Lack of protection of N-acetylcysteine (NAC) in acute renal failure related to elective aortic aneurysm repair—a randomized controlled trial

Nephrol Dial Transplant (2006) 21: 1863–1869 doi:10.1093/ndt/gfl079 Advance Access publication 7 March 2006 Original Article Lack of protection of N-acetylcysteine (NAC) in acute renal failure related to elective aortic aneurysm repair—a randomized controlled trial 1 Renal Division and 2Vascular Surgery Division, Hospital das Clı́nicas, University of São Paulo, São Paulo, Brazil Abstract Background. N-acetylcysteine (NAC) is an antioxidant drug largely tested in different clinical situations. Recently, NAC has been employed with variable success in the prevention of radiocontrast nephropathy. Since aortic aneurysm surgical repair is a condition that is frequently accompanied by acute renal failure (ARF), we sought to investigate whether NAC has any role in preventing ARF in this scenario. Methods. A randomized, placebo-controlled, doubleblind trial with the following inclusion criteria: elective aortic aneurysm repair in patients with stable renal function. The groups were randomly matched for age, gender, presence of diabetes and pre-existent renal failure. NAC or placebo (control) was administered p.o. for 24 h before operation and maintained i.v. for 48 h after operation. The dose of NAC was 1200 mg b.i.d. the day before surgery and 600 mg b.i.d. after. The primary endpoint was the development of ARF up to the third post-operative day, defined as an increase in SCr
25% from baseline. Secondary endpoints were: ICU mortality and ICU length of stay. Results. Forty-two patients (n ¼ 18 for NAC group and n ¼ 24 for control) were studied. The baseline SCr and calculated GFR did not differ between the groups (1.19±0.33 vs 1.37±0.49 mg/dl; and 64.6±26.22 vs 65.7±28.32 ml/min, NAC vs control, respectively, P ¼ 0.17 and P ¼ 0.90). Need for suprarenal aortic cross-clamping and its duration, occurrence of major bleeding, intra-operative hypotension and the postoperative peak of CPK did not differ between NAC and control groups. The overall incidence of ARF in the study was 36% (13/36), but it was not significantly different between groups (7/14, 50% in NAC vs 6/22, 27.3% in control, P ¼ 0.16). The overall mortality was Correspondence and offprint requests to: Dr José M. Vieira, Jr, Av. Dr Arnaldo 455, Sala 3342, CEP 01246-903, São Paulo-SP, Brazil. Email: josemvjr@usp.br 23% (10/42) and was not different (P ¼ 0.209) in NAC group (33.3%) when compared with control (16.7%), the same occurring with the length of ICU stay (2.93±1.53 vs 2.52±1.36 days, P ¼ 0.40). Conclusion. This study suggests that the putative beneficial effects of NAC on radiocontrast nephropathy might not be applicable to other situations, such as ARF associated with elective aortic aneurysm repair. Keywords: N-acetylcysteine; acute renal failure; aortic aneurysm; ischaemia; randomized controlled trial; surgery Introduction N-acetylcysteine (NAC) is a well-known drug with pleiotropic effects. Its antioxidant property made this drug useful in paracetamol intoxication and drove several studies evaluating its role in ischaemiareperfusion conditions [1–4]. Besides that, several studies have shown that NAC interferes in intracellular signalling pathways involved in cell stress [1,5,6] and regulates nitric oxide production [7]. In renal diseases, NAC was initially tested in an experimental model of ischaemic acute renal failure (ARF), resulting in protective effects on renal function and structure [6]. Since the pivotal study of Tepel et al. [8], many studies have evaluated the effect of NAC in the radiocontrast nephropathy, yielding conflicting results [8–10]. Two recent meta-analyses were able to demonstrate an overall beneficial effect of NAC in the prevention of radiocontrast nephropathy [11,12]. However, it is not known whether NAC protection is extended to other causes of ARF, such as ischaemic surgical ARF. The surgical treatment of aortic aneurysms carries a high risk to develop ARF, which is a consequence ß The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org Downloaded from https://academic.oup.com/ndt/article/21/7/1863/1821853 by guest on 13 June 2022 Etienne Macedo1, Regina Abdulkader1, Isac Castro1, Augusto C. C. Sobrinho2, Lius Yu1 and Jose M. Vieira Jr1 1864 E. Macedo et al. of renal and systemic ischaemia-reperfusion injury, both associated with the clamping of the