Prophylactic Hemodialysis after Radiocontrast Media in Patients with ...

Prophylactic Hemodialysis after Radiocontrast Media in Patients with Renal Insufficiency is Potentially Harmful Bruno Vogt, MD, Paolo Ferrari, MD, Carlo Scho¨nholzer, MD, Hans-Peter Marti, MD, Markus Mohaupt, MD, Michael Wiederkehr, MD, Claudio Cereghetti, MD, Andreas Serra, MD, Uyen Huynh-Do, MD, Dominik Uehlinger, MD, Felix J. Frey, MD PURPOSE: Acute renal failure induced by contrast media is an important cause of hospital-acquired renal insufficiency. Preexisting renal failure and the dose of contrast media are known risk factors for the development of radiocontrast nephropathy. We performed a randomized trial to test whether radiocontrast nephropathy can be avoided by prophylactic hemodialysis immediately after the administration of contrast media in patients with impaired renal function. SUBJECTS AND METHODS: Renal function and other parameters, hemodialysis requirement, and relevant clinical events were recorded before and during the 6 days after administration of contrast media in 113 patients with a baseline serum creatinine level ⬎200 ␮m/L (⬎2.3 mg/dL). Patients were randomly assigned to either hemodialysis (n ⫽ 55) or nonhemodialysis (n ⫽ 58) treatment after parenteral low-osmolality contrast media. RESULTS: The characteristics of the patients in the two groups were similar. Compared with baseline levels, the mean [⫾ SD]

serum creatinine level decreased at day 1 (277 ⫾ 95 ␮m/L), peaked at day 4 (353 ⫾ 126 ␮m/L), and returned to baseline at day 6 (327 ⫾ 119 ␮m/L, P ⬍0.05 by analysis of variance) after administration of contrast media in the hemodialysis group, whereas in the nonhemodialysis group, no significant changes in mean serum creatinine level were observed. Eleven patients required 1 or more hemodialyses (8 in the hemodialysis group and 3 in the nonhemodialysis group, P ⫽ 0.12), 6 of whom (4 vs. 2, P ⫽ 0.44) required 3 or more hemodialyses. Clinically relevant events included pulmonary edema (1 vs. 4 patients, P ⫽ 0.36), myocardial infarction (2 vs. 2), stroke (2 vs. 0, P ⫽ 0.24), and death (1 vs. 1). CONCLUSION: The strategy of performing hemodialysis immediately after the administration of low-osmolality contrast media in all patients with a reduced renal function did not diminish the rate of complications, including radiocontrast nephropathy. Am J Med. 2001;111:692– 698. 䉷2001 by Excerpta Medica, Inc.

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Several prophylactic approaches, such as hydration, acetylcysteine, mannitol, calcium antagonists, and other drugs, have been advocated to prevent radiocontrast nephropathy (7–9). Although hydration is a generally accepted preventive measure (10), the other strategies either await confirmation or are controversial, especially among patients with more advanced renal insufficiency. In patients with impaired renal function, the half-lives of contrast media are increased severalfold because most contrast media are excreted in the urine (11). Hemodialysis removes contrast media effectively (12–15) and therefore might prevent radiocontrast nephropathy. One study, which compared the prophylactic effect of hemodialysis with conservative management (16), found that hemodialysis removes contrast media, but had no significant effect on the incidence of radiocontrast nephropathy. There were only 15 patients in the dialysis group, however, and patients with only moderate renal insufficiency (serum creatinine level ⬎124 ␮m/L [⬎1.4 mg/ dL]) were included in the study. We therefore performed a randomized trial of the effects of prophylactic hemodialysis on the incidence and outcome of radiocontrast nephropathy in a large number of patients with moderately to severely impaired renal function who underwent radiographic procedures with the use of contrast media.

iagnostic and interventional procedures using radiocontrast media are being performed with increasing frequency. In parallel, radiocontrast nephropathy has become a more frequent cause of hospital-acquired acute renal failure, from 5% of all cases in 1977 to 32% in 1987 (1,2). The mechanisms of radiocontrast nephropathy are not fully understood, but may involve renal ischemia induced by an imbalance of vasodilatory and vasoconstrictive factors, and direct toxic effects on tubular epithelial cells (3,4). Preexisting renal insufficiency and the dose of contrast media administered, as well as diabetes mellitus, congestive heart failure, volume depletion, and the concomitant administration of drugs that interfere with the regulation of renal perfusion, including angiotensin-converting enzyme (ACE) inhibitors, are risk factors for radiocontrast nephropathy (5,6).

