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Ann Thorac Surg 1995;59:1359-1362
© 1995 The Society of Thoracic Surgeons
Cardiothoracic Surgery Unit, Hammersmith Hospital, London, United Kingdom
Successful intracardiac surgery was first carried out in the early 1920s by Souttar. In his report of his first case [1], he stressed the danger to the brain of the surgical techniques involved. Approximately 35 years ago, Tufo and associates [2] studied 100 cardiac surgical patients and found new signs of stroke in 6% of them.
Approximately 20 years ago in Sweden, Åberg [3] carried out his fundamental studies on the neuropsychologic consequences of cardiopulmonary bypass. His work again stimulated attention 10 years later when journalists of the Sunday Times, a national newspaper printed in the United Kingdom, wrote as a major headline ``Surgeons pinpoint brain risks to heart patients.'' This roused in me a research interest in this field that has continued to this day.
It is instructive to consider whether the intense research activity relating to the problem of cerebral damage caused by cardiac surgery carried out in the past decade by groups from all over the world has produced major changes in practice with significant reduction in the neurologic and neuropsychologic consequences of cardiopulmonary bypass. It is also instructive to consider the possible future efforts that may be made to further understand and possibly reduce these complications.
Research Into Practice?
The overwhelming neurologic complication of coma (in the absence of sedation) after a cardiac operation with cardiopulmonary bypass is much rarer today than in the early years of cardiac surgery. At that time, coma was uniformly associated with a poor prognosis and tended to occur because of a major bypass catastrophe [4, 5]. Today, central nervous dysfunction after a cardiac surgical procedure can be divided into two major types: stroke and neuropsychologic deficit. I will not consider the neuropsychiatric effects of major heart surgery in this short presentation.
The incidence of stroke after a cardiac operation with cardiopulmonary bypass is well known. In 1985, Shaw and colleagues [6] published data showing that among 418 patients studied, the serious stroke rate was approximately 2%. In the early 1980s, many authors, among them Breuer [7], Bojar [8], Coffey [9], Gardner [10], and their colleagues, had reported this finding. More recently Lynn and associates [11] presented a review of 1,000 patients who had undergone coronary artery bypass grafting. They noted a postoperative serious stroke rate of approximately 2.7%.
Has the incidence of major stroke after a cardiac procedure decreased in the last 10 years? The answer is probably no. While obtaining a consent from patients for a cardiac operation, most surgeons would still, I believe, quote a stroke risk of approximately 2%. This has been unchanged for many years. This stroke risk, however, is not an obligatory one that surgeons can do nothing about. Most cases of stroke after a cardiac surgical intervention with cardiopulmonary bypass are due to macroemboli, usually particulate and usually atheromatous or calcific in nature. These emboli can be associated with the aorta or a calcified disorganized valve. Some strokes are due to macroemboli associated with clot that may be attached to the left ventricular surface after a myocardial infarction or associated in the left atrium with mitral valve disease. Other strokes are associated with air emboli, as in cases where the cardiac chambers are opened and vigorous deairing has not successfully removed them at the end of the procedure. Strokes from air emboli are often less severe and more transitory than those from particulate emboli.
At the Hammersmith Hospital for approximately the last 18 months, we have been recording on computers all complications as they happen during the hospital stay or at the outpatient appointment. Analysis shows that my colleagues and I have carried out 710 first-time coronary artery bypass graft operations in this period with 6 patients sustaining a stroke (0.8%). This rate is at the lower end of the spectrum of stroke rates after coronary artery bypass grafting. It is probably due to a policy of minimum clamping of the aorta and minimum handling of the heart involving little use of vents and suction.
Stroke rate can be reduced to less than 1%. Whether it can be reduced further is a matter of conjecture at this time. High-risk patients should be identified. Advancing age is probably the greatest risk factor for stroke during a cardiac operation. Identification of the patient who has a particularly atheromatous calcific aorta or clot in the left ventricle or left atrium or indeed carotid stenosis should enable one to formulate preoperative strategies to minimize risk in these known high risk patients.
