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. Author manuscript; available in PMC: 2013 Feb 1.
Published in final edited form as: Resuscitation. 2011 Oct 6;83(2):159–167. doi: 10.1016/j.resuscitation.2011.09.023

Therapeutic Hypothermia and Prevention of Acute Kidney Injury: A Meta-Analysis of Randomized Controlled Trials

Paweena Susantitaphong 1,2, Mansour Alfayez 1, Abraham Cohen Bucay 1, Ethan M Balk 3, Bertrand L Jaber 1
PMCID: PMC3273643  NIHMSID: NIHMS335083  PMID: 21983123

Abstract

Background

Therapeutic hypothermia has been shown to reduce neurological morbidity and mortality in the setting of out-of-hospital cardiac arrest and may be beneficial following brain injury and cardiopulmonary bypass. We conducted a systematic review to ascertain the effect of therapeutic hypothermia on development of acute kidney injury (AKI) and mortality.

Methods

We searched for randomized controlled trials in MEDLINE through February 2011. We included trials comparing hypothermia to normothermia that reported kidney-related outcomes including, development of AKI, dialysis requirement, changes in serum creatinine, and mortality. We performed Peto fixed-effect and random-effects model meta-analyses, and meta-regressions.

Results

Nineteen trials reporting on 2,218 patients were included; in the normothermia group, the weighted rate of AKI was 4.2%, dialysis requirement 3.7%, and mortality 10.8%. By meta-analysis, hypothermia was not associated with a lower odds of AKI (odds ratio [OR] 1.01, 95% confidence interval [CI] 0.68, 1.51; P = 0.95) or dialysis requirement (OR 0.81; 95% CI 0.30, 2.19; P = 0.68); however, by meta-regression, a lower target cooling temperature was associated with a lower odds of AKI (P = 0.01). Hypothermia was associated with lower mortality (OR 0.69; 95% CI 0.51, 0.92; P = 0.01).

Conclusions

In trials that ascertained kidney endpoints, therapeutic hypothermia prevented neither the development of AKI nor dialysis requirement, but was associated with lower mortality. Different definitions and rates of AKI, differences in mortality rates, and concerns about the optimal target cooling temperature preclude definitive conclusions.

Keywords: critical illness (or critically ill), hypothermia, acute kidney injury, mortality, meta-analysis

Introduction

On the basis of the published evidence, the Advanced Life Support Task Force of the International Liaison Committee on Resuscitation has adopted therapeutic hypothermia into its guidelines for the treatment of unconscious adult patients with spontaneous circulation after out-of-hospital cardiac arrest 1. These recommendations are based on a clear demonstrable benefit of therapeutic hypothermia on neurological morbidity and mortality following out-of hospital cardiac arrest 2, 3, and some potential benefit in the setting of traumatic brain injury 4, 5 and cardiopulmonary bypass for major cardiovascular surgery6. As a result, therapeutic hypothermia has been widely used in critically ill adults in the intensive care unit7, 8.

Acute kidney injury (AKI), as defined by a wide range of serum creatinine increments 9, is a consistent and powerful predictor of in-hospital mortality, and is associated with an increase in hospital length of stay, hospital costs, and resource utilization 10, 11. Acute kidney injury is commonly observed in patients who have undergone cardiopulmonary bypass 12, 13, and following resuscitation from spontaneous cardiac arrest 14, 15, and carries an increased mortality risk 15. Previously published trials comparing the effect of therapeutic hypothermia vs. normothermia on kidney endpoints have yielded conflicting results16 due in part to the small sample size and low study quality. To shed further light on this question, we conducted a systematic review and meta-analysis of the existing randomized controlled trials (RCTs) comparing the effect of therapeutic hypothermia vs. normothermia in adults on the development of AKI (primary outcome) and all-cause mortality (secondary outcome).

Methods

Data Sources and Search Strategy

We searched Medline (1965 - February 2011) using the following MeSH database search terms: “Hypothermia”, “Hypothermia Induced”, and “Deep Hypothermia Induced”. The search was limited to human RCTs with no language restrictions. We also searched http://www.ClinicalTrials.gov for completed trials using similar search terms, reviewed abstracts from the annual scientific meetings of the American Society of Nephrology (2000-2010), and performed a manual search of references in narrative and systematic reviews on therapeutic hypothermia.

