Systemic Hypothermia to Prevent Radiocontrast Nephropathy (from the COOL-RCN Randomized Trial)

Systemic Hypothermia to Prevent Radiocontrast Nephropathy (from the COOL-RCN Randomized Trial) Gregg W. Stone, MDa,*, Kishor Vora, MDb, John Schindler, MDc, Claro Diaz, MDd, Tift Mann, MDe, George Dangas, MD, PhDf, Patricia Best, MDg, and Donald E. Cutlip, MDh, for the COOL-RCN Investigators Radiocontrast nephropathy (RCN) develops in a substantial proportion of patients with chronic kidney disease (CKD) after invasive cardiology procedures and is strongly associated with subsequent mortality and adverse outcomes. We sought to determine whether systemic hypothermia is effective in preventing RCN in patients with CKD. Patients at risk for RCN (baseline estimated creatinine clearance 20 to 50 ml/min) undergoing cardiac catheterization with iodinated contrast >50 ml were randomized 1:1 to hydration (control arm) versus hydration plus establishment of systemic hypothermia (33°C to 34°C) before first contrast injection and for 3 hours after the procedure. Serum creatinine levels at baseline, 24 hours, 48 hours, and 72 to 96 hours were measured at a central core laboratory. The primary efficacy end point was development of RCN, defined as an increase in serum creatinine by >25% from baseline. The primary safety end point was 30-day composite rate of adverse events consisting of death, myocardial infarction, dialysis, ventricular fibrillation, venous complication requiring surgery, major bleeding requiring transfusion >2 U, or rehospitalization. In total 128 evaluable patients (mean creatinine clearance 36.6 ml/min) were prospectively randomized at 25 medical centers. RCN developed in 18.6% of normothermic patients and in 22.4% of hypothermic patients (odds ratio 1.27, 95% confidence interval 0.53 to 3.00, p ⴝ 0.59). The primary 30-day safety end point occurred in 37.1% versus 37.9% of normothermic and hypothermic patients, respectively (odds ratio 0.97, 95% confidence interval 0.47 to 1.98, p ⴝ 0.93). In conclusion, in patients with CKD undergoing invasive cardiology procedures, systemic hypothermia is safe but is unlikely to prevent RCN. © 2011 Elsevier Inc. All rights reserved. (Am J Cardiol 2011;108:741–746) Depending on baseline risk factors, radiocontrast nephropathy (RCN) develops in as many as 50% of patients with chronic kidney disease (CKD) undergoing invasive cardiology procedures with iodinated contrast.1– 4 RCN is strongly associated with subsequent early and late mortality, myocardial infarction (MI), heart failure, and other adverse events and substantially increases health care resource use and costs.3– 6 By inhibiting contrast-induced cellular adenosine triphosphate depletion, preserving mitochondrial function, and decreasing the formation of reactive oxygen a Columbia University Medical Center/New York–Presbyterian Hospital and the Cardiovascular Research Foundation, New York, New York; b Owensboro Hospital, Owensboro, Kentucky; cUniversity of Pittsburgh Medical Center, Presbyterian Hospital, Pittsburgh, Pennsylvania; dMethodist North Hospital, Memphis, Tennessee; eWake Medical Health and Hospitals, Raleigh, North Carolina; fMount Sinai Medical Center and the Cardiovascular Research Foundation, New York, New York; gMayo Clinic, Rochester, Minnesota; hHarvard, Clinical Research Institute, Boston, Massachusetts. Manuscript received March 24, 2011; revised manuscript received and accepted April 10, 2011. The names of investigators, institutions, and research organizations participating in the cooling to prevent radiocontrast nephropathy in patients undergoing diagnostic or interventional catheterization (COOL-RCN) trial appear in the Appendix. The COOL-RCN trial was funded by Radiant Medical, Redwood City, California and ZOLL Circulation, Sunnyvale, California. *Corresponding author: Tel: 646-434-4131; fax: 646-434-4715. E-mail address: [email protected] (G.W. Stone).

