA, even when the head was packed in ice [12]. Flow and metabolic data revealed that only a very small proportion of retrograde flow was returned to the isolated aortic arch, and that this blood was significantly desaturated. It was also noted that the group with HCA alone had higher epidural temperatures at the end of the 90-minute interval than any of the other groups [12]. Taken together, these observations suggest that RCP provides some nutritive flow to the brain, and support the idea that cerebral outcome after prolonged HCA is slightly improved by RCP in a way that cannot be explained simply by the ability of RCP to assure maintenance of hypothermic temperature during HCA. In one of the earliest investigations of RCP, Crittenden and colleagues [26] had shown that retrograde perfusion was much less effective than antegrade perfusion when used for 2 hours at 15°C in sheep, and had no apparent benefit over HCA alone. Many subsequent studies have confirmed that the gap between the support of cerebral function provided by selective antegrade perfusion and what is provided by RCP is much larger than the difference between RCP and HCA [11–13, 22, 23, 25]. In the wake of these studies, claims regarding the magnitude of effective retrograde flow and its potential for enhancing cerebral protection have gradually become more modest [16, 18, 19, 30]. Recently, Deslauriers and colleagues [25] compared antegrade perfusion with RCP and HCA for 120 minutes at 15°C in pigs. Little or no histologic cerebral injury was seen with antegrade perfusion, and slightly but significantly less damage was found with RCP than with HCA in the total number of brain lesions, and specifically in injury to mesencephalic grey matter. The same authors [22] demonstrated that RCP for 2 hours at 28°C results in much more histologic damage than at 15°C, emphasizing the importance of deep hypothermia during RCP.
Our second study was undertaken to investigate the other possible benefit of RCP: to determine whether a short interval of RCP (25 minutes) would effectively wash out particulate emboli [13]. Although the overall statistics did not demonstrate that RCP after embolization was helpful, a detailed analysis showed that the treated animals fell into two distinct groups: those in which retrograde perfusion required high SVC pressures and those in which perfusion could be accomplished at lower SVC pressures. Among the animals perfused retrograde at low SVC pressures, some had excellent outcomes after embolization, but the combination of embolization and RCP at high SVC pressures was associated with a poor outcome [13]. The observation that RCP at high SVC pressures might be harmful after embolization led us to examine more carefully the methodology of retrograde perfusion, and forced us to consider the possibility that, at least under some circumstances, RCP might aggravate cerebral injury. In our third study, we compared the effectiveness of a 25-minute interval of RCP with and without inferior vena caval (IVC) occlusion in mitigating the damage from particulate embolization [11]. Retrograde cerebral perfusion with IVC occlusion left significantly fewer emboli lodged in the brain than either continued antegrade perfusion or RCP without IVC occlusion. The greater effectiveness of RCP when the IVC was snared was also evident from metabolic parameters such as oxygen extraction and lactate production. However, behavioral evaluation and histologic analysis did not show significantly improved outcome after embolization in the RCP group with IVC occlusion [11]. Careful scrutiny of the results showed that the group that underwent RCP with IVC occlusion without prior embolization had slower behavioral recovery and a worse histologic outcome than either of the other control groups. Electrophysiologic evidence of early recovery of brainstem evoked potentials followed by later diminution suggested that animals in which the IVC was occluded during RCP had suffered a postoperative rather than an intraoperative insult: a high level of fluid sequestration suggested that the problem might be due to cerebral edema [11]. If this interpretation is correct, then embolized animals treated with IVC occlusion during RCP may have failed to show improved recovery largely because the late development of cerebral edema masked
Ann Thorac Surg 1997;64:913– 6
the anticipated favorable impact of the successful removal of emboli. The pattern of distribution of histologic lesions in the various experimental groups supports the concept that the potential benefit of RCP was prevented from becoming significant by the superimposition of a distinct type of retroperfusion-related cerebral injury. Several other investigators have noted both the sequestration of blood that occurs during retrograde perfusion, particularly when the IVC is occluded [31], and the development of cerebral edema [15, 17, 20, 24]. Yoshimura and associates [21] measured intracranial pressure, cerebral blood flow and vascular resistance, glucose and oxygen extraction and metabolism, and brain water content in three groups of dogs during and after 120 minutes of RCP at 20°C: untreated controls, a group given a single dose of mannitol at the beginning of rewarming, and a third group treated with a continuous infusion of a free radical scavenger during reperfusion. In the untreated controls, intracranial pressure and cerebrovascular resistance rose significantly higher during reperfusion than in the treated groups, and brain water content was also significantly higher [21].