From the University Hospital of Berne, Berne, Switzerland Supported in part by Grant 32-49585.96 from the Swiss National Foundation for Scientific Research. Requests for reprints should be addressed to Felix J. Frey, MD, Division of Nephrology and Hypertension, Inselspital, University of Berne, Freiburgstrasse 10, 3010 Berne, Switzerland. Manuscript submitted March 7, 2001, and accepted in revised form August 3, 2001. 692

䉷2001 by Excerpta Medica, Inc. All rights reserved.

0002-9343/01/$–see front matter PII S0002-9343(01)00983-4

Prophylactic Hemodialysis after Radiocontrast Media/Vogt et al

METHODS Patients We studied 113 patients with known chronic stable renal failure (serum creatinine level ⬎200 ␮m/L [⬎2.3 mg/ dL]). The causes of renal insufficiency included diabetic nephropathy (n ⫽ 36), hypertensive nephroangiosclerosis (n ⫽ 18), glomerulonephritis (n ⫽ 13), tubulointerstitial nephritis (n ⫽ 12), and chronic graft dysfunction (n ⫽ 7), or were undetermined (n ⫽ 27). Patients underwent either elective percutaneous transluminal renal angioplasty (n ⫽ 36), percutaneous transluminal angioplasty of the lower extremities (n ⫽ 26), coronary angiography (n ⫽ 38), computed tomography (n ⫽ 11), or other radiographic investigations (n ⫽ 2) with nonionic, low-osmolality contrast media. Each patient’s physician determined the indications for the radiographic investigation. The dose of the nonionic, low-osmolality contrast agent ranged from 20 to 740 mL (mean [⫾ SD], 176 ⫾ 133 mL). None of the patients received acetylcysteine, theophylline, dopamine, mannitol, or furosemide during the study (8,9). The intake of chronic diuretic or ACE inhibitor therapy on the day of the administration of contrast media was postponed until after the radiographic investigation. Serum levels of creatinine, urea nitrogen, and potassium, as well as body weight, were measured before and daily for the 6 days after administration of the contrast media. Creatinine clearance was estimated (17). All patients gave their informed consent before enrollment. The study was approved by the institutional review board for research in humans of the University of Berne, Switzerland.

Study Protocol Patients were assigned randomly to receive either intravenous saline at 1 mL·kg⫺1·h⫺1 for 12 hours before and after administration of the contrast agent (nonhemodialysis group) or saline before and hemodialysis after administration of contrast media (hemodialysis group). In the hemodialysis group, dialysis was started as soon as technically possible after the radiographic investigation. The study design was chosen to reflect conditions used in clinical practice, as it is not usually possible to take dialysis machines into angiography suites. Hemodialysis access was either through a double-lumen intravenous femoral catheter (n ⫽ 36) or a single-lumen intra-arterial introducer used for catheter insertion during coronary angiography (n ⫽ 19). Hemodialysis was started between 30 and 280 minutes (median, 120 minutes) after administration of the first bolus of contrast media. The dialyser used was a high-flux polysulphone membrane (F50 [n ⫽ 37] or F60 [n ⫽ 18], Fresenius, Germany) (15). The mean blood flow was 180 ⫾ 42 mL/min, the duration of dialysis averaged 3.1 ⫾ 0.7 hours, and the dialysate flow was 500 mL/min. Ultrafiltration was not used in 48 patients and was between 0.3 and 1.0 liters in 7 patients.

The primary endpoints were acute radiocontrast nephropathy requiring hemodialysis within 1 to 6 days after administration of contrast media, cardiovascular (myocardial infarction, pulmonary edema, or stroke) or dialysis-related complications, or death. Secondary endpoints were transitory or persistent radiocontrast nephropathy not requiring renal replacement therapy. These were defined either as a maximum increase in the serum creatinine level ⬎132 ␮m/L (1.5 mg/dL) or ⬎50% above baseline at any time point (6). Because radiocontrast nephropathy is often defined as an increase in the serum creatinine level ⬎44 ␮m/L (0.5 mg/dL) or ⬎25% above baseline at any time point, data were also analyzed according to these criteria (defined as renal function impairment). Endpoints in the hemodialysis group also included hemodialysis-related complications (arteriovenous fistula, thrombosis, or infection at the puncture site).