0002-9149/11/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2011.04.026

species, systemic hypothermia also holds promise to decrease RCN.7–10 We therefore performed a prospective randomized controlled trial to evaluate the safety and efficacy of systemic hypothermia for prevention of RCN in patients with CKD. Methods Patients ⱖ18 years of age were eligible for randomization if they had CKD (defined as estimated creatinine clearance 20 to 50 ml/min by the Cockcroft–Gault formula) and were scheduled to undergo coronary arteriography (with or without percutaneous coronary intervention [PCI]) with likely use of iodinated contrast ⱖ50 ml. Exclusion criteria included acute renal failure or unstable renal function; current or planned dialysis; performance of renal artery angiography, renal drug infusion, or known renal artery stenosis; use of mannitol or intravenous diuretics; presence of decompensated heart failure, respiratory failure, or hypotension; acute or recent ST-segment elevation MI; allergy to contrast, heparin, meperidine, or buspirone that could not be adequately premedicated; recent monoamine oxidase inhibitor use; additional contrast administration 10 days before or after the procedure; presence of an inferior vena cava filter; height ⬍1.5 m; hypersensitivity to hypothermia (Raynaud); bleeding diathesis, coagulopathy, sickle cell disease, or severe hepatic impairment; cryoglobulinemia, untreated hypothyroidism, Addison disease, prostatic hypertrophy or urethral www.ajconline.org

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stricture; would refuse blood transfusions; pregnancy; inability or unwillingness to sign informed consent; enrollment in another investigational drug or device trial; or any condition possibly leading to noncompliance with any study procedures. The protocol was approved by the institutional review board of each participating center, and all patients signed written informed consent (http://www.Clinicaltrials.gov, identifier NCT00306306). Patients were randomized 1:1 to standard treatment (normothermia) including hydration versus systemic hypothermia plus hydration. Intravenous hydration was began 2 to 12 hours fefore catheterization with 0.9% saline at 1.5 ml/kg/ hour (1.0 ml/kg/hour of 0.45% normal saline for patients with congestive heart failure or left ventricular dysfunction). One hour before the procedure saline was replaced with sodium bicarbonate (150 mEq in 5% dextrose in water 1,000 ml) at 0.45 mEq/kg (3 ml/kg/hour) for the first hour and then 0.15 mEq/kg/hour (1 ml/kg/hour) for 5 to 7 hours after the procedure. All fluid input and output were recorded until 24 hours after the procedure. N-acetyl cysteine use was permitted according to the operator’s discretion. Iodixanol was recommended, but other low osmolar contrast agents were permitted according to the operator’s choice. Blood draws at baseline, 24 hours, 48 hours, and 72 to 96 hours were sent to a central core laboratory for serum creatinine measurement. Patients with a serum creatinine increase ⱖ25% from baseline at 72 to 96 hours had an additional blood draw at days 7 to 10. Blood was drawn by a visiting phlebotomist in discharged patients unable to return to the clinic. For patients undergoing PCI, creatine kinase-MB values were assessed at baseline, and at 8, 16, and 24 hours after the procedure. Clinical follow-up was completed at 30 days. The Reprieve Endovascular Temperature Therapy System (Radiant Medical, Redwood City, California) is a heparin-coated endovascular heat-exchange catheter consisting of a 3-lobe helically wound balloon (16.0-mm diameter when expanded) mounted on the distal portion of a multilumen shaft. The device consists of a central venous heatexchange catheter and cassette, a microprocessor-driven controller, and a central temperature probe. The catheter is placed in the inferior vena cava through the femoral vein over a 0.038-inch guidewire through a 12Fr introducer sheath. The system actively achieves and maintains core temperatures within the range of 32°C to 37°C by continuously circulating cool or warm sterile saline through the catheter. A shivering suppression regimen is initiated 45 to 60 minutes before cooling, consisting of buspirone 60 mg orally, meperidine 50-mg slow intravenous bolus with a second bolus of 25 to 50 mg given in 15 minutes, followed 15 minutes later by meperidine infusion at 25 to 35 mg/ hour, and use of a forced-air warming blanket. The Reprieve catheter is then inserted and initiated to achieve a central temperature of 33°C to 34°C before first contrast injection and for 3 hours after the procedure, after which rewarming is initiated toward a target of 36°C at a rate of 1°C/hour. The primary efficacy end point was development of RCN, defined as a relative increase in serum creatinine by ⱖ25% from baseline anytime within the 96-hour postprocedure period. Secondary end points included RCN, defined

