A New Protocol Using Sodium Bicarbonate for the Prevention of Contrast-Induced Nephropathy in Patients Undergoing Coronary Angiography

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1 A New Protocol Using Sodium for the Prevention of Contrast-Induced Nephropathy in Patients Undergoing Coronary Angiography Masayuki Motohiro, MD a, *, Hiroshi Kamihata, MD b, Satoshi Tsujimoto, MD b, Takeshi Seno, MD b, Kenichi Manabe, MD b, Tsuyoshi Isono, MD b, Yasuo Sutani, MD c, Fumio Yuasa, MD b, and Toshiji Iwasaka, MD b Contrast-induced nephropathy (CIN) is associated with increased morbidity and mortality rates. Although a previous study reported that pretreatment with sodium bicarbonate is more effective than sodium chloride for prophylaxis of CIN, this has not been a universal finding. We performed a prospective randomized trial to investigate whether CIN can be avoided using sodium bicarbonate. In total 155 patients with a glomerular filtration rate (GFR) <60 ml/min/1.73 m 2 who were undergoing coronary angiography were enrolled. We assigned patients to sodium chloride plus sodium bicarbonate (bicarbonate group, n 78) or sodium chloride alone (chloride group, n 77). Infusion of sodium bicarbonate at 1 ml/kg/hour continued from 3 hours before to 6 hours after coronary angiography. CIN was defined as a 25% increase in serum creatinine from baseline value or an absolute increase of >0.5 mg/dl, which appeared within 2 days of contrast. Baseline GFR was not significantly different between the 2 groups. Patients in the bicarbonate group had a higher GFR than those in the chloride group on day 2 ( vs ml/min/1.73 m 2,p 0.031) and at 1 month ( vs ml/min/1.73 m 2,p 0.019). CIN occurred in 10 patients (13%) in the chloride group but in only 2 patients (2.6%) in the bicarbonate group (p 0.012). Sodium chloride plus sodium bicarbonate is more effective than sodium chloride alone for prophylaxis of CIN and can lead to retention of better long-term renal function Elsevier Inc. All rights reserved. (Am J Cardiol 2011;107: ) a Department of Cardiology, Kyoto Kujo Hospital, Kyoto, Japan; b Cardiovascular Division, Department of Medicine II, Kansai Medical University, Hirakata, Japan; c Department of Internal Medicine, Kobe Tokushukai Hospital, Kobe, Japan. Manuscript received December 1, 2010; revised manuscript received and accepted January 22, *Corresponding author: Tel: ; fax: address: m3uk-motohiro@kujohp.or.jp (M. Motohiro). Reactive oxygen species have an important role in the pathogenesis of contrast-induced nephropathy (CIN). 1 In animal studies, superoxide dismutase, a scavenger of reactive oxygen species, prevented renal damage by contrast agents. 2 The reported benefit of the free radical scavenger N-acetylcysteine supports the hypothesis that CIN is caused by free radical generation. 3,4 Sodium bicarbonate has antioxidant effects and scavenges reactive free radicals. 2 Recent studies have reported that hydration with sodium bicarbonate is more effective than with sodium chloride. 5 7 However, contradictory results regarding the efficacy of sodium bicarbonate have been reported, 8 and the protective effect of sodium bicarbonate is equivocal. In addition, the effect of prophylactic sodium bicarbonate on renal function over the long term is unknown. To fill these gaps in knowledge, we conducted a prospective, randomized, multicenter, openlabeled trial to test the hypothesis that infusion of sodium bicarbonate plus sodium chloride would be more effective at inhibiting CIN in patients with chronic kidney dysfunction undergoing planned coronary angiography or intervention than infusion of sodium chloride alone. In addition, we hypothesized that infusion of sodium bicarbonate would prevent CIN and have a long-term benefit in renal function. Methods We prospectively enrolled patients undergoing coronary angiography or intervention at 2 Japanese hospitals from November 2004 through May Indications for coronary angiography or intervention for each patient were left to the discretion of each clinical cardiologist. All patients were 20 years old and had an estimated glomerular filtration rate (egfr) 60 ml/min/1.73 m 2. Exclusion criteria included serum creatinine levels 4 mg/dl, changes in serum creatinine levels of 0.5 mg/dl during the previous 24 hours, pre-existing dialysis, pulmonary edema, uncontrolled hypertension (treated systolic blood pressure 160 mm Hg or diastolic blood pressure 100 mm Hg), emergency catheterization, exposure to radiographic contrast within previous 2 days, and any allergy to radiographic contrast medium. No patients received any treatment that influenced renal function including dopamine, mannitol, fenoldopam, or N-acetylcysteine during the intended period of the study. Patients were randomly assigned to receive sodium bicarbonate plus sodium chloride (bicarbonate group) or sodium chloride alone (sodium chloride group) based on random numbers generated by computer. All patients received 0.9% sodium chloride for 12 hours before and after the /11/$ see front matter 2011 Elsevier Inc. All rights reserved. doi: /j.amjcard

