Intensive Care Medicine

, Volume 31, Issue 3, pp 327–337 | Cite as

Antioxidant nutrients: a systematic review of trace elements and vitamins in the critically ill patient

  • Daren K. HeylandEmail author
  • Rupinder Dhaliwal
  • Ulrich Suchner
  • Mette M. Berger
Systematic Review



Critical illness is associated with the generation of oxygen free radicals and low endogenous antioxidant capacity leading to a condition of oxidative stress. We investigated whether supplementing critically ill patients with antioxidants, trace elements, and vitamins improves their survival.


We searched four bibliographic databases from 1980 to 2003 and included studies that were randomized, reported clinically important endpoints in critically ill patients, and compared various trace elements and vitamins to placebo.


Eleven articles met the inclusion criteria. When the results of all the trials were aggregated, overall antioxidants were associated with a significant reduction in mortality [Risk Ratio (RR) 0.65, 95% confidence intervals (CI) 0.44–0.97, p=0.03] but had no effect on infectious complications. Studies that utilized a single trace element were associated with a significant reduction in mortality [RR 0.52, 95% CI 0.27–0.98, p=0.04] whereas combined antioxidants had no effect. Studies using parenteral antioxidants were associated with a significant reduction in mortality [RR 0.56, 95% CI 0.34–0,92, p=0.02] whereas studies of enteral antioxidants were not. Selenium supplementation (alone and in combination with other antioxidants) may be associated with a reduction in mortality [RR 0.59, 95% CI 0.32–1.08, p=0.09] while nonselenium antioxidants had no effect on mortality.


Trace elements and vitamins that support antioxidant function, particularly high-dose parenteral selenium either alone or in combination with other antioxidants, are safe and may be associated with a reduction in mortality in critically ill patients.


Enteral nutrition Parenteral nutrition Antioxidants Oxidative stress Trace elements Meta-analyses 


