Nutritional Support: Monitoring (Which Tests and How Often?) (UPDATE IN PROCESS)

I. Statement of the Problem

Previous sections of this guideline contain recommendations regarding the quantity of calories and protein required by the trauma patient (see Section D -Assessment of Energy and Substrate Requirements for the Trauma Patient). The majority of these recommendations are based on formulas that provide, at best, only a rough estimate of the patient's nutritional needs, and thus the potential exists to either over- or under-feed any given patient. Therefore, some form of nutritional monitoring is essential to assess the adequacy of the initial nutritional prescription. There are a myriad of monitoring tests available, highlighting the fact that no single test can accurately assess the appropriateness of the nutritional support provided to the patient. Furthermore, any test used to monitor nutritional support must take into account the unique hypermetabolic response of the injured patient and the massive fluid shifts which occur in this patient population. Accordingly, nutritional monitoring tests which are reliable in the cancer or chronically malnourished patient may not be valid in the trauma patient. This section of the Nutritional Support of the Trauma Patient guideline reviews the available scientific literature to determine answers to the following questions:

1. Which nutrition monitoring tests best reflect the appropriateness of nutritional support in the trauma patient?
2. How often should nutritional monitoring be performed in the trauma patient?
3. Is there evidence to support improved outcomes when nutritional support is modified as a result of nutrition monitoring?

II. Process

A. Identification of References

References were identified from a computerized search of the National Library of Medicine for English language citations between 1974 and 2001. Keywords included: nutrition, monitoring, enteral nutrition, parenteral nutrition, albumin, nitrogen balance, indirect calorimetry, injury, and trauma. The bibliographies of the selected references were reviewed for relevant articles not found by the computerized search. Literature reviews, case reports, and editorials were excluded. Eighteen 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. No Class I articles were identified.

Class II: A prospective, non-comparative clinical study or a retrospective analysis based on reliable data. Fourteen articles were identified and analyzed.

Class III: A retrospective case series or database review. Four articles were identified and analyzed.

III. Recommendations

A. Level I

1. No recommendations

B. Level II

1. In head-injured patients, serum pre-albumin levels appear to correlate well with nitrogen balance. Albumin and transferin levels correlate poorly with nitrogen balance. Retinol binding protein also correlates well with nitrogen balance but lags behind pre-albumin.
2. In multi-trauma patients, serum pre-albumin levels appear to correlate well with nitrogen balance. Albumin levels correlate poorly with nitrogen balance.
3. In burn patients, there are insufficient data to make any recommendations regarding the correlation between serum levels of pre-albumin, retinol binding protein, or transferrin and nitrogen balance. However, serum levels of these proteins must be interpreted with caution as they are affected not only by nutritional state but also by other factors (age, burn wound size, post-burn day and nitrogen intake). Albumin levels correlate poorly with nitrogen balance.
4. Nitrogen balance calculation in burn patients may not be accurate due to inability to account for nitrogen losses via the burn wound.
5. When calculating nitrogen balance in burn patients, use of urinary urea nitrogen instead of total urinary nitrogen may result in overestimation of nitrogen balance.

C. Level III

1. Nitrogen balance is the gold standard for monitoring the appropriateness of a trauma patient’s nutritional prescription.
2. Serial determinations of serum levels of acute phase reactants (C-reactive protein, fibrinogen, alpha-1-glycoprotein, etc.), along with constituent proteins (pre-albumin, retinol binding protein, transferrin) may improve the latter’s value as a nutritional monitoring tool.

