Nutritional Support: Type (Standard versus Enhanced) (UPDATE IN PROCESS)

I. Statement of the Problem

An accumulating body of evidence in animal models suggests that the addition of specific micronutrients to enteral formulations can improve outcomes with regard to immune function, septic morbidity, and overall mortality. Although a host of these additives have been examined, glutamine (GLN), arginine (ARG), omega-3 fatty acids (w-3 FAs) and nucleotides (RNA) have received the greatest attention. Whether the enhancement of standard enteral formulas with any of these micronutrients is beneficial in humans, and if so, in which patient populations, remains unclear. This document examines the existing literature, focusing specifically on clinically relevant endpoints in trauma (including burn) patients.

II. Process

A. Identification of References

References were identified from a computerized search of the National Library of Medicine for English language citations between 1980 and 2000. Keywords included enhanced nutrition, nutrition support, trauma, burn, enteral, parenteral, and micronutrients. The bibliographies of the selected references were reviewed for relevant articles not found in the computerized search. Literature reviews, case reports, and editorials were excluded. Ten articles were identified.

B. Quality of the References

The quality assessment instrument applied to the references was developed by the Brain Trauma Foundation and subsequently adopted by the EAST Practice Management Guidelines Committee. Articles were classified as Class I, II, or III according to the following definitions:

Class I: A prospective, randomized clinical trial. Ten articles were chosen and analyzed.

Class II: A prospective, non-comparative clinical study or a retrospective analysis based on reliable data. No Class II articles were identified.

Class III: A retrospective case series or database review. No Class III articles were identified.

III. Recommendations

A. Level I

No recommendations

B. Level II

No recommendations

C. Level III

1. The use of enteral formulations enhanced with “adequate” doses of arginine and glutamine appears to reduce length of stay and septic morbidity in severely injured trauma patients (ISS >20, ATI >25). The precise doses of and lengths of treatment with arginine and glutamine required to obtain this effect have not yet been determined. Whether an additional benefit is gained from further supplementation with omega-3 fatty acids, nucleotides, and trace elements is unclear.
2. No recommendations can be made at this time regarding the role of enhanced enteral formulations in patients with severe burns.

IV. Scientific Foundation

The concept of “immuno-nutrition”, wherein the addition of specific micronutrients to standard enteral or parenteral formulations enhances host immunologic function, is well supported by many animal studies dating back to the mid-1980s.^[1-11] Although the roles of several of these additives have been examined, including branched chain amino acids, selenium, and zinc, the best studied (and most commercially available) micronutrients are glutamine, arginine, nucleotides, and the omega-3 fatty acids.

Glutamine, despite being the most abundant amino acid in the body, appears to become conditionally essential in various critical care states. It is the major fuel source for enterocytes, lymphocytes, and macrophages, and thus, its deficiency can cause not only compromise of the barrier function of the intestinal epithelium but also impaired immunologic function.^[12] Arginine is another non-essential amino acid that can become conditionally essential under conditions of stress and sepsis. Administration of pharmacologic doses of arginine has been shown to enhance secretion of many hormones including growth hormone, insulin-like growth factor, pituitary growth hormone, prolactin, and others. It is also a precursor for synthesis of nitrates, nitrites, and nitric oxide, which seems to play an important role in macrophage killing capacity.^[13-14] The omega-3 fatty acids (the so-called fish oils) have a number of advantageous properties compared with the more commonly used omega-6 fatty acids (vegetable oils). The latter are generally considered immunosuppressive (inhibit antibody formation, lymphocyte and macrophage activity, and T-suppressor cell proliferation), while the former are less inflammatory and more immunostimulatory.^{[12] [15]} Finally, the purine and pyrimidine nucleotides (adenine, guanine, thymidine, and uracil), being precursors for DNA and RNA, appear to be essential for cell energetics (ATP) and may also play a role as physiologic mediators (c-AMP). Administration of these agents improves natural killer cell activity and enhances resistance to infection.^[16]

