Sodium Bicarbonate for the Prevention of Contrast-Induced Nephropathy: The Efficacy of High Concentration Solution

Abstract: Background. The appropriate dose of sodium bicarbonate to prevent contrast-induced nephropathy (CIN) has not been established. Methods and Results. To determine the efficacy of high-concentration sodium bicarbonate, 123 consecutive patients with renal dysfunction undergoing coronary angiography with/without intervention were administrated either high-concentration (group H: 833 mEq/L, n = 87) or low-concentration (group L: 160 mEq/L, n = 36) sodium bicarbonate at the rate of 3 mL/kg/h for 1 hour before the contrast exposure, and followed by 1 mL/kg/h for 7 hours. A total of 77 patients (group H, n = 54; group L, n = 23) without prophylactic continuous hemodiafiltration were analyzed in this study. Urine pH (n = 10 for each group and n = 5 for control) was increased by concentration and time-dependent manner in each group. Urine pH at 3 hours after administration of sodium bicarbonate was significantly higher in group H than group L and control (8.50 ± 0.94 vs 6.95 ± 1.17 vs 5.70 ± 0.97, respectively; P<.001). Incidence of CIN (0% vs 17.3%; P=.005) was lower in group H than group L. Percent change in creatinine within 48 hours was significantly lower in group H than group L (-2.65 ± 9.83% vs 9.14 ± 14.0%; P=.001). Percent change in estimated glomerular filtration rate within 48 hours was significantly higher in group H than group L (3.97 ± 11.8 vs -7.43 ± 13.3; P<.001). Conclusion. Administration of a higher concentration of sodium bicarbonate was more effective for urine alkalization and prevention of CIN.

J INVASIVE CARDIOL 2012;24(9):439-442

Key words: contrast-induced nephropathy, sodium bicarbonate, renal dysfunction, urine alkalization

_____________________________________________________

Contrast-induced nephropathy (CIN) is one of the important complications of radiographic procedures, especially in patients with chronic kidney disease, and has been associated with the third leading cause of acute renal failure in hospitalized patients, which leads to prolonged hospitalization, acceleration toward end-stage renal disease, and in-hospital death.^1-5

The mechanism of CIN remains unknown, but previous studies indicated that oxidative stress by the reactive oxygen species in the renal medulla plays a role in CIN.^6,7 It was reported that the production of superoxide is most active at acid environment,⁷ and urine alkalization by sodium bicarbonate has been regarded as resulting in reduction of CIN.^7-11 However, recent larger randomized studies reported that sodium bicarbonate is not more effective than normal saline for the prevention of CIN.^12,13 The appropriate concentration of sodium bicarbonate to prevent CIN has not been established. The concentration of sodium bicarbonate administrated in the previous studies was 154 mEq/L, which is the same as the concentration of sodium chloride of saline control, or less.^7-11 In one of the recent studies that suggested that hydration by sodium bicarbonate was not effective, the concentration of sodium bicarbonate was 130 mEq/L.¹³

The purpose of this study was to determine the efficacy of the pre-contrast exposure administration of high-concentration sodium bicarbonate on urine alkalization and the reduction of the incidence of CIN.

Methods

Study population. Between January 2008 and August 2010, consecutive patients with renal dysfunction (estimated glomerular filtration rate [eGFR], 60 mL/min/1.73 m² or less) who underwent elective or emergent coronary angiography (CAG) with/without percutaneous coronary intervention (PCI) at our institution were enrolled. The eGFR was calculated using the formula of the Japanese Society of Nephrology: 194 x creatinine – 1.094 x age – 0.287 (x 0.739 for women).¹⁴ The exclusion criteria included preexisting dialysis and prophyractic hemodiafiltration (CHDF), recent (within 48 hours) exposure to radiographic contrast,7 severe congestive heart failure, and emergent angiography.

Protocol. Sodium bicarbonate was administrated to the patients undergoing elective procedures from 1 hour before exposure to the nonionic radiographic contrast agent iopamidol (796 mOsm/kgH₂O, 370 mg iodine/mL), at a rate of 3 mL/kg/h for the first hour, decreased to 1 mL/kg/h for 7 hours by the 2 protocols described below. High-concentration sodium bicarbonate (833 mEq/L) was designated as group H, and low-concentration sodium bicarbonate (160 mEq/L) was designated as group L.

The patients were hydrated with lactated ringer’s at 1 mL/kg/h for at least several hours before exposure to the contrast. The protocol was determined according to the concentration and timing of administration, depending on the period of procedure, but not randomized.

Serum creatinine, blood urine nitrogen, and potassium were measured in all patients before and at 24 and 48 hours post angiography.

