ATS
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

 Click here to read this article as a CME activity

Ann Thorac Surg 2009;87:139-147. doi:10.1016/j.athoracsur.2008.09.026
© 2009 The Society of Thoracic Surgeons
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Personal Folders
Right arrow Download to citation manager
Right arrow Permission Requests
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Nigwekar, S. U.
Right arrow Articles by Kandula, P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Nigwekar, S. U.
Right arrow Articles by Kandula, P.
Related Collections
Right arrow Cardiac - pharmacology

Original Articles: Adult Cardiac

N-Acetylcysteine in Cardiovascular-Surgery–Associated Renal Failure: A Meta-Analysis

Sagar U. Nigwekar, MDa,*, Praveen Kandula, MD, MPHb

a Department of Internal Medicine, Rochester General Hospital and University of Rochester School of Medicine, Rochester, New York
b Department of Internal Medicine, Southern Illinois University, Springfield, Illinois

Accepted for publication September 9, 2008.

* Address correspondence to Dr Nigwekar, Rochester General Hospital, 1425 Portland Ave, Rochester, NY 14621 (Email: sagar.nigwekar{at}rochestergeneral.org).


Cardiothoracic anesthesiology: The Annals of Thoracic Surgery CME Program is located online at http://cme.ctsnetjournals.org. To take the CME activity related to this article, you must have either an STS member or an individual non-member subscription to the journal.

 

   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Background: Clinical trials with N-acetylcysteine (NAC) in perioperative cardiovascular settings have shown inconsistent effects for renal endpoints. We aimed to systematically review these trials to ascertain its role in prevention of post–cardiovascular surgery acute renal failure.

Methods: We searched MEDLINE, EMBASE, Cochrane Renal Health Library, and Google Scholar for randomized controlled studies that evaluated NAC in adult patients undergoing cardiovascular surgery. Acute renal failure, acute renal failure requiring dialysis, and mortality were the primary outcomes. Additional outcomes studied were length of intensive care unit stay, postoperative serum creatinine, creatinine clearance, renal biomarkers, and adverse effects of NAC.

Results: Twelve studies comprising 1,324 patients were found to be eligible. Meta-analytic estimates showed that NAC was not associated with reduction in acute renal failure (odds ratio [OR]: 0.89, 95% confidence interval [CI]: 0.68 to 1.15), acute renal failure requiring dialysis (OR: 1.09, 95% CI: 0.57 to 2.09) or mortality (OR: 0.95, 95% CI: 0.53 to 1.71). N-acetylcysteine was well tolerated but was not associated with any reduction in the length of intensive care unit stay. It had inconsistent effects on postoperative serum creatinine, creatinine clearance, and renal biomarkers. Subgroup analysis restricted to studies using intravenous NAC preparation showed a nonsignificant trend toward reduction in acute renal failure (OR: 0.81, 95% CI: 0.61 to 1.08) without any significant change in other outcomes.

Conclusions: Overall analysis of the existent literature shows that NAC is not beneficial in the prevention of post–cardiovascular surgery renal dysfunction. Routine use of NAC for this indication should be avoided.

Acute renal failure is among the most serious complications in patients undergoing cardiovascular surgeries. The incidence of acute renal failure in cardiac bypass and thoracoabdominal aortic surgeries depends on its definition and has been reported to be between 1% and 30% [1–3]. Acute renal failure in these settings is associated with increased mortality [4–6], more complicated hospital course [7, 8], higher risk for infections [9], and a substantial increase in the risk for permanent dialysis [10].

Acute renal failure after cardiovascular surgery is mostly due to renal parenchymal damage and is thought to be related to several factors, including hypovolemia due to operative complications, inflammation, ischemia-reperfusion, neurohumoral activation, aortic cross-clamping, and increased oxygen free-radical generation [3, 11]. N-acetylcysteine (NAC), with its pleiotropic effects, such as oxygen radical neutralization and endothelium-mediated vasodilatation [12] seems to be a promising agent to counteract some of these factors. However, randomized controlled studies evaluating the role of NAC in this setting have been largely underpowered and have produced conflicting results. In addition, NAC is thought to increase the risk of postoperative bleeding through its anticoagulant and platelet inhibitor activities [13]. The purpose of this review was to undertake a systematic analysis of randomized controlled studies to ascertain the therapeutic potential of NAC in the prevention of renal failure that occurs after cardiovascular surgery.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 Acknowledgments
 References
 
