Best of ATS Conferences - ATS CDs/DVDs - Click Here!
The Foundation of the American Thoracic Society
Patient Education
Presidential Drop Box
BACK TO: Home > Clinical Information > Critical Care > Evidence-based Critical Care > Literature Reviews > CCCATS Library

N-acetylcysteine and other Preventive Measures for Contrast-induced Nephropathy (CIN) in the Critically Ill

Search
PubMed search limited to: adult, humans, clinical trial, English language.
Search strategy: ("nephropathy" AND "Media, contrast[Mesh]") AND ("prevention and control"[Subheading] OR "prevention").
  
Studies on patients who are not critically ill

N-acetylcysteine
Sixteen randomized controlled trials to date have investigated the efficacy of N-acetylcysteine as a preventive measure for contrast-induced nephropathy [1-16]. Fourteen studies compared N-acetylcysteine plus hydration with hydration alone [1-12,14,15]. While 5 trials showed a significant protective effect of N-acetylcysteine compared with standard treatment [1,4,6,9,11], 8 studies did not show any beneficial effect of administration of N-acetylcysteine [2,3,5,7,8,10,12,15].

Three meta-analyses on the protective effect of N-acetylcysteine on contrast-induced nephropathy have been performed [17-19]: Birck et al [17] and Isenbarger et al [18] included 7 of the aforementioned trials in the meta-analysis, Alonso et al included 8 trials [19]. All three meta-analyses conclude that prophylactic use of N-acetylcysteine reduced the relative risk of contrast-induced nephropathy (Birck et al found a relative risk reduction of 56% (RR 0.435; 95% CI 0.215-0.879), Isenbarger et al and Alonso et al found a relative risk reduction of 63% (RR 0.37; 95% CI 0.16-0.84) and 59% (RR 0.41: 95% CI 0.22-0.79), respectively). The reliability of these results may be limited by important differences in study design, dose and timing of N-acetylcysteine administration, volumes of contrast used, and the severity of pre-existing renal impairment. Importantly, several studies have been published after these 3 meta-analyses; these latter studies were all having negative results. Overall, the results of these studies do not provide compelling evidence to support the use of N-acetylcysteine, but its excellent side effect profile and low cost contribute to its widespread use.

Theophylline and aminophylline (adenosine antagonists)

Eight randomized controlled trials and 1 non-randomized study investigated the protective effect of theophylline or aminophylline on contrast-induced nephropathy [20-28]. From 7 trials it was concluded that theophylline had a preventive effect [20-22,25-28], while 2 trials did not show any beneficial effect [23,24].

Because the studies were performed in small groups of patients, it is hard to draw firm conclusions from the available results. The adenosine inhibitors theophylline and aminophylline may offer some renoprotection against CIN, but no single study has clearly demonstrated their use results in a better outcome than saline hydration alone, especially in patients with pre-existing renal dysfunction.

Fenoldopam

Five trials have been performed evaluating fenoldopam infusion as a preventive measure for contrast-induced nephropathy [2,16,29-31]; 4 of them were randomized controlled trials. None of the randomized controlled studies showed any beneficial effect regarding prevention of contrast-induced nephropathy. One study suggested that fenoldopam is as effective as N-acetylcysteine in preventing contrast-induced nephropathy (while being vastly more expensive). Despite promising early reports, the positive findings of the initial non-randomized trials were soon brought into question by the reports of larger controlled series. Perhaps the most definitive trial to date involving fenoldopam was a multi-center, double-blind trial involving 315 patients led by Stone et al in 2003 [31], showed no difference versus placebo in the incidence of CIN, 30-day mortality, or re-hospitalization.

Sodium bicarbonate

One study evaluated the protective effect of sodium bicarbonate against CIN [32]. This study, involving 119 patients, showed a strong beneficial effect of infusion of sodium bicarbonate, reducing the incidence of CIN to 1.7% (versus 13.6% in controls hydrated with normal saline). A follow-up data registry of an additional 191 patients treated exclusively with sodium bicarbonate confirmed the incidence of CIN to be in the range of 1.5%.

While the positive results of this study have not (yet) been confirmed by other trials, this simple and inexpensive approach was touted by one of the reviewers in the accompanying JAMA editorial as the "treatment of choice for prevention of radiocontrast nephropathy" [33].