Urine pH was measured in 10 patients in each group and in 5 control patients with normal renal function, before and at 1 hour and 3 hours after administration of sodium bicarbonate (only hydration for control group).

The Mehran risk score¹⁵ for predicting CIN was calculated in all patients.

Frequency of CIN, change in creatinine, percent change in creatinine, percent change in eGFR, change in blood urine nitrogen (BUN)/creatinine ratio, change in serum potassium, and urine pH were compared between the 2 groups. Side effects of high-dose sodium bicarbonate, such as congestive heart failure, respiratory disorder, and low potassium, were carefully evaluated during the study.

CIN was defined as an increase of more than absolute 0.5 mg/dL and/or relative 25% in serum creatinine within 48 hours.

Written informed consent was obtained from all study patients for the cardiac catheterization and interventions and administration of planned doses of sodium bicarbonate.

Statistical analysis. Continuous variables are shown as mean ± standard deviation. Categorical variables were expressed as frequencies and percentages. The continuous variables were compared using t-test. Categorical data were compared using the chi-square test or Fisher’s exact test. Repeated measure ANOVA were used to compare urine pH at each time. A probability (P) value <.05 was considered statistically significant. All analyses were performed using SPSS for Windows (SPSS, Inc).

Results

A total of 123 patients were enrolled in this study. Excluding 46 patients with CHDF, 77 patients were analyzed in this study. Fifty-four patients were assigned to group H, and 23 patients to group L.

No side effects of high-dose sodium bicarbonate were observed, and discontinuation of protocol dose of infusion was not necessary in all patients.

Table 1 represents baseline clinical characteristics. There were no significant differences between the 2 groups in age, gender, body weight, BUN level, BUN/creatinine ratio, hemoglobin A1c level, brain natriuretic peptide (BNP), urine pH, urine gravity, frequencies of positive for urine protein, diabetes mellitus, hypertension, dyslipidemia, percutaneous coronary intervention, medications at baseline, and the Mehran index. BNP was measured only in limited patients with potential cardiac dysfunction at the discretion of the attending physicians. Serum creatinine level was higher and eGFR was lower in group H than group L.

Table 2 represents procedural and renal outcomes. Serum sodium concentration was significantly more increased, and potassium concentration was significantly more decreased in group H than group L after the procedure.

Incidence of CIN was lower than the risk predicted by Mehran risk score in each group. Incidence of CIN of group H was significantly lower than in group L (0% vs 17.3%, P=.005). Percent change in creatinine was significantly lower in group H than group L (-2.65 ± 9.83% vs 9.14 ± 14.0%; P=.001), and percent change in eGFR was significantly higher in group H than group L (4.0 ± 11.8% vs -7.4 ± 13.3%; P<.001) (Table 3).

In the urine study, urine pH was elevated in a time- and concentration-dependent manner (Figure 2). In group H, group L, and control, urine pH was 5.50 ± 0.78, 5.60 ± 0.84, 5.40 ± 0.89 at baseline, 6.35 ± 1.41, 6.30 ± 1.11, and 5.40 ± 0.41 at 1 hour after administration of sodium bicarbonate, and 8.50 ± 0.94, 6.95 ± 1.16, and 5.70 ± 0.97 at 3 hours, respectively. Urine pH at 1 hour after administration of sodium bicarbonate was significantly higher than baseline in groups H and L (P=.011 and P=.042). At 3 hours after administration, urine pH was significantly higher than at 1 hour after administration in group H (P<.001) and significantly higher than at baseline in groups H and L (P<.001 and P<.001). At 1 hour after administration, urine pH was not significantly different in each group, but at 3 hours after administration, urine pH was higher in group H than group L and control (P=.009 and P<.001).

Discussion

The present study showed that administration of high-concentration sodium bicarbonate before administration of contrast medium was more effective in preventing CIN than low-concentration (even higher than concentrations previously reported) protocol.^7-13

The mechanism of CIN remains still unknown, but previous studies indicated that oxidative stress by the reactive oxygen species in the renal medulla plays a role in CIN. The superoxide generated by the Haber-Weiss reaction accounts for free radical production in the renal medulla. This reaction is most active in an acid (pKa = 4.9) environment. Sodium bicarbonate might protect from oxidant injury by increasing medullary pH, and slowing free radical production.^7,16-18

The concentration of sodium bicarbonate in the previous studies was 154 mEq/L, the same concentration as sodium chloride of normal saline control, or less.^7-13 A recent randomized controlled study of large sample size suggested that hydration by sodium bicarbonate is no more effective than normal saline, but the concentration of sodium bicarbonate (130 mEq/L) is lower than other studies.¹³ It was suggested in a pediatric study that the dose of bicarbonate used by the previous studies might have been less than optimal, with the urine pH correlating inversely with CIN.¹⁹ A high concentration of sodium bicarbonate might result in a high urine pH and good efficacy, but there has been no study comparing the efficacy of high-concentration and low-concentration sodium bicarbonate for the prevention of CIN.

