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J Am Coll Cardiol Intv, 2009; 2:1116-1124, doi:10.1016/j.jcin.2009.07.015
© 2009 by the American College of Cardiology Foundation
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Clinical Research

Sodium Bicarbonate Plus N-Acetylcysteine Prophylaxis

A Meta-Analysis

Jeremiah R. Brown, PhD*,{ddagger},*, Clay A. Block, MD{dagger}, David J. Malenka, MD{ddagger}, Gerald T. O'Connor, PhD, ScD*, Anton C. Schoolwerth, MD, MSHA{dagger}, Craig A. Thompson, MD, MMSc§

* The Dartmouth Institute for Health Policy and Clinical Practice, Lebanon, New Hampshire
{dagger} Section of Nephrology and Hypertension, Department of Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire
{ddagger} Section of Cardiology, Department of Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire
§ Department of Invasive Cardiology and Vascular Medicine, Yale University School of Medicine, New Haven, Connecticut


   Abstract
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 Abstract
Methods
 Results
 Discussion
 REFERENCES
 
Objectives: We sought to conduct a meta-analysis to compare N-acetylcysteine (NAC) in combination with sodium bicarbonate (NaHCO3) for the prevention of contrast-induced acute kidney injury (AKI).

Background: Contrast-induced AKI is a serious consequence of cardiac catheterizations and percutaneous coronary interventions (PCI). Despite recent supporting evidence for combination therapy, not enough has been done to prevent the occurrence of contrast-induced AKI prophylactically.

Methods: Published randomized controlled trial data were collected from OVID/PubMed, Web of Science, and conference abstracts. The outcome of interest was contrast-induced AKI, defined as a ≥25% or ≥0.5 mg/dl increase in serum creatinine from baseline. Secondary outcome was renal failure requiring dialysis.

Results: Ten randomized controlled trials met our criteria. Combination treatment of NAC with intravenous NaHCO3 reduced contrast-induced AKI by 35% (relative risk: 0.65; 95% confidence interval: 0.40 to 1.05). However, the combination of N-acetylcysteine plus NaHCO3 did not significantly reduce renal failure requiring dialysis (relative risk: 0.47; 95% confidence interval: 0.16 to 1.41).

Conclusions: Combination prophylaxis with NAC and NaHCO3 substantially reduced the occurrence of contrast-induced AKI overall but not dialysis-dependent renal failure. Combination prophylaxis should be incorporated for all high-risk patients (emergent cases or patients with chronic kidney disease) and should be strongly considered for all interventional radio-contrast procedures.

Key Words: acute kidney injury • contrast • epidemiology • meta-analysis • renal pharmacology

Abbreviations and Acronyms
  AKI = acute kidney injury
  CI = confidence interval
  NAC = N-acetylcysteine
  NaHCO3 = sodium bicarbonate
  PCI = percutaneous coronary interventions
  RCT = randomized controlled trial
  RR = relative risk
  {Delta}Cr = increase in serum creatinine

Contrast-induced acute kidney injury (AKI) is a serious consequence of the more than 1.3 million cardiac catheterizations and percutaneous coronary interventions (PCI) in the U.S. each year. Researchers hypothesize contrast-induced AKI results from direct toxicity to the renal tubules by contrast medium or renal hemodynamic changes (1,2). Up to 15% of patients develop contrast-induced AKI after PCI with a 5-fold increased risk of in-hospital (3) and long-term mortality (4).

Contrast-induced AKI is commonly defined as a 25% increase or 0.5 mg/dl increase in serum creatinine from baseline within 48 h of exposure (4–7). Chertow et al. (8) and Rihal et al. (9) showed that contrast-induced AKI was associated with an increased risk of in-hospital mortality. Patients with contrast-induced AKI had a 22% mortality rate compared with 1.4% for those without AKI (9). Patients admitted to the hospital for all causes and developing contrast-induced AKI were 6.5 times more likely to die in the hospital compared with patients not developing AKI; on average these patients had 3.5 more days in the hospital and $7,500 additional hospital costs (8).

Variation exists in prophylactic strategies, and there is a lack of consensus on prevention tactics according to a recent taskforce (10). Despite the ease of identifying patients at risk (11,12), preventive measures to reduce contrast-induced AKI have not been consistent (13). However, 2 recent randomized controlled trials (RCTs) among high-risk patients using N-acetylcysteine (NAC) and sodium bicarbonate (NaHCO3) (14,15) demonstrated the combination of NAC and NaHCO3 were significantly effective at preventing the contrast-induced AKI. Both NAC and NaHCO3 are oxygen-derived free radical scavengers and therefore block injury to the renal tubules (16–21). There has been no formal synthesis of the combination prophylactic trial data. Consequently, there are no consensus protocols for prophylactic strategies or contrast dosing to prevent contrast-induced AKI. These gaps have identified opportunities to adopt effective evidence-based measures to reduce contrast-induced AKI.