Statistical Analysis Sample size was estimated assuming a 10% incidence of contrast media nephropathy requiring hemodialysis in one of the groups, and a between-group difference of 20%, with a two-sided 5% significance level and a power of 90%. The type 2 error rate was also evaluated by bootstrap sampling of the control group (18). Between-group differences in serum creatinine level were analyzed with the nonparametric Mann-Whitney U test and by analysis of variance. Categorical variables (e.g., the incidence of acute radiocontrast-induced reduction in renal function) were analyzed with the Fisher exact test. A multiple logistic regression analysis was used to examine the effect of prophylactic hemodialysis or no hemodialysis on the incidence of acute radiocontrast nephropathy, after adjustment for baseline creatinine level, age, history of diabetes, contrast media volume, and type of concomitant medication. In addition, the interval between the first bolus of contrast media and the start of hemodialysis, and the blood volume processed during prophylactic hemodialysis, were analyzed in the hemodialysis group. Subgroup analyses compared patients with serum creatinine levels ⱕ300 or ⬎300 ␮m/L (3.4 mg/dL), and among those who received ⱕ150 or ⬎150 mL of contrast media. In addition, the effects of different angiographic procedures and potentially harmful drugs such as diuretics, ACE inhibitors, and nonsteroidal anti-inflammatory drugs (NSAIDs) on the requirement for subsequent hemodialysis were analyzed. Analyses were performed with the SYSTAT 9.0 software (SPSS, Chicago, Illinois). All statistical tests were two sided.

RESULTS Of the 113 patients enrolled in the study (Table 1), 2 died (1 from each group) during the first day of the study. One

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Table 1. Baseline Characteristics of the Patients

Characteristic

Nonhemodialysis (n ⫽ 58)

Prophylactic Hemodialysis (n ⫽ 55)

P Value

Number (%) or Mean ⫾ SD Male sex Age (years) Body weight (kg) History of hypertension Blood pressure (mm Hg) Serum creatinine (␮m/L) Serum blood urea nitrogen (mM/L) Cause of renal insufficiency Diabetes mellitus Glomerulonephritis Allograft dysfunction Nephroangiosclerosis Interstitial nephritis Others Drugs Calcium antagonists Diuretics ACE inhibitors Cyclosporine A NSAIDs Other nephrotoxic agents Radiocontrast procedure Renal angioplasty Peripheral angioplasty Computerized tomography Coronary angiography Other Radiocontrast media Dose (mL)

35 (60) 69 ⫾ 10 76 ⫾ 16 30 (52) 146/81 ⫾ 28/16 308 ⫾ 106 24.8 ⫾ 8.5

33 (60) 70 ⫾10 74 ⫾19 28 (51) 147/78 ⫾29/14 316 ⫾112 23.0 ⫾7.4

0.84 0.53 0.48 1.00 0.82/0.43 0.69 0.30

19 (33) 3 (5) 5 (9) 11 (19) 8 (14) 12 (20)

17 (31) 10 (18) 2 (4) 7 (13) 4 (7) 15 (27)

0.73 0.05 0.44 0.43 0.16 0.49

28 (48) 36 (62) 27 (46) 4 (7) 2 (4) 6 (10)

23 (42) 31 (56) 19 (35) 2 (4) 5 (9) 6 (11)

0.37 0.45 0.28 0.68 0.11 1.00

23 (40) 13 (22) 7 (12) 13 (22) 2 (4)

13 (24) 13 (24) 4 (7) 25 (45) —

0.10 1.00 0.32 0.006 0.49

143 ⫾ 115

210 ⫾ 143

0.007

ACE ⫽ angiotensin-converting enzyme; NSAID ⫽ nonsteroidal anti-inflammatory drug.

patient had sudden cardiac death, and another died during rescue coronary angioplasty for acute coronary occlusion. Follow-up laboratory measurements were not available for 6 additional patients (2 in the hemodialysis group and 4 in the nonhemodialysis group), none of whom had a clinical event. The estimated creatinine clearance at baseline was 20 ⫾ 7 mL/min in the hemodialysis group and 22 ⫾ 8 mL/min in the nonhemodialysis group.

