Do daily 'vitamins' make a difference to the tube-fed?

1 October 2014

CYNTHIA WENSLEY in this Clinically Appraised Topic (CAT) looks at whether or not enriching tube feeding with immune-boosting nutrients reduces infection.



In critically ill, mechanically-ventilated adults in intensive care, adding nutrients thought to boost immunity (glutamine, omega-3 fatty acid, and antioxidants) to the patient’s high-protein enteral nutrition does not reduce infection risk or improve recovery. Instead, it is associated with a 57 per cent increased risk of dying within six months of follow-up when compared with standard high-protein nutrition. The lack of benefit – and potential for harm – in this group of patients means supplementing enteral nutrition with these nutrients is not supported.



You are an intensive care nurse caring for a critically ill, ventilated patient starting enteral feeding. The family say their mum takes antioxidants daily for immunity support and worries that without these she has less chance of pulling through. You know that some units supplement enteral feeding with immunonutrition – nutrients to modulate the immune and inflammatory response to illness – in the critically ill and wonder what difference this makes.



In critically ill, ventilated patients, does the supplementation of enteral feeding with immune-modulating nutrients reduce infection risk compared with standard enteral feeding?



PubMed Clinical Queries (therapy, narrow): enteral nutrition AND Immunomodulation



Van Zanten, AR: Sztark: F, Kaisers UX et al. (2014). High-protein enteral nutrition enriched with immune-modulating nutrients vs standard high-protein enteral nutrition and nosocomial infections in the ICU: a randomised clinical trial. Jama, 312(5), 514-524. doi: 10.1001/jama.2014.7698



The MetaPlus study is a randomised, multi-centre, international, parallel group, two-arm, double-blind trial conducted in 14 intensive care units (ICUs) in the Netherlands, France, Germany, and Belgium, commencing February 2010. Clinical records of patients in participating ICUs were pre-screened for eligible patients; inclusion criteria were mechanically-ventilated adults who were expected to require ventilation for more than 72 hours and enteral feeding for longer than 72 hours, commencing within 48 hours of ICU admission. The main exclusion criteria was Sequential Organ Failure Assessment Score (SOFA) of >12. The number pre-screened or who declined consent (sought from patient or legal representative) was not stated; 301 patients were randomised. Participants were fed according to routine practice, although a study protocol provided recommendations for early enteral feeding, energy requirement, and complementary feeding. Patients received study treatment for a maximum of 28 days. The study duration was six months.

Interventions: (n=152) High-protein enteral nutrition (IMHP) enriched with immune-modulating nutrients glutamine, omega-3 fatty acid, and antioxidants (experimental product, NV Nutricia, Zoetermeer). Full nutritional supplementation details provided in supplemental material.

Comparison: (n= 149) High-protein enteral nutrition (HP) commercially available as Nutrison Advanced Protison (NV Nutricia, Zoetermeer).

Outcomes: Primary outcome measure was the incidence of new infections from start of study product until either ICU discharge or a maximum of 28 ICU days. Secondary outcome measures included mortality (at ICU and hospital discharge, day-28 and six months), SOFA scores, mechanical-ventilation duration, ICU and hospital length of stay, sub-types of infections, and severe adverse events. Infections were classified using the Center for Disease Control and Prevention (CDC) definitions.



Patients were randomised using computer generated randomisation lists. Allocation concealment method was not described, although blinding technique would restrict prediction of upcoming allocation. Participants, clinicians, and investigators were blinded via study products that were ready-to-use and identical in packaging, appearance, texture, and smell. Minimal loss to follow up. All analyses performed on an intention-to-treat basis. Study groups were similar at baseline for prognostic characteristics that included morbidity risk, baseline levels of immune-modulating nutrients, infections and antibiotic use. There was no evidence that groups not treated equally. Study quality was high.



The study population was a mix of mechanically-ventilated, intensive care patients (36 per cent medical, 52 per cent surgical, 12 per cent non-surgical trauma). Study product was administered for a median of 12 to 13 days (IMHP and HP groups respectively). Compliance to the study product was good. There was no significant difference in the incidence of new infections between the IMHP and HP group (see table); this lack of benefit was consistent across predefined subgroup analyses. There was no significant difference between groups for any secondary outcomes or adverse events except for a statistically significant increase in six-month mortality in the medical group receiving IMHP (54 per cent) compared with HP (35 per cent). Mortality at six months (adjusted for age and Acute Physiology and Chronic Health Evaluation ll score) was significantly increased in those receiving IMHP (see table below).


Table: Results with 95% Confidence Intervals (CI)
Outcome IMHP n=152 HP n=149 RR (95% CI) * HR (95% CI) ** P Value
Incidence of new infections 80 (53%) 78 (52%) 1.01 (0.8 -1.25)  - 0.96
Six-month mortality 53 (35%) 42 (28%)  - 1.57 (1.03 - 2.39) 0.04
IMHP – High-protein enteral nutrition enriched with immune modulating nutrients; HP – High protein enteral nutrition * RR (95% CI) – Relative Risk (95% Confidence Interval) ** HR (95% CI) – Hazard Ratio (95% Confidence Interval)



The results of this high-quality study add to the growing body of evidence for lack of benefit and possible harm of immunonutrition in the critically ill. The involvement of multiple, international centres, and a heterogeneous intensive care patient population increases applicability of the study results to other ICU settings. Given the biological rationale for immunonutrition, the reason for the lack of benefit seen with IMHP is unclear. The benefit of individual components of the IMHP study treatment, and immune modulation for specific subgroups of the critically ill population, require further examination with robust clinical trials. :



Cynthia Wensley RN MHSc is a PhD candidate who also works at the School of Nursing, University of Auckland as an honorary professional teaching fellow.