Conclusion Although RCP has been enthusiastically espoused by many aortic surgeons, most laboratory investigations have shown only a small improvement in cerebral outcome when RCP is compared with HCA for the same duration at the same temperature. The apparent superiority of RCP over HCA in a number of clinical and laboratory studies can probably be explained by the sustained cooling during prolonged HCA that is afforded by RCP, in contrast to the gradual upward drift of brain temperature that is almost inevitable with prolonged HCA unless the head is packed in ice [12, 14, 19]. Retrograde cerebral perfusion provides only a small percentage of the nutritive flow necessary to sustain cerebral metabolism at optimal levels even in the presence of moderate hypothermia [11–13, 16 –19, 30], and reliance on RCP for cerebral protection must therefore be limited to its use at the very low temperatures advocated for HCA, when metabolic demands are minimal, and for a similarly limited duration. A recent clinical analysis of 228 patients in Japan [32] has indicated that the risk of permanent neurologic injury increases abruptly when RCP duration exceeds 60 minutes. Retrograde cerebral perfusion may ultimately prove more useful for the mitigation of injury from particulate embolization than as a means of prolonging safe HCA, as indicated by the low rate of focal cerebral injury in some recent clinical reports [8, 33, 34]. In our own practice, the use of RCP is restricted to patients having loose atheromata in the aorta or other risk factors thought to make embolism very likely, but it has not thus far resulted in a dramatic reduction in permanent focal neurologic injury [2]. In the laboratory, truly effective RCP seems to require relatively high perfusion pressures or clamping of the IVC. These measures appear to increase the incidence of cerebral sequelae even in controls and may aggravate
OUTCOMES ’97 GRIEPP ET AL IS RCP EFFECTIVE DURING DHCA?
915
intraoperative cerebral insults, including damage from unremoved emboli. If retroperfusion-related cerebral injury is principally a consequence of the rapid development of cerebral edema, it may respond to aggressive pharmacologic intervention. Until the potential for benefit can be disentangled from the risk of producing or aggravating cerebral injury, however, RCP should be used sparingly and with caution.
References 1. Ergin MA, Galla JD, Lansman SL, et al. Hypothermic circulatory arrest in operations on the thoracic aorta: determinants of operative mortality and neurologic outcome. J Thorac Cardiovasc Surg 1994;107:788–99. 2. Ergin MA, Griepp EB, Lansman SL, et al. Hypothermic circulatory arrest and other methods of cerebral protection during operations on the thoracic aorta. J Card Surg 1994;9: 525–37. 3. Oates RK, Simpson JM, Turnbull JAB, Cartmill TB. The relationship between intelligence and duration of circulatory arrest with deep hypothermia. J Thorac Cardiovasc Surg 1995;110:786–92. 4. Svensson LG, Crawford ES, Hess KR, et al. Deep hypothermia with circulatory arrest: determinants of stroke and early mortality in 656 patients. J Thorac Cardiovasc Surg 1993;106: 19–31. 5. Bavaria JE, Woo YJ, Hall RA, Carpenter JP, Gardner TJ. Retrograde cerebral and distal aortic perfusion during ascending and thoracoabdominal aortic operations. Ann Thorac Surg 1995;60:345–53. 6. Deeb GM, Jenkins E, Bolling SF, et al. Retrograde cerebral perfusion during hypothermic circulatory arrest reduces neurologic morbidity. J Thorac Cardiovasc Surg 1995;109: 259– 68. 