2 Coronary Artery Disease/Sodium to Prevent Contrast Nephropathy 1605 Table 1 Baseline clinical characteristics of patients Figure 1. Study protocol. In the bicarbonate group, patients received sodium chloride 154 meq/l as an infusion at 1 ml/kg/hour before and after the procedure and then received sodium bicarbonate 154 meq/l in 5% dextrose as an infusion at 1 ml/kg/hour 3 hours before the procedure and 6 hours after the procedure. In the sodium chloride group, patients received sodium chloride 154 meq/l as an infusion at 1 ml/kg/hour before and after the procedure. CAG/PCI coronary angiography/percutaneous coronary intervention. procedure. The sodium bicarbonate solution was prepared by adding 154 ml of sodium bicarbonate 1,000 meq/l to 846 ml of 5% dextrose in water. In the sodium bicarbonate group the sodium bicarbonate solution was changed 3 hours before contrast administration (Figure 1 shows treatment schedule). Echocardiographic evaluation of left ventricular function was performed in all patients on admission. The nonionic, low-osmolality contrast medium, iopamidol (Isovue, Bracco Diagnostics, Inc., Princeton, New Jersey) was used in all cases. Diuretics were stopped 24 hours before contrast administration and restarted only when renal function had been shown to be stable after the procedure. Serum creatinine concentration was assessed at time of hospital admission and on days 1 and 2 and at 1 month after the procedure. egfr obtained using a model excluding urine biochemistry values 9 was calculated at time of hospital admission and on days 1 and 2 and at 1 month after the procedure. All tests were performed in the hospital-based laboratory with consistent methods. Data were recorded in a dedicated database. The study protocol was approved by the local ethics committee and all patients gave written informed consent. The primary end point of the study was development of CIN, defined as a 25% increase or an absolute increase of 0.5 mg/dl in serum creatinine from baseline value, which appeared within 2 days of the produce. Additional end points were (1) change in serum creatinine and egfr calculated on days 1 and 2 and (2) long-term renal function assessed 1 month after the procedure. The sample size was selected to demonstrate a decrease in the primary end point of CIN from 15% in the chloride group 10 to 2% in the bicarbonate group. 5 Using Fisher s exact probability test with a significance level of 0.05, 158 randomized patients were calculated to give the study 90% power. Analysis was conducted on an intention-to-treat basis. Categorical variables such as incidence of CIN were analyzed by Fisher s exact test. Differences between groups were analyzed by nonparametric Wilcoxon Mann Whitney Age (years) Men 59 (76%) 49 (64%) Weight (kg) Smoking 48 (61%) 37 (48%) Diabetes mellitus 44 (56%) 49 (63%) Hypertension 67 (86%) 64 (83%) Hyperlipidemia 38 (48%) 42 (54%) Old myocardial infarction 30 (38%) 25 (32%) Angiotensin-converting enzyme inhibitor 62 (79%) 69 (90%) or angiotensin receptor blocker Cardiac catheterization 44 (56%) 36 (47%) Percutaneous coronary intervention 34 (44%) 41 (53%) Target coronary lesion Left anterior descending coronary 13 (17%) 15 (19%) artery Left circumflex coronary artery 8 (10%) 12 (16%) Right coronary artery 13 (17%) 14 (18%) Ejection fraction (%) Contrast volume (ml) Table 2 Baseline biochemical characteristics and biochemical responses P Value Baseline urine ph Baseline serum creatinine (mg/dl) Baseline estimate glomerular filtration rate (ml/min/1.73 m 2 ) Baseline serum potassium (meq/dl) Baseline serum bicarbonate (meq/dl) Urine ph immediately before procedure Change in serum potassium (meq/l) Change in serum bicarbonate (meq/l) Data are presented as mean SD. Change from admission to day 1 after contrast administration. test. Analyses were performed with StatView 5.0 (SAS Institute, Cary, North Carolina). All statistical tests were 2-sided and a p value 0.05 was considered statistically significant. Results In total 158 patients were randomized to receive sodium bicarbonate plus sodium chloride (n 79) or sodium chloride (n 79), with 155 patients completing the study. Of the 158 patients, 3 did not complete the study. Two patients in the chloride group had no follow-up laboratory test re-

