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CARDIOVASCULAR ANESTHESIA

N-Acetylcysteine for the Prevention of Kidney Injury in Abdominal Aortic Surgery: A Randomized, Double-Blind, Placebo-Controlled Trial

Department of Anesthesia and Intensive Care Medicine, Department of Vascular Surgery, Helsinki University Hospital, Helsinki, Finland

Address correspondence and reprint requests to Marja Hynninen Department of Anesthesia and Intensive Care Medicine Helsinki University Hospital, PO Box 340, Haartmaninkatu 4, 00029 HUS, Helsinki, Finland. Address e-mail to marja.hynninen{at}hus.fi.

	Abstract

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In this prospective, randomized, placebo-controlled, double-blind trial we studied the effects of IV N-acetylcysteine for prevention of renal injury in patients undergoing abdominal aortic surgery. Seventy patients without previously documented renal dysfunction were randomly allocated to receive either N-acetylcysteine (150 mg/kg mixed in 250 mL of 5% dextrose infused in 20 min, followed by an infusion of 150 mg/kg in 250 mL of 5% dextrose over 24 h) or placebo. The infusion was started after the induction of anesthesia. The primary outcome measure was renal injury as measured by the increases in urinary N-acetyl-ß-d-glucosaminidase (NAG)/creatinine ratio (indicator of renal tubular injury) and urinary albumin/creatinine ratio (indicator of glomerular injury). Renal function was assessed by measuring plasma creatinine and serum cystatin C concentrations. The urinary NAG/creatinine ratio increased significantly from baseline to before crossclamp and remained increased on day 5 in both groups. The urinary albumin/creatinine ratio increased significantly from baseline to 6 h after declamping in the N-acetylcysteine group. However, the changes in the NAG/creatinine ratio and the albumin/creatinine ratio were not significantly different between the two groups. Plasma creatinine and serum cystatin C values remained unchanged during the study period in both groups. In conclusion, N-acetylcysteine did not offer any significant protection from renal injury during elective aortic operation in patients with normal preoperative renal function, and some degree of tubular injury seems to occur before aortic crossclamp.

	Introduction

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Acute renal failure is a serious surgical complication. Even modest acute renal dysfunction (ARD) increase the risk of death approximately fivefold (1). The incidence of ARD after elective abdominal aortic surgery varies between 1.7% and 23% (2,3). The risk is markedly increased in emergency surgery, if suprarenal aortic crossclamp is needed or if the patient has diminished renal function preoperatively. The mortality of acute postoperative renal failure may exceed 70% and is associated with markedly increased length of intensive care (4,5).

ARD in the surgical patient is usually multifactorial: the most common cause is acute tubular necrosis as a result of hypoxic damage to nephrons in the medullary region of the kidney secondary to hypotension or hypovolemia. Nephrotoxins, inflammatory mediators, and genetic factors may also play a role in the etiology of ARD (6). However, randomized clinical studies with various pharmacological substances have failed to show efficacy in the prevention of this complication (7).

Injury to renal tubules precedes biochemical evidence of decreased renal function. N-acetyl-ß-d-glucosaminidase (NAG), a brush border enzyme indicating renal tubular injury, has been shown to predict ARD in critically ill patients (8). The most widely used clinical marker, serum creatinine is insensitive for detecting acute deterioration of renal function, especially in patients with normal kidney function. According to one meta-analysis, serum cystatin C concentration may be a more sensitive indicator of renal dysfunction than serum creatinine (9).

N-acetylcysteine has become the treatment of choice for paracetamol intoxication, as it can prevent hepatic failure if administered within 8 h of paracetamol ingestion (10). N-acetylcysteine has direct and indirect antioxidant properties that could be beneficial in acute ischemic renal injury. It replenishes the glutathione (GSH) stores in the body, and the thiol groups on the N-acetylcysteine molecule may afford it direct antioxidant activity. It increases cyclic guanosine monophosphate levels and thereby acts as a vasodilator and inhibitor of platelet aggregation. N-acetylcysteine stimulates endothelium-derived relaxing factor thereby improving microvascular flow (11). A protective effect of N-acetylcysteine against contrast nephropathy was demonstrated by Tepel et al. (12). However, further studies have shown conflicting results (13). The beneficial effect of N-acetylcysteine in ARD has been associated with amelioration of the effects of oxidative stress-induced tubular injury (14).