aorta. Moreover, the occurrence of ARF in this population increases mortality at least 10-fold [13,14]. Therefore, we sought to evaluate the effect of NAC in the prevention of ARF related to elective aortic aneurysm repair in a prospective, randomized and controlled trial. Subjects and methods ruptured aneurysms or emergent surgery; renovascular disease (>50% obstruction in at least one renal artery); severe congestive heart failure (left ventricular fraction of ejection <35% and use of radiocontrast 1 week prior to surgery. After obtaining an informed consent, they were randomized to either placebo (control) or NAC treatment. The randomization was performed through a predefined randomization that took into account: age, gender, presence of diabetes mellitus and pre-existent renal failure (1.5<baseline SCr<3.0 mg/dl). Figure 1 depicts the doubleblind study design and the reason for exclusion. Patients Study protocol NAC or placebo was administered p.o. 24 h before operation and maintained i.v. for 48 h after operation. The study was double-blinded, and the set of pills (600 mg of NAC or starch) and ampoules (300 mg NAC or vehicle) were provided by the pharmacy under a code number. The dose of NAC was 85 eligible patients underwent aortic aneurysm repair (thoraco-abdominal or abdominal) 43 patients excluded: 25 endovascular procedure 4 urgent operations 4 denied participation in the study 2 received radiocontrast infusion 48 h prior to operation 2 enrolled in another study 1 low platelet count 1 severe chronic obstructive pulmonary disease 1 renal tumour 1 cirrhosis 2 unknown 45 patients randomized 1 refused operation 2 cancelled operations NAC group=18 7 ARF 3 intra-operative deaths 1 death within the 1st post-operative day Control group=24 6 ARF 1 intra-operative death 1 death within the 1st post-operative day Fig. 1. Flow chart of the patients included in the protocol. NAC, N-acetylcysteine; ARF, acute renal failure defined as an increase in SCr
25% from the baseline up to the third post-operative day. Downloaded from https://academic.oup.com/ndt/article/21/7/1863/1821853 by guest on 13 June 2022 The study was undertaken in a tertiary, 900-bed University Hospital. From March 2001 to July 2003, patients aged 18–80 years, admitted as candidates to surgical open repair of either abdominal or thoraco-abdominal aortic aneurysms were enrolled. Exclusion criteria were: baseline serum creatinine (Scr) >3.0 mg/dl, endovascular aneurysm repair, Lack of protection of NAC in the acute renal failure 1200 mg b.i.d. the day before surgery and 600 mg b.i.d. for 48 h after surgery. Post-operative care was carried on in a surgical ICU, according to the standard intensive care practice by the routine personnel staff. The operation was always performed by a vascular surgeon. Anaesthesia, surgical technique and intra-operative care, regarding blood autotransfusion and haemodynamic support, were standardized and did not differ between groups. Biochemical parameters were ordered and collected by the staff as usual. Data were daily collected by the investigators (EM, RCRMA or JMVJ), the prescription was checked in order to assure that the patient had received the correct dose of the coded drug, and side effects related to drug infusion was sought. The study protocol was approved by the Ethics Committee of the institution. Baseline SCr considered was the mean of at least two samples, collected during the week before the surgery and with stable values. The GFR was calculated according to Cockroft–Gault equation. The ARF was defined as an increase in SCr
25% from baseline up to the third postoperative day. Previous diseases: (i) diabetes mellitus: use of oral hypoglycaemic agents or insulin; (ii) arterial hypertension: use of antihypertensive drugs; (iii) coronary artery disease: as reported in the pre-operative evaluation by the cardiologist. Intra-operative parameters: (i) hypotension: mean arterial pressure <70 mmHg for at least 15 min; (ii) major bleeding: as reported by the surgeon. Endpoints The primary endpoint was the occurrence of ARF in the patients who survived the first post-operative day. Secondary endpoints were: ICU mortality and ICU length of stay. Statistical analysis Data are reported as mean±SD for continuous variables and percentage for discrete variables. Categorical variables were analysed with Fisher’s exact and chi-square tests, as appropriated. Non-paired continuous variables were