Many prospective randomized trials in many different patient populations have evaluated the impact of these immunologically enhanced nutritional formulations. However, because of differences in the patient populations studied, the composition of the diets, and the clinical and laboratory outcomes measured, it has been extremely difficult to gain consensus regarding the proper role for these expensive formulations. Several recent evidence-based reviews^[17-19] and the recently published consensus statement from the American Society for Parenteral and Enteral Nutrition^[20] reflect the limitations of the currently available literature and the need for additional scientific study in specific patient populations. Our purpose in performing this review was to examine the role of enterally-enhanced formulas in the trauma patient, to determine if distinct recommendations could be made regarding this patient population that might not have been evident in the reviews of less-specifically defined patient groups. Unfortunately, the same shortcomings that plague the immuno-nutrition literature as a whole apply to the currently available studies of trauma patients. Despite our review comprising 10 Class I (prospective, randomized, controlled) studies (see evidentiary table that follows), small patient numbers in the individual studies and methodological differences between the studies prevent us from making Level I recommendations. Future studies need to address the following limitations in the immuno-nutrition-in-trauma literature:

Lack of Uniformity in the Study Population:

Of the 10 studies included in this review, only six focus specifically on trauma patients,^{[11] [21- 25]} while two are limited to burn patients.^{[26] [27]} The final two studies, in ICU patients, were included because they clearly specified the percentage of trauma patients in their ICU patient population.^{[28] [29]} In one of these studies, however, only 13% of the patients were trauma patients,^[29] and in neither study is the severity of injury for the trauma patient subset provided. The inclusion criteria for both burn studies are relatively broad, and the resulting differences in mean age (20 years versus 35 years) make it difficult to justify the conflicting outcomes. Furthermore, the inclusion of pediatric patients in both studies adds yet another variable that must be taken into account when interpreting these results. Even the six studies in trauma patients may not necessarily be comparable given the rather wide variations in mean ATI (20-34) and mean GCS score (8.6-14) in the studies reporting these scores. On the other hand, age, ISS, and APACHE II scores (for the three studies reporting this score), are similar.

Lack of Uniformity in Composition of Enhanced Formulations:

The evidentiary table shows a lack of uniformity concerning the additives comprising the enhanced diets. While most recent enhanced formulas contain arginine, glutamine, omega-3 fatty acids, and nucleotides, one study compares two formulas which differ only in their glutamine concentrations.^[25]Another study features an enhanced formula that contains no glutamine but instead has added zinc, cysteine, and histidine to the arginine/ glutamine/omega-3 fatty acid/nucleotide mix.^[26]. Similarly, there is inconsistency in the composition of the control enteral formulation. In the study by Saffle et al, the control formula actually contains more glutamine, total protein, and omega-3 fatty acids than does the enhanced formula.^[27]

Lack of Consistent Outcome Parameters:

Despite the fact that we confined our analysis to studies with clinically relevant endpoints, the existing literature demonstrates a fairly broad array of outcome parameters. Recognizing that noneof the 10 prospective, randomized studies demonstrated a reduction in mortality associated with enhanced enteral formulations, various secondary outcome parameters were examined by the various authors. While there was consistency regarding some endpoints (hospital length of stay, ICU length of stay, ventilator days and overall septic morbidity), there was significant variability in others, particularly those involving sepsis (pneumonia rates, intra-abdominal abscess rates, major infection rates, bacteremia rates, antibiotic use). Some studies compare overall complication rates in addition to the more commonly reported septic morbidity rates. The use of the MSOF syndrome and ARDS as clinical endpoints was also inconsistent.

Lack of Consistent Time of Initiation of Enteral Feeding:

The time of initiation of enteral feeding varied from as early as 24 hours following admission to as late as 7 days, although 48 hours was the most frequently employed deadline (6 of 10 studies). One study did not specify a deadline for initiation of feedings but stated an attempt to institute early feeding.^[26] Atkinson et al. not only specified a 48-hour deadline for initiation but also limited their analysis to patients who received > 2.5L of formula within 72 hours of ICU admission.^[29] Although there appears to be no consensus regarding a specific absolute deadline for institution of enteral feedings, the concept of early enteral feeding is generally accepted, and therefore, attempts should be made to standardize this variable in future studies.