Study Selection

We included all RCTs that examined primary or secondary kidney endpoints (as defined below) in adults undergoing therapeutic hypothermia vs. normothermia. We excluded trials of newborns and children, as well as duplicate publications. If authors published more than one manuscript on the same study, data from the most inclusive report were used.

The primary outcome of interest was AKI, as defined by the authors of individual trials. We also assessed other kidney endpoints including continuous changes in serum creatinine, creatinine clearance and dialysis requirement. The secondary outcome of interest was all-cause mortality, which was only evaluated in the trials reporting kidney endpoints.

Data Extraction and Quality Assessment

Two of the authors independently reviewed and screened the titles and abstracts of all the MEDLINE citations (PS and MA), and the scientific abstracts of the annual meetings of the American Society of Nephrology (ACB and PS). The full-text articles were retrieved for comprehensive review and re-screened, and the data were extracted and tabulated. The following variables were extracted: country of origin, year of publication, study design, population setting, (e.g., out-of hospital cardiac arrest, brain injury, and cardiopulmonary bypass for major cardiovascular surgery), total number of patients, sex, mean age, mean duration of cardiac arrest, mean aortic cross clamp time (for on-pump cardiovascular surgery), cooling target temperature, control arm temperature, cooling technique (including infusate type), duration of cooling, development of AKI, definition of AKI, mean baseline serum creatinine, mean baseline creatinine clearance, mean follow-up serum creatinine, mean follow up creatinine clearance, duration of follow-up, and mortality rate. Disagreements were resolved through consensus and arbitration by a third author (BLJ). In the case of trials with more than 2 groups, separate analyses were performed comparing each therapeutic hypothermia intervention group with the normothermia control group. Corresponding authors of 4 trials were contacted by e-mail for data clarification, and 2 provided additional information.

Study quality was assessed using a modified Jadad scale 17, which is based on the adequacy of randomization, blinding and attrition 18. A score of 0-1, 2-3, and 4-5 corresponds to a study of poor, fair, and good quality, respectively.

Data Synthesis and Analysis

For our primary analysis, due to the low number of events in most studies (often zero in one study group) 19, we performed a Peto fixed-effect meta-analysis to assess the odds ratio (OR) (with 95% confidence interval [CI]) for the development of AKI, dialysis requirement, and mortality in the therapeutic hypothermia group relative to the normothermia group. We also performed a random-effects model meta-analysis as a sensitivity analysis 20. Trials with no events in both groups were excluded from the analyses. A random-effects model meta-analysis was also performed to assess the net change in serum creatinine and creatinine clearance in the therapeutic hypothermia group relative to the normothermia group.

Existence of heterogeneity among effect sizes estimated by individual trials was tested using the I2 index, and chi-squared P value. Heterogeneity was explored by subgroup analyses based on the 3 population settings, mainly traumatic brain injury, out-of hospital cardiac arrest, and cardiopulmonary bypass, as well as the cooling technique, infusion type, study quality and sample size (≤ vs. >100 patients). The Student t-test was used to compare subgroups. Meta-regression analyses were also performed to explore heterogeneity including the cooling target temperature, cardiac arrest duration, and duration of cooling against the odds of AKI and mortality rate. Finally, publication bias was formally assessed using funnel plots. The meta-analyses were performed using Comprehensive Meta-Analysis version 2.0 and MetaAnalyst beta version 3.1 (Tufts University, Boston, MA)

Results

Characteristics and Quality of the Studies

A total of 792 potentially relevant citations were identified and screened; 257 articles were retrieved for detailed evaluation, of which 19 fulfilled eligibility criteria (Figure 1) 21-39. Three trials tested 2 therapeutic hypothermia interventions 22, 25, 26, which were each compared with the control group. One parent study providing data on rate of AKI 32 had a subsequent report on a subset of patients where changes in serum creatinine were examined 34; the latter report was used for the meta-analysis of continuous change in serum creatinine.

