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Ann Thorac Surg 2009;87:489-495. doi:10.1016/j.athoracsur.2008.10.078
© 2009 The Society of Thoracic Surgeons
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Right arrow Coronary disease

Original Articles: Adult Cardiac

Effects of Mild Hypothermia and Rewarming on Renal Function After Coronary Artery Bypass Grafting

Munir Boodhwani, MD, MMSca, Fraser D. Rubens, MD, MSca, Denise Wozny, BAb, Howard J. Nathan, MDb,*

a Division of Cardiac Surgery, University of Ottawa Heart Institute, Ottawa, Ontario, Canada
b Division of Cardiovascular Anesthesia, University of Ottawa Heart Institute, Ottawa, Ontario, Canada

Accepted for publication October 28, 2008.

* Address correspondence to Dr Nathan, H341, 40 Ruskin St, Ottawa, Ontario, K1Y 4W7, Canada (Email: hnathan{at}ottawaheart.ca).


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Comment
 Acknowledgments
 References
 
Background: Hypothermia is a potential strategy for visceral organ protection during cardiopulmonary bypass (CPB). We report data from two randomized studies evaluating mild hypothermia and rewarming on postoperative renal function in cardiac surgical patients.

Methods: Patients undergoing nonemergency, isolated coronary artery bypass grafting were enrolled into two studies. In the first, 223 patients were cooled to 32°C during CPB and randomly assigned to rewarming to 37°C (RW-37°) or 34°C (RW-34°). The second study randomized 267 patients to sustained mild hypothermia at 34°C (S-34°) or normothermia (S-37°) without rewarming. Serum creatinine levels were measured. Creatinine clearance was calculated. Significant renal dysfunction was defined as a 25% increase in serum creatinine or a 25% decrease in creatinine clearance postoperatively.

Results: Postoperative serum creatinine levels were persistently higher in the RW-37° patients than in the RW-34° group (p < 0.01). RW-37° patients had a higher incidence of renal dysfunction (17%) than RW-34° patients (9%, p = 0.07). Sustained mild hypothermia had no beneficial effect on postoperative serum creatinine levels (p = 0.44) or significant renal dysfunction: S-34°, 20% vs S-37°, 15% (p = 0.28). Diabetes (odds ratio [OR], 1.6; 95% confidence interval [CI] 1.3 to 2.1), prolonged CPB time (OR, 1.1; 95% CI, 1.0 to 1.2), and rewarming (OR, 1.4; 95% CI, 1.0 to 1.9) were independent risk factors for significant renal dysfunction. Renal dysfunction was associated with longer hospital stay (8.4 ± 0.8 vs 6.8 ± 04 days, p < 0.001).

Conclusions: Sustained mild hypothermia does not improve renal outcome. However, rewarming on CPB is associated with increased renal injury and should be avoided.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Comment
 Acknowledgments
 References
 
Renal injury after cardiac operations is associated with increased death, need for dialysis, and longer intensive care unit and hospital length of stay [1–3]. In addition to its clinical effect, renal failure also significantly increases resource consumption and the economic burden of cardiac operations [4]. The prevalence of preoperative renal insufficiency in the cardiac surgical population, which is an important risk factor for postoperative renal dysfunction, appears to be increasing [5]. Various pharmacologic interventions, such as N-acetylcysteine, fenoldopam, and sodium nitroprusside have been evaluated in clinical trials to ameliorate renal injury, but none have been shown to have significant clinical benefit [6–9].

A number of mechanisms have been proposed to explain the renal dysfunction that occurs after a cardiac operation, including ischemic injury that may be due to hypoperfusion or abnormal perfusion associated with nonpulsatile flow, inadequate venous drainage during cardiopulmonary bypass (CPB) [10, 11], and hemodilution [12, 13]. Ischemic injury may also be secondary to emboli, consisting of atheromatous debris, fat, or gaseous material. Toxin exposure from endogenous (inflammatory cytokines) or exogenous (nephrotoxic medications) sources may cause direct injury. Patient factors [14, 15], including preexisting renal insufficiency, diabetes, older age, and even genetic factors [16], predispose patients to postoperative renal dysfunction.