Hemodialysis/hemofiltration

Four studies evaluated the effect of hemodialysis or hemofiltration on contrast-induced nephropathy [34-37]. Three studies were randomized trials [34,35,37]. While one study did not show any effect of hemofiltration [35], another study suggested that hemofiltration was a very effective preventive measure: contrast-induced nephropathy developed in only 5% of patients treated with hemofiltration versus 50% of controls [37]. However, in this study patients were admitted to different wards (patients assigned to receive hemofiltration were admitted to an intensive care unit, while control patients were admitted to a step down facility), which may have had impact on outcome by itself. Additionally, the replacement fluids used in the hemofiltration arm contained 30 mEq/L of sodium bicarbonate and 4 mEq/L of acetate, an alkali dose similar to that of the sodium bicarbonate study above, begging the question of whether the derived benefit is due to the hemofiltration process or simply due to urinary alkalinization. It must further be realized that the lower plasma creatinine concentration found in the hemofiltration group did not imply less renal dysfunction: hemofiltration itself lowers the plasma creatinine concentration.

Studies on intensive care patients

Only one published paper on measures to prevent contrast-induced nephropathy included critically ill patients [25]. In this prospective study it was determined whether theophylline reduced the incidence of contrast-induced nephropathy. Only 2% of patients receiving theophylline developed contrast-induced nephropathy, which was significantly lower than that of 14% of patients in the retrospectively obtained control series with patients at comparable risk of contrast-induced nephropathy. Side effects like tachyarrhythmias were not described. Unfortunately there was no control group.
  
Comment

It can be argued whether contrast-induced nephropathy is an important entity in intensive care medicine. Various studies attribute longer hospital stays, longer stays in the ICU and higher in-hospital mortality to the development of acute renal failure after exposure to radiocontrast [38-40]. The critically ill conceivably form an important risk group for development of contrast-induced nephropathy. At present there are no published (randomized controlled) studies on use of N-acetylcysteine, bicarbonate hydration, and hemofiltration/hemodialysis as a preventive measure for contrast nephropathy specifically in critically ill patients.

Since N-acetylcysteine has only few side-effects, based on studies in non-critically ill patients this preventive measure may be suggested in critically ill patients. Theophylline or sodium bicarbonate hydration present viable options, either in conjunction with N-acetylcysteine or as alternatives.

Future studies are needed to determine whether the suggested preventive measures really have beneficial effects in critically ill patients.

Submitted by:

 Marcus J Schultz, internist-intensivist
Watske Smit, internist-nephrologist		 5-1-2005
Reviewed by: Gregory J Merten, internist-nephrologist

Reference:

