Early enteral nutrition, provided within 24 h of injury or intensive care unit admission, significantly reduces mortality in critically ill patients: a meta-analysis of randomised controlled trials



To determine whether the provision of early standard enteral nutrition (EN) confers treatment benefits to critically ill patients.


Medline and EMBASE were searched. Hand citation review of retrieved guidelines and systematic reviews were undertaken, and academic and industry experts were contacted.

Methodologically sound randomised controlled trials (RCTs) conducted in critically ill patient populations that compared the delivery of standard EN, provided within 24 h of intensive care unit (ICU) admission or injury, to standard care were included.

The primary analysis was conducted on clinically meaningful patient-oriented outcomes. Secondary analyses considered vomiting/regurgitation, pneumonia, bacteraemia, sepsis and multiple organ dysfunction syndrome. Meta-analyses were conducted using the odds ratio (OR) metric and a fixed effects model. The impact of heterogeneity was assessed using the I 2 metric.


Six RCTs with 234 participants were analysed. The provision of early EN was associated with a significant reduction in mortality [OR = 0.34, 95% confidence interval (CI) 0.14–0.85] and pneumonia (OR = 0.31, 95% CI 0.12–0.78). There were no other significant differences in outcomes. A sensitivity analysis and a simulation exercise confirmed the presence of a mortality reduction.


Although the detection of a statistically significant reduction in mortality is promising, overall trial quality was low, trial size was small, and the findings may be restricted to the patient groups enrolled into included trials. The results of this meta-analysis should be confirmed by the conduct of a large multi-centre trial enrolling diverse critically ill patient groups.

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  1. 1.

    Kreymann KG, Berger MM, Deutz NE, Hiesmayr M, Jolliet P, Kazandjiev G, Nitenberg G, van den Berghe G, Wernerman J, DGEM (German Society for Nutritional Medicine), Ebner C, Hartl W, Heymann C, Spies C, ESPEN (European Society for Parenteral, Enteral Nutrition) (2006) ESPEN guidelines on enteral nutrition: intensive care. Clin Nutr 25:210–223

    Article  PubMed  CAS  Google Scholar 

  2. 2.

    Martin CM, Doig GS, Heyland DK, Morrison T, Sibbald WJ (2004) Cluster randomized clinical trial of algorithms for critical care enteral and parenteral therapy (ACCEPT). CMAJ 170:197–204

    PubMed  Google Scholar 

  3. 3.

    Heyland DK, Dhaliwal R, Drover JW, Gramlich L, Dodek P (2003) Canadian clinical practice guidelines for nutrition support in mechanically ventilated, critically ill adult patients. J Parenter Enteral Nutr 27:355–373

    Article  Google Scholar 

  4. 4.

    Doig GS, Simpson F, Finfer S, Delaney A, Davies AR, Mitchell I, Dobb G, Nutrition Guidelines Investigators of the ANZICS Clinical Trials Group (2008) Effect of evidence-based feeding guidelines on mortality of critically ill adults: a cluster randomized controlled trial. JAMA 300:2731–2741

    Article  PubMed  CAS  Google Scholar 

  5. 5.

    Heyland DK, Schroter-Noppe D, Drover JW, Jain M, Keefe L, Dhaliwal R, Day A (2003) Nutrition support in the critical care setting: current practice in Canadian ICUs–opportunities for improvement? J Parenter Enteral Nutr 27:74–83

    Article  Google Scholar 

  6. 6.

    Lewis SJ, Andersen HK, Thomas S (2009) Early enteral nutrition within 24 h of intestinal surgery versus later commencement of feeding: a systematic review and meta-analysis. J Gastrointest Surg 13:569–575

    Article  PubMed  Google Scholar 

  7. 7.

    Marik PE, Zaloga GP (2001) Early enteral nutrition in acutely ill patients: a systematic review. Crit Care Med 29:2264–2270

    Article  PubMed  CAS  Google Scholar 

  8. 8.

    Haynes RB, McKibbon KA, Wilczynski NL, Walter SD, Werre SR (2005) Optimal search strategies for retrieving scientifically strong studies of treatment from Medline: analytical survey. BMJ 330:1179

    Article  PubMed  Google Scholar 

  9. 9.

    Wong SS, Wilczynski NL, Haynes RB (2006) Developing optimal search strategies for detecting clinically sound treatment studies in EMBASE. J Med Libr Assoc 94:41–47

    PubMed  Google Scholar 

  10. 10.

    Egger M, Juni P, Bartlett C, Holenstein F, Sterne J (2003) How important are comprehensive literature searches and the assessment of trial quality in systematic reviews? Empirical study. Health Technol Assess 7:1–76

    PubMed  CAS  Google Scholar 

  11. 11.

    Juni P, Holenstein F, Sterne J, Bartlett C, Egger M (2002) Direction and impact of language bias in meta-analyses of controlled trials: empirical study. Int J Epidemiol 31:115–123

    Article  PubMed  Google Scholar 

  12. 12.

    Prentice RL (1989) Surrogate endpoints in clinical trials: definition and operational criteria. Stat Med 8:431–440

    Article  PubMed  CAS  Google Scholar 

  13. 13.

    Doig GS, Simpson F, Delaney A (2005) A review of the true methodological quality of nutritional support trials conducted in the critically ill: time for improvement. Anesth Analg 100:527–533

    Article  PubMed  Google Scholar 

  14. 14.

    Graf J, Doig GS, Cook DJ, Vincent JL, Sibbald WJ (2002) Randomized, controlled clinical trials in sepsis: has methodological quality improved over time? Crit Care Med 30:461–472

    Article  PubMed  Google Scholar 

  15. 15.

    Juni P, Altman DG, Egger M (2001) Systematic reviews in health care: assessing the quality of controlled clinical trials. BMJ 323:42–46

    Article  PubMed  CAS  Google Scholar 

  16. 16.

    Villar J, Mackey ME, Carroli G, Donner A (2001) Meta-analyses in systematic reviews of randomized controlled trials in perinatal medicine: comparison of fixed and random effects models. Stat Med 20:3635–3647

    Article  PubMed  CAS  Google Scholar 

  17. 17.

    Deeks JJ (2002) Issues in the selection of a summary statistic for meta-analysis of clinical trials with binary outcomes. Stat Med 21:1575–1600

    Article  PubMed  Google Scholar 

  18. 18.

    Higgins JP, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21:1539–1558

    Article  PubMed  Google Scholar 

  19. 19.

    Hatala R, Keitz S, Wyer P, Guyatt G (2005) Tips for learners of evidence-based medicine: 4 assessing heterogeneity of primary studies in systematic reviews and whether to combine their results. CMAJ 172:661–665

    PubMed  Google Scholar 

  20. 20.

    Glasziou PP, Sanders SL (2002) Investigating causes of heterogeneity in systematic reviews. Stat Med 21:1503–1511

    Article  PubMed  CAS  Google Scholar 

  21. 21.

    Minard G, Kudsk KA, Melton S, Patton JH, Tolley EA (2000) Early versus delayed feeding with an immune-enhancing diet in patients with severe head injuries. J Parenter Enteral Nutr 24:145–149

    Article  CAS  Google Scholar 

  22. 22.

    Eyer SD, Micon LT, Konstantinides FN, Edlund DA, Rooney KA, Luxenberg MG, Cerra FB (1993) Early enteral feeding does not attenuate metabolic response after blunt trauma. J Trauma 34:639–643

    Article  PubMed  CAS  Google Scholar 

  23. 23.

    Singh G, Ram RP, Khanna SK (1998) Early postoperative enteral feeding in patients with nontraumatic intestinal perforation and peritonitis. J Am Coll Surg 187:142–146

    Article  PubMed  CAS  Google Scholar 

  24. 24.

    Grahm TW, Zadrozny DB, Harrington T (1989) The benefits of early jejunal hyperalimentation in the head-injured patient. Neurosurgery 25:729–735

    Article  PubMed  CAS  Google Scholar 

  25. 25.

    Cabre E, Rodriguez-Iglesias P, Caballeria J, Quer JC, Sanchez-Lombrana JL, Pares A, Papo M, Planas R, Gassull MA (2000) Short- and long-term outcome of severe alcohol-induced hepatitis treated with steroids or enteral nutrition: a multicenter randomized trial. Hepatology 32:36–42

    Article  PubMed  CAS  Google Scholar 

  26. 26.

    Dvorak MF, Noonan VK, Belanger L, Bruun B, Wing PC, Boyd MC, Fisher C (2004) Early versus late enteral feeding in patients with acute cervical spinal cord injury: a pilot study. Spine 29:E175–E180

    Article  PubMed  Google Scholar 

  27. 27.

    Malhotra A, Mathur AK, Gupta S (2004) Early enteral nutrition after surgical treatment of gut perforations: a prospective randomised study. J Postgrad Med 50:102–106

    PubMed  Google Scholar 

  28. 28.

    Page RD, Oo AY, Russell GN, Pennefather SH (2002) Intravenous hydration versus naso-jejunal enteral feeding after esophagectomy: a randomised study. Eur J Cardiothorac Surg 22:666–672

    Article  PubMed  Google Scholar 

  29. 29.

    De Ledinghen V, Beau P, Mannant P-R, Borderie C, Ripault M-P, Silvain C, Beauchant M (1997) Early feeding or enteral nutrition in patients with cirrhosis after bleeding from esophageal varices? A randomized controlled study. Dig Dis Sci 42:536–541

    Article  PubMed  Google Scholar 

  30. 30.

    Seri S, Aquilio E (1984) Effects of early nutritional support in patients with abdominal trauma. Ital J Surg Sci 14:223–227

    PubMed  CAS  Google Scholar 

  31. 31.

    Carr CS, Ling KDE, Boulos P, Singer M (1996) Randomised trial of safety and efficacy of immediate postoperative enteral feeding in patients undergoing gastrointestinal resection. BMJ 312:869–871

    PubMed  CAS  Google Scholar 

  32. 32.

    Kaur N, Gupta MK, Minocha VR (2005) Early enteral feeding by nasoenteric tubes in patients with perforation peritonitis. World J Surg 29:1023–1027

    Article  PubMed  Google Scholar 

  33. 33.

    Schroeder D, Gillanders L, Mahr K, Hill GL (1991) Effects of immediate postoperative enteral nutrition on body composition, muscle function, and wound healing. J Parenter Enteral Nutr 15:376–383

    Article  CAS  Google Scholar 

  34. 34.

    Hasse JM, Blue LS, Liepa GU, Goldstein RM, Jennings LW, Mor E, Hyusberg BS, Levy MF, Gonwa TA, Klintmalm GB (1995) Early enteral nutrition support in patients undergoing liver transplantation. J Parenter Enteral Nutr 19:437–443

    Article  CAS  Google Scholar 

  35. 35.

    Watters JM, Kirkpatrick SM, Norris SB, Shamji FM, Wells GA (1997) Immediate postoperative enteral feeding results in impaired respiratory mechanics and decreased mobility. Ann Surg 226:369–380

    Article  PubMed  CAS  Google Scholar 

  36. 36.

    Sagar S, Harland P, Shields R (1979) Early postoperative feeding with elemental diet. Br Med J 1:293–295

    Article  PubMed  CAS  Google Scholar 

  37. 37.

    Beier-Holgersen R, Brandstrup B (1999) Influence of early postoperative enteral nutrition versus placebo on cell-mediated immunity, as measured with the Multitest CMI. Scand J Gastroenterol 34:98–102

    Article  PubMed  CAS  Google Scholar 

  38. 38.

    Schilder JM, Hurteau JA, Look KY, Moore DH, Raff G, Stehman FB, Sutton GP (1997) A prospective controlled trial of early postoperative oral intake following major abdominal gynecologic surgery. Gynecol Oncol 67:235–240

    Article  PubMed  CAS  Google Scholar 

  39. 39.

    Ibrahim EH, Mehringer L, Prentice D, Sherman G, Schaiff R, Fraser V, Kolleff MH (2002) Early versus late enteral feeding of mechanically ventilated patients: results of a clinical trial. J Parenter Enteral Nutr 26:174–181

    Article  Google Scholar 

  40. 40.

    Taylor SJ, Fettes SB, Jewkes C, Nelson RJ (1999) Prospective, randomized, controlled trial to determine the effect of early enhanced enteral nutrition on clinical outcome in mechanically ventilated patients suffering head injury. Crit Care Med 27:2525–2531

    Article  PubMed  CAS  Google Scholar 

  41. 41.

    Heslin MJ, Latkany L, Leung D, Brooks AD, Hochwald SN, Pisters PW, Shike M, Brennan MF (1997) A prospective, randomized trial of early enteral feeding after resection of upper gastrointestinal malignancy. Ann Surg 226:567–577

    Article  PubMed  CAS  Google Scholar 

  42. 42.

    Pupelis G, Austrums E, Jansone A, Sprucs R, Wehbi H (2000) Randomised trial of safety and efficacy of postoperative enteral feeding in patients with severe pancreatitis: preliminary report. Eur J Surg 166:383–387

    Article  PubMed  CAS  Google Scholar 

  43. 43.

    Moore EE, Jones TN (1986) Benefits of immediate jejunostomy feeding after major abdominal trauma—a prospective, randomized study. J Trauma 26:874–881

    Article  PubMed  CAS  Google Scholar 

  44. 44.

    Peck MD, Kessler M, Cairns BA, Chang YH, Ivanova A, Schooler W (2004) Early enteral nutrition does not decrease hypermetabolism associated with burn injury. J Trauma 57:1143–1148

    Article  PubMed  Google Scholar 

  45. 45.

    Nguyen NQ, Fraser RJ, Bryant LK, Burgstad C, Chapman MJ, Bellon M, Wishart J, Holloway RH, Horowitz M (2008) The impact of delaying enteral feeding on gastric emptying, plasma cholecystokinin, and peptide YY concentrations in critically ill patients. Crit Care Med 36:1469–1474

    Article  PubMed  Google Scholar 

  46. 46.

