CON: Temperature Regimens and Neuroprotection During Cardiopulmonary Bypass: Does Rewarming Rate Matter?

Change in medical practice is a complex and evolutionary process. It proceeds by a series of incremental and sometimes dramatic steps. It may progress in one direction, fall back, and subsequently continue again, perhaps redirected, based on new information, experience, and sometimes further critical review of what has been published. The dynamic nature of practice evolution is well exemplified in the management of cardiopulmonary bypass (CPB) temperature during adult cardiac surgery. For reasons of organ protection, for the first 30 years, most adult cardiac surgery was largely conducted with hypothermic bypass. A radical shift in direction was offered in 1991 with the report of “The Warm Heart Investigators” who described CPB at near normothermia in more than 1000 patients.1–3 Within a few years, normothermic bypass swept across much of North America.4 With these changes, management of CPB temperature became a subject of intense academic discussion. CPB temperature management continued to evolve from 1991 to 2000 and that change represents a dialectic wherein a point was made (normothermic bypass),2,3 a counterpoint was generated (normothermic bypass worsens outcomes!),5 and a synthesis resulted (conduct of CPB at about 34°C).6,7 This evolution was informed by study, experience, and discussion of subtle practice differences that were not discernible until those discussions took place. This represents the obligation of academic medicine. It is the strength of the “pro-con” format and the reason why some of the conclusions of the Grigore et al. review8 demand objection. There are 2 primary conclusions/recommendations of the Grigore et al. review8 that are objectionable. The first (and less important) is that there is meaningful evidence to support slow warming during CPB, and the second is the recommendation to wean from CPB at 34°C–35°C. Each of these will be discussed separately. DOES SLOW WARMING IMPROVE NEUROLOGIC OUTCOME? No conclusion should be stated more strongly than the strength of the evidence supporting it. The evidence supporting an outcome’s advantage to slow warming is scarcely discernible. As such, the specific clinical recommendation to adopt slow warming is poorly justified. A handful of interrelated reports, which include much republished data, are the foundation for the recommendation for slow warming. In 2001, Grigore et al.9 published a randomized trial examining the effect of normothermic and hypothermic bypass on cognitive outcomes. With 300 patients randomized, the authors concluded that “There were no differences in neurologic or neurocognitive outcomes between normothermic and hypothermic groups….” In addition to that report, there have been at least 14 studies describing the effect of bypass temperature on neurologic outcomes.1,10–21 Of 14 studies, 9 showed no difference in outcome between normothermic and hypothermic CPB groups, 1 showed worse outcomes with cold bypass, and 4 showed worse outcomes with warm bypass. Of the latter 4 studies, 1 had approximately 30 patients in each of 3 groups, and the report was followed by a commentary that faulted the study’s statistical power, cognitive testing methods, and data analysis. Although a wide range of study design, practice, and forms of analysis are included in these 14 reports, 10 showed no benefit to hypothermia. With thousands of patients included in this group of studies, one must conclude that CPB temperature is not a primary determinant of neurologic outcome and therefore (indirectly), if hypothermic CPB is not neuroprotective, then it is unlikely that management of rewarming rate during that brief period would result in improved outcomes. When the randomized trial of CPB temperature by Grigore et al. did not show a difference in cognitive outcomes as a function of bypass temperature, the investigators looked at postoperative temperature in the same patients and published the data separately.22 The hypothesis was that postoperative cerebral hyperthermia was a determinant of cognitive dysfunction. In that study, cerebral hyperthermia was defined in either of 2 ways: 1) the maximum temperature in the first 24 hours and/or 2) the area under the curve for temperature more than 37°C. They found that peak temperature was not a determinant of cognitive outcome, whereas area under the curve for temperature >37°C was associated “… albeit weakly, with a greater amount of cognitive dysfunction.”22 Data from the original randomized 2001 study by Grigore et al.9 was reported a third time when a subset of that negative outcome trial was used to examine the effect of rewarming speed on cognitive outcomes.23 The cognitive data were analyzed as a continuous variable (better or worse) and as a dichotomous variable (defect present or not). The final group sizes completing 6-week cognitive assessment with usable data were 78 and 49 patients in the control and slow warming groups, respectively. Univariate analysis did not show a rewarming effect on cognitive outcome nor did treatment of cognitive outcome as a dichotomous variable in multivariate analysis. Additionally, a model controlling for comorbidities, using multivariable logistic regression, found that “… treatment group did not predict the presence of cognitive deficit.”23 However, despite these analyses, the authors concluded a positive effect of slow rewarming because treatment of cognitive outcome as a continuous variable was associated with greater improvement in cognitive performance than conventional rewarming.6 These are the data on which the author of the review advocates “slow rewarming.” As a practicing anesthesiologist at a very busy cardiac surgical center and as an academic with expertise in CPB temperature, cerebral blood flow and metabolism, and postcardiac surgical neurologic outcomes, it is very difficult to support the reviewer’s conclusion to rewarm slowly based