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1.  Intravenous N-Acetylcysteine for Prevention of Contrast-Induced Nephropathy: A Meta-Analysis of Randomized, Controlled Trials 
PLoS ONE  2013;8(1):e55124.
Background
Contrast-induced nephropathy (CIN) is one of the common causes of acute renal insufficiency after contrast procedures. Whether intravenous N-acetylcysteine (NAC) is beneficial for the prevention of contrast-induced nephropathy is uncertain. In this meta-analysis of randomized controlled trials, we aimed to assess the efficacy of intravenous NAC for preventing CIN after administration of intravenous contrast media.
Study Design
Relevant studies published up to September 2012 that investigated the efficacy of intravenous N-acetylcysteine for preventing CIN were collected from MEDLINE, OVID, EMBASE, Web of Science, Cochrane Central Register of Controlled Trials, and the conference proceedings from major cardiology and nephrology meetings. The primary outcome was CIN. Secondary outcomes included renal failure requiring dialysis, mortality, and length of hospitalization. Data were combined using random-effects models with the performance of standard tests to assess for heterogeneity and publication bias. Meta-regression analyses were also performed.
Results
Ten trials involving 1916 patients met our inclusion criteria. Trials varied in patient demographic characteristics, inclusion criteria, dosing regimens, and trial quality. The summary risk ratio for contrast-induced nephropathy was 0.68 (95% CI, 0.46 to 1.02), a nonsignificant trend towards benefit in patients treated with intravenous NAC. There was evidence of significant heterogeneity in NAC effect across studies (Q = 17.42, P = 0.04; I2 = 48%). Meta-regression revealed no significant relation between the relative risk of CIN and identified differences in participant or study characteristics.
Conclusion
This meta-analysis showed that research on intravenous N-acetylcysteine and the incidence of CIN is too inconsistent at present to warrant a conclusion on efficacy. A large, well designed trial that incorporates the evaluation of clinically relevant outcomes in participants with different underlying risks of CIN is required to more adequately assess the role for intravenous NAC in CIN prevention.
doi:10.1371/journal.pone.0055124
PMCID: PMC3559541  PMID: 23383076
2.  N-Acetylcysteine for the Prevention of Contrast-induced Nephropathy 
OBJECTIVE
Contrast-induced nephropathy is a common cause of acute renal failure in hospitalized patients. Although patients are often given N-acetylcysteine to prevent renal injury from contrast agents, there are no clear guidelines supporting its use. We conducted a systematic review to determine whether administering N-acetylcysteine around the time of contrast administration reduces the risk of contrast-induced nephropathy.
DESIGN
We searched MEDLINE, EMBASE, the Cochrane Collaboration Database, bibliographies of retrieved articles, and abstracts of conference proceedings, and consulted with experts to identify relevant studies. Randomized controlled trials of N-acetylcysteine in hospitalized patients receiving contrast were included. Studies were excluded if they did not report change in creatinine or incidence of contrast-induced nephropathy at 48 hours.
MEASUREMENTS AND MAIN RESULTS
Nine randomized controlled trials satisfied all inclusion criteria and were included in the analysis. The difference in mean change in creatinine between the N-acetylcysteine-treated group and controls was −0.27 mg/dl (95% confidence interval [CI], −0.43 to −0.11). The relative risk of developing contrast-induced nephropathy was 0.43 (95% CI, 0.24 to 0.75) in subjects randomized to N-acetylcysteine. Significant heterogeneity existed among studies, suggesting differences in patient populations or study methodology not identified by sensitivity analyses. The incidence of dialysis was rare (0.2%).
CONCLUSIONS
Our findings suggest that N-acetylcysteine helps prevent declining renal function and contrast-induced nephropathy. While N-acetylcysteine is inexpensive and nontoxic, undeviating insistence for dosing at least 12 hours in advance of contrast exposure may delay diagnostic and therapeutic procedures. Future studies are needed to address the longer-term clinical outcomes and cost-effectiveness of this agent.
doi:10.1111/j.1525-1497.2005.30323.x
PMCID: PMC1490056  PMID: 15836554
N-acetylcysteine; contrast-induced nephropathy; acute renal failure; kidney disease
3.  Acetylcysteine for prevention of contrast-induced nephropathy after intravascular angiography: A systematic review and meta-analysis 
BMC Medicine  2004;2:38.
Background
Contrast-induced nephropathy is an important cause of acute renal failure. We assess the efficacy of acetylcysteine for prevention of contrast-induced nephropathy among patients undergoing intravascular angiography.
Methods
We conducted a systematic review and meta-analysis of randomized controlled trials comparing prophylactic acetylcysteine plus hydration versus hydration alone in patients undergoing intravascular angiography. Studies were identified by searching MEDLINE, EMBASE, and CENTRAL databases. Our main outcome measures were the risk of contrast-induced nephropathy and the difference in serum creatinine between acetylcysteine and control groups at 48 h.
Results
Fourteen studies involving 1261 patients were identified and included for analysis, and findings were heterogeneous across studies. Acetylcysteine was associated with a significantly reduced incidence of contrast-induced nephropathy in five studies, and no difference in the other nine (with a trend toward a higher incidence in six of the latter studies). The pooled odds ratio for contrast-induced nephropathy with acetylcysteine relative to control was 0.54 (95% CI, 0.32–0.91, p = 0.02) and the pooled estimate of difference in 48-h serum creatinine for acetylcysteine relative to control was -7.2 μmol/L (95% CI -19.7 to 5.3, p = 0.26). These pooled values need to be interpreted cautiously because of the heterogeneity across studies, and due to evidence of publication bias. Meta-regression suggested that the heterogeneity might be partially explained by whether the angiography was performed electively or as emergency.