Data Sources, Search Strategy, and Study Selection
Two reviewers searched MEDLINE (1966 to June 2008), EMBASE (1980 to June 2008), Cochrane Renal Health Library (Issue 4, 2007), and Google Scholar for randomized controlled studies that compared any dose or form of NAC to placebo in adult (aged more than 18 years) patients undergoing cardiovascular surgical procedures. To retrieve the eligible studies, we employed the following search terms: N-acetylcysteine, N acetylcysteine, N-acetyl-L-cysteine, surgery, operation, cardiovascular surgical procedures, acute renal failure, acute kidney failure, ARF, acute renal insufficiency, acute kidney insufficiency, acute kidney injury, AKI, acute tubular necrosis, and ATN. In addition, we studied reference lists and bibliographical data from all retrieved articles and reviews for any additional relevant material. There was no language restriction.

To be included, the studies had to report at least one of the following renal outcomes: incidence of acute renal failure, incidence of acute renal failure requiring dialysis, postoperative serum creatinine, creatinine clearance, glomerular filtration rate, or renal biomarkers. Studies evaluating role of NAC in noncardiovascular surgical settings (such as radiocontrast nephropathy, sepsis, and so forth) and those that did not report the specified renal outcomes were excluded.

Data Extraction and Quality Assessment
Two authors (S.U.N., P.K.) independently assessed the studies for eligibility and extracted relevant data regarding study design and setting, participant characteristics, and outcome measures using a standardized data extraction form. We accepted the outcome definitions used by the original researchers. Descriptions such as "no major complications were observed in the study" were not considered as zero events. Only explicit descriptions of outcome events were tabulated.

The results of the individual studies were reported in many different ways, including mean and standard deviation (SD), standard error of the mean (SEM), or interquartile range (IQR). We converted SEMs and IQRs to SD, using appropriate formulas. We considered IQR to be 1.35 times the SD. Standard deviation was calculated as square root of sample size times the SEM. All data were converted to uniform measurements; thus, serum creatinine is presented as mg/dL and creatinine clearance as mL/min.

The method of all included studies was rated by means of the validated scale by Jadad and colleagues [14]. This scale considers randomization, blinding, and withdrawal/dropouts. Studies were considered of low quality if the Jadad score was from 0 to 2, of moderate quality if the score was from 3 to 4, and of high quality if the score was 5.

Outcome Measures
The primary outcomes of interest for the current review were acute renal failure, acute renal failure requiring dialysis, and mortality. Secondary outcomes analyzed included duration of intensive care unit stay, postoperative serum creatinine, creatinine clearance/glomerular filtration rate, and indicators of renal injury, for example, urine N-acetyl glucosaminidase and urine albumin to creatinine ratio. We also abstracted data regarding any adverse effects of NAC reported in the included studies, such as bleeding complications (assessed by the amount of blood loss, postoperative blood transfusion requirement, and incidence of reoperation).

Data Analysis and Quantitative Data Synthesis
We analyzed data according to guidelines in the Cochrane Reviewers' Handbook [15]. All the analyses were performed using RevMan 4.2.10 (Cochrane Collaboration, Oxford, United Kingdom). Dichotomous data outcomes from individual studies were analyzed according to the Mantel-Haenszel model to compute individual odds ratio (OR) with 95% confidence intervals (CI). Where continuous scales of measurement were used to assess the effects of treatment, the weighted mean difference was used. Statistical significance was set at the two-tailed 0.05 level for hypothesis testing. Statistical heterogeneity was analyzed using heterogeneity {chi}2 (Cochrane Q) statistic and I2 test [15, 16]. The I2 values of 25%, 50%, and 75% correspond to low, medium, and high levels of statistical heterogeneity. Treatment effects were analyzed with the random-effects model. If there was a significant heterogeneity (I2 >25%), then we explored possible sources of heterogeneity (for example, participants, study quality, and so forth).

