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An immune-enhancing enteral diet reduces mortality rate and episodes of bacteremia in septic intensive care unit patients.

Galban C, Montejo JC, Mesejo A, et al.

Crit Care Med. 2000;28(3):643-8. [abstract]

Reviewed by Reza Rastmanesh PhD, National Institute of Nutrition, Tehran, Iran

Review posted February 27, 2005

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I. What is being studied?:

The study objective:

To determine whether enteral feeding in septic intensive care unit (ICU) patients, using a formula supplemented with arginine , mRNA, and omega-3 fatty acids from fish oil improves clinical outcomes, when compared with a common use, high protein enteral feed without these nutrients.

The study design:

A prospective, randomized, multicentered trial

The patients included:

Men and nonpregnant women >14 yrs old (n=181) in six ICUs in Spain from September 1994 to January 1997 who were septic and had an Acute Physiology and Chronic Health Evaluation (APACHE) II score ≥ 10 at the time of admission to the ICU.

The patients excluded:

If patients had previous radiotherapy, treatment with immunosuppressive drugs, acquired immunodeficiency syndrome, neoplasia, or if they had already received immune-enhancing (branched-chain amino acids, omega-3 fish oil, glutamines, or nucleotides enteral or parenteral nutritional support.

The interventions compared:

Treated patients were given a specific enteral feed containing arginine, omega-3 fatty acids and nucleotides (Impact, Novartis). Control patients were given a common use, high protein formula (Precitene Hiperproteico, Novartis). Feedings were started within 36 hours of the diagnosis of sepsis, administered based on the Harris-Benedict formula, with a goal of reaching full feedings within 4 days of entry into the trial.

The outcomes evaluated:

Mortality rate, infection rate and ICU length of stay

II. Are the results of the study valid?

Primary questions:

1. Was the assignment of patients to treatments randomized?

Yes, Randomization was provided by a computer-generated randomization program. There was no comment regarding stratification by hospital.

2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?

Was followup complete?

Yes, five patients in the treatment group were excluded from the intention-to-treat analysis. Two patients did not meet inclusion criteria and three met exclusion criteria. The authors do not describe why one patient with tetanus was excluded. Perhaps he/she did not tolerate feeding. Anyway, the tetanus patient does not appear to violate their inclusion/exclusion criteria.

The patients were not followed up through the entire hospital stay, but were followed until ICU discharge or death, whichever came first.

Were patients analyzed in the groups to which they were randomized?

Yes, there were no cross-overs betweeen groups.

Secondary questions:

3. Were patients, health workers, and study personnel "blind" to treatment?

There is no indication that anyone - patients, physicians (specifically not blinded) or investigators were blinded. This could certainly introduce a significant bias in other aspects of patient care or even willingness to diagnose new infections. (Certainly this would not bias the diagnosis of death!)

4. Were the groups similar at the start of the trial?

There were not significant differences between patient groups in terms of important variables: age, height, ideal weight, gender, ICU admission APACHE II score or type of primary infection.

5. Aside from the experimental intervention, were the groups treated equally?

There is no mention of any other aspect of patient care except for the feeding. We are not reassured at all that, particularly since the study was not blinded, that other important aspects of care were, in fact, the same between the two groups. Use of mechanical ventilation, antibiotics, inotropic support - nothing is reported at all.

There were significantly more calories given to the control group for the first 7 days (1414 ± 471 kcal/day vs. 1231 ± 411 kcal/day, p < 0.004, Table 5). There was not a statistically significant difference in the amount of nitrogen received by the two groups nor in nitrogen balance between the two feeding groups. Total caloric intake is an important variable which could influence outcomes considered in this study.

III. What were the results?

1. How large was the treatment effect?

	Relative risk (treated vs control) (95% CI)	Absolute risk reduction (95% CI)
Mortality	0.59 (0.35, 0.99)	0.131 (0.002, 0.25)
Mortality for APACHE II 10-15	0.139 (0.02, 0.76)	0.23 (0.05-0.42)
Bacteremia	0.36 (0.16, 0.79)	0.14 (0.04, 0.22)
> 1 Nosocomial infection	0.29 (0.11, 0.75)	0.14 (0.04, 0.24)

In the intention-to-treat analysis, there was a significant difference between the two groups' mortality rates with a relative risk of 0.59 and 95% confidence intervals of 0.35 and 0.99. The effect was even stronger in the APACE II 10-15 subgroup (RR 0.14, 95% CI 0.02-0.76). In addition, the treated group had 1/3^rd the incidence of bacteremia or more than one nosocomial infection.

There were no significant difference between the two groups in terms of ICU LOS, and days of ventilation.

2. How precise was the estimate of the treatment effect?

The 95% confidence intervals for the relative risk regarding the primary outcome were relatively wide, but did not cross 1.0, suggesting a difference between groups.

• The overall NNT for mortality will be 8 (4-522) patients. We'd have to treat eight patients in order to prevent one event (in this case, to prevent one death). Although the NNT is low, the 95% confidence intervals are quite wide.
• The mortality NNT in the APACE II 10-15 subgroup would be 4 (2-19) patients. We'd have to treat four patients in order to prevent one event (in this case, to prevent one death). The confidence intervals here are narrower despite the smaller sample size due to the larger effect size!
• NNT in subgroup of patients with bacteremia would be 7 (4-28) patients. We'd have to treat seven patients in order to prevent one event (in this case, to prevent one case of bactermia).
• NNT in subgroup of patients with more than 1 nosocomial infection would be 7 (5-23) patients. We'd have to treat seven patients in order to prevent one event (in this case, to prevent one death).

IV. Will the results help me in caring for my patients?

1. Can the results be applied to my patient care?

Results here from an adult trial are of questionable applicability to children. This study included only patients with APACHE II score of ≥ 10. It is not known whether this mortality rate benefit is the same for patients with APACHE II score of < 10 and it is difficult to think about comparing severity of illness scores betweens adults and children.

How do these results compare to others in the literature?

Jones et al. studied 78 critically ill adult patients with APACHE II scores of 11 and greater and found that administration of enteral immunonutrition to their general, critically ill population did not affect mortality (1). Caparros et al. found similar results among 220 patients, also a general ICU population (2). Finally, Atkinson et al. studied enteral immunonutrition in a general, critically ill population (n=398). They found no affect on mortality, but those patients in whom it was possible to achieve early enteral nutrition with Impact had a significant reduction in the morbidity of their critical illness (3).

2. Were all clinically important outcomes considered?

Yes, the most common and clinically important endpoints (mortality rate, bacteremias, length of stay, and ventilator days), complications and causes of death for the two groups had been considered.

3. Are the likely treatment benefits worth the potential harms and costs?

No harm from treatment was noted and the costs of therapy are not disclosed.

References:

1. Jones C, Palmer TE, Griffiths RD. Randomized clinical outcome study of critically ill patients given glutamine-supplemented enteral nutrition. Nutrition. 1999 Feb; 15 (2):158-9. [abstract]
2. Caparros T, Lopez J, Grau T. 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. 2001 Nov-Dec; 25(6):299-308; discussion 308-9. [abstract]
3. Atkinson S, Sieffert E, Bihari D. A prospective, randomized, double-blind, controlled clinical trial of enteral immunonutrition in the critically ill. Guy's Hospital Intensive Care Group. Crit Care Med. 1998 Jul; 26(7):1164-72. [abstract]

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