Conclusion
These findings indicate that published studies of acetylcysteine for prevention of contrast-induced nephropathy yield inconsistent results. The efficacy of acetylcysteine will remain uncertain unless a large well-designed multi-center trial is performed.
doi:10.1186/1741-7015-2-38
PMCID: PMC526263  PMID: 15500690
4.  Rationale, design, and baseline characteristics of the Acetylcystein for Contrast-Induced nephropaThy (ACT) Trial: a pragmatic randomized controlled trial to evaluate the efficacy of acetylcysteine for the prevention of contrast-induced nephropathy 
Trials  2009;10:38.
Background
Aceltylcysteine has been evaluated in several small trials as a means of reducing the risk of contrast-induced nephropathy (CIN), however systematic reviews of these studies do not provide conclusive answers. Therefore, a large randomized controlled trial (RCT) is needed to provide a reliable answer as to whether acetylcysteine is effective in decreasing the risk of CIN in high-risk patients undergoing angiographic procedures.
Methods
ACT is a RCT of acetylcysteine versus placebo in 2,300 patients at-risk for CIN undergoing an intravascular angiographic procedure. The randomization list will be concealed. Participants, health care staff, investigators and outcome assessors will be blinded to whether patients receive acetylcysteine or placebo. All analysis will follow the intention-to-treat principle. The study drugs (acetylcysteine 1200 mg or placebo) will be administered orally twice daily for two doses before and two doses after the procedure. The primary outcome is the occurrence of CIN, defined as a 25% elevation of serum creatinine above baseline between 48 and 96 hours after angiography.
Discussion
The first patient entered the trial on September, 2008. Up to April 7, 2009, 810 patients had been included in 35 centers. The mean age was 69 (Standard deviation: 10), 18% had a baseline serum creatinine >1.5 mg/dL, 57% were diabetics and 13% had a history of heart failure. The ongoing ACT Trial is the largest multicentre RCT that will determine whether acetylcysteine is effective in decreasing the risk of CIN in patients at risk undergoing angiography.
Trial registration
Clinicaltrials.gov NCT00736866
doi:10.1186/1745-6215-10-38
PMCID: PMC2706243  PMID: 19497091
5.  A Multi-center Comparison of the Safety of Oral versus Intravenous Acetylcysteine for Treatment of Acetaminophen Overdose 
Oral and intravenous (IV) acetylcysteine are used for treatment of acetaminophen poisoning. The objective of this multi-center study was to compare the safety of these two routes of administration.
METHODS
We conducted a multi-center chart review of all patients treated with acetylcysteine for acetaminophen poisoning. The primary safety outcome was the percentage of patients with of acetylcysteine-related adverse events.
RESULTS
A total of 503 subjects were included in the safety analysis (306 IV only, 145 oral only and 52 both routes).There were no serious adverse events related to acetylcysteine for either route. Nausea and vomiting were the most common related adverse events and were more common with oral treatment (23% vs 9%). Anaphylactoid reactions were more common with IV administration (6% vs 2%).
Conclusions
Intravenous and oral acetylcysteine are both associated with minimal side effects and are safe for treatment of acetaminophen toxicity.
doi:10.3109/15563650.2010.486381
PMCID: PMC2894984  PMID: 20524832
6.  N-acetylcysteine does not prevent contrast-induced nephropathy after cardiac catheterization in patients with diabetes mellitus and chronic kidney disease: a randomized clinical trial 
Trials  2009;10:45.
Background
Patients with diabetes mellitus (DM) and chronic kidney disease (CKD) constitute to be a high-risk population for the development of contrast-induced nephropathy (CIN), in which the incidence of CIN is estimated to be as high as 50%. We performed this trial to assess the efficacy of N-acetylcysteine (NAC) in the prevention of this complication.
Methods
In a prospective, double-blind, placebo controlled, randomized clinical trial, we studied 90 patients undergoing elective diagnostic coronary angiography with DM and CKD (serum creatinine ≥ 1.5 mg/dL for men and ≥ 1.4 mg/dL for women). The patients were randomly assigned to receive either oral NAC (600 mg BID, starting 24 h before the procedure) or placebo, in adjunct to hydration. Serum creatinine was measured prior to and 48 h after coronary angiography. The primary end-point was the occurrence of CIN, defined as an increase in serum creatinine ≥ 0.5 mg/dL (44.2 μmol/L) or ≥ 25% above baseline at 48 h after exposure to contrast medium.
Results
Complete data on the outcomes were available on 87 patients, 45 of whom had received NAC. There were no significant differences between the NAC and placebo groups in baseline characteristics, amount of hydration, or type and volume of contrast used, except in gender (male/female, 20/25 and 34/11, respectively; P = 0.005) and the use of statins (62.2% and 37.8%, respectively; P = 0.034). CIN occurred in 5 out of 45 (11.1%) patients in the NAC group and 6 out of 42 (14.3%) patients in the placebo group (P = 0.656).
Conclusion
There was no detectable benefit for the prophylactic administration of oral NAC over an aggressive hydration protocol in patients with DM and CKD.
Trial registration
NCT00808795
doi:10.1186/1745-6215-10-45
PMCID: PMC2714294  PMID: 19563648
7.  Prevention of Contrast-Induced Acute Kidney Injury: Is Simple Oral Hydration Similar To Intravenous? A Systematic Review of the Evidence 
PLoS ONE  2013;8(3):e60009.
Background
Pre-procedural intravenous fluid administration is an effective prophylaxis measure for contrast-induced acute kidney injury. For logistical ease, the oral route is an alternative to the intravenous. The objective of this study was to compare the efficacy of the oral to the intravenous route in prevention of contrast-induced acute kidney injury.