analysed by Student’s t-test or Mann–Whitney U-test. A two-tailed P<0.05 was considered statistically significant. All analyses were done with assistance of SPSS 10.0 software. Despite a non-significant trend towards a higher SCr in the control group (1.37±0.49 in control vs 1.19±0.33 in NAC, P ¼ NS), the calculated GFR was not different between groups (64.6±26.2 in control vs 65.7±28.3 in NAC, P ¼ NS). The number of diabetic patients were also equally distributed between groups. Delivered drug/placebo treatment Seventy-three percent of patients in the NAC group received the programmed total dose of treatment. Before the operation, 89% of NAC received the total number of pills, compared with 92% of control patients. In the NAC group, 96% of patients received at least three pills (1800 mg) and the remaining received two pills (1200 mg) and the time elapsed between the intake of last pill and the beginning of operation was 9±3 h. After the operation, 83.3% of patients in the NAC group received at least 1200 mg of NAC and 68% of patients received the total post-operative treatment (2400 mg). Intra and post-operative variables In order to exclude the role of several factors which might have possibly interfered with the development of ARF in control and NAC groups, we examined intraoperative and post-operative characteristics. During the post-operative period, we looked at variables either immediately (during the remaining of the day after operation) or the days thereafter. Intra-operative variables are depicted in Table 2. We did not find any difference between groups regarding the rate of major bleeding, as described by the surgeon’s report, rate of hypotension [mean arterial pressure (MAP) less than 70 mmHg for any time], as well as the minimal intraoperative MAP. Importantly, the need for an aortic suprarenal cross-clamping was similar between groups (six out of 24 patients in control vs seven out of 18 patients in the NAC group, P ¼ 0.501). For these patients, the duration of the clamping was not different between the two groups: 34±18 min in control and 45±38 min in NAC group (P ¼ 0.545). Indirect markers of volume status, such as the rate of infused Table 1. Baseline characteristics of the patients Results Baseline characteristics of the patients Figure 1 depicts the double-blind study design and outcomes. Table 1 shows the demographics and clinical features of the patients. Fifty percent of the patients in NAC group were regularly taking statins and 38% in control group (P ¼ 0.53). No significant difference was found between the two groups in these baseline characteristics. The groups were matched regarding age, sex, presence of diabetes or pre-existent chronic renal failure, defined as SCr
1.5 mg/dl (20.8% vs 11.1%, NAC vs control, P ¼ 0.403). Age (years) Gender (M:F) Baseline serum creatinine (mg/dl) Baseline GFR (ml/min) Previous diseases Diabetes mellitus (%) Chronic renal failure (%) Arterial hypertension (%) Coronary artery disease (%) Continuous variables N-acetylcysteine. are Control (n ¼ 24) NAC (n ¼ 18) P 65.7±11.7 21:3 1.37±0.49 64.6±26.2 69.0±7.8 16:2 1.19±0.33 65.7±28.3 0.314 0.891 0.174 0.902 8% 21% 88% 38% 11% 11% 89% 39% 0.762 0.403 1.0 1.0 presented as mean±SD. NAC, Downloaded from https://academic.oup.com/ndt/article/21/7/1863/1821853 by guest on 13 June 2022 Definitions 1865 1866 E. Macedo et al. Table 2. Intra-operative variables Duration of operation (min) Duration of infrarenal clamping (min) Duration of suprarenal clamping (min) Rate of fluid infusion (ml/min) Net fluid balance (ml) Minimum MAP (mmHg) Complications Vaso-active drugs (%) Major bleeding (%) Hypotension (%) Control (n ¼ 24) NAC (n ¼ 18) P 345±126 69±36 31±16 n ¼ 6 2.8±2.2 5366±5478 62±13 391±124 89±57 45±38 n ¼ 7 2.6±1.7 7701±9192 58±20 0.269 0.225 0.545 0.717 0.350 0.342 30.4% (7/23) 37.5% (9/24) 58.3% (14/24) 37.5% (6/16) 50.0% (9/18) 55.6% (10/18) 0.645 0.418 0.857 Continuous variables are presented as mean±SD. NAC, N-acetylcysteine; MAP, mean arterial pressure. Control MAP (mmHg) NAC 75 50 Base line IOP iPO 1st PO 2nd PO Fig. 2. Evolution of MAP from the baseline period up to second post-operative day in control and NAC groups. Control group (squares) and N-acetylcysteine group (NAC, triangles). MAP, mean arterial pressure; IOP, intra-operative period; iPO, immediate postoperative period; PO, post-operative day. The MAP curves are not different between control and NAC groups. volume