as an absolute increase in serum creatinine by ⱖ0.5 mg/dl over the baseline value or with either criteria being met. The primary safety end point was 30-day composite rate of adverse events, defined as all-cause death, MI, dialysis, ventricular fibrillation, venous complication requiring surgery, major bleeding requiring transfusion of blood products ⱖ2 U, or rehospitalization. For the primary effectiveness hypothesis, assuming a 35% incidence of RCN for the control group and 21% for the treatment group (40% relative decrease), 179 patients per group would provide 85% power with a 2-sided 0.05 level of significance. For the primary safety hypothesis, assuming a 30% adverse event rate in each arm, 179 patients per group would provide 80% power to demonstrate noninferiority with a relative margin of 1.5 at a 1-sided 0.05 level of significance. All analyses are by intention to treat. Differences in baseline data between study groups were tested with Student’s t test for continuous variables and chi-square or Fisher’s exact test for categorical variables. Secondary multivariable analyses were performed using stepwise logistic regression. Prespecified logistic model covariates included age, gender, diabetes, weight, dyslipidemia, N-acetyl cysteine use, total contrast volume, hydration volume, qualifying creatinine clearance, performance of coronary intervention, renal medication use, baseline serum creatinine, and anemia (hematocrit ⬍39% in men and ⬍36% in women). Significance tests and confidence intervals (CIs) for individual regression coefficients (unadjusted and adjusted odds ratios [ORs]) in each model were computed using the Wald z-statistic. All statistical tests were 2-sided and a p value ⬍0.05 was regarded as statistically significant. All statistical tests were performed with STATA 10.0 (STATA Corporation, College Station, Texas). Results From March 2006 through August 2007, 136 patients were enrolled (63 randomized to hypothermia and 73 to normothermia) at 25 medical centers in the United States and Australia. The study was subsequently terminated because of financial insolvency of the sponsor, Radiant Medical. ZOLL Circulation (Sunnyvale, California) subsequently purchased the assets of Radiant Medical and funded the follow-up and data analysis. Five patients did not have case-report forms submitted by the sites and 3 patients were withdrawn after randomization but before initiating study procedures (decompensated heart failure in 2 patients and polycythemia in 1 patient). The study analysis is thus based on 128 evaluable subjects (58 randomized to hypothermia and 70 to normothermia). As presented in Table 1, baseline characteristics of the study groups were well matched, except that diabetes was more prevalent in the control group. Mean age was 73 years, and 40% of patients were women. Mean qualifying creatinine clearance was 36.5 ml/min. A mean of 142 ml of contrast was used per procedure, most commonly iodixanol (Table 2). Patients in the 2 groups were extensively hydrated before and after the procedure, and N-acetyl cysteine was used in most patients, although slightly more frequently in the control arm.

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Table 1 Baseline characteristics of randomized groups

Age (years) Women Weight (kg) Diabetes mellitus Hypertension Dyslipidemia Current smoker Previous myocardial infarction Previous percutaneous coronary intervention Previous coronary artery bypass grafting Hemoglobin (g/dl) Serum creatinine (mg/dl) Creatinine clearance (ml/min)

Normothermia (n ⫽ 70)

Hypothermia (n ⫽ 58)

p Value

72 ⫾ 10 22 (31.4%) 81 ⫾ 14 43 (61.4%) 62 (88.6%) 64 (91.4%) 10/68 (26.3%) 25/69 (36.2%) 34 (49.6%)

74 ⫾ 10 28 (48.3%) 82 ⫾ 17 19 (32.8%) 53 (91.4%) 49 (84.5%) 6/57 (17.5%) 21 (36.2%) 25 (43.1%)

0.45 0.07 0.74 ⬍0.01 0.77 0.27 0.47 1.00 0.59

23/69 (33.3%)

17 (29.3%)

0.70

12.1 ⫾ 2.2 1.97 ⫾ 0.8 36.2 ⫾ 8.1

12.7 ⫾ 3.0 1.78 ⫾ 0.6 36.8 ⫾ 8.8

0.22 0.16 0.70

Normothermia (n ⫽ 70)

Hypothermia (n ⫽ 58)

p Value

41 (58.6%) 29 (41.4%) 9 (12.9%) 138 ⫾ 78.3

30 (51.7%) 28 (48.3%) 9 (15.5%) 150 ⫾ 94.3

0.46 0.44 0.66 0.44

52/69 (75.4%) 17 (24.3%) 6.3 ⫾ 4.7

46 (79.3%) 14 (24.1%) 8.0 ⫾ 8.3

0.60 0.98 0.18

799 ⫾ 492

1,114 ⫾ 1,556

0.12

9.0 ⫾ 5.5

9.3 ⫾ 8.2

0.86

854 ⫾ 791

882 ⫾ 760

0.84

54 (77.1%) 36.1 ⫾ 0.7

36 (62.1%) 33.6 ⫾ 0.5

0.06 ⬍0.001

Figure 1. Aggregate rate of cooling in 50 patients presented as mean (solid line) ⫾ 95% confidence interval (dotted lines).