The objective of the current study was to evaluate, in a blinded, randomized, placebo-controlled fashion, whether IV N-acetylcysteine prevents renal injury in abdominal aortic surgery patients who have no documented kidney dysfunction.

	Methods

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All patients scheduled for an elective repair of the abdominal aorta between April 2002 and December 2003 were considered for inclusion in this study. Patients with renal insufficiency (plasma creatinine >130 µg/L) or severe renal artery disease or planned suprarenal or renal artery clamp during the surgery were excluded from the study. Formal sample size analysis was not performed, as the rate of renal injury in aortic surgery is not known. Our aim was to include 80 patients in this study, but it had to be terminated after recruitment of 70 patients, as funding was restricted to the years 2002 and 2003. The local ethics committee approved the study and all patients provided written informed consent.

The patients were randomly assigned to two groups to receive either IV N-acetylcysteine (Parvolex®, Celltech Pharmaceuticals Ltd, Slough, UK) or placebo. Randomization was performed in blocks of 10. The allocation into the treatment or the placebo group and the preparation of the study drug was performed by the hospital pharmacy. None of the clinical or study personnel was aware of the randomization assignment of each patient during the study. The study medication was started after the induction of anesthesia. In the treatment group, patients received 150 mg/kg of N-acetylcysteine mixed in 250 mL of 5% dextrose infused in 20 min (bolus), followed by an infusion of 150 mg/kg in 250 mL of 5% dextrose over 24 h. In the placebo group, patients received 250 mL of dextrose in 20 min, followed by an infusion of 250 mL of 5% dextrose over 24 h.

The primary outcome measure was renal injury, as measured by the increases in urinary NAG/creatinine ratio (indicator of renal tubular injury) and urinary albumin/creatinine ratio (indicator of glomerular injury) (8,15) Renal function was assessed by measuring plasma creatinine and serum cystatin C concentration (16).

Blood samples for measurement of plasma creatinine and serum cystatin C were collected preoperatively and on days 1, 3, and 5 postoperatively. Urine concentrations of NAG, albumin, and creatinine were measured preoperatively, before the aortic crossclamp, 6 and 24 h after declamping, and on the fifth postoperative day. Collection periods for urine were from induction of anesthesia to aortic clamp, from aortic clamp to 6 h, and from 6 to 24 h after declamping. Plasma and urine creatinine and urinary albumin were analyzed using routine laboratory methods.

Cystatin C concentrations were measured by particle-enhanced immunoturbidimetry using the Dako Cytomation (Denmark A/S) Cystatin C method adapted for the Hitachi 917 analyzer (Hitachi Ltd., Tokyo, Japan). Within-assay imprecision was 2.0 CV% at 0.71 mg/L and between-day imprecisions were 4.2 CV% at 1.25 mg/L, 2.9 CV% at 5.08 mg/L, and 5.7 CV% at 0.66 mg/L. The method is accredited by FINAS Accreditation (SFS-EN ISO/IEC 17025).

NAG was measured by a colorimetric assay (Roche, Cat. No. 875406) adapted for the Hitachi 917 analyzer (Hitachi Ltd.) and calibrated with the Roche NAG standard (Cat. No. 982962) from beef kidney. Within-assay imprecision was 2.1 CV% at 8.9 U/L and 3.0 CV% at 4.7 U/L and between-day imprecision was 5.2 CV% at 8.0 U/L.

Hemodynamic measurements (mean arterial blood pressure [MAP], heart rate, central venous pressure, pulmonary artery occlusion pressure [PAOP], and cardiac output) were recorded after the induction of anesthesia, before the study drug bolus, after the bolus, 5 min after aortic crossclamp, 5 min after removal of the clamp, at the end of the operation, and at 6 and 24 h postoperatively.

Patients were premedicated with oral diazepam. An epidural catheter was placed before the induction of anesthesia, but epidural analgesia was not started until the postoperative period. Anesthesia was induced using weight-related doses of thiopental, fentanyl, and rocuronium. Isoflurane was used for the maintenance of anesthesia. All patients were monitored using a five-lead electrocardiogram, an arterial catheter, and a pulmonary artery catheter (Edwards Lifesciences LLC, Irvine, CA). All patients received 500 mL of Ringer's acetate solution IV before the induction of anesthesia; thereafter Ringer's acetate solution or 6% hydroxyethyl starch was infused to keep the PAOP within 12–14 mm Hg. The maximum dose for hydroxyethyl starch was 20 mL/kg. Prophylactic IV antibiotics, cefuroxime 1.5 g every 8 h and vancomycin 1g every 12 h, were given during the first 24 h, starting after the study drug bolus infusion.

