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Original Investigation |

Prevention of Contrast Media–Associated Nephropathy Randomized Comparison of 2 Hydration Regimens in 1620 Patients Undergoing Coronary Angioplasty FREE

Christian Mueller, MD; Gerd Buerkle, MD; Heinz J. Buettner, MD; Jens Petersen, MD; André P. Perruchoud, MD; Urs Eriksson, MD, PhD; Stephan Marsch, MD, PhD; Helmut Roskamm, MD
[+] Author Affiliations

From the Herz-Zentrum, Bad Krozingen, Germany (Drs Mueller, Buerkle, Buettner, Petersen, and Roskamm), and Department of Internal Medicine, Universitätsklinik, Basel, Switzerland (Drs Mueller, Perruchoud, Eriksson, and Marsch).


Arch Intern Med. 2002;162(3):329-336. doi:10.1001/archinte.162.3.329.
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Published online

Background  The administration of radiographic contrast agents remains an important cause of acute renal failure. The optimal infusion for hydration has not been evaluated.

Objective  To compare the incidence of contrast media–associated nephrotoxicity with isotonic or half-isotonic hydration.

Design  Prospective, randomized, controlled, open-label study.

Methods  Patients scheduled for elective or emergency coronary angioplasty were randomly assigned to receive isotonic (0.9% saline) or half-isotonic (0.45% sodium chloride plus 5% glucose) hydration beginning the morning of the procedure for elective interventions and immediately before emergency interventions. An increase in serum creatinine of at least 0.5 mg/dL (44 µmol/L) within 48 hours was defined as contrast media–associated nephrotoxicity. Secondary end points were cardiac and peripheral vascular complications.

Results  A total of 1620 patients were assigned to receive isotonic (n = 809) or half-isotonic (n = 811) hydration. Primary end point analysis was possible in 1383 patients. Baseline characteristics were well matched. Contrast media–associated nephropathy was significantly reduced with isotonic (0.7%, 95% confidence interval, 0.1%-1.4%) vs half-isotonic (2.0%, 95% confidence interval, 1.0%-3.1%) hydration (P = .04). Three predefined subgroups benefited in particular from isotonic hydration: women, persons with diabetes, and patients receiving 250 mL or more of contrast. The incidence of cardiac (isotonic, 5.3% vs half-isotonic, 6.4%; P = .59) and peripheral vascular (isotonic, 1.6% vs half-isotonic, 1.5%, P = .93) complications was similar between the 2 hydration groups.

Conclusion  Isotonic hydration is superior to half-isotonic hydration in the prevention of contrast media–associated nephropathy.

Figures in this Article

PREVENTION OF disease should always be the highest priority, particularly if there is no effective therapy and the disease is iatrogenic. The administration of radiographic contrast agents remains an important cause of hospital-acquired acute renal failure, which contributes to morbidity and mortality during hospitalization, prolongs hospital stay, and increases the incidence of chronic end-stage renal disease and costs of health care.15

However, coronary angiography and angioplasty, diagnostic and interventional studies in other vascular territories, and computed tomography rely on the use of radiographic contrast agents. The incidence of contrast media–associated nephropathy depends on its definition and the patient cohort studied. Chronic renal insufficiency, diabetes mellitus, contrast media volume, and recurrent administration are considered important risk factors.513 These risk factors have a high prevalence in patients undergoing coronary angioplasty, rendering it a high-risk intervention for the development of contrast media–associated nephropathy.12,13

Several agents have been suggested for the prevention of contrast media–associated nephropathy, including hydration, furosemide, mannitol, dopamine hydrochloride, aminophylline, atrial natriuretic peptide, acetylcysteine, alprostadil, and captopril.1223 Only hydration with isotonic sodium chloride is uniformly accepted and used in clinical practice. The optimal infusion for hydration (isotonic or hypotonic), however, has not been evaluated. Most authorities recommend hydration with half-normal isotonic sodium chloride 12 hours before and after the administration of radiocontrast.1216,24,25

We aimed in a randomized controlled study to test the hypothesis that isotonic hydration is superior to half-isotonic hydration in the prevention of contrast media–associated nephropathy. Because these hydration regimens may differ in their effects on platelet aggregation, the coagulation system, and arterial blood pressure, cardiac and peripheral vascular complications were analyzed as secondary end points.

PATIENT POPULATION AND CORONARY ANGIOPLASTY PROCEDURE

Patients scheduled for elective or emergency coronary angioplasty were asked to participate in the study. End-stage renal failure with regular hemodialysis, cardiogenic shock, and mechanical ventilation were the only exclusion criteria. In patients with acute coronary syndromes and in selected patients with stable coronary disease, coronary angioplasty was performed immediately after diagnostic angiography ("emergency procedures"). Coronary angioplasty was generally scheduled 2 days after the diagnostic procedure in patients with stable angina ("elective procedures") Eligible patients were weekly randomly assigned in equal proportions with the use of a prespecified randomization sequence to one of the hydration regimens. Coronary angioplasty was performed by standard technique via the femoral artery. Decisions regarding the procedure were left to the discretion of the investigator. To reduce the number of variables that may affect contrast media–associated nephropathy, all procedures were performed with the use of low-osmolar nonionic contrast media (Ultravist 370; Schering, Berlin, Germany; and Imeron 350; Byk Gulden, Konstanz, Germany). Acetylcysteine was not used in this study. No changes in medication were allowed during the study.

