Probiotics and other Immunomodulation


Joint guidelines published by Society of Critical Care Medicine (SCCM) [Martindale RG et al: Crit Care Med 37: 1757, 2009] and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) state “Immune-modulating enteral formulations (supplemented with agents such as arginine, glutamine, nucleic acid, ω-3 fatty acids, and antioxidants) should be used for the appropriate patient population (major elective surgery, trauma, burns, head and neck cancer, and critically ill patients on mechanical ventilation), with caution in patients with severe sepsis (for surgical ICU patients, Grade: A)” and “A combination of antioxidant vitamins and trace minerals (specifically including selenium) should be provided to all critically ill patients receiving specialized nutrition therapy” (Grade B) and specifically mention arginine, vitamin E, ascorbic acid, and selenium.

Based on recently published data, ω-3 fatty acids can no longer be recommended (see [Rice TW et al. JAMA 306: 1574, 2011]).

Regarding vitamins E and C – see Nathens AB et al.’s randomized, controlled trial of 595 trauma patients at the University of Washington suggesting that α-tocopherol (1,000 IU [20 mL] q8h per naso- or orogastric tube) and ascorbic acid (1,000 mg intravenously) reduced the risk of multiorgan failure (RR 0.43, CI 0.19-0.96) [Nathens AB et al. Ann Surg 236: 814, 2002]. Also see Crimi et al. who found a that supplementation with antioxidant vitamins C (500 mg/d) and E (400 IU/d) resulted in a significant reduction in mortality in critically ill patients [Crimi E, et al. Anesth Analg 2004; 99: 857—863].

[Anstwurm MWA, Schottdorf J, Schopohl J, et al. Selenium replacement in patients with severe inflammatory response syndrome improves clinical outcome. Crit Care Med 27: 1807, 1999]: selenium and renal failure (reduces ARF but no change in mortality).


Probiotics are living microorganisms that upon enteral delivery exert a wide range of health-promoting properties [Int J Food Microbiol 1998; 39: 237–238]. It is hypothesized that probiotics exert an effect on all three mechanisms involved in bacterial translocation: (1) intestinal motility and small bowel bacterial overgrowth; (2) structural mucosal barrier function, and (3) the immune system. Since many of these effects are strain-specific it can be regarded impossible to find a single probiotic strain harboring all these desired properties. Therefore, a multispecies probiotic preparation is to be preferred [Int J Food Microbiol 2004; 96: 219–233]. As of now, three randomized-controlled studies have shown statistically-significant effects of probiotics in surgical patients (liver transplant, pancreatitis) [Br J Surg 89: 1103, 2002; Transplantation: 74: 123, 2002; Transplant: 5: 125, 2005]. To date, no trials have shown a significant effect in patients undergoing general abdominal surgery, although this may be a result of inferior probiotic use (ex. monospecies)

Probiotics may be helpful in specific patient populations (e.g. transplantation) but are not recommended in general ICU patient populations (Grade C) [Martindale RG et al: Crit Care Med 37: 1757, 2009]

Minerals and Amino Acids

L-Arginine is the best-studied immunomodulatory agent and its use in critically ill patients was given a Grade A recommendation by the SCCM [Martindale RG et al: Crit Care Med 37: 1757, 2009]. According to the SCCM, enteral glutamine should be considered in trauma, burn, and mixed ICU patients (Grade B) [Martindale RG et al: Crit Care Med 37: 1757, 2009].

Omege 3 Fatty Acids

The SCCM guidelines advocate omega-3 containing feeds for patients with ARDS (Grade A), based on three prior studies (all of which were supported, in some form, by Ross Laboratories) [Martindale RG et al: Crit Care Med 37: 1757, 2009]. A more recent, independent, larger RCT suggests that omega-3 containing feeds are not useful and may cause harm in the ARDS patient population [Rice TW et al. JAMA 306: 1574, 2011].