Neuropsychologic impairment after cardiac surgical intervention is a more complex issue. Surgeons without expertise in neuropsychologic assessment have difficulty making judgments as to whether the neuropsychologic test battery chosen is appropriate and whether the chosen method of scoring the test battery is relevant and apposite. Whether the deficit demonstrated in the chosen test battery is major often appears to be an arbitrary assessment. Surgeons tend to ask whether in daily life, the patient is in any way demonstrating a disability or whether the family has noticed a disability that interferes with his or her function either in terms of employment or social environment.
The amount of neuropsychologic impairment found after a cardiac procedure has varied enormously in published series. In fact, an incidence anywhere between 0% and 79% can be found depending on which report one reads. Much attention has been given to the problems of methodology and the measurement of neuropsychologic impairment. It appears that even today there is no consistency in the methods, the statistical analysis carried out, and the results of neuropsychologic test batteries used by various research groups. Judgment as to whether there has been a change or an overall reduction in intellectual impairment after cardiopulmonary bypass in cardiac surgery units over the last 10 years is therefore difficult to make. It must be borne in mind that results of this kind of investigation are often being published by units with a long history of an interest in cerebral dysfunction after cardiac operations with surgeons who are extremely aware of the problem. The groups publishing tend to have the best results possible because they have an interest in that field.
Initial large studies of the effect of cardiac surgery on intellectual function were first published by Gilberstadt and Sako [12] in 1967. Similarly Tufo and associates [2] in 1970 and Lee and co-workers [13] in 1972 confirmed significant neuropsychologic deficit after cardiac operations. At this time, Frank and colleagues [14] confounded the previous results by showing improvement in all measured areas of intellectual function 6 months after cardiac surgical intervention. In 1982, Savageau and associates [15] showed impairment in 19% of 227 cardiac surgical patients studied. A few years later, Shaw and co-workers [16] found that 31% of 259 patients were impaired neuropsychologically 6 months after a cardiac operation, and Venn's group [17] in London showed that 35% of a smaller group of patients had a major deficit 1 year postoperatively.
In 1989, Townes and colleagues [18] in Seattle, WA, published their findings of neurobehavioral outcome after cardiac operations. Their prospective, controlled study included 65 patients undergoing coronary artery bypass grafting, 25 patients undergoing intracardiac operations with cardiopulmonary bypass, and 47 nonsurgical controls. The authors wrote that ``the finding of improved patient performance over pre-test levels at follow up evaluation suggested the absence of any overall long term negative influence of cardiac surgery on mental functioning.''
Although it can be appreciated that there can be major methodological questions raised by this study, it is quoted extensively by surgeons. The consequences of neuropsychologic impairment to the average cardiac surgeon without an interest in this field are, I think, of less importance than other major morbidity. There is a general belief that it is not a critical long-term problem. The risk factors that surgeons might identify are again, I think, largely those of increasing age and, possibly, increasing cardiopulmonary bypass time. The conduct of bypass and the bypass equipment do affect the incidence of measured neuropsychologic deficit after cardiac surgical interventions. Venn and his group [19] have shown that alpha-stat management is beneficial compared with the pH-stat strategy, and Pugsley and co-workers [20] have demonstrated the benefit of a filter. The evidence supporting the use of a membrane oxygenator versus a bubble oxygenator in terms of neuropsychologic morbidity is less strong, though there are extremely good data on the benefit of a membrane oxygenator when one considers the work carried out by Blauth and colleagues [21]. Heparin-coated bypass equipment and cerebroprotective drugs await further investigation with respect to their efficacy in reducing neuropsychologic morbidity.
The Future
Much work still remains to be done in terms of the mechanisms of cerebral damage during cardiopulmonary bypass and most importantly in the further development of strategies to reduce this damage once it has occurred. Currently, three important research fields are being productively investigated in many institutions. Imaging, particularly positron emission tomography and spectroscopy, will be very useful in assessing the effectiveness of various strategies to reduce cerebral dysfunction after cardiopulmonary bypass.
