HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Inderpaul Birdi Mohammad Bashar Izzat Alan J. Bryan Gianni D. Angelini Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Birdi, I. Articles by Angelini, G. D. Search for Related Content PubMed PubMed Citation Articles by Birdi, I. Articles by Angelini, G. D.

Ann Thorac Surg 1996;61:1573-1580
© 1996 The Society of Thoracic Surgeons

---

Current Reviews

Normothermic Techniques During Open Heart Operations

Bristol Heart Institute, University of Bristol, Bristol, United Kingdom

	Abstract

Top Footnotes Abstract Introduction Pathophysiologic Basis for... Warm Blood Cardioplegia ``Warm Heart'' Versus ``Warm''... Hypothermic Versus Normothermic... Conclusion Acknowledgments References

 
There has been considerable interest in the use of normothermic techniques during cardiac operations, both as a means of myocardial protection and as a more physiologic environment for other organs during cardiopulmonary bypass. Although a limited number of uncontrolled studies have suggested superior clinical results compared with conventional hypothermic regimens, these claims have not been thoroughly investigated using randomized protocols. The limited available data suggest that the successful use of warm blood cardioplegia requires adequate delivery of the solution to all parts of the myocardium at optimal flow rates to maintain aerobic arrest, so those who advocate the use of normothermic arrest must pay particular attention to ensure that their myocardial protection is effective. The advantages of employing normothermic systemic perfusion in regard to factors such as improved hemodynamic performance and reduced blood loss postoperatively need to be balanced against concerns regarding the inadequacy of cerebral protection offered by this method.

	Introduction

Top Footnotes Abstract Introduction Pathophysiologic Basis for... Warm Blood Cardioplegia ``Warm Heart'' Versus ``Warm''... Hypothermic Versus Normothermic... Conclusion Acknowledgments References

 
Normothermic techniques have been proposed by a number of groups as an improved method of myocardial protection compared with conventional hypothermic regimens and as a more physiologic means of maintaining the body's homeostatic functions during cardiopulmonary bypass (CPB). The independent effects of normothermic cardioplegic arrest and normothermic systemic perfusion have been confused, however, by a growing volume of literature in which both myocardial preservation techniques and definitions of ``normothermic perfusion'' have varied. The purpose of this review is to discuss the scientific basis on which the use of warm blood cardioplegia has been based and to consider the prerequisites for the successful application of such techniques in clinical practice. The important advantages and disadvantages of normothermic CPB in regard to hemodynamic and subsystem function will also be addressed in detail.

	Pathophysiologic Basis for Normothermic Myocardial Protection

Top Footnotes Abstract Introduction Pathophysiologic Basis for... Warm Blood Cardioplegia ``Warm Heart'' Versus ``Warm''... Hypothermic Versus Normothermic... Conclusion Acknowledgments References

 
Hypothermia has remained a cornerstone of cardiac surgical practice since its introduction in the early 1950s [1], with a large body of evidence demonstrating that it decreases myocardial oxygen consumption, resulting in an increased tolerance for ischemia [2]. However, hypothermia also produces a number of changes that may result in major myocardial cell injury, such as activation of the sodium-potassium adenosine triphosphatase and calcium adenosine triphosphatase systems of the sarcoplasmic reticulum. Impaired membrane function leads to cell swelling and mitochondrial rupture [3], and as temperature decreases to less than 25°C, ion pump inactivation and unfolding and denaturation of proteins occur. Various ion complexes precipitate out at different temperatures, and the resulting fluctuations in intracellular pH and osmotic shifts also become deleterious to cellular integrity.

These concepts are well appreciated by physiologists but have had little impact on surgical practice. This is mainly because of the widespread belief among surgeons that the advantages of reducing myocardial oxygen consumption during hypothermia greatly outweigh any potential drawbacks of this approach. Bernhard and colleagues [4] demonstrated that with electromechanical arrest alone, one could reduce the oxygen requirements of the heart by nearly 90%, with only a slight further decrease attributable to lowering myocardial temperature to 11°C. Similar findings have been reported by others [5]. Thus, the benefits of hypothermia to myocardial integrity may not be as important as once thought.

Increasing the supply of oxygen and substrates to the arrested heart may improve myocardial protection. Rat hearts perfused with oxygenated crystalloid cardioplegia at 20°C have been shown to possess greater adenosine triphosphate levels and contractility after perfusion than similar nonoxygenated preparations [6]. Incidentally, further reduction in temperature to 4°C showed no difference in functional preservation, a finding suggesting that inhibition of the glycolytic pathways occurs at lower temperatures. Clearly, the extent of tissue oxygenation is dependent on both the oxygen-carrying capacity of the perfusate and its ability to liberate oxygen. Crystalloid solutions possess a linear oxygen dissociation curve and are poor carriers of oxygen. Hemoglobin, on the other hand, is an extremely good carrier of oxygen, and the sigmoid dissociation curve that it exhibits allows efficient delivery of oxygen at the cellular level. The erythrocyte component of a blood cardioplegic solution has also been shown to possess non-oxygen-related effects that are beneficial to myocardial function, such as hydrogen ion buffering and free radical scavenging [7]. These concepts have formed the basis for the use of blood cardioplegia in clinical practice.

There are certain disadvantages in administering cold blood cardioplegia, however. Hemoglobin at low temperatures increases its affinity for oxygen [8], and thus it becomes less efficient in oxygen delivery. This increased affinity is potentiated by the relative alkalosis of cardioplegic solutions. Lichtenstein and co-workers [9–12] have postulated that chemical arrest using warm blood cardioplegia may represent a superior technique of myocardial protection because it results in a considerable reduction in myocardial oxygen demands, improves oxygen delivery to the tissues at the cellular level, and avoids the damaging effects of hypothermia.

	Warm Blood Cardioplegia

Top Footnotes Abstract Introduction Pathophysiologic Basis for... Warm Blood Cardioplegia ``Warm Heart'' Versus ``Warm''... Hypothermic Versus Normothermic... Conclusion Acknowledgments References

 
The application of normothermic cardioplegic techniques in clinical practice has not been as clear-cut as the scientific principles on which they have been based. Studies have been inconsistent in their design, so that many are not comparable, or they have yielded conflicting results. The critical factors that seem to be important to the successful use of warm blood cardioplegia include adequate delivery of the solution to all parts of the myocardium at optimal flow rates to maintain aerobic arrest.