  1. 1.
    Lovat R, Preiser JC (2003) Antioxidant therapy in intensive care. Curr Opin Crit Care 9:266–270CrossRefPubMedGoogle Scholar
  2. 2.
    Brealey D, Brand M, Hargreaves I, Heales S, Land J, Smolenski R, Davies NA, Cooper CE, Singer M (2002) Association between mitochondrial dysfunction and severity and outcome of septic shock. Lancet 360:219–223CrossRefPubMedGoogle Scholar
  3. 3.
    Grimble RF (1994) Nutritional antioxidants and the modulation of inflammation: theory and practice. New Horiz 2:175–185PubMedGoogle Scholar
  4. 4.
    Hammerman C, Kaplan M (2000) Ischemia and reperfusion injury. Clin Perinatol 25:757–777Google Scholar
  5. 5.
    Therond P, Bonnefont-Rousselot D, Davit-Spraul A, Conti M, Legrand A (2000) Biomarkers of oxidative stress: an analytical approach. Curr Opin Clin Nutr Metab Care 3:373–384CrossRefPubMedGoogle Scholar
  6. 6.
    Metnitz PGH, Bartens C, Fischer M, Fridrich P, Steltzer H, Druml W (1999) Antioxidant status in patients with acute respiratory distress syndrome. Intensive Care Med 25:180–185CrossRefPubMedGoogle Scholar
  7. 7.
    Alonso de Vega JM, Diaz J, Serrano E, Carbonell LF (2002) Oxidative stress in critically ill patients with systemic inflammatory response syndrome. Crit Care Med 30:1782–1786CrossRefPubMedGoogle Scholar
  8. 8.
    Motoyama T, Okamoto K, Kukita I, Hamaguchi M, Kinoshita Y, Ogawa H (2003) Possible role of increased oxidant stress in multiple organ failure after systemic inflammatory response syndrome. Crit Care Med 31:1048–1052CrossRefPubMedGoogle Scholar
  9. 9.
    Goode HF, Cowley HC, Walker BE Howdle PD, Webster NR (1995) Decreased antioxidant status and increased lipid peroxidation in patients with septic shock and secondary organ dysfunction. Crit Care Med 23:646–651CrossRefPubMedGoogle Scholar
  10. 10.
    Heyland DK, Dhaliwal R, Berger M, Suchner U (2003) Antioxidant nutrients: a systematic review of vitamins and trace elements in the critically ill patient. Crit Care Med 31:A83Google Scholar
  11. 11.
    Heyland DK, MacDonald S, Keefe L Drover JW (1998) Total parenteral nutrition in the critically ill patient: a meta-analysis. JAMA 280:2013–2019CrossRefPubMedGoogle Scholar
  12. 12.
    Berger MM, Recmond MJ, Shenkin A, Rey F, Wardle C, Cayeux C, Schindler C, Chiolero (2001) Influence of selenium supplements on the post-traumatic alterations of the thyroid axis: a placebo-controlled trial. Intensive Care Med 27:91–100CrossRefPubMedGoogle Scholar
  13. 13.
    Berger MM, Baines M, Chiolero R, Wardle C, Cayeux MC, Shenkin A (2001) Influence of early trace element and vitamin E supplements on antioxidant status after major trauma: a controlled trial. N Res 21:41–54CrossRefGoogle Scholar
  14. 14.
    Porter JM, Ivatury RR, Azimuddin K, Swami R (1999) Antioxidant therapy in the prevention of organ dysfunction syndrome and infectious complications after trauma: early results of a prospective randomized study. Am Surg 65:478–483PubMedGoogle Scholar
  15. 15.
    Nathens AB, Neff MJ, Jurkovich GJ, Klotz P, Farver K, Ruzinski JT, Radella F, Garcia I, Maier RV (2002) Randomized, prospective trial of antioxidant supplementation in critically ill surgical patients. Ann Surg 236:814–822CrossRefPubMedGoogle Scholar
  16. 16.
    DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7:177–188CrossRefPubMedGoogle Scholar
  17. 17.
    Anonymous (2000). RevMan 4.2.7 user’s guide. Cochrane CollaborationGoogle Scholar
  18. 18.
    Kuklinski B, Buchner M, Schweder R, Nagel R (1991) Akute Pancreatitis—eine “free radical disease. Letalitatssenkung durch Natriumselenit (Na2SeO3)-Therapie. Z Gesamte Inn Med 46:S145–S149Google Scholar
  19. 19.
    Berger MM, Spertini F, Shenkin A, Wardle C, Wiesner L, Schindler C, Chioléro RL (1998) Trace element supplementation modulates pulmonary infection rates after major burns: a double-blind, placebo-controlled trial. Am J Clin Nutr 68:365–371PubMedGoogle Scholar
  20. 20.
    Zimmermann T, Albrecht S, Kühne H, Vogelsang U, Grützmann R, Kopprasch S (1997) Selensubstitution bei Sepsispatienten. Med Klin 92 [Suppl III]:3–4Google Scholar