The hemodynamic management consisted of maintaining the MAP between 70 and 90 mm Hg using dopamine or norepinephrine infusion when required. The hemoglobin level was maintained intraoperatively >90 g/L and postoperatively >80 g/L. If PAOP was at the target level and cardiac index was <2.4 L/min/m², dobutamine was administered.

After surgery, patients were transferred to the intensive care unit sedated and the lungs were mechanically ventilated until a target temperature of 36°C was reached. Sedation was then discontinued and patients were tracheally extubated when they were hemodynamically stable, awake, and obeying commands. If they were normothermic and hemodynamically stable at the end of the operation, tracheal extubation occurred in the operating room. PAOP was kept within 10–14 mm Hg. Postoperative pain was treated with a continuous infusion of epidural ropivacaine and fentanyl combined with IV propacetamol if needed. Nonsteroidal antiinflammatory drugs or mannitol were not given during the investigation period.

Statistical analyses were performed using the statistical software SigmaStat for Windows version 2.03 (SPSS Inc., Chicago, IL). Comparisons were made using Student's t-test, Fisher's exact test or Pearson ² test and two-way analysis of variance followed by Fisher least significant differences multiple comparison test, as appropriate. A P value <0.05 was considered statistically significant. All analyses were by intention-to- treat.

	Results

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Baseline clinical characteristics were well matched between the two groups (Table 1). The indication for surgery was abdominal aortic aneurysm in 49 patients and aortic occlusive disease in 21 patients. One patient with aortic occlusive disease was withdrawn from the study intraoperatively, as the laparotomy revealed widespread carcinosis, and aortic reconstruction was not performed. Data from 69 patients were analyzed. There were no significant differences in hemodynamic measurements between the placebo and the treatment group (Table 2). The vasoactive drugs used in the perioperative and postoperative periods are shown in Table 3, there were no differences between the groups.

Two patients in the treatment group experienced a possible anaphylactoid reaction during the bolus infusion. The reaction consisted of flushing of the skin and a severe decrease of MAP. The airway pressures increased and there was some wheezing. The bolus infusion was discontinued and the hypotension was readily reversible with vasopressors in both cases. The study infusion was continued later without further decrease of MAP and both patients received the full bolus dose. The hypotension was treated with boluses of phenylephrine as well as dopamine and norepinephrine infusions. One of these two patients also received IV hydrocortisone and a dose of salbutamol. No other immediate adverse effects were detected.

Further perioperative and postoperative data were comparable between the groups. Aortic clamping time was similar in the two groups; two patients in the placebo group underwent suprarenal clamping (Table 4). Three patients in the treatment arm and one patient in the placebo group required reoperation as a result of bleeding. One patient in the treatment arm died of multiorgan failure in the intensive care unit.

The urinary NAG/creatinine ratio increased significantly from baseline during the study in both groups (Fig. 1). However, the change in the NAG/creatinine ratio was not significantly different between the two groups. The urinary albumin/creatinine ratio increased significantly from baseline to 6 h after declamping in the treatment group (Fig. 2). Similarly, the changes in albumin/creatinine ratio were not significantly different between the groups.

View larger version (12K): [in this window] [in a new window]   Figure 1. Urinary N-acetyl-ß-d-glucosaminidase (NAG)/creatinine ratio (mean ± sd). NAC = N-acetylcysteine. *P < 0.05 in comparison with Pre within both groups (except at 24 h in the placebo group).

View larger version (12K): [in this window] [in a new window]   Figure 2. Urinary albumin/creatinine ratio (mean ± sd). NAC = N-acetylcysteine. *P < 0.05 in comparison with Pre in the NAC group.

Plasma creatinine and serum cystatin C values did not increase during the study, and the levels remained similar in the two groups (Fig. 3). There were no significant differences in the urine output between groups (Table 5). No patient required dialysis in the postoperative period.

View larger version (10K): [in this window] [in a new window]   Figure 3. Plasma creatinine and serum cystatin C concentrations (mean ± sd). NAC = N-acetylcysteine.

	Discussion

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The principal finding in this prospective randomized, double-blind study was that infusion of N-acetylcysteine in patients undergoing abdominal aortic repair does not decrease the renal injury as measured by increases in urinary NAG/creatinine and albumin/creatinine ratios. Unexpectedly, the NAG/creatinine ratio increased before the aortic crossclamp was instituted, but the amount of increase was similar in both groups. Despite the signs of renal injury, we did not detect any change in serum markers of renal function. None of the patients required dialysis postoperatively.