7. Kitamura M, Hashimoto A, Akimoto T, et al. Operation for type A dissection: introduction of retrograde cerebral perfusion. Ann Thorac Surg 1995;59:1195–9. 8. Kouchoukos NT. Adjuncts to reduce the incidence of embolic brain injury during operations on the aortic arch. Ann Thorac Surg 1994;57:243–5. 9. Lytle BW, McCarthy PM, Meaney KM, et al. Systemic hypothermia and circulatory arrest combined with arterial perfusion of the superior vena cava: effective intraoperative cerebral protection. J Thorac Cardiovasc Surg 1995;109: 738– 43. 10. Pagano D, Carey JA, Patel RL, et al. Retrograde cerebral perfusion: clinical experience in emergency and elective aortic operations. Ann Thorac Surg 1995;59:393–7. 11. Juvonen T, Weisz DJ, Wolfe D, et al. Can retrograde perfusion mitigate cerebral injury following particulate embolization? A study in a chronic porcine model. J Thorac Cardiovasc Surg (in press). 12. Midulla PS, Gandsas A, Sadeghi AM, et al. Comparison of retrograde cerebral perfusion to antegrade cerebral perfusion and hypothermic circulatory arrest in a chronic porcine model. J Card Surg 1994;9:560–75. 13. Yerlioghu ME, Wolfe D, Mezrow CK, et al. The effect of retrograde cerebral perfusion after particulate embolization to the brain. J Thorac Cardiovasc Surg 1995;110:1470– 85. 14. Imamaki M, Koyagani H, Hashimoto A, et al. Retrograde cerebral perfusion with hypothermic blood provides efficient protection of the brain: a neuropathologic study. J Card Surg 1995;10:325–33. 15. Nojima T, Magara T, Nakajima Y, et al. Optimal perfusion pressure for experimental retrograde cerebral perfusion. J Card Surg 1994;9:548–59. 16. Oohara K, Usui A, Murase M, Tanaka M, Abe T. Regional cerebral tissue blood flow measured by the colored microsphere method during retrograde cerebral perfusion. J Thorac Cardiovasc Surg 1995;109:772–9.
916
OUTCOMES ’97 GRIEPP ET AL IS RCP EFFECTIVE DURING DHCA?
17. Sakurada T, Kazui T, Tanaka H, Komatsu S. Comparative experimental study of cerebral protection during aortic arch reconstruction. Ann Thorac Surg 1996;61:1348–54. 18. Usui A, Oohara K, Liu T, et al. Determination of optimum retrograde cerebral perfusion conditions. J Thorac Cardiovasc Surg 1994;107:300– 8. 19. Usui A, Oohara K, Liu T, et al. Comparative experimental study between retrograde cerebral perfusion and circulatory arrest. J Thorac Cardiovasc Surg 1994;107:1228–36. 20. Watanabe T, Iijima Y, Abe K, et al. Retrograde brain perfusion beyond the venous valves: hemodynamics and intracellular pH mapping. J Thorac Cardiovasc Surg 1996;111:36– 44. 21. Yoshimura N, Okada M, Ota T, Nohara H. Pharmacologic intervention for ischemic brain edema after retrograde cerebral perfusion. J Thorac Cardiovasc Surg 1995;109:1173– 81. 22. Filgueiras CL, Ryner L, Ye J, et al. Cerebral protection during moderate hypothermic circulatory arrest: histopathology and magnetic resonance spectroscopy of brain energetics and intracellular pH in pigs. J Thorac Cardiovasc Surg 1996; 112:1073– 80. 23. Filgueiras CL, Winsborrow B, Ye J, et al. A 31-P-magnetic resonance study of antegrade and retrograde cerebral perfusion during aortic arch surgery in pigs. J Thorac Cardiovasc Surg 1995;110:55– 62. 24. Safi HJ, Iliopoulos DC, Gopinath SP, et al. Retrograde cerebral perfusion during profound hypothermia and circulatory arrest in pigs. Ann Thorac Surg 1995;59:1107–12. 25. Ye J, Yang L, DelBigio MR, et al. Neuronal damage after
Ann Thorac Surg 1997;64:913– 6
26. 27. 28. 29. 30. 31. 32. 33. 34.