  21. 21.
    Angstwurm MW, Schottdorf J, Schopohl J, Gaertner R (1999) Selenium replacement in patients with severe systemic inflammatory response syndrome improves clinical outcome. Crit Care Med 27:1807–1813CrossRefPubMedGoogle Scholar
  22. 22.
    Preiser JC, Van Gossum A, Berré J, Vincent JL, Carpentier Y (2000) Enteral feeding with a solution enriched with antioxidant vitamins A, C, E enhances the resistance to oxidative stress. Crit Care Med 28:3828–3832CrossRefPubMedGoogle Scholar
  23. 23.
    Young B, Ott L, Kasarskis E, Rapp R, Moles K, Dempsey RJ, Tibbs PA, Kryscio R, McClain C (1996) Zinc supplementation is associated with improved neurologic recovery rate and visceral protein levels of patients with severe closed head injury. J Neurotrauma 13:25–34PubMedGoogle Scholar
  24. 24.
    Maderazo EG, Woronick CL, Hickingbotham N, Jacobs L, Bhagavan HN (1991) A randomized trial of replacement antioxidant vitamin therapy for neutrophil locomotory dysfunction in blunt trauma. J Trauma 31:1142–1150PubMedGoogle Scholar
  25. 25.
    Berger MM, Baines M, Wardle CA, Cayeux MC, Chiolero R, Shenkin A (2002) Trace element supplements modulate tissue levels, antioxidant status and clinical course after major burns—preliminary results. Clin Nutr 21 [Suppl 1]:66Google Scholar
  26. 26.
    Berger MM, Cavadini C, Chioléro R, Dirren H (1996) Copper, selenium, and zinc status and balances after major trauma. J Trauma 40:103–109PubMedGoogle Scholar
  27. 27.
    Kuklinski B, Buchner M, Muller T, Schweder R (1992) [Anti-oxidative therapy of pancreatitis-an 18-month interim evaluation]. Z Gesamte Inn Med 47:239–245PubMedGoogle Scholar
  28. 28.
    Kuklinski B, Zimmermann T, Schweder R (1995) Letalitätssenkung der akuten Pankreatitis mit Natriumselenit [Decreasing mortality in acute pancreatitis with sodium selenite. Clinical results of 4 years antioxidant therapy]. Med Klin 90 [Suppl I]:36–41Google Scholar
  29. 29.
    Barquist E, Kirton O, Windsor J, Hudson-Civetta J, Lynn M, Herman M, Civetta J (1998) The impact of antioxidant and splanchnic-directed therapy on persistent uncorrected gastric mucosal pH in the critically injured trauma patient. J Trauma 44:355–360PubMedGoogle Scholar
  30. 30.
    Mingjian Z, Qifang W, Lanxing G, Hong J, Zongyin W (1992) Comparative observation of the changes in serum lipid peroxides influenced by the supplementation of vitamin E in burn patients and healthy controls. Burns 18:19–21PubMedGoogle Scholar
  31. 31.
    Gärtner R, Angstwurm M (1999) Die Bedeutung von Selen in der Intensivmedizin. Med Klin 94 [Suppl III]:54–57Google Scholar
  32. 32.
    Lehmann C, Weber M, Krausch D, Wauer H, Newie T, Rohr U, Hensel M, Glatzel E, Priem F, Grune T, Kox WJ (1998) Parenteral selenium supplementation in critically ill patients-effects on antioxidant metabolism. Z Ernahrungswiss 37 [Suppl 1]:106–109Google Scholar
  33. 33.
    Tanaka H, Matsuda T, Miyagantani Y, Yukioka T, Matsuda H, Shimazaki S (2000) Reduction of resuscitation fluid volumes in severely burned patients using ascorbic acid administration. Arch Surg 135:326–331CrossRefPubMedGoogle Scholar
  34. 34.
    Börner J, Zimmermann T, Albrecht S, Roesner D (1999) Selensubstitution bei Kindern mit SIRS. Med Klin 94 [Suppl III]:93–96Google Scholar
  35. 35.
    Cerwenka H, Bacher H, Werkgartner G, El-Shabrawi A, Quehenberger F, Hauser H, Mischinger HJ (1998) Antioxidant treatment during liver resection for alleviation of ischemia-reperfusion injury. Hepatogastroenterology 45:777–782PubMedGoogle Scholar
  36. 36.
    Cerwenka H, Khoschsorur G, Bacher H, Werkgartner G, El-Shabrawi A, Quehenberger F, Rabl H, Mischinger HJ (1999) Normothermic liver ischemia and antioxidant treatment during hepatic resections. Free Radic Res 30:463–469PubMedGoogle Scholar
  37. 37.
    Heaney AP, Sharer N, Rameh B, Braganza JM, Durrington PN (1999) Prevention of recurrent pancreatitis in familial lipoprotein lipase deficiency with high-dose antioxidant therapy. J Clin Endocrinol Metab 84:1203–1205CrossRefPubMedGoogle Scholar