Acute renal failure is a serious complication with frequent mortality and increased hospital costs (17). The mortality after surgical repair of abdominal aortic aneurysm exceeds 60% if these patients need renal replacement therapy (11). No single drug has yet been shown to be of benefit for prevention of renal insufficiency in critically ill or surgical patients (18). The optimal treatment of these patients still consists of maintaining an adequate intravascular volume and renal perfusion pressure, as well as avoiding nephrotoxic drugs. Therefore a continuing search for effective renal protective drugs is highly important.

N-acetylcysteine has been widely studied in hepatic failure and in other critically ill patient groups because of its antioxidant properties. However, these trials have been small, and the clinical outcomes have been inconsistent. N-acetylcysteine does not seem to be of benefit in patients undergoing hepatic transplantation, although N-acetylcysteine has been reported to improve renal function in hepatorenal syndrome (19,20). The role of N-acetylcysteine for prevention of contrast-induced nephropathy remains controversial. In the current study, our aim was to evaluate the protective effects of IV N-acetylcysteine in a different clinical model with an equally clearly defined time frame for the occurrence of ARD.

The diversity of pharmacological applications of N-acetylcysteine is the result of the chemical properties of the cysteinyl thiol group of the N-acetylcysteine molecule. N-acetylcysteine is an antioxidant that reacts best with hydroxyl radical and hypochlorous acid. However, this direct antioxidant effect has been demonstrated mainly in vitro. It may also exert its antioxidant effect directly by serving as a precursor of GSH biosynthesis and supplying GSH for GSH peroxidase-catalyzed reactions. In the kidney, GSH has been shown to be reduced in an experimental ischemia/reperfusion model of acute renal failure (21). In animal models administration of N-acetylcysteine increases renal GSH concentrations (22) and attenuates ischemic renal failure (23).

The etiology of ARD in infrarenal aortic surgery is probably multifactorial. Infrarenal aortic crossclamping induces a sustained decrease in renal perfusion with a redistribution of renal blood flow toward the cortical compartment (24). Increased renin activity may induce renal vasoconstriction during the surgery (25). The declamping of the aorta may also induce an ischemia-reperfusion injury in the kidneys and tissues distal to the site of the aortic clamp. This reaction has been shown to be attenuated by N-acetylcysteine (26). Hypovolemia and nephrotoxic drugs given to the patients during the operation may contribute to the development of ARD.

In this study, we searched for renal injury with sensitive markers of tubular and glomerular injury and found signs of tubular injury in abdominal aortic surgical patients. However, N-acetylcysteine had no significant effect on the degree of injury. As we did not include patients with preexisting renal disease, we cannot exclude the possibility that N-acetylcysteine could be effective in this patient group. NAG is a lysosomal enzyme found predominantly in renal proximal tubuli. It has been found to be a sensitive marker of the necrosis of the tubular cells. Among other markers, NAG permitted detection of acute renal failure 12 hours to 4 days earlier than standard variables of renal function (8). Pathological enzymuria may also be induced by reversible dysfunction of the cells. Bäcklund et al. (27) showed in their pilot study that the urinary NAG/creatinine ratio increases during aortic operations. They found that the NAG/creatinine ratio increased after the induction of anesthesia before the aortic crossclamp, as in the current trial.

Possible explanations for the early increase in NAG/creatinine ratio need to be considered. Hemodynamic instability would probably not explain tubular injury, as these patients were monitored invasively using an arterial catheter and a pulmonary artery catheter and all untoward hemodynamic deviations were treated rapidly. Also, at this stage of the operation there was usually a very limited amount of bleeding. A toxic drug effect remains one possible explanation for the injury. The potential nephrotoxicity of IV vancomycin hydrochloride is well established (28,29). The underlying mechanism is still unclear, but oxidative injury may play a role as administration of superoxide dismutase attenuates the degree of vancomycin nephrotoxicity in rats (30).

Anaphylactoid reactions to N-acetylcysteine have been reported in 3%–48% of cases (31,32). Usually these reactions are mild but a fatal case has been described (33). Reactions may include flushing, urticarial rash, bronchospasm, and hypotension. Usually, symptoms respond to stopping the infusion and treatment with antihistamines; in most cases the infusion can be restarted later without further reaction. The hypotension seen in our patients could have been accentuated by general anesthesia. These two patients were not excluded from analysis according to the intention-to-treat principle.