Table 2 Procedural summary

Procedure Diagnostic Interventional Renal angiography Procedural contrast volume (ml) Contrast type* Nonionic, iso-osmolar Nonionic, low osmolar Precontrast hydration time (hours) Precontrast hydration volume (ml) Postcontrast hydration time (hours) Postcontrast hydration volume (ml) N-acetyl cysteine use Temperature at first contrast injection (°C)

* Some patients received 2 types of contrast during the index procedure.

Before first contrast injection, 49 of 53 patients (92.5%) randomized to hypothermia with available data reached 34°C. As shown in Figure 1, mean times to reach 35°C, 34°C, and 33°C were 6.2 ⫾ 3.8, 12.9 ⫾ 5.2, and 29.1 ⫾ 16.0 minutes, respectively. In no patient was it necessary to prematurely discontinue cooling because of discomfort or adverse events. Mean dose of meperidine used to control shivering was 245.3 ⫾ 69.8 mg (range 70 to 393). One patient (who received meperidine 125 mg) required naloxone for oversedation. In the entire study population RCN developed in 26 patients (20.3%) when defined as a relative increase in serum creatinine by ⱖ25% from baseline, in 24 patients (18.8%) when defined as an absolute increase in serum creatinine by ⱖ0.5 mg/dl, and in 29 patients (22.7%) when

Figure 2. Mean serum creatinine levels in normothermic patients (n ⫽ 70) (diamonds) and hypothermic patients (n ⫽ 58) (squares) measured at the 4 study time points by an independent biochemistry core laboratory.

defined by either criterion. Criteria for RCN were first met in the 24-hour blood draw in 5 patients (17.2%), at 48 hours in 20 patients (69.0%), and at 72 to 96 hours in 4 patients (13.8%). As shown in Figure 2, there were no significant differences in mean serum creatinine levels between the 2 groups at any of the 4 prespecified periods. The primary end point of RCN, an unadjusted increase in serum creatinine by ⱖ25% within the first 96 hours after contrast administration, developed in 18.6% of normothermic patients and in 22.4% of hypothermic patients (OR 1.27, 95% CI 0.53 to 3.00, p ⫽ 0.59). Frequency of RCN was also not significantly different between groups when alternative definitions of RCN were used (Table 3) or after multivariable adjustment for differences in baseline characteristics, N-acetyl cysteine use, and hydration. The primary composite 30-day safety adverse event end point occurred in 37.1% and 37.9% of normothermic and hypothermic patients, respectively (OR 0.97, 95% CI 0.47 to 1.98, p ⫽ 0.93; Table 4). Dialysis was required in only 2 study patients who were in the control arm. Other adverse events occurred with similar frequency in the 2 treatment arms, except for nausea or vomiting and bradycardia requiring treatment, which were more common with hypothermia. One patient with known peripheral arterial disease developed leg ischemia and peripheral cyanosis during hypothermia, which resolved with warming without other sequelae.

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Table 3 Occurrence of radiocontrast nephropathy at any time point Change in Serum Creatinine

Normothermia (n ⫽ 70)

Hypothermia (n ⫽ 58)

13 (18.6%) 14 (20.0%) 15 (21.4%)

13 (22.4%) 10 (17.2%) 14 (24.1%)

Relative increase by ⱖ25% (primary end point) Absolute increase by ⱖ0.5 mg/dl (secondary end point) Either increase (secondary end point)

Table 4 Major and minor safety end points

30-day composite major adverse events Mortality, all-cause Myocardial infarction Dialysis Ventricular fibrillation Venous complication requiring surgery Bleeding requiring transfusion ⱖ2 U Rehospitalization Other in-hospital events Nausea or vomiting Bradycardia requiring treatment Atrial fibrillation Supraventricular tachycardia Ventricular tachycardia Repeat percutaneous coronary intervention Coronary artery bypass graft surgery Pulmonary edema Hypotension or shock Stroke Hematoma ⱖ6 cm Urinary tract infection Sepsis

Normothermia (n ⫽ 70)

Hypothermia (n ⫽ 58)

p Value

26 (37.1%)

22 (37.9%)