Inflammatory Response to Cardiopulmonary Bypass
In recent work from the Royal Postgraduate Medical School [22] in London, cerebral magnetic resonance images obtained within 1 hour to 2 hours after cardiopulmonary bypass for routine coronary artery bypass grafting revealed extremely edematous brain tissue essentially in all patients; the condition later resolved. It is well known that cardiopulmonary bypass produces a whole-body inflammatory response, which can lead to multiorgan injury. It particularly involves complement activation with activation of the coagulation pathways, the fibrinolytic and kallikrein cascade, and neutrophils with degranulation and protease enzyme release, oxygen radical formation, and synthesis of various cytokines [23, 24].
Especially in the lung and the intestinal tract, these mechanisms have been shown to be associated with disruption of normal membrane physiology and biochemistry with the increased capillary permeability and accumulation of interstitial fluid with organ dysfunction. It is reasonable to assume that the brain is at least to some extent affected by this general systemic inflammatory response in the body during cardiopulmonary bypass and that this in some way is involved in the cerebral dysfunction after a cardiac operation. This panendothelial injury consequent to wide-ranging humoral and cellular activation during cardiopulmonary bypass can be reduced by the use of broad-spectrum antiinflammatory agents such as aprotinin (a protease inhibitor), which has been shown to be effective in similar situations, eg, in the septic syndrome. Other protease inhibitors are being investigated at this time in this field [25].
Normothermic Cardiopulmonary Bypass
Many units are now using true normothermic cardiopulmonary bypass during cardiac operations. They do so because of the noted hemodynamic stability during normothermic cardiopulmonary bypass with the persistent low systemic vascular resistance associated with a high cardiac output in the early postoperative period associated with less acidosis, less use of sodium bicarbonate, and less use of postoperative intravenous fluid, inotropic agents, and vasodilators. It is likely that blood loss and coagulopathy are less after normothermic cardiopulmonary bypass, as is capillary leakage. It has been well shown that hypothermia per se is protective of the brain, which is injured particularly by ischemic damage. If cerebral damage can be reduced to low levels by addressing its causes, then the advantages of normothermic bypass in terms of overall patient well-being are considerable, as there are many disadvantages to hypothermia and rewarming (particularly if it is relatively rapid).
There is conflicting evidence as to the incidence of neurologic deficit after cardiopulmonary bypass conducted at either normothermia or hypothermia. In a 1994 report, Martin and associates [26] randomized 1,001 patients to normothermia, which was greater than 35°C, and hypothermia, which was less than or equal to 28°C. The incidence of stroke was higher in the warm group than in the cold group (3.1% versus 1%). However, also in 1994, the Warm Heart Investigators [27] reported the results of a trial involving 1,732 patients randomized to normothermia or hypothermia; there was no difference in the stroke rate between the two groups. In an ongoing study at the Royal Postgraduate Medical School, I have operated on 39 patients with true normothermic bypass (37° or 38°C). To date, there has been no incidence of stroke. Indeed, a colleague tells me that among his last 220 patients randomized to normothermic or hypothermic cardiopulmonary bypass, there was no difference in stroke rate between the two groups; it was 2.1% for the normothermic patients and 1.8% for the hypothermic group.
In 1992, Engelman [28] even suggested that normothermic patients do better in terms of subclinical neurologic outcome. He thought that the increase in cerebral dysfunction after hypothermic cardiopulmonary bypass could be due to reperfusion injury.
Much of the work detailing the protective effect of hypothermia on the brain relates particularly to ischemic injury. It is likely that brain injury in cardiopulmonary bypass is only partly ischemic, and therefore hypothermia could actually be damaging by enhancing the biochemical and physiologic abnormalities associated with the widespread inflammatory response and vascular abnormalities seen during bypass.