Lack of Consistent Duration of Enhanced Feeding:

Similarly, the duration of administration of enhanced formula feeding varies considerably in the selected studies. While most studies required a minimum of 5-7 days of assigned product infusion, one study required only 72 hours.^[22] Several studies did not specify a minimum or maximum duration of enteral feeding, but simply continued feedings until oral intake was adequate.^{[23] [26] [27] [30]}Others mandated that feedings be continued for a prescribed period of time^[21] or until ICU discharge.^[29] Given these observations, it is not surprising that the average number of days spent receiving the study formulations also varied considerably from a low of approximately 7 days^[22] to almost 4 weeks.^[26] Despite the fact that a minimum effective infusion volume or infusion duration for these enhanced enteral formulations has not been determined, future investigators should consider adopting a uniform prescribed course of therapy to facilitate data interpretation.

Inconsistency Regarding Supplemental Use of Parenteral Nutrition:

Two of the ten studies included in this section’s evidentiary table use TPN in addition to the studied enteral formulations.^{[26] [30]} In one study, 10 of 50 patients (20%) were provided TPN during approximately 50% of their study time, although the exact caloric and protein contribution of the TPN to the patient’s overall nutritional support is not stated.^[26] In the other study, TPN was provided to allpatients in significant amounts. While patients received their enteral formulations for an average of about 22 days, TPN accounted for the majority of protein and calorie intake for the first 6 days.^[30]Clearly, the use of TPN to these extents at best clouds the discernment of a potential benefit of enhanced enteral formulations.

Inconsistent Use of Isocaloric, Isonitrogenous Formulations:

Of the ten prospective, randomized, controlled trials reviewed here, only six involved comparisons of isocaloric, isonitrogenous formulations.^{[23-26] [29-30]} Two trials compare isocaloric but non-isonitrogenous diets,^{[22] [27]} and the remaining two studies compare diets, which are neither isocaloric nor isonitrogenous.^{[21] [28]} Given the well-documented association between increased protein feeding and improved outcomes,^[31] conclusions drawn from studies comparing non-isonitrogenous formulas must be viewed with considerable suspicion.

Inadequately Powered Studies:

Six of the 10 studies reviewed contained 50 or fewer patients.^{[21] [23] [24] [26] [27] [30]} Only two studies randomized more than 100 patients, and both are really ICU studies containing vastly different percentages (13% and 84%) of vaguely defined trauma patients.^{[28] [29]} Looking more closely at the eight remaining smaller studies, two demonstrated significant reductions in ventilator days, overall LOS, and various measures of septic morbidity,^{[22] [23]} one study identified statistically insignificant trends toward poorer outcomes,^[24] one noted no impact,^[27] and four studies reported mixed results.^{[21] [25] [26] [30]} Furthermore, no study, including both ICU studies, demonstrated a reduction in mortality with enhanced formulas. While larger studies are not likely to demonstrate an impact of enhanced feedings on mortality, they may yield more consistent results with regard to other clinical endpoints.

In light of the shortcomings identified in the currently existing literature, several studies, although they are prospective, randomized Class I trials, cannot be used to formulate recommendations in this guideline. Simply limiting our analysis to trials comparing isocaloric, isonitrogenous formulations without the supplemental use of TPN excludes six of the ten studies discussed in the evidentiary table.^{[21] [22] [26-28] [30]} Of the four remaining studies,^{[23-25] [29]} none focuses on patients with burns, and thus no recommendations can be made in this guideline with regard to the use of enhanced formulas in burn patients. One of the four studies is ICU-focused, with only 13% of the study participants being trauma patients, thus greatly limiting its applicability to this guideline.^[29]Another study focuses specifically on the impact of supplemental glutamine and therefore can only generate recommendations about this specific additive.^[25]

The remaining two studies reach conflicting conclusions, one citing improved outcomes^[23] and the other reporting statistically insignificant trends toward poorer outcomes.^[24] Both studies enrolled patients of similar injury severity, initiated enteral feedings within 3 days of hospital admission, and continued the enhanced diets for 9 to 10 days. There were, however, some significant differences among the four formulas in these two studies, which could explain some of the conflicting results.