3 1606 The American Journal of Cardiology ( Table 3 Changes in serum creatinine and estimated glomerular filtration rate p Value Baseline serum creatinine (mg/dl) Serum creatinine at day 1 (mg/dl) Serum creatinine at day 2 (mg/dl) Serum creatinine at 1 month (mg/dl) Baseline estimated glomerular filtration rate (ml/min/1.73 m 2 ) Estimated glomerular filtration rate at day 1 (ml/min/1.73 m 2 ) Estimated glomerular filtration rate at day 2 (ml/min/1.73 m 2 ) Estimated glomerular filtration rate at 1 month (ml/min/ 1.73 m 2 ) Data are presented as mean SD. Figure 3. Incidence of contrast-induced nephropathy (relative risk 0.176, p 0.012). Figure 2. Percent change in estimated glomerular filtration rate ([estimated glomerular filtration rate on any day minus estimated glomerular filtration rate at baseline]/estimated glomerular filtration rate at baseline 100) in the bicarbonate group (white bars) and chloride group (black bars). sults. In the bicarbonate group, 1 patient had to interrupt the infusion of sodium bicarbonate because of angialgia. Clinical characteristics of the 155 patients who completed the study are listed in Table 1. There were no significant differences between groups with regard to age, gender, or incidence of diabetes mellitus. No significant differences in baseline procedural characteristics were found between the 2 groups. Urine ph measurements before procedures confirmed that patients receiving sodium bicarbonate developed urinary alkalinization (Table 2). In addition, as expected, a significant increase in serum bicarbonate occurred in patients receiving sodium bicarbonate. There was a small but not significant decrease in serum potassium in the bicarbonate group, indicating that the alkaline load from sodium bicarbonate did not induce a decrease in serum potassium sufficient to create a risk for disturbances of cardiac rhythm. Mean serum creatinine for all patients was mg/dl. Regarding serum creatinine levels (Table 3), the bicarbonate group tended to have a lower level than the chloride group on day 1, day 2, and 1 month after the procedure. In the chloride group, mean serum creatinine increased from baseline on day 1, day 2, and at 1 month (p 0.41, , and respectively) after contrast administration. In the bicarbonate group, mean serum creatinine level decreased significantly from baseline on day 1 and 1 month after contrast administration (p and , respectively). Mean egfr for all patients was ml/min/1.73 m 2. egfr was significantly higher in the bicarbonate group than in the chloride group on day 1, day 2, and 1 month after the procedure (Table 3). In the chloride group, mean egfr decreased from baseline on days 1 and 2 after contrast administration (p 0.37 and , respectively). In the bicarbonate group, mean egfr increased from baseline on day 1, day 2, and at 1 month after contrast administration (p 0.020, 0.97, and , respectively). Post hoc analysis revealed that percent change in egfr after contrast administration (Figure 2) improved significantly in the bicarbonate group compared to the chloride group on day 1 ( % vs %, p 0.014), day 2 ( % vs %, p 0.031), and at 1 month ( % vs %, p 0.020) after the procedure. CIN occurred in 12 of 155 patients (7.7%), 2 of 78 (2.6%) in the bicarbonate group and 10 of 77 in the chloride group (13.0%, relative risk 0.176, 95% confidence interval to 0.83, p 0.012; Figure 3). No patient required hemodialysis. Ten of 12 patients with CIN had diabetes mellitus. Mean contrast dose in patients who developed CIN was higher than that administered to those who did not develop CIN ( vs ml, p 0.01). There were no adverse effects related to active treatments with sodium bicarbonate or sodium chloride. Discussion The major finding of this study is that treatment of patients with sodium bicarbonate plus sodium chloride be-

4 Coronary Artery Disease/Sodium to Prevent Contrast Nephropathy 1607 fore and after coronary angiography decreased the incidence of CIN compared to use of sodium chloride alone. In addition, egfr was improved not only in the short term but also for the long term in patients treated with sodium bicarbonate plus sodium chloride. The mechanism by which CIN occurs is not well understood. The 2 major theories are renal vasoconstriction and direct renal tubular toxicity. 2,11 15 Renal vasoconstriction occurs relatively often; it is mediated in part by the contrastinduced release of endothelin and adenosine, by alterations in nitric oxide, and by the high osmolality of the contrast agent. 7,13 15 There is also strong support for the other theory. Toxic renal damage may cause tubular injury, thus leading to generation of oxygen free radicals, which are considered important modulators of renal blood flow and egfr. 2,6,16,17 The pathophysiologic rationale for the protective effect of sodium bicarbonate on prevention of CIN is still unclear. However, animal studies have suggested that bicarbonate can scavenge reactive oxygen free radicals, protecting against ischemic acute renal failure. 18 Free radical formation is promoted by an acidic environment typical of tubular urine but is inhibited by the higher ph of normal extracellular fluid. 19,20 As a result, it has been hypothesized that alkalinizing renal tubular fluid with bicarbonate may decrease injury. 