This prospective, randomized, controlled, open-label study was carried out according to the principles of the Declaration of Helsinki and approved by the local hospital's investigational review board. Written informed consent was obtained from all participating patients.

HYDRATION REGIMENS

In patients scheduled for elective intervention, hydration with 0.9% saline (the sodium concentration in isotonic saline is 154 mmol/L) or 0.45% sodium chloride plus 5% glucose (the sodium concentration in half-isotonic saline is 77 mmol/L) was started with an infusion rate of 1 mL/kg of body weight per hour at 8 AM on the day of coronary angioplasty. In addition, patients were encouraged to drink plenty of fluids (tea and mineral water). In patients undergoing emergency intervention, no protocol-defined prehydration could be given. However, the subgroup of patients with acute coronary syndromes received a 500-mL crystalloidal infusion (the sodium concentration in Ringer solution is 147 mmol/L) as their standard medical care before admission to the hospital. The assigned infusion was started immediately on arrival in the catheter laboratory. The infusion rate during angioplasty was adjusted to clinical conditions by the operator. After the procedure, hydration was continued at 1 mL/kg of body weight per hour until 8 AM the next morning.

FOLLOW-UP AND END POINTS
Serum Creatinine

A venous blood sample for serum creatinine analysis was drawn on the morning before and 24 and 48 hours after coronary angioplasty. All samples were analyzed in a central laboratory with the use of an enzymatic kit (CREA Plus; Boehringer Mannheim Systems, Mannheim, Germany).

Renal insufficiency is defined as a decrease in glomerular filtration rate.26 Glomerular filtration rate has to be reduced by 50% before a rise in serum creatinine occurs.26,27 Therefore, we decided to use the upper limit of normal of the serum creatinine level as the cutoff point for the definition for chronic renal insufficiency. The most common definition of contrast media–associated nephropathy,8,1214,20,22 an increase in serum creatinine concentration of at least 0.5 mg/dL (44 µmol/L) within 48 hours, was used as the primary end point in this study. To obtain a variable for baseline renal function independent of age and body mass, we used a model of calculated creatinine clearance based on lean body mass.28,29 Creatinine clearance per lean body mass (ClLBM) may be calculated according to the formula ClLBM = E/S, where E is the age-dependent urinary creatinine excretion rate in milligrams per minute per 50 kg of lean body mass, and S corresponds to the serum creatinine level at baseline.

Major Adverse Cardiac Events

It is unknown whether isotonic and half-isotonic infusions have different effects on platelet aggregation and the coagulation system. Therefore, a predefined subgroup of patients with the placement of coronary artery stents between September 15, 1998, and February 28, 1999, had extensive clinical follow-up to monitor major adverse cardiac events within 30 days. A major adverse cardiac event was defined as death, myocardial infarction, urgent target vessel revascularization, or hospitalization for unstable angina.

Peripheral Vascular Complications

Duplex sonography of the groin was performed in all patients with new femoral bruits after removal of the pressure bandage. Peripheral vascular events were defined as false aneurysms requiring surgery, or prolonged ultrasound-guided compression or bleeding requiring surgery or transfusion.

STATISTICAL ANALYSIS

The primary analysis compared the incidence of contrast media–associated nephropathy with isotonic or half-isotonic hydration. The sample size was determined on the assumption that isotonic hydration would lower the incidence of contrast media–associated nephropathy by 40%. The expected event rate for half-isotonic hydration was 6% (α error of .05, β error of .20). Patients who underwent coronary artery bypass grafting or a second catheterization within 48 hours of coronary angioplasty were analyzed for secondary end points only to exclude the effect of extracorporeal circulation and the second contrast challenge on serum creatinine values. Predefined subgroups were those undergoing elective procedures, women, persons with diabetes, patients with preexisting renal dysfunction, and patients receiving higher contrast volumes (≥250 mL of contrast medium).

Discrete variables were expressed as counts, and continuous variables were expressed as means ± SDs. Comparisons were made among continuous variables using analysis of variance for independent samples and repeated-measures analysis of variance for paired samples (change in serum creatinine level). Comparison of discrete variables was made by χ2 test. All hypothesis testing was 2-tailed. To identify independent risk factors for the development of contrast media–associated nephropathy, patients of both hydration groups were analyzed together. For multivariate analysis, backward stepwise logistic regression analysis was used (SPSS version 9.0; SPSS Inc, Chicago, Ill).

