Meta Analysis
 Should Immunonutrition become Routine in Critically Ill Patients? A systematic review of the evidence.
This review may be edited
Summary
Posted By: Gordon S. Doig
E-Mail: Gordon.Doig@EvidenceBased.net
Posted Date: 28 Nov 2001
Title: Should Immunonutrition become Routine in Critically Ill Patients? A systematic review of the evidence.
Authors: Heyland DK, Novak F, Drover J et al
Reference: JAMA 2001;286:944-953
Link: Click here for a direct link to the paper. A password may be required for access to fulltext.
Abstract: CONTEXT: Several nutrients have been shown to influence immunologic and inflammatory responses in humans. Whether these effects translate into an improvement in clinical outcomes in critically ill patients remains unclear.
OBJECTIVE: To examine the relationship between enteral nutrition supplemented with immune-enhancing nutrients and infectious complications and mortality rates in critically ill patients.
DATA SOURCES: The databases of MEDLINE, EMBASE, Biosis, and CINAHL were searched for articles published from 1990 to 2000. Additional data sources included the Cochrane Controlled Trials Register from 1990 to 2000, personal files, abstract proceedings, and relevant reference lists of articles identified by database review.
STUDY SELECTION: A total of 326 titles, abstracts, and articles were reviewed. Primary studies were included if they were randomized trials of critically ill or surgical patients that evaluated the effect of enteral nutrition supplemented with some combination of arginine, glutamine, nucleotides, and omega-3 fatty acids on infectious complication and mortality rates compared with standard enteral nutrition, and included clinically important outcomes, such as mortality.
DATA EXTRACTION: Methodological quality of individual studies was scored and necessary data were abstracted in duplicate and independently.
DATA SYNTHESIS: Twenty-two randomized trials with a total of 2419 patients compared the use of immunonutrition with standard enteral nutrition in surgical and critically ill patients. With respect to mortality, immunonutrition was associated with a pooled risk ratio (RR) of 1.10 (95% confidence interval [CI], 0.93-1.31). Immunonutrition was associated with lower infectious complications (RR, 0.66; 95% CI, 0.54-0.80). Since there was significant heterogeneity across studies, we examined several a priori subgroup analyses. We found that studies using commercial formulas with high arginine content were associated with a significant reduction in infectious complications and a trend toward a lower mortality rate compared with other immune-enhancing diets. Studies of surgical patients were associated with a significant reduction in infectious complication rates compared with studies of critically ill patients. In studies of critically ill patients, studies with a high-quality score were associated with increased mortality and a significant reduction in infectious complication rates compared with studies with a low-quality score.
CONCLUSION: Immunonutrition may decrease infectious complication rates but it is not associated with an overall mortality advantage. However, the treatment effect varies depending on the intervention, the patient population, and the methodological quality of the study.
 
Are the Results Valid?
1. Did the overview address a focused clinical question?
Yes. The stated purpose of the overview is "to systematically review, critically appraise, and systhesize randomized clinical trial data evaluating the effect of enteral immunonutirtion in critically ill patients."
2. Were the criteria used to select articles for inclusion appropriate?
Yes. The authors included all papers that:
1) were randomized clinical trials
2) studied critically ill or surgical patients
3) compared enteral nutrition supplemented with any combination of arginine, glutamine, omega-3 fatty acids or nucleotides with standard enteral nutrition; and
4) reported clinically important outcomes such as mortality, infectious complications and length of stay.
3. Is it unlikely that important, relevant studies were missed?
It is very unlikely that important studies were missed. The authors searched Medline, EMBASE, Biosis, CINAHL and the Cochrane Controlled Trials Registrar from 1990 to 2000. They also hand searched all reference lists of review and primary articles, searched personal files and abstract proceedings of recent meetings. Major manufacturers and recognized experts were also contacted.
4. Was the validity of the included studies appraised?
Yes. Study validity was appraised using a 9 parameter scale that addressed internal validity issues such as: randomization concealment, blinding, patient selection, follow-up etc.
5. Were assessments of studies reproducible?
Although a direct measure of reproducibility of the validity assessment was not reported, (i.e. kappa or intra-class correlation) the authors resolved any disagreement by consensus.
6. Were the results similar from study to study?
Although there was no statistical heterogeneity for studies reporting mortality as the primary outcome, there was significant heterogeneity for both infectious complications and length of stay. This would suggest that it might be inappropriate to interpret the results of the overall analysis for infectious complications or length of stay.
What are the Results?
1. What are the overall results of the overview?
Overall results:
  • There was no mortality advantage to the use of immunonutrition (RR 1.10, 95%CI 0.93 to 1.31)
  • Overall estimate of infectious complication reduction is uninterpretable due to heterogeneity.
  • Overall estimate of length of stay is uninterpretable due to heterogeneity.