Hyperthermia during rewarming on CPB has been considered a possible cause for exacerbation of ischemic renal injury. In animal models, hyperthermia has been shown to exacerbate ischemic organ injury, whereas hypothermia has been shown to reduce it [17–19]. A number of clinical studies have attempted to study the effect of temperature on renal outcome after cardiac procedures and all have failed to demonstrate an effect [20–22].

We examined the effects of mild hypothermia on postoperative renal dysfunction in the context of two randomized protocols, initially designed to assess the effect of temperature on neurocognitive outcome after coronary artery bypass grafting (CABG). In the first protocol, patients were cooled to 32°C during aortic cross-clamping and randomized to warming to 34°C or 37°C, without hyperthermia. In the second protocol, patients were randomized to sustained mild hypothermia at 34°C vs normothermia (37°C) without any rewarming on CPB. These treatment arms represent four clinically relevant patient management strategies and present a unique opportunity to determine the independent effects of hypothermia and rewarming on postoperative renal function.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Comment
 Acknowledgments
 References
 
Patient Population
The studies were conducted at the University of Ottawa Heart Institute to examine the effects of temperature on postoperative neurologic outcome after CABG. Study protocols were approved by the institutional Ethics Review Board and written informed consent was obtained from all patients. In study 1 [23], patients were recruited between August 1995 and February 1998 and randomly assigned to rewarming to 34° or 37°C (nasopharyngeal) after being cooled to 32°C during aortic cross-clamping. In study 2 [24], patients recruited between September 2000 and December 2004 were randomly assigned to 34° or 37°C sustained throughout the operative period (Fig 1).


Figure 1
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  		Fig 1. Schematic shows temperature management in the two study protocols. In study 1 (dashed line), all patients were cooled to 32°C during aortic cross-clamping and randomized to 34° or 37°C after unclamping. In study 2 (solid line), patients were randomized to 34° or 37°C during the entire operative period. (CPB = cardiopulmonary bypass; OR = operating room.)

 
In both studies, patients aged older than 60 years undergoing nonemergency, isolated CABG and without history of stroke or other neurologic disease were included. Patients with a serum creatinine concentration greater than twice normal (normal reference range of 62 to 106 µmol/L for men and 35 to 88 µmol/L for women) were excluded (Fig 2).


Figure 2
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  		Fig 2. Patient recruitment and enrollment for study 1 and study 2. (CNS = central nervous system; RW = rewarming group; S = sustained temperature.)

 
Randomization was performed in blocks of eight and stratified according to age older than 75 years. Treatment assignment was concealed in opaque sealed envelopes that were assigned sequentially as patients were enrolled and opened immediately before the initiation of the intervention. Patients were unaware of the treatment assignment, which was not concealed from the operating room staff.

Intraoperative Protocol
The intraoperative protocols have been previously described in detail for both studies [23, 24]. CPB was performed by way of an ascending aortic cannula and a two-stage right atrial cannula using membrane oxygenators and 43-µm arterial line filters (Cobe Cardiovascular, Arvada, CO) maintaining a nonpulsatile flow at 2.5 to 2.8 L/min/m2. Mean arterial pressure was maintained between 50 and 80 mm Hg using phenylephrine or isoflurane. Blood gases were not temperature corrected. After application of the aortic cross-clamp, cardiac arrest was induced and maintained with antegrade cold crystalloid or blood cardioplegia.