BASELINE PATIENT CHARACTERISTICS AND PROCEDURAL DETAILS

From April 1, 1998, to May 31, 1999, 1620 patients scheduled for elective or emergency angioplasty were enrolled in the study. Eight hundred nine patients were initially assigned to receive isotonic hydration, and 811 patients were to receive half-isotonic hydration (Figure 1). Of these, 237 patients had to be excluded from the analysis of the primary end point because of coronary artery bypass grafting (n = 1), a second catheterization (n = 137), or incomplete data (n = 99). Therefore, 685 patients assigned to receive isotonic infusion and 698 patients assigned to receive half-isotonic infusion remained for the analysis of contrast media–associated nephropathy.

Place holder to copy figure label and caption
Figure 1.

Patient flow through the study.

Graphic Jump Location

The demographic characteristics of these 1383 patients were well balanced across treatment groups (Table 1). Three hundred fifty-four patients (25.6%) were women, 286 (20.7%) had chronic renal insufficiency, and 217 (15.7%) had diabetes. Most patients had multivessel coronary artery disease with preserved left ventricular function.

Table Graphic Jump LocationTable 1. Baseline Clinical Characteristics*

Angiographic and procedural details were similar in both groups (Table 2). About 50% of coronary lesions were complex (lesion type B2 or C). Emergency interventions accounted for almost 60% of all procedures. The mean volume of contrast used in the isotonic group was 232 mL vs 236 mL in the half-isotonic group. The total amount of intravenous hydration (2022 mL vs 2028 mL) and the volumes administered before (443 mL vs 428 mL), during (362 mL vs 369 mL), and after angioplasty (1217 mL vs 1229 mL) were comparable in both groups. The baseline characteristics of the patients who were excluded from the analysis of the primary end point were similar between the 2 treatment groups (data not shown) and were similar to those shown in Table 1 and Table 2.

Table Graphic Jump LocationTable 2. Angiographic and Procedural Characteristics*

Baseline renal function was normal in most patients. In addition, renal insufficiency was predominantly mild in 288 patients defined as having chronic renal insufficiency. Baseline creatinine (Table 3) was in the normal range, and mean baseline creatinine clearance per 50 kg of lean body mass was 84 mL/min in both groups.

Table Graphic Jump LocationTable 3. Outcome Variables (for All Interventions)*
PRIMARY END POINT

Contrast media–associated nephropathy developed in 5 patients with isotonic infusion vs 14 patients with half-isotonic infusion. Therefore, as shown in Figure 2, the incidence of contrast media–associated nephropathy was significantly reduced with isotonic (0.7%, 95% confidence interval [CI], 0.1%-1.4%) vs half-isotonic (2.0%, 95% CI, 1.0%-3.1%) hydration (P = .04). Three predefined subgroups benefited in particular from isotonic hydration (Table 4): women (reduction in contrast media–associated nephropathy from 5.1% [95% CI, 1.8%-8.4%] to 0.6% [95% CI, 0%-1.7%]; P = .01), persons with diabetes (reduction from 5.5% [95% CI, 1.1%-9.8%] to 0%; P = .01), and patients receiving 250 mL or more of contrast (reduction from 3.0% [95% CI, 0.9%-5.0%] to 0%; P = .01).

Place holder to copy figure label and caption
Figure 2.

Incidence of contrast media–associated nephropathy (CN), mortality, and peripheral vascular complications (Vascular).

Graphic Jump Location
Table Graphic Jump LocationTable 4. Outcome Variables: Subgroup Analysis*

In patients undergoing elective procedures and receiving study prehydration, the superiority of isotonic infusion was more pronounced than in patients undergoing emergency procedures, with a reduction in contrast media–associated nephropathy to 0.7% (95% CI, 0.3%-1.6%) vs 2.7% (95% CI, 0.9%-4.6%) for half-isotonic infusion (Table 4, P = .06). For emergency angioplasty, the incidence of contrast media–associated nephropathy was 1.1% (95% CI, 0.4%-1.9%), with no significant difference between the hydration groups.

Changes in serum creatinine level were small when considering all patients. At 48 hours, serum creatinine increased in women 0.04 mg/dL (3.5 µmol/L) (95% CI, 0.02-0.07 mg/dL [1.8-6.2 µmol/L]) with isotonic hydration vs 0.10 mg/dL (8.8 µmol/L) (95% CI, 0.05-0.15 mg/dL [4.4-13.3 µmol/L]) with half-isotonic hydration (P = .06). In persons with diabetes, serum creatinine increased 0.04 mg/dL (3.5 µmol/L) (95% CI, 0.01-0.07 mg/dL [0.9-6.2 µmol/L]) with isotonic hydration vs 0.12 mg/dL (10.6 µmol/L) (95% CI, 0.05-0.18 mg/dL [4.4-15.9 µmol/L]) with half-isotonic hydration (P = .04). In patients receiving 250 mL or more of contrast, serum creatinine increased 0.05 mg/dL (4.4 µmol/L) (95% CI, 0.03-0.07 mg/dL [2.7-6.2 µmol/L]) with isotonic hydration vs 0.08 mg/dL (7.1 µmol/L) (95% CI, 0.05-0.11 mg/dL [4.4-9.7 µmol/L]) with half-isotonic hydration (P = .06).