and the net balance, and the need for vasoactive drugs did not differ between groups either. The evolution of MAP in the two groups, from baseline period to the second post-operative day, is shown in Figure 2. Other parameters evaluated postoperatively are shown in Table 3. The muscular lesion evaluated by creatine-kinase (CPK) peak post-operatively was similar in both groups: 1086±1097 UI/l in control and 1011±1830 IU/l in NAC group (P ¼ 0.884) consistent with the finding of a similar duration of infrarenal clamping of aorta in both groups as seen in Table 2. Haemoglobin levels equally decreased from the intra-operative period up to the second post-operative day, from 12.9±1.4 to 10.6±1.0 g/dl in control and from 12.6±1.1 to 10.5±1.7 in the NAC group, P ¼ NS. Outcomes (Table 4) The incidence of ARF among the 36 patients who were alive after the first post-operative day was 36%, and was not different between the two groups: 6/22 patients in the control group (27%) and 7/14 patients in the NAC group (50%) developed ARF (P ¼ 0.16). When we analysed the maximum SCr increase, this parameter also did not differ between both groups (Table 4). As can be seen in Figure 3, the evolution of SCr and calculated GFR from baseline period to the second post-operative day were fairly similar. Only one patient, from NAC group, needed haemodialysis treatment. The ARF was associated with suprarenal aortic cross-clamping, 88% of those cases developed ARF, compared with only 22% in the infrarenal clamping patients (P ¼ 0.0007). Overall mortality was 10/42 (23.8%); 6/10 deaths occurred within the first post-operative day (four intraoperative). The deaths were caused by acute surgical complications or cardiovascular events. Mortality was higher among the patients who underwent suprarenal clamping of aorta (61%) than among those who underwent only infrarenal clamping of aorta (7%, P ¼ 0.0004). Importantly, NAC treatment did not change the mortality rate or the length of ICU stay as can be seen in Table 4. Discussion The surgical treatment of aortic aneurysms carries a high rate of complications, of which ARF is one of the most important. The ARF related to open repair of aortic aneurysms is estimated to occur in 5–20% of the cases, depending on the definition chosen [13,14]. The overall incidence of ARF among our patients was 36%, higher than the just mentioned incidence in larger series encompassing aortic aneurysms. However, it is important to point out that our ARF definition was based on mild increases in SCr, not on the need for dialysis, which can explain the increased incidence of ARF in our study. Many authors have demonstrated that when ARF occurs after aortic aneurysm surgical repair, the mortality significantly increases. Indeed, ARF occurrence appears to be an independent factor for mortality [13,15,16]. Therefore, a protective intervention that could decrease the incidence of postoperative ARF would be greatly desirable. The mechanism of ARF in this scenario is probably multifactorial, including rhabdomyolysis, splanchnic and lower limb ischaemia-reperfusion, Downloaded from https://academic.oup.com/ndt/article/21/7/1863/1821853 by guest on 13 June 2022 100 Lack of protection of NAC in the acute renal failure 1867 Table 3. Post-operative variables Control (n ¼ 24) Minimum MAP (mmHg) Infused volume (ml/min) Net fluid balance (ml) NAC (n ¼ 18) I PO 1st PO I PO 1st PO 71±14 1.6±0.8 1327±934 74±12 1.6±0.8 975±1806 76±15 1.9±0.9 1459±977 73±12 1.6±0.9 1693±1708 Continuous variables are presented as mean±SD. NAC, N-acetylcysteine; MAP, mean arterial pressure; PO, post-operative day; I, immediate. P>0.05 for all comparisons between the two groups. Table 4. Outcomes in control and NAC groups NAC 6/22 (27%) 1.59±0.13 0.31±0.67 4/24 (16.7%) 2.52±1.36 7/14 (50%) 1.74±0.27 0.88±1.69 6/18 (33.3%) 2.93±1.53 SCr (mg/dl) Control NAC 1.0 Continuous variables are presented as mean±SD. NAC, N-acetylcysteine; ARF, acute renal failure. P>0.05 for all comparisons between the two groups. 