Renal Function after Radiocontrast Media

Among patients in the nonhemodialysis group (n ⫽ 53) for whom follow-up measurements were available, the serum creatinine level increased from 308 ⫾ 106 ␮m/L at baseline to a peak of 322 ⫾ 126 ␮m/L 96 hours after administration of contrast media (P ⫽ 0.98; Figure, upper panel). Among patients in the hemodialysis group (n ⫽ 52) for whom follow-up measurements were available, the baseline serum creatinine level was 316 ⫾ 112 ␮m/L, which decreased to 277 ⫾ 95 ␮m/L after 24 hours and 694

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peaked to 353 ⫾ 126 ␮m/L at 96 hours after administration of contrast media (P ⫽ 0.04; Figure). Serum urea nitrogen levels paralleled the changes in serum creatinine level in the two groups. The mean weights of the patients were similar at the start and the end of the study (76 ⫾ 16 kg vs. 77 ⫾ 21 kg in the nonhemodialysis group and 74 ⫾ 19 kg vs. 74 ⫾ 20 kg in the hemodialysis group), suggesting similar fluid balance in the two groups. Because the volume of contrast media administered to patients in the nonhemodialysis group was approximately 30% less than that administered in the hemodialysis group (Table 1), we compared the effects of hemodialysis among patients who received ⬎150 mL of radiocontrast media. There was no beneficial effect of hemodialysis on serum creatinine levels in this subgroup of patients (Figure). Twenty-two of the 111 patients (9 in the nonhemodialysis group and 13 in the hemodialysis group) developed acute radiocontrast nephropathy (Ta-

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from baseline at any time point) occurred in 11 patients (6 in the nonhemodialysis group and 5 in the hemodialysis group; Table 2). The serum creatinine level was increased at day 6 in 8 patients (4 in each group). Hospital discharge was delayed because of radiocontrast nephropathy in 6 patients in the nonhemodialysis group and 10 patients in the hemodialysis group. Logistic regression analyses did not show any effects of prophylactic hemodialysis, diabetes mellitus, or concomitant treatment with calcium antagonists, diuretics, ACE inhibitors, or NSAIDs on the endpoints of subsequent hemodialysis or radiocontrast nephropathy. The interval before the start of hemodialysis and the processed blood volume were not associated with the risk of endpoints in the hemodialysis group. Bootstrap sampling showed that the probability that 8 or more patients in the nonhemodialysis group would have required hemodialysis was 0.005, suggesting that the study had sufficient power to detect a difference between the two groups.

All Clinical Events A total of 21 (19%) of the 113 patients experienced a clinical event (radiocontrast nephropathy requiring hemodialysis, major cardiovascular event, death, or hemodialysis-related complications [8 in the nonhemodialysis group and 13 in the hemodialysis group]; Table 3). Figure. Mean (⫾ SE) serum creatinine concentrations before and after the administration of radiocontrast media in patients with chronic renal insufficiency. Only data from patients who did not require subsequent hemodialysis are included. Upper panel: serum creatinine levels for the nonhemodialysis group (50 patients, dotted line) and the hemodialysis group (44 patients, solid line). The changes in serum creatinine levels were significant in the hemodialysis group only (P ⫽ 0.04 by analysis of variance). There were no between-group differences in serum creatinine levels (P ⫽ 0.22). Lower panel: serum creatinine levels for the nonhemodialysis group (25 patients, dotted line) and the hemodialysis group (24 patients, solid line), in patients receiving ⬎150 mL of radiocontrast media. There were no between-group differences (P ⫽ 0.58).

ble 2). Eleven of these patients required 1 or more subsequent hemodialyses, for a total of 23 treatments within the first 6 days (Table 2). Indications for subsequent hemodialysis were hyperkalemia (n ⫽ 2), pulmonary edema (n ⫽ 2), and oligoanuria (n ⫽ 7). Three patients (1 in the nonhemodialysis group and 2 in the hemodialysis group) required permanent hemodialysis treatment (Table 3). None of the patients requiring subsequent hemodialysis had evidence of cholesterol embolism or atheroembolic complications. In the remaining patients, a radiocontrast-induced reduction in renal function (an increase in the serum creatinine level of at least 130 ␮m/L [1.5 mg/dL] or ⬎50%