Thus, we determined the efficacy of high-concentration (833 mEq/L) sodium bicarbonate from 1 hour before contrast exposure (group H), compared with lower (but even higher than previous reports) concentration solution (160 mEq/L; group L). The higher concentration of sodium bicarbonate might have led to greater urine alkalization and better efficacy for the prevention of CIN than the low-concentration solution.

On the urine study, urine pH increased in a time- and concentration-dependent manner. The maximal effect of sodium bicarbonate on urine alkalization seemed to need at least 3 hours. To the best of our knowledge, the time course of changes in the urine pH after administration of sodium bicarbonate has not been reported. Our result in this study may indicate that sodium bicarbonate doses for elective patients in the protocols of the previous studies (154 mEq/L or less, beginning 1 hour before contrast exposure)^7,9,12,13 might be inadequate in terms of urine alkalization.

Some recent studies suggested the efficacy of long-term administration before contrast exposure,^10,20 but comparison of the efficacy between long-term and short-term have not been done. Three hours of high-dose sodium bicarbonate administration before contrast exposure might be more effective. Further examination on the protocol of longer duration (more than 3 hours) of high-dose sodium bicarbonate administration before contrast exposure might be necessary.

Although our study included the patients with relatively high level of BNP, which suggests reduced cardiac function and/or renal insufficiency, there were no side effects regarding the overload of bicarbonate in both groups. This fact might indicate the safety and tolerability of the protocol in this study.

Study limitations. First, this is a single-center study of small sample size. Because the incidence of CIN is low, a small change may influence the results. However, significantly lower percent change in creatinine and higher percent change in eGFR as well as low incidence of CIN in group H support the superiority of high-concentration sodium bicarbonate. Although serum creatinine was different at baseline between two groups, the difference was disadvantageous in the H group, leading to little influence on the results. A large, randomized study is necessary to confirm the results in this study. Second, we could not measure urine volume for all patients, which were useful factors to assess the status of circulating volume. Third, urine examinations were not performed for all cases. Thus, association of urine pH and CIN was not clarified because of the small number. Fourth, it is reported that serum creatinine usually starts rising within the first 24 hours in the CIN patients, and typically peaks 2 to 5 days after contrast exposure.²¹ The definition of an increase of more than absolute 0.5 mg/dL and/or relative 25% in serum creatinine within 48 hours may underestimate the incidence of CIN. Other new biomarkers, such as cystatin C,^22,23 kidney injury molecule-1,²⁴ neutrophil gelatinase-associated lipocalin,²⁵ and interleukin-18²⁶ may detect CIN more correctly at an earlier phase.

Conclusion

Administration of high-concentration sodium bicarbonate (833 mEq/L) before contrast exposure was more effective than low-concentration solution (160 mEq/L) for the prevention of CIN. 