We performed the following subgroup analyses: (1) to explore the effect of nondialysis-dependent preexisting renal insufficiency, we performed an analysis from studies that specifically included patients with preexisting renal insufficiency; (2) to explore the effect of underlying surgery, we performed an analysis for cardiac versus vascular surgical studies; (3) to explore the effect of different formulations of NAC, we performed a separate analysis for studies using only intravenous preparations; and (4) to explore the effect of dose of NAC preparations, we performed a separate analysis for studies using high-dose NAC preparations. Studies included in the high-dose category were those that administered a cumulative dose of >150 mg/kg of NAC.

Sensitivity Analysis
We assessed the robustness of findings from the primary analysis to the effects of study population and baseline risk of any of the primary outcomes through sensitivity analyses by switching from random-effect to fixed-effect models, computing relative risks and repeating the analyses to assess the influence of study quality.


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 Acknowledgments
 References
 
Details of the flow of study identification are reported in Figure 1. Database searches and snowballing yielded a total of 108 citations. Excluding 89 nonrelevant titles and abstracts, we retrieved 19 studies in complete form and assessed them according to the selection criteria. A total of seven studies were further excluded for the following reasons: studies did not report the specified renal outcomes (n = 3), surgery involved use of radiocontrast exposure (n = 1), and duplicate publication (n = 3). Our analysis finally identified 12 eligible studies comprising 1,324 patients (668 NAC group; 656 control group) [17–28]. Characteristics of the included studies are summarized in Table 1. Mean age of the patients was 69 years, and 22% patients were female. Nine studies (1,191 patients) evaluated NAC in patients undergoing cardiac surgery [17–22, 25–27], and three studies (153 patients) evaluated NAC in patients undergoing aortic aneurysm repair [23, 24, 28]. One study involved patients undergoing thoracoabdominal aortic aneurysm repair [24], and two other studies included patients undergoing abdominal aneurysm repair [23, 28]. Five studies (694 patients) were designed to assess the effects of NAC in patients with impaired preoperative renal function [17, 18, 25–27]. Eight studies used intravenous NAC preparations [19, 21–23, 25-28], two studies used oral NAC preparations [17, 18], and two studies used combined oral and intravenous preparations [20, 24]. NAC was administered only during the surgery in one study [21], and in other studies, it was administered during and after the surgery, mostly for as long as 24 to 48 hours. In one study, NAC was administered for an extended duration of as long as 6 days [17]. Eight studies administered NAC at a cumulative dose of more than 150 mg/kg and were included in the high-dose category [20–25, 27, 28]. In one study, NAC was administered as a part of antioxidant regimen that also included allopurinol, vitamin C, vitamin E, and mannitol [28]. In a study by Barr and colleagues [18], there were two arms that received NAC; one arm received NAC only and the other received NAC along with fenoldopam [18]. We analyzed data from these two arms separately.


Figure 1
View larger version (16K):
[in this window]
[in a new window]

  		Fig 1. Flow chart of study identification.

 

View this table:
[in this window]
[in a new window]

  		Table 1 Characteristics of Included Randomized Controlled Trials
 
Jadad scores for the included studies are outlined in Table 1. Eight studies were of high quality, three studies were of moderate quality, and one study was of low quality.

Primary Outcomes
Acute renal failure and acute renal failure requiring dialysis were reported in seven and 11 studies, respectively. Meta-analytic estimate showed that the use of NAC was not associated with reduction in acute renal failure (OR: 0.89, 95% CI: 0.68 to 1.15; Fig 2) and acute renal failure requiring dialysis (OR: 1.09, 95% CI: 0.57 to 2.09; Fig 3). Mortality was reported in all studies, and meta-analytic estimate showed that NAC was not associated with any reduction in mortality (OR: 0.95, 95% CI: 0.53 to 1.71; Fig 4). There was no statistical heterogeneity among the studies for any of the primary outcomes.


Figure 2
View larger version (15K):
[in this window]
[in a new window]

  		Fig 2. Meta-analytic estimates of acute renal failure comparing N-acetylcysteine (NAC) to control. (CI = confidence interval; OR = odds ratio.)

 

Figure 3
View larger version (19K):
[in this window]
[in a new window]

  		Fig 3. Meta-analytic estimates of acute renal failure requiring dialysis comparing N-acetylcysteine (NAC) to control. (CI = confidence interval; OR = odds ratio.)