0.5 Baseline iPO 1st PO 2nd PO 100 Control 90 NAC 80 (ml/min) hypovolaemia/hypotension due to operative complications and aortic cross-clamping above the renal arteries, whenever it occurs during some operations. Most modern intra-operative measures are successful in attenuating rhabdomyolysis and hypotension associated with the operation. Nevertheless, the requirement for an aortic cross-clamping in open repair procedures, either above or below the renal arteries, is associated with ischaemia-reperfusion and its consequences. Splanchnic and lower limb (muscles) ischaemia-reperfusion induces the release of several inflammatory mediators and reactive oxygen species (ROS), which can contribute to the genesis of ARF. Moreover, the transient renal arterial clamping is a well-known experimental model of ARF in rodents [6,17], and greatly contributes to ARF in the minority of cases where an aortic aneurysm localizes above or encompasses the renal arteries. Because of its well-known antioxidant properties and multiple effects in ischaemia-reperfusion [7,18,19], NAC has been tested in different conditions, such as myocardial infarction, liver transplantation and Adult Respiratory Distress Syndrome (ARDS), with conflicting results [2,4,20,21]. The NAC has been successfully used in the prevention of radiocontrast-induced nephropathy [8–10]. Recently, meta-analysis revealed that NAC decreases the risk of radiocontrast-induced nephropathy by 55% [11,12]. However, the first evidence of the role of NAC in the prevention of ARF was obtained using an experimental model of ischaemic-ARF, due to renal arteries clamping [6]. DiMari et al. [6] demonstrated a functional and morphological benefit with NAC treatment. This finding was the rationale behind our randomized, double-blind, placebo-controlled study, designed to evaluate the role of NAC in the prevention Control 1.5 70 60 50 40 30 Baseline iPO 1st PO 2nd PO Fig. 3. Evolution of SCr and GFR in control and NAC groups from the baseline period up to the second post-operative day. Both curves are not different between the two groups. Scr, serum creatinine; GFR, calculated GFR; NAC, N-acetylcysteine group (triangles); Control group (squares); iPO, immediate post-operative period; PO, post-operative day. of the ARF associated with open aortic aneurysm surgical repair, which is caused predominantly by ischaemic insult and partially dependent on ROS release. The studied groups were equally matched regarding the main risk factors to ARF, e.g. presence of diabetes, age and pre-existent renal failure. As commonly described in other series, the most prevalent type of aortic aneurysm was the exclusive infrarenal. The prevalence of thoraco-abdominal aneurysm requiring aortic cross-clamping above renal arteries was similar in both groups. Analysis of the intra- and postoperative variables which could have potentially interfered with the development of ARF showed that they were similar in both groups regarding: hypotension, volume infusion, peak of CPK and duration Downloaded from https://academic.oup.com/ndt/article/21/7/1863/1821853 by guest on 13 June 2022 ARF incidence SCr peak (mg/dl) Maximum SCr increase (mg/dl) Mortality Length of ICU stay (days) 2.0 1868 Further studies assessing the role of NAC in different ARF scenarios are encouraged, but this study reinforces that the beneficial effects of NAC observed in radiocontrast nephropathy might not be applicable to other acute renal insults. Conflict of interest statement. None declared. References 1. Khan M, Sekhon B, Jatana M et al. Administration of N-acetylcysteine after focal cerebral ischemia protects brain and reduces inflammation in a rat model of experimental stroke. J Neurosci Res 2004; 76: 519–527 2. Regueira FM, Hernandez JL, Sola I et al. 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Am J Physiol 1997; 272: F292–F298 7. Jiang B, Haverty M, Brecher P. N-acetyl-L-cysteine enhances interleukin-1beta-induced nitric oxide synthase expression. Hypertension 1999; 34: 574–579 8. Tepel M, van der Giet M, Schwarzfeld C, Laufer U, Liermann D, Zidek W. Prevention of radiographic-contrastagent-induced reductions in renal function by acetylcysteine. N Engl J Med 2000; 343: 180–184 9. Durham JD, Caputo C, Dokko J et al. A randomized controlled trial of N-acetylcysteine to prevent contrast nephropathy in cardiac angiography. Kidney Int 2002; 62: 2202–2207 10. Kay J, Chow WH, Chan TM et al. Acetylcysteine for prevention of acute deterioration of renal function following elective coronary angiography and intervention: a randomized controlled trial. JAMA 2003; 289: 553–558 11. Birck R, Krzossok S, Markowetz F, Schnulle P, van der Woude FJ, Braun C. Acetylcysteine for prevention of contrast nephropathy: meta-analysis. Lancet 2003; 362: 598–603 12. Duong MH, MacKenzie TA, Malenka DJ. N-acetylcysteine prophylaxis significantly