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Ann Thorac Surg 1999;67:1547-1555
© 1999 The Society of Thoracic Surgeons

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J. Maxwell Chamberlain Memorial Paper

Influence of cardiopulmonary bypass perfusion temperature on neurologic and hematologic function after coronary artery bypass grafting

^a Division of Cardiac Surgery, Department of Surgery, Baystate Medical Center, Springfield, Massachusetts, USA
^b Division of Neurology, Department of Medicine, Baystate Medical Center, Springfield, Massachusetts, USA

Address reprint requests to Dr Engelman, Division of Cardiac Surgery, Baystate Medical Center, 759 Chestnut St, Springfield, MA 01107
e-mail: richard.engelman{at}bhs.org

Presented at the Thirty-fifth Annual Meeting of the Society of Thoracic Surgeons, San Antonio, TX, Jan 25–27, 1999.

Abstract

Background and Methods. A National Institutes of Health-sponsored trial (1994 to 1998) randomized patients undergoing coronary artery bypass grafting that required three or more grafts to receive perfusion at either cold (20°C), tepid (32°C), or warm (37°C) temperature. The goal of the study was to evaluate morbidity, primarily neurologic dysfunction and secondarily hematologic factors. One thousand seven hundred seventy-seven patients were screened and 291 enrolled. Neurologic function was studied by a dedicated pool of blinded neurologists. A standard test battery termed the Mathew Scale using three subscales—cognitive function, elemental skills, and disability—was used to study central nervous system function. Hematologic function was assessed in 53 of the 291 patients with measurements of postoperative fibrinolytic potential.

Results. All preoperative and operative data were comparable between groups. A decrease in Mathew Scale was seen in 69% of patient from before operation to immediately after operation. However, between the early postoperative study and the 1-month follow-up, 48% of patients had returned to baseline. There was no difference noted across temperature groups in any neurologic parameter of function. In all, 55% of the group were at or above their preoperative level at 1 month. Forty-nine patients suspect for cerebrovascular accident had a computed tomographic scan, but only 13 (4.5%) had a documented cerebrovascular accident (4 patients in the warm, 3 in the tepid, and 6 patients in the cold group). Fibrinolytic changes correlated with perfusion temperature documented that fibrinolysis was most active at 37°C. Thus, increasing perfusate temperature increases fibrinolysis, which was associated with reoperation for bleeding in 4% warm group patients, 1% tepid, and 0% cold group patients (0.1 > p >0.05). No other perioperative complications were temperature related. There were 4 deaths (1.4%) (1 in the warm group, 2 in the tepid group, and 1 in the cold group).

Conclusions. (1) Persistent postoperative neurologic dysfunction at 1 month occurs in 36% of patients undergoing coronary artery bypass grafting and is not related to a cerebrovascular accident; 2) perfusion temperature has no relationship to neurologic function after bypass; and 3) fibrinolytic activity is greatest at warm temperatures.

The concept of warm myocardial preservation was first introduced to us in 1990 at the Oxford (England) International Symposium on Myocardial Preservation [1]. It was clearly a very reasonable approach when combined with retrograde cardioplegia and soon became our preservation technique of choice at the Baystate Medical Center. When no longer faced with the need for myocardial hypothermia, the choice of optimal perfusion temperature became an issue to be addressed. We were then using either warm (37°C), tepid (32°C), or cold (25°C) perfusion for coronary revascularization. The notion of a random trial was developed in 1991 in which perfusion and myocardial preservation temperature would be chosen in the operating room by random assignment with patients entering an IRB-approved protocol. The primary goal of the trial was to study neurologic and neuropsychologic function before operation, at 3 to 4 days after operation, and at 1 month. This would provide objective data regarding choice of a perfusion temperature for routine cardiopulmonary bypass.

The issues raised by this trial were first addressed by Martin and associates [2] from Emory University in 1993 who documented a significant increase in perioperative stroke (3.1% warm versus 1.0% cold) in a large series of patients undergoing coronary artery bypass grafting randomized to either warm or cold perfusion. Because this finding was contrary to our own pilot data and was also contradicted by a very large Toronto Warm Heart Study [3], it was our strong belief that another in-depth random trial should be reported. This was supported and funded by the National Institutes of Health in 1994.