IV. Scientific Foundation

In an excellent review of nutritional monitoring in critically ill patients, Manning recommends that “nutritional assessment should be repeated frequently in patients requiring prolonged nutritional support, to assess the adequacy of the support provided and to guide adjustments to the nutritional regimen”.^[1] Unfortunately, in the case of the trauma patient, the scientific evidence to support this recommendation is weak overall, and in some instances, non-existent. Although a recommendation can be made for the relative superiority of pre-albumin as a marker for the adequacy of nutritional support, there certainly are no data to suggest how often this laboratory parameter should be repeated. Nor is there evidence to suggest that adjustments to the nutritional regimen based on the pre-albumin level or any other monitoring tool will improve patient outcome. As Manning states, "whether improved nutritional state is directly responsible for the improvement in the condition of a sick patient or whether the patient's recovery leads to improvement in these measures of nutritional status is unclear". ^[1] Although firm scientific evidence is lacking, it seems intuitive that, in the catabolic trauma patient, nitrogen balance studies would provide the best evidence of adequacy of the nutritional support prescription. According to Manning, "improvement in nitrogen balance is a single nutritional parameter most consistently associated with improved outcomes, and the primary goal of nutritional support should be the attainment of nitrogen balance".^[1] Winkler agrees. "Because nitrogen balance measures the net effect of protein synthesis and degradation, it should be the standard against which other tests are compared".^[2] Thus, there appears to be adequate scientific support for a Level III recommendation establishing nitrogen balance as the "gold standard" for nutritional monitoring. However, the accurate determination of nitrogen balance is fraught with difficulty, both in terms of assuring complete collection of nitrogenous waste (urine, feces, wound exudate, etc.) and in the mathematical calculation of nitrogen balance itself.

Specifically, the use of the Urinary Urea Nitrogen (UUN) in the calculation of nitrogen balance, as opposed to the total Total Urea Nitrogen (TUN), can possibly lead to a significant overestimation in nitrogen balance in burn patients.^[3] Iapichino, in a series of multiply injured patients receiving parenteral nutrition, demonstrated that nitrogen output was remarkably constant during the first 6 days after trauma and that nitrogen balance was primarily determined by the nitrogen intake^[4]. Thus, nitrogen output, if properly determined, might not need to be repeated frequently, at least early on following trauma. Given the theoretical, as well as practical, concerns associated with nitrogen balance determinations in trauma patients, additional monitoring tools are needed that correlate well with nitrogen balance. Thus, for this section of the guideline, particular emphasis was placed on studies that used nitrogen balance as the "gold standard." Only one study cited in the evidentiary table claims a monitoring tool to be superior to nitrogen balance. However, this study contained a small number of subjects, and the criteria employed for "successful" nutritional outcomes included gains in body weight and serum albumin, parameters widely accepted as unreliable in burn and trauma patients.^[5]

Multiple diagnostic tests have been proposed to monitor the response to nutritional support. For classification purposes, these tests can be placed into one of the following categories: body measurements (weight change, anthropometric determinations, etc.), body composition studies (determinations of body fat, lean body mass, total body water, etc.), urine analyses for metabolic byproducts (urea, creatinine, etc.), immunological tests (antibody production, delayed hypersensitivity skin tests, etc.), functional tests (handgrip strength, etc.), and serum chemistry analyses (albumin, pre-albumin, etc.).^[6] The interested reader is referred to the excellent review by Manning for a more thorough listing and discussion of these particular tests.^[1] Many of these tests are insufficiently sensitive or specific for clinical use in any patient population, while others have been used primarily in research settings. For the trauma patient in particular, there is insufficient literature support for the use of any of these tests for nutritional monitoring purposes with the exception of serum chemistry assays and calorimetric studies. Recommendations provided within this guideline, therefore, are limited to these two categories of monitoring tests.

Spiekerman has outlined the requirements for the ideal serum protein to be used for nutritional assessment purposes. These requirements include a short biological half-life, a relatively small body pool, a rapid rate of synthesis, and a constant catabolic rate. In addition, the protein marker to be followed should reflect the entire protein compartment status by measurable concentration changes in the serum levels of the protein and should be responsive only to protein and energy restrictions.^[7]By far, the most commonly assayed serum proteins used in nutritional monitoring are albumin, pre-albumin, transferrin, and retinol binding protein. Other proteins that have been used for monitoring purposes include somatomedin C (insulin-like growth factor-1) and fibronectin. These six serum proteins are compared as to their suitability for nutritional monitoring purposes in Table 1 below.^{[2] [7-9]}

