intravenously in one study46 and intra-arterially in the other six studies. The seven studies were completed between 2007 and 2014 and were conducted in the United States,58 Italy,36 Denmark,70 Argentina,132 Iran,74 and Turkey.46,56 The mean age of patients in these studies ranged from 59 to73. The study population for three of the RCTs included only individuals with kidney dysfunction.36,56,132 The patients in one study58 had kidney dysfunction alone (17%), diabetes mellitus alone (59%), or both (24%). Patients in the study by Kama, et al.46 were considered to be at moderate or high risk of developing CIN (73% had an estimated glomerular filtration rate of 60 mL/min/1.73 m2 or less). Only 8 percent of the patients in the study by Thayssen et al.70 had an estimated glomerular filtration rate less than 60 mL/min/1.73 m2 . The percentage of patients with diabetes mellitus ranged from 8.5 percent to 68 percent. The studies had a total follow up period of 48 hours to 30 days; the outcomes of CIN were reported at 48 hours;56,74 at 48 to 72 hours;46,70,132 at 24, 48, and 120 hours (5 days)36 (personal communication with Diego Castini, April 28, 2014); and at 24, 48, and 168 hours (7 days).58 (Appendix E, Evidence Tables E-1, E-3, E-15) All studies compared N-acetylcysteine plus IV saline (sometimes in 5% dextrose in water) with IV sodium bicarbonate. However, in the studies by Thayssen70 and Kama,46 all arms also received IV normal saline. Our search identified two observational studies97,133 comparing N-acetylcysteine plus IV saline with IV sodium bicarbonate. There were 977 study participants. The first study was published in 2009 and was conducted in Israel,133 and the other97 was published in 2008 and conducted in the United States. The mean age of patients ranged from 60 to 71. All of the patients had comorbid disease at baseline in both studies. Contrast-Induced Nephropathy The incidence of CIN in the IV sodium bicarbonate groups ranged from 4.5 to 40.0 percent and from 4.7 to19.4 percent in the N-acetylcysteine plus IV saline groups. Three of the RCTs favored IV sodium bicarbonate, three favored N-acetylcysteine plus IV saline, and one was equivocal because it had very few CIN events58 (Appendix E, Evidence Table E-16). The overall pooled risk ratio for CIN in the RCTs comparing IV sodium bicarbonate with the combination of N-acetylcysteine and IV saline, using the Knapp-Hartung method, was 1.11 (95% CI: 0.51 to 2.41). The point estimate of the risk ratio indicates a very small increase in risk with sodium bicarbonate that was less than clinically important. The CI was too wide to rule out the possibility of either an important decrease or important increase in risk. The studies were inconsistent and had moderate heterogeneity, with an I-squared of 24 percent (Figure 9). The Harbord’s modified test for small study effects did not show evidence of asymmetry in results by study precision (bias coefficient of -0.65, standard error of 1.80, p=0.735). The strength of 30 evidence was insufficient to support a conclusion about the comparative effectiveness of these two interventions in the ability to prevent CIN (Table 5; Appendix E, Evidence Table E-16; see Appendixes F and G for study limitations). Limitations of this comparison included the small number of studies, the varying regimens of fluid administration and N-acetylcysteine dosing, and the variations in follow up time. Four of the studies were exclusively in individuals with kidney disease (a population at higher risk for CIN), although the inclusion criteria were not exactly the same across all studies. One of the RCTs was conducted in individuals with either kidney dysfunction or diabetes mellitus. Another potential concern with the Ratcliffe, et al. study58 was that only 66 percent of the participants completed the study.58 In the observational studies, the rate of CIN was similar in both groups’ comparison groups. The results of the observational studies were similar to those reported in the RCTs regarding the comparison of the risk of CIN with N-acetylcysteine plus IV saline against IV sodium bicarbonate (Appendix E, Evidence Table E-16). Other Outcomes Of the seven RCTs that compared N-acetylcysteine plus IV saline with IV sodium bicarbonate for the development of CIN, five reported on secondary outcomes, including the need for renal replacement therapy, cardiac events, and mortality. 36,46,56,70,132 However, insufficient evidence existed to support firm conclusions about the comparative effects of Nacetylcysteine versus sodium bicarbonate for the outcomes of need for renal replacement therapy, cardiac events, or mortality (Table 5, see Appendixes F and G for study limitations). In those studies, no statistically significant difference was reported, no cases were reported, or statistics were not reported. Although all of these studies reported on specific adverse events or reported that there were no adverse events, adverse events were not reported in a standardized manner, and were rarely analyzed. Thus, we were not able to draw any firm conclusions about whether or not the incidence of adverse events differed between N-acetylcysteine with IV saline and IV sodium bicarbonate (Appendix E, Evidence Table E-18). 31 Figure 9. Meta-analysis of N-acetylcysteine plus IV saline versus sodium bicarbonate for the prevention of contrast-