0.93

1 (1.4%) 1 (1.4%) 2 (2.9%) 0 (0%) 0 (0%)

3 (5.2%) 2 (3.4%) 0 (0%) 0 (0%) 0 (0%)

0.33 0.59 0.50 — —

9 (12.9%)

4 (6.9%)

0.26

13 (18.6%)

13 (22.4%)

0.59

6 (8.6%) 2 (2.9%)

26 (44.8%) 7 (12.1%)

⬍0.0001 0.04

2 (2.9%) 0 (0%) 1 (1.4%) 1 (1.4%)

3 (5.2%) 2 (3.4%) 1 (1.7%) 1 (1.7%)

0.66 0.20 1.0 1.0

4 (5.7%)

1 (1.7%)

0.38

4 (5.7%) 1 (1.4%) 0 (0%) 0 (0%) 3 (0.4%) 1 (1.4%)

1 (1.7%) 3 (5.2%) 1 (1.7%) 3 (5.2%) 1 (1.7%) 0 (0%)

0.38 0.33 0.45 0.09 0.65 1.0

Discussion The present study, representing the first multicenter randomized trial evaluating the use of systemic hypothermia to prevent RCN after iodinated contrast administration in patients with CKD, demonstrates that establishing hypothermia before invasive cardiology procedures (1) is feasible, with 92.5% of patients reaching the target core temperature of 34°C before contrast injection; (2) is generally safe, with no increase in major adverse advents in hospital or within 30 days; and (3) is unlikely to be effective in significantly decreasing the occurrence of RCN. Previous studies of systemic hypothermia as an adjunct to decrease infarct size after primary PCI in patients with ST-segment elevation MI have demonstrated that a low core temperature must be reached before reperfusion for significant myocardial salvage to occur.11–13 This may be difficult to achieve with an endovascular catheter in the ST-segment elevation MI setting given the emphasis on short door-toballoon times. In contrast, in the present study of patients

Unadjusted

Adjusted

OR (95% CI)

p Value

OR (95% CI)

p Value

1.27 (0.53–3.00) 0.83 (0.34–2.05) 1.16 (0.51–2.67)

0.59 0.69 0.71

0.83 (0.18–3.78) 0.57 (0.14–2.38) 0.90 (0.25–3.40)

0.81 0.44 0.87

with CKD undergoing nonurgent cardiac catheterization, target levels of hypothermia were achieved in nearly all patients within 15 to 30 minutes of femoral venous access, before first contrast administration, demonstrating the feasibility of this approach in this setting. Systemic hypothermia was also well tolerated, with shivering effectively suppressed with buspirone, intravenous meperidine, and use of a forced-air warming blanket to maintain surface temperature. Although nausea or vomiting (presumably because of meperidine) and bradycardia requiring treatment were more common with hypothermia, the theoretical risks of myocardial ischemia, ventricular arrhythmias, and heart failure were not increased, generally confirming previous favorable experiences with hypothermia in patients with postcardiac arrest and ST-segment elevation MI.13–17 Individual patients did develop oversedation because of narcosis (requiring reversal) and peripheral arterial ischemia (in the setting of diffuse vascular disease), which resolved after rewarming, emphasizing the close patient attention that this therapy entails. Unfortunately, despite promising experimental data,7–10 the incidence of RCN was not decreased with hypothermia in this trial. The extent to which this negative finding might be explained by inadequate power must be considered. First, the rate of RCN in the control group (18.6% to 21.4%, depending on definition) was lower than the 35% control rate assumed. Compared to the CONTRAST trial, in which RCN developed in 32% of control patients,18 baseline creatinine clearance was somewhat higher in the control arm of Cooling to Prevent Radiocontrast Nephropathy in Patients Undergoing Diagnostic or Interventional Catheterization (COOL-RCN) (36.2 vs 29.1 ml/min) and less contrast was used (138 vs 162 ml), in part explaining the lower observed RCN rate. In future trials, the control arm event rate may be more precisely predicted using a simple risk score calculator (assuming that risk factors for RCN can be accurately anticipated).2 Second, evaluable data were available from only 128 patients, significantly less than the 358 planned. This sample, however, is larger than that which was required to show a beneficial effect for hemofiltration in preventing RCN in high-risk patients with CKD.19 Third, there were several baseline imbalances between study groups that might have affected the rates of RCN, most notably the incidence of diabetes mellitus. Diabetes was more common in the control arm, however, which if anything would have biased the results in favor of hypothermia. After multivariable adjustment for baseline imbalances, there were still no statistically significant differences between groups regardless of the definition of RCN. Fourth, the rate of RCN with hypothermia in the present trial was 22.4%, substantially higher than the 10% rate seen in 30 patients with compa-