Figure 1.

Figure 1

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Study selection flow diagram.

Characteristics of the individual trials are displayed in Table 1. The trials spanned more than 10 years, varied in sample size (23-291 patients) and involved the three population settings. All trials had mostly men (range of 53-95%) with a mean age ranging from 29 to 69 years.

Table 1. Characteristics of the randomized controlled trials included in the meta-analysis.

Author Year Country Population
setting		 Total number
of patients		 Mean
age
(years)		 Men
(%)		 Mean cardiac
arrest
duration
(min)		 Hypothermia
group target
temperature
(°C)		 Normothermia
group
temperature
(°C)		 Cooling technique Infusion type Duration of
cooling
(min)		 Study
Quality		 Definition of AKI
Clifton 1993 USA Traumatic brain injury 46 29 NR NA 32-33 37 Cooling blanket NA 2880 1 Not specified
Lajos 1993 USA CABG-CPB 163 63 71 73 30 37 Fluid infusion Crystalloid 91 1 Not specified
30 37 Fluid infusion Blood 98
Ip-Yam 1994 UK CABG-CPB 23 60 83 62 28 37 Fluid infusion Hartmann's solution 112 1 Change in Cr clearance
Kaukoranta 1995 Finland CABG-CPB 101 59 81 103 32-33 37 Fluid infusion Blood 126 1 Not specified
Regragui 1995 UK CABG-CPB 30 59 57 35 28 37 Fluid infusion Crystalloid 75 2 Change in sCr and
32 37 Fluid infusion Crystalloid 72 Cr clearance
Engelman 1999 USA CABG-CPB 291 63 77 86 23-28 35-36 Fluid infusion (Blood:crystall oid 4:1) 135 2 Not specified
32-33 35-36 Fluid infusion (Blood:crystall oid 4:1) 139
Jacquet 1999 Belgium CABG-CPB 200 65 73 65 30 37 Fluid infusion Crystalloid 115 1 Change in sCr not specified; need for dialysis
Kuhn-Regnier 1999 Germany CABG-CPB 60 65 77 55 NR NR Fluid infusion Blood 89 1 Change in sCr
Bernard 2002 Australia Out-of hospital cardiac arrest 77 59 67 26 33 37 Ice packs NA 720 3 Change in sCr
Gaudino 2002 Italy CABG-CPB 113 NA 93 62 26 37 Fluid infusion Blood 88 2 Not specified
Koksoy 2002 USA AAA-CPB 34 64 53 62 15a 37 Fluid infusion Ringer' solution 23 3 > 50% increase in sCr within first 10 postoperative days; need for dialysis
HACA 2002 European countries Out-of hospital cardiac arrest 275 59 76 22 32-34 37 Mattress & ice packs NA 1440 3 Not specified
Baron 2003 France CABG-CPB 69 64 87 49 15b 37 Fluid infusion Blood+ crystalloid 98 1 Not specified
Zeiner 2004 Austria Out-of hospital cardiac arrest 88 54 73 22 32-34 37 Mattress & ice pack NA 1440 3 Change in sCr and Cr clearance, need for dialysis
Qiu 2007 China Traumatic brain injury 80 41 65 NA 34.5-36 37 Cooling blanket, and cooling cap ice pack NA 5760 4 Not specified
Boodhwani 2009 Canada CABG-CPB 267 69 88 46 34 37 Thermal pads connected to thermal control system NA 77.3 2 >25% increase in sCr or decrease in Cr clearance
Kamarainen 2009 Finland Out-of hospital cardiac arrest 43 61 95 23 33 37 Fluid infusion Ringer' solution 37 3 Single sCr measurement (in emergency room)
Castrén 2010 European countries Out-of hospital cardiac arrest 200 65 75 31 34 37 Intranasal cooling NA 32 3 Not specified
Hemmen 2010 USA Ischemic stroke 58 66 55 NA 33 37 Intravascular cooling with thermal control system NA 1440 3 sCr & urea nitrogen measurement at day 2 & 7
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AAA denotes abdominal aortic aneurysm; CABG, coronary artery bypass graft; CPB, cardiopulmonary bypass pump; HACA, Hypothermia after Cardiac Arrest Study Group; NR, not reported; Cr, creatinine; sCr, serum creatinine;

a

renal temperature

b

temperature of solution. A study quality score of 0-1, 2-3, and 4-5 corresponds to a study of poor, fair, and good quality, respectively.