Study Design
A systematic review and meta-analysis of randomised trials with a stratified analysis and metaregression. Databases included MEDLINE (1950 to November 23 2011), EMBASE (1947 to week 47 2011), Cochrane CENTRAL (3rd quarter 2011). Two reviewers identified relevant trials and abstracted data.
Settings and Population
Trials including patients undergoing a contrast enhanced procedure.
Selection Criteria
Randomised controlled trial; adult (>18 years) population; comparison of oral versus intravenous volume expansion.
Intervention
Oral route of volume expansion compared to the intravenous route.
Outcomes
Any measure of acute kidney injury, need for renal replacement therapy, hospitalization and death.
Results
Six trials including 513 patients met inclusion criteria. The summary odds ratio was 1.19 (95% CI 0.46, 3.10, p = 0.73) suggesting no difference between the two routes of volume expansion. There was significant heterogeneity (Cochran’s Q = 11.65, p = 0.04; I2 = 57). In the stratified analysis, inclusion of the five studies with a prespecified oral volume expansion protocol resulted in a shift towards oral volume expansion (OR 0.75, 95% CI 0.37, 1.50, p = 0.42) and also resolved the heterogeneity (Q = 3.19, P = 0.53; I2 = 0).
Limitations
Small number of studies identified; lack of hard clinical outcomes.
Conclusion
The oral route may be as effective as the intravenous route for volume expansion for contrast-induced acute kidney injury prevention. Adequately powered trials with hard endpoints should be done given the potential advantages of oral (e.g. reduced patient burden and cost) over intravenous volume expansion.
doi:10.1371/journal.pone.0060009
PMCID: PMC3608617  PMID: 23555863
8.  N-acetylcysteine does not prevent contrast nephropathy in patients with renal impairment undergoing emergency CT: a randomized study 
BMC Nephrology  2013;14:119.
Background
Patients admitted to the emergency room with renal impairment and undergoing a contrast computed tomography (CT) are at high risk of developing contrast nephropathy as emergency precludes sufficient hydration prior to contrast use. The value of an ultra-high dose of intravenous N-acetylcysteine in this setting is unknown.
Methods
From 2008 to 2010, we randomized 120 consecutive patients admitted to the emergency room with an estimated clearance lower than 60 ml/min/1.73 m2 by MDRD (mean GFR 42 ml/min/1.73 m2) to either placebo or 6000 mg N-acetylcysteine iv one hour before contrast CT in addition to iv saline. Serum cystatin C and creatinine were measured one hour prior to and at day 2, 4 and 10 after contrast injection. Nephrotoxicity was defined either as 25% or 44 μmol/l increase in serum creatinine or cystatin C levels compared to baseline values.
Results
Contrast nephrotoxicity occurred in 22% of patients who received placebo (13/58) and 27% of patients who received N-acetylcysteine (14/52, p = 0.66). Ultra-high dose intravenous N-acetylcysteine did not alter creatinine or cystatin C levels. No secondary effects were noted within the 2 groups during follow-up.
Conclusions
An ultra-high dose of intravenous N-acetylcysteine is ineffective at preventing nephrotoxicity in patients with renal impairment undergoing emergency contrast CT.
Trial registration
The study was registered as Clinical trial (NCT01467154).
doi:10.1186/1471-2369-14-119
PMCID: PMC3682900  PMID: 23731573
Computerized Tomography; Contrast media; Emergency medicine; N-acetylcysteine; Nephrotoxicity
9.  Intravenous acetylcysteine in paracetamol induced fulminant hepatic failure: a prospective controlled trial. 
BMJ : British Medical Journal  1991;303(6809):1026-1029.
OBJECTIVE--To see whether intravenous acetylcysteine would improve outcome in patients with fulminant hepatic failure after paracetamol overdose. DESIGN--A prospective randomised controlled study. SETTING--The Institute of Liver Studies, King's College Hospital, London. PATIENTS--50 consecutive patients (21 male) aged 16-60 with fulminant hepatic failure after paracetamol overdose who had not previously received acetylcysteine. INTERVENTIONS--Conventional intensive liver care plus either acetylcysteine (25 patients) in the same dose regimen as used early after a paracetamol overdose, except that the infusion was continued until recovery from encephalopathy or death, or an equivalent volume of 5% dextrose (25 patients). MAIN OUTCOME MEASURES--Survival; incidence of cerebral oedema, renal failure, and hypotension requiring inotropic support; liver function as assessed by prolongation of the prothrombin time; and degree of encephalopathy. RESULTS--The rate of survival was significantly higher in the acetylcysteine treated group than in the controls (48% (12/25 patients) v 20% (5/25); p = 0.037, 95% confidence interval for difference in proportions surviving 3% to 53%). Acetylcysteine treated patients had a lower incidence of cerebral oedema (40% (10/25) v 68% (17/25); p = 0.047, 95% confidence interval for difference in incidence 2% to 54%), and fewer developed hypotension requiring inotropic support (48% (12/25) v 80% (20/25); p = 0.018, 95% confidence interval 7% to 57%). Rates of deterioration and recovery of liver function, however, were similar in the two groups. No adverse reactions to acetylcysteine were seen. CONCLUSIONS--Acetylcysteine is safe and effective in fulminant hepatic failure after paracetamol overdose.
PMCID: PMC1671790  PMID: 1954453
10.  N-acetylcysteine does not prevent contrast induced nephropathy after cardiac catheterisation with an ionic low osmolality contrast medium: a multicentre clinical trial 
Heart  2005;91(6):774-778.