Delivery of Cardioplegia
Clinical and experimental studies [13, 14] have shown that antegrade administration of cardioplegia in the presence of coronary artery disease results in nonhomogeneous delivery to the myocardium. Alternatively, the use of retrograde cardioplegia, although overcoming this problem, is believed to be associated with inadequate protection of the right side of the heart. Using the techniques of microsphere recovery, Caldarone and associates [15] demonstrated that retrograde warm cardioplegia was poorly distributed to the right ventricle and posterior septum in pigs. In a series of experiments using the pig model, Matsuura and coauthors [16] demonstrated that antegrade warm blood cardioplegia resulted in the least optimal myocardial protection of the area at risk compared with antegrade cold blood, retrograde warm blood, and antegrade plus retrograde cold blood cardioplegia. Although retrograde warm blood techniques resulted in a significantly smaller area of necrosis than antegrade warm blood delivery, it was not superior to the protection afforded by combined antegrade and retrograde cold blood cardioplegia.

In a similar model involving left anterior descending coronary artery occlusion and reperfusion in pigs, Misare and co-workers [17] demonstrated that antegrade intermittent cold blood cardioplegia produced significantly improved recovery of global and regional systolic function compared with antegrade continuous warm blood cardioplegia. In a different series of experiments, they [18] also demonstrated that retrograde warm blood cardioplegia was superior to antegrade warm blood cardioplegia in the preservation of regional and global left ventricular function. The information collated from such animal studies suggests that the route of cardioplegia delivery may be as important as the temperature of the solution, if not more so.

Using contrast echocardiography and coronary ostial effluent analysis, Allen and associates [19] demonstrated poor retrograde delivery of warm blood cardioplegia that was insufficient to fulfill the requirements of the myocardium. However, no functional evaluation was carried out. Menasché and his team [20] demonstrated that right ventricular stroke work was similar in 30 patients receiving either antegrade cold crystalloid cardioplegia or retrograde warm blood cardioplegia. Lactate washout concentrations were alike in the right ventricle and coronary sinus when retrograde cardioplegia was used, which suggests comparable protection of the right and left sides of the heart.

Adequate distribution of cardioplegia to all parts of the myocardium is always desirable but becomes an absolute prerequisite for the successful use of warm blood cardioplegia techniques.

Optimal Hematocrit
There is evidence that the hematocrit of warm blood cardioplegic solutions is critical to the maintenance of aerobic arrest and the avoidance of repayment of an oxygen debt on reperfusion [21]. In a randomized, controlled trial involving 35 patients, warm blood cardioplegia with a hemoglobin content of 5 g/dL was found to result in increased myocardial oxygen consumption and coronary sinus blood flow after aortic cross-clamp release, whereas warm blood cardioplegia with 8 g/dL of hemoglobin was not associated with this phenomenon; rather, it produced myocardial metabolic and functional recovery comparable with that of intermittent cold blood cardioplegia. Menasché [22] suggests that hematocrit values of 24% or even higher are necessary to maintain adequate oxygen delivery to the arrested myocardium.

Optimal Cardioplegic Flow Rate
When one is deciding on the optimal flow rate of warm blood cardioplegia, the balance lies between the maintenance of aerobic conditions and the requirements of a bloodless surgical field for the construction of the coronary anastomoses. In addition, administration of large volumes of cardioplegia may in itself be detrimental because it induces marked hyperkalemia, hemodilution, and potential exposure to high coronary sinus pressures with resultant perivascular hemorrhage and edema [23].

Ikonomidis and co-workers [24] demonstrated that retrograde continuous warm blood cardioplegia administered at 200 mL/min minimized lactate production and maintained coronary venous pH within physiologic limits while avoiding the effects of excessive cardioplegia administration. Lower flow rates were associated with high lactate production and oxygen extraction during cardioplegia administration, whereas flow rates of 300 mL/min or greater did not reduce lactate production or improve myocardial oxygen utilization. There is some evidence that reducing flow rate further can be undertaken with safety, but this requires meticulous monitoring: By recording coronary artery effluent pH, Gundry and co-workers [25] reported near physiologic myocardial metabolism with retrograde administration of warm blood cardioplegia (4:1 dilution) initially at 250 to 300 mL/min until induction of myocardial arrest, followed by a continuous infusion of 110 to 150 mL/min, which was increased when coronary artery effluent pH fell to less than 7.30. Some surgeons would undoubtedly find such techniques both cumbersome and perhaps unreliable.

Continuous or Intermittent Administration?
To minimize the obscured surgical view during construction of the coronary artery anastomoses, Lichtenstein and associates [9–11, 26] employed intermittent delivery of cardioplegia and suggested that cessation of flow should be limited to no more than 15 minutes. During periods in which warm blood cardioplegia administration is not maintained, the heart is subjected to a degree of warm ischemic arrest. Cessation of cardioplegia delivery for up to 15 minutes for each distal coronary anastomosis has been shown to result in increased myocardial lactate content and increased lactate washout on removal of the aortic cross-clamp [23, 27].

Changes in glycolytic metabolism are closely related to both hydrogen ion concentration and adenosine triphosphate degradation. Under circumstances in which ischemia prevails, lactate extraction by myocardial tissue changes to myocardial production (a net release of lactate), a finding indicating inhibition of the Krebs cycle and oxidative phosphorylation. Thus, the elevated tissue lactate levels noted under conditions of warm cardioplegic arrest may indicate either anaerobic metabolism by the myocytes or inefficient washout during retrograde delivery. There is some evidence that lactate may be a preferred substrate for oxidative metabolism during and after cardioplegic arrest and that elevated arterial lactate levels serve to promote aerobic metabolism and systolic function after coronary revascularization [28, 29]. This may help to explain the observations of improved hemodynamic function in the early postoperative period after warm blood cardioplegia, despite the concomitant presence of high arterial lactate washout [23]. One may have expected inferior myocardial function in the warm group.

Menasché [22] argued that it would be virtually impossible to predict the safe ischemic interval in individual patients and suggested that ``oxygen must be delivered in a continuous fashion because it is consumed over time.'' The hypothesis that repetitive periods of short ischemia somehow protect the heart by a form of ``preconditioning'' has still to be evaluated, but it defeats the principle of warm aerobic arrest, which is then perhaps better described as intermittent warm ischemia.