In the first study, all patients were cooled to 32°C. When the surgeon asked for rewarming to begin, usually about 10 minutes before release of the aortic cross-clamp, patients were randomly assigned to rewarming to 34°C (RW-34°C) or 37°C (RW-37°C). Oxygenator outlet temperatures were kept below 37.5°C to avoid hyperthermia. In the second study, the temperature intervention was begun upon the patient's entry into the operating room and sustained throughout the operative period. High-efficiency thermal pads were applied to the patient's back and posterior aspect of the upper leg. The pads were connected to a water-circulating thermal control system (Arctic Sun, Medivance Corp, Louisville, CO), and cooling to 34°C (S-34°C) or warming to 37°C (S-37°C) was begun. Patients were kept as close as possible to nasopharyngeal temperatures of 37° or 34°C throughout the intraoperative period. The CPB heater/cooler was used only to make small corrections in temperature during CPB; the temperature of blood leaving the oxygenator was monitored and recorded and was not allowed to exceed 37.5° or 34.5°C in the normothermic and hypothermic groups, respectively. Patients were maintained at the study temperatures until arrival in the intensive care unit (ICU), where forced-air warming blankets were applied.

Outcome Measures
A variety of definitions have been proposed for renal dysfunction after cardiac operations using two clinical measures, namely serum creatinine level and estimated creatinine clearance. No consensus currently exists regarding the best definition of postoperative renal dysfunction. Renal dysfunction, defined either as an absolute postoperative serum creatinine value or a 25% increase compared with baseline, has been shown to be closely associated with early and late mortality, morbidity, and need for dialysis [3, 25]. Recently, the Acute Dialysis Quality Initiative (ADQI) has recommended that the definition of renal dysfunction should preferably reflect change from baseline rather than absolute values, and that estimated creatinine clearance, which has also been shown to be correlated with clinical outcome [26], is a preferred index for determining renal dysfunction [27]. For this study, renal dysfunction was defined using both of these clinical indicators as follows:

Serum creatinine levels were measured on all patients preoperatively, on the day of operation, on postoperative days 1, 2, and 4, and on other occasions if clinically indicated. The estimated creatinine clearance (ECrCl) was calculated using the Cockroft-Gault formula [28]:


Formula



Formula

The maximum change in serum creatinine and estimated creatinine clearance was determined using the preoperative and the highest postoperative serum creatinine values. Patients were classified as having renal dysfunction if they had either a 25% or more reduction in estimated creatinine clearance or a 25% or more increase in serum creatinine values.

The studies were prospectively designed to evaluate the postoperative incidence of neurocognitive deficits, which has been previously reported [23, 24]. A number of safety variables were also recorded. These included nasopharyngeal, bladder, and oxygenator outlet temperatures, use of blood products, bleeding from chest tubes for 24 hours, use of inotropic and vasopressor drugs, time on CPB, and aortic cross-clamp time. Time until extubation, days in the ICU, and days in the hospital were noted. Myocardial infarction was defined as the appearance of new Q waves exceeding 0.04 seconds in duration in at least 2 contiguous leads. Creatine kinase concentration was measured on the morning after the operation. Troponin T was determined if the total creatine kinase was greater than 800 U/L. Abnormal left ventricular function was defined as left ventricular class II or greater on left ventricular angiography. Chest and leg wound infections were documented by the infection control service using established definitions [24].

Statistical Analysis
Data are presented as mean ± standard error of the mean or median (interquartile range). Continuous variables were compared by using unpaired t tests if normally distributed or the Wilcoxon rank sum test for nonnormally distributed variables. The {chi}2 test was used to compare categoric data. The Fisher exact test was used when an expected cell count was less than 5. Since serum creatinine values represented correlated repeated measures data, they were analyzed using mixed models using an unstructured covariance matrix. The models included a term for treatment, time (ie, postoperative day), and time by treatment interaction, representing differential changes over time between groups.

Multivariate regression models were constructed to determine predictors of significant postoperative renal dysfunction. A total of 15 preoperative variables were assessed as univariate predictors and included in the construction of the multivariate model if they met the liberal threshold of p < 0.2. The design variable (ie, temperature assignment) was included in the final model. A stepwise selection algorithm was used for the development of the multivariable model to minimize collinearity. Confounding was assessed using a threshold of 10% change in the β estimate of the variable of interest. Interaction terms between significant variables were evaluated but only included if statistically significant. Finally, the final model was bootstrapped 1000 times to assess whether the model was overfit to the data.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Comment
 Acknowledgments
 References
 
Baseline characteristics were similar between treatment and control groups in the two studies. However, patients in the second study had a higher incidence of diabetes and peripheral vascular disease and a lower incidence of left ventricular dysfunction. Preoperative serum creatinine levels and estimated creatinine clearance were similar across all groups in both studies (Table 1). Intraoperative and postoperative characteristics were largely similar between groups (Table 2).