Objective: To evaluate oral N-acetylcysteine in the prevention of contrast induced nephropathy (CIN) in patients at low to moderate risk undergoing cardiac catheterisation with ionic low osmolality contrast medium.
Methods: In a multicentre double blind clinical trial 156 patients undergoing coronary angiography or percutaneous coronary intervention with serum creatinine ⩾ 106.08 μmol/l or creatinine clearance < 50 ml/min or diabetes mellitus were randomly assigned to receive N-acetylcysteine 600 mg orally twice daily for two days or placebo. Only low osmolality ionic contrast medium was used.
Results: Sixteen patients developed CIN, defined as an increase of 44.2 μmol/l in creatinine in 48 hours: eight of 77 patients (10.4%) in the N-acetylcysteine group and eight of 79 patients (10.1%) in the placebo group (p  =  1.00). The mean (SD) change in serum creatinine was similar in both groups: 7.96 (35.36) μmol/l in the N-acetylcysteine group and 6.19 (25.64) μmol/l in the placebo group (p  =  0.67). No difference was observed in the change in endogenous creatinine clearance (−0.54 (10.4) ml/min v –2.52 (12.3) ml/min, N-acetylcysteine and placebo, respectively, p  =  0.28).
Conclusion: Oral N-acetylcysteine did not prevent CIN in patients at low to moderate risk undergoing cardiac catheterisation with ionic low osmolality contrast medium.
doi:10.1136/hrt.2004.039636
PMCID: PMC1768952  PMID: 15894775
N-acetylcysteine; contrast media; prevention; contrast induced nephropathy; low osmolality contrast media
11.  N-Acetylcysteine as adjunctive treatment in severe malaria: A randomized double blinded placebo controlled clinical trial 
Critical care medicine  2009;37(2):516-522.
Objective
Markers of oxidative stress are reported to be increased in severe malaria. It has been suggested that the antioxidant N-acetylcysteine (NAC) may be beneficial in treatment. We studied the efficacy and safety of parenteral N-acetylcysteine as an adjunct to artesunate treatment of severe falciparum malaria.
Design
A randomized double-blind placebo controlled trial on the use of high dose intravenous NAC as adjunctive treatment to artesunate.
Setting
A provincial hospital in Western Thailand and a tertiary referral hospital in Chittagong, Bangladesh.
Patients
One hundred and eight adult patients with severe falciparum malaria.
Interventions
Patients were randomized to receive N-acetylcysteine or placebo as adjunctive treatment to intravenous artesunate.
Measurements and main results
A total of 56 patients were treated with NAC and 52 received placebo. NAC had no significant effect on mortality, lactate clearance times (p=0.74) or coma recovery times (p=0.46). Parasite clearance time was increased from 30h (range 6h to 144h) to 36h (range 6h to 120h) (p=0.03), but this could be explained by differences in admission parasitemia. Urinary F2-isoprostane metabolites, measured as a marker of oxidative stress, were increased in severe malaria compared to patients with uncomplicated malaria and healthy volunteers. Admission red cell rigidity correlated with mortality, but did not improve with NAC.
Conclusion
Systemic oxidative stress is increased in severe malaria. Treatment with N-acetylcysteine had no effect on outcome in patients with severe falciparum malaria in this setting.
doi:10.1097/CCM.0b013e3181958dfd
PMCID: PMC2731834  PMID: 19114891
N-Acetylcysteine; Severe malaria; Adjunctive treatment
12.  Role of Reactive Oxygen Species in Pathogenesis of Radiocontrast-Induced Nephropathy 
BioMed Research International  2013;2013:868321.
In vitro and in vivo studies have demonstrated enhanced hypoxia and formation of reactive oxygen species (ROS) in the kidney following the administration of iodinated contrast media, which play a relevant role in the development of contrast media-induced nephropathy. Many studies indeed support this possibility, suggesting a protective effect of ROS scavenging or reduced ROS formation with the administration of N-acetylcysteine and bicarbonate infusion, respectively. Furthermore, most risk factors, predisposing to contrast-induced nephropathy, are prone to enhanced renal parenchymal hypoxia and ROS formation. In this review, the association of renal hypoxia and ROS-mediated injury is outlined. Generated during contrast-induced renal parenchymal hypoxia, ROS may exert direct tubular and vascular endothelial injury and might further intensify renal parenchymal hypoxia by virtue of endothelial dysfunction and dysregulation of tubular transport. Preventive strategies conceivably should include inhibition of ROS generation or ROS scavenging.
doi:10.1155/2013/868321
PMCID: PMC3891610  PMID: 24459673
13.  Contrast induced nephropathy in urology 
Intravenous contrast agents have a distinct role in urological imaging: to study precise anatomical delineation, vascularity, and to assess the function of the renal unit. Contrast induced nephropathy (CIN) is a known adverse effect of intravenous contrast administration. The literature on incidence, pathophysiology, clinical features, and current preventive strategies available for CIN relevant to urologists was reviewed. A search of the PubMed database was done using the keywords nephropathy and media, prevention and control or prevention Contrast media (explode), all adverse effects, and kidney diseases (explode). An online search of the EMBASE database for the time ranging from 1977 to February 2009 was performed using the keywords ionic contrast medium, adverse drug reaction, major or controlled clinical study, human, nephrotoxicity, and kidney disease. Current publications and data most relevant to urologists were examined. CIN was the third most common cause of hospital-acquired renal failure. The incidence is less common with intravenous contrast administration as compared with intra-arterial administration. The pathogenesis of contrast mediated nephropathy is due to a combination of toxic injury to renal tubules and medullary ischemic injury mediated by reactive oxygen species. CIN most commonly manifests as a nonoliguric and asymptomatic transient decline in renal function. Patients who developed CIN were found to have increased mortality, longer hospital stay, and complicated clinical course. An overview of risk factors and risk prediction score for prognostication of CIN are elaborated. Preventive strategies including choice of contrast agents, maximum tolerated dose, role of hydration, hydration regime, etc. are discussed. The role of N- acetyl cysteine, Theophylline, Fenoldapam, Endothelin receptor antagonists, iloprost, atrial natriuretic peptide, and newer therapies such as targeted renal therapy (TRT) are discussed. A working algorithm based on current evidence is proposed. No current treatment can reverse or ameliorate CIN once it occurs, but prophylaxis is possible.