reduces the risk of radiocontrastinduced nephropathy: comprehensive meta-analysis. Catheter Cardiovasc Interv 2005; 64: 471–479 13. Cambria RP, Davison JK, Zannetti S, L’Italien G, Atamian S. Thoracoabdominal aneurysm repair: perspectives over a decade with the clamp-and-sew technique. Ann Surg 1997; 226: 294–303 14. Kashyap VS, Cambria RP, Davison JK, L’Italien GJ. Renal failure after thoracoabdominal aortic surgery. J Vasc Surg 1997; 26: 949–955 15. Sayers RD, Thompson MM, Nasim A, Healey P, Taub N, Bell PR. Surgical management of 671 abdominal aortic aneurysms: a 13 year review from a single centre. Eur J Vasc Endovasc Surg 1997; 13: 322–327 Downloaded from https://academic.oup.com/ndt/article/21/7/1863/1821853 by guest on 13 June 2022 of aortic clamping. We decided to analyse ARF incidence and creatinine changes up to the third postoperative day, in order to exclude later ARF, which is associated with causes other than the ischaemiareperfusion of the kidneys, intestines and limbs, such as sepsis and nephrotoxicity. In our study, NAC did not change the incidence of ARF, the serum creatinine peak or even its maximum increase. In contrary to what other groups have suggested, in the NAC group the serum creatinine did not significantly decrease, due to an alleged direct effect of NAC on muscle metabolism [22]. Moreover, NAC did not decrease either the length of ICU stay or the mortality rate. It is noteworthy that the high mortality rate was found in this group of patients, particularly in the suprarenal clamping type. Although our study has not been designed to study the risk factors for death, we can speculate that the high prevalence of patients with mild to moderate degrees of renal dysfunction (baseline GFR 60 ml/min), and severe coronary artery disease might justify the high rates of intra-operative or early death. Some explanations why NAC did not work in this study may be considered: the dose we used exceeded the average dose in other studies, but it is still conceivable that for a severe injury such as renal ischaemiareperfusion, the dose necessary for blocking the ROS generation must be higher. Although higher doses of NAC have been recently employed in outpatients submitted to cardiac angiography [23], it is known that it can decrease the oxidative burst of neutrophils [24]. Since our patients were expected to undergo an extensive surgical trauma, and were at great risk of infections, we were cautious about administering higher doses of NAC. It is also possible that the small number of patients of this study decreased the statistical power to discriminate a putative protective effect of NAC. Moreover, we cannot discard some biological unmeasured effect of NAC. Drager et al. [25] demonstrated that NAC acutely decreases the urinary excretion of isoprostane, a lipid marker of renal oxidative stress. Lastly, since the ARF related to aortic aneurysm open repair is a severe, multifactorial insult, it is possible that in this clinical setting NAC is unable to prevent renal injury. More recent studies using NAC in the prevention of ARF related to coronary artery bypass grafting, and the micro-albuminuria that follows severe sepsis did not obtain any beneficial effect with this drug [26,27]. Recently, large randomized studies have compared the open repair with endovascular procedures to correct aortic aneurysms [28,29]. 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Nakajima H, Takenaka M, Kaimori JY et al. Activation of the signal transducer and activator of transcription signaling pathway in renal proximal tubular cells by albumin. J Am Soc Nephrol 2004; 15: 276–285 20. Bernard GR, Wheeler AP, Arons MM et al. A trial of antioxidants N-acetylcysteine and procysteine in ARDS. The antioxidant in ARDS Study Group. Chest 1997; 112: 164–172 21. Jepsen S, Herlevsen P, Knudsen P, Bud MI, Klausen NO. Antioxidant treatment with N-acetylcysteine during adult respiratory distress syndrome: a prospective, randomized, placebo-controlled study. Crit Care Med 1992; 20: 918–923 22. Hoffmann U, Fischereder M, Kruger B, Drobnik W, Kramer BK. The value of N-acetylcysteine in the prevention of radiocontrast agent-induced nephropathy seems questionable. J Am Soc Nephrol 2004; 15: 407–410 23. Baker CS, Wragg A, Kumar S, De Palma R, Baker LR, Knight CJ. A rapid protocol for the prevention of contrast-induced renal dysfunction: the RAPPID study. 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