Warm Blood Cardioplegia and Clinical Outcome
Early clinical reports [9–11] compared patients having warm blood cardioplegia with retrospective controls who received intermittent cold crystalloid cardioplegia. These studies demonstrated significant reductions in the incidence of ventricular fibrillation on myocardial reperfusion, postoperative low-output states, and myocardial infarction rates in the normothermic group. Significant improvements in mortality were demonstrated only in high-risk patients undergoing myocardial revascularization after recent myocardial infarction [10] or after long cross-clamp times [11]. These studies were flawed, however, because they were not prospectively randomized and used retrospective cohorts of comparable patients to represent the hypothermic group.

Prospectively randomized trials are now beginning to emerge, the largest of which compared the effects of warm versus cold blood cardioplegia in 1,732 patients [30]. The 30-day all-cause mortality was not significantly different between groups, and although the enzymatic infarction rates evaluated by the serial creatine kinase MB fraction was lower after warm blood cardioplegia, there was no difference in the incidence of nonfatal Q-wave infarction. Surgeon identity was a more powerful predictor of these two clinical end points than temperature.

Thus, there is at present insufficient evidence from carefully conducted randomized studies on which to base firm conclusions about clinical outcome after warm blood cardioplegia compared with established hypothermic regimens, except that good results can be achieved using both techniques.

	``Warm Heart'' Versus ``Warm'' Heart Surgery

Top Footnotes Abstract Introduction Pathophysiologic Basis for... Warm Blood Cardioplegia ``Warm Heart'' Versus ``Warm''... Hypothermic Versus Normothermic... Conclusion Acknowledgments References

 
The initial intention of Lichtenstein and his group when using continuous warm blood cardioplegia was to perfuse the body and brain at hypothermia. Normothermic perfusion ``arose fortuitously in some of the earliest cases done'' when it was observed that this approach seemed to confer certain further advantages such as absence of shivering, hemodynamic stability, minimum use of inotropic agents, and early extubation [12]. Much of the research into the use of normothermic perfusion has served only to confuse our understanding because of the inconsistent cardioplegic regimens employed between the groups being compared. The concomitant use of ``normothermic perfusion'' has also been poorly defined. Whereas some workers have advocated the use of active rewarming throughout bypass, others have allowed perfusion temperature to drift down to 32°C.

The separate effects of normothermic myocardial preservation and normothermic perfusion have not been clearly delineated to date, and terms such as warm heart surgery have fueled the controversy further. Normothermic electromechanical arrest is fundamentally a method of myocardial preservation and implies a ``warm heart,'' whereas the use of normothermic perfusion implies ``warm'' heart surgery. Recognition of the term warm body-cold heart surgery [31] to describe the use of normothermic systemic perfusion with hypothermic myocardial protection is a further distinction that needs to be appreciated. The use of such labels should perhaps be avoided. A large body of literature is flawed in this regard, however, and it will be difficult to dispose of such terms.

	Hypothermic Versus Normothermic Perfusion

Top Footnotes Abstract Introduction Pathophysiologic Basis for... Warm Blood Cardioplegia ``Warm Heart'' Versus ``Warm''... Hypothermic Versus Normothermic... Conclusion Acknowledgments References

 
By understanding the effects of systemic hypothermia on cellular and end-organ function, it may be possible to predict how the alternative approach of normothermic perfusion may be either beneficial or harmful.

The Inflammatory Response
Many of the detrimental effects of CPB on end-organ dysfunction are believed to be mediated by activation of the inflammatory response [32, 33]. A range of systemic inflammatory pathways are activated during CPB including the complement system [32, 33], neutrophil activity [34], and cytokine release from mononuclear cells [35]. There are a number of cytokines that have been shown to produce specific types of dysfunction. When in excess, interleukin-1ß (IL-1ß) and tumor necrosis factor- may produce endothelial dysfunction with enhanced vascular permeability, decreased systemic vascular resistance, and myocardial depression [33]. Although hypothermia has been associated with increased production of intracellular IL-1 [36], no circulating IL-1ß has been found in patients undergoing hypothermic bypass [37]. Neutrophil activation described after CPB might be induced by IL-8, a powerful neutrophil chemotactic factor. Hypothermic bypass also induces IL-8 release [38].

On the other hand, hypothermia may protect the body from harmful complement activation by reducing both the activation of factors such as C3a and C5a and the cellular responses to activation of these factors [32].

One may expect that the activation of the inflammatory system is enhanced during normothermia, as most enzymatic processes occur optimally at 37°C. Increased complement activation and IL-1 release have been documented in vitro [36], and in a clinical study by Menasché and co-workers [39], normothermic bypass was associated with significantly elevated levels of IL-1ß and tumor necrosis factor- compared with hypothermic bypass. The incidence of vasodilation, presumed to result from the presence of these mediators, was twofold higher in the normothermic group, necessitating the increased use of vasopressor agents.

Although these studies have provided some insight into the effects of normothermic bypass on the inflammatory response, the practical importance in regard to end-organ dysfunction requires further evaluation.

Hemodynamic Effects
One of the most consistent observations during normothermic bypass is a reduced systemic vascular resistance [40–42], a finding substantiated by the greater requirements of fluid administration and vasopressor agents [40, 41, 43]. Several factors can cause vasodilation including preoperative medical therapies, various anesthetic drugs, and hemodilution. The large volumes of blood cardioplegia delivered during continuous normothermic arrest produce major hemodilution and have been implicated as a possible mechanism. Menasché and associates [44] reduced the volumes of cardioplegia delivered by effectively concentrating the cardioplegic solution into a small volume and administering this through a separate port to the blood perfusing the coronary sinus. This technique resulted in a decreased incidence of systemic vasodilatation without compromising myocardial protection.

We have already discussed the effects of cytokine release as a possible mechanism for the vasodilatation observed during normothermic bypass. The increased activity of inflammatory mediators during normothermic bypass has been blamed for anecdotal reports of myocardial edema, hepatic failure, pancreatitis, renal tubular necrosis, and multiorgan failure [45].