Methods/Systemic Hypothermia for Contrast Nephropathy

rable risk factors treated with hypothermia that was observed in a 30-patient pilot trial (G.W. Stone, unpublished data) and slightly higher than the control arm rate in the present trial. Thus, even if more patients had been enrolled, it seems unlikely that hypothermia as tested in COOL-RCN would have shown sufficient efficacy to clinically warrant the logistic complexity and resource use required for its routine implementation. However, the wide CIs around the point estimates for RCN observed in the present trial preclude statistically excluding a beneficial effect (or harm) from systemic hypothermia. The major limitation of the present study is the small sample after early trial termination, which also resulted in imbalances in several baseline features between groups. A trend was present for more frequent vascular complications in the hypothermia group, which might have become significant had the full sample been enrolled. The trial has numerous strengths, however, including its multicenter multinational prospective, randomized design, use of an independent biochemistry core laboratory blinded to treatment arm for assessment of the primary end point (with visiting phlebotomists to ensure complete sample collection), and specification of the amount and type of hydration in the preand postprocedure intervals, the 1 controllable variable (other than contrast dose) widely accepted to affect the rate of RCN. In this regard we required hydration first with saline and then sodium bicarbonate based on several trials demonstrating that alkalization of the urine may decrease RCN.20,21 Although findings from a subsequent randomized trial contradicted these previous studies,22 routine use of sodium bicarbonate plus considerable hydration with normal saline in the present trial may have contributed to the lower than expected rate of RCN in the 2 study groups. Acknowledgment: The authors are grateful to Zoll Circulation for completing the data collection and allowing a full analysis of the available results as requested by the principal investigator. Appendix COOL-RCN Trial Organization and List of Participating Sites and Investigators Principal investigator: G.W. Stone, New York, New York. Data management: Harvard Clinical Research Institute, Boston, Massachusetts. Site and data monitoring: Radiant Medical, Redwood City, California. Clinical Events Committee: Harvard Clinical Research Institute (D.E. Cutlip, chair). Biochemistry core laboratory: ACM Medical Laboratory, Rochester, New York. Data safety and monitoring board: J. Aroesty (Chair), J. Lopez, F. Ling, J Orav. Sponsor: Radiant Medical, Redwood City, California, subsequently assumed by ZOLL Circulation, Sunnyvale, California. Participating centers and principal investigators: Michael Azrin, University of Connecticut Health Center,

