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Mild hypothermia versus normothermia in patients undergoing cardiac surgery

Objective Temperature during cardiopulmonary bypass (CPB) for cardiac surgery has been controversial. The aim of the current study is to compare the outcomes for patients with mild hypothermia versus normothermic CPB temperatures. Methods All patients who underwent cardiac surgery with CPB and temperatures ≥32°C from 2011 to 2018 were included, which consisted of mild hypothermia (32°C-35°C) and normothermia (>35°C) cohorts. Propensity matching (1:1) was performed for risk adjustment. Primary outcomes included operative and long-term survival. Secondary outcomes included postoperative complications. Results A total of 6525 patients comprised 2 cohorts: mild hypothermia (32°C-35°C; n = 3148) versus normothermia (>35°C; n = 3377). Following adjustment for surgeon preference, there were 1601 propensity-matched patients who had similar baseline characteristics (standard mean difference, ≤0.10), including CPB time, crossclamp time, and intra-aortic balloon pump placement. Kaplan-Meier analysis showed no difference in long-term survival (82.6% vs 81.6%; P = .81). Over a median follow-up of 4.4 years, there were no differences in overall mortality (18.1% vs 18.1%; P = 1.1) or readmission (50.3% vs 48.3%; P = .2). Acute renal failure (3.7% vs 2.4%; P = .03) and intensive care unit hours (46.5 vs 45.1; P = .04) were significantly higher with hypothermia. There was no difference between cohorts for postoperative stroke (2.0% vs 2.0%; P = 1.0), reoperation (5.9% vs 6.0%; P = .9), or operative intra-aortic balloon pump placement (1.7% vs 1.8%; P = .9). Conclusions Patients with mild hypothermia during CPB had increased postoperative renal failure and length of intensive care unit stay. Although there was no difference in long-term survival, mild hypothermia does not appear to offer patients appreciable benefits, compared with normothermia.

Conclusions: Patients with mild hypothermia during CPB had increased postoperative renal failure and length of intensive care unit stay. Although there was no difference in long-term survival, mild hypothermia does not appear to offer patients appreciable benefits, compared with normothermia. (

CENTRAL MESSAGE
Following risk adjustment, use of mild hypothermia in cardiac surgery does not offer patients any substantial benefits and may increase postoperative complications.

PERSPECTIVE
Debate surrounds the appropriate core temperature during open heart surgery. Mild hypothermia can confer myocardial and end organ protection from ischemic insult. The current study shows that mild hypothermia is associated with increased postoperative events and minimal, if any, benefits. These findings support the use of normothermia in patients with similar preoperative risk.

See Commentaries on pages 243 and 245.
Cardiopulmonary bypass (CPB) is among the most significant medical advancements over the past century and its use has made modern cardiac surgery possible. However, CPB is associated with numerous perioperative complications, including renal dysfunction, coagulopathy, and neurologic decline. [1][2][3] Although no clear mechanism has been identified, some groups support the use of hypothermic CPB temperatures during bypass for myocardial and multiorgan protection from ischemic injury. 4 The appropriate temperature for CPB is a topic of controversy in cardiac surgery, with proponents of both mild hypothermia and normothermia.
Although mild hypothermia has been shown to preserve myocardial function and reduce postoperative neurological dysfunction, 5 hypothermic CPB bypass temperatures have been associated with numerous perioperative complications, including coagulopathy, slow postanesthesia recovery times, and impaired drug metabolism. 4,6 Moreover, there is evidence that mild hypothermia during CPB does not offer any benefit regarding neuroprotective effects compared to normothermia. 7,8 The objective of the current study was to provide a detailed analysis comparing outcomes for patients who underwent cardiac surgery with normothermic versus mildly hypothermic CBP temperatures. Primary outcomes included early and late survival. Secondary outcomes included postoperative complications and hospital readmission.