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  		Table 1 Baseline Patient Characteristics
 

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  		Table 2 Intraoperative and Postoperative Characteristics
 
Overall, the incidence of significant renal dysfunction (defined as a 25% increase in serum creatinine levels or 25% reduction in estimated creatinine clearance) was 16% (76 of 484). Patients with renal dysfunction had longer in-hospital length of stay (8.4 ± 0.8 vs 6.8 ± 04 days, p < 0.001). No patients in this cohort required postoperative dialysis.

Preoperative and postoperative serum creatinine values are depicted in Figure 3. In study 1, patients in the rewarmed group demonstrated increased postoperative creatinine values compared with controls (Fig 3A, p < 0.01). Furthermore, the incidence of significant renal dysfunction was higher in the rewarmed group compared with controls, but this difference did not reach statistical significance (17% vs 9%, p = 0.07). In study 2, postoperative serum creatinine levels were similar between the hypothermic and normothermic groups (Fig 3B, p = 0.44), and there was no difference in the incidence of renal dysfunction between groups (hypothermic, 20% vs normothermic, 15%; p = 0.28).


Figure 3
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  		Fig 3. Postoperative serum creatinine levels of patients in (A) study1 and (B) study 2 are presented with the standard error of the mean (range bars). (A) Patients undergoing rewarming had significantly higher postoperative serum creatinine levels than controls (*p < 0.001). (B) The difference in serum creatinine levels in the sustained hypothermic and normothermic patients was not statistically significant (p = 0.44).

 
Univariate predictors of significant renal dysfunction in the entire cohort included diabetes, CPB time, temperature protocol used, use of an intraaortic balloon pump, preoperative serum creatinine level, and preoperative estimated creatinine clearance. Multivariate analysis demonstrated that diabetes (odds ratio [OR], 1.6; 95% confidence interval [CI], 1.3 to 2.1), prolonged CPB time (OR, 1.1; 95% CI, 1.0 to 1.2 for every 10 minutes), and rewarming (OR, 1.4; 95% CI, 1.0 to 1.9) were independent risk factors for significant renal dysfunction. Preoperative estimated creatinine clearance showed a strong trend as an independent predictor of renal dysfunction per 10-mL/min change (OR, 1.1; 95% CI, 1.0 to 1.2; p = 0.05).


   Comment
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
Acknowledgments
 References
 
Data from our two randomized controlled trials, with more than 450 patients, demonstrate that in a low-risk CABG population, postoperative renal dysfunction occurred commonly (16%). Sustained mild intraoperative hypothermia did not appear to have a nephroprotective effect, as determined by postoperative serum creatinine levels or by the occurrence of the dichotomous end point of renal dysfunction. On the other hand, rewarming from 32° to 37°C during a period of 10 to 15 minutes resulted in elevated postoperative serum creatinine levels and higher incidence of postoperative renal dysfunction compared with control patients rewarmed to 34°C. In addition to rewarming, CPB time and the presence of diabetes were predictors of renal dysfunction after CABG.

Acute renal failure requiring dialysis is a relatively rare postoperative complication that occurs in 1% to 4% of patients [2, 4, 14]. Although it is associated with dramatic increases in mortality (upwards of 50% to 70%), its rare occurrence makes it a difficult end point to study in clinical trials. Renal dysfunction has been frequently used as a surrogate outcome measure for reporting renal outcomes, determining risk factors, and assessing treatment benefits. Varying definitions have been proposed for postoperative renal dysfunction using serum creatinine levels, estimated or measured creatinine clearance, as well as urinary excretion of certain proteins.