Therefore, we sought to synthesize RCT evidence for prophylactic combination strategies incorporating oral or intravenous NAC and intravenous NaHCO3 in cardiac catheterization or PCI.


   Methods
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 Methods
Results
 Discussion
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Data and sources of searches.   We conducted a meta-analysis of RCTs with combination prophylaxis of NAC and NaHCO3 among patients undergoing catheterization or PCI. MEDLINE (OVID and PubMed, 1960 through February 2009), Web of Knowledge, Cochrane Library databases, and conference abstracts (American Heart Association, American College of Cardiology, Transcatheter Cardiovascular Therapeutics, National Kidney Foundation, American Society of Nephrology Renal Week) were used to identify published RCTs from 2006 through February 2009.

Study selection.   Key words used to search included: "N-acetylcysteine" and "sodium bicarbonate" and "catheterization or angiography or percutaneous coronary intervention or PCI." The search yielded 10 published human RCTs (Fig. 1, Table 1) (14,15,22–29). We searched the ClinicalTrials website; we found 1 additional trial: CONTRAST (COmbined N-Acetylcysteine and Bicarbonate in PCI To Reduce Adverse Side Effect of contrasT) (Singapore). However, the trial is still enrolling patients and has not reported the interim results.


Figure 1
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  		Figure 1 Study Selection

RCT = randomized controlled trial.

 

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  		Table 1 Study Characteristics
 
Data abstraction and quality assessment.   We abstracted data from the trials on contrast-induced AKI (defined as ≥25%, ≥0.5 mg/dl, ≥25%, and ≥0.5 mg/dl increase in creatinine from baseline) and renal failure (new onset of dialysis). We followed the appropriate methods for conducting a meta-analysis as stipulated in the Quality of Reporting of Meta-analysis statement (30). Two independent reviewers (J.B., C.B.) selected trials for information outcomes and recorded data on spreadsheets. The Jadad criteria were used to assess study quality and were reported with the study characteristics (Table 1) (31).

Data synthesis and analysis.   All outcome comparisons and treatment effects were calculated with the Cochrane Collaborative software, RevMan 4.2.8 (Baltimore, Maryland). We calculated the I2 to evaluate the percentage of heterogeneity among all the trials incorporated in the summary estimate (32). Heterogeneity was observed in the 3 comparisons; therefore, we used random effects modeling. For all comparisons, a fixed effects relative risk (RR) and 95% confidence interval (CI) was calculated for each independent study and for the summary statistic. Methods for the calculation of the aforementioned statistics have been reported previously (33,34).


   Results
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Discussion
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Ten trials met our eligibility criteria for combination therapy including NaHCO3 plus NAC before and after contrast administration (Table 1). All studies reported contrast-induced AKI as a ≥25% increase in serum creatinine; 4 reported contrast-induced AKI separately by ≥0.5 (mg/dl) increase in serum creatinine. Nine studies compared combination treatment (NaHCO3 and NAC) with NAC and hydration with normal saline; 1 study compared combination therapy with NAC alone; 1 study compared combination therapy with NAC with normal saline and a separate arm with NAC and ascorbic acid (we have included this arm in the analysis).

Contrast-induced AKI was defined in 3 ways. The first analysis with contrast-induced AKI defined as a ≥25% increase in serum creatinine ({Delta}Cr) (Fig. 2A) demonstrated that the combination of NAC plus NaHCO3 did not significantly reduce contrast-induced AKI (≥25% {Delta}Cr) by 33% with the combined RR of 0.67 (95% CI: 0.42 to 1.07); however, this effect demonstrated a strong trend toward protection against contrast-induce AKI. Alternatively, when using an alternative definition for contrast-induced AKI (≥0.5 creatinine) (Fig. 2B), a statistically significant benefit was observed for combination treatment with a significant 69% reduction (RR: 0.31; 95% CI: 0.11 to 0.87). When using the greater of the 2 definitions (≥25% {Delta}Cr and ≥0.5) (Fig. 2C), the results were similar to the ≥25%-{Delta}Cr definition with a nonsignificant 35% reduction in contrast-induced AKI (RR: 0.65; 95% CI: 0.40 to 1.05).


