protection against CIN. Although early studies showed benefits of N-acetylcysteine in patients receiving HOCM or LOCM, subsequent studies and meta-analyses offer mixed results concerning the efficacy of Nacetylcysteine for prevention of CIN. It is possible that the effectiveness of N-acetylcysteine depends on the administered dose and route of administration of N-acetylcysteine, the osmolality of contrast media and its route of administration, and study population characteristics. Study Characteristics Seventy eight studies (67 RCTs and 11 observational studies) were identified that compared N-acetylcysteine with IV saline. Of these, 74 reported on CIN directly, and three reported on serum creatinine or glomerular filtration rate without reporting the incidence of CIN. Of the studies reporting on CIN directly, we found 54 RCTs that compared N-acetylcysteine plus IV saline with IV saline with or without placebo, published between 2002 and 2014, which we included in a meta-analysis. The number of patients in each trial ranged from 40 to 3382, and the study populations were very heterogeneous across the studies. Study patients had renal dysfunction at baseline (defined as baseline serum creatinine greater than 1.2 mg/dl) in 35 studies.28-62 The mean age of patients included in the studies was 55 to 79 years, the mean percentage of patients with diabetes was 39 percent (range 0% to 100%), and the mean percentage of females was 32 percent (range 12% to 59%). Across all of the studies included in the meta-analysis, 4749 patients received IV saline with or without placebo, and 4775 received N-acetylcysteine. The route and dose of N-acetylcysteine varied between studies. Forty studies administered N-acetylcysteine orally,28-33,36-43,45-47,49,50,52- 56,59-74 13 administered it intravenouly,34,35,44,48,51,57,58,75-80 and one used a combination of IV and oral N-acetylcysteine.81 Thirty-four studies,28-36,39,41-47,49-52,56,59-63,65,67,68,70,71,74,78 used a low-dose of N-acetylcysteine (1200 mg/day or less), and 18 studies used a higher dose (greater than 1200 mg/day)37,38,40,48,53-55,57,58,64,66,69,75-77,79-81 One study had one arm with low-dose N-acetylcysteine, a second arm with high-dose N-acetylcysteine, and a control arm that received a placebo in IV saline.81 Contrast media was administered intravenously in seven studies,36,44,49,57,62,68,79 not described in one study,46 and intra-arterially in the remaining studies. Seven studies used IOCM,32,36,39,69,70,76 six used either IOCM or LOCM;28,29,60,67,69,79 one used IOCM, LOCM, or HOCM; 69 one did not report the contrast media type,73 and the remainder used LOCM. Variation existed in the protocols for giving fluids, with studies using 0.45 percent saline; normal saline; 5 percent dextrose in normal saline, or alone; or Ringer’s lactate solutions. The studies administered varying volumes and used three definitions of CIN: 0.5 mg/dl absolute increase, 25 percent increase in serum creatinine, and a combination of both. All of the studies except three measured the change in serum creatinine between 48 and72 hours. One measured the change in serum creatinine at 24 hours,48 one measured it between 48 and 96 hours,69 and one study measured the change five days after contrast media administration71 (Appendix E, Evidence Table E-4). 16 Contrast-Induced Nephropathy The 54 RCTs comparing N-acetylcysteine plus IV saline to IV saline with or without placebo in the reduction of CIN showed a range of results included in the meta-analyses: seven reported a clinically important reduction in the risk of CIN that was statistically significant, 20 reported a clinically important reduction in the risk of CIN that was not statistically significant, 10 did not show a clinically important reduction in the risk of CIN, 12 did not show a clinically important increased risk of CIN, two showed a clinically important increased risk of CIN that was not statistically significant, and three showed a clinically and statistically significant increased risk of CIN. The pooled risk ratio of CIN, using the DerSimonian and Laird random effects model, was 0.78 (95% CI: 0.59 to 1.03) for high-dose N-acetylcysteine (greater than 1200 mg/day), indicating that, on average, the effect is at a level consistent with a clinically unimportant reduction in CIN (Figure 3). There was moderate statistical heterogeneity across studies with an I-squared of 38%. The pooled risk ratio for CIN from the studies using intra-arterially administered contrast media and high-dose N-acetylcysteine was 0.78 (95% CI: 0.55 to 1.12) (high-dose N-acetylcysteine with intra-arterial contrast media administration pooled risk ratio was run with Knapp-Hartung method). Two studies used IV contrast media and high-dose Nacetylcysteine, and their results were too imprecise to draw conclusions (pooled risk ratio 0.55; 95% CI: 0.12 to 2.62). Using Harbord’s modified test for small study effects, we did not find evidence of asymmetry in results by study precision (bias coefficient of -0.61, standard error of 0.66, p=0.37). The strength of evidence was low that high-dose N-acetylcysteine with IV saline had a small clinically unimportant effect in preventing CIN compared with IV saline with or without placebo. (Table 3; see Appendixes F and G for study limitations). The pooled risk ratio for CIN using a random