 

Figure 4
View larger version (20K):
[in this window]
[in a new window]

  		Fig 4. Meta-analytic estimates of mortality comparing N-acetylcysteine (NAC) to control. (CI = confidence interval; OR = odds ratio.)

 
Secondary Outcomes
Duration of intensive care unit stay was reported in eight studies, and it was not different between the NAC and placebo groups (weighted mean difference, 0.34 days; 95% CI: –0.56 to 1.25). There was a significant heterogeneity among the studies for this outcome (I = 82.7%, p < 0.001), which may have been due to differences in individual institution criteria for intensive care unit requirement and differences in baseline characteristics of the patients.

Ten studies reported postoperative serum creatinine values [17, 19–27], four studies reported estimated creatinine clearance or glomerular filtration rate [18, 21, 26, 27], and one study reported 24-hour creatinine clearance [28]. Fischer and colleagues [21], Barr and associates [18], and Winjen and colleagues [28] demonstrated that the postoperative decrease in creatinine clearance was significantly attenuated by NAC, without any other significant difference between the NAC and control groups. Postoperative urine albumin to creatinine ratio [23, 28], urine N-acetyl glucosaminidase/creatinine ratio [23, 25], and serum cystatin C values [22, 23, 25] were not significantly different between the NAC and control groups.

Adverse Effects
We analyzed the adverse effects profile of NAC as reported in individual studies. Incidence of adverse effects such as nausea, headache, anaphylaxis, and hypotension was not different in the NAC group compared with the control group (OR: 0.90, 95% CI: 0.55 to 1.48). Amount of blood loss during the first 24 hours after the surgery was reported in one study, and it was significantly more in the NAC group compared with the control group; however, that did not translate into increased requirement of blood transfusion [25]. Similarly, Hynninen and coworkers [23] and Sisillo and associates [26] reported no difference between the NAC and control groups for the perioperative blood transfusion requirement. Risk of surgical reoperation was reported in 6 studies, and it was not different between the NAC and control groups (OR: 1.16, 95% CI: 0.62 to 2.17).

Subgroup Analyses
To explore the effect of nondialysis-dependent preexisting renal insufficiency on outcomes, we performed a subgroup analysis on studies that specifically included patients with preexisting renal insufficiency (nondialysis dependent). Restricting the analysis to these studies did not change the effects of NAC on acute renal failure (OR: 0.79, 95% CI: 0.57 to 1.10), acute renal failure requiring dialysis (OR: 1.26, 95% CI: 0.62 to 2.58), or mortality (OR: 0.57, 95% CI: 0.25 to 1.30). After restricting the analysis to cardiac surgical patients, the effects of NAC on acute renal failure (OR: 0.86, 95% CI: 0.66 to 1.13), acute renal failure requiring dialysis (OR: 1.03, 95% CI: 0.53 to 2.00), and mortality (OR: 0.77, 95% CI: 0.39 to 1.50) remained nonsignificant. Restricting the analysis to studies that used intravenous NAC only did not change the effects on acute renal failure (OR: 0.81, 95% CI: 0.61 to 1.08), acute renal failure requiring dialysis (OR: 1.04, 95% CI: 0.37 to 2.94), and mortality (OR: 0.58, 95% CI, 0.24 to 1.41). Restricting the analysis to studies that administered high-dose NAC did not change the effects on acute renal failure (OR: 0.89, 95% CI: 0.57 to 1.39), acute renal failure requiring dialysis (OR: 0.75, 95% CI: 0.17 to 3.23), and mortality (OR: 0.92, 95% CI, 0.28 to 3.08).

Sensitivity Analysis
Sensitivity analyses performed by switching from random-effect to fixed-effect models, computing relative risks did not change the overall results for the primary outcomes. Restricting the analysis to studies of high quality did not change the effects of NAC on primary outcomes.


   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
Acknowledgments
 References
 
Acute renal failure after cardiovascular surgery is a major cause of postoperative morbidity and mortality [1, 4, 5]. Many pharmacologic interventions have been tried to provide renal protection in the perioperative period [1]. In a recent review by Zacharias and coworkers [29], investigators systematically analyzed available agents to prevent postsurgical acute renal failure and reported that there are no effective pharmacologic interventions to prevent acute renal failure after major surgeries including cardiovascular surgeries. However, this review analyzed dopamine, diuretics, calcium channel blockers, angiotensin-converting enzyme inhibitors, and hydration fluids but did not address the role of NAC.