on critical and detailed review of all the available evidence. It is important to note that this reviewer agrees that cerebral hyperthermia should be avoided, but this is clearly a different conclusion from advocating slow rewarming. In cardiac surgery, ours was the first group to report: 1) cerebral hyperthermia during rewarming, 2) the gradient that exists between nasopharyngeal (NP) and brain temperature, and 3) the probable cause of this phenomenon.24 Broad dissemination and attention to these findings and subsequent practice change are important practical improvements in CPB practice in the last decade. A variety of practices will prevent cerebral hyperthermia during bypass.25 These include less cooling and less need to rewarm, rewarming earlier, facilitated warming, and better monitoring of brain temperature. Slow warming can reduce the likelihood of cerebral hyperthermia but should not, as the authors suggest, be advocated for its own sake. SHOULD WE WEAN FROM BYPASS HYPOTHERMIC? The second major conclusion of the Grigore et al. review8 that is objectionable is the recommendation to wean from bypass at 34°C–35°C in high-risk patients. This is far more important than advocating slow rewarming because it puts patients at risk for a theoretical benefit. The foundations of what we do in the operating room or intensive care unit (ICU) are threefold: strength of scientific evidence, practicality, and our experience and judgment. If we consider coming off bypass “cool,” from each of these perspectives, the recommendation by Grigore et al. to come off “cool” is untenable. Body temperature profoundly affects most of the physiologic variables relevant to a cardiac surgical patient. Even mild hypothermia can affect whole-body oxygen consumption, shivering, systemic vascular resistance, cardiac output, respiratory demands, and glucose homeostasis, as well as duration of mechanical ventilation, risk of myocardial ischemia, bleeding, and infection. As our surgical population has aged and become more complex, outcomes and our resource utilization will be meaningfully influenced by such variables. Coming off “cool” has been reported in study populations of 111, 13, and 133 patients.11,26,27 In the study by Nathan et al.,26 patients were randomized to undergo CPB with rewarming either to 37°C or 34°C NP temperature. The primary end point of the trial was cognitive outcomes at 1 week, with ICU variables such as chest tube output, intubation time, myocardial infarction, and infection as secondary outcomes. At 1 week, 62% of the control patients had cognitive decline versus 48% in the hypothermic group.26 Although incomplete rewarming in the operating room is feasible, there is insufficient evidence that the theoretical benefit offsets probable disadvantages. The problem with terminating bypass hypothermic is that body temperature will continue to decrease after bypass, and the magnitude of this afterdrop is related to the temperature at the termination of bypass28 (Fig. 1). If bypass is terminated with an NP or venous return temperature of 37°C, core temperature is often near 35°C on leaving the operating room. This occurs, in part, because bypass rewarming is not uniform. Blood flow to muscle and viscera may be reduced by 50%–80% during bypass29; therefore, temperature in the deep quadriceps may still be 32°C when NP or cardiac temperature is 37°C at the end of CPB.30 Subsequently, after weaning, heat is shifted from the core to the periphery and core temperature decreases. The patient also continues to lose heat to the environment. One would predict that, for most patients, weaning from CPB with a core temperature of 34°C–35°C will be associated with unacceptably large whole-body thermal debt in the ICU.Figure 1.: Relationship between temperature afterdrop and bladder temperature at termination of bypass. (Reproduced from Ramsay et al.28 with permission).Postoperative hypothermia may contribute to reduced cardiac output and increased systemic vascular resistance, a more frequent incidence of ischemia, increased respiratory demands, and more bleeding.31,32 In cardiac surgery patients, inadequate rewarming profoundly increases systemic vascular resistance and reduces cardiac output. It is only after reestablishment of body temperature that these normalize. This was well demonstrated by Joachimsson et al.31 who showed these deleterious physiologic effects nearly 20 years ago (Fig. 2). The study by Nathan et al.26 was underpowered to assess these important outcomes. Related, hypothermia is not compatible with early extubation. In the report by Nathan et al., the mean intubation time was about 17 hours. A 6-h postoperative intubation time is a quality indicator according to the Society of Thoracic Surgeons, so arriving in the unit cold is not compatible with current practice and quality goals.Figure 2.: Postoperative systemic vascular resistance and cardiac index in cardiopulmonary bypass (CPB) patients undergoing extended (•) or standard (○) rewarming. Standard: T rectal 33.8°C at termination of CPB, Extended: T rectal 36.8°C. Postoperative ventilatory and circulatory effects of extended rewarming during CPB. (Reproduced from Joachimsson et al.31 with permission).Whereas most of the reports of the adverse effects of postoperative hypothermia are in noncardiac surgical patients, the article by Insler et al.32 is a notable exception. In a multiyear study at the Cleveland Clinic, the adverse effects of postoperative hypothermia were described in a study population of 5700 coronary artery bypass graft patients. Patients were classified as hypothermic when their temperature on arrival in the ICU was <36°C. There were approximately 1600 patients who were hypothermic and after adjusting for overall severity of preoperative condition, patients arriving in the ICU at <36°C had increased mortality, more blood transfusions, longer intubation time, and a longer ICU stay.32 Although the study can be faulted because it was