The ADQI group [27], in an attempt to obtain consensus on definitions of renal failure, made recommendations that the change from baseline in serum creatinine or estimated creatinine clearance be used whenever possible rather than single absolute values and that urinary biomarkers and calculated creatinine clearance have questionable clinical relevance and can be cumbersome to obtain. They further suggest a 25% reduction in estimated creatinine clearance as a definition of mild renal dysfunction.

Wijeysundera and colleagues [26] examined a variety of definitions of postoperative renal dysfunction and also found that using a 25% change in estimated creatinine clearance as a cutoff point provided the optimum balance between sensitivity and specificity for the hard clinical end points of mortality, need for dialysis, and ICU stay. Loef and colleagues [25] reported increased hospital mortality (14%) as well as increased long-term mortality in patients who have a 25% postoperative increase in serum creatinine levels. Numerous other studies have used a variety of definitions that are quantitatively similar to the 25% cutoff point and verified that patients meeting this definition have a higher mortality, need for dialysis, and longer ICU and hospital length of stay. In unselected populations of patients undergoing cardiac operations, this degree of renal dysfunction occurs in 10% to 25% [15, 22, 26].

Consistent with the recommendations of the ADQI, we defined renal dysfunction as either a 25% increase in serum creatinine levels or a 25% decrease in estimated creatinine clearance. We sought to use a sensitive definition that would identify patients with renal dysfunction in our low-risk population (patients with significant preoperative renal insufficiency were excluded by design) while still maintaining the clinical relevance of this end point. A more conservative definition would result in a lower incidence of the complication and potentially miss an effect of the intervention. In our entire cohort, the incidence of this end point was 16%, which is consistent with previous reports. Although the mortality rate (n = 4) was too low to evaluate its association with the occurrence of renal dysfunction, multiple previous reports have demonstrated the clinical relevance of these definitions [3, 26]. Furthermore, we found, consistent with previous reports, that patients with renal dysfunction had longer in-hospital stay.

A more stringent definition of postoperative renal dysfunction (≥50% change in serum creatinine level) has also been reported and has stronger correlation with "hard" clinical end points. However, this definition of renal dysfunction has lower sensitivity and only occurred in 5% of patients in our cohort. A post hoc sample size analysis reveals that for an {alpha} level of 0.05, power of 80%, and an incidence of renal dysfunction of 16% in the control population, our study was powered to detect an incidence of 5.8% in the treated group. The actual incidence was 17% in the rewarmed group vs 9% in the non-rewarmed group. Thus, adequately powered prospective studies are needed to validate and confirm these findings. Whether postoperative renal dysfunction has implications for the later occurrence of chronic renal insufficiency remains to be answered.

The protective effects of hypothermia on organ function in the setting of ischemic injury have been previously demonstrated in animal models. In rodent models of renal ischemia and reperfusion, hyperthermia is associated with increased renal injury whereas hypothermia is protective [17, 18]. The effects of temperature on tissue metabolic rate and related effects on energy and nutrient demand, as well as effects of hypothermia on mediation of reperfusion oxidative injury, are likely mechanisms responsible for this phenomenon.

In the clinical setting, however, the benefits of hypothermia remain debated. Swaminathan and colleagues [22] examined the effects of warm (35.5° to 36.5°C) vs cold (28° to 30°C) CPB management and found no difference between patient groups in renal outcome. Notably, active rewarming was used in both groups. Regragui and colleagues [20] reported the results of a small, randomized trial of 30 patients that evaluated three temperature management protocols and found no difference in urinary proteins measured.

Our study suggests a clinically measurable effect of temperature on postoperative renal dysfunction. Although no difference was noted between the sustained mild hypothermia and normothermia groups, rewarming was associated with higher levels of postoperative serum creatinine and a higher incidence of renal dysfunction. This was confirmed on multivariate analysis, which identified rewarming as an independent risk factor for renal dysfunction with a 40% greater odds of dysfunction in rewarmed patients compared with controls. The mechanisms for this increased renal dysfunction were not specifically explored in this study, but evidence suggests that different tissue beds rewarm at different rates during whole body rewarming. In fact, animal studies have suggested that the kidney, with its high perfusion, rewarms even more rapidly than the brain, and renal temperatures likely exceed the temperatures monitored clinically during rewarming (email communication, Dr David A. Stump, August 2004). It is, therefore, plausible that these clinical findings may be due to hyperthermia-induced exacerbation of injury. These observations also have clinical relevance for situations in which rewarming cannot be avoided, like deep hypothermic circulatory arrest.