As expected, the incidence of contrast media–associated nephropathy was higher in patients with chronic renal insufficiency and particularly high with more advanced chronic renal insufficiency (Table 4).

SECONDARY END POINTS

Overall, 2 patients (0.1%) required dialysis during their hospitalization. One 70-year-old woman with mild chronic renal insufficiency and mitral regurgitation (half-isotonic hydration group) developed pulmonary edema during coronary angioplasty that required dialysis. A 77-year-old man with severe chronic renal insufficiency (isotonic hydration group) had already undergone a shunt operation in the preceding week and was scheduled to begin long-term dialysis in 4 weeks. Therefore, the arterial sheath was left for acute dialysis after coronary angiography and coronary angioplasty.

The length of hospital stay was significantly increased in patients developing contrast media–associated nephropathy (8.1 vs 4.7 days without nephropathy, P<.001). However, it was similar in both treatment groups.

For the analysis of cardiac complications, 530 consecutive patients with stent implantation (265 with isotonic hydration and 265 with half-isotonic hydration) had extensive clinical follow-up. Major adverse cardiac events occurred in 14 patients (5.3%) with isotonic hydration and in 17 (6.4%) with half-isotonic hydration (Table 3, P = .59). Mortality at 30-day follow-up was 0.4% and 1.1%, respectively (P = .35).

Peripheral vascular complications, assessed in all 1620 patients, occurred in 13 patients (1.6%) with isotonic hydration and 12 (1.5%) with half-isotonic hydration (P = .93).

RISK FACTOR ANALYSIS

Backward stepwise logistic regression analysis revealed female sex and baseline creatinine level as independent risk factors for contrast media–associated nephropathy (Table 5). The odds ratio for female sex was 3.9 (95% CI, 1.5-10.1), and the odds ratio for an increase in baseline creatinine of 1.0 mg/dL (88 µmol/L) was 6.6 (95% CI, 3.2-13.8). In patients with a baseline creatinine higher than 1.6 mg/dL (141 µmol/L), the incidence of contrast media–associated nephropathy was higher than 10%. Age, diabetes mellitus, and contrast volume were not independent risk factors. The odds ratio for isotonic hydration was 0.3 (95% CI, 0.1-0.9).

Table Graphic Jump LocationTable 5. Multivariate Risk Factor Analysis (Backward Stepwise Logistic Regression) for the Development of Contrast Media−Associated Nephropathy

The individual risk for contrast media–associated nephropathy (ProbCN) can be calculated using the following equations: (1) ProbCN = 1/(1 + e-z), where e is a constant (ie, negative exponential of z) (2) z = −4.9 + (1.36 × sex) + (1.89 × baseline creatinine) – (1.18 × hydration) (3) sex = 0 for men and 1 for women, and hydration = 0 for hypotonic and 1 for isotonic hydration.

Our prospective, randomized, controlled, open-label study compared isotonic hydration with half-isotonic hydration for the prevention of contrast media–associated nephropathy in a large cohort of patients undergoing elective or emergency coronary angioplasty. To our knowledge, this is the largest randomized study on the prevention of contrast media–associated nephropathy to date. The key finding was that the incidence of contrast media–associated nephropathy was significantly reduced with isotonic hydration. Three predefined subgroups benefited in particular from isotonic hydration: women, persons with diabetes, and patients receiving high volumes of contrast.

Alterations in renal hemodynamics (ischemia due to vasoconstriction) and direct tubular toxicity are considered to be the primary factors in the pathogenesis of contrast media–associated nephropathy.12,13,19 Atheroembolism may be of additional importance in patients undergoing invasive contrast studies. These factors lead to a decrease in renal blood flow and glomerular filtration rate. The predominant mechanism and the ability to affect the predominant mechanism by hydration may differ in different patient settings. This may in part explain the finding that isotonic hydration is particularly more effective in certain subgroups of patients. Sodium load seems to be crucial for the preventive effect of hydration. More potent intravascular volume expansion and inhibition of the renin-angiotensin pathway may be achieved by higher sodium concentration with isotonic sodium chloride solution. This hypothesis is supported by studies showing detrimental effects of furosemide14 and beneficial effects of captopril.20 The finding that persons with diabetes appeared to benefit most from isotonic hydration is in concordance with the documented preventive effect of captopril in these patients. Our data suggest that isotonic hydration with 0.9% saline should be favored for the prevention of contrast media–associated nephropathy and raise concern about current recommendations favoring hypotonic hydration.1216,21,22

At first glance, it is surprising that in patients undergoing emergency coronary angioplasty the incidence of contrast media–associated nephropathy is not higher than in patients undergoing elective coronary angioplasty. However, 319 patients with acute coronary syndromes, representing 40% of patients in the emergency angioplasty group, received a 500-mL crystalloidal (the sodium concentration in Ringer solution is 147 mmol/L) infusion high in sodium as their standard medical care before admission to the hospital. Therefore, they too had intravenous prehydration. This identical prehydration with sufficient sodium load may have in part blunted the differences between the isotonic and hypotonic hydration regimens started at the time of the angioplasty procedure in the emergency group and resulted in the low incidence of contrast media–associated nephropathy in these patients.