hypothermic circulatory arrest and retrograde cerebral perfusion in the pig. Ann Thorac Surg 1996;61:1316–22. Crittenden MD, Roberts CS, Rosa L, et al. Brain protection during circulatory arrest. Ann Thorac Surg 1991;51:942–7. Boeckxstaens CJ, Flameng WJ. Retrograde cerebral perfusion does not perfuse the brain in nonhuman primates. Ann Thorac Surg 1995;60:319–28. De Brux JL, Subayi J-B, Pegis JD, Pillet J. Retrograde cerebral perfusion: anatomic study of the distribution of blood to the brain. Ann Thorac Surg 1995;60:1294– 8. Pagano D, Boivin CM, Faroqui MH, Bonser RS. Retrograde perfusion through the superior vena cava perfuses the brain in human beings. J Thorac Cardiovasc Surg 1996;111:270–2. Fukae K, Nakashima A, Hisahara M, et al. Maldistribution of the cerebral blood flow in retrograde cerebral perfusion. Eur J Cardiothorac Surg 1995;9:496 –501. Shima N, Hatanaka T, Fukui M, et al. Oxygen transport and hemodynamics during retrograde whole body perfusion. J Cardiothorac Vasc Anesth 1995;9:164–7. Usui A, Abe T, Murase M. Early clinical results of retrograde cerebral perfusion for aortic arch operations in Japan. Ann Thorac Surg 1996;62:94 –104. Coselli JS, Buket S, Djukanovic B. Aortic arch operations: current treatment and results. Ann Thorac Surg 1995;59: 19–27. Raskin SA, Fuselier VW, Reeves-Viets JL, Coselli JS. Deep hypothermic circulatory arrest with and without retrograde cerebral perfusion. Int Anesthesiol Clin 1996;34:177–93.
A
s surgical mortality and morbidity from cardiac and aortic operations have steadily improved over the past decade, interest has increasingly been directed toward the cerebral sequelae of these operations. In adults, it has become apparent that focal embolic events are the most frequent cause of serious permanent neurologic morbidity and subsequent mortality, but that at least transient diffuse cerebral dysfunction occurs in a large proportion of patients [1, 2]. In children with congenital heart disease, in whom operation is now carried out most frequently in the neonatal period and often requires prolonged hypothermic circulatory arrest (HCA), disturbing evidence is accumulating that later intellectual function may be compromised [3]. The recognition that cerebral function after cardiac or aortic operations is frequently impaired at least transiently has led to reevaluation of techniques for cerebral protection, especially when the operation requires interruption of antegrade flow. A consensus has emerged that prolonged durations of HCA are a frequent risk factor for later cerebral dysfunction [3, 4], fueling a search for alternatives to HCA and for adjuncts that would increase its safety. Among these, retrograde cerebral perfusion (RCP) has become very popular and has been adopted for clinical use, especially in aortic surgery, despite the fact that very little convincing evidence exists to document either its efficacy or safety. Enthusiasm for RCP stems from its appeal as a possible way of reducing embolic injury in addition to its potential usefulness in improving cerebral protection during HCA. Although a number of clinical studies extol the virtues of RCP, many suffer from serious shortcomings: the typical report includes fewer than 50 patients, the majority of whom had RCP for short intervals, which should have resulted in a good outcome with HCA alone [5–10]. Although ostensibly evaluating cerebral protection, none of these studies involve formal psychometric evaluation, and most make no distinction between permanent and temporary neurologic dysfunction or between focal and diffuse cerebral injury: they simply cite the incidence of permanent neurologic damage and perhaps compare this with unmatched historical controls. But because most permanent neurologic injury after aortic operations is
Address reprint requests to Dr Randall B. Griepp, Department of Cardiothoracic Surgery, Mount Sinai Medical Center, One Gustave Levy Pl, New York, NY 10029.
© 1997 by The Society of Thoracic Surgeons Published by Elsevier Science Inc
focal in nature, and therefore is likely to be embolic in origin [1, 2], its occurrence is probably only marginally related to the adequacy of cerebral protection. This is in contrast with the relatively more frequent syndrome of prolonged postoperative obtundation and confusion, which rarely results in obvious permanent sequelae but is clearly more prevalent with longer durations of HCA [1, 2] and is therefore a much more sensitive and appropriate indicator of the extent of cerebral protection. The theoretical appeal of RCP and the failure of clinical studies to answer vital questions about its possible benefits and risks prompted us to undertake a series of laboratory investigations [11–13]. These studies have convinced us that although RCP has promise for improving cerebral outcome after HCA, there is also potential for harm associated with its use.