This study has some limitations to be considered. The use of dopamine was not controlled in this study. Small-dose dopamine has been advocated for decades for the prevention of renal insufficiency in surgical and critically ill patients. Dopamine may influence renal blood flow and increase diuresis via dopamine receptors in the kidneys, but it does not confer clinically significant protection from renal dysfunction in critically ill patients (34). As dopamine concentrations were not measured in this study, the effect of dopamine infusion remains speculative. Although vancomycin is a potentially nephrotoxic drug, it was not possible to omit it from the study protocol, as it is considered routine prophylactic treatment in operations involving placement of a vascular prosthesis at our institution. To separate the effect of vancomycin and the aortic crossclamp, one sample was taken before the aortic crossclamping. Finally, it is possible that the timing or the dose of NAC was not optimal in our study.

In conclusion, N-acetylcysteine does not decrease the amount of renal injury occurring in patients with normal preoperative renal function undergoing abdominal aortic surgery and therefore should not be used as a prophylactic measure for ARD. Further studies to test this in patients with preoperative renal dysfunction are encouraged.

We would like to thank our study nurse Anne Karhu for her valuable help with data collection.

	Footnotes

 
Supported by grants from Helsinki University Hospital, as well as the Karin and Erik Stroem's Foundation and the Instrumentarium Foundation.