Alterations in histamine levels during CPB have also been shown to coincide directly with changes in temperature, and it is possible that increases in histamine concentration may also contribute to the low systemic vascular resistance of normothermic perfusion [41, 46].

Higher doses of vasoconstrictor drugs are required during CPB at normothermic temperatures [40, 41, 47], and this raises concerns regarding blood flow along arterial conduits. DiNardo and coauthors [48] demonstrated a significant decrease in internal mammary artery graft flow when phenylephrine hydrochloride (76 ± 31 µg/min) was used to elevate mean arterial pressures by 20 mm Hg. Using a canine model in which blood pressure, heart rate, and cardiac output remained constant, Jett and co-workers [49] produced a significant reduction in internal mammary artery flow after administration of phenylephrine (2 µg/min). However, little is known about the duration of these effects on arterial conduit flow, and because there is no evidence that normothermic bypass is associated with an increased vasoconstrictor requirement after bypass, the effects of such therapy may not be clinically important.

Hypothermia of even mild degrees is known to potentiate ventricular fibrillation after removal of the aortic cross-clamp. Ventricular fibrillation may result in the consumption of high-energy phosphates and is accepted as undesirable during reperfusion. Both warm blood cardioplegia [41] and normothermic systemic perfusion [50] are associated with a lower incidence of fibrillation on reperfusion and may allow conservation of myocardial energy stores during this critical period of myocardial recovery.

Although the lower systemic vascular resistance and the concomitant increased requirements of vasoconstrictor administration may result in difficulties in maintaining a steady perfusion pressure during bypass, it is possible that the favorable hemodynamic effects of warm blood cardioplegia may in part be attributable to the reduction in afterload that the dilated systemic vasculature produces during normothermic perfusion rather than a result of superior myocardial protection.

The use of normothermic perfusion in association with conventional hypothermic regimens (``warm body-cold heart'') has been employed by some with good results [31, 50]. There are concerns regarding the potential for rewarming of the myocardium from contiguous structures, but this does not seem to occur if careful hypothermic myocardial protection techniques (cold cardioplegia and topical cooling) are employed [51].

Cerebral Function
The scenario of lower perfusion pressures, increased requirements of vasoconstrictors, and relative hyperglycemia produced by some blood cardioplegic regimens must serve to increase the risk of injury to the warm, metabolically active brain during normothermic perfusion. Hypothermia to 27°C has been shown to reduce cerebral metabolic rate and oxygen consumption by up to 64% [52]. Even mild degrees of hypothermia produce substantial levels of cerebral protection [53].

Martin and colleagues [54] conducted a randomized trial of warm blood cardioplegia and systemic normothermia (35°C) versus cold crystalloid cardioplegia and hypothermic perfusion (28°C) and demonstrated significantly higher stroke rates in the normothermic group (3.1% versus 1.0%). One major criticism of this study was the elevated blood glucose level observed in the normothermic group, a finding resulting from the blood cardioplegic solution used. In 1991, Lanier [55] reported that there is evidence of an increased susceptibility to cerebral injury during ischemia in the presence of hyperglycemia. However, Craver and associates [54, 56, 57] have subsequently reported that multivariate analysis did not identify systemic blood glucose level as a predictor of stroke in the series.

Another confounding factor was the observation [58] that the normothermic group received large volumes of retrograde cardioplegia, whereas the hypothermic group received only antegrade cardioplegia. Becker and colleagues [58] remarked on the potential for dislodgment of atheromatous debris from native coronary arteries that, if flushed into the ascending aorta, could travel to the brain on removal of the cross-clamp. This theoretic risk requires further evaluation. However, in a recent study [59] using transcranial Doppler ultrasound, the number of microembolic events was found to be significantly higher after the use of retrograde warm cardioplegia than either warm or cold antegrade techniques. In a subsequently published report by Craver and co-workers [57], 379 patients undergoing coronary artery bypass grafting with retrograde hypothermic blood cardioplegia and hypothermic perfusion (29° to 33°C) were compared with retrospective controls receiving retrograde warm blood cardioplegia and normothermic perfusion. The incidence of Q-wave infarction or death was no lower in the normothermic group even though this was a cohort of relatively lower risk patients (lower age, angina severity, and incidence of previous coronary procedures) compared with those in the hypothermic group. The incidence of postoperative neurologic events, however, was significantly higher in the normothermic group (4.7% versus 1.8%), a finding substantiating concerns regarding the deleterious effects of normothermic perfusion on cerebral integrity.

Contrary to these observations, Singh and colleagues [60] examined the incidence of stroke in a group of 2,585 consecutive patients undergoing normothermic bypass (active rewarming to 37°C) using antegrade cold crystalloid cardioplegia and compared this group with 1,605 retrospective controls undergoing hypothermic perfusion (25° to 30°C). Neurologic complications, occurring in 1% and 1.3% of patients in the normothermic and hypothermic groups, respectively, were no different between the groups.

Neuropsychologic outcome has been studied by a number of workers, and the results are again difficult to interpret. Martin and co-workers [54] examined neuropsychologic outcome in a subset of 150 patients and found no significant difference between patients undergoing normothermic versus hypothermic perfusion. Wong and associates [61], in a prospective, randomized study, found no evidence of cerebral protection or improved neuropsychologic outcome after hypothermic perfusion. Similarly, this group [62] randomized 201 patients into two cohorts according to perfusion temperature (warm >34°C and cold 28°C). Of the 153 patients completing the neuropsychologic profile, no difference was observed between the groups. In both of these studies, the normothermic group received a degree of moderately hypothermic ``protection,'' and it is not surprising that the outcomes were similar.

Our group [63] recently completed a prospective, randomized study comparing perfusion temperature as the only changing variable. Ninety-six patients were randomized into one of three groups according to CPB temperature (28°C, 32°C, and 37°C), and antegrade cold crystalloid cardioplegia was used in all instances. Patients underwent detailed neurologic examination postoperatively, and neuropsychologic evaluation was undertaken both before and 6 weeks after operation using the Wechsler adult intelligence scale, revised. Although no focal neurologic deficits were recorded in the study, detailed multivariate analyses suggested that the incidence of neuropsychologic deficit was higher after normothermic perfusion (37°C) than moderate hypothermic perfusion (32°C) and that no added benefit was conferred by lowering perfusion temperature to 28°C.