    Chiarelli A, Enzi G, Casadei A, Baggio B, Valerio A, Mazzoleni F (1990) Very early nutrition supplementation in burned patients. Am J Clin Nutr 51:1035–1039

    PubMed  CAS  Google Scholar 

  47. 47.

    Pupelis G, Selga G, Austrums E, Kaminski A (2001) Jejunal feeding, even when instituted late, improves outcomes in patients with severe pancreatitis and peritonitis. Nutrition 17:91–94

    Article  PubMed  CAS  Google Scholar 

  48. 48.

    Kompan L, Kremzar B, Gadzijev E, Prosek M (1999) Effects of early enteral nutrition on intestinal permeability and the development of multiple organ failure after multiple injury. Intensive Care Med 25:157–161

    Article  PubMed  CAS  Google Scholar 

  49. 49.

    Kompan L, Vidmar G, Spindler-Vesel A, Pecar J (2004) Is early enteral nutrition a risk factor for gastric intolerance and pneumonia? Clin Nutr 23:527–532

    Article  PubMed  Google Scholar 

  50. 50.

    Chuntrasakul C, Siltharm S, Chinswangwatanakul V, Pongprasobchai T, Chockvivatanavanit S, Bunnak A (1996) Early nutritional support in severe traumatic patients. J Med Assoc Thai 79:21–26

    PubMed  CAS  Google Scholar 

  51. 51.

    Marshall JC (2001) Inflammation, coagulopathy, and the pathogenesis of multiple organ dysfunction syndrome. Crit Care Med 29:S99–S106

    Article  PubMed  CAS  Google Scholar 

  52. 52.

    Vincent JL, Zambon M (2006) Why do patients who have acute lung injury/acute respiratory distress syndrome die from multiple organ dysfunction syndrome? Implications for management. Clin Chest Med 27:725–731

    Article  PubMed  Google Scholar 

  53. 53.

    Carrico CJ, Meakins JL, Marshall JC, Fry D, Maier RV (1986) Multiple-organ-failure syndrome. Arch Surg 121:196–208

    PubMed  CAS  Google Scholar 

  54. 54.

    Clark JA, Coopersmith CM (2007) Intestinal crosstalk: a new paradigm for understanding the gut as the “motor” of critical illness. Shock 28:384–393

    Article  PubMed  CAS  Google Scholar 

  55. 55.

    Kudsk KA (1998) Early enteral nutrition in surgical patients. Nutrition 14:541–544

    Article  PubMed  CAS  Google Scholar 

  56. 56.

    Magnotti LJ, Deitch EA (2005) Burns, bacterial translocation, gut barrier function, and failure. J Burn Care Rehabil 26:383–391

    Article  PubMed  Google Scholar 

  57. 57.

    Tuin A, Poelstra K, Jager-Krikken A, Bok L, Raaben W, Velders MP, Dijkstra G (2009) Role of alkaline phosphatase in colitis in man and rats. Gut 58:379–387

    Article  PubMed  CAS  Google Scholar 

  58. 58.

    Goldberg RF, Austen WG Jr, Zhang X, Munene G, Mostafa G, Biswas S, McCormack M, Eberlin KR, Nguyen JT, Tatlidede HS, Warren HS, Narisawa S, Millán JL, Hodin RA (2008) Intestinal alkaline phosphatase is a gut mucosal defense factor maintained by enteral nutrition. Proc Natl Acad Sci USA 105:3551–3556

    Article  PubMed  Google Scholar 

  59. 59.

    Doig GS, Simpson F, Sweetman EA (2009) Evidence-based nutrition support in the intensive care unit: an update on reported trial quality. Curr Opin Clin Nutr Metab Care 12:201–206

    Article  PubMed  Google Scholar 

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The conduct of this study was not funded. Ethics approval was not required to conduct this integrative meta-epidemiological study.

Conflict of interest statement

GSD has received academic research grants from Fresenius Kabi Deutschland GmbH and Baxter Healthcare Pty Ltd., and speaker's honoraria from Baxter Healthcare Pty Ltd. FS has received academic research grants from Fresenius Kabi Deutschland GmbH and Baxter Healthcare Pty Ltd., and speakers honoraria from Pharmatel-Fesenius Kabi Pty Ltd. EAS has received an academic research grant from Baxter Healthcare Pty Ltd. ARD has received an academic research grant from Cook Medical. PTH declares no competing interests.

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Correspondence to Gordon S. Doig.

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Doig, G.S., Heighes, P.T., Simpson, F. et al. Early enteral nutrition, provided within 24 h of injury or intensive care unit admission, significantly reduces mortality in critically ill patients: a meta-analysis of randomised controlled trials. Intensive Care Med 35, 2018–2027 (2009). https://doi.org/10.1007/s00134-009-1664-4

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  • Early enteral nutrition
  • Critical illness
  • Intensive care unit
  • Meta-analysis
  • Systematic review