Material and methods

The study was designed to compare three perfusate temperatures, cold (20°C), tepid (32°C), and warm (37°C), for cardiopulmonary bypass in association with three myocardial preservation temperatures, hypothermia (8 to 12°C), tepid (32°C), and warm (37°C), respectively. The patients considered for the study had either elective or urgent coronary revascularization and required three or more coronary bypass grafts, thus ensuring at least a 60-minute bypass time. To limit the risk of aortic, carotid, or intracerebral atherosclerosis, the patients had to be younger than 76 years of age and have no previous history of neurologic dysfunction. Other exclusion criteria were poor left ventricular function (specifically an ejection fraction < 30% by RAO ventriculography), ongoing myocardial ischemia requiring an intraaortic balloon, renal dysfunction with a serum creatinine > 2.0 mg/L, or recent (< 7 days) postinfarction angina. The presence of a carotid bruit was not a contraindication, but significant carotid stenosis by duplex of > 70% was an exclusion criterion. The randomization process (based on a random table) took place in the operating room immediately before operation by choosing the temperature from a sealed envelope. This study was approved March 4, 1993, by our Institutional Human Research Committee.

Neurologic evaluation methodology
Patient enrollment began on February 7, 1994, and the last patient underwent operation on December 4, 1997, just under 4 years of study. A total of 1,777 patients were screened, with 291 enrolled. The major thrust of the study was the neurologic evaluation with patients having preoperative evaluation, usually the day before operation, then 3 to 4 postoperative days before discharge, and at 1 month when returning for a postoperative visit. The neurologist was blinded as to perfusate temperature, and, in fact, the perfusate temperature was known only to the surgeon (RME, JAR, JEF, or DWD) and the study coordinator (CAG). The neurologic vehicle used was the Mathew Scale, as modified by Gelmers and associates [4], which is a recognized monitor of neurologic function and predated the more recent stroke scales. This approach uses an ordinal scale of 0 to 100 and looks at three facets of neurologic assessment: cognitive function, elemental examination, and degree of disability (Table 1 ).

Fast track methodology
Anesthesia was used in a consistent manner across all temperature groups, premedication with lorazepam (1 to 2 mg orally); induction with fentanyl (5 to 15 µg/kg intravenously), midazolam (0.05 mg/kg intravenously), and pancuronium (0.15 mg/kg intravenously); and maintenance with fentanyl (< 10 µg/kg intravenously), and isoflurane titrated as tolerated (usually 0.5% to 1.0%). Extubation occurred as expeditiously as possible consistent with patient safety. Although no medication was given after operation to maintain paralysis, no patients had reversal of the pancuronium. In patients who were hypothermic after operation and shivering, medication was administered to facilitate a comfortable recovery. Fast track extubation and recovery was attempted in every patient [5].

Cardiopulmonary bypass methodology
Cardiopulmonary bypass (CPB) used a Cobe roller pump (Cobe Cardiovascular Inc, Arvada, CO) and the Affinity hollow fiber membrane (Avecor Cardiovascular Inc, Plymouth, MN). Heparin bonding was not used in perfusion tubing or oxygenator. An 8.0-mm Sarns aortic arch cannula (Sarns/3M Health Care, Ann Arbor, MI) or a 20F DLP arterial cannula (DLP Inc, Grand Rapids, MI) was used for aortic cannulation and a 36F dual-drainage single venous catheter from Research Medical (Midvale, UT) was used for venous return. A DLP Gundry RCSP 15F coronary sinus catheter was used for retrograde cardioplegia. For patients undergoing 20°C perfusion, CPB was given at 2 L · min^-1 · m^-2 body surface area and for those undergoing 32 or 37°C perfusion, nearly 3 L · min^-1 · m^-2 body surface area. Venous saturation was maintained at > 70% and mean perfusion pressure regulated to 60 to 80 mm Hg by use of phenylephrine for vasoconstriction and isoflurane for vasodilatation. The hematocrit was maintained 20% during perfusion and at 22% during recovery. Activated clotting times and heparin levels were monitored before bypass and every 30 minutes during CPB. Initial heparin dose was 500 U/kg intravenously and additional heparin was given if the activated clotting time was < 600 seconds or heparin level < 3 mg/kg. The pH regulation throughout the operation was maintained by alpha-stat management. Antifibrinolytics, including amicar and aprotinin, were not administered in this study.