Overall study quality was mostly poor 21-24, 27, 28, 33 to fair 25, 26, 29-32, 34, 36-39, with only one study being rated as good 35. Reported randomization methods were adequate in only 12 of the 19 trials 25, 26, 29-32, 34-39, and 7 trials described the number of withdrawals or dropouts, and used an intention-to-treat analysis 29, 31, 32, 34, 37-39.

Effect of Therapeutic Hypothermia on Development of AKI

Twelve RCTs reported on the development of AKI in a total of 1,839 analyzable patients; however 2 of these studies 22,33 had no patients with AKI in either group and thus did not contribute to the meta-analysis. The overall weighted rate of AKI in the normothermia group was 4.2% (range of 0 to 59%). By meta-analysis, therapeutic hypothermia was not associated with a lowed odds of AKI (OR 1.01, 95% CI 0.68, 1.51; P = 0.95; Figure 2). Although the trials differed considerably in their size, quality score, and population setting, the test for heterogeneity was not significant (I2 = 0%; P = 0.46); however, this is largely due to the small number of AKI events in most studies, and thus the very wide confidence intervals.

Figure 2.

Figure 2

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Forest plot of therapeutic hypothermia vs. normothermia on the development of AKI. HACA denotes Hypothermia after Cardiac Arrest Study Group. * Refers to the second therapeutic hypothermia intervention tested in the same trial.

By meta-regression, a lower target cooling temperature was associated with a lower odds of AKI (P = 0.01, Figure 3), whereas the duration of therapeutic hypothermia (P = 0.31), and the duration of cardiac arrest were not (P = 0.49). Of note, however, after the removal of an influential trial that delivered intra-renal arterial cooling of 15°C 31, the target cooling temperature was no longer associated with a lower odds of AKI (P = 0.68).

Figure 3.

Figure 3

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Meta-regression plot examining the relationship between the target cooling temperature and the log of the Peto odds ratio for the development of AKI (P = 0.011). The meta-regression equation is as follows: Log Peto odds ratio = −3.004 + 0.096(°C).

Effect of Therapeutic Hypothermia on Serum Creatinine and Creatinine Clearance

Five trials reported changes in serum creatinine 25, 28, 29, 34, 36 in a total of 522 analyzable patients. By meta-analysis, therapeutic hypothermia resulted in a net decrease in serum creatinine of 0.5 mg/dL (95% CI -1.8, 0.7 mg/dL), which did not reach statistical significance (P = 0.40). Three trials reported changes in creatinine clearance 23, 25, 34, with a total of 141 analyzable patients. By meta-analysis, therapeutic hypothermia resulted in a net increase in creatinine clearance of 0.4 mL/min (95% CI -2.2, 3.0 mL/min), which was also not significant (P = 0.76).

In one study, compared to normothermia, therapeutic hypothermia resulted in higher serum urea nitrogen at day 2 (23 vs. 13 mg/dL) but not at day 7 (16 vs. 15 mg/dL), but there was no significant difference in serum creatinine at the same time points (no reported values) 39. In another study, there was no significant difference in the serum creatinine between the normothermia and therapeutic hypothermia group (1.06 vs. 1.05 mg/dL) 37.

Effect of Therapeutic Hypothermia on Dialysis Requirement

Three RCTs reported on dialysis requirement totaling 509 analyzable patients 27, 31, 32. One study had no patients who required dialysis in either group and thus did not contribute to the meta-analysis 31. The overall weighted incidence of dialysis requirement in the normothermia group was 3.7% (range of 0 to 4.3%). By meta-analysis, therapeutic hypothermia was not associated with a significantly lower odds for dialysis requirement (OR 0.81; 95% CI 0.30, 2.19; P = 0.68).