retrospective and sicker patients are more likely to arrive in the ICU cold, it has the power of huge numbers and, as we will see later, these observations are very consistent with the experience of cardiac anesthesiologists at major cardiac centers. The report by Nathan et al.26 is the primary source of clinical support for recommending weaning from CPB at 34°C. In addition to the host of problems with postoperative hypothermia in cardiac surgery patients, it is not clear whether any meaningful neurologic benefit is achievable with such a practice. In the Nathan et al. study, coming off bypass cold was associated with a 48% incidence of cognitive impairment at 1 week versus 62% in the control group. This 14% difference in incidence is clinically negligible and was seen 1 week after surgery. This early postoperative period has a tremendous amount of “noise” in cognitive testing and, for that reason, testing during that interval is not recommended by the consensus conference on cognitive testing in cardiac surgery.33 More meaningful results, obtained 3 months postoperatively,26 showed that in 10 of 11 cognitive tests there was no difference between groups. Relative to the downside of postoperative hypothermia, a difference in 1 of 11 tests is not clinically meaningful even if it is statistically significant. Nathan et al.34 followed up this report 5 years later and concluded that no difference in cognitive outcomes could be conclusively demonstrated in long-term follow-up. A third study by Nathan’s group11 examined the cognitive effect of 34°C bypass without rewarming. Compared with a 37°C group, no improvement in cognitive outcome was demonstrated. As such, there is negligible evidence to support the contention that incomplete warming improves neurologic outcomes. Another observation bears on the recommendation by Grigore et al. to wean from CPB cold to reduce cognitive injury. There is growing evidence that postoperative cognitive dysfunction is not primarily determined by intraoperative ischemia. It is likely that cognitive dysfunction is the expression of underlying chronic brain disease. Multiple lines of reasoning are converging on this conclusion, but the hypothesis is most strongly supported by neuroimaging studies. In a study limited to older patients, we used diffusion-weighted magnetic resonance imaging to document perioperative brain ischemia in cardiac surgical patients and conducted postoperative cognitive testing.35 We found that the incidence of postoperative cognitive dysfunction was unrelated to perioperative cerebral ischemia (Fig. 3). Patients with and without cerebral ischemia had the same incidence of cognitive decline. This suggests that postoperative cognitive dysfunction may be an epiphenomenon. If postoperative cognitive decline is primarily an expression of preexisting chronic brain disease, then there is no benefit to coming off bypass cold, only risk, and the practice of weaning cold to prevent cognitive dysfunction (or maintaining postoperative hypothermia) is indefensible.Figure 3.: Incidence of cognitive decline in patients with and without acute cerebral infarction (□ = ischemia; ▪ = no ischemia). Postcardiac surgical cognitive impairment in the aged using diffusion-weighted magnetic resonance imaging. (Reproduced from Cook et al.35 with permission).Medical practice evolves from the intersection of investigation and experience. We potentially place our patients and ourselves at risk if we are strictly academic and divorced from experience. Four of the largest cardiac surgical institutions in North America are the Cleveland Clinic, the Mayo Clinic, the Texas Heart Institute, and the University of Pittsburgh hospitals. After reviewing the literature, I solicited the opinion of the cardiac division heads at each of these institutions, informed them of this editorial piece, and asked if they advocated weaning from bypass at 34°C–35°C or if this was part of their practice. Their responses were as follows: “It is not our standard to wean patients from cardiopulmonary bypass at 35°C. We typically rewarm to between 36°C and 36.5°C. It is rare that we warm all the way to 37°C, as we worry that the brain temperature will be above 38°C in that situation.”—Martin Giesecke, MD (formerly of) Texas Heart Institute.* “Occasionally our surgeons come off bypass cold, 34.8°C to 35.8°C, and it’s a problem. The patients bleed excessively, require products and red cells, and no one likes it, especially up in the unit … But otherwise, no, we never come off at 35°C …”—Michael Licina, MD and Michael O’Connor, DO, Cleveland Clinic.† “… We do not adhere to the practice of weaning from CPB at 34–35°C as risk seems to outweigh potential benefit. Our standard practice is to separate from bypass when the patient’s temperature reaches 37–37.5°C. Rather than using hypothermia for neurologic protection, we tend to maintain higher mean arterial blood pressures throughout the case and we have started to use cerebral oximetry as a monitor to gauge cerebral perfusion.”—Erin Sullivan, MD, University of Pittsburgh.‡ “Bleeding and heart failure are the major morbidities in cardiac surgery; the sicker the patient, the warmer they need to be. Postoperative cognitive dysfunction is probably an epiphenomenon.”—David Cook, MD, Mayo Clinic, Rochester.§ Bleeding and heart failure are the major morbidities in cardiac surgery. For these, hypothermia is the problem, not the solution. CPB creates physiologic conditions (pulselessness, temperature change, and acute hemodilution) that are outside the mammalian evolutionary experience. Neither hyperthermia nor hypothermia is normal. There is no evidence to support slow warming independent of preventing hyperthermia. Tepid bypass, 34°C–35°C, is probably the ideal compromise and requires subjecting the brain to minimal temperature change (up or down). Furthermore, do not come off bypass at 34°C–35°C, and, if I am old and sick, get me warm and keep me warm. Everything else is academic.