The Experimental Model One of the factors that has made it difficult to synthesize a clear picture of the physiology of RCP has been that the dog, traditionally the animal of choice for cardiac surgical studies, is not an ideal candidate for RCP: venous valves in the head and neck often preclude effective retrograde flow via the traditional superior vena caval (SVC) route. Some investigators have overcome this difficulty by using stratagems, such as maxillary vein cannulation, whose clinical relevance has been called into question [14 –21]; we, like several other groups, have elected to do our studies in the pig [11–13, 22–25], and still other investigations have been carried out in sheep [26], primates [27], and even humans [28, 29]. Unfortunately, like HCA, RCP may depend to a considerable extent for its success on exactly how it is implemented, and this makes it difficult to compare studies in different species using different routes of perfusion, different perfusion pressures, different types of perfusates, different temperatures, and different durations, to name but a few of the relevant factors. Another obstacle in making a unified whole from the results of disparate studies has been the use of different end points to judge whether or not retrograde perfusion has provided effective cerebral protection: the correlation among different process variables, such as levels of high-energy phosphates, cerebral oxygen content, and degree of cerebral edema, is uncertain, and their relationship to the preservation of neuronal integrity and Ann Thorac Surg 1997;64:913– 6 • 0003-4975/97/$17.00 PII S0003-4975(97)00745-5
914
OUTCOMES ’97 GRIEPP ET AL IS RCP EFFECTIVE DURING DHCA?
functional recovery is tenuous at best. In our studies [11–13], proof of efficacy has been based on several direct measures of outcome: behavioral and neurologic recovery over a period of 7 days postoperatively, electrophysiologic studies, and postmortem histology. We have also monitored physiologic variables such as temperature, flow, vascular resistance, oxygen consumption, and lactate production to help us understand the physiology of RCP, but have not relied on these metabolic data to establish its overall worth.
Ann Thorac Surg 1997;64:913– 6
Similarly, a neuropathologic study in dogs by Imamaki and associates [14] evaluated 120 minutes of HCA versus the same interval of RCP at 15°C and at 20°C. Cerebral histologic damage was more severe in the HCA group than with RCP at 15°C, but no worse than with RCP at 20°C: the temperature in the HCA group had drifted from 15°C to 20°C during the interval of interrupted antegrade flow. These results make clear that the small amount of metabolic support that can be provided by RCP is only meaningful at very low temperatures, when only minimal levels of metabolic activity are required.
Retrograde Cerebral Perfusion and Cerebral Protection
Retrograde Cerebral Perfusion and Embolism
In our initial study [12], we compared the outcome of 90 minutes of HCA in 4 groups of 6 pigs at 20°C: RCP was compared with selective antegrade perfusion, HCA, and HCA with the head packed in ice. Behavioral outcome was best in the group with continued antegrade perfusion and worst in the group that underwent HCA without the head packed in ice, but was equally good whether the animals underwent RCP or HCA with the head packed in ice. Histologic examination, however, showed a clear superiority of RCP over HCA, even when the head was packed in ice [12]. Flow and metabolic data revealed that only a very small proportion of retrograde flow was returned to the isolated aortic arch, and that this blood was significantly desaturated. It was also noted that the group with HCA alone had higher epidural temperatures at the end of the 90-minute interval than any of the other groups [12]. Taken together, these observations suggest that RCP provides some nutritive flow to the brain, and support the idea that cerebral outcome after prolonged HCA is slightly improved by RCP in a way that cannot be explained simply by the ability of RCP to assure maintenance of hypothermic temperature during HCA. In one of the earliest investigations of RCP, Crittenden and colleagues [26] had shown that retrograde perfusion was much less effective than antegrade perfusion when used for 2 hours at 15°C in sheep, and had no apparent benefit over HCA alone. Many subsequent studies have confirmed that the gap between the support of cerebral function provided by selective antegrade perfusion and what is provided by RCP is much larger than the difference between RCP and HCA [11–13, 22, 23, 25]. In the wake of these studies, claims regarding the magnitude of effective retrograde flow and its potential for enhancing cerebral protection have gradually become more modest [16, 18, 19, 30]. Recently, Deslauriers and colleagues [25] compared antegrade perfusion with RCP and HCA for 120 minutes at 15°C in pigs. Little or no histologic cerebral injury was seen with antegrade perfusion, and slightly but significantly less damage was found with RCP than with HCA in the total number of brain lesions, and specifically in injury to mesencephalic grey matter. The same authors [22] demonstrated that RCP for 2 hours at 28°C results in much more histologic damage than at 15°C, emphasizing the importance of deep hypothermia during RCP.