Subgroup Analysis The incidence of radiocontrast nephropathy or need for subsequent hemodialysis did not differ between patients with baseline serum creatinine levels ⱕ300 or ⬎300 ␮m/L (Table 4). These two groups of patients were given similar amounts of contrast media (176 ⫾ 146 mL and 181 ⫾ 122 mL). Similarly, when the patients were analyzed according to whether the volume of contrast media was ⱕ150 or ⬎150 mL, no differences were found in the incidence of radiocontrast nephropathy or need of subsequent hemodialysis (Table 4). The time courses of serum creatinine levels among patients who received ⬎150 mL of contrast media were similar in the hemodialysis and nonhemodialysis groups (Figure, lower panel). Subsequent hemodialysis was necessary in 4 patients who underwent peripheral angioplasty (1 in the nonhemodialysis group and 3 in the hemodialysis group), 3 who underwent coronary angiography (1 vs. 2), 2 who underwent renal angioplasty (1 in each group), and 2 who underwent computerized tomography (both in the hemodialysis group). Before administration of contrast media, 34 patients were treated with diuretics and 13 with ACE inhibitors alone; none developed radiocontrast nephropathy. Three of the 32 patients on combined diuretic and ACE inhibitor therapy required subsequent hemodialysis.

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Table 2. Radiocontrast Media-induced Renal Dysfunction Prophylactic Hemodialysis (n ⫽54)


Measurement

P Value

Number (%) Renal function impairment day 0 to day 6 Change in serum creatinine ⬎44 ␮m/L from baseline ⬎25% from baseline ⬎44 ␮m/L and ⬎25% from baseline Radiocontrast nephropathy day 0 to day 6 Patients requiring subsequent hemodialysis Patients not requiring subsequent hemodialysis Change in serum creatinine ⬎130 ␮m/L from baseline ⬎50% from baseline ⬎130 ␮m/L and ⬎50% from baseline Persistent renal function impairment after day 6 Patients requiring subsequent hemodialysis Patients not requiring subsequent hemodialysis Change in serum creatinine ⬎130 ␮m/L from baseline ⬎50% from baseline ⬎130 ␮m/L and ⬎50% from baseline

20 (35)

24 (44) 20 (35) 15 (26) 15 (26)

9 (16)

0.43 24 (44) 17 (31) 17 (31)

13 (24) 3 (5) 6 (10)

8 (15) 5 (9)

2 (4) 3 (5) 1 (2)

1 (2) 1 (2) 3 (6)

0.43 0.67 0.67 0.35 0.12 1.00

2 (4) 4 (7)

4 (7) 4 (7)

1.00 0.62 0.36 0.58 0.44 1.00

— 3 (5) 1 (2)

— 2 (4) 2 (4)

1.00 1.00 0.62

6 (11)

8 (15)

44 ␮m/L ⫽ 0.5 mg/dL; 130 ␮m/L ⫽ 1.5 mg/dL.

DISCUSSION We found that a greater percentage of patients who were treated with prophylactic hemodialysis after the administration of contrast media required additional hemodialysis treatment, or had declines in renal function, than did those treated with saline hydration alone. Although the overall need for hemodialysis (11 of 113 patients) was greater than that previously reported in studies of mea-

sures to avoid radiocontrast nephropathy (5,7–9), this is most likely because the mean serum creatinine levels were greater in our patients than in those reported in previous studies (5,7–9) and because we included patients with substantial comorbid conditions. The latter point may also explain the high rate of clinical events, including mortality, in our study. After completion of the present study, the efficacy of prophylactic administration of acetylcysteine in patients

Table 3. Clinical Events during the Study

Characteristic

Prophylactic Hemodialysis (n ⫽55)


P Value

Number (%) Number of patients with events* Need for subsequent hemodialysis Transient Permanent Pulmonary edema Requiring hemodialysis Myocardial infarction Stroke Death Hemodialysis-related complications Arteriovenous fistula formation

8 (14) 3 (5) 2 (4) 1 (2) 4 (7)

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0.23 0.12 6 (11) 2 (4)

1 (2) 1 (2)

0.36 1 (2)

2 (4) 0 1 (2)

2 (4) 2 (4) 1 (2)

1.00 0.24 1.00

NA

2 (4)

