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Immunonutrition for Acute Respiratory Distress Syndrome (ARDS) in Adults; A Cochrane Meta-Analysis


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Immonunutrition for Acute Respiratory Distress Syndrome; A Cochrane Meta-Analysis


Acute Respiratory Distress Syndrome (ARDS) is a syndrome characterised by severe hypoxic respiratory failure with a significant global inflammatory process and multi-organ dysfunction. In the lung there is diffuse epithelial and endothelial injury leading to increased alveolar capillary permeability and florid pulmonary oedema, patients present clinically with acute severe hypoxia and poor lung compliance. This often necessitates invasive mechanical ventilation.

The reported incidence varies  from 16 to 78 per 100,000 population1. Predisposing risk factors that contribute to the development of ARDS include sepsis, shock, pneumonia, aspiration, and pancreatitis.  The hospital mortality of ARDS varies between 27% and 45%2.  Survivors of ARDS have long term physical, cognitive, and psychological sequelae

Immunonutrition Intervention

Immunonutrition is  the modulation of the immune system by providing specific interventions that modify dietary nutrients. It has been long recognised that supplemented immunonutrients may alter the course of critical illness following sepsis, trauma, or surgery. Several specialised enteral and parental formulas with immunonutrients are currently available, these primarily consist of a combination of anti-oxidant vitamins, trace elements, essential amino acids, essential fatty acids, and gamma-linolenic acid.3

Therapeutic supplementation of these nutrients with immunomodulatory properties has been shown to moderate the inflammatory response of critical illness and ARDS by:

•Suppression of pro-inflammatory eicosanoid biosynthesis4
•Attenuation of pulmonary neutrophil accumulation5
•Reduction of lung permeability5
•Attenuation of cardiopulmonary dysfunction6


Recent studies have shown conflicting results, some studies even suggesting a lack of benefit and even potential increased harm from immunonutrition. This Cochrane Review aims to provide a comprehensive evaluation of the effects of immunonutrition in patients with ARDS.

We searched MEDLINE, Embase, CENTRAL, conference proceedings and trial registrations for appropriate studies up to March 2017. All randomised controlled trials (RCT’s) of adult patients with ARDS and/or acute lung injury were included. Two authors independently assessed the quality of the studies and extracted data from the included trials. Quality of evidence and analytical methods were presented in accordance to Cochrane standards. All cause mortality, duration of mechanical ventilation, ICU and hospital length of stay, new organ failures, and adverse reaction were assessed.


We included all randomised controlled trials, with or without blinding of participants. We included all studies involving adult, mechanically ventilated patients with ARDS defined by either the Berlin definition2, or the American-European Consensus Criteria. The intervention group consisted of participants given either enteral or parental immunonutrients, additionally supplemented or as part of a nutritional formula. The immunonutrients could be amino acids, antioxidants, or essential fatty acids supplemented for any duration and at any dose.


Ten RCT’s comprising 1020 patients were included. Immunonutrition intervention was omega-3 fatty acids (eicosapentaenoic acid, docosahexaenoic acid) and gamma-linolenic acid (GLA), and antioxidants. Some studies had a high risk of bias, others were heterogeneous in nature and varied in a number of ways; the type and duration of intervention given, calorific targets, and outcomes reported.

Primary Outcome:

•There was no significant difference in all cause mortality between groups (RR 0.79, P=0.13 Figure 1). The mortality for the immunonutrition and control groups was 23% and 28% respectively.

Secondary Outcomes:

•6 studies reported 28-day mortality. There was a significant difference in mortality at 28-days between groups with RR 0.61 (95% CI 0.46 to 0.81).
•ICU LOS was reported by 8 studies. There was a significant decrease in the intervention group by 3 days (95% CI -4.95 to -1.06), this was only evident when the EPA, GLA, antioxidant rich enteral formula was given continuously rather than as additional supplementation.
•There was a significant reduction in ventilator days (3 days P=0.0002), and ICU length of stay (2.5 days P=0.0009).
•Indices of oxygenation was commonly reported as Pa02/Fi02 ratio, and 9 studies reported this outcome at day 4. There was a significant difference in Pa02/Fi02 ratio at day 4 of 43mmHg (95% CI 17-69mmHg). 
•There was no difference in ventilator or ICU free days between groups or in adverse events reported.
•Only 2 studies reported number of patients with new organ failures. We were unable to pool other studies due to the variation in reporting this outcome (MODS score, worse MODS score, SOFA scores, organ failure free days, changes in sofa scoring).