References

1. Hou SH, Bushinsky DA, Wish JB, et al. Hospital-acquired renal insufficiency: a prospective study. Am J Med. 1983;74(2):243-248.
2. McCullough PA, Wolyn R, Rocher LL, et al. Acute renal failure after coronary intervention: incidence, risk factors, and relationship to motality. Am J Med. 1997;103(5):368-375.
3. Best PJ, Lennon R, Ting HH, et al. The impact of renal insufficiency on clinical outcomes in patients undergoing percutaneous coronary interventions. J Am Coll Cardiol. 2002;39(7):1113-1119.
4. Rihal CS, Textor SC, Grill DE, et al. Incidence and prognostic importance of acute renal failure after percutaneous coronary intervention. Circulation. 2002;105(19):2259-2264.
5. Abe M, Kimura T, Morimoto T, et al. Incidence of and risk factors for contrast-induced nephropathy after cardiac catheterization in Japanese patients. Circ J. 2009;73(8):1518-1522.
6. Tajiri K, Maruyama H, Sato A, et al. Prediction of chronic renal insufficiency after coronary angioplasty by an early increase in oxydative stress and decrease in glomerular filtration rate. Circ J. 2011;75(2):437-442.
7. Merten GJ, Burgess WP, Gray LV, et al. Prevention of contrast-induced nephropathy with sodium bicarbonate: a randomized controlled trial. JAMA. 2004;291(19):2328-2334.
8. Recio-Mayoral A, Chaparro M, Prado B, et al. The reno-protective effect of hydration with sodium bicarbonate plus N-acetyicystaine in patients undergoing emergency percutaneous coronary intervention: the RENO study. J Am Coll Cardiol. 2007;49(12):1283-1288.
9. Briguori C, Airoldi F, D’ Andrea D, Ricciardelli B, Colombo A. Renal insufficiency following contrast media administration trial (REMEDIAL): a randomized comparison of 3 preventive strategies. Circulation. 2007;115(10):1211-1217.
10. Ozcan EE, Guneri S, Akdeniz B, et al. Sodium bicarbonate, N-acetylcysteine, and saline for prevention of radiocontrast-induced nephropathy. A comparison of 3 regimens for contrast-induced nephropathy in patients undergoing coronary procedures. A single-center prospective controlled trial. Am Heart J. 2007;154(3):539-544.
11. Masuda M, Yamada T, Mine T, et al. Comparison of usefulness of sodium bicarbonate versus sodium chrolide to prevent contrast-induced nephropathy in patients undergoing an emergent coronary procedure. Am J Cardiol. 2007;100(5):781-786.
12. Maioli M, Toso A, Leoncini M, et al. Sodium bicarbonate versus saline for the prevention of contrast-induced nephropathy in patients with renal dysfunction undergoing coronary angiography or intervention. J Am Coll Cardiol. 2008;52(8):599-604.
13. Brar SS, Shen AY, Jorgensen MB, et al. Sodium bicarbonate vs sodium chloride for the prevention of contrast medium-induced nephropathy in patients undergoing coronary angiography: a randomized trial. JAMA. 2008;300(9):1038-1046.
14. Matsuo S, Imai E, Horio M, et al. Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis. 2009;53(6):982-992.
15. Mehran R, Aymong ED, Nikolsky E, et al. A simple risk score for prediction of contrast-induced nephropathy after percutaneous coronary intervention: development and initial validation. J Am Coll Cardiol. 2004;44(7):1393-1399.
16. Halliwell B, Gutteridge JMC. Role of free radicals and catalytic metal ions in human diseases: an overview. Methods Enzymol. 1990;186:1-85.

17. Bakris GL, Lass N, Gaber AO, et al. Radiocontrast medium-induced declines in renal function: a role for oxygen free radicals. Am J Physiol. 1990;258(1 Pt 2):F115-F120.
18. Katholi RE, Woods WT Jr, Taylor GJ, et al. Oxygen free radicals and contrast nephropathy. Am J Kidney Dis. 1998;32(1):64-71.
19. Assadi F. Acetazolamide for prevention of contrast-induced nephropathy: a new use for an old drug. Pediatr Cardiol. 2006;27(2):238-242.
20. Motohiro M, Kamihata H, Tsujimoto S, et al. A new protocol using sodium bicarbonate for the prevention of contrast-induced nephropathy in patients undergoing coronary angiography. Am J Cardiol. 2011;107(11):1604-1608 
21. Guitterez NV, Diaz A, Timmis GC, et al. Determinants of serum creatinine trajectory in acute contrast nephropathy. J Interv Cardiol. 2002;15(5):349-354.
22. Briguori C, Visconti G, Rivera NV, et al. Cystatin C and contrast-induced acute kidney injury. Circulation. 2010;121(19):2117-2122.
23. Funayama A, Watanabe T, Tamabuchi T, et al. Elevated cystatin C levels predict the incidence of vasospastic angina. Circ J. 2011;75(10):2439-2444.
24. Han WK, Bailly V, Abichandani R, et al. Kidney injury molecule-1 (KIM-1): a novel biomarker for human renal proximal tubule injury. Kidney Int. 2002;62(1):237-244.
25. Haase M, Bellomo R, Devarajan P, et al. NGAL Meta-analysis Investigator Group. Accuracy of neutrophil gelatinase-associated lipocalin (NGAL) in diagnosis and prognosis in acute kidney injury: a systematic review and meta-analysis. Am J Kidney Dis. 2009;54(6):1012-1024.
26. Porazko T, Kúzniar J, Kusztal M, et al. IL-18 is involved in vascular injury in end-stage renal disease patients. Nephrol Dial Transplant. 2009;24(2):589-596.

_____________________________________________________

From ¹the Division of Cardiology, Nagoya City East Medical Center, Aichi, Japan, and ²the Division of Cardiology, Asahi Rosai Hospital, Aichi, Japan.
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.
Manuscript submitted February 22, 2012, provisional acceptance given March 12, 2012, final version accepted April 5, 2012.
Address for correspondence: Nozomu Tamai, MD, Division of Cardiology, Nagoya City East Medical Center: 1-2-23 Wakamizu, Chikusa-ku, Nagoya, Aichi, 464-8547 Japan. Email: tamain04mfk@peace.ocn.ne.jp