Study Population
Patient outcomes were retrospectively gathered from our center's prospectively maintained cardiac surgical database. Use and analysis of the database was approved by the institutional review board and consent waived (STUDY18120143 approved and consent waived April 17, 2019). Patients from 2011 to 2018 were divided into 2 CPB temperature cohorts: mild hypothermia (32 C-35 C) and normothermia (>35 C). Core body temperature measurements were based on bladder probe temperatures.
Elective and urgent cases were included in the analysis; emergency cases were excluded. All Society of Thoracic Surgeons index cardiac surgery procedures were analyzed, including isolated coronary artery bypass grafting (CABG), isolated valve, and CABG with valve procedures. All hypothermic circulatory arrest cases and any patient who underwent cardiac surgery with CPB temperatures <32 C were excluded from primary analysis. The decision to cool a patient was based on a combination of surgeon preference and patient characteristics. Patients were weaned to 35.5 C to 36 C before ceasing CPB.

Statistical Analysis
Baseline patient characteristics. Baseline patient characteristics were compared between temperature cohorts. Wilcoxon rank-sum was used for continuous variables. The c 2 (or Fisher exact test when 25% cell has expected number < 5) was used for categorical variables.
Propensity matching. Propensity score matching used logistic regression that included all baseline characteristics (Table 1) to reduce selection bias in a saturated manner. The individual surgeon and the effect of surgeon preference for CPB temperature was included in the propensity matching. Histograms comparing cohorts before and after matching can be found in Figures E1 and E2.
We used 1:1 greedy nearest neighbor matching, with specified caliper width (0.2) of the standard deviation of the logit of the propensity score. The difference in propensity score between groups was less than or equal to the caliper width. Finally, we checked the balance of the two cohorts using standardized mean difference (SMD). All SMD values were below 0.1, or well balanced.
After propensity score matching, because matched pairs were no longer independent, all calculations were based on matched pairs. McNemar tests were used for categorical variables. Paired t tests (or Wilcoxon signed-rank tests for nonnormal distributions) were used for continuous variables.
Mortality and survival. Long-term survival was compared for each group with the use of Kaplan-Meier curves. A cluster log rank test was used to compare mortality between the Kaplan-Meier curves of each group.
All baseline characteristics were assessed in the univariate Cox proportional hazard model to predict time to death. A shared frailty model for mortality was used to account for the effect of surgeon preference on CPB temperature. Significant covariables were adjusted in the multivariable models of time to death and readmission separately. After matching, a stratified Cox regression with robust variance estimator was used to determine the marginal effect of mortality.
Readmission. All readmissions to systemwide hospitals (>40 branches) were captured in our institution's database. In the event of multiple readmissions for the same patient, time to the first readmission was used in the model.
For readmission over time, cause-specific hazard was calculated using the cumulative incidence function (CIF) (death as a competing risk) in both univariate and multivariable models. CIF was used to generate a curve for long-term readmissions. A competing risk analysis with Fine and Gray regression was used to estimate the risk of readmission and account for the effect of surgeon preference on CPB temperature. After matching, a stratified Gray K-sample test was used to estimate the difference of CIF of readmissions between groups. Figure 1 displays the patient flow diagram. We identified 6525 patients. There were differences between the 2 groups in baseline characteristics before matching (Table E1), including, but not limited to, body mass index, CPB time, and crossclamp time.

Baseline Characteristics
Following adjustment for surgeon preference for CPB temperature, there were 3202 propensity-matched patients (1601 each in the mild hypothermia and normothermia groups) ( Table 1) well-matched (SMD, 0.10) for baseline characteristics and intraoperative variables, including CPB time (101 minutes vs 100 minutes; SMD, 0.036) and crossclamp time (75 minutes vs 74 minutes; SMD, 0.011). Propensity scores histograms before and after matching are in Figures E1 and E2.

Abbreviations and Acronyms
CABG ¼ coronary artery bypass grafting CIF ¼ cumulative incidence functions CPB ¼ cardiopulmonary bypass

Survival and Hospital Readmission
Kaplan-Meier survival showed that there was no difference between mild hypothermia and normothermia cohorts (82.6% vs 81.63%; P ¼ .81) for long-term survival (Figure 3).