It seems reasonable to conclude that the potential risk of cerebral injury may be higher during normothermic perfusion.

Blood Coagulation
There is a large body of evidence that clearly documents the adverse effects of systemic hypothermia on blood coagulation. Reversible platelet membrane dysfunction, disordered fibrinolytic cascade activity, inhibition of clotting factors, and thrombocytopenia during hypothermia result in exaggerated postoperative bleeding [64, 65]. By performing CPB at normothermia, one would expect to ameliorate these pathophysiologic responses and thus reduce the incidence of postbypass coagulopathy and blood loss. Tönz and co-authors [66] reported reductions in both postoperative bleeding volume and reoperation for bleeding after normothermic CPB in a small, prospective study in which patients underwent either normothermic (37°C) or hypothermic (28°C) perfusion. Similar findings have been reported by others [64, 67].

Boldt and colleagues [65] demonstrated improved platelet function and reduced bleeding in patients undergoing normothermic bypass (>34°C) compared with those having hypothermic perfusion (<28°C). In addition, although aprotinin blunted the effects of hypothermia on platelet dysfunction, it failed to have any beneficial effects in patients undergoing normothermic bypass. In a recent study, the effects of hypothermic (28° to 30°C) and normothermic (37°C) bypass on platelet function were compared. In both groups, there was an observed decrease in postoperative platelet count and glycoprotein 1b expression and an increase in the percentage of GMP-140-positive platelets. Temperature had no influence on these changes, however. Another possible mechanism of improved coagulation after normothermia may be related to the heparin-protamine reversal reaction, which occurs more efficiently at higher temperatures [67].

Respiratory Function
In sheep, hypothermia is associated with a fall in pulmonary compliance that may not be completely reversed on rewarming [68]. In addition, hypothermia leads to increased pulmonary vascular resistance, greater anatomic and physiologic dead space [69], and decreased rate and depth of respiration that may be prolonged if incomplete rewarming occurs after bypass. There also may be disturbance of oxygen delivery caused by the leftward shift of the oxygen dissociation curve. Conversely, the potential for complement-mediated lung injury and the resulting increase in pulmonary capillary permeability during normothermic bypass may result in adverse effects.

The available clinical data suggest that normothermic CPB is associated with a reduced intubation time postoperatively [41, 66]. Whether this reflects improved respiratory function, more stable hemodynamics, or more rapid and consistent return to normal body temperature has not been determined. The alveolar-arterial gradient, considered to represent a noninvasive measure of pulmonary gas exchange, was compared in 45 patients after coronary artery operations in our institution [70]. Patients were again randomized to one of three perfusion temperatures (28°C, 32°C, and 37°C), and no differences were demonstrated between groups.

Renal Function
Although the use of warm blood cardioplegia has been shown to result in significantly higher serum potassium levels, increased volume overload, and increased requirement of diuretic or insulin infusions or both to decrease potassium levels [41, 71], the limited uncontrolled clinical data available suggest that the risks of renal failure associated with normothermic and hypothermic CPB perfusion are comparable [31, 42]. As part of a prospective, randomized, controlled trial [72] of CPB perfusion temperature (28°C, 32°C, and 37°C) conducted in our institution, a subgroup of patients with normal preoperative renal function was studied. Creatinine clearance was measured before induction of anesthesia, during CPB, and every 12 hours thereafter for 48 hours postoperatively. Glomerular and tubular function were further assessed by measurement of urinary creatinine, albumin, total protein, and retinol-binding protein levels. No differences in renal function were seen between the three groups. Ip-Yam and associates [47] demonstrated no difference in creatinine clearance, fractional sodium excretion, microalbuminuria, and urinary N-acetyl-ß-D-glucosaminidase after normothermic (37°C) versus hypothermic (28°C) bypass. In both of these studies, the normothermic group received greater amounts of vasoconstrictors during bypass to maintain a mean pressure of 40 to 50 mm Hg. The effects of vasoconstrictor use on renal blood flow have yet to be evaluated.

Splanchnic Function
Gastrointestinal complications after CPB occur in perhaps 0.6% to 2% of patients, but the associated mortality can be as high as 15% to 63% [73]. There is evidence to suggest that hypothermia is detrimental to splanchnic function. Splanchnic blood flow is known to fall with decreasing temperature [74], and both gut motility and hepatic function are impaired [75]. Reduced carrier-mediated transport and increased gut permeability in conjunction with reduced mucosal blood flow have also been demonstrated [73], and the potential for endotoxin entry into the circulation resulting from this is clearly of concern. Little is known about the effects of normothermic bypass on splanchnic function. This represents a useful area for further research.

	Conclusion

Top Footnotes Abstract Introduction Pathophysiologic Basis for... Warm Blood Cardioplegia ``Warm Heart'' Versus ``Warm''... Hypothermic Versus Normothermic... Conclusion Acknowledgments References

 
The most important prerequisite for the successful use of warm myocardial protection is the maintenance of aerobic arrest. This depends on ensuring adequate delivery of this essentially ``nutritive'' solution to all parts of the myocardium. The critical flow rates required to produce this are still not clearly defined, and the use of intermittent administration by some surgeons raises concerns that this practice results in periods of normothermic ischemic arrest. The consequences of this are not understood but do not appear to be a practical clinical problem. In addition, there is some evidence that retrograde delivery of cardioplegia may not be sufficient to supply the requirements of the right ventricle. Despite this, evidence of substantial functional impairment is lacking. Thus, although surgeons employing hypothermic cardioplegic regimens can feel safe in the knowledge that they do not lower the level of myocardial protection by using techniques that result in intermittent periods of ischemia, those who advocate warm blood techniques must pay particular attention to ensure that their myocardial protection is effective. There is still a relative paucity of randomized, controlled trials addressing the effects of warm blood cardioplegia on clinical outcome. The only available data fail to demonstrate any significant improvement in mortality after warm blood cardioplegia compared with conventional regimens.

The relative contributions of warm blood cardioplegia techniques and normothermic systemic perfusion are still not clearly delineated. The improved hemodynamics after warm blood cardioplegia may be related, in part, to the use of normothermic CPB. This requires further study using standardized protocols in which perfusion temperature is the only variable altered. Other potential advantages of normothermic perfusion are nevertheless very limited, and the concerns regarding the potentially inferior degree of cerebral protection and the lack of protection offered in the event of a perfusion accident during CPB must question its safety. Allowing perfusion temperature to ``drift'' to moderately hypothermic levels (``tepid body'') during ``warm heart'' surgery may be a safer approach.