Although the volume of contrast media used was high and a substantial subgroup of patients had already been exposed to contrast media in the preceding days, the incidence of contrast media–associated nephropathy was lower than previously reported in comparable patient cohorts.523 We consider 2 main factors responsible for the excellent outcome of our patients: their normal mean baseline creatinine levels and the effective hydration regimens.

Assuming that persons with diabetes and patients receiving larger contrast volumes are more likely to develop nephropathy, we had expected a higher incidence of contrast media–associated nephropathy in this study. However, in accordance with more recent analyses,12,13 our multivariate risk factor analysis showed that baseline renal function was the most important independent risk factor for the development of contrast media–associated nephropathy and that the implications of diabetes, age, and contrast volume may have been overestimated. A patient with a baseline creatinine of 2 mg/dL (177 µmol/L) had 7 times the risk of developing contrast media–associated nephropathy of a patient with a baseline creatinine of 1 mg/dL (88 µmol/L).

To our knowledge, this is the first study to include a sufficient number of women to show by multivariate analysis that female sex is an independent risk factor for the development of contrast media–associated nephropathy. Although contrast volume was not an independent predictor of contrast media–associated nephropathy in our study, the increased risk in women may be at least in part explained by the higher ratio of contrast volume to body weight or body surface area in women. In fact, for women, the risk of developing contrast media–associated nephropathy was 4 times that of men. Additional mechanisms responsible for this difference may include impaired thirst sensation and inadequate oral fluid intake in women after menopause.

Our protocol did not include precatheterization overnight intravenous hydration. The infusions were started the morning of the procedure. The PREPARED trial25 showed in 36 patients with mild to moderate renal insufficiency scheduled for coronary angiography that an outpatient oral precatheterization hydration strategy is equivalent to overnight intravenous hydration. The low incidence of contrast media–associated nephropathy in our subgroup with predominantly mild chronic renal insufficiency at baseline raises the possibility that neither overnight intravenous hydration nor outpatient oral hydration may be necessary in these patients.

It was the aim of this study to compare the efficacy and safety of 2 different infusions applied in a hydration regimen that can easily be used in daily practice. Patients did not all undergo the procedure at the same time, nor did all patients receive the same amount of hydration. The volume administered depended on body weight (infusion rate, 1 mL/kg per hour). The later the angioplasty procedure was performed, the higher the volume administered before and the lower the volume administered after the procedure. Because of the comparable mean volumes used in both study groups, this design allows a valid comparison between both infusions. However, it does not allow definition of the optimal fluid volume or the optimal infusion rate for the prevention of contrast media–associated nephropathy.

By study protocol, 137 patients undergoing a second contrast exposure were excluded from the primary end point analysis. Two (1.5%) of these patients developed contrast media–associated nephropathy. Therefore, the second contrast exposure did not significantly increase the incidence of contrast media–associated nephropathy in these patients. However, we consider this subgroup too small and too heterogeneous to draw definite conclusions from it.

In patients with impaired left ventricular function, oral and intravenous hydration was adjusted to clinical conditions. With this precaution, hydration-induced pulmonary edema was not observed. However, only 40 patients (2%) had severely impaired left ventricular function in this study. Additional studies are necessary in these patients.

There is considerable debate whether the preventive strategy of hydration should be restricted to patients with preexisting renal dysfunction. Although our results confirm previous studies4,69,11,14,18 establishing preexisting renal dysfunction as the most important risk factor for the development of contrast media–associated nephropathy, hydration should not be restricted to this high-risk group. Hydration is a simple, safe, effective, and inexpensive measure that should not be withheld from patients in whom perhaps only minor renal damage is to be expected. Any degree of renal damage should be prevented, if possible.

Grines and colleagues30 recently reported a reduced risk of ischemic complications with the use of ionic contrast media compared with nonionic contrast media. Profound platelet degranulation has been reported as an important adverse effect of some types of contrast media used in interventional cardiology.31 In addition, hemodilution with isotonic sodium chloride solution was shown to exert a procoagulant effect,32 which could not be inhibited by aspirin.33 We, therefore, sought to test the hypothesis that isotonic and half-isotonic hydration have different effects on platelet aggregation or the coagulation system that may eventually affect cardiac outcome. Patients receiving coronary stents are particularly prone to acute thrombotic events within the first month of implantation.34 However, an intense follow-up for 30 days in this high-risk cohort showed similar rates of major adverse cardiac events (isotonic, 5.3% vs half-isotonic, 6.4%; P = .59) with both infusions. Although this finding does not rule out different effects on platelet aggregation or the coagulation system, these differences do not seem to be clinically relevant in this setting.