  38. 38.
    Keith ME, Jeejeebhoy KN, Langer A, Kurian R, Barr A, O’Kelly B, Sole MJ (2001) A controlled clinical trial of vitamin E supplementation in patients with congestive heart failure. Am J Clin Nutr 73:219–224PubMedGoogle Scholar
  39. 39.
    Sisto T, Paajanen H, Metsä-Ketelä T, Harmoinen A, Nordback I, Tarkka M (1995) Pretreatment with antioxidants and allopurinol diminishes cardiac onset events in coronary artery bypass grafting. Ann Thorac Surg 59:1519–1523CrossRefPubMedGoogle Scholar
  40. 40.
    Uden S, Bilton D, Nathan L, Hunt LP, Mains C, Braganza JM (1990) Antioxidant therapy for recurrent pancreatitis: placebo-controlled trial. Aliment Pharmacol Ther 4:357–371PubMedGoogle Scholar
  41. 41.
    Uden S, Schofield D, Miller PF, Day JP, Bottiglier T, Braganza JM (1992) Antioxidant therapy for recurrent pancreatitis: biochemical profiles in a placebo-controlled trial. Aliment Pharmacol Ther 6:229–240PubMedGoogle Scholar
  42. 42.
    Yamaguchi T, Sano K, Takakura K, Saito I, Shinohara Y, Asano T, Yasuhara H (1998) Ebselen in acute ischemic stroke: a placebo-controlled, double-blind clinical trial. Ebselen Study Group. Stroke 29:12–17PubMedGoogle Scholar
  43. 43.
    Saito I, Asano T, Sano K, Takakura K, Abe H, Yoshimoto T, Kikuchi H, Ohta T, Ishibashi S (1998) Neuroprotective effect of an antioxidant, ebselen, in patients with delayed neurological deficits after aneurysmal subarachnoid hemorrhage. Neurosurgery 42:269–277CrossRefPubMedGoogle Scholar
  44. 44.
    Watters JM, Vallerand A, Kirkpatrick SM, Abbott HE, Norris S, Wells G, Barber GG (2002) Limited effects of micronutrient supplementation on strength and physical function after abdominal aortic aneurysmectomy. Clin Nutr 21:321–327CrossRefPubMedGoogle Scholar
  45. 45.
    Berger MM, Cavadini C, Chioléro R, Guinchard S, Krupp S, Dirren H (1994) Influence of large intakes of trace elements on recovery after major burns. Nutrition 10:327–334PubMedGoogle Scholar
  46. 46.
    Faure H, Peyrin JC, Richard MJ, Favier A (1991) Parenteral supplementation with zinc in surgical patients corrects postoperative serum-zinc drop. Biol Trace Elem Res 30:37–45PubMedGoogle Scholar
  47. 47.
    Lehmann C, Egerer K, Weber M, Krausch D, Wauer H, Newie T, Kox WJ (1997) Effect of selenium administration on various laboratory parameters of patients at risk for sepsis syndrome. Med Klin 15 [Suppl 3]:14–16Google Scholar
  48. 48.
    Rock CL, Dechert RE, Khilnani R, Parker RS, Rodriguez JL (1997) Carotenoids and antioxidant vitamins in patients after burn injury, J Burn Care Rehabil 18:269–278Google Scholar
  49. 49.
    Rümelin A, Dörr, S, Depta A, Fauth U (2001) Preoperative oral ascorbic acid (AA) and postoperative plasma levels of AA. Clin Nutr 20 [Suppl 3]:47Google Scholar
  50. 50.
    Sawyer MA, Mike JJ, Chavin K, Marino PL (1989) Antioxidant therapy and survival in ARDS (abstract). Crit Care Med 17:S153Google Scholar
  51. 51.
    Galley HF, Howdle PD, Walker BE, Webster NR (1997) The effects of intravenous antioxidants in patients with septic shock. Free Radic Biol Med 23:768–774CrossRefPubMedGoogle Scholar
  52. 52.
    Ortolani O, Conti A, Raffaele De Gaudio A, Moraldi E, Cantini Q, Novelli G (2000) The effect of glutathione and N-acetylcysteine on lipoperoxidative damage in patients with early septic shock. Am J Respir Crit Care Med 161:1907–1911PubMedGoogle Scholar
  53. 53.
    Molnar Z, MacKinnon KL, Shearer E, Lowe D, Watson ID (1998) The effect of N-acetylcysteine on total serum anti-oxidant potential and urinary albumin excretion in critically ill patients. Intensive Care Med 24:230–235CrossRefPubMedGoogle Scholar
  54. 54.
    Domenighetti G, Suter PM, Schaller MD, Ritz R, Perret C (1997) Treatment with N-acetylcysteine during acute respiratory distress syndrome: a randomized, double-blind, placebo-controlled clinical study. J Crit Care 12:177–182CrossRefPubMedGoogle Scholar
  55. 55.