Although normothermic techniques have provided a stimulus to reevaluate many of the strategies related to both myocardial protection and perfusion during bypass, claims that they yield superior clinical results are still largely unsubstantiated. Remaining concerns about the potential for cerebral injury with normothermic perfusion limit any recommendation for their generalized adoption at least until more information becomes available.

	Acknowledgments

Top Footnotes Abstract Introduction Pathophysiologic Basis for... Warm Blood Cardioplegia ``Warm Heart'' Versus ``Warm''... Hypothermic Versus Normothermic... Conclusion Acknowledgments References

 
This study has been supported by the Garfield Weston Trust and the Sir Jules Thorn Trust.

	Footnotes

Top Footnotes Abstract Introduction Pathophysiologic Basis for... Warm Blood Cardioplegia ``Warm Heart'' Versus ``Warm''... Hypothermic Versus Normothermic... Conclusion Acknowledgments References

 
Address reprint requests to Mr Birdi, British Heart Institute, University of Bristol, Bristol Royal Infirmary, Bristol BS2 8HW, United Kingdom.

	References

Top Footnotes Abstract Introduction Pathophysiologic Basis for... Warm Blood Cardioplegia ``Warm Heart'' Versus ``Warm''... Hypothermic Versus Normothermic... Conclusion Acknowledgments References

 