Our second study was undertaken to investigate the other possible benefit of RCP: to determine whether a short interval of RCP (25 minutes) would effectively wash out particulate emboli [13]. Although the overall statistics did not demonstrate that RCP after embolization was helpful, a detailed analysis showed that the treated animals fell into two distinct groups: those in which retrograde perfusion required high SVC pressures and those in which perfusion could be accomplished at lower SVC pressures. Among the animals perfused retrograde at low SVC pressures, some had excellent outcomes after embolization, but the combination of embolization and RCP at high SVC pressures was associated with a poor outcome [13]. The observation that RCP at high SVC pressures might be harmful after embolization led us to examine more carefully the methodology of retrograde perfusion, and forced us to consider the possibility that, at least under some circumstances, RCP might aggravate cerebral injury. In our third study, we compared the effectiveness of a 25-minute interval of RCP with and without inferior vena caval (IVC) occlusion in mitigating the damage from particulate embolization [11]. Retrograde cerebral perfusion with IVC occlusion left significantly fewer emboli lodged in the brain than either continued antegrade perfusion or RCP without IVC occlusion. The greater effectiveness of RCP when the IVC was snared was also evident from metabolic parameters such as oxygen extraction and lactate production. However, behavioral evaluation and histologic analysis did not show significantly improved outcome after embolization in the RCP group with IVC occlusion [11]. Careful scrutiny of the results showed that the group that underwent RCP with IVC occlusion without prior embolization had slower behavioral recovery and a worse histologic outcome than either of the other control groups. Electrophysiologic evidence of early recovery of brainstem evoked potentials followed by later diminution suggested that animals in which the IVC was occluded during RCP had suffered a postoperative rather than an intraoperative insult: a high level of fluid sequestration suggested that the problem might be due to cerebral edema [11]. If this interpretation is correct, then embolized animals treated with IVC occlusion during RCP may have failed to show improved recovery largely because the late development of cerebral edema masked
Ann Thorac Surg 1997;64:913– 6
the anticipated favorable impact of the successful removal of emboli. The pattern of distribution of histologic lesions in the various experimental groups supports the concept that the potential benefit of RCP was prevented from becoming significant by the superimposition of a distinct type of retroperfusion-related cerebral injury. Several other investigators have noted both the sequestration of blood that occurs during retrograde perfusion, particularly when the IVC is occluded [31], and the development of cerebral edema [15, 17, 20, 24]. Yoshimura and associates [21] measured intracranial pressure, cerebral blood flow and vascular resistance, glucose and oxygen extraction and metabolism, and brain water content in three groups of dogs during and after 120 minutes of RCP at 20°C: untreated controls, a group given a single dose of mannitol at the beginning of rewarming, and a third group treated with a continuous infusion of a free radical scavenger during reperfusion. In the untreated controls, intracranial pressure and cerebrovascular resistance rose significantly higher during reperfusion than in the treated groups, and brain water content was also significantly higher [21].
Conclusion Although RCP has been enthusiastically espoused by many aortic surgeons, most laboratory investigations have shown only a small improvement in cerebral outcome when RCP is compared with HCA for the same duration at the same temperature. The apparent superiority of RCP over HCA in a number of clinical and laboratory studies can probably be explained by the sustained cooling during prolonged HCA that is afforded by RCP, in contrast to the gradual upward drift of brain temperature that is almost inevitable with prolonged HCA unless the head is packed in ice [12, 14, 19]. Retrograde cerebral perfusion provides only a small percentage of the nutritive flow necessary to sustain cerebral metabolism at optimal levels even in the presence of moderate hypothermia [11–13, 16 –19, 30], and reliance on RCP for cerebral protection must therefore be limited to its use at the very low temperatures advocated for HCA, when metabolic demands are minimal, and for a similarly limited duration. A recent clinical analysis of 228 patients in Japan [32] has indicated that the risk of permanent neurologic injury increases abruptly when RCP duration exceeds 60 minutes. Retrograde cerebral perfusion may ultimately prove more useful for the mitigation of injury from particulate embolization than as a means of prolonging safe HCA, as indicated by the low rate of focal cerebral injury in some recent clinical reports [8, 33, 34]. In our own practice, the use of RCP is restricted to patients having loose atheromata in the aorta or other risk factors thought to make embolism very likely, but it has not thus far resulted in a dramatic reduction in permanent focal neurologic injury [2]. In the laboratory, truly effective RCP seems to require relatively high perfusion pressures or clamping of the IVC. These measures appear to increase the incidence of cerebral sequelae even in controls and may aggravate
OUTCOMES ’97 GRIEPP ET AL IS RCP EFFECTIVE DURING DHCA?