Despite being easy to measure on a serial basis and relatively inexpensive, the measurement of serum protein levels in trauma patients may not accurately reflect nutritional status for several reasons. First, capillary permeability is increased in critical illness, causing a loss of protein from the intravascular compartment. Secondly, the massive fluid shifts that occur in trauma patients may compound the apparent hypoproteinemia via a hemodilution mechanism. Finally, trauma is associated with a profound up-regulation in the acute phase response, resulting in a shift in protein synthesis toward acute phase proteins, such as C-reactive protein and others, and a net decrease in synthesis of constitutive proteins, including albumin and pre-albumin. Thus, it has been suggested that the increase in serum levels of the short-lived constitutive proteins (pre-albumin, transferrin, retinol binding protein) may not, in fact, be a reflection of appropriate nutritional support but rather a reflection of resolution of the acute phase response, with restoration of constitutive protein synthesis.^{[1] [7]} These authors have therefore recommended simultaneous measurement of the levels of acute phase proteins along with constitutive proteins, to better identify this reprioritization in protein synthesis. It may be that the impact of appropriate nutritional support, as reflected in increasing levels of short-lived constitutive proteins, may only be evident after resolution of the acute phase response.

As shown in Table 1, albumin is unsuitable as a marker of the acute efficacy of nutritional support. This appears to be due primarily to its long half-life and its high exchange rate between the intravascular and extravascular fluid compartments, which is ten times higher than its synthetic rate.^[1] Consequently, changes in serum albumin level lag significantly behind those seen with nitrogen balance. Boosalis documented this phenomenon in 20 burn patients and 27 patients with head injuries. In this series, pre-albumin levels reflected changes in nitrogen balance much more quickly than did serum albumin levels.^[10] Similar observations were made by Vehe and Erstad in trauma patients^{[11] [12]} and by Brose in burn patients.^[9] An ancillary observation in the latter study was that serum levels of both albumin and pre-albumin appeared to be affected not only by nutritional status but also by the extent of the burn injury; albumin and pre-albumin levels were lower in patients with total body surface area burns exceeding 40%.^[9] Carlson, in a small series of thermally injured patients, noted similar findings, concluding that serum levels of pre-albumin, transferrin, and retinol binding protein, though reflective of nutritional status, also appeared to be affected by the extent of the burn injury, patient age, post burn day, and nitrogen intake. Serum albumin levels correlated poorly with nitrogen balance.^[13] Finally, the improved performance of pre-albumin relative to albumin was also demonstrated in a prospective study of elderly women undergoing hip fracture repair, although no comparison with the nitrogen balance studies was made.

These studies, taken together, reveal a pattern of improved performance of pre-albumin as a monitoring tool for nutritional support relative to serum albumin levels. Design of the various studies, however, precludes a recommendation regarding the frequency of serum pre-albumin determinations, with some authors making these determinations on a daily basis, while others only on a weekly basis.

In addition to serum pre-albumin, other serum markers have been investigated as nutritional monitoring tools. In a relatively large study of 45 head-injured patients, only pre-albumin and retinol binding protein were found to correlate with nitrogen balance, with pre-albumin performing better than retinol binding protein. Serum transferrin and albumin levels did not correlate with nitrogen balance.^[15] These same four serum proteins were used to monitor the response to two parenteral diets that differed only in their nitrogen content. Although nitrogen balance was better in the high nitrogen group, no difference was noted between the two groups with respect to any of the serum protein levels. However, it is important to note that positive nitrogen balance was never achieved in either of the two groups, nor was there even a trend of improving nitrogen balance ^[16].