The perfusate temperature used in this study was the only difference between the three groups. In the normothermic group perfusate temperature was maintained at 37°C and no higher. In the hypothermic group (20°C) we deliberately decreased the temperature to the chosen level gradually so that a 10°C maximal difference existed between arterial and venous blood. Core temperature reached 35 to 36°C in the normothermic, 32 to 33°C in the tepid, and 23 to 28°C in the hypothermic patient. Cooling, if indicated, began soon after commencement of CPB and continued until arterial perfusate temperature reached either 32°C (soon after commencing cooling) or 20°C (often taking 15 to 30 minutes). Cross-clamp application and coronary artery bypass grafting were performed immediately upon initiation of CPB. Rewarming began with initiation of the last distal anastomosis, usually the left internal mammary artery to the left anterior descending coronary artery. Again, rewarming was slow with maintenance of a 10°C maximal gradient between arterial and venous blood. Rewarming never exceeded a perfusate temperature of 39°C until 1996 and 38°C from 1996 to 1998.

Myocardial preservation methodology
Three of the 4 surgeons (RME, JAR, and DWD) administered antegrade–retrograde blood cardioplegia to the coronary sinus and each completed vein graft with a DLP octopus adaptor. The proximal anastomoses were performed after declamping using an aortic side-biting clamp. One of the surgeons (JEF) used a single cross-clamp and completed distal and proximal anastomoses in turn using only retrograde cardioplegia for preservation. The cardioplegia solution initially was 4:1 blood-to-crystalloid at the temperature chosen for the study (cold 8 to 12°C, tepid 32°C, and warm 37°C). The solution was changed in 1996 to pure blood using the Quest MPS cardioplegia infusion pump (Quest Medical Inc, Dallas, TX). No change was made in the temperature of administration. Aortic venting was used in each patient. The continuous administration of cardioplegia was interrupted whenever the field to perform the anastomoses was affected. This duration of interruption was documented by us to be about 30% of the arrest time overall when no cardioplegia was given, and the interruption interval did not exceed 10 minutes in any patient [6].

Hyperkalemia was avoided by using a low potassium cardioplegia (total K⁺ at 10 mEq/L) except for induction (total K⁺ at 28 mEq/L). Hyperglycemia was avoided by reducing glucose in the crystalloid when using 4:1 cardioplegia before 1996, and avoiding crystalloid entirely after 1996. The final administered cardioplegia solution was normoglycemic in this study.

Fibrinolytic potential methodology
Measurements of fibrinolytic and prothrombotic potential were studied in a subset of patients with tests done by Colorado Coagulation Consultants, Inc. (Denver, CO). Six tests were performed: tissue plasminogen activator antigen (t-PA), plasminogen activator inhibitor-1 (PAI), plasma antithrombin (or antithrombin III), plasminogen, prekallikrein, and ₂-antiplasmin. Each test was done immediately before operation, immediately after operation, and at 2, 4, 12, and 24 hours. The samples were collected in 3.8% buffered citrate, and the plasma extracted and frozen at -70°C. It was shipped in dry ice to Colorado for analysis.

The specific techniques used for the hematologic studies were (1) t-PA (measured in nanograms per milliliter), the BioPool TintElize test (BioPool/Meditec, Inc, Ventura, CA), which uses the double antibody principle and enzyme-linked immunosorbent assay methods; (2) PAI (measured in units per milliliter), the BioPool Spectrolyse test (BioPool/Meditec), which is a two-stage, enzymatic assay; (3)plasma antithrombin (measured in percent activity), the antithrombin III chromogenic assay, which measures the functional levels of plasma antithrombin by an amidolytic method with use of a synthetic chromogenic substrate (Dade-Behring, Inc, Chicago, IL); (4) plasminogen (measured in percent activity), the chromogenic assay that measures the functional levels of plasminogen by an amidolytic method with use of a synthetic chromogenic substrate (Pharmacia/Kabi, Franklin, OH); (5) prekallikrein (measured in percent activity), the generally accepted one-stage activated partial thromboplastin time measurement (Colorado Coagulation Consultants); and (6) ₂-antiplasmin (measured in percent activity), the chromogenic assay that measures the functional levels in plasma by an amidolytic method with use of a synthetic substrate (Pharmacia/Kabi). Analyses were corrected in each instance for hemodilution by the following calculation: .