These analyses were subject to significant statistical heterogeneity and the effect was sensitive to analytical methods.


We identified 10 RCT’s comparing the effect of omega-3 fatty acids and anti-oxidants, either supplemented or as part of an enteral nutrition formula.

There was no significant difference in primary outcome of all cause mortality over the longest period reported. However studies have shown clinical heterogeneity with variation in the type, mode, duration of the intervention, and in the type of enteral nutrition in the control group. When a sub-group analysis of studies which used a lipid-based enteral formula enriched in omega-3 fatty acids and antioxidants against a standard lipid rich formula was conducted, there was a significant difference in mortality.

Secondary outcomes such as mortality at 28 days, ICU LOS, and ventilator days were significantly lower in patients who received immune modulating nutrition. However, as ventilator days can be influenced by the death rate, more recently ventilator-free and ICU-free days are more widely used, and we found no difference in this as a result of immunonutrition. We viewed this with caution as most studies  did not comment specifically on ventilator-free and ICU-free outcome measures. A standardised reporting of ICU and ventilator outcomes should be considered by future randomised control trials to improve outcome reporting.

All studies used omega-3 fatty acid based nutritional formula with or without antioxidants for their intervention group. Overall there was no evidence for giving omega-3 fatty acids in combination with an antioxidant to improve mortality, However, when the intervention was given as a continuous enteral infusion against a high fat based control formula, there was a significant difference with a lower mortality rate in the omega-3 treatment group.

Adverse effects were similar between groups.

Poor methodological quality, small sample sizes, different control formulas, and large number of patient drop-outs due to poor tolerance are some of the criticisms of these included studies, and may have influenced the results. Ideal dose, route, and timing of administration is still yet to be established. However, lipid formulas seem to be safe and well tolerated. Further studies are needed to assess the effectiveness.

Summary box:

•There is no long term mortality benefit from immunonutrition
•There may be improvements in duration of mechanical ventilation, ICU LOS, and oxygenation
•There is no significant increase in serious adverse events reported in association with immunonutrition
•The Quality of evidence is moderate, and the reporting of outcome measures needs to be standardised in order to improve this in future RCT’s
•Lipid formulas seem to be safe and well tolerated, but further studies are needed to assess the effectiveness


1.Walkey 2012; Walkey AJ, Ho V, Alkana P; Acute Respiratory Distress Syndrome: Epidemiology and management Approaches. Clinical Epidemiology, 2012;4:159-169. Pubmed: 22866017
2.Ranieri 2012; ARDS Definition Task Force; Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, Fan E, et al; Acute Respiratory Distress Syndrome the Berlin Definition; JAMA; 2012307(23):2526-33. Pubmed: 22797452
3.Mizock 2010; Mizock BA, Immunonutrition and Critical Illness: An Update, Nutrition, 2010:26(7-8):701-707
4.Calder 2007; Calder PC, Immunonutrition in Surgical and Critically Ill Patients, British Journal of Nutrition, 2007;98(Supp 1). Pubmed 17922951
5.Mancuso 119b; Mancuso et al, Effects of Eicosapentaenoic and Gamma-linolenic Acid on Lung Permeability and Alveolar Macrophage Eicosanoid Synthesis in Endotoxic Rats, Critical Care Medicine, 1997;25(3):523-532. Pubmed 9118672
6.Murray 1995; Murray MJ et al, Select Dietery Fatty Acids Attenuate Cardiopulmonary Dysfunction During Acute Lung Injury in Pigs, American Journal of Physiology, 1995;269(6pt2):H2090-9
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