Effect of Therapeutic Hypothermia on Mortality

This analysis was restricted to the 16 RCTs that reported kidney and mortality endpoints, totaling 2,077 analyzable patients. Mortality was ascertained post-operatively in 2 trials 26, 33, in-hospital in 5 trials 28, 32, 36-38, at 15 days in 3 trials 24, 27, 30, at 30 days in 2 trials 29, 31, and at 90 days in one trial 39. The duration of follow up was not documented in the 3 remaining studies 21, 22, 35. There was no death in either group in one study, which did not contribute to the meta-analysis 28. The overall weighted mortality rate in the normothermia group was 10.8% (range of 0 to 87.5%). By meta-analysis, therapeutic hypothermia was associated with a significant 31% lower odds for mortality (OR 0.69; 95% CI 0.51, 0.92; P = 0.01; Figure 4). Although the trials differed considerably in their size, quality score, and population setting, the test for heterogeneity was not significant (I2 = 0%; P = 0.63). By meta-regression, the duration of cardiac arrest, the cooling target temperature, and the duration of hypothermia were not associated with mortality.

Figure 4.

Figure 4

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Forest plot of therapeutic hypothermia vs. normothermia on mortality. HACA denotes Hypothermia after Cardiac Arrest Study Group. * Refers to the second therapeutic hypothermia intervention tested in the same trial.

Sensitivity and Subgroup Analyses

Despite the absence of significant heterogeneity among the trials, we performed random-effects meta-analyses, which generated similar results (data not shown). Subgroup analyses by population settings, cooling technique, type of fluid, study quality, and sample size did not influence the odds of AKI (data not shown). However, although therapeutic hypothermia was associated with lower odds for mortality in patients suffering from out-of-hospital cardiac arrest (OR 0.64; 95% CI 0.45, 0.91), compared to those with brain injury (OR 0.83; 95% CI 0.43, 1.60) or those undergoing cardiopulmonary bypass surgery (OR 0.75; 95% CI 0.33, 1.68), there was no significant difference between these clinical settings. Subgroup analyses stratified according to the cooling technique, type of fluid, and sample size (>100 patients) did not significantly influence the mortality analysis (data not shown). However, low-quality studies did not demonstrate a mortality benefit of therapeutic hypothermia (OR 0.58; 95% CI 0.25, 1.33) whereas in fair-to-good-quality studies, there was a demonstrable mortality benefit of hypothermia (OR 0.70; 95% CI 0.51, 0.96, P=0.03). In addition, compared to studies that excluded patients with pre-existing chronic kidney disease 26, 30, 36, those that included patients with chronic kidney disease 24, 27, 31 displayed lower odd ratio for development of AKI (OR 1.30, 95% CI 0.72-2.35; vs. OR 0.46, 95% CI 0.19-1.14), but this did not reach statistical significance (P = 0.42).

Although funnel plots were slightly asymmetric for the development of AKI with 2 unpublished studies favoring hypothermia, they were symmetric for the outcome of dialysis requirement and mortality.

Discussion

The present meta-analysis suggests that therapeutic hypothermia applied in different population settings including out-of-hospital cardiac arrest, major cardiovascular surgery with cardiopulmonary bypass, and brain injury is associated with a reduction in mortality, but has no impact on the prevention of AKI and dialysis requirement.

Acute kidney injury is a common occurrence following out-of-hospital cardiac arrest with spontaneous return of circulation, and on-pump cardiovascular surgery 12, 14, and is associated with an increased risk for mortality, dialysis requirement, and prolonged hospital length of stay 15, 40. With an incidence of out-of-hospital cardiac arrest estimated at 38 per 100,000 person-years 41, and greater than 163,000 cardiac surgeries performed annually in the US 42, several strategies have been explored to prevent AKI including minimization of ischemic time, use of an off-pump technique, and adoption of therapeutic hypothermia 18, 23, 25, 31, 34.