The data were analyzed in two ways: first, as the absolute change in activity, X_c - X_p, where X_c is the corrected postoperative value and X_p is the preoperative or baseline value, and second, as the relative change in activity, or percent change from baseline, 100 x (X_c - X_p)/X_p. In the first calculation, the measurement expressed either a change in concentration or percent activity. In the second, the calculation expressed a percent change from the baseline (preoperative) level. If the level increased during CPB, the value was positive and if it decreased, the value was negative.

Statistical and data analysis
All data were collected prospectively and entered into both The Society of Thoracic Surgeons database and the National Institutes of Health Study Database. Temperature groups were compared with the use of simple descriptive statistics such as the mean ± standard error and selected percentiles for some variables. Significance, defined at the = 0.05 level, was determined by ² or Fisher’s exact tests for association, Mantel-Haenszel ² tests for ordered trend across temperature groups for categorical variables, and by least squares or Kruskal-Wallis analysis of variance for continuous scale data. Nonparametric methods were used when the distributional assumptions were in doubt, particularly with the presence of extreme values, which skew the distribution and can result in large differences in error variances across groups. Values reported in the tables are means ± standard errors, even when a nonparametric test was used to assess significance. When differences among the three groups were noted, pairwise t tests (or a t test approximation to Wilcoxon rank-sum statistic), with use of a Bonferroni correction for multiple comparisons, were used to determine wherein lay the differences. Factors associated with either neurologic testing or the temperature group with a p < 0.20 were entered into multifactor analysis of variance models to control for confounding variables and to evaluate for interaction effects.

A multivariate analysis of variance was used to evaluate differences across the temperature groups in "within patient" change from preoperative values (absolute and percent change) for the six hematologic factors. Significance tests for differences among the temperature groups, as well as ordered trend across temperature, were conducted for each factor and across all factors.

Results

General data
There were 291 patients (225 men, 66 women) enrolled, 40% elective and 60% urgent. As can be seen in Table 2 , there was no difference between groups in any preoperative or operative characteristics. All patients except 10 were operated on at the temperature chosen by the random assignment. Operative mortality was 1.4% (4 of 291 patients), and there was no association with temperature. One tepid patient succumbed to a stroke (CVA), one tepid of an anaphylactic reaction to protamine in the operating room, and two patients died of a perioperative myocardial infarction (one cold, one warm). Reoperation for bleeding occurred in 4 warm, 1 tepid, and 0 cold. This has a suggestion of a difference by Fisher’s exact test (two-tailed) with 0.05 < p < 0.10. Measured blood loss after operation was least in cold (844 ± 39 mL) and most in warm (962 ± 69 mL), but this difference was not significant. Administration of blood products was also not temperature related. In each group only 40% to 44% of the patients received blood products during their hospitalization. Myocardial preservation, as expected, was excellent regardless of temperature. There were only three perioperative infarctions, 1 cold, 1 tepid, and 1 warm, and 2 died (1 cold and 1 warm). Four patients developed renal failure, 2 cold, 1 tepid, and 1 warm. As expected, the cold patients had the longest time to extubation, but the difference did not reach significance (Table 2). Consistent with this was the postoperative length of stay, which was longest in the cold group with the lowest percentage of population discharged at 3 to 5 days. Again the difference did not reach significance. Atrial arrhythmias requiring specific antiarrhythmics, occurred in 29% cold, 24% tepid, and 32% warm. This difference was not significant.

There are three logical divisions of the Mathew Score: cognition, the elemental examination, and disability (Table 1). These were recorded and analyzed separately. There were no temperature-related changes in any of these subscales, and therefore they were treated as a whole. Computed tomographic scans were performed in 49 (17%) of the 291 patients to diagnose the presence of a CVA. Positive scans were present in 13 of the 49 for a CVA incidence of 4.5% (13 of 291 patients). The breakdown of scan and of CVA by temperature documented no association with temperature and no association with any individual surgeon. Stroke was diagnosed in 6 cold, 3 tepid, and 4 warm patients, an incidence of 6% cold, 3% tepid, and 4% warm. Intraoperatively, the use of a single cross-clamp technique was associated with three CVAs and partial aortic clamping with 10. Because only one surgeon used a single clamp technique, there was no significant difference in CVA incidence associated with partial aortic clamping.