DISCUSSION
To our knowledge, the current study is among the largest single-center analyses comparing propensity-matched outcomes for CPB temperature cohorts. For cardiac surgery patients who underwent mild hypothermia (32 C-35 C) versus normothermia (>35 C), we reported no significant differences for short-or long-term survival and hospital readmission. Although long-term survival was not different between CPB temperature cohorts in this study, the increased risks associated with heightened acute postoperative renal failure, calls for close examination of the potential risks versus benefits of mild hypothermia.
In a large meta-analysis, including 44 randomized controlled trials from 14 nations, Ho and colleagues 4 compared the relative risks of normothermic (>34 C) versus hypothermic (34 C) CPB temperatures in adult cardiac surgery. Mortality between bypass temperature cohorts was not significantly different. Likewise, there was no difference in the risk of postoperative stroke and infections, which is consistent with the current study's results. Furthermore, the meta-analysis did indicate a significantly increased risk of requiring blood transfusions, including fresh frozen plasma, red blood cells, and platelets; whereas the current study did not find a statistically significant difference [33.8% vs 31.0%; P ¼ .089]. However, the importance of increased blood transfusions should not be understated, as substantial literature has shown an impact on patient morbidity and mortality. [9][10][11][12][13][14][15] Other randomized prospective data 16 found a reduced need for blood products in patients who had cardiac operations with normothermic CPB temperatures. This is not surprising, given that wellestablished data have shown that even very mild perioperative hypothermia (<1 C below normal temperatures) in patients undergoing surgery is associated with significantly   increased blood loss and transfusion requirements, compared with patients with normothermia. 17 Important findings in the current study include increased blood product use and significantly increased postoperative acute renal failure in the mild hypothermia cohort. Although intraoperative decision making is hard to delineate, it may be that surgeons chose to use mild hypothermia to increase multisystemic organ protection from ischemic injury and myocardial tissue preservation 18 in cases with concerning perioperative patient characteristics or intraoperative factors. If intraoperative protection from cardiac ischemia was improved by hypothermia, we could see an increased need for IABP placement in the normothermia group. However, there is no difference in IABP requirements between temperature cohorts in this investigation, consistent with prior work. 4,16 Although not the primary focus of the current study, it is important to address the often-touted neuroprotective  FIGURE 4. Cumulative incidence of hospital readmission was not significantly different between normothermia and mild hypothermia cohorts. benefits of mildly hypothermic CPB temperatures, 5,19,20 despite accumulating evidence to the contrary. 7,8,21,22 Existing evidence includes prospective randomized data showing increased subclinical cognitive impairment in patients who underwent mild hypothermia 21 and noninferiority of normothermic bypass temperatures 7 in terms of neuroprotection. Indeed, we did not find any difference between CPB temperature cohorts regarding clinically apparent neurologic complications, indicated by similar postoperative stroke. Nonetheless, subclinical neurological deficits are potentially influential to patients' postoperative quality of life and merit further investigation. The decision to offer mild systemic hypothermia during CPB should be based on the available evidence of risks versus benefits. Although prior literature has established the potential efficacy of normothermic temperatures for CPB, in the contemporary era there remains debate as to the appropriate temperature for routine cardiac surgery. The current study provides a large, propensity-matched sample. After accounting for surgeon preference, these outcomes may hold relevance for future decision making regarding CPB temperature. Our results indicate that mild hypothermia does not offer sufficient benefits and may increase patient risk. Therefore, we do not routinely use mild hypothermia for CPB during cardiac surgery.

Limitations
The study is limited in that it was designed based on retrospective data and is influenced by potential confounding and selection bias, which was somewhat controlled for by propensity matching of baseline characteristics. There is a chance that some of the patients were lost to follow-up or were readmitted to out-of-system centers. There may be inherent differences in patients who underwent mild hypothermia that are not accounted for in the study risk adjustment. Variability in surgeon preference for when and if they cooled patients to mild hypothermia is an additional potential source of selection bias. Factors such as transient regional wall motion abnormalities, including concern for poor protection or heightened ischemia risk may have influenced the surgeon's preference for hypothermia. As a retrospective investigation, these data can detect associations but not a causal relationship between hypothermia and outcomes.

CONCLUSIONS
Patients who had mild hypothermic temperatures during CPB had increased postoperative renal failure and length of intensive care unit stay. There was no difference between cohorts for the incidence of postoperative stroke, longterm overall mortality, and readmissions. Moreover, in prior subgroup analysis, we found no significant difference for operative mortality and survival for a comparison between cohorts with hypothermic CPB temperatures (<32 C) and normothermia. This may suggest that normothermia can be appropriate even in patients that some surgeons may cool to lower temperatures. Given these data, there are risks associated with the use of mild hypothermia for cardiac surgery and no clear benefits over normothermia, indicating that patients may fare better with the routine use of normothermia.