    A priori defined sub-group analysis:
    High arginine feeds: both surgical and crit ill pts

  • No mortality difference (RR 1.05, 95%CI 0.88 to 1.25)
  • Reduced infectious conplications for high arginine feeds (RR 0.55, 95%CI 0.46 to 0.67)
  • Shorter LoS for high arginine feeds ( -4.19 days, 95%CI -5.52 to -2.86 days)
    Low arginine feeds: both surgical and crit ill pts
  • Higher mortality with low-arginine immunonutrition. (RR 2.13, 95%CI 1.08 to 4.21)
  • No difference in infectious complications. (RR 1.27, 95%CI 0.74 to 2.22)
  • Trend towards increase LoS in low-arginine group.

    High quality studies (quality score >8): both surgical and crit ill pts

  • Suggested increased mortality from immunonutrition. (RR 1.19, 95%CI 0.99 to 1.43)
  • Reported reduced infectious complications with immunonutrition. (RR 0.53, 95%CI 0.42 to 0.68)
    Lower quality studies (quality score <8): both surgical and crit ill pts
  • Trend towards lower mortality with immunonutrition. (RR 0.74, 95%CI 0.49 to 1.14)
  • No difference in infectious complications. (RR 1.01, 95%CI 0.68 to 1.5)

    All studies of Critically Ill Pts only:

  • No difference in mortality. (RR 1.18 95%CI 0.88 to 1.58)
  • No effect on infectious complications. (RR 0.96, 95%CI 0.77 to 1.20)
  • Significantly reduced LoS with immunonutrition. (-3.34 days, p=0.047)
    Studies of Critically Ill Pts: Feeds with high arginine content.
  • No effect on mortality. (RR 1.03, 95%CI 0.75 to 1.41)
  • Trend towards fewer infections in high-arginine group. (RR 0.87, 95%CI 0.75 to 1.02)
  • Significantly shorter LoS in high-arginine group (-7.19 days, 95%CI -13.25 to -1.08 days)
    Studies of Critically Ill Pts: Feeds with low arginine content.
  • Significanty higher mortality with low arginine feeds. (RR 2.13, 95%CI 1.08 to 4.21)
  • No effect on infectious complications. (RR 1.28, 95%CI 0.74 to 2.22)
  • Trend towards a longer LoS in feeds with low arginine. (6.51 days, 95%CI -0.06 to 13.1 days)
    Studies of Critically Ill Pts: High quality studies (quality score >8)
  • Significantly higher mortality with immunonutrition. (RR 1.46, 95%CI 1.01 to 2.11)
  • Fewer infectious complications with immunonutrition. (RR 0.80, 95%CI 0.64 to 1.01)
  • Significantly shorter LoS with immunonutrition. (-5.35 days, 95%CI -14.9 to 1.21 days)
    Studies of Critically Ill Pts: Lower quality studies (quality score <8)
  • Trend towards decreased mortality with immunonutrition. (RR 0.74, 95%CI 0.49 to 1.14)
  • No difference in infectious complications. (RR 1.12, 95%CI 0.74 to 1.70)
  • No difference in LoS.

    All studies of Elective Surgical Pts:

  • No difference in mortality (RR 0.99, 95%CI 0.42 to 2.34)
  • Significantly lower infectious complications with immunonutrition. (RR 0.53, 95%CI 0.42 to 0.68)
  • Significant decrease in LoS with immunonutrition. (-3.39 days, -4.55 to -2.23 days)
  • N.B. - all studies of elective surgery pts involved a high arginine content feed (Impact) and all except 1 study involving 14 pts per group were considered high quality.
    • 2. How precise were the results?
    See 95% Confidence Intervals (listed above) for estimates of precision.
    Will the Results Help Me In Caring For My Patients?
    1. Can the results be applied to my patient care
    Not necessarily. Although the trials reviewed in this paper are fairly representative of critically ill and elective surgery patients, the authors remind us that the sub-group analysis was hypothesis generating. Interesting results of these sub-group analyses should be reproduced in clinical trials before the findings can be used to change practice.
    2. Were all clinically important outcomes considered?
    The authors reported on mortality, infectious complications and length of stay. These are probably the three most relevant outcomes.
    3. Are the benefits worth the harms and costs?
    Due to the hypothesis generating sub-group analysis, it is unclear as to what the overall benefits are in the critically ill.

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