The computed tomographic scan can be used to suggest cerebral embolism as an etiologic factor for ischemic stroke. Four patients had lacunar strokes (1 cold, 2 tepid, and 1 warm), whereas 9 patients had hemispheric strokes (4 right and 5 left-sided). Although the etiology of ischemic stroke is often uncertain, our neurologist believed them to be embolic, and all but one occurred at time of operation. The latter occurred from new onset atrial fibrillation during recovery. Of the 13 strokes, 8 were only noted on sophisticated neurologic examination and 5 were clearly apparent to patient, family, and physicians. Thus, without this study, the apparent stroke rate would have been recorded as only 1.7%. None of the lacunar strokes would have been apparent other than to a neurologist.

The evaluation of neurologic function as a measurement of the changes associated with cardiopulmonary bypass were examined for sex, age, operative time, cardiopulmonary bypass duration, as well as blood loss after operation. The influence of specific surgeon and interactions among these multiple factors were examined as well. There was no difference noted in Mathew scores by surgeon or in looking at either operative or bypass time. Remarkably, the length of the procedure was unrelated to any measurable decrease in neurologic function. The influence of sex in this analysis documented greater postoperative deterioration in neurologic function in women (-5.6 ± 0.74 compared to -4.5 ± 0.36 in men, p = 0.083), which is of borderline significance. Not unexpectedly, age is a significant (p = 0.003) predictor of worsening postoperative neurologic function by Kruskal-Wallis analysis. The difference in neurologic deficits with operation clearly breaks at age 65, confirmed by pair-wise testing. This is illustrated in Table 4.

Comment

Neurologic studies
The primary goal of this study was to define the role of perfusion temperature on postoperative neurologic function of patients undergoing routine coronary revascularization. A number of studies have looked at a similar patient population but each has differed from this report in an essential way. Martin and associates [2] and Mora and associates [8] used a randomized approach, but their warm group was perfused deliberately at > 37°C to maintain a core temperature of 35° to 37°C during CPB. This may have been a factor in the higher incidence of neurologic dysfunction ascribed to warm perfusion in their study. Singh and associates [9] in 1995 reported on a large series of patients having 37°C perfusion compared retrospectively to a hypothermic group. There was no difference in stroke rates, but detailed neurologic examinations were only performed after focal deficits were noted. This was also not a random concurrent trial. Two prospective random trials were reported in 1994 and 1997 by McLean and associates [10] and Heyer and associates [11] with patients receiving either normothermic or moderate hypothermic perfusion (34° to 37° or 28°C). There was no detectable difference in cerebral dysfunction with sophisticated neurologic evaluation at the two temperatures in either of the two studies. This was, however, different from our own study, which compares 37°, 32°, and 20°C perfusion with core temperature at 35° to 36°C, 32° to 33°C, and 23° to 28°C, respectively.

The influence of temperature on cerebral perfusion and metabolism has been well addressed by Dwyer and associates [12]. Cerebral oxygen consumption is directly related to perfusion temperature, decreasing 7% per °C reduction in temperature [13]. In fact, with the decline in temperature, cerebral flood flow decreases due to increased cerebral vascular resistance. It has been known for many years that this effect of hypothermia affords significant cerebral protection from ischemia during CPB [14]. This protective effect is manifested by both decreased high energy phosphate degradation and the inhibition of excitatory neurotransmitter release [15]. There is, however, a point of diminishing returns. Mild hypothermia (tepid perfusion at 32°C) allows cerebral blood flow to remain in excess of metabolic demands [16]. A more profound degree of hypothermia (< 24°C) impairs cerebral autoregulation and increases cerebral vascular resistance [17]. Despite this, there is no evidence in this study to indicate that hypothermia is detrimental to cerebral function as long as perfusion pressure and flow are maintained.

Hypothermia requires rewarming, and there is substantial data to support the dangers of hyperthermia [18]. In fact, perfusion at only 39°C can accelerate ischemic cerebral injury [18]. Because most CPB procedures are performed with ascending aortic cannulation, the brain is subjected to CBF very near the chosen perfusion temperature. Rewarming hyperthermia is easy to accomplish and leads to cerebral oxygen deprivation with jugular venous bulb desaturation [19]. For this reason since 1996 we deliberately did not use temperatures above 38°C during rewarming and saw no difference in neurologic function between groups either before 1996 or for the entire study. Patients in the hypothermic group were, however, systemically cold when returned to the intensive care unit from the operating room, delaying fast track recovery. This is considered detrimental to the optimal care of the cardiac surgical patient.