915
intraoperative cerebral insults, including damage from unremoved emboli. If retroperfusion-related cerebral injury is principally a consequence of the rapid development of cerebral edema, it may respond to aggressive pharmacologic intervention. Until the potential for benefit can be disentangled from the risk of producing or aggravating cerebral injury, however, RCP should be used sparingly and with caution.
References 1. Ergin MA, Galla JD, Lansman SL, et al. Hypothermic circulatory arrest in operations on the thoracic aorta: determinants of operative mortality and neurologic outcome. J Thorac Cardiovasc Surg 1994;107:788–99. 2. Ergin MA, Griepp EB, Lansman SL, et al. Hypothermic circulatory arrest and other methods of cerebral protection during operations on the thoracic aorta. J Card Surg 1994;9: 525–37. 3. Oates RK, Simpson JM, Turnbull JAB, Cartmill TB. The relationship between intelligence and duration of circulatory arrest with deep hypothermia. J Thorac Cardiovasc Surg 1995;110:786–92. 4. Svensson LG, Crawford ES, Hess KR, et al. Deep hypothermia with circulatory arrest: determinants of stroke and early mortality in 656 patients. J Thorac Cardiovasc Surg 1993;106: 19–31. 5. Bavaria JE, Woo YJ, Hall RA, Carpenter JP, Gardner TJ. Retrograde cerebral and distal aortic perfusion during ascending and thoracoabdominal aortic operations. Ann Thorac Surg 1995;60:345–53. 6. Deeb GM, Jenkins E, Bolling SF, et al. Retrograde cerebral perfusion during hypothermic circulatory arrest reduces neurologic morbidity. J Thorac Cardiovasc Surg 1995;109: 259– 68. 7. Kitamura M, Hashimoto A, Akimoto T, et al. Operation for type A dissection: introduction of retrograde cerebral perfusion. Ann Thorac Surg 1995;59:1195–9. 8. Kouchoukos NT. Adjuncts to reduce the incidence of embolic brain injury during operations on the aortic arch. Ann Thorac Surg 1994;57:243–5. 9. Lytle BW, McCarthy PM, Meaney KM, et al. Systemic hypothermia and circulatory arrest combined with arterial perfusion of the superior vena cava: effective intraoperative cerebral protection. J Thorac Cardiovasc Surg 1995;109: 738– 43. 10. Pagano D, Carey JA, Patel RL, et al. Retrograde cerebral perfusion: clinical experience in emergency and elective aortic operations. Ann Thorac Surg 1995;59:393–7. 11. Juvonen T, Weisz DJ, Wolfe D, et al. Can retrograde perfusion mitigate cerebral injury following particulate embolization? A study in a chronic porcine model. J Thorac Cardiovasc Surg (in press). 12. Midulla PS, Gandsas A, Sadeghi AM, et al. Comparison of retrograde cerebral perfusion to antegrade cerebral perfusion and hypothermic circulatory arrest in a chronic porcine model. J Card Surg 1994;9:560–75. 13. Yerlioghu ME, Wolfe D, Mezrow CK, et al. The effect of retrograde cerebral perfusion after particulate embolization to the brain. J Thorac Cardiovasc Surg 1995;110:1470– 85. 14. Imamaki M, Koyagani H, Hashimoto A, et al. Retrograde cerebral perfusion with hypothermic blood provides efficient protection of the brain: a neuropathologic study. J Card Surg 1995;10:325–33. 15. Nojima T, Magara T, Nakajima Y, et al. Optimal perfusion pressure for experimental retrograde cerebral perfusion. J Card Surg 1994;9:548–59. 16. Oohara K, Usui A, Murase M, Tanaka M, Abe T. Regional cerebral tissue blood flow measured by the colored microsphere method during retrograde cerebral perfusion. J Thorac Cardiovasc Surg 1995;109:772–9.