    Spapen H, Zhang H, Demanet C, Vleminckx W, Vincent JL, Huyghens L (1998) Does N-acetyl-L-cysteine influence cytokine response during early human septic shock? Chest 113:1616–1624PubMedGoogle Scholar
  56. 56.
    Bernard GR, Wheeler AP, Arons MM, Morris PE, Paz HL, Russell JA, Wright PE (1997) A trial of antioxidants N-acetylcysteine and procysteine in ARDS. The Antioxidant in ARDS Study Group. Chest 112:164–172PubMedGoogle Scholar
  57. 57.
    Gadek JE, DeMichele SJ, Karlstad MD, Pacht ER, Donahoe M, Albertson TE, Van Hoozen C, Wennberg AK, Nelson JL, Noursalehi M (1999) Effect of enteral feeding with eicosapentaenoic acid, gamma-linolenic acid, and antioxidants in patients with acute respiratory distress syndrome. Crit Care Med 27:1409–1420CrossRefPubMedGoogle Scholar
  58. 58.
    Caparros T, Lopez J, Grau T (2001) Early enteral nutrition in critically ill patients with a high-protein diet enriched with arginine, fiber, and antioxidants compared with a standard high-protein diet. The effect on nosocomial infections and outcome. JPEN J Parenter Enteral Nutr 25:299–308PubMedGoogle Scholar
  59. 59.
    Wernerman J, Hammarqvist F (1999) Modulation of endogenous glutathione availability. Curr Opin Clin Nutr Metab Care 2:487–492CrossRefPubMedGoogle Scholar
  60. 60.
    Rayman MP (2000) The importance of selenium to human health. Lancet 356:233–241CrossRefGoogle Scholar
  61. 61.
    Neve J (2002) Selenium as a ‘nutraceutical’: how to conciliate physilogocial and supra-nutritional effects for an essential trace element. Curr Opin Clin Nutr Metab Care 5:659–663CrossRefPubMedGoogle Scholar
  62. 62.
    Paterson, RL, Galley HF, Webster NR (2003) The effect of N-acetylcysteine on nuclear factor-kB activation, interleukin-6, interluekin-8, and intercellular adhesion molecule-1 expression in patients with sepsis. Crit Care Med 31:2574–2578CrossRefPubMedGoogle Scholar
  63. 63.
    Sacks HS, Chalmers TC, Smith H Jr (1983) Randomized versus historical assignment in controlled trials. N Engl J Med 309:1353–1361PubMedGoogle Scholar
  64. 64.
    Kelly F (1994) Vitamin E supplementation in the critically ill patient: too narrow of view? Nutr Clin Pract 9:19–25Google Scholar
  65. 65.
    Burk RE, Hill KE (1999) Orphan selenoproteins. Bioessays 21:231–237PubMedGoogle Scholar
  66. 66.
    Flaring UB, Rooyackers OE, Wernerman J, Hammarqvist F (2003) Glutamine attenuates post-traumatic glutathione depletion in human muscle. Clin Sci (Lond) 104:275–282Google Scholar
  67. 67.
    Manhart N, Vierlinger K, Spittler A, Bergmeister H, Sautner T, Roth E (2001) Oral feeding with glutamine prevents lymphocyte and glutathione depletion of Peyer’s patches in endotoxemic mice. Ann Surg 234:92–97CrossRefPubMedGoogle Scholar
  68. 68.
    Forceville X, Vitoux D, Gauzit R, Combes A, Lahilaire P, Chappuis P (1998) Selenium, systemic immune response syndrome, sepsis and outcome in critically ill patients. Crit Care Med 26:1536–1544CrossRefPubMedGoogle Scholar
  69. 69.
    Abuja PM (1998) When might an antioxidant become a prooxidant? Acta Anaesthesiol Scand 42 [Suppl 112]:229–230Google Scholar
  70. 70.
    Spallholz JE (1998) The negative effects of excessive amounts of naturally occurring selenium. Selenium-Tellurium Development AssociationGoogle Scholar
  71. 71.
    Deitch EA, Adams C, Lu Q, Xu DZ (2001) A time course study of the protective effect of mesenteric lymph duct ligation on hemorrhagic shock-induced pulmonary injury and the toxic effects of lymph from shocked rats on endothelial cell monolayer permeability. Surgery 129:39–47CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Daren K. Heyland
    • 1
    • 2
    Email author
  • Rupinder Dhaliwal
    • 1
  • Ulrich Suchner
    • 3
  • Mette M. Berger
    • 4
  1. 1.Department of MedicineQueen’s UniversityKingstonCanada
  2. 2.Kingston General Hospital76 Stuart StreetKingstonCanada
  3. 3.Ludwig Maximilian UniversityMunichGermany
  4. 4.Soins Intensifs de ChirurgieCHUVLausanneSwitzerland

Personalised recommendations