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Original Article

Effects of Saline, Mannitol, and Furosemide on Acute Decreases in Renal Function Induced by Radiocontrast Agents

Richard Solomon, Craig Werner, Denise Mann, John D'Elia, and Patricio Silva

N Engl J Med 1994; 331:1416-1420November 24, 1994

Abstract

Background

Injections of radiocontrast agents are a frequent cause of acute decreases in renal function, occurring most often in patients with chronic renal insufficiency and diabetes mellitus.

Methods

We prospectively studied 78 patients with chronic renal insufficiency (mean [±SD] serum creatinine concentration, 2.1 ±0.6 mg per deciliter [186 ±53 μmol per liter]) who underwent cardiac angiography. The patients were randomly assigned to receive 0.45 percent saline alone for 12 hours before and 12 hours after angiography, saline plus mannitol, or saline plus furosemide. The mannitol and furosemide were given just before angiography. Serum creatinine was measured before and for 48 hours after angiography, and urine was collected for 24 hours after angiography. An acute radiocontrast-induced decrease in renal function was defined as an increase in the base-line serum creatinine concentration of at least 0.5 mg per deciliter (44 μmol per liter) within 48 hours after the injection of radiocontrast agents.

Results

Twenty of the 78 patients (26 percent) had an increase in the serum creatinine concentration of at least 0.5 mg per deciliter after angiography. Among the 28 patients in the saline group, 3 (11 percent) had such an increase in serum creatinine, as compared with 7 of 25 in the mannitol group (28 percent) and 10 of 25 in the furosemide group (40 percent) (P = 0.05). The mean increase in serum creatinine 48 hours after angiography was significantly greater in the furosemide group (P = 0.01) than in the saline group.

Conclusions

In patients with chronic renal insufficiency who are undergoing cardiac angiography, hydration with 0.45 percent saline provides better protection against acute decreases in renal function induced by radiocontrast agents than does hydration with 0.45 percent saline plus mannitol or furosemide.

Media in This Article

Figure 1Serum Creatinine Concentrations Immediately before the Administration of Radiocontrast Agent (after 12 Hours of Hydration) and 48 Hours Later in Patients with Chronic Renal Insufficiency.
Table 1Demographic Characteristics of the Patients with Chronic Renal Insufficiency in the Three Treatment Groups.
Article

Acute decreases in renal function induced by the administration of radiocontrast agents are an important cause of hospital-acquired renal insufficiency, which contributes to morbidity and mortality during hospitalization and to the incidence of chronic end-stage renal disease1-4. Although the pathogenesis of acute renal insufficiency induced by radiocontrast agents is not fully understood, it appears to be due to medullary ischemia caused by decreased renal blood flow resulting from an imbalance of vasodilative and vasoconstrictive factors5. Because procedures involving the use of radiocontrast agents are scheduled beforehand and their occurrence is therefore predictable, a variety of prophylactic approaches have been suggested, including saline hydration and the administration of mannitol or furosemide6. There are, however, no prospective randomized trials directly comparing these approaches. We therefore undertook to compare the prophylactic efficacy of saline hydration alone with that of saline hydration plus either mannitol or furosemide in a group of patients at high risk for an acute decrease in renal function induced by radiocontrast agents.

Methods

Patients

Patients scheduled for cardiac angiography who had serum creatinine concentrations exceeding 1.6 mg per deciliter (140 μmol per liter) or rates of creatinine clearance below 60 ml per minute (<1.0 ml per second), calculated on the basis of serum creatinine concentration, weight, age, and sex,7 were eligible for the study. The indications for angiography were determined by each patient's cardiologist. Most patients were studied because of symptomatic coronary ischemia. The choice of radiocontrast agent was also made by the cardiologist. There were no differences in the types of radiocontrast agents used in the three treatment groups. Of the 78 patients enrolled in the study, 25 (32 percent) received ionic, high-osmolality radiocontrast agents, and the remainder received ionic, low-osmolality or non-ionic, low-osmolality radiocontrast agents (32 percent and 35 percent, respectively). The protocol was approved by the Committee on Human Research of New England Deaconess Hospital, and all patients gave written informed consent.