doi:10.4103/0970-1591.57904
PMCID: PMC2808644  PMID: 19955665
Fenoldopam; isoosmolar agents; N-acetylcysteine; radiocontrast-induced nephropathy; ultrafiltration
14.  Structural, chemical and biological aspects of antioxidants for strategies against metal and metalloid exposure 
Oxidative stress contributes to the pathophysiology of exposure to heavy metals/metalloid. Beneficial renal effects of some medications, such as chelation therapy depend at least partially on the ability to alleviate oxidative stress. The administration of various natural or synthetic antioxidants has been shown to be of benefit in the prevention and attenuation of metal induced biochemical alterations. These include vitamins, N-acetylcysteine, α-lipoic acid, melatonin, dietary flavonoids and many others. Human studies are limited in this regard. Under certain conditions, surprisingly, the antioxidant supplements may exhibit pro-oxidant properties and even worsen metal induced toxic damage. To date, the evidence is insufficient to recommend antioxidant supplements in subject with exposure to metals. Prospective, controlled clinical trials on safety and effectiveness of different therapeutic antioxidant strategies either individually or in combination with chelating agent are indispensable. The present review focuses on structural, chemical and biological aspects of antioxidants particularly related to their chelating properties.
PMCID: PMC2763257  PMID: 20716905
chelation therapy; oxidative stress; antioxidant; metal toxicity; combination therapy
15.  Compliance with QUOROM and quality of reporting of overlapping meta-analyses on the role of acetylcysteine in the prevention of contrast associated nephropathy: case study 
BMJ : British Medical Journal  2006;332(7535):202-209.
Objective To appraise multiple systematic reviews on the same clinical topic, focusing on predictors and correlates of quality of reporting of meta-analysis (QUOROM) scores.
Design Case study.
Setting Reviews providing at least individual quantitative estimates on role of acetylcysteine in the prevention of contrast associated nephropathy.
Data sources PubMed, the database of abstracts of reviews of effects, and the Cochrane database of systematic reviews (updated March 2005).
Main outcome measures Funding, compliance with the QUOROM checklist, scores on the Oxman and Guyatt quality index, and authors' recommendations.
Results 10 systematic reviews, published August 2003 to March 2005, were included. Nine pooled events despite heterogeneity and five recommended routine use of acetylcysteine, whereas the remaining studies called for further research. Compliance with the 18 items on the QUOROM checklist was relatively high (median 16, range 11 to 17), although shorter manuscripts had significantly lower scores (R = 0.73; P = 0.016). Reviewers who reported previous not for profit funding were more likely to score higher on the Oxman and Guyatt quality index. No association was found between QUOROM and Oxman and Guyatt scores (R = -0.06; P = 0.86), mainly because of greater emphasis of the Oxman and Guyatt scores on the appraisal of bias in selection and validity assessment (inadequate in five reviews).
Conclusions Multiple systematic reviews on the same clinical topic varied in quality of reporting and recommendations. Longer manuscripts and previous not for profit funding were associated with higher quality.
doi:10.1136/bmj.38693.516782.7C
PMCID: PMC1352049  PMID: 16415336
16.  Oral N-acetylcysteine and exacerbation rates in patients with chronic bronchitis and severe airways obstruction. British Thoracic Society Research Committee. 
Thorax  1985;40(11):832-835.
The influence of oral N-acetylcysteine on the exacerbation rate in patients with chronic bronchitis and severe airways obstruction has been studied. Two hundred and forty four patients entered the study during October and November 1983 and took placebo sachets for a run in month. One hundred and eighty one who completed this month satisfactorily were randomised to receive either active (acetylcysteine 200 mg three times a day) or matching placebo sachets for five months in a double blind parallel group study. The two groups were well matched. Patients kept detailed daily symptom diaries and were assessed monthly. At the end of the five months' study the outcome in the group taking acetylcysteine appeared a little better, but the differences did not reach conventional levels of statistical significance for the mean (SD) number of exacerbations (2.1 (0.2) for acetylcysteine, 2.6 (0.2) for placebo; p = 0.08); total days taking an antibiotic (13.5 (1.7), 18.0 (2.8); p = 0.17); total days spent in bed (4.8 (0.8), 5.1 (1.1); p = 0.9); number of withdrawals (13 (15%), 20 (21%); p = 0.4); incidence of side effects (which were few); drug compliance (which was good); and the patients' assessment of the treatment.
PMCID: PMC1020560  PMID: 2866607
17.  Randomised, double blind, placebo controlled trial of intravenous antioxidant (n‐acetylcysteine, selenium, vitamin C) therapy in severe acute pancreatitis 
Gut  2007;56(10):1439-1444.
Background
Based on equivocal clinical data, intravenous antioxidant therapy has been used for the treatment of severe acute pancreatitis. To date there is no randomised comparison of this therapy in severe acute pancreatitis.