Peripheral vascular complications continue to be a considerable limitation of percutaneous interventional procedures.34,35 Arterial blood pressure and inhibition of the coagulation system (heparin, aspirin, and ticlopidine hydrochloride) at the time of sheath removal are thought to be of particular importance for the development of false aneurysms and hemorrhagic events. We hypothesized that reduced sodium load36 with half-isotonic sodium chloride solution might lead to reduced peripheral vascular complications by reducing hypertensive episodes during sheath removal. However, the incidence was similar in both groups (isotonic, 1.6% vs half-isotonic, 1.5%; P = .93). All patients had intensive blood pressure monitoring in the hours after coronary angioplasty, allowing rapid adjustments in intravenous antihypertensive medication (nitroglycerin) for optimal blood pressure control. Therefore, a small difference in actual arterial blood pressure may have been blunted by adjustments in antihypertensive medication.

Although this is, to our knowledge, the largest randomized study reporting on the prevention of contrast media–associated nephropathy, there are several limitations. First, this study included 286 patients with chronic renal insufficiency. Renal dysfunction was predominantly mild in these patients. Because only a small number of patients with severe renal dysfunction were included in this study, additional studies are warranted to define the optimal infusion for these patients at highest risk. Second, we can rule out a selection bias in patients scheduled for elective coronary angioplasty in whom diagnostic coronary angiography was performed in our center. Coronary angioplasty was not delayed or canceled because of acute renal failure in any of these patients. However, about 10% of our study patients had their diagnostic procedures performed at another hospital. Because this proportion is small, any remaining selection bias would be only minor and would not affect the principal findings. Third, oral fluid intake was not quantified in this study. All patients in stable clinical conditions were encouraged to drink plenty of tea and mineral water. Although it is unlikely that there was a significant difference in oral fluid intake between the 2 groups, we cannot quantify total precatheterization and postcatheterization fluid volume and net fluid balance. Fourth, low-osmolarity nonionic radiocontrast media were used in this study. Low-osmolarity nonionic contrast agents differ in various aspects from high-osmolarity ionic agents.911 Although the preventive strategy of hydration seems to be effective with both agents, we suggest that our results should be only cautiously applied to procedures using high-osmolarity agents. Fifth, in addition to the nephrotoxic effect of the contrast medium, atheroemboli may have been dislodged into the renal arteries by the introduction of the guiding catheter. This should be kept in mind if comparing our findings with those of intravenous contrast studies. However, because the incidence of contrast media–associated nephropathy was low in this study, the clinical effects of atheroemboli were probably minor. Sixth, to obtain a variable for baseline renal function independent of age and body mass, we used a model of calculated creatinine clearance based on lean body mass.28,29 This calculated creatinine clearance may not be as accurate a measure of glomerular filtration rate as an insulin clearance.

In conclusion, our findings show that the incidence of contrast media–associated nephropathy is significantly reduced with isotonic hydration. Women, persons with diabetes, and patients receiving large volumes of contrast seem to benefit in particular from isotonic hydration.

Accepted for publication June 6, 2001.

Presented in part at the 22nd Congress of the European Society of Cardiology, Amsterdam, the Netherlands, August 30, 2000, and at the 73rd Congress of the American Heart Association, New Orleans, La, November 14, 2000.

We thank Kika Peitz and her team for assistance in the catheter laboratories, Ludger Kessler and his team for support in the postcatherization unit, Anita Abels for help in data acquisition, and Dietmar Trenk, MD, Jürgen Drewe, MD, Felix Brunner, MD, and John McB Hodgson, MD, for expert advice.

Corresponding author and reprints: Christian Mueller, MD, Department of Internal Medicine, University Hospital, Petersgraben 4, CH-4031 Basel, Switzerland (e-mail: chmueller@uhbs.ch).

