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 = 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 = 0.93). In conclusion, in patients with CKD undergoing invasive cardiology procedures, systemic hypothermia is safe but is unlikely to prevent RCN.
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. 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. By inhibiting contrast-induced cellular adenosine triphosphate depletion, preserving mitochondrial function, and decreasing the formation of reactive oxygen species, systemic hypothermia also holds promise to decrease RCN. 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 ≥18 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 ≥50 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 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 ≥25% 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 heat-exchange 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 ≥25% from baseline anytime within the 96-hour postprocedure period. Secondary end points included RCN, defined as an absolute increase in serum creatinine by ≥0.5 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 ≥2 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.
| Normothermia (n = 70) | Hypothermia (n = 58) | p Value | |
|---|---|---|---|
| Age (years) | 72 ± 10 | 74 ± 10 | 0.45 |
| Women | 22 (31.4%) | 28 (48.3%) | 0.07 |
| Weight (kg) | 81 ± 14 | 82 ± 17 | 0.74 |
| Diabetes mellitus | 43 (61.4%) | 19 (32.8%) | <0.01 |
| Hypertension | 62 (88.6%) | 53 (91.4%) | 0.77 |
| Dyslipidemia | 64 (91.4%) | 49 (84.5%) | 0.27 |
| Current smoker | 10/68 (26.3%) | 6/57 (17.5%) | 0.47 |
| Previous myocardial infarction | 25/69 (36.2%) | 21 (36.2%) | 1.00 |
| Previous percutaneous coronary intervention | 34 (49.6%) | 25 (43.1%) | 0.59 |
| Previous coronary artery bypass grafting | 23/69 (33.3%) | 17 (29.3%) | 0.70 |
| Hemoglobin (g/dl) | 12.1 ± 2.2 | 12.7 ± 3.0 | 0.22 |
| Serum creatinine (mg/dl) | 1.97 ± 0.8 | 1.78 ± 0.6 | 0.16 |
| Creatinine clearance (ml/min) | 36.2 ± 8.1 | 36.8 ± 8.8 | 0.70 |
| Normothermia (n = 70) | Hypothermia (n = 58) | p Value | |
|---|---|---|---|
| Procedure | |||
| Diagnostic | 41 (58.6%) | 30 (51.7%) | 0.46 |
| Interventional | 29 (41.4%) | 28 (48.3%) | 0.44 |
| Renal angiography | 9 (12.9%) | 9 (15.5%) | 0.66 |
| Procedural contrast volume (ml) | 138 ± 78.3 | 150 ± 94.3 | 0.44 |
| Contrast type ⁎ | |||
| Nonionic, iso-osmolar | 52/69 (75.4%) | 46 (79.3%) | 0.60 |
| Nonionic, low osmolar | 17 (24.3%) | 14 (24.1%) | 0.98 |
| Precontrast hydration time (hours) | 6.3 ± 4.7 | 8.0 ± 8.3 | 0.18 |
| Precontrast hydration volume (ml) | 799 ± 492 | 1,114 ± 1,556 | 0.12 |
| Postcontrast hydration time (hours) | 9.0 ± 5.5 | 9.3 ± 8.2 | 0.86 |
| Postcontrast hydration volume (ml) | 854 ± 791 | 882 ± 760 | 0.84 |
| N -acetyl cysteine use | 54 (77.1%) | 36 (62.1%) | 0.06 |
| Temperature at first contrast injection (°C) | 36.1 ± 0.7 | 33.6 ± 0.5 | <0.001 |
⁎ 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 ≥25% from baseline, in 24 patients (18.8%) when defined as an absolute increase in serum creatinine by ≥0.5 mg/dl, and in 29 patients (22.7%) when 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 ≥25% 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.
| Change in Serum Creatinine | Normothermia (n = 70) | Hypothermia (n = 58) | Unadjusted | Adjusted | ||
|---|---|---|---|---|---|---|
| OR (95% CI) | p Value | OR (95% CI) | p Value | |||
| Relative increase by ≥25% (primary end point) | 13 (18.6%) | 13 (22.4%) | 1.27 (0.53–3.00) | 0.59 | 0.83 (0.18–3.78) | 0.81 |
| Absolute increase by ≥0.5 mg/dl (secondary end point) | 14 (20.0%) | 10 (17.2%) | 0.83 (0.34–2.05) | 0.69 | 0.57 (0.14–2.38) | 0.44 |
| Either increase (secondary end point) | 15 (21.4%) | 14 (24.1%) | 1.16 (0.51–2.67) | 0.71 | 0.90 (0.25–3.40) | 0.87 |
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