Study Protocol

All the patients received 0.45 percent saline intravenously at a rate of 1 ml per kilogram of body weight per hour beginning 12 hours before the scheduled angiography. This saline infusion was continued during the angiography (saline group) or was supplemented with 25 g of mannitol, infused intravenously during the 60 minutes immediately before angiography (mannitol group), or with 80 mg of furosemide, infused intravenously during the 30 minutes immediately before angiography (furosemide group). A hospital pharmacist who had no knowledge of the patients assigned each patient to one of the three groups using a random-allocation table. All the patients continued to receive 0.45 percent saline intravenously at the same rate for 12 hours after angiography and were encouraged to drink if thirsty. Serum creatinine and blood urea nitrogen were measured 12 to 24 hours before angiography, at the time of angiography, and on the next two mornings (i.e., 24 and 48 hours later). Urine was collected for the first 24 hours after angiography. Urinary sodium and potassium were measured by flame photometry, and creatinine by AutoAnalyzer. A radiocontrast-induced decrease in renal function was defined as an increase in the base-line serum creatinine concentration of at least 0.5 mg per deciliter ( ≥ 44 μmol per liter) within 48 hours after the injection of radiocontrast medium.

Statistical Analysis

Continuous variables were analyzed by analysis of variance, and categorical variables by the chi-square test. Analyses indicating significant differences among the three treatment groups were followed by two-tailed pairwise analyses with the t-test for continuous variables and Fisher's exact test for categorical variables. Data are expressed as means ±SD. All analyses were performed with Systat (version 5.1, Systat, Evanston, Ill.).

Results

A total of 78 patients were enrolled, and all completed the protocol. Their demographic characteristics are shown in Table 1Table 1Demographic Characteristics of the Patients with Chronic Renal Insufficiency in the Three Treatment Groups.. The number of patients with diabetes mellitus or congestive heart failure was similar in each of the three groups, as was the number receiving diuretics or calcium-channel antagonists before angiography. The volume of radiocontrast agent and the total dose of iodine given in the three groups were also similar.

The changes in the serum creatinine concentration of each patient are shown in Figure 1Figure 1Serum Creatinine Concentrations Immediately before the Administration of Radiocontrast Agent (after 12 Hours of Hydration) and 48 Hours Later in Patients with Chronic Renal Insufficiency.. The mean serum creatinine concentration at the time the radiocontrast agents were administered was similar in each treatment group. The increase in the serum creatinine concentration was significantly greater 24 hours after angiography in the mannitol group (P = 0.01) and the furosemide group (P = 0.02) than in the saline group, and was also significantly greater 48 hours after angiography in the furosemide group (P = 0.01) (Table 2Table 2Absolute Changes in Serum Creatinine Concentration after the Administration of Radiocontrast Agents and the Incidence of Acute Renal Dysfunction, According to Treatment Group.). The serum creatinine concentration increased by at least 0.5 mg per deciliter in 20 of the 78 patients (26 percent): 3 of the 28 patients who received saline (11 percent), 7 of the 25 patients who received mannitol (28 percent), and 10 of the 25 patients who received furosemide (40 percent, P = 0.02 for the comparison with the saline group alone). There was no significant difference between the mannitol and furosemide groups. When the prehydration serum creatinine concentration was used to estimate the incidence of radiocontrast-induced increases in serum creatinine, there was still a significant difference between the saline group and the furosemide group (7 percent and 32 percent, respectively; P = 0.02). Increases in the serum creatinine concentration were not limited to patients with the most severe chronic renal insufficiency. When patients with serum creatinine concentrations of at least 3.0 mg per deciliter (265 μmol per liter) before hydration were excluded from the analysis, the pattern of radiocontrast-induced increases in serum creatinine among the groups was similar: 4 percent in the saline group, 24 percent in the mannitol group, and 35 percent in the furosemide group had such increases (P = 0.02 for the comparison of the furosemide group with the saline group).

The changes in weight 24 hours after angiography were similar in all three groups (Table 3Table 3Measures of Volume Status in the Three Treatment Groups.). The three groups also did not differ significantly in the ratio of blood urea nitrogen to serum creatinine, total urinary output, or urinary sodium excretion during the initial 24 hours after angiography. These results suggest that extracellular volume depletion, potentially caused by mannitol or furosemide, did not contribute to the higher incidence of acute radiocontrast-induced decreases in renal function in these two groups.

In each treatment group, the incidence of increases in serum creatinine was slightly but not significantly higher in the diabetic than in the nondiabetic patients (Table 4Table 4Incidence of Acute Radiocontrast-Induced Renal Dysfunction, According to Treatment Group, Diabetic Status, and Need for Therapy with Calcium-Channel Antagonists.). There were no significant differences in the incidence of decreased renal function between patients who received calcium-channel antagonists and those who did not receive them in any treatment group.

In patients who had increases in the serum creatinine concentration, the peak response was on day 4, and it was still above the prehydration level on day 7. Although only one patient (in the furosemide group) required dialysis, the average length of hospitalization for all patients with radiocontrast-induced acute renal dysfunction was increased by four days.

There were too few cases of radiocontrast-induced increases in the serum creatinine concentration to analyze the effect of radiocontrast agents independently of treatment group. For each of the three radiocontrast agents used in this study, more of the patients who were treated with furosemide had acute renal dysfunction than did saline-treated patients. There were no differences when non-ionic and ionic radiocontrast agents were compared with respect to the incidence of acute renal dysfunction.

Discussion

Angiography remains an important cause of hospital-acquired acute renal insufficiency. In previous studies, the incidence varied from 0 to 90 percent depending on the group studied. We chose to study patients with chronic renal insufficiency, many of whom also had diabetes, because they are generally considered to be at greatest risk for renal insufficiency induced by radiocontrast agents8-16.

We defined an acute radiocontrast-induced decrease in renal function as an increase of at least 0.5 mg per deciliter in the serum creatinine concentration within 48 hours after the administration of radiocontrast agents. Through a questionnaire sent to attending physicians before the study, we asked them to specify the minimal change in the serum creatinine concentration after the administration of radiocontrast agents that would lead to a delay in elective surgery or a follow-up procedure and thus, presumably, increase the length of hospitalization. Eighty percent of the 84 respondents reported that an increase of 0.5 mg per deciliter after angiography would cause them to delay an elective procedure. Thus, this value represented a clinically important adverse event.

The most important finding of this study is that hydration with 0.45 percent saline alone was associated with the lowest incidence of radiocontrast-induced acute renal dysfunction in the patients studied. Only 11 percent of the patients who received saline alone had such a decrease in renal function. This value is less than that reported for similar patients in most previous studies8,11,14,15,17-22. In only one other study involving patients undergoing cardiac angiography was the incidence as low, and the hydration protocol in that study was similar to the saline treatment in our study14. Other studies have also supported the efficacy of hydration in preventing radiocontrast-induced renal dysfunction. Among 518 patients with a mean serum creatinine concentration of 1.9 mg per deciliter (168 μmol per liter) who were undergoing cardiac angiography, 76 had radiocontrast-induced renal dysfunction (defined as in our study). The only significant differences between these patients and a matched group of 82 patients with no changes in renal function were the volume of radiocontrast agent given, the diastolic pressure before angiography, and the frequency of hydration in the previous 24 hours23. In an uncontrolled study of 25 patients with chronic renal insufficiency (serum creatinine concentration, >1.8 mg per deciliter [159 μmol per liter]), no patient who received 550 ml of 0.9 percent saline per hour during a variety of angiographic procedures had radiocontrast-induced renal dysfunction24. Among 18 patients with serum creatinine values above 1.7 mg per deciliter (150 μmol per liter) who were randomly assigned to receive hydration (3000 ml total) or hydration plus furosemide (110 mg intravenously), the group receiving hydration alone had no change in the serum creatinine concentration at 24 hours whereas the group receiving furosemide had an increase25. In another group of patients (mean serum creatinine concentration, 2.5 mg per deciliter [222 μmol per liter]), saline reduced the incidence of radiocontrast-induced renal dysfunction in those who had diabetes but not in those without diabetes26. The incidence of acute renal dysfunction was 40 percent in the saline-treated group, which was similar to that in the furosemide-treated patients in our study.

Mannitol has been recommended for the prevention of radiocontrast-induced acute renal dysfunction because of its efficacy in preventing or reducing the severity of ischemic renal insufficiency in humans27,28. In uncontrolled studies, mannitol protected against such renal dysfunction in patients with chronic renal insufficiency who were undergoing angiography. In one study of patients with a mean serum creatinine concentration of 4.1 mg per deciliter (362 μmol per liter), 22 percent of 37 patients given saline and 50 g of mannitol had radiocontrast-induced renal dysfunction, as compared with 70 percent of historical controls given saline alone29. In a prospective, randomized trial of 24 patients (mean serum creatinine concentration, 2.2 mg per deciliter [194 μmol per liter]) who were undergoing a mixed group of angiographic procedures, the infusion of 25 g of mannitol immediately after the administration of radiocontrast agents was beneficial, especially in those with diabetes30. Another study found no cases of radiocontrast-induced renal insufficiency in nondiabetic patients given an infusion of 30 g of mannitol during angiography26. We found no evidence that mannitol was beneficial in either diabetic or nondiabetic patients. Finally, in another prospective trial of 60 patients with a mean serum creatinine concentration of 4.2 mg per deciliter (371 μmol per liter), an infusion of 25 g of mannitol immediately after angiography did not prevent radiocontrast-induced renal dysfunction31.

The use of furosemide for the prevention of radiocontrast-induced renal dysfunction is also controversial. In an uncontrolled study of 17 patients with a mean serum creatinine concentration of 4.0 mg per deciliter (354 μmol per liter) who were given furosemide after infusion pyelography, the incidence of such renal dysfunction was only 18 percent, as compared with 70 percent in a group of historical controls32. No cases were reported in another uncontrolled study in which the patients received hydration and various doses of furosemide to maintain a urinary output of 300 ml per hour33. However, in a prospective, randomized study of 18 patients with chronic renal insufficiency, pretreatment with furosemide (1.5 mg per kilogram 30 minutes before the administration of radiocontrast agents) was associated with a greater increase in serum creatinine at 24 hours than was hydration alone25.

We found that neither mannitol nor furosemide offered additional protection against acute radiocontrast-induced decreases in renal function as compared with saline hydration alone in either diabetic or nondiabetic patients. The significantly higher incidence in the furosemide group is provocative but unexplained. On the basis of data obtained during the 24 hours after the administration of the radiocontrast agents, furosemide did not induce volume depletion. Indeed, furosemide was associated with a significantly greater increase in the serum creatinine concentration at 24 hours even in patients who gained weight. However, since furosemide was given 30 minutes before the administration of radiocontrast agents, it may have caused systemic or renal hemodynamic changes that exacerbated those produced by the radiocontrast agent itself. For example, a decrease in cortical vascular resistance could divert blood from the medullary circulation. In concert with radiocontrast-induced renal vasoconstriction, this may produce a critical reduction in oxygen tension in the medullary nephrons, resulting in ischemic injury.

In conclusion, we found that hydration with 0.45 percent saline for 12 hours before and 12 hours after the administration of radiocontrast agents was the most effective means of preventing acute decreases in renal function in patients with chronic renal insufficiency with or without diabetes mellitus. Neither mannitol nor furosemide offered any additional benefit when added to this hydration protocol.

Presented at the 25th Annual Meeting of the American Society of Nephrology, Baltimore, November 15-18, 1992.

Supported by a grant from the Extramural Grant Program of Baxter HealthCare Corporation.

Source Information

From New England Deaconess Hospital, Joslin Diabetes Center, and Harvard Medical School -- all in Boston.

Address reprint requests to Dr. Solomon at Joslin Diabetes Center, 1 Joslin Pl., Boston, MA 02215.

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