21 Results of recent trials have indicated that the benefit of using sodium bicarbonate for prevention of CIN is unclear. Three trials by Merten et al, 5 Ozcan et al, 6 and Briguori et al 7 showed clear evidence of benefit, whereas a trial by Maioli et al 8 found no evidence of benefit. In the 3 studies by Merten et al, 5 Briguori et al, 7 and Maioli et al, 8 patients received sodium bicarbonate as a bolus at 3 ml/kg/hour 1 hour before contrast administration, followed by an infusion at 1 ml/kg/hour for 6 hours after the procedure. Because 1/3 of our population had an old myocardial infarction, we used a lower-dose but longer pretest hydration protocol to prevent any deterioration in hemodynamics from a high-dose bolus. In the study by Ozcan et al 6 patients received sodium bicarbonate as an infusion at 1 ml/kg/hour for 6 hours before and after the procedure. Although longer hydration with sodium bicarbonate in the study by Ozcan et al 6 was compared to other studies, the results agreed with findings of other studies regarding decrease in CIN. Therefore, our study protocol assigned patients to receive sodium bicarbonate as an infusion at 1 ml/kg/hour for 3 hours before and 6 hours after the procedure. The resulting protective effect against CIN was impressive, and no significant side effects were observed in any patient. In general, administration of sodium chloride is cornerstone treatment to decrease the risk of CIN Although the optimal hydration strategy is uncertain, available data support a regimen of 0.9% sodium chloride at 1 ml/kg/hour intravenously for 12 hours before and after contrast administration In the 2 studies by Merten et al 5 and Briguori et al 7 duration of sodium chloride was shorter than the standard duration. Moreover, in studies by Ozcan et al 6 and Maioli et al 8 total volume of intravenous hydration was smaller in patients receiving sodium bicarbonate compared to those receiving sodium chloride because of the use of the standard duration of sodium chloride administration. In our study total volume of intravenous hydration was the same in the 2 groups. Prophylactic use of sodium bicarbonate plus sodium chloride was therefore found to be beneficial. This supports the concept that the mechanism of action underlying the efficacy of sodium bicarbonate in preventing CIN is the result of volume expansion in addition to the alkalinizing effect of sodium bicarbonate on renal tubular fluid. Incidence of CIN in our study (2.6%) was not different from patients treated sodium bicarbonate by Merten et al 5 (1.7%), Ozcan et al 6 (4.5%), and Briguori et al 7 (1.9%). Addition of sodium chloride to sodium bicarbonate infusion might not offer any additional benefit over hydration with sodium bicarbonate alone. However, the hydration protocol with sodium bicarbonate was unconventional, and it does not allow for direct comparisons when using it alone. Further studies are therefore required to confirm these outcomes. Our study is the first to examine the effect of sodium bicarbonate on renal function in the long term in patients who were treated with sodium bicarbonate plus sodium chloride. In general, progression of renal dysfunction in patients with chronic kidney disease is thought to be caused by glomerular overfiltration by residual nephrons and release of neurohormones that decrease renal blood flow. This progression is thought to be irreversible. However, our study demonstrated that mean egfr after 1 month significantly improved in patients who received sodium bicarbonate plus sodium chloride. It is difficult to comment on the significance of the improved mean egfr after 1 month. Our data suggest that prophylactic and therapeutic use of sodium bicarbonate plus sodium chloride for preventing CIN improved long-term renal function and further decrease mortality after percutaneous coronary intervention in patients with chronic kidney disease. The limitations of our study include the small sample and that it was 2-center study, which may decrease the power of the study. The study design, however, allowed us to make sodium bicarbonate-specific inferences. In addition, our data were limited to 1 month after coronary procedures; effect of sodium bicarbonate on more long-term outcomes in patients with abnormal renal function remains unknown. The dose of sodium bicarbonate chosen was, it may be argued, higher than necessary to prevent CIN. A substantially lower intravenous dose may have been equally effective and this question merits further study. 1. Katholi RE, Woods TT Jr, Taylor GJ, Deitrick CL, Womack KA, Katholi CR, McCann WP. Oxygen free radicals and contrast nephropathy. Am J Kidney Dis 1998;32: Bakris GL, Lass N, Gaber AO, Jones JD, Burnett JC Jr. Radiocontrast medium-induced declines in renal function: a role for oxygen free radicals. 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