0.24

* Some patients had more than 1 event. NA ⫽ not applicable. 696

13 (24) 8 (15)

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Table 4. Radiocontrast Media-induced Renal Dysfunction among Patients with Baseline Serum Creatinine Levels ⱕ or ⬎300 ␮n/L or Volume of Contrast Media ⱕ or ⬎150 mL Group, Outcome

Nonhemodialysis

Prophylactic Hemodialysis

P Value

Number (%) Baseline creatinine ⱕ300 ␮m/L Number of patients Patients (%) with radiocontrast nephropathy Patients (%) requiring hemodialysis Baseline creatinine ⬎300 ␮m/L Number of patients Patients (%) with radiocontrast nephropathy Patients (%) requiring hemodialysis Contrast volume ⱕ150 mL Number of patients Patients (%) with radiocontrast nephropathy Patients (%) requiring hemodialysis Contrast volume ⬎150 mL Number of patients Patients (%) with radiocontrast nephropathy Patients (%) requiring hemodialysis

with mildly impaired renal function was reported (9). It is possible that acetylcysteine would favorably affect the use of prophylactic hemodialysis, as dialysis induces free radical production (19). Nonionic, low-osmolality contrast agents are water soluble and excreted by the kidney. Their elimination half-life increases with declining renal function, approaching several days in anuric subjects. A hemodialysis treatment of 3 to 4 hours can remove about 80% of contrast media (13–15). Thus, the efficacy of prophylactic hemodialysis might be most evident in patients with severely reduced renal function, such as those in our study, who had a mean estimated glomerular filtration rate of about 20 mL/min. The reasons why hemodialysis treatment was not beneficial in our study are not known. Perhaps the rapid onset of renal injury after administration of contrast media—renal hypoperfusion occurs within 20 minutes after the injection of contrast media (3,20)— explains the lack of efficacy. Although patients in our study were dialyzed as soon as possible after the radiological intervention, the time from the initial injection of the contrast agent and the start of dialysis was longer than 20 minutes. It is also possible that hemodialysis treatment per se was nephrotoxic and might have offset the beneficial effect of the removal of contrast media. Nephrotoxicity due to dialysis has been linked with the activation of inflammatory reactions and the induction of hypovolemia (21–23). All pa-

35 4 (11)

30 9 (30)

0.12

1 (3)

4 (13)

0.18

22 5 (23)

24 4 (16)

0.71

2 (9)

4 (16)

0.67

31 5 (16)

24 4 (17)

1.00

2 (6)

3 (12)

0.34

26 4 (15)

30 9 (30)

0.43

1 (4)

5 (17)

0.39

tients were treated with a biocompatible polysulfone filter; thus, activation of inflammation is less likely. In addition, hypovolemia-induced hypotension is not likely, as 48 patients did not undergo ultrafiltration, and the remaining 7 patients underwent only low levels of ultrafiltration. (None of these latter 7 patients subsequently required hemodialysis.) However, an osmotic shift of fluid from the intravascular to the interstitial space during hemodialysis should be considered. The osmolality of nonionic contrast media is higher than that of plasma, leading to an increase in blood and plasma volume (24). Removal of contrast media by hemodialysis could result in a shift of water from the intravascular to the interstitial and intracellular compartments, leading to a decrease in blood volume. This intra-arterial volume depletion could result in sympathetic nervous system activation with impaired renal hemodynamics. Finally, the amount of contrast media administered was significantly greater in the hemodialysis group than in the nonhemodialysis group, perhaps explaining the higher incidence of radiocontrast nephropathy in the hemodialysis group. However, subgroup analyses in patients who received similar amounts of contrast media did not demonstrate between-group differences. Coronary angiography was performed twice as often in the hemodialysis group, raising the possibility that these patients had worse cardiac function and a greater risk of radiocontrast nephropathy (25). However, only 2 of the 25 patients in the hemodialysis group who

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underwent coronary angiography required subsequent hemodialysis. Determining the efficacy of an invasive intervention such as acute hemodialysis requires consideration of all clinical events related to the procedure. Overall, the rates of these events, such as pulmonary edema or dialysisrelated complications, were similar in the two groups. Thus, there was no net benefit from prophylactic hemodialysis, which therefore cannot be recommended in patients with renal impairment who have received radiocontrast media.

11.

12.

13. 14.

15.

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