Our meta-analysis assessed whether NAC, an inexpensive medicine with antioxidant properties, would be beneficial in improving renal outcomes in patients undergoing cardiovascular surgery. We found that the prophylactic use of NAC was overall well tolerated but was not beneficial in improving acute renal failure, dialysis requirement, and mortality in the cardiovascular surgical setting when radiocontrast dye is not used. In our review, NAC did not reduce the length of intensive care unit stay and did not have consistent beneficial effects on surgery serum creatinine, creatinine clearance, and renal injury markers (urine N-acetyl glucosaminidase and urine albumin to creatinine ratio) after surgery.

Several mechanisms are thought to be playing a role in the development of post–cardiovascular surgery renal dysfunction. Release of reactive free oxygen radicals and neutrophil activation leading to increased levels of tumor necrosis factor-{alpha} and interleukin-8 are known to contribute to this renal dysfunction along with other factors such as hypovolemia, ischemia-reperfusion, neurohumoral activation, and aortic cross-clamping [11, 30]. In experimental studies, NAC has attenuated renal dysfunction through different anti-inflammatory and antioxidant effects such as antagonism of tumor necrosis factor-{alpha} and inhibition of the vascular cell adhesion molecule expression [30]. In radiocontrast nephropathy, NAC has been demonstrated to provide renal protection by acting as an antioxidant and arteriolar vasodilator through the nitrous oxide pathway [31]. Furthermore, NAC has been shown to prevent cardiopulmonary bypass pump–induced inflammatory response [32]. Despite these positive experimental and clinical findings, it is intriguing to see NAC was not found to be beneficial in the prevention of renal dysfunction in cardiovascular surgical setting. There may be several possible explanations for this. Mechanisms other than those inhibited by NAC possibly contribute more toward the pathogenesis of post–cardiovascular surgery acute renal failure. Antioxidant and vasodilatory actions of NAC are not enough to negate these other mechanisms. Although our review included studies involving NAC doses well above those used for radiocontrast nephropathy prevention [33], the optimal dose of NAC needed to prevent post–cardiovascular surgery renal dysfunction is unknown and may well be much higher than used so far in any study. The route of administration of NAC might have played role as bioavailability of oral NAC may be unpredictable in the perioperative setting. In subgroup analysis, however, we did not observe any benefit from intravenous NAC preparations.

Our systematic review has limitations. Some of the studies included patients undergoing cardiac surgery using off-pump technique and that could have attenuated the potential beneficial effects of NAC as cardiopulmonary bypass pump is known to induce a significant inflammatory response, which has been previously shown to be reduced by NAC [32]. In fact, Sisillo and colleagues [26] reported in their study that the use of NAC was associated with statistically significant reduction in acute renal failure when analysis was restricted to patients who underwent cardiac surgery using on-pump technique. However, NAC was not consistently beneficial in studies that specifically excluded patients who underwent cardiac surgery using off-pump technique. Individual study definitions of acute renal failure were not reported in some studies and varied among those that reported them, and that reduces the validity of the meta-analytic estimate for this outcome. Future studies related to acute renal failure should use standard definitions such as the one proposed by the Acute Kidney Injury Network [34]. The outcomes considered in our review were not necessarily the primary outcomes of interest to the study authors, and hence, the included studies were underpowered to detect any significant difference, especially for outcomes such as acute renal failure requiring dialysis and mortality. For definitive evaluation of outcome such as acute renal failure requiring dialysis, the sample size required will be approximately 2,400 (two-sided alpha 0.05, 80% power) [35]. Because the required sample size is large, it is unlikely that a future single randomized controlled trial will be able to address the role of NAC in this setting, and the findings of our comprehensive review provide the best available evidence to address its role in the prevention of post–cardiovascular surgery renal dysfunction.