1. Bigelow WG, Lindsay WK, Greenwood WF. Hypothermia: its possible role in cardiac surgery. Ann Surg 1950;132: 849–66.[Medline]
2. Buckberg GD. A proposed ``solution'' to the cardioplegic controversy. J Thorac Cardiovasc Surg 1979;77:803–15.[Medline]
3. Leaf A. Cell swelling. A factor in ischemic tissue injury. Circulation 1973;48:455–8.[Free Full Text]
4. Bernhard WF, Schwarz HF, Malick NP. Selective hypothermic cardiac arrest in normothermic animals. Ann Surg 1961;153:43–51.[Medline]
5. Chitwood WR, Sink JD, Hill RC, et al. The effects of hypothermia on myocardial oxygen consumption and transmural coronary blood flow in the potassium-arrested heart. Ann Surg 1979;190:106–16.[Medline]
6. Coetzee A, Kotze J, Louw J, et al. Effects of oxygenated crystalloid cardioplegia on the functional and metabolic recovery of the isolated perfused rat heart. J Thorac Cardiovasc Surg 1986;91:259–69.[Abstract]
7. Illes RW, Silverman NA, Krukenkamp IB, et al. The efficacy of blood cardioplegia is not due to oxygen delivery. J Thorac Cardiovasc Surg 1989;98:1051–6.[Abstract]
8. Digerness SB, Vanini V, Wideman FE. In vitro comparison of oxygen availability from asanguineous and sanguineous cardioplegic media. Circulation 1981;60(Suppl 2):80–3.[Abstract/Free Full Text]
9. Lichtenstein SV, El-Dalati H, Panos A, et al. Long cross-clamp times with warm heart surgery. Lancet 1989;1:1443.[Medline]
10. Lichtenstein SV, Abel JG, Salerno TA. Warm heart surgery and results of operation for recent myocardial infarction. Ann Thorac Surg 1991;52:455–60.[Abstract]
11. Lichtenstein SV, Abel JG, Panos A, Slutsky AS, Salerno TA. Warm heart surgery: experience with long cross-clamp times. Ann Thorac Surg 1991;52:1009–13.[Abstract]
12. Lichtenstein SV, Abel JG, Slutsky AS. Warm heart surgery [Letter]. Lancet 1992;339:1304–5.[Medline]
13. Menasché P, Subayi J-B, Veyssié L, Le Dref O, Chevret S, Piwnica A. Efficacy of coronary sinus cardioplegia in patients with complete coronary artery occlusions. Ann Thorac Surg 1991;51:418–23.[Abstract]
14. Quintilio C, Voci P, Bilotta F, et al. Risk factors for incomplete distribution of cardioplegic solution during coronary artery grafting. J Thorac Cardiovasc Surg 1995;109:439–47.[Abstract/Free Full Text]
15. Caldarone CA, Krukenkamp IB, Misare BD, Levitsky S. Perfusion deficits with retrograde warm blood cardioplegia. Ann Thorac Surg 1994;57:403–6.[Abstract]
16. Matsuura H, Lazar HL, Yang X, et al. Warm versus cold blood cardioplegia-is there a difference? J Thorac Cardiovasc Surg 1993;105:45–51.[Abstract]
17. Misare BD, Krukenkamp IB, Lazer ZP, et al. Antegrade warm blood cardioplegia exacerbates acute regional ischemic injury. Surg Forum 1991;50:232–4.
18. Misare BD, Krukenkamp IB, Lazer ZP, et al. Retrograde is superior to antegrade continuous warm blood cardioplegia for acute cardiac ischemia. Circulation 1991;84(Suppl 2):687.
19. Allen BS, Winkelmann JW, Hanafy H, et al. Retrograde cardioplegia does not adequately perfuse the right ventricle. J Thorac Cardiovasc Surg 1995;109:1116–26.
20. Menasché P, Fleury JP, Droc L, et al. Metabolic and functional evidence that retrograde warm blood cardioplegia does not injure the right ventricle in human beings. Circulation 1994;90(Suppl 2):310–5.
21. Yau TM, Weisel R, Mickle DA, et al. Optimal delivery of blood cardioplegia. Circulation 1991;84(Suppl 3):380–8.
22. Menasché P. Warm cardioplegia or aerobic cardioplegia? Let's call a spade a spade [Editorial]. Ann Thorac Surg 1994;58:5–6.[Medline]
23. Yau TM, Ikonomidis JS, Weisel RD, et al. Which techniques of cardioplegia prevent ischemia? Ann Thorac Surg 1993;56:1020–8.[Abstract]
24. Ikonomidis JS, Yau TM, Weisel RD, et al. Optimal flow rates for retrograde warm cardioplegia. J Thorac Cardiovasc Surg 1994;107:510–9.[Abstract/Free Full Text]
25. Gundry SR, Wang N, Bannon D, et al. Retrograde continuous warm blood cardioplegia: maintenance of myocardial homeostasis in humans. Ann Thorac Surg 1993;55:358–63.[Abstract]
26. Lichtenstein S, Ashe K, El-Dalati H, et al. Warm heart surgery. J Thorac Cardiovasc Surg 1991;101:269–74.[Abstract]
27. Pelletier LC, Carrier M, Leclerc Y, Cartier R, Wesolowska E, Solymoss BL. Intermittent antegrade warm versus cold blood cardioplegia: a prospective, randomized study. Ann Thorac Surg 1994;58:41–9.[Abstract]
28. Teoh KH, Mickle DAG, Weisel RD, et al. Improving myocardial and functional recovery after cardioplegic arrest. J Thorac Cardiovasc Surg 1988;95:788–98.[Abstract]
29. Teoh KH, Mickle DAG, Weisel RD, et al. The effect of lactate infusion on myocardial metabolism and ventricular function following ischemia and cardioplegia. Can J Cardiol 1990;6:38–46.[Medline]
30. Naylor DC, Lichtenstein SV, Fremes SE, et al. Randomized trial of normothermic versus hypothermic coronary bypass surgery. Lancet 1994;343:559–63.[Medline]
31. Singh AK, Feng WC, Bert AA, et al. Warm body, cold heart surgery. Eur J Cardio-thorac Surg 1993;7:225–30.[Abstract]
32. Moore FD, Warner KG, Assousa S, et al. The effects of complement activation during cardiopulmonary bypass. Attenuation by hypothermia, heparin and hemodilution. Ann Surg 1987;208:95–103.
33. Kirklin JK, Westaby S, Blackstone EH, et al. Complement and the damaging effects of cardiopulmonary bypass. J Thorac Cardiovasc Surg 1983;86:845–57.[Abstract]
34. Faymonville ME, Pincemail J, Duchateau J, et al. Myeloperoxidase and elastase as markers of leukocyte activation during cardiopulmonary bypass in humans. J Thorac Cardiovasc Surg 1991;102:309–17.[Abstract]
35. Butler J, Rocker GM, Westaby S. Inflammatory response to cardiopulmonary bypass. Ann Thorac Surg 1993;55:552–9.[Abstract]
36. Haeffner-Cavaillon N, Roussellier N, Ponzio O, et al. Induction of interleukin-1 production in patients undergoing cardiopulmonary bypass. J Thorac Cardiovasc Surg 1989;98:1100–6.[Abstract]
37. Butler J, Pillai R, Rocker GM, et al. Effect of cardiopulmonary bypass on systemic release of neutrophil elastase and tumor necrosis factor. J Thorac Cardiovasc Surg 1993;105:25–30.[Abstract]
38. Finn A, Naik S, Klein N, et al. Interleukin 8 release and neutrophil degranulation after pediatric cardiopulmonary bypass. J Thorac Cardiovasc Surg 1993;105:234–41.
39. Menasché P, Haydar S, Peynet J, et al. A potential mechanism of vasodilation after warm heart surgery. J Thorac Cardiovasc Surg 1994;107:293–9.[Abstract/Free Full Text]
40. Arom KV, Emery RW, Northrup WF III. Warm heart surgery: a prospective comparison between normothermic and tepid temperature. J Cardiac Surg 1995;10:221–6.[Medline]
41. Christakis GT, Koch JP, Deemar KA, et al. A randomized study of the systemic effects of warm heart surgery. Ann Thorac Surg 1992;54:449–59.[Abstract]
42. Lehot JJ, Villar J, Piriz H, et al. Hemodynamic and hormonal responses to hypothermic and normothermic cardiopulmonary bypass. J Cardiothorac Vasc Anesth 1992;6:132–9.[Medline]
43. Massimino RJ, Stearns GT, Gough JD, et al. Moderate hypothermic versus normothermic total cardiopulmonary bypass for coronary artery surgery: a retrospective study. J Extra-Corpor Technol 1991;23:5–8.
44. Menasché P, Fleury J-P, Veyssié L, et al. Limitation of vasodilation associated with warm heart operation by a ``mini-cardioplegia'' delivery technique. Ann Thorac Surg 1993;56:1148–53.[Abstract]
45. Mills SA. Warm retrograde blood cardioplegia: a prospective trial [Editorial]. Ann Thorac Surg 1994;57:281–2.[Medline]
46. Mann WK, Steger AC, Hosking SW, et al. Histamine release during cardiopulmonary bypass. Perfusion 1990;5:107–16.
47. Ip-Yam PC, Murphy S, Baines M, et al. Renal function and proteinuria after cardiopulmonary bypass: the effects of temperature and mannitol. Anesth Analg 1994;78:842–7.[Abstract/Free Full Text]
48. DiNardo JA, Bert A, Schwartz MJ, et al. Effects of vasoactive drugs on flows through left internal mammary artery and saphenous vein grafts in man. J Thorac Cardiovasc Surg 1991;102:730–5.[Abstract]
49. Jett GK, Arcidi JM, Dorsey LMA, et al. Vasoactive drug effect on blood flow in internal mammary artery and saphenous vein grafts. J Thorac Cardiovasc Surg 1987;94:2–11.[Abstract]
50. Birdi I, Regragui IA, Izzat MB, Bryan AJ, Angelini GD. Effects of cardiopulmonary perfusion temperature: a randomized, controlled trial [Letter]. Ann Thorac Surg 1995;60:747.[Free Full Text]
51. Regragui I, Izzat MB, Bryan A, et al. Myocardial rewarming during normothermic cardiopulmonary bypass. J Thorac Cardiovasc Surg 1995;109:595–7.[Free Full Text]
52. Croughwell ND, Frasco P, Blumenthal JA, Leone BJ, White WD, Reves JG. Warming during cardiopulmonary bypass is associated with jugular bulb desaturation. Ann Thorac Surg 1992;53:827–32.[Abstract]
53. Moyer DJ, Welsh FA, Zagar EL. Spontaneous cerebral hypothermia diminishes focal infarction in rat brain. Stroke 1992;23:1812–6.[Abstract/Free Full Text]
54. Martin TD, Craver JM, Gott JP, et al. Prospective, randomized trial of retrograde warm blood cardioplegia: myocardial benefit and neurologic threat. Ann Thorac Surg 1994;57:298–304.[Abstract]
55. Lanier WL. Glucose management during cardiopulmonary bypass: cardiovascular and neurologic implications. Anesth Analg 1991;72:423–7.[Free Full Text]
56. Mellitt RJ, Weintraub WS, Craver JM, et al. The interrelationship of age and normothermic blood vs cold crystalloid cardioplegia on the incidence of stroke in elective coronary artery bypass grafting: results of the Emory randomized trial. Circulation 1993;88(Suppl 1):288.
57. Craver JM, Bufkin BL, Weintraub WS, Guyton RA. Neurologic events after coronary bypass grafting: further observations with warm cardioplegia. Ann Thorac Surg 1995;59:1429–34.[Abstract/Free Full Text]
58. Becker RM, Rich AA, Reed JR. Normothermic cardiopulmonary bypass [Letter]. Ann Thorac Surg 1995;59:547.[Free Full Text]
59. Baker AJ, Naser B, Benaroia M, Mazer CD. Cerebral microemboli during coronary artery bypass using different cardioplegia techniques. Ann Thorac Surg 1995;59:1187–91.[Abstract/Free Full Text]
60. Singh AK, Bert AA, Feng WC, Rotenberg FA. Stroke during coronary artery bypass grafting using hypothermic versus normothermic perfusion. Ann Thorac Surg 1994;59:84–9.[Abstract/Free Full Text]
61. Wong B, McLean R, Naylor C, et al. Central nervous system dysfunction after warm or hypothermic cardiopulmonary bypass. Lancet 1992;339:1383–4.[Medline]
62. McLean R, Wong B, Naylor C, et al. Cardiopulmonary bypass, temperature, and central nervous system dysfunction. Circulation 1994;90:250–5.
63. Regragui I, Birdi I, Izzat MB, et al. The effects of cardiopulmonary bypass temperature on neuropsychological outcome after coronary artery surgery. A prospective randomized trial. J Thorac Cardiovasc Surg (in press).
64. Yau T. The effect of warm heart surgery on postoperative bleeding. J Thorac Cardiovasc Surg 1992;103:1155–63.[Abstract]
65. Boldt J, Knothe C, Zickmann B, Bill S, Dapper F, Hempelmann G. Platelet function in cardiac surgery: influence of temperature and aprotinin. Ann Thorac Surg 1993;55:652–8.[Abstract]
66. Tönz M, Mihaljevic T, von Segesser LK, et al. Normothermia versus hypothermia during cardiopulmonary bypass: a randomized, controlled trial. Ann Thorac Surg 1995;59:137–43.[Abstract/Free Full Text]
67. Vaughn CC, Opie JC, Florendo FT, Lowell PA, Austin J. Warm blood cardioplegia. Ann Thorac Surg 1993;55:1227–32.[Abstract]
68. Severinghaus JW, Stupfel M, Bradley AF Jr. Alveolar dead space and arterial to end-tidal carbon dioxide differences during hypothermia in dogs and man. J Appl Physiol 1957;10:349–55.[Abstract/Free Full Text]
69. Severinghaus JW, Stupfel M. Respiratory dead space increase following atropine in man and atropine, vagal or ganglionic blockade and hypothermia in dogs. J Appl Physiol 1955;8:81–7.[Free Full Text]
70. Birdi I, Regragui IA, Izzat MB, et al. Effects of cardiopulmonary bypass temperature on pulmonary gas exchange after coronary artery operations. Ann Thorac Surg 1996;61:118–23.[Abstract/Free Full Text]
71. Salerno TA, Christakis GT, Abel J, et al. Technique and pitfalls of retrograde continuous warm blood cardioplegia. Ann Thorac Surg 1991;51:1023–5.[Abstract]
72. Regragui IA, Izzat MB, Birdi I, Lapsley M, Bryan AJ, Angelini GD. Cardiopulmonary bypass perfusion temperature does not influence perioperative renal function. Ann Thorac Surg 1995;60:160–4.[Abstract/Free Full Text]
73. Ohri SK, Bjarnason I, Pathi V, et al. Cardiopulmonary bypass impairs small intestinal transport and increases gut permeability. Ann Thorac Surg 1993;55:1080–6.[Abstract]
74. Hallet EB. Effect of decreased body temperature on liver function and splanchnic blood flow in dogs. Surg Forum 1955;5:362.
75. Maclean D, Emslie-Smith D. Accidental hypothermia. Oxford: Blackwell Scientific, 1977.