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Koch  JAPlum  JGrabensee  BMödder  Uand the PGE1 Study Group, Prostaglandin E1: a new agent for the prevention of renal dysfunction in high risk patients caused by radiocontrast media? Nephrol Dial Transplant. 2000;1543- 49
Link to Article
Gupta  RKKapoor  ATewari  SSinha  NSharma  RK Captopril for prevention of contrast-induced nephropathy in diabetic patients: a randomised study. Indian Heart J. 1999;51521- 526
Kolonko  AWiecek  AKokot  F The nonselective adenosine antagonist theophylline does prevent renal dysfunction induced by radiographic contrast agents. J Nephrol. 1998;11151- 156
Kurnik  BRAllgren  RLGenter  FCSolomon  RJBates  ERWeisberg  LS Prospective study of atrial natriuretic peptide for the prevention of radiocontrast-induced nephropathy. Am J Kidney Dis. 1998;31674- 680
Link to Article
Tepel  Mvan der Giet  MSchwarzfeld  CLaufer  ULiermann  DZidek  W Prevention of radiographic-contrast-agent–induced reductions in renal function by acetylcysteine. N Engl J Med. 2000;343180- 184
Link to Article
Oliveira  D Prophylaxis against contrast-induced nephropathy. Lancet. 1999;3531638- 1639
Link to Article
Taylor  AJHotchkiss  DMorse  RWMcCabe  J PREPARED: preparation for angiography in renal dysfunction: a randomized trial of inpatient versus outpatient hydration protocols for cardiac catheterization in mild to moderate renal dysfunction. Chest. 1998;1141570- 1574
Link to Article
Levey  ASMadaio  MPPerrone  RD Laboratory assessment of renal disease: clearance, urinalysis, and renal biopsy. Brenner  BMRector  FC  Jreds.The Kidney 4th ed. Philadelphia, Pa Saunders1991;919- 961
Levey  AS Measurement of renal function in chronic renal disease. Kidney Int. 1990;38167- 184
Link to Article
Hallynck  TSoep  HHThomis  J  et al.  Prediction of creatinine clearance from serum creatinine concentration based on lean body mass. Clin Pharmacol Ther. 1981;30414- 421
Link to Article
Hallynck  THSoep  HHThomis  J  et al.  Should creatinine clearance be normalised to body surface or to lean body mass? Br J Clin Pharmacol. 1981;11523- 526
Link to Article
Grines  CLSchreiber  TLSavas  V  et al.  A randomized trial of low osmolar ionic versus nonionic contrast media in patients with myocardial infarction or unstable angina undergoing percutaneous transluminal coronary angioplasty. J Am Coll Cardiol. 1996;271381- 1386
Link to Article
Chronos  NAFGoodall  AHWilson  DJ  et al.  Profound platelet degranulation is an important side effect of some types of contrast media used in interventional cardiology. Circulation. 1993;882035- 2044
Link to Article
Ruttmann  TGJames  MFAronson  I In vivo investigation into the effects of haemodilution with hydroxyethyl starch (200/0.5) and normal saline on coagulation. Br J Anaesth. 1998;80612- 616
Link to Article
Ruttmann  TGJames  MF Pro-coagulant effect of in vitro haemodilution is not inhibited by aspirin. Br J Anaesth. 1999;83330- 332
Link to Article
Schömig  ANeumann  FJKastrati  A  et al.  A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents. N Engl J Med. 1996;3341084- 1089
Link to Article
Popma  JJSatler  LFPichard  AD  et al.  Vascular complications after balloon and new device angioplasty. Circulation. 1993;881569- 1578
Link to Article
Weinberger  MH Salt and blood pressure. Curr Opin Cardiol. 2000;15254- 257
Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Patient flow through the study.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Incidence of contrast media–associated nephropathy (CN), mortality, and peripheral vascular complications (Vascular).

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Baseline Clinical Characteristics*
Table Graphic Jump LocationTable 2. Angiographic and Procedural Characteristics*
Table Graphic Jump LocationTable 3. Outcome Variables (for All Interventions)*
Table Graphic Jump LocationTable 4. Outcome Variables: Subgroup Analysis*
Table Graphic Jump LocationTable 5. Multivariate Risk Factor Analysis (Backward Stepwise Logistic Regression) for the Development of Contrast Media−Associated Nephropathy