In conclusion, overall analysis of the existent literature shows that the perioperative use of NAC is not beneficial in the prevention of post–cardiovascular surgery acute renal failure, and the routine use of NAC for this indication should be avoided.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
References
 
The authors would like to thank Miss Cathy Carey for her valuable help as a librarian.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 

  1. Rosner MH, Okusa, MD. Acute kidney injury associated with cardiac surgery Clin J Am Soc Nephrol 2006;1:19-32.[Abstract/Free Full Text]
  2. Hertzer NR, Mascha EJ, Karafa MT, O'Hara PJ, Krajewski LP, Beven EG. Open infrarenal abdominal aortic aneurysm repair: the Cleveland Clinic experience from 1989 to 1998 J Vasc Surg 2002;35:1145-1154.[Medline]
  3. Wahlberg E, Dimuzio PJ, Stoney RJ. Aortic clamping during elective operations for infrarenal disease: the influence of clamping time on renal function J Vasc Surg 2002;36:13-18.[Medline]
  4. Chertow GM, Levy EM, Hammermeister KE, Grover F, Daley J. Independent association between acute renal failure and mortality following cardiac surgery Am J Med 1998;104:343-348.[Medline]
  5. Levy EM, Viscoli CM, Horwitz RI. The effect of acute renal failure on mortality. A cohort analysis. JAMA 1996;275:1489-1494.[Abstract/Free Full Text]
  6. Mangano CM, Diamondstone LS, Ramsay JG, Aggarwal A, Herskowitz A, Mangano DT. Renal dysfunction after myocardial revascularization: risk factors, adverse outcomes, and hospital resource utilization. The Multicenter Study of Perioperative Ischemia Research Group. Ann Intern Med 1998;128:194-203.[Abstract/Free Full Text]
  7. Conlon PJ, Stafford-Smith M, White WD, et al. Acute renal failure following cardiac surgery Nephrol Dial Transplant 1999;14:1158-1162.[Abstract/Free Full Text]
  8. Garwood S. Renal insufficiency after cardiac surgery Semin Cardiothorac Vasc Anesth 2004;8:227-241.[Abstract/Free Full Text]
  9. Thakar CV, Yared JP, Worley S, Cotman K, Paganini EP. Renal dysfunction and serious infections after open-heart surgery Kidney Int 2003;64:239-246.[Medline]
  10. Leacche M, Rawn JD, Mihaljevic T, et al. Outcomes in patients with normal serum creatinine and with artificial renal support for acute renal failure developing after coronary artery bypass grafting Am J Cardiol 2004;93:353-356.[Medline]
  11. Bellomo R, Auriemma S, Fabbri A, et al. The pathophysiology of cardiac surgery-associated acute kidney injury (CSA-AKI) Int J Artif Organs 2008;31:166-178.[Medline]
  12. Sochman J. N-acetylcysteine in acute cardiology: 10 years later: what do we know and what would we like to know? J Am Coll Cardiol 2002;39:1422-1428.[Abstract/Free Full Text]
  13. Niemi TT, Munsterhjelm E, Pöyhiä R, Hynninen MS, Salmenperä MT. The effect of N-acetylcysteine on blood coagulation and platelet function in patients undergoing open repair of abdominal aortic aneurysm Blood Coag Fibrinolysis 2006;17:29-34.[Medline]
  14. Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trial 1996;17:1-12.[Medline]
  15. In: Alderson P, Green S, Higgins JPT, editors. Analysing and presenting results. Section 8. Cochrane reviewer's handbook 4.2.2. The Cochrane Library, issue 1. New York: Wiley & Sons; 2004.
  16. Higgins JP, Thompson SG, Deeks JJ, et al. Measuring inconsistency in meta-analyses Br Med J 2003;327:557-560.[Free Full Text]
  17. Adabag AS, Ishani A, Koneswaran S, et al. Utility of N-acetylcysteine to prevent acute kidney injury after cardiac surgery: a randomized controlled trial Am Heart J 2008;155:1143-1149.[Medline]
  18. Barr LF, Kolodner K. N-acetylcysteine and fenoldopam protect the renal function of patients with chronic renal insufficiency undergoing cardiac surgery Crit Care Med 2008;36:1427-1435.[Medline]
  19. Burns KE, Chu MW, Novick RJ, et al. Perioperative N-acetylcysteine to prevent renal dysfunction in high-risk patients undergoing cabg surgery: a randomized controlled trial JAMA 2005;294:342-350.[Abstract/Free Full Text]