  1. Tepel M, van der Giet M, Schwarzfeld C, Laufer U, Liermann D, Zidek W. (2000) Prevention of radiographic-contrast-agent-induced reductions in renal function by acetylcysteine. N Engl J Med 343:180-184.
  2. Allaqaband S, Tumuluri R, Malik AM, Gupta A, Volkert P, Shalev Y, Bajwa TK. (2002) Prospective randomized study of N-acetylcysteine, fenoldopam, and saline for prevention of radiocontrast-induced nephropathy. Catheter Cardiovasc Interv 57:279-283.
  3. Briguori C, Manganelli F, Scarpato P, Elia PP, Golia B, Riviezzo G, Lepore S, Librera M, Villari B, Colombo A, Ricciardelli B. (2002) Acetylcysteine and contrast agent-associated nephrotoxicity. J Am Coll Cardiol 40:298-303.
  4. Diaz-Sandoval LJ, Kosowsky BD, Losordo DW. (2002) Acetylcysteine to prevent angiography-related renal tissue injury (the APART trial). Am J Cardiol 89:356-358.
  5. Durham JD, Caputo C, Dokko J, Zaharakis T, Pahlavan M, Keltz J, Dutka P, Marzo K, Maesaka JK, Fishbane S. (2002) A randomized controlled trial of N-acetylcysteine to prevent contrast nephropathy in cardiac angiography. Kidney Int 62:2202-2207.
  6. Shyu KG, Cheng JJ, Kuan P. (2002) Acetylcysteine protects against acute renal damage in patients with abnormal renal function undergoing a coronary procedure. J Am Coll Cardiol 40:1383-1388.
  7. Baker CS, Wragg A, Kumar S, De Palma R, Baker LR, Knight CJ. (2003) A rapid protocol for the prevention of contrast-induced renal dysfunction: the RAPPID study. J Am Coll Cardiol 41:2114-2118.
  8. Boccalandro F, Amhad M, Smalling RW, Sdringola S. (2003) Oral acetylcysteine does not protect renal function from moderate to high doses of intravenous radiographic contrast. Catheter Cardiovasc Interv 58:336-341.
  9. Kay J, Chow WH, Chan TM, Lo SK, Kwok OH, Yip A, Fan K, Lee CH, Lam WF. (2003) Acetylcysteine for prevention of acute deterioration of renal function following elective coronary angiography and intervention: a randomized controlled trial. Jama 289:553-558.
  10. Kefer JM, Hanet CE, Boitte S, Wilmotte L, De Kock M. (2003) Acetylcysteine, coronary procedure and prevention of contrast-induced worsening of renal function: which benefit for which patient? Acta Cardiol 58:555-560.
  11. MacNeill BD, Harding SA, Bazari H, Patton KK, Colon-Hernadez P, DeJoseph D, Jang IK. (2003) Prophylaxis of contrast-induced nephropathy in patients undergoing coronary angiography. Catheter Cardiovasc Interv 60:458-461.
  12. Oldemeyer JB, Biddle WP, Wurdeman RL, Mooss AN, Cichowski E, Hilleman DE. (2003) Acetylcysteine in the prevention of contrast-induced nephropathy after coronary angiography. Am Heart J 146:E23.
  13. Briguori C, Colombo A, Violante A, Balestrieri P, Manganelli F, Paolo Elia P, Golia B, Lepore S, Riviezzo G, Scarpato P, Focaccio A, Librera M, Bonizzoni E, Ricciardelli B, Elia PP, Villari B. (2004) Standard vs double dose of N-acetylcysteine to prevent contrast agent associated nephrotoxicity. Acetylcysteine and contrast agent-associated nephrotoxicity. Eur Heart J 25:206-211.
  14. Fung JW, Szeto CC, Chan WW, Kum LC, Chan AK, Wong JT, Wu EB, Yip GW, Chan JY, Yu CM, Woo KS, Sanderson JE. (2004) Effect of N-acetylcysteine for prevention of contrast nephropathy in patients with moderate to severe renal insufficiency: a randomized trial. Am J Kidney Dis 43:801-808.
  15. Goldenberg I, Shechter M, Matetzky S, Jonas M, Adam M, Pres H, Elian D, Agranat O, Schwammenthal E, Guetta V. (2004) Oral acetylcysteine as an adjunct to saline hydration for the prevention of contrast-induced nephropathy following coronary angiography. A randomized controlled trial and review of the current literature. Eur Heart J 25:212-218.
  16. Briguori C, Colombo A, Airoldi F, Violante A, Castelli A, Balestrieri P, Paolo Elia P, Golia B, Lepore S, Riviezzo G, Scarpato P, Librera M, Focaccio A, Ricciardelli B. (2004) N-Acetylcysteine versus fenoldopam mesylate to prevent contrast agent-associated nephrotoxicity. J Am Coll Cardiol 44:762-765.
  17. Birck R, Krzossok S, Markowetz F, Schnulle P, van der Woude FJ, Braun C. (2003) Acetylcysteine for prevention of contrast nephropathy: meta-analysis. Lancet 362:598-603.
  18. Isenbarger DW, Kent SM, O'Malley PG. (2003) Meta-analysis of randomized clinical trials on the usefulness of acetylcysteine for prevention of contrast nephropathy. Am J Cardiol 92:1454-1458.
  19. Alonso A, Lau J, Jaber BL, Weintraub A, Sarnak MJ. (2004) Prevention of radiocontrast nephropathy with N-acetylcysteine in patients with chronic kidney disease: a meta-analysis of randomized, controlled trials. Am J Kidney Dis 43:1-9.
  20. Erley CM, Duda SH, Schlepckow S, Koehler J, Huppert PE, Strohmaier WL, Bohle A, Risler T, Osswald H. (1994) Adenosine antagonist theophylline prevents the reduction of glomerular filtration rate after contrast media application. Kidney Int 45:1425-1431.
