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.
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.
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.
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.
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.
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%).
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.
N-acetylcysteine; contrast-induced nephropathy; acute renal failure; kidney disease
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.
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.
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.
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.
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.
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.
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%).
Intravenous and oral acetylcysteine are both associated with minimal side effects and are safe for treatment of acetaminophen toxicity.
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.
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.
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.
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.
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.
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).
There was no detectable benefit for the prophylactic administration of oral NAC over an aggressive hydration protocol in patients with DM and CKD.
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.
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.
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.
An ultra-high dose of intravenous N-acetylcysteine is ineffective at preventing nephrotoxicity in patients with renal impairment undergoing emergency contrast CT.
The study was registered as Clinical trial (NCT01467154).
Computerized Tomography; Contrast media; Emergency medicine; N-acetylcysteine; Nephrotoxicity
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.
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.
Randomised controlled trial; adult (>18 years) population; comparison of oral versus intravenous volume expansion.
Oral route of volume expansion compared to the intravenous route.
Any measure of acute kidney injury, need for renal replacement therapy, hospitalization and death.
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).
Small number of studies identified; lack of hard clinical outcomes.
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.
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.
N-acetylcysteine; contrast media; prevention; contrast induced nephropathy; low osmolality contrast media
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.
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.
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.
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.
A randomized double-blind placebo controlled trial on the use of high dose intravenous NAC as adjunctive treatment to artesunate.
A provincial hospital in Western Thailand and a tertiary referral hospital in Chittagong, Bangladesh.
One hundred and eight adult patients with severe falciparum malaria.
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.
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.
N-Acetylcysteine; Severe malaria; Adjunctive treatment
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.
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.
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.
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.
acetaminophen poisoning; N-acetylcysteine; acetaminophen overdose
The factors that affect the implementation of preventive care for contrast-induced acute kidney injury (CIAKI) are unknown.
To assess patient and provider factors associated with the use of preventive care for CIAKI.
Prospective cohort study.
Patients with kidney disease undergoing procedures with intravascular iodinated radiocontrast.
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.
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).
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.
predictors; contrast-induced acute kidney injury; patients; providers; preventive care
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.
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.
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).
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.
Cardiac catheterization; Contrast-induced nephropathy; N-acetylcysteine; Prevention; Sodium bicarbonate
Previous studies show that the acute administration of N-acetylcysteine inhibits the desire for cocaine in addicts and cocaine seeking in animals
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.
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.
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.
heroin; N-acetylcysteine; reinstatement; addiction; self-administration; extinction
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.
Fenoldopam; isoosmolar agents; N-acetylcysteine; radiocontrast-induced nephropathy; ultrafiltration
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.
chelation therapy; oxidative stress; antioxidant; metal toxicity; combination therapy
Introduction: There are few reports summarizing the effectiveness of oral and intravenous (IV) acetylcysteine. We determined the proportion of acetaminophen poisoned patients who develop hepatotoxicity (serum transaminase > 1000 IU/L) when treated with oral and IV acetylcysteine.
Methods: Studies were double abstracted by trained researchers. We determined the proportions of patients who developed hepatotoxicity for each route using a random effects model. Studies were further stratified by early and late treatment.
Results: We screened 4,416 abstracts; 16 articles, including 5,164 patients, were included in the meta-analysis. The overall rate of hepatotoxicity for the oral and IV routes were 12.6% and 13.2%, respectively. Treatment delays are associated with a higher rate of hepatotoxicity.
Conclusion: Studies report similar rates of hepatotoxicity for oral and IV acetylcysteine, but direct comparisons are lacking. While it is difficult to disentangle the effects of dose and duration from route, our findings suggest that the rates of hepatotoxicity are similar for oral and IV administration.
An increasing number of diagnostic imaging procedures requires the use of intravenous radiographic contrast agents, which has led to a parallel increase in the incidence of contrast-induced nephropathy. Risk factors for development of contrast-induced nephropathy include pre-existing renal dysfunction (especially diabetic nephropathy and multiple myeloma-associated nephropathy), dehydration, congestive heart failure and use of concurrent nephrotoxic medication (including aminoglycosides and amphotericin B). Because contrast-induced nephropathy accounts for a significant increase in hospital-acquired renal failure, several strategies to prevent contrast-induced nephropathy are currently advocated, including use of alternative imaging techniques (for which contrast media are not needed), use of (the lowest possible amount of) iso-osmolar or low-osmolar contrast agents (instead of high-osmolar contrast agents), hyperhydration and forced diuresis. Administration of N-acetylcysteine, theophylline, or fenoldopam, sodium bicarbonate infusion, and periprocedural haemofiltration/haemodialysis have been investigated as preventive measures in recent years. This review addresses the literature on these newer strategies. Since only one (nonrandomized) study has been performed in intensive care unit patients, at present it is difficult to draw firm conclusions about preventive measures for contrast-induced nephropathy in the critically ill. Further studies are needed to determine the true role of these preventive measures in this group of patients who are at risk for contrast-induced nephropathy. Based on the available evidence, we advise administration of N-acetylcysteine, preferentially orally, or theophylline intravenously, next to hydration with bicarbonate solutions.
contrast-induced nephropathy; fenoldopam; haemodialysis; haemofiltration; intensive care medicine; N-acetylcysteine; sodium bicarbonate; theophylline
We sought to evaluate the cardiac and renal effects of an N-Acetylcysteine (NAC) enhanced intracoronary radiographic contrast agent.
Recent studies suggest that high dose NAC dosing provides better protection from contrast induced nephropathy and the anti-oxidant properties of NAC may also provide cardiac protection. The use of angiographic contrast agents as a drug delivery vehicle for cardiorenal protection effects has not been investigated.
In a pig model of prolonged cardiac ischemia-reperfusion NAC-enhanced contrast (C-NAC) was tested and compared to Iopamidol contrast-only (C). Myocardium and renal function were assessed after 24 hours.
There was no significant difference in the area-at-risk for myocardial infarction (MI) between C and C-NAC. In contrast, MI size was about 40% smaller in C-NAC treated animals. These findings were associated with a significant difference in MI morphology. MI’s in the C-NAC group had a mottled appearance, whereas in C they were homogeneous and had a discrete border zone. These differences could explain a higher incidence of periprocedural ventricular arrhythmias in the C-NAC group. Histopathological analysis of the myocardium revealed a reduction in programmed cell death by C-NAC that may explain the increase in ischemia tolerance. Last, C-NAC administration blunted the rise in serum creatinine levels by about 60 percent and protected from renotubular apotosis.
N-Acetylcysteine enhanced contrast medium reduces MI size and protects renal function in a pig model of ischemia and reperfusion.
Contrast medium; ischemia; reperfusion; antioxidants
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.
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.
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.
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.
pancreatitis; antioxidants; randomised controlled trial
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.
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.
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.
One hundred cases of severe paracetamol poisoning were treated with intravenous N-acetylcysteine (acetyl-cysteine). There was virtually complete protection against liver damage in 40 patients treated within eight hours after ingestion (mean maximum serum alanine transaminase activity 27 IU/1). Only one out of 62 patients treated within 10 hours developed severe liver damage compared with 33 out of 57 patients (58%) studied retrospectively who received supportive treatment alone. Early treatment and acetylcysteine also prevented renal impairment and death. The critical ingestion-treatment interval for complete protection against severe liver damage was eight hours. Efficacy diminished progressively thereafter, and treatment after 15 hours was completely ineffective. Intravenous acetylcysteine was more effective than cysteamine and methionine and noticeably free of adverse effects. It is the treatment of choice for paracetamol poisoning.