First, the non-protein:calorie ratios of the formulas in the Mendez study were much greater (86,89) than the formulas compared in the study by Kudsk (52, 55). Thus, although the amounts of protein provided in the two studies were comparable, patients in the Mendez study received much greater caloric loads (26-27 kcal/kg/day by day 6 of feeding) than the patients in the study by Kudsk (~18 kcal/kg/day). Micronutrient composition of the formulas also varied. While the two formulas compared in the Kudsk study differed primarily in their glutamine, arginine, nucleotide, and w-3 fatty acid contents, there was no difference in the glutamine content of the two formulas compared in the Mendez study, and in fact, both formulas contained more glutamine than Kudsk’s enhanced formula. Furthermore, although Mendez’s enhanced formula contained almost twice the amount of arginine found in her control formula, there was a five-fold difference in arginine content between the two formulas in Kudsk’s study. Given these observations, one plausible explanation for the failure of Mendez to demonstrate an advantage with her enhanced formula is that the control formula contained too much glutamine relative to the enhanced formula, whereas the enhanced formula lacked sufficient arginine compared with the enhanced formula employed by Kudsk. Our explanation for the divergent conclusions reached by these two authors is supported by Houdijk’s work, which showed improved outcomes when a standard enteral formula was supplemented only with glutamine.^[25]

Beyond arginine and glutamine, there are also differences in omega-3 fatty acid content in these two studies (Mendez: 0 gm/L versus ~ 1.4 gm/L; Kudsk: 0.65 gm/L versus 1.1 gm/L), and only Kudsk’s enhanced formula contained a nucleotide supplementation at all (1.0 gm/L). Whether an additional nutritional impact can be ascribed to these two additives at these dosages is unclear, especially considering the 5- to 9-fold differences in glutamine and arginine concentrations in the two studies. Recognizing, therefore, the statistically significant improvement in outcomes reported by Kudsk, the statistically insignificant poorer outcomes noted by Mendez, and the differences in design and implementation between the two studies, we believe there is sufficient scientific support for a Level III recommendation for the use of enteral formulations enhanced with “adequate” doses of arginine and glutamine in severely injured trauma patients.

V. Summary

The currently existing medical literature regarding enhanced enteral formulations in severely injured patients is characterized by small numbers of inconsistently-defined patients who receive various non-comparable nutritional formulas for variable periods of time. Clinical outcome parameters are similarly poorly defined and/or agreed on. Until larger studies with improved methodology are completed, only a relatively weak recommendation can be made in severely injured patients (ISS >20, ATI >25) for the use of enteral formulations enhanced by the addition of arginine and/or glutamine. The specific impact of further supplementation with omega-3 fatty acids, nucleotides, and trace elements cannot be determined at this time. Similarly, the current literature gives no support to recommendations regarding the use of enhanced enteral formulas in patients with severe burns.

VI. Future Investigation

There is a dire need for additional studies that examine the role of enhanced enteral formulas in critically ill and injured patients. These studies must employ large numbers of well-defined subsets of trauma patients (ISS, ATI, GCS score, penetrating/blunt, burn), with well-designed feeding strategies (time of initiation of feedings, duration of enhanced feeding, use of supplemental TPN) that are consistent from study to study. Most importantly, the composition of both the control and the enhanced formulas must be isonitrogenous and isocaloric and must also be standardized with regard to arginine, glutamine, omega-3 fatty acid, nucleotide, and trace element content. Finally, investigators should design studies limited to mutually agreed on clinically relevant outcome parameters.

References

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5. Trocki O, Heyd TJ, Waymack JP, Alexander JW. Effects of fish oil on postburn metabolism and immunity. J Parenter Enteral Nutr. 1987;11:521-528.
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18. Beale RJ, Bryg DJ, Bihari DJ. Immunonutrition in the critically ill: a systematic review of clinical outcome. Crit Care Med. 1999;27:2799-2805.
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20. Anonymous Consensus recommendations from the US summit on immune-enhancing enteral therapy. J Parenter Enteral Nutr. 2001;25:S61-S63
21. Brown RO, Hunt H, Mowatt-Larssen CA, Wojtysiak SL, Henningfield MF, Kudsk KA. Comparison of specialized and standard enteral formulas in trauma patients. Pharmacotherapy. 1994;14:314-320.
22. Moore FA, Moore EE, Kudsk KA, Brown RO, Bower RH, Koruda MJ, Baker CC, Barbul A. Clinical benefits of an immune-enhancing diet for early postinjury enteral feeding. J Trauma. 1994;37:607-615.
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Table

Standard Versus Enhanced Nutritional Support Evidentiary Table