Several authors have questioned the monitoring capabilities of these serum proteins. Lown was unable to document an increase in transferrin or pre-albumin level despite providing 3 weeks of nutritional support. However, only six patients were included in this study, and nitrogen balance studies were not performed.^[17] Clark attempted to correlate pre-albumin and transferrin levels, not with nitrogen balance but with measurements of total body protein. No correlation was noted between total body protein, which fell significantly through study day 15, and serum levels of pre-albumin, transferrin, or insulin-like growth factor-1, which showed significant increases throughout the same time period. Once again, no nitrogen balance studies were performed, and it was suggested that these increases in serum protein levels may be related more to restoration of hepaticconstituitive protein synthesis than they are markers of nutritional progress.^[18] Rettmer performed a comparison of serum protein levels against functional tests of nutritional status as measured against nitrogen balance. Although there was poor correlation between serum protein levels and positive nitrogen balance, serum protein levels were determined only once during the study, on post-burn day 15, thus precluding any possibility of detecting a trend of improvement in these serum markers. Furthermore, the authors acknowledged the possibility that their nitrogen determinations might not have been accurate due to inability to measure nitrogen losses from the burn wound.^[19] This inability to quantitate protein loss from burn wounds is a major obstacle in performing accurate nitrogen balance studies in this patient population. Waxman attempted to quantitate this protein loss through the use of occlusive wound sponges, the effluent from which was then analyzed for total protein, albumin and globulin content. Protein losses were found to fluctuate throughout the post-burn course and were affected by dressing type as well as wound care.^[20] Thus it seems that protein loss via burn wounds will continue to be a source of potential error, both in the clinical and the research environment in this patient group.

Two studies have evaluated the potential of fibronectin and somatomedin C to serve as markers of nutritional progress in patients receiving enteral feedings. One study demonstrated significant correlations between fibronectin levels and nitrogen balance,^[21] while the other study demonstrated significant correlations between somatomedin C and nitrogen balance.^[22] Both of these serum markers have demonstrated promise as nutritional monitoring tools in other patient populations;^[23-27]however, their use in trauma patients cannot be recommended at this time based on the available scientific literature. Similarly, the use of indirect calorimetry as a monitoring tool for patients with thermal injury cannot be recommended based on the existing literature. In the single prospective study evaluating this technology in burn patients, there were significant variations in resting energy expenditure observed, both within the entire patient group over the course of burn wound closure, and also in individual patients, with daily fluctuations as large as 100%. Although adjustments in nutritional support were made on the basis of data derived from indirect calorimetry, there is no evidence to suggest that this improved patient outcome.^[28] A small retrospective study in burn patients compared caloric balance (using indirect calorimetry) with nitrogen balance as nutritional monitoring tools, concluding that the former correlated better with good nutritional outcomes. However, the criteria used by the authors for "good" nutritional outcomes included gains in body weight and serum albumin, parameters widely accepted as unreliable in burn and trauma patients.^[5]

V. Summary

Serial monitoring of the response to nutritional support can be performed, although there is no evidence to suggest that this practice improves clinical outcomes. Nitrogen balance determination, if performed correctly, is likely the best currently available means of assessing the adequacy of nutritional support, and is the standard to which all other monitoring tests should be compared. However, difficulties in specimen collection and mathematical computation may result in significant overestimations in nitrogen balance, particularly in burn patients. Serial determination of serum pre-albumin levels seem to correlate reasonably well with nitrogen balance determinations in trauma and burn patients, although there is no evidence available to recommend how often monitoring should be carried out.

VI. Future Investigation

Much work remains to be done in the field of nutrition monitoring. Serum protein markers, due to their simplicity, ready availability, and relatively low cost, will likely remain the mainstay of nutritional monitoring tests in the future. Prospective randomized studies are needed to identify the optimal serum protein marker and the frequency with which it should be assayed. Most importantly, prospective studies are needed to determine whether changes in the nutritional prescription based on routine nutritional monitoring actually improve patient outcomes.

References

1. Manning EM, Shenkin A. Nutritional assessment in the critically ill. Crit Care Clin. 1995;11:603-634.
2. Winkler MF, Gerrior SA, Pomp A, Albina JE. Use of retinol-binding protein and prealbumin as indicators of the response to nutrition therapy. J Am Diet Assoc. 1989;89:684-687.
3. Konstantinides FN, Radmer WJ, