Prevention of Radiocontrast-Induced Nephropathy with N-Acetylcysteine in Patients Undergoing
Coronary Angiography

George M. Tadros, MD, *Elie N. Mouhayar, MD, *Akindolapo O. Akinwande, MD, *Brenda Campbell, RN, **Craig Wood, MS, *James C. Blankenship, MD, *Elias A. Iliadis, MD
George M. Tadros, MD, *Elie N. Mouhayar, MD, *Akindolapo O. Akinwande, MD, *Brenda Campbell, RN, **Craig Wood, MS, *James C. Blankenship, MD, *Elias A. Iliadis, MD
Acute transient renal insufficiency after exposure to radiocontrast agents has been well described. The incidence varies among studies depending on the definition and the patient population studied.1 One of the more commonly accepted definitions for radiocontrast-induced nephropathy (RCIN) is a greater than 25% increase in serum creatinine within 48 hours of contrast exposure.2 Risk factors for RCIN include baseline renal dysfunction, congestive heart failure, diabetes mellitus, dehydration, peripheral vascular disease, hypertension, multiple myeloma and treatment with nephrotoxic drugs.1,3,4 RCIN has been associated with increased morbidity and mortality.5 Various agents and different strategies for the prevention of RCIN have been investigated.6–10 The only preventive measures that have been validated in the setting of coronary angiography are pre- and post-procedure hydration.8 N-acetylcysteine, an antioxidant agent with few side effects, was shown to have clinical benefit in preventing RCIN if administered orally for 24 hours before and after computerized tomography studies.11 Patients undergoing cardiac catheterization receive, on average, a higher volume of contrast agent, are usually older and have variable hemodynamic conditions compared to patients undergoing regular computerized tomography. Accordingly, we studied the potential benefit of oral N-acetylcysteine in preventing renal dysfunction in patients undergoing cardiac catheterization. Methods Patients. Fifty-five consecutive patients scheduled for coronary angiography after July 2000 (with a persistent and stable serum creatinine above 1.2 mg/dl [involving at least 2 measurements pre-catheterization] or a creatinine clearance below 50 ml per minute) were enrolled in the study. Creatinine clearance was estimated based on the Cockroft-Gault equation using each patient’s serum creatinine concentration, weight, age and sex.12 All patients received four doses of 600 mg N-acetylcysteine, twice on the day before, once in the morning prior to cardiac catheterization, and once after catheterization. Fifty-five consecutive patients with serum creatinine level above 1.2 mg/dl in one year prior to July 2000 were identified as the control group. All patients in both groups received intravenous hydration according to the discretion of the attending cardiologist. All hydration protocols involved 0.45% or 0.9% saline at 0.5–1.0 ml/kg/hour for 6–12 hours prior to and after the procedure. Patients who were on hemodialysis prior to the coronary catheterization were excluded. Data recorded prospectively, including the amount and type of contrast are listed in Table 1. Angiography protocol. Angiography was performed on digital imaging systems. Routinely 10 coronary angiograms and a left ventriculogram were performed. The type of contrast media used (ionic versus non-ionic), and the need for same-sitting ad hoc coronary intervention were left to the discretion of the invasive cardiologist. After the angiography or coronary intervention, patients were kept under observation for 6 more hours with intravenous hydration. Serum creatinine was measured 24 and 48 hours after angiography. The occurrence of RCIN, defined as > 25% and/or > 0.5 mg/dl increase from baseline creatinine, was recorded. The occurrence of any radiographic-contrast-induced nephropathy requiring dialysis in the month after angiography was noted. Statistical analysis. Baseline characteristics were compared between both groups using t-test for continuous variables and Chi-square test for categorical variables. All continuous variables will be presented in the form of mean ± standard deviation. Categorical variables will be presented as a percentage from total patient population. A multiple logistic-regression analysis was performed to examine the effect of N-acetylcysteine, with adjustment of all baseline characteristics. All statistical data analyses were performed using SAS statistical software, version 8.1 (Cary, North Carolina). Results Demographics and procedural variables for both the treatment and control groups are shown in Table 1. Comparison of the pre-procedural variables revealed no significant difference between the treatment and the control groups except for baseline creatinine and weight. The treatment group had a trend towards higher weights (88 vs. 81.6 kg; p = 0.064) and a significantly higher baseline creatinine (2.0 ± 0.7 vs. 1.8 ± 0.4 mg/dl; p = 0.04). Pre-procedural blood urea nitrogen (BUN) and bicarbonate were similar between both groups. The total amount of peri-procedural intravenous hydration was similar in both groups. (860 ml [± 45] vs. 800 ml [± 53]; p = 0.15). The distribution of the type of fluid was similar between both groups. Thirty-four of 55 and 32/55 patients in the treatment and control group received 0.9% saline while the rest received 0.45% saline (p = 0.2). Similar amounts of contrast media were given in both groups (144 cc vs. 134 cc; p = 0.5). The use of non-ionic contrast media was similar in both groups (14/55 vs. 8/55; p = 0.153). The rest of the patients received ionic contrast media. The number of patients that underwent a coronary intervention was similar between both groups (16/55 vs. 14/55; p = 0.4). All coronary interventions were done in the same sitting after the coronary angiography. The mean change in creatinine after 48 hours was -0.4 ± 0.3 versus +0.1 ± 0.3 mg/dl for treatment and control groups respectively (p 2 mg/dl, the benefit of N-acetylcysteine (Figures 1 and 2) was more pronounced (-0.4 ± 0.4) vs. +0.5 ± 0.3) mg/dl; p 1.2 mg/dl) undergoing computerized tomography studies.11 In the 42 patients that received N-acetylcysteine, the mean serum creatinine concentration decreased significantly (p 2 mg/dl benefited more from prophylactic administration of N-acetylcysteine than did patients with creatinine less than 2.0. The results of our study are different from what was reported by Boccalandro, probably due to multiple confounding factors. Our patients received a less amount of contrast and almost half the amount of hydration. Also, fewer patients had diabetes and hypertension, both factors known to be risk factors for RCIN. Results of both studies could be reconciled in the conclusion that high-risk patients who have not received enough hydration prior to contrast studies may benefit from acetylcysteine.26 There were several limitations to our study. First, it was not randomized, and used historical controls. Second, it included a small number of subjects, especially those with higher levels of serum creatinine. Third, although the total amount of hydration given to each group was similar, there was no standard protocol for hydration. While the study subjects and controls were recruited from different time periods, strategies for treating cardiac catheterization patients with chronic renal insufficiency were unchanged over these time periods except for the use of N-acetylcysteine. While non-ionic contrast was used more frequently in N-acetylcysteine patients, we do not believe that this affected our results because the difference was small, statistically not significant and because other studies have suggested that non-ionic contrast does not prevent RCIN.27,28 We conclude that in addition to adequate intravenous hydration, N-acetylcysteine is of benefit to patients with baseline renal dysfunction undergoing cardiac catheterization. Larger randomized trials are needed to confirm this finding. Also, its benefit in the subgroups of creatinine > 2 mg/dl versus
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