This article has been cited by other articles:

				W. J Gomes, D. A Strisiver, A. J. Penco, K. Rampersad, and G. D Angelini Successful Treatment of Accidental Air Embolism in Warm Heart Surgery Asian Cardiovasc Thorac Ann, March 1, 2003; 11(1): 68 - 69. [Abstract] [Full Text] [PDF]

				J. A. Macoviak, J. Hwang, K. L. Boerjan, and D. D. Deal Comparing dual-stream and standard cardiopulmonary bypass in pigs Ann. Thorac. Surg., January 1, 2002; 73(1): 203 - 208. [Abstract] [Full Text] [PDF]

				L. Shore-Lesserson, H. E. Manspeizer, M. DePerio, S. Francis, F. Vela-Cantos, and M. A. Ergin Thromboelastography-Guided Transfusion Algorithm Reduces Transfusions in Complex Cardiac Surgery Anesth. Analg., February 1, 1999; 88(2): 312 - 312. [Abstract] [Full Text] [PDF]

				A. C. Fiore, M. T. Swartz, R. Nevett, P. J. Vieth, R. A. Magrath, A. Sherrick, and H. B. Barner Intermittent Antegrade Tepid Versus Cold Blood Cardioplegia in Elective Myocardial Revascularization Ann. Thorac. Surg., June 1, 1998; 65(6): 1559 - 1564. [Abstract] [Full Text] [PDF]

This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Inderpaul Birdi Mohammad Bashar Izzat Alan J. Bryan Gianni D. Angelini Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Birdi, I. Articles by Angelini, G. D. Search for Related Content PubMed PubMed Citation Articles by Birdi, I. Articles by Angelini, G. D.