Fibrinolytic potential
There is both a contact and a tissue factor pathway for coagulation that have a role in the development of fibrinolysis associated with CPB. The contact or intrinsic pathway is initiated during CPB when plasma Factor XII (or Hageman factor) is activated to Factor XIIa by coming into contact with the foreign material of the bypass circuit [20]. As shown in Figure 1 , Factor XIIa activates Factor XI and through the intrinsic clotting cascade, leads to the generation of thrombin [20, 21]. In additionally, Factor XIIa converts prekallikrein to kallikrein, which in turn activates plasminogen to plasmin [20, 21]. Plasmin acts on fibrin to produce small soluble fragments, termed fibrin degradation products, that are inherently injurious to organ function, and the breakdown of fibrin itself promotes postoperative bleeding [20].

View larger version (43K): [in this window] [in a new window]   Fig 1. The clotting cascade that occurs during cardiopulmonary bypass (CPB) is associated with activation of fibrinolytic enzymes or increased fibrinolytic potential. The contact of blood with an artificial surface leads to activation of Factor XII (Hageman factor) and activated Factor XII leads to conversion of prekallikrein to kallikrein. Both the activated Factor XII and kallikrein degrade plasminogen into plasmin. Activated Factor XII also initiates the clotting cascade and promotes formation of thrombin from prothrombin. Perturbations involving endothelial cells, such as ischemia, cardioplegia, and reperfusion, lead to their stimulation during cardiopulmonary bypass, promoting formation of tissue plasminogen activator antigen, which is an active fibrinolytic enzyme supporting the degradation of plasminogen to plasmin. An antifibrinolytic, plasminogen activator inhibitor-1, is also generated from activated endothelial cells and acts to interrupt this degradation of plasminogen. Plasmin, when formed, acts on fibrinogen and fibrin to form its degradation products, the end stage of fibrinolysis. Interfering with the activity of plasmin is 2-antiplasmin, whereas plasma antithrombin interrupts the activity of thrombin in degrading fibrinogen to fibrin. This analysis specifically measured the following studies marked by an asterisk in the figure: tissue plasminogen activator, plasminogen activator inhibitor-1, plasma antithrombin, plasminogen, prekallikrein, and 2-antiplasmin (-2-ANTIPL). (This figure is modified from an illustration in J Thorac Cardiovasc Surg 1996;112:1622–33).

The present study showed how increased perfusion temperature led to greater fibrinolytic potential immediately postoperatively with significantly increased degradation of prekallikrein (p = 0.017). This indicates greater activity of the contact or intrinsic pathway in the presence of normothermic perfusion. The tissue factor or extrinsic pathway while activated by CPB had no relationship to perfusion temperature. During the first 24 hours of recovery, fibrinolytic activity (decreased plasminogen, increased t-PA) continued but was not increased from the levels measured immediately after operation (data not given).

One consideration that should be addressed regarding the activation of fibrinolysis during CPB concerns the use of heparin-bonded surfaces for extracorporeal circulation. te Velthius and associates [25] have documented a significant reduction in contact activation of kallikrein when using heparin-bonded circuits, which would be associated with less fibrinolytic potential during CPB. The level of endothelial activation during CPB generating t-PA was also markedly reduced by heparin bonding [26]. Such decreased activation will also likely reduce fibrinolytic potential to a large degree. We have not, however, ourselves measured the effect of CPB using heparin-bonded circuits.

In conclusion, the concept that perfusion temperature would have a role in postpump neurologic dysfunction was based on the association of temperature with cerebral metabolic demands [12]. Cardiac surgeons are most concerned about the adequacy of cerebral perfusion at normothermic temperatures. Our study has shown perfusion temperature not to be a factor in central nervous system dysfunction. However, the effect of warm perfusion on fibrinolytic potential was clearly shown to be increased. This was associated with a slight increase in postoperative bleeding and a higher incidence of reoperation for bleeding. It is recommended that the optimal perfusion temperature is the one that permits easy and expeditious rewarming. Tepid perfusion, or allowing the temperature to drift to 32° to 34°C, appears to be best for clinical perfusion.

Acknowledgments

This study was supported by National Institutes of Health grant #1R01 HL-48631.

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