Figure 2
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  		Figure 2 CI-AKI

Individual randomized controlled trials are listed in order by year of publication. Outcome is contrast-induced acute kidney injury (CI-AKI). (A) CI-AKI (25% relative increase in serum creatinine from baseline). (B) CI-AKI (≥0.5 mg/dl increase in serum creatinine from baseline). (C) CI-AKI (≥25% or ≥0.5 mg/dl increase in serum creatinine from baseline). The size of each square denotes the weight of each trial's relative risk (RR) in calculating the combined RR. The diamond represents the combined RR at the center; opposing points of the diamond represent the 95% confidence intervals (CIs). Treatment: N-acetylcysteine (NAC) plus sodium bicarbonate (Bicarb). AA = N-acetylcysteine plus ascorbic acid; NS = normal saline.

 
Dialysis.   When the combination of NAC and NaHCO3 was compared with control subjects or head-to-head with NAC, the combination treatment did not significantly reduce dialysis-dependent renal failure (RR: 0.47; 95% CI: 0.16 to 1.41) (Fig. 3).


Figure 3
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  		Figure 3 Renal Failure Requiring Dialysis

Individual randomized controlled trials are listed in order by year of publication. Outcome is dialysis. The size of each square denotes the weight of each trial's RR in calculating the combined RR. The diamond represents the combined RR at the center; opposing points of the diamond represent the 95% CIs. Treatment: NAC plus Bicarb. Abbreviations as in Figure 2.

 

   Discussion
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 Discussion
REFERENCES
 
We conducted a meta-analysis on the clinical effectiveness of NAC in combination with intravenous NaHCO3 compared with NAC. We found 10 RCTs that met our criteria. Collectively, combination treatment of NAC with intravenous NaHCO3 reduced contrast-induced AKI by 35% (RR: 0.65; 95% CI: 0.40 to 1.05). Therefore, combination treatment with NAC plus NaHCO3 prevented contrast-induced AKI in 4 of 10 patients over NAC alone. However, the combination of NAC plus NaHCO3 did not significantly reduce renal failure requiring dialysis (RR: 0.47; 95% CI: 0.16 to 1.41), although only 5 patients (0.7%) receiving the combination therapy went on dialysis compared with 11 (1.6%) who received N-acetylcysteine.

Multiple strategies have been used independently to reduce contrast-induced AKI: hydration alone, NaHCO3 alone, NAC alone, and others. However, there has been a lack of consensus about the implementation of these strategies in practice, likely due to much confusion about their clinical efficacy.

Hydration.   In a small prospective RCT, hydration with 0.45% normal saline for 12 h before and after angiography has been shown to be effective in reducing contrast-induced AKI by 65% (35). In a large prospective RCT, hydration with one-half isotonic (0.45%) or isotonic (0.9%) saline for the morning before elective PCI and immediately before emergency PCI reduced contrast-induced AKI by 0.7% and 2.0%, respectively (36).

NaHCO3.   Isotonic NaHCO3 through the alkalinization of renal tubular fluid and subsequent reduction in free oxygen radicals has shown beneficial results (although mixed) in reducing contrast-induced AKI. Merten et al. (37) reported patients receiving isotonic (154 mEq/l) infusion of NaHCO3 before and after contrast administration (370 mg iodine/ml) had an 89% reduction in contrast-induced AKI compared with patients that received hydration with isotonic sodium chloride. Four recent meta-analyses (38–41) evaluating the protective effects of hydration with NaHCO3 compared with hydration with normal saline have shown NaHCO3 to be more effective in preventing contrast-induced AKI by 54% to 63%: (RR: 0.37, 95% CI: 0.18 to 0.74); (RR: 0.45; 95% CI: 0.26 to 0.79); (RR: 0.46; 95% CI: 0.26 to 0.82); and (RR: 0.52; 95% CI: 0.34 to 0.80).

NAC.   NAC is postulated to act as a free radical scavenger. Tepel et al. (42) was the first to report a protective effect of NAC (600 mg twice daily on the day before and day of intervention with one-half isotonic saline) in reducing contrast-induced AKI by 91%. Seven meta-analyses of NAC have shown beneficial treatment effects in reducing contrast-induced AKI (43–49). However, 5 meta-analyses were inconclusive (50–54). Marenzi et al. (55) demonstrated a dose-dependent effect of NAC (600 mg intravenously before and 600 mg orally twice daily for 48 h after), whereby both single and double doses of NAC reduced contrast-induced AKI and in-hospital mortality, with the more beneficial treatment being the double dose of NAC in patients undergoing primary PCI. Unfortunately, NAC might cause an artificial transient decline in serum creatinine without changing renal function, and therefore additional markers of renal function should be incorporated to confirm these effects, such as Cystatin C (45,56). Recently, Kelly et al. (57) performed a meta-analysis of NAC compared with hydration alone. They found that oral or intravenous NAC significantly reduced contrast-induced AKI by 38% when compared with hydration controls (RR: 0.62; 95% CI: 0.44 to 0.88). Current systematic reviews and meta-analyses have identified a statistically significant benefit for either hydration with NaHCO3 or prophylaxis with NAC. Our meta-analysis focused on the question of combined hydration and prophylaxis with both NaHCO3 and NAC, demonstrating a significant benefit for combination prophylaxis over NAC with or without hydration alone.