Methods
We conducted a randomised, double blind, placebo controlled trial of intravenous antioxidant (n‐acetylcysteine, selenium, vitamin C) therapy in patients with predicted severe acute pancreatitis. Forty‐three patients were enrolled from three hospitals in the Manchester (UK) area over the period June 2001 to November 2004. Randomisation stratified for APACHE‐II score and hospital site, and delivered groups that were similar at baseline.
Results
Relative serum levels of antioxidants rose while markers of oxidative stress fell in the active treatment group during the course of the trial. However, at 7 days, there was no statistically significant difference in the primary end point, organ dysfunction (antioxidant vs placebo: 32% vs 17%, p = 0.33) or any secondary end point of organ dysfunction or patient outcome.
Conclusions
This study provides no evidence to justify continued use of n‐acetylcysteine, selenium, vitamin C based antioxidant therapy in severe acute pancreatitis. In the context of any future trial design, careful consideration must be given to the risks raised by the greater trend towards adverse outcome in patients in the treatment arm of this study.
doi:10.1136/gut.2006.115873
PMCID: PMC2000286  PMID: 17356040
pancreatitis; antioxidants; randomised controlled trial
18.  A retrospective evaluation of shortened-duration oral N-acetylcysteine for the treatment of acetaminophen poisoning 
Journal of Medical Toxicology  2009;5(4):183-190.
Introduction
The use of less than the traditional 72-hour course of oral N-acetylcysteine has been an alternative treatment option following potentially toxic acute and chronic acetaminophen ingestions felt to be at low risk of developing hepatotoxicity. While clinical experience with shortened treatment duration is extensive, there are few studies evaluating the effectiveness and extent to which these regimens may be used.
Methods
A large statewide poison center database was reviewed for all acetaminophen exposures involving potentially toxic acute and chronic ingestions, in addition to those taking place at unknown times. Patients were identified who met laboratory criteria for early N-acetylcysteine (NAC) discontinuation (APAP < 10 μm/mL, INR ≤ 1.3, and AST/ALT ≤ 60 IU) after a minimum of a 140-mg/kg oral NAC loading dose and 5 additional 70-mg/kg doses over 20 hours. A further search of the poison center database was conducted for individuals who received shortened-course (20–48 hours) oral NAC treatment who developed subsequent hepatotoxicity or death.
Results
Of 3303 individuals with potentially toxic acetaminophen ingestions, 1932 met criteria for early NAC discontinuation. Mean treatment duration was 36.4±7.7 hours (acute=37.3±7.6 hours; chronic=34.8±7.4 hours; unknown=35.2±7.6 hours). The poison center database search identified no short-course eligible subjects who developed subsequent hepatotoxicity or death following ≤48 hours of oral NAC.
Conclusion
Treatment with shortened-course oral NAC in patients meeting criteria for early discontinuation may be an effective treatment option in a sizeable proportion of individuals with potentially toxic acetaminophen ingestions.
doi:10.1007/BF03178264
PMCID: PMC3550405  PMID: 19876849
acetaminophen poisoning; N-acetylcysteine; acetaminophen overdose
19.  Factors Associated with the Use of Preventive Care for Contrast-Induced Acute Kidney Injury 
BACKGROUND
The factors that affect the implementation of preventive care for contrast-induced acute kidney injury (CIAKI) are unknown.
OBJECTIVE
To assess patient and provider factors associated with the use of preventive care for CIAKI.
DESIGN
Prospective cohort study.
PARTICIPANTS
Patients with kidney disease undergoing procedures with intravascular iodinated radiocontrast.
MEASUREMENTS
We recorded the use of preventive care defined as the administration of: (1) pre- and post-procedure isotonic intravenous (IV) fluid, (2) N-acetylcysteine, and (3) iso-osmolal radiocontrast. We surveyed patients’ providers to assess their knowledge, experience, and training on CIAKI and used multiple logistic regression to assess the independent associations of patient and provider factors with the use of these preventive interventions.
RESULTS
We enrolled 660 patients and 87 providers. Patient factors associated with use of IV fluid and N-acetylcysteine were higher baseline serum creatinine (OR 1.5 and 5.0, p < 0.05) and inpatient status (OR 3.0 and 6.3, p < 0.05), while higher baseline serum creatinine was associated with the use of iso-osmolal contrast (OR = 13.4, p < 0.01). The primary provider characteristics associated with the use of IV fluid and N-acetylcysteine were a greater degree of prior training on CIAKI (OR 1.9 and 2.8, p < 0.05) and higher number of prior patients with CIAKI (OR 2.7 and 2.6, p < 0.05).
CONCLUSIONS
Patient baseline kidney function and provider training and experience with CIAKI are independently associated with the use of preventive care. Efforts to increase and intensify the training providers receive on CIAKI may help decrease the incidence of this costly iatrogenic condition.
doi:10.1007/s11606-008-0894-4
PMCID: PMC2642579  PMID: 19156472
predictors; contrast-induced acute kidney injury; patients; providers; preventive care
20.  Prevention of contrast-induced nephropathy: A randomized controlled trial of sodium bicarbonate and N-acetylcysteine 
BACKGROUND:
Contrast-induced nephropathy (CIN) continues to be a common cause of acute renal failure in high-risk patients undergoing radiocontrast studies. However, there is still a lack of consensus regarding the most effective measures to prevent CIN.
METHODS:
One hundred eighteen patients with diabetes mellitus and/or renal insufficiency, scheduled for coronary angiography or intervention, were randomly assigned to one of four treatment groups: intravenous (IV) 0.9% NaCl alone, IV 0.9% NaCl plus N-acetylcysteine (NAC), IV 0.9% sodium bicarbonate (NaHCO3) alone or IV 0.9% NaHCO3 plus NAC. All patients received IV hydration as a preprocedure bolus and as maintenance. Iso-osmolar contrast was used in all patients. CIN was defined as an increase of greater than 25% in the serum creatinine concentration from baseline to 72 h.