References

Menashe  PIRoss  SAGottlieb  JE Acquired renal insufficiency in critically ill patients. Crit Care Med. 1988;161106- 1109
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Hou  SHBushinsky  DAWish  JBCohen  JJHarrington  JT Hospital-acquired renal insufficiency: a prospective study. Am J Med. 1983;74243- 248
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Levy  EMViscoli  CMHorwitz  RI The effect of acute renal failure on mortality: a cohort analysis. JAMA. 1996;2751489- 1494
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McCullough  PAWolyn  RRocher  LLLevin  RNO'Neill  WW Acute renal failure after coronary intervention: incidence, risk factors, and relationship to mortality. Am J Med. 1997;103368- 375
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Gruberg  LMintz  GSMehran  R  et al.  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;361542- 1548
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Manske  CLSprafka  JMStrony  JTWang  Y Contrast nephropathy in azotemic diabetic patients undergoing coronary angiography. Am J Med. 1990;89615- 620
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Parfrey  PSGriffiths  SMBarrett  BJ  et al.  Contrast material–induced renal failure in patients with diabetes mellitus, renal insufficiency, or both. N Engl J Med. 1989;320143- 149
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Schwab  SJHlatky  MAPieper  KS  et al.  Contrast nephrotoxicity: a randomized controlled trial of a nonionic and an ionic radiographic contrast agent. N Engl J Med. 1989;320149- 153
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Barrett  BJParfrey  PSVavasour  HMO'Dea  FKent  GStone  E A comparison of nonionic, low-osmolarity radiocontrast agents with ionic, high-osmolarity agents during cardiac catheterization. N Engl J Med. 1992;326431- 436
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American College of Cardiology Cardiovascular Imaging Committee, Use of nonionic or low osmolar contrast agents in cardiovascular procedures. J Am Coll Cardiol. 1993;21269- 273
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Rudnick  MRGoldfarb  SWexler  L  et al.  Nephrotoxicity of ionic and nonionic contrast media in 1196 patients: a randomized trial. Kidney Int. 1995;47254- 261
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Rudnick  MRBerns  JSCohen  RMGoldfarb  S Contrast media–associated nephrotoxicity. Curr Opin Nephrol Hypertens. 1996;5127- 133
Link to Article
Erley  CM Nephrotoxicity: focusing on radiocontrast nephropathy. Nephrol Dial Transplant. 1999;14 ((suppl 4)) 13- 15
Link to Article
Solomon  RWerner  CMann  DD'Elia  JSilva  P Effects of saline, mannitol, and furosemide to prevent acute decreases in renal function induced by radiocontrast agents. N Engl J Med. 1994;3311416- 1420
Link to Article
Abizaid  ASClark  CEMintz  GS  et al.  Effects of dopamine and aminophylline on contrast-induced acute renal failure after coronary angioplasty in patients with preexisting renal insufficiency. Am J Cardiol. 1999;83260- 263
Link to Article
Barrett  BJParfrey  PS Prevention of nephrotoxicity induced by radiocontrast agents. N Engl J Med. 1994;3311449- 1450
Link to Article
Weisberg  LSKurnik  PBKurnik  BR Risk of radiocontrast nephropathy in patients with and without diabetes mellitus. Kidney Int. 1994;45259- 265
Link to Article
Stevens  MAMcCullough  PATobin  KJ  et al.  A prospective randomized trial of prevention measures in patients at high risk for contrast nephropathy. J Am Coll Cardiol. 1999;33403- 411
Link to Article
Koch  JAPlum  JGrabensee  BMödder  Uand the PGE1 Study Group, Prostaglandin E1: a new agent for the prevention of renal dysfunction in high risk patients caused by radiocontrast media? Nephrol Dial Transplant. 2000;1543- 49
Link to Article
Gupta  RKKapoor  ATewari  SSinha  NSharma  RK Captopril for prevention of contrast-induced nephropathy in diabetic patients: a randomised study. Indian Heart J. 1999;51521- 526
Kolonko  AWiecek  AKokot  F The nonselective adenosine antagonist theophylline does prevent renal dysfunction induced by radiographic contrast agents. J Nephrol. 1998;11151- 156
Kurnik  BRAllgren  RLGenter  FCSolomon  RJBates  ERWeisberg  LS Prospective study of atrial natriuretic peptide for the prevention of radiocontrast-induced nephropathy. Am J Kidney Dis. 1998;31674- 680
Link to Article
Tepel  Mvan der Giet  MSchwarzfeld  CLaufer  ULiermann  DZidek  W Prevention of radiographic-contrast-agent–induced reductions in renal function by acetylcysteine. N Engl J Med. 2000;343180- 184
Link to Article
Oliveira  D Prophylaxis against contrast-induced nephropathy. Lancet. 1999;3531638- 1639
Link to Article
Taylor  AJHotchkiss  DMorse  RWMcCabe  J PREPARED: preparation for angiography in renal dysfunction: a randomized trial of inpatient versus outpatient hydration protocols for cardiac catheterization in mild to moderate renal dysfunction. Chest. 1998;1141570- 1574
Link to Article
Levey  ASMadaio  MPPerrone  RD Laboratory assessment of renal disease: clearance, urinalysis, and renal biopsy. Brenner  BMRector  FC  Jreds.The Kidney 4th ed. Philadelphia, Pa Saunders1991;919- 961
Levey  AS Measurement of renal function in chronic renal disease. Kidney Int. 1990;38167- 184
Link to Article
Hallynck  TSoep  HHThomis  J  et al.  Prediction of creatinine clearance from serum creatinine concentration based on lean body mass. Clin Pharmacol Ther. 1981;30414- 421
Link to Article
Hallynck  THSoep  HHThomis  J  et al.  Should creatinine clearance be normalised to body surface or to lean body mass? Br J Clin Pharmacol. 1981;11523- 526
Link to Article
Grines  CLSchreiber  TLSavas  V  et al.  A randomized trial of low osmolar ionic versus nonionic contrast media in patients with myocardial infarction or unstable angina undergoing percutaneous transluminal coronary angioplasty. J Am Coll Cardiol. 1996;271381- 1386
Link to Article
Chronos  NAFGoodall  AHWilson  DJ  et al.  Profound platelet degranulation is an important side effect of some types of contrast media used in interventional cardiology. Circulation. 1993;882035- 2044
Link to Article
Ruttmann  TGJames  MFAronson  I In vivo investigation into the effects of haemodilution with hydroxyethyl starch (200/0.5) and normal saline on coagulation. Br J Anaesth. 1998;80612- 616
Link to Article
Ruttmann  TGJames  MF Pro-coagulant effect of in vitro haemodilution is not inhibited by aspirin. Br J Anaesth. 1999;83330- 332
Link to Article
Schömig  ANeumann  FJKastrati  A  et al.  A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents. N Engl J Med. 1996;3341084- 1089
Link to Article
Popma  JJSatler  LFPichard  AD  et al.  Vascular complications after balloon and new device angioplasty. Circulation. 1993;881569- 1578
Link to Article
Weinberger  MH Salt and blood pressure. Curr Opin Cardiol. 2000;15254- 257
Link to Article

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