If the effect of temperature is indeed clinically relevant, then one would expect hypothermia to be nephroprotective, which was not observed in our study. There are several possible reasons for this. First, we used mild hypothermia (nasopharyngeal temperature of 34°C) as the intervention and perhaps a greater degree of hypothermia is needed. Second, although we attempted to measure temperature at different sites, it is unclear what the temperature of the renal parenchyma is during systemic mild hypothermia. Third, it may be that the dT/dt (ie, the rate of change in temperature over time) is a more important variable than the absolute temperature reached, as has been suggested for neurologic outcome [29]. Finally, this study specifically excluded individuals with preexisting renal dysfunction, who are at highest risk of postoperative renal dysfunction and who stand to benefit most from a nephroprotective intervention.

Previous studies have identified a variety of risk factors for postoperative renal dysfunction, including increased age, impaired preoperative renal function, recent radiocontrast use, active endocarditis, prolonged CPB time, and diabetes [2, 4,10, 14, 15]. Of note, the effect of off-pump operations on renal outcome remains debated [10, 30]. We, too, identified diabetes and prolonged CPB time as predictors of renal dysfunction. In our study, preoperative creatinine clearance approached statistical significance, but age was not an independent predictor, likely due to the exclusion of younger patients (< 60 years).

It is also interesting to note that neurologic outcome in the two study protocols was similar to the renal outcome reported here. Patients with sustained mild hypothermia did not demonstrate significant differences in the early incidence of neurocognitive deficits compared with normothermic patients (49% vs 45%, p = 0.49) [24]. On the other hand, patients rewarmed from 32° to 37°C in the first protocol had a higher incidence of neurocognitive deficits compared with those rewarmed to 34°C (62% vs 48%, p = 0.048) [23]. The similar findings in two different organ systems lend further support to the idea that rewarming during CPB bypass is potentially harmful and can exacerbate organ injury.

This study offers a proof of concept that temperature management may have a clinically significant effect on renal outcome, but it has several limitations that deserve mention. First, the studies were initially designed to assess the effects of intraoperative temperature management on neurocognitive function and therefore may not be adequately powered or have included the optimal patient population to demonstrate differences in renal outcome. Second, although intraoperative and postoperative patient management was rigorously standardized within each study protocol, differences in clinical care during the course of the two studies can potentially confound any inferences made between them. As such, comparisons are restricted to randomized patients within each study and not across studies. Ultimately, the effects of intraoperative temperature on clinically relevant renal dysfunction need to be further evaluated in adequately powered clinical trials in high-risk patients who are most susceptible to renal injury and thus stand to benefit most from nephroprotective strategies.

In conclusion, in randomized clinical trials of temperature management in low-risk CABG patients, we found that intraoperative temperature does have an effect on postoperative renal function. Although mild hypothermia did not have a nephroprotective effect, even careful rewarming resulted in increased postoperative serum creatinine levels and increased renal dysfunction. Clinicians should pay close attention to temperature management during CPB with the goal of avoiding rewarming.


   Acknowledgments
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 Acknowledgments
References
 
These clinical trials were funded by the Canadian Institutes for Health Research and the Heart and Stroke Foundation of Canada. Clinical Trial Registration: ISRCTN59467488. We would like to thank Medivance (Louisville, CO) for providing the thermal control system and pads and would also like to acknowledge the expert assistance of Carmen Altoft, RN, Sharon Finlay, RN, Lynn Gagné, RN, Linda Vasudev, PhD, and Denyse Winch, RN.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 Acknowledgments
 References
 

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Munir Boodhwani
Fraser D. Rubens
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