Accepted for publication February 9, 2006.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Levy EM, Viscoli CM, Horwitz RI. The effect of acute renal failure on mortality: a cohort analysis. JAMA 1996;275:1489–94.[Abstract/Free Full Text]
2. Hertzer NR, Mascha EJ, Karafa MT, et al. Open infrarenal abdominal aortic repair: The Cleveland Clinic experience from 1989 to 1998. J Vasc Surg 2002;35:1145–54.[Web of Science][Medline]
3. Wahlberg E, DiMuzio PJ, Stoney RJ. Aortic clamping during elective operations for infrarenal disease: The influence of clamping time on renal function. J Vasc Surg 2002;36:13–8.[Web of Science][Medline]
4. Braams R, Vossen V, Lisman BAM, Eikelboom BC. Outcome in patients requiring renal replacement therapy after surgery for ruptured and non-ruptured aneurysm of the abdominal aorta. Eur J Vasc Endovasc Surg 1999;18:323–7.[Web of Science][Medline]
5. Barratt J, Parajasingam R, Sayers RD, Feehally J. Outcome of acute renal failure following surgical repair of ruptured abdominal aortic aneurysms. Eur J Vasc Endovasc Surg 2000;20:163–8.[Web of Science][Medline]
6. Sear JW. Kidney dysfunction in the postoperative period. Br J Anaesthesia 2005;95:20–32.[Abstract/Free Full Text]
7. Tang IY, Murray P. Prevention of perioperative acute renal failure: what works. Best Pract Res Clin Anaesthesiol 2004;18:91–111.[Medline]
8. Westhuyzen J, Zoltan HE, Reece G, et al. Measurement of tubular enzymuria facilitates early detection of acute renal impairment in the intensive care unit. Nephrol Dial Transplant 2003;18:543–51.[Abstract/Free Full Text]
9. Dhamidharka VR, Kwon C, Stevens G. Serum cystatin C is superior to serum creatinine as a marker of kidney function: a meta-analysis. Am J Kidney Dis 2002;40:221–6.[Web of Science][Medline]
10. Smilkstein MJ, Knapp GL, Kulig KW, Rumack BH. Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose: analysis of the national multicenter study (1976 to 1985). N Engl J Med 1988;319:1557–62.[Abstract]
11. Kiefer P, Vogt J, Radermacher P. From mucolytic to antioxidant and liver protection: new aspects in the intensive care unit career of N-acetylcysteine. Crit Care Med 2000;28:3935–6.[Web of Science][Medline]
12. Tepel M, Van der Giet M, Schawarzfeld C, et al. Prevention of radiographic-contrast-agent-induced reductions in renal function by acetylcysteine. N Engl J Med 2000;343:180–4.[Abstract/Free Full Text]
13. Alonso A, Lau J, Jaber BL, et al. Prevention of radiocontrast nephropathy with N-acetylcysteine in patients with chronic kidney disease: a meta-analysis of randomized, controlled trials. Am J Kidney Dis 2004;43:1–9.[Web of Science][Medline]
14. Drager LF, Andrade L, Barros de Toledo JF, et al. Renal effects of N-acetylcysteine in patients at risk for contrast nephropathy: decrease in oxidant stress-mediated renal tubular injury. Nephrol Dial Transplant 2004;19:1803–7.[Abstract/Free Full Text]
15. Verhave JC, Gansevoort RT, Hillege HL, et al. An elevated urinary albumin excretion predicts de novo development of renal function impairment in the general population. Kidney Int Suppl 2004;92:S18–21.[Medline]
16. Villa P, Jimenez M, Soriano M-C, et al. Serum cystatin C concentration as marker of acute renal function in critically ill patients. Critical Care 2005;9:R139–43.[Web of Science][Medline]
17. Pronovost P, Garrett E, Dorman T, et al. Variations in complications rates and opportunities for improvement in quality of care for patients having abdominal aortic surgery. Langenbeck's Arch Surg 2001;386:249–56.[Web of Science][Medline]
18. Lameire N, DeVriese An, Vanholder R. Prevention and nondialytic treatment of acute renal failure. Curr Opin Crit Care 2003;9:481–90.[Medline]
19. Steib A, Freys G, Collin F, et al. Does N-acetylcysteine improve hemodynamics and graft function in liver transplantation? Liver Transpl Surg 1998;4:152–7.
20. Holt S, Goodier D, Marley R, et al. Improvement in renal function in hepatorenal syndrome with N-acetylcysteine. Lancet 1999;353:294–5.[Web of Science][Medline]
21. Sehirli AO, Sener G, Satiroglu H, Ajanoglu-Dulger G. Protective effect of N-acetylcysteine on renal ischemia/reperfusion injury in the rat. J Nephrol 1993;16:75–80.[Medline]
22. Scaduto RC, Martin VH. Elevation of renal glutathione enhances ischemic injury. Renal Physiol Biochem 1991;14:259–70.[Medline]
23. DiMari J, Megyesi J, Udvarhelyl J, et al. N-acetyl cysteine ameliorates ischemic renal failure. Am J Physiol 1997;272:F292–8.[Web of Science][Medline]
24. Gamulin Z, Forster A, Morel D, et al. Effects of infrarenal aortic cross-clamping on renal hemodynamics in humans. Anesthesiology 1984;61:394–9.[Web of Science][Medline]
25. Gal TJ, Cooperman LH, Berkowitz HD. Plasma renin activity in patients undergoing surgery of the abdominal aorta. Ann Surg 1974;178:65–9.
26. Kretzschmar M, Klein U, Palutke M, Schirrmeister W. Reduction of ischemia-reperfusion syndrome after abdominal aortic aneurysmectomy by N-acetylcysteine but not mannitol. Acta Anaesthesiol Scand 1996;40:657–64.[Web of Science][Medline]
27. Bäcklund M, Pere P, Lepäntalo M, et al. Effect of intra-aortic magnesium on renal function during and after abdominal aortic surgery: a pilot study. Acta Anaesth Scand 2000;44:605–11.[Medline]
28. Gudmundsson GH, Jensen LJ Vancomycin and nephrotoxicity. Lancet 1989;I:625.
29. Rybak MJ, Albrecht LM, Boike SC, Chandrasekar PH. Nephrotoxicity of vancomycin, alone and with an aminoglycoside. J Antimicrob Chemother 1990;25:679–87.[Abstract/Free Full Text]
30. Nishino Y, Takemura S, Minamiyama Y, et al. Targeting superoxide dismutase to renal proximal tubule cells attenuates vancomycin-induced nephrotoxicity in rats. Free Radic Res 2003;37:373–9.[Medline]
31. Schmidt LE, Dalhoff K. Risk factors in the development of adverse reactions to N-acetylcysteine in patients with paracetamol poisoning. Br J Clin Pharmacol 2001;51:87–91.[Web of Science][Medline]
32. Lynch RM, Robertson R. Anaphylactoid reactions to intravenous N-acetylcysteine: a prospective case controlled study. Accid Emerg Nurs 2004;12:10–5.[Medline]
33. Appelboam AV, Dargan PI, Knighton J. Fatal anaphylactoid reaction to N-acetylcysteine: caution in patients with asthma. Emerg Med J 2002;19:594–5.[Abstract/Free Full Text]
34. Bellomo R, Chapman M, Finfer S, et al. Low-dose dopamine in patients with early renal dysfunction: a placebo-controlled randomised trial. Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group. Lancet 2000;356:2139–43.[Web of Science][Medline]

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999