RESULTS:
The overall incidence of CIN was 6%. There was no statistically significant difference in the incidence of CIN among the groups. There was a CIN incidence of 7% in the NaCl only group, 5% in the NaCl/NAC group, 11% in the NaHCO3 only group and 4% in the NaHCO3/NAC group (P=0.86). The maximum increase in serum creatinine was 14.14±12.38 μmol/L in the NaHCO3 group, 10.60±29.14 μmol/L in the NaCl only group, 9.72±13.26 μmol/L in the NaCl/NAC group and 0.177±15.91 μmol/L for the NaHCO3/NAC group (P=0.0792).
CONCLUSION:
CIN in high-risk patients may be effectively minimized solely through the use of an aggressive hydration protocol and an iso-osmolar contrast agent. The addition of NaHCO3 and/or NAC did not have an effect on the incidence of CIN.
PMCID: PMC2903033  PMID: 22477552
Cardiac catheterization; Contrast-induced nephropathy; N-acetylcysteine; Prevention; Sodium bicarbonate
21.  Early detection and intervention using neutrophil gelatinase-associated lipocalin (NGAL) may improve renal outcome of acute contrast media induced nephropathy: A randomized controlled trial in patients undergoing intra-arterial angiography (ANTI-CIN Study) 
BMC Nephrology  2011;12:39.
Background
Patients with pre-existing impaired renal function are prone to develop acute contrast media induced nephropathy (CIN). Neutrophil gelatinase-associated lipocalin (NGAL), a new biomarker predictive for acute kidney injury (AKI), has been shown to be useful for earlier diagnosis of CIN; however, urinary NGAL values may be markedly increased in chronic renal failure at baseline. Results from those studies suggested that urinary NGAL values may not be helpful for the clinician. An intravenous volume load is a widely accepted prophylactic measure and possibly a reasonable intervention to prevent deterioration of renal function. The aim of our study is to evaluate NGAL as an early predictor of CIN and to investigate the clinical benefit of early post-procedural i.v. hydration.
Methods/Design
The study will follow a prospective, open-label, randomized controlled design. Patients requiring intra-arterial contrast media (CM) application will be included and receive standardized, weight-based, intravenous hydration before investigation. Subjects with markedly increased urinary NGAL values after CM application will be randomized into one of two study groups. Group A will receive 3-4 ml/kg BW/h 0.9% saline intravenously for 6 hours. Group B will undergo only standard treatment consisting of unrestricted oral fluid intake. The primary outcome measure will be CIN defined by an increase greater than 25% of baseline serum creatinine. Secondary outcomes will include urinary NGAL values, cystatin C values, contrast media associated changes in cardiac parameters such as NT-pro-BNP/troponin T, changes in urinary cytology, need for renal replacement treatment, length of stay in hospital and death.
We assume that 20% of the included patients will show a definite rise in urinary NGAL. Prospective statistical power calculations indicate that the study will have 80% statistical power to detect a clinically significant decrease of CIN of 40% in the treatment arm if 1200 patients are recruited into the study.
Discussion
A volume expansion strategy showing a benefit from earlier intervention for patients with markedly elevated urinary NGAL values, indicating a CIN, might arise from data from this study.
Trial registration
ClinicalTrials.gov NCT01292317
doi:10.1186/1471-2369-12-39
PMCID: PMC3170259  PMID: 21849080
22.  Efficacy of concomitant administration of clarithromycin and acetylcysteine in bronchiolitis obliterans in seventeen sulfur mustard—exposed patients: An open-label study 
Background:
Victims of sulfur mustard (SM) gas exposure experience different types of chronic pulmonary disease, manifested as cough, sputum production, and dyspnea. Conventional therapies (eg, immunosuppressive drugs, corticosteroids) have not been effective in these patients.
Objective:
This study was carried out to determine the efficacy of concomitant administration of the macrolide clarithromycin and the mucolytic agent acetylcysteine in the treatment of bronchiolitis obliterans in SM-exposed patients.
Methods:
This open-label clinical study was conducted at the Research Center of Chemical Injuries, Baqiyatallah Medical Sciences University, Tehran, Iran. Clarithromycin and acetylcysteine were administered concomitantly for 6 months to male SM-exposed patients with chronic bronchitis and bronchiolitis obliterans who were nonresponsive to conventional treatments. Efficacy analysis included symptom assessment and pulmonary function tests (forced expiratory volume in 1 second [FEV1], forced vital capacity [FVC], and FEV1/FVC ratio) using spirometry, performed at baseline and after 2 and 6 months of treatment.
Results:
Seventeen male patients (mean [SD] age, 38.3 [5.3] years [range, 31–50 years]; mean [SD] body weight, 77.9 [15.7] kg) were included in the study. Cough and sputum production were each found in 10 of 17 patients (58.8%) at baseline and were improved in all 10 patients after the administration of clarithromycin and acetylcysteine. FEV1 and FVC also were improved, by mean (SD) 10.6% (9.7%) (P < 0.001 vs baseline) and 12.9% (13.6%) (P = 0.001 vs baseline). No significant change in FEV1/FVC ratio was found.