Other pharmacological strategies have been used over the years. Theophylline causes arrhythmias and therefore is not useful for cardiac patients. In a recent meta-analysis, Kelly et al. (57) showed that theophylline, with a nonsignificant but impressive 51% reduction in contrast-induced AKI (RR: 0.49; 95% CI: 0.23 to 1.06); this report suggests a promising protective effect for theophylline. Prostaglandins can cause severe hypotension. Other agents include antioxidant ascorbic acid and trimetazidine, but limited evidence has been reported on these agents for preventing contrast-induced AKI (58). Hypoperfusion of the kidney through vasoconstriction might play a role in contrast-induced AKI; however, vasodilators have not been shown to be successful in reducing contrast-induced AKI. All 4 RCTs for dopamine showed no benefit in reducing contrast-induced AKI (59–62). Two trials have reported on fenoldopam, neither showing a protective effect against contrast-induced AKI (57,63,64). A meta-analysis demonstrated that renal replacement therapy does not reduce the risk of contrast-induced AKI (0.97; 95% CI: 0.44 to 2.14) (65). Continuous veno-venous hemofiltration after PCI in 1 study was not shown to protect renal function (66). However, a recent trial by Lee et al. (67) reported that prophylactic hemodialysis resulted in a 95% reduction in post-catheterization dialysis for chronic kidney disease patients undergoing coronary angiography.

There have been several hypotheses generated around the pharmacodynamics of NAC and NaHCO3. Merten et al. (37) postulated that alkalizing the renal tubule fluid with NaHCO3 might reduce acute tubule necrosis brought on by nephrotoxic contrast media. In a recent study examining renal cell apoptosis by contrast agents, Romano et al. (68) proposed that NaHCO3 scavenges free radicals and the presence of bicarbonate in the proximal convoluted tubules might work to either buffer the production of hydrogen cation from cellular hypoxia or to drive sodium cation reabsorption. However, they reported that NaHCO3 did not raise the pH of the media in vitro compared with contrast alone and postulated that the protective action of NaHCO3 works through a different mechanism than NAC and ascorbic acid and therefore provides an additive effect (68). Romano et al. (68) were able to demonstrate that NAC and ascorbic acid works in vitro on the proximal renal tubule and prevents renal cell apoptosis but not NaHCO3. This finding was supported by an earlier report by Briguori et al. (69), showing that NAC works in a dose-dependent manner. Our meta-analysis compares the additive effect of NaHCO3 with the use of NAC or ascorbic acid and demonstrates a distinct advantage in reducing contrast-induced AKI. Although the mechanism of the prophylactic effect of NaHCO3 in the renal tubules is not confirmed, because of the summary of evidence, there does seem to be an additive effect either through more regimented hydration or through free-radical scavenging in the renal tubules.

The barriers to reducing contrast-induced AKI after PCI have been due to inconsistencies in the RCT evidence and meta-analysis reporting either NAC or NaHCO3. Cardiology and nephrology historically have compartmentalized patient care within each discipline. These barriers create a chasm between current practice and the best evidence-based care for patients.

Additional trials are needed to comment on the clinical effectiveness of combination protocols for the prevention of contrast-induced AKI. Recommendations differ surrounding the prevention of contrast-induced AKI, and not enough has been done to establish a working protocol to prevent contrast-induced AKI among all patients. Until a large-scale RCT can be conducted to evaluate the clinical effectiveness of these prophylactic strategies, clinical action must be taken on the evidence that exists. We recommend that a comprehensive prophylactic protocol needs to be incorporated into practice to prevent contrast-induced AKI, incorporating both NaHCO3 and NAC. We encourage institutions to form a multidisciplinary team of nephrologists, cardiologists, and epidemiologists to work together to develop evidence-based benchmarks for high-quality care and standardize their prophylactic strategies in preventing contrast-induced AKI.


   Footnotes
 
Funding for this research was provided by a National Research Service Award post-doctoral training grant from the Agency for Healthcare Research and Quality, T32HS000070.

* Reprint requests and correspondence: Dr. Jeremiah R. Brown, Clinical Research Section, Dartmouth-Hitchcock Medical Center, One Medical Center Drive, Lebanon, New Hampshire 03756 (Email: jbrown{at}Dartmouth.edu).

Manuscript received July 14, 2009; accepted July 25, 2009.


   REFERENCES
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