Induction of moderate hypothermia has been successfully used since the 1950s to protect the brain against global ischemia after cardiac arrest 43, but was subsequently abandoned due to uncertain benefit and difficulties with its use. In more recent years, this strategy has regained recognition following the completion of several RCTs demonstrating a clear benefit on neurological morbidity and mortality following out-of hospital cardiac arrest 2, 3, 29, 32. Although therapeutic hypothermia has been adopted into the treatment guidelines of adults with spontaneous circulation after out-of-hospital cardiac arrest 1, there is scant data on the potential protective benefit of this strategy on kidney endpoints.

Unfortunately, in the present meta-analysis, we were unable to demonstrate a kidney-related benefit of therapeutic hypothermia. That may be due in part to the induction of renal vasoconstriction by systemic therapeutic hypothermia, resulting in possible kidney injury 44, whereas locally applied therapeutic hypothermia may decrease the metabolic demand of the kidneys 45 and oxygen consumption 46, 47. These effects correlate with the temperature of the kidney. Indeed, following temperature reduction to 30°C, 20°C, and 10°C, the kidney oxygen consumption is reduced to 40%, 15% and less than 5%, respectively 47.

In the present meta-analysis, we identified only one study that measured kidney temperature, demonstrating a protective effect of hypothermia against AKI 31. Although our meta-regression analysis suggests that a target cooling temperature cut-off point of 31°C might confer kidney protection, this hypothesis requires formal testing, as this association was highly influenced by a single study 31. Moreover, therapeutic hypothermia appeared to be associated with a lower risk of AKI in studies that included patients with pre-existing chronic kidney disease, but this still did not reach statistical significance.

Strengths of our synthesis include the demonstrable survival benefit of therapeutic hypothermia especially in studies of fair-to-good quality, which is in agreement with previously published meta-analyses 4. Mild hypothermia is thought to suppress many of the biological responses associated with ischemia reperfusion injury. These include the generation of free radicals, the release of amino acids, and transcellular calcium shifts, which can lead to mitochondrial injury and apoptosis 48-50, especially following out-of hospital cardiac arrest. The main limitation of our meta-analysis is the variable or lack of definition of AKI reported in the individual studies. The small sample size of most of the trials is also an important limitation of the evidence. The analysis was restricted to adults and excluded newborns and children. Furthermore, the trials included in this analysis were not originally designed to examine the effect of therapeutic hypothermia on kidney endpoints as their primary endpoint. In addition, we were unable to address the safety of therapeutic hypothermia including, the potential risk for the development of arrhythmias, infections, and coagulopathy 2, 4. Our analysis of mortality is limited by the lack of inclusion of trials that did not report kidney outcomes.

In conclusion, the currently available trials indicate that therapeutic hypothermia does not prevent AKI including dialysis requirement, but is associated with lower mortality following out-of-hospital cardiac arrest, major cardiovascular surgery and brain injury. The present analysis however, calls for the design of future studies to formally test whether therapeutic hypothermia prevents AKI in the setting of major cardiovascular surgery and out-of-hospital cardiac arrest, two clinical settings known to be associated with this complication. Such studies would need to explore a range of cooling temperatures with the hope of identifying the optimal kidney protective hypothermic strategy, and monitor for adverse effects.

Acknowledgments

This work has been made possible in part through Dr. Susantitaphong's International Society of Nephrology funded Fellowship. This work was supported in part by Grant number UL1 RR025752 from the National Center for Research Resources. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

Footnotes

Authors' Contributions: Conception and design: M. Alfayez, B.L. Jaber

Analysis and interpretation of the data: P. Susantitaphong, B.L. Jaber, E.M. Balk

Drafting of the article: P. Susantitaphong, B.L. Jaber

Critical revision of the article for important intellectual content: P. Susantitaphong, E.M. Balk B.L. Jaber

Final approval of the article: P. Susantitaphong, M. Alfayez, A.C. Bucay, E.M. Balk, B.L. Jaber

Provision of study materials or patients: not applicable

Statistical expertise: E.M. Balk, B.L. Jaber

Administrative, technical, or logistic support: not applicable

Collection and assembly of data: P. Susantitaphong, M. Alfayez, A.C. Bucay

Statement of Competing Financial Interests: The authors have no competing financial interests.

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