Summary of SCCM / ASPEN Guidelines

Summary of SCCM / ASPEN Guidelines Regarding Supplementation

  • Immune-Modulating Enteral Formulations: includes arginine, glutamine, antioxidants; Grade A evidence in surgical ICU patients
  • Antioxidants: administer vitamin E, ascorbic acid, and selenium (Grade B)
  • Amino Acids: in burn, trauma, and mixed ICU patients, consider glutamine (Grade B)
  • Probiotics: may be helpful in specific patient populations (transplantation) but not recommended in general ICU patients (Grade C)

*Note that while ω-3 fatty acids were recommended in section E1 of the Guidelines, based on new data [Rice TW et al. JAMA 306: 1574, 2011], they can no longer be recommended

Additional Studies

Clin Sci (Lond) 106: 287, 2004 (20 Brain Injury Patients)

20 brain injury patients (GCS 5-12) were randomized to receive either an early isocaloric and isonitrogenous enteral diet (control group, n=10) or the same formula with glutamine and probiotics added (study group, n=10) for a minimum of 5 days. The infection rate was higher in controls (100%) when compared with the study group (50%; p = 0.03) and the median (range) number of infections per patient was significantly greater (p < 0.01) in the control group [3 (1-5)] compared with the study group [1 (0-3)]. Both the critical care unit stay [22 (7-57) compared with 10 (5-20) days; p < 0.01; median (range)] and days of mechanical ventilation [14 (3-53) compared with 7 (1-15) days; p = 0.04; median (range)] were higher in the patients in the control group than in the study group [Clin Sci (Lond) 106: 287, 2004]

J Parenter Enteral Nutr. 31: 119, 2007 (113 ICU Patients)

A recent, prospective Slovenian study of 113 multiple injured patients randomized patients into 4 groups (A, glutamine; B, fermentable fiber; C, peptide diet; and D, standard enteral formula with fibers combined with Synbiotic 2000, a formula containing live lactobacilli and specific bioactive fibers). No differences in days of mechanical ventilation, ICU stay, or MOF scores were found. A total of 51 infections, including 38 pneumonia, were observed, with only 5 infections and 4 pneumonias in group D, which was significantly less than combined infections (p = .003) and pneumonias (p = .03) in groups A, B, and C. Intestinal permeability decreased only in group D (p < .05) [J Parenter Enteral Nutr. 31: 119, 2007]

Crit Care Med 34: 1033, 2006 (100 Patients with ALI)

There is emerging data to suggest that in ICU patients other modulatory feeds may be beneficial – In one study of 100 patients with acute lung injury, randomized to receive an enteral diet enriched with eicosapentaenoic acid (EPA), gamma-linolenic acid (GLA), and antioxidants for 14 days, a significant difference was found in length of ventilation (p < .04) in favor of the EPA + GLA group. There was no between-group difference in survival [Crit Care Med 34: 1033, 2006].

Crit Care Med 34: 2325, 2006 (165 patients with Sepsis)

A prospective, double-blind, placebo-controlled, randomized trial in three different Brazilian ICUs. The study enrolled 165 patients with severe sepsis or septic shock, randomized to be continuously tube-fed with either a diet enriched with EPA, GLA, and elevated antioxidants or an isonitrogenous and isocaloric control diet, delivered at a constant rate to achieve a minimum of 75% of basal energy expenditure x 1.3 during a minimum of 4 days. Patients who were fed with the study diet experienced a significant reduction in mortality rate compared with patients fed with the control diet, the absolute mortality reduction amounting to 19.4% (p = .037). The group who received the study diet also experienced significant improvements in oxygenation status, more ventilator-free days (13.4 +/- 1.2 vs. 5.8 +/- 1.0, p < .001), more intensive care unit (ICU)-free days (10.8 +/- 1.1 vs. 4.6 +/- 0.9, p < .001), and a lesser development of new organ dysfunctions (p < .001) [Crit Care Med 34: 2325, 2006] [Transplantation 2005;80: 1363–1368] (see Table 1 in text, not yet reproduced here)

[Young B, Ott L, Kasarskis E, et al. Zinc supplementation is associated with improved neurologic recovery rate and visceral protein levels of patients with severe closed head injury. J Neurotrauma 13: 25, 1996]: this trial was flawed due to selection bias.

[Heyland DK, Dhaliwal R, Suchner U, Berger MM. Antioxidant nutrients: a systematic review of trace elements and vitamins in the critically ill patient. Intensive Care Med 2005; 31:327—337]: systematic review of trials of trace elements and vitamins supports antioxidant function in critically ill patients. Using meta-analysis techniques, demonstrates that 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.