  20. El-Hamamsy I, Stevens LM, Carrier M, et al. Effect of intravenous N-acetylcysteine on outcomes after coronary artery bypass surgery: a randomized, double-blind, placebo-controlled clinical trial J Thorac Cardiovasc Surg 2007;133:7-12.[Abstract/Free Full Text]
  21. Fischer UM, Tossios P, Mehlhorn U. Renal protection by radical scavenging in cardiac surgery patients Curr Med Res Opin 2005;21:1161-1164.[Medline]
  22. Haase M, Haase-Fielitz A, Bagshaw SM, et al. Phase II, randomized, controlled trial of high-dose N-acetylcysteine in high-risk cardiac surgery patients Crit Care Med 2007;35:1324-1331.[Medline]
  23. Hynninen MS, Niemi TT, Pöyhiä R, et al. N-acetylcysteine for the prevention of kidney injury in abdominal aortic surgery: a randomized, double-blind, placebo-controlled trial Anesth Analg 2006;102:1638-1645.[Abstract/Free Full Text]
  24. Macedo E, Abdulkader R, Castro I, Sobrinho AC, Yu L, Vieira JM. Lack of protection of N-acetylcysteine (NAC) in acute renal failure related to elective aortic aneurysm repair—a randomized controlled trial Nephrol Dial Transplant 2006;21:1863-1869.[Abstract/Free Full Text]
  25. Ristikankare A, Kuitunen T, Kuitunen A, et al. Lack of renoprotective effect of i.v. N-acetylcysteine in patients with chronic renal failure undergoing cardiac surgery Br J Anaesth 2006;97:611-616.[Abstract/Free Full Text]
  26. Sisillo E, Ceriani R, Bortone F, et al. N-acetylcysteine for prevention of acute renal failure in patients with chronic renal insufficiency undergoing cardiac surgery: a prospective, randomized, clinical trial Crit Care Med 2008;36:81-86.[Medline]
  27. Wijeysundera DN, Beattie WS, Rao V, Granton JT, Chan CT. N-acetylcysteine for preventing acute kidney injury in cardiac surgery patients with pre-existing moderate renal insufficiency Can J Anaesth 2007;54:872-881.[Medline]
  28. Wijnen MH, Roumen RM, Vader HL, Goris RJ. A multiantioxidant supplementation reduces damage from ischaemia reperfusion in patients after lower torso ischaemia. A randomised trial. Eur J Vasc Endovasc Surg 2002;23:486-490.[Medline]
  29. Zacharias M, Gilmore IC, Herbison GP, et al. Interventions for protecting renal function in the perioperative period Cochrane Database Syst Rev 2005;3CD003590.
  30. Meldrum DR, Donnahoo KK. Role of TNF in mediating renal insufficiency following cardiac surgery: evidence of a postbypass cardiorenal syndrome J Surg Res 1999;85:185-199.[Medline]
  31. Tepel M, van der Giet M, Schwarzfeld C, Laufer U, Liermann D, Zidek W. Prevention of radiographic-contrast-agent-induced reductions in renal function by acetylcysteine N Engl J Med 2000;343:180-184.[Abstract/Free Full Text]
  32. Sucu N, Cinel I, Unlu A, et al. N-acetylcysteine for preventing pump-induced xidoinflammatory response during cardiopulmonary bypass Surg Today 2004;34:237-242.[Medline]
  33. Baker CS. Prevention of radiocontrast-induced nephropathy Cathet Cardiovasc Interv 2003;58:532-538.[Medline]
  34. Mehta RL, Kellum JA, Shah SV, et al. Acute Kidney Injury Network Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury Crit Care 2007;11:R31.[Medline]
  35. Cohen J. Statistical power analysis for the behavioral sciencesHillsdale, NJ: Lawrence Erlbaum Associates; 1988.




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Personal Folders
Right arrow Download to citation manager
Right arrow Permission Requests
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Nigwekar, S. U.
Right arrow Articles by Kandula, P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Nigwekar, S. U.
Right arrow Articles by Kandula, P.
Related Collections
Right arrow Cardiac - pharmacology

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
ANN THORAC SURG ASIAN CARDIOVASC THORAC ANN EUR J CARDIOTHORAC SURG
J THORAC CARDIOVASC SURG ICVTS ALL CTSNet JOURNALS