  21. Katholi RE, Taylor GJ, McCann WP, Woods WT, Jr., Womack KA, McCoy CD, Katholi CR, Moses HW, Mishkel GJ, Lucore CL, et al. (1995) Nephrotoxicity from contrast media: attenuation with theophylline. Radiology 195:17-22.
  22. Kolonko A, Wiecek A, Kokot F. (1998) The nonselective adenosine antagonist theophylline does prevent renal dysfunction induced by radiographic contrast agents. J Nephrol 11:151-156.
  23. Abizaid AS, Clark CE, Mintz GS, Dosa S, Popma JJ, Pichard AD, Satler LF, Harvey M, Kent KM, Leon MB. (1999) Effects of dopamine and aminophylline on contrast-induced acute renal failure after coronary angioplasty in patients with preexisting renal insufficiency. Am J Cardiol 83:260-263, A265.
  24. Erley CM, Duda SH, Rehfuss D, Scholtes B, Bock J, Muller C, Osswald H, Risler T. (1999) Prevention of radiocontrast-media-induced nephropathy in patients with pre-existing renal insufficiency by hydration in combination with the adenosine antagonist theophylline. Nephrol Dial Transplant 14:1146-1149.
  25. Huber W, Jeschke B, Page M, Weiss W, Salmhofer H, Schweigart U, Ilgmann K, Reichenberger J, Neu B, Classen M. (2001) Reduced incidence of radiocontrast-induced nephropathy in ICU patients under theophylline prophylaxis: a prospective comparison to series of patients at similar risk. Intensive Care Med 27:1200-1209.
  26. Huber W, Ilgmann K, Page M, Hennig M, Schweigart U, Jeschke B, Lutilsky L, Weiss W, Salmhofer H, Classen M. (2002) Effect of theophylline on contrast material-nephropathy in patients with chronic renal insufficiency: controlled, randomized, double-blinded study. Radiology 223:772-779.
  27. Kapoor A, Kumar S, Gulati S, Gambhir S, Sethi RS, Sinha N. (2002) The role of theophylline in contrast-induced nephropathy: a case-control study. Nephrol Dial Transplant 17:1936-1941.
  28. Huber W, Schipek C, Ilgmann K, Page M, Hennig M, Wacker A, Schweigart U, Lutilsky L, Valina C, Seyfarth M, Schomig A, Classen M. (2003) Effectiveness of theophylline prophylaxis of renal impairment after coronary angiography in patients with chronic renal insufficiency. Am J Cardiol 91:1157-1162.
  29. Kini AA, Sharma SK. (2001) Managing the high-risk patient: experience with fenoldopam, a selective dopamine receptor agonist, in prevention of radiocontrast nephropathy during percutaneous coronary intervention. Rev Cardiovasc Med 2:S19-25.
  30. Tumlin JA, Wang A, Murray PT, Mathur VS. (2002) Fenoldopam mesylate blocks reductions in renal plasma flow after radiocontrast dye infusion: a pilot trial in the prevention of contrast nephropathy. Am Heart J 143:894-903.
  31. Stone GW, McCullough PA, Tumlin JA, Lepor NE, Madyoon H, Murray P, Wang A, Chu AA, Schaer GL, Stevens M, Wilensky RL, O'Neill WW. (2003) Fenoldopam mesylate for the prevention of contrast-induced nephropathy: a randomized controlled trial. Jama 290:2284-2291.
  32. Merten GJ, Burgess WP, Gray LV, Holleman JH, Roush TS, Kowalchuk GJ, Bersin RM, Van Moore A, Simonton CA, 3rd, Rittase RA, Norton HJ, Kennedy TP. (2004) Prevention of contrast-induced nephropathy with sodium bicarbonate: a randomized controlled trial. Jama 291:2328-2334.
  33. Chertow GM. (2004) Prevention of radiocontrast nephropathy: back to basics. Jama 291:2376-2377.
  34. Vogt B, Ferrari P, Schonholzer C, Marti HP, Mohaupt M, Wiederkehr M, Cereghetti C, Serra A, Huynh-Do U, Uehlinger D, Frey FJ. (2001) Prophylactic hemodialysis after radiocontrast media in patients with renal insufficiency is potentially harmful. Am J Med 111:692-698.
  35. Frank H, Werner D, Lorusso V, Klinghammer L, Daniel WG, Kunzendorf U, Ludwig J. (2003) Simultaneous hemodialysis during coronary angiography fails to prevent radiocontrast-induced nephropathy in chronic renal failure. Clin Nephrol 60:176-182.
  36. Marenzi G, Bartorelli AL, Lauri G, Assanelli E, Grazi M, Campodonico J, Marana I. (2003) Continuous veno-venous hemofiltration for the treatment of contrast-induced acute renal failure after percutaneous coronary interventions. Catheter Cardiovasc Interv 58:59-64.
  37. Marenzi G, Marana I, Lauri G, Assanelli E, Grazi M, Campodonico J, Trabattoni D, Fabbiocchi F, Montorsi P, Bartorelli AL. (2003) The prevention of radiocontrast-agent-induced nephropathy by hemofiltration. N Engl J Med 349:1333-1340.
  38. Chertow GM, Lazarus JM, Christiansen CL, Cook EF, Hammermeister KE, Grover F, Daley J. (1997) Preoperative renal risk stratification. Circulation 95:878-884.
  39. Levy EM, Viscoli CM, Horwitz RI. (1996) The effect of acute renal failure on mortality. A cohort analysis. Jama 275:1489-1494.
  40. Rihal CS, Textor SC, Grill DE, Berger PB, Ting HH, Best PJ, Singh M, Bell MR, Barsness GW, Mathew V, Garratt KN, Holmes DR, Jr. (2002) Incidence and prognostic importance of acute renal failure after percutaneous coronary intervention. Circulation 105:2259-2264.

61 Broadway · New York, NY 10006-2755 · Voice: 212-315-8600 · Fax: 212-315-6498
Questions or comments? Contact Us.
Copyright © 2008 American Thoracic Society · Web Site Requirements