916
OUTCOMES ’97 GRIEPP ET AL IS RCP EFFECTIVE DURING DHCA?
17. Sakurada T, Kazui T, Tanaka H, Komatsu S. Comparative experimental study of cerebral protection during aortic arch reconstruction. Ann Thorac Surg 1996;61:1348–54. 18. Usui A, Oohara K, Liu T, et al. Determination of optimum retrograde cerebral perfusion conditions. J Thorac Cardiovasc Surg 1994;107:300– 8. 19. Usui A, Oohara K, Liu T, et al. Comparative experimental study between retrograde cerebral perfusion and circulatory arrest. J Thorac Cardiovasc Surg 1994;107:1228–36. 20. Watanabe T, Iijima Y, Abe K, et al. Retrograde brain perfusion beyond the venous valves: hemodynamics and intracellular pH mapping. J Thorac Cardiovasc Surg 1996;111:36– 44. 21. Yoshimura N, Okada M, Ota T, Nohara H. Pharmacologic intervention for ischemic brain edema after retrograde cerebral perfusion. J Thorac Cardiovasc Surg 1995;109:1173– 81. 22. Filgueiras CL, Ryner L, Ye J, et al. Cerebral protection during moderate hypothermic circulatory arrest: histopathology and magnetic resonance spectroscopy of brain energetics and intracellular pH in pigs. J Thorac Cardiovasc Surg 1996; 112:1073– 80. 23. Filgueiras CL, Winsborrow B, Ye J, et al. A 31-P-magnetic resonance study of antegrade and retrograde cerebral perfusion during aortic arch surgery in pigs. J Thorac Cardiovasc Surg 1995;110:55– 62. 24. Safi HJ, Iliopoulos DC, Gopinath SP, et al. Retrograde cerebral perfusion during profound hypothermia and circulatory arrest in pigs. Ann Thorac Surg 1995;59:1107–12. 25. Ye J, Yang L, DelBigio MR, et al. Neuronal damage after
Ann Thorac Surg 1997;64:913– 6
26. 27. 28. 29. 30. 31. 32. 33. 34.
hypothermic circulatory arrest and retrograde cerebral perfusion in the pig. Ann Thorac Surg 1996;61:1316–22. Crittenden MD, Roberts CS, Rosa L, et al. Brain protection during circulatory arrest. Ann Thorac Surg 1991;51:942–7. Boeckxstaens CJ, Flameng WJ. Retrograde cerebral perfusion does not perfuse the brain in nonhuman primates. Ann Thorac Surg 1995;60:319–28. De Brux JL, Subayi J-B, Pegis JD, Pillet J. Retrograde cerebral perfusion: anatomic study of the distribution of blood to the brain. Ann Thorac Surg 1995;60:1294– 8. Pagano D, Boivin CM, Faroqui MH, Bonser RS. Retrograde perfusion through the superior vena cava perfuses the brain in human beings. J Thorac Cardiovasc Surg 1996;111:270–2. Fukae K, Nakashima A, Hisahara M, et al. Maldistribution of the cerebral blood flow in retrograde cerebral perfusion. Eur J Cardiothorac Surg 1995;9:496 –501. Shima N, Hatanaka T, Fukui M, et al. Oxygen transport and hemodynamics during retrograde whole body perfusion. J Cardiothorac Vasc Anesth 1995;9:164–7. Usui A, Abe T, Murase M. Early clinical results of retrograde cerebral perfusion for aortic arch operations in Japan. Ann Thorac Surg 1996;62:94 –104. Coselli JS, Buket S, Djukanovic B. Aortic arch operations: current treatment and results. Ann Thorac Surg 1995;59: 19–27. Raskin SA, Fuselier VW, Reeves-Viets JL, Coselli JS. Deep hypothermic circulatory arrest with and without retrograde cerebral perfusion. Int Anesthesiol Clin 1996;34:177–93.