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Farmington, Connecticut; Simon Dixon, William Beaumont Hospital, Royal Oak, Michigan; Claro Diaz, Methodist North Hospital, Memphis, Tennessee; Phillip Kraft, Troy William Beaumont Hospital, Troy, Michigan; Ramon Quesada, Baptist Hospital of Miami, Miami, Florida; Patricia Best, Mayo Clinic, Rochester, Minnesota; George Nseir, Chandler Regional Hospital, Chandler, Arizona; John Schindler, UPMC Presbyterian Hospital, Pittsburgh, Pennsylvania; Kishor Vora, Owensboro Hospital, Owensboro, Kentucky; George Dangas, Columbia University Medical Center, New York–Presbyterian Hospital, New York, New York; Tift Mann, Wake Med Health and Hospitals, Raleigh, North Carolina; Joseph Carrozza, Beth Israel Deaconess Medical Center, Boston, Massachusetts; Mark Turco, Washington Adventist Hospital, Tacoma Park, Maryland; Steven Yakubov, Riverside Methodist Hospital, Columbus, Ohio; Michael Ragosta, University of Virginia Health System, Charlottesville, Virginia; Andrew Wang, Duke University Medical Center, Durham, North Carolina; Kathleen Brady, St. Mary’s Hospital, Duluth, Minnesota; John Griffin, Sentara Virginia Beach Hospital, Virginia Beach, Virginia; Barry Bertolet, North Mississippi Medical Center, Tupelo, Mississippi; Malcolm Foster, Baptist Hospital of East Tennessee, Knoxville, Tennessee; Mary Ann Peberdy, Virginia Commonwealth University, Richmond, Virginia; Paul Casale, Lancaster General Hospital, Lancaster, Pennsylvania; Brent Muhlestein, Intermountain Medical Center (LDS), Murray, Utah; Geoffrey Cope, Royal Perth Hospital, Perth, Western Australia, Australia; Suku Thambar, John Hunter Hospital, New Lambton Heights, New South Wales, Australia. 1. Manske CL, Sprafka JM, Strony JT, Wang Y. Contrast nephropathy in azotemic diabetic patients undergoing coronary angiography. Am J Med 1990;89:615– 620. 2. Mehran R, Aymong ED, Nikolsky E, Lasic Z, Iakovou I, Fahy M, Mintz GS, Lansky AJ, Moses JW, Stone GW, Leon MB, Dangas G. A simple risk score for prediction of contrast-induced nephropathy after percutaneous coronary intervention: development and initial validation. J Am Coll Cardiol 2004;44:1393–1399. 3. Nikolsky E, Aymong ED, Dangas G, Mehran R. Radiocontrast nephropathy: identifying the high-risk patient and the implications of exacerbating renal function. Rev Cardiovasc Med 2003;4(suppl 1):S7– S14. 4. Gruberg L, Mintz GS, Mehran R, Dangas G, Lansky AJ, Kent KM, Pichard AD, Satler LF, Leon MB. The prognostic implications of further renal function deterioration within 48 h of interventional coronary procedures in patients with pre-existent chronic renal insufficiency. J Am Coll Cardiol 2000;36:1542–1548. 5. McCullough PA, Wolyn R, Rocher LL, Levin RN, O’Neill WW. Acute renal failure after coronary intervention: incidence, risk factors, and relationship to mortality. Am J Med 1997;103:368 –375. 6. Levy EM, Viscoli CM, Horwitz RI. The effect of acute renal failure on mortality. A cohort analysis. JAMA 1996;275:1489 –1494. 7. Zager RA, Altschuld R. Body temperature: an important determinant of severity of ischemic renal injury. Am J Physiol 1986;251:F87–F93. 8. Zager RA, Gmur DJ, Bredl CR, Eng MJ. Temperature effects on ischemic and hypoxic renal proximal tubular injury. Lab Invest 1991; 66:766 –776. 9. Ning XH, Xu CS, Song YC, Xiao Y, Hu YJ, Lupinetti FM, Portman MA. Hypothermia preserves function and signaling for mitochondrial biogenesis during subsequent ischemia. Am J Physiol Heart Circ Physiol 1998;274:H786 –H793. 10. Zar HA, Lancaster JR. Mild hypothermia protects against postischemic hepatic endothelial injury and decreases the formation of reactive oxygen species. Redox Rep 2000;5:303–310.

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11. Duncker DJ, Klassen CL, Ishibashi Y, Herrlinger SH, Pavek TJ, Bache RJ. Effect of temperature on myocardial infarction in swine. Am J Physiol Heart Circ Physiol 1996;270:H1189 –H1199. 12. Dixon SR, Whitbourn RJ, Dae MW, Grube E, Sherman W, Schaer GL, Jenkins JS, Baim DS, Gibbons RJ, Kuntz RE, Popma JJ, Nguyen TT, O’Neill WW. Induction of mild systemic hypothermia with endovascular cooling during primary percutaneous coronary intervention for acute myocardial infarction. J Am Coll Cardiol 2002;40:1928 –1934. 13. Gotberg M, Olivecrona GK, Koul S, Carlsson M, Engblom H, Ugander M, van der Pals J, Algotsson L, Arheden L, Erlinge D. A pilot study of rapid cooling by cold saline and endovascular cooling before reperfusion in patients with ST-elevation myocardial infarction. Circ Cardiovasc Interv 2010;3:400 – 407. 14. The Hypothermia After Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve neurologic outcome after cardiac arrest. N Engl J Med 2002;346:549 –556. 15. Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, Smith K. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002;346:557–563. 16. Janata A, Holzer M. Hypothermia after cardiac arrest. Prog Cardiovasc Dis 2009;52:168 –179. 17. Kandzari DE, Chu A, Brodie BR, Stuckey TA, Hermiller JB, Vetrovec GW, Hannan KL, Krucoff MW, Christenson RH, Gibbons RJ, Sigmon KN, Garg J, Hasselblad V, Collins K, Harrington RA, Berger PB, Chronos NA, Hochman JS, Califf RM. Feasibility of endovascular cooling as an adjunct to primary percutaneous coronary intervention

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