Conclusions:
In this study of concomitant administration of clarithromycin and acetylcysteine for the treatment of bronchiolitis obliterans in SM-exposed patients, symptoms and pulmonary function were improved. These results may have been related to the therapeutic effects of a macrolide antibiotic on chronic bronchitis and bronchiolitis obliterans in these patients. Based on the results of this study, we recommend this treatment for chemical warfare victims with recurrent exacerbation of bronchitis who do not respond to conventional treatment.
doi:10.1016/j.curtheres.2004.12.001
PMCID: PMC3964536  PMID: 24672101
sulfur mustard; chemical warfare; chronic bronchitis; bronchiolitis; clarithromycin; acetylcysteine
23.  N-acetylcysteine reduces extinction responding and induces enduring reductions in cue- and heroin-induced drug-seeking 
Biological psychiatry  2007;63(3):338-340.
Background
Previous studies show that the acute administration of N-acetylcysteine inhibits the desire for cocaine in addicts and cocaine seeking in animals
Methods
Rats were trained to self-administer heroin and the reinstatement model of drug seeking was used to determine if chronic N-acetylcysteine treatment inhibited heroin seeking.
Results
Daily N-acetylcysteine administration inhibited cue- and heroin-induced seeking. Moreover, repeated N-acetylcysteine administration during extinction training reduced extinction responding and inhibited cue- and heroin-induced reinstatement for up to 40 days after discontinuing daily N-acetylcysteine injection.
Conclusions
These data show that daily N-acetylcysteine inhibits heroin-induced reinstatement and produces an enduring reduction in cue- and heroin-induced drug seeking for over a month after the last injection of N-acetylcysteine. Both the inhibitory effect of N-acetylcysteine on the reinstatement of heroin-seeking and the ability of N-acetylcysteine to reduce extinction responding support clinical evaluation of repeated N-acetylcysteine administration to decreases in drug seeking in heroin addicts.
doi:10.1016/j.biopsych.2007.06.008
PMCID: PMC2709691  PMID: 17719565
heroin; N-acetylcysteine; reinstatement; addiction; self-administration; extinction
24.  Scottish and Newcastle Antiemetic Pre-treatment for paracetamol poisoning study (SNAP) 
Background
Paracetamol (acetaminophen) poisoning remains the commonest cause of acute liver injury in Europe and North America. The intravenous (IV) N-acetylcysteine (NAC) regimen introduced in the 1970s has continued effectively unchanged. This involves 3 different infusion regimens (dose and time) lasting over 20 hours. The same weight-related dose of NAC is used irrespective of paracetamol dose. Complications include frequent nausea and vomiting, anaphylactoid reactions and dosing errors. We designed a randomised controlled study investigating the efficacy of antiemetic pre-treatment (ondansetron) using standard NAC and a modified, shorter, regimen.
Methods/Design
We designed a double-blind trial using a 2 × 2 factorial design involving four parallel groups. Pre-treatment with ondansetron 4 mg IV was compared against placebo on nausea and vomiting following the standard (20.25 h) regimen, or a novel 12 h NAC regimen in paracetamol poisoning. Each delivered 300 mg/kg bodyweight NAC. Randomisation was stratified on: paracetamol dose, perceived risk factors, and time to presentation. The primary outcome was the incidence of nausea and vomiting following NAC. In addition the frequency of anaphylactoid reactions and end of treatment liver function documented. Where clinically necessary further doses of NAC were administered as per standard UK protocols at the end of the first antidote course.
Discussion
This study is primarily designed to test the efficacy of prophylactic anti-emetic therapy with ondansetron, but is the first attempt to formally examine new methods of administering IV NAC in paracetamol overdose. We anticipate, from volunteer studies, that nausea and vomiting will be less frequent with the new NAC regimen. In addition as anaphylactoid response appears related to plasma concentrations of both NAC and paracetamol anaphylactoid reactions should be less likely. This study is not powered to assess the relative efficacy of the two NAC regimens, however it will give useful information to power future studies. As the first formal randomised clinical trial in this patient group in over 30 years this study will also provide information to support further studies in patients in paracetamol overdose, particularly, when linked with modern novel biomarkers of liver damage, patients at different toxicity risk.
Trial registration
EudraCT number 2009-017800-10, ClinicalTrials.gov IdentifierNCT01050270
doi:10.1186/2050-6511-14-20
PMCID: PMC3626543  PMID: 23556549
Paracetamol; Acetylcysteine; Overdose; Antidotes; Hepatotoxicity
25.  Contrast-induced nephropathy; A literature review 
Journal of Nephropathology  2014;3(2):51-56.
Context: Contrast-induced nephropathy (CIN) is a common cause of acute kidney dysfunction.
Evidence Acquisitions: Directory of Open Access Journals, Google Scholar, PubMed, EBSCO and Web of Science have been searched.
Results: It is necessary to identify at risk patients at early stages to implement preventive strategies to decrease the incidence of this nephropathy. However, mechanisms of CIN have not fully explained yet. It seems that mechanisms which mediated by nitric oxide and prostaglandin-induced vasodilatation have been played a crucial role in the CIN. Hemodynamic changes of renal blood flow, which causes hypoxia in the renal medulla and direct toxic effects of contrast media on renal cells, are thought to contribute to the pathogenesis of CIN. Contrast media is normally divided into iso-osmolar, low-osmolar, and high-osmolar. N-acetylcysteine is considered as one of the best choices to prevent CIN in high-risk groups.
Conclusions: The first aim to prevent CIN is identifying high-risk subjects and controlling associate risk factors. As significant differences existed between contrasts agents due to their physicochemical properties, low-osmolar or iso-osmolar contrast media should be used to prevent CIN in at-risk patients. The volume of contrast media should be as low as possible.
doi:10.12860/jnp.2014.12
PMCID: PMC3999584  PMID: 24772397
Contrast-induced nephropathy; Contrast media; Percutaneous coronary intervention

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