Cerebroprotective Drugs
Cerebral injury caused by cardiopulmonary bypass has a multifactorial etiology. Although much of the injury may be ischemic in origin, possibly associated with hypoperfusion or emboli, some may also be associated with a general inflammatory response, release of vasoactive substances causing endothelial damage and generalized damage to the membrane physiology within the brain. There are therefore many ways in which possible cerebroprotective drugs can act. Both sodium thiopental and propofol have been investigated as possible cerebroprotective agents, presumably having their major effect by reducing cerebral metabolic rate. Nussmeier and Fish [29] have demonstrated an improved psychologic outcome after normothermic cardiopulmonary bypass in patients given thiopental. Calcium-channel blockers such as nimodipine, which has a potent dilating effect on the cerebral vasculature, have been investigated in a cerebroprotective capacity. Improvements in neurologic status have been shown in stroke patients after the use of this drug [30]. Prostacyclins have also been investigated but probably have no place in the prevention of the neurologic and neuropsychologic sequelae of cardiopulmonary bypass [31].
More recently, several new groups of cerebroprotective agents have received attention. Glutamate is neurotoxic, and cerebral ischemia results in a massive increase in extracellular glutamate concentration. It is an excitatory neural transmittor. If glutamate receptors are blocked, eg, with an NMDA antagonist, less cerebral neuronal ischemic damage results [32, 33]. Dizocilpine (MK801), a specific N-methyl-D-aspartate glutamate receptor antagonist, has been shown to be directly neuroprotective in terms of both neurologic function and neurologic injury in a group of dogs studied by Redmond and colleagues [34].
Many other classes of drugs have been used in an attempt to reduce the cerebral injury associated with cardiopulmonary bypass or ischemia. They include antioxidants, magnesium, 
-aminobutyric acid (GABA) stimulators, and steroids. However, none of them have yet been unequivocally successful to a degree that would urge a recommendation that they be used routinely in cardiopulmonary bypass.
Footnotes
Presented at the Conference on CNS Dysfunction After Cardiac Surgery: Defining the Problem, Fort Lauderdale, FL, Dec 10–11, 1994.
Address reprint requests to Mr Smith, Cardiothoracic Surgery Unit, 2nd Floor B Block, Hammersmith Hospital, Ducane Rd, London W12 0HS, United Kingdom.
References
This article has been cited by other articles:
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  D. Zervakis, P. Angelidakis, P. Dedeilias, and A. Koutsoukou Cerebral vein thrombosis after coronary artery bypass surgery Interactive CardioVascular and Thoracic Surgery, August 1, 2007; 6(4): 514 - 516. [Abstract] [Full Text] [PDF]
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 J. P. Mathew, H. M. Rinder, B. R. Smith, M. F. Newman, and C. S. Rinder Transcerebral Platelet Activation After Aortic Cross-Clamp Release is Linked to Neurocognitive Decline. Ann. Thorac. Surg., May 1, 2006; 81(5): 1644 - 1649. [Abstract] [Full Text] [PDF]
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 M de Baar, J C Diephuis, K G M Moons, J Holtkamp, R Hijman, and C J Kalkman The effect of zero-balanced ultrafiltration during cardiopulmonary bypass on S100b release and cognitive function Perfusion, January 1, 2003; 18(1): 9 - 14. [Abstract] [PDF]
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 E. D. Sivak Liberation From Mechanical Ventilation Following Heart Surgery Seminars in Cardiothoracic and Vascular Anesthesia, September 1, 2002; 6(3): 203 - 217. [Abstract] [PDF]
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 M. Herrmann, A. D. Ebert, I. Galazky, M. T. Wunderlich, W. S. Kunz, and C. Huth Neurobehavioral Outcome Prediction After Cardiac Surgery : Role of Neurobiochemical Markers of Damage to Neuronal and Glial Brain Tissue Stroke, March 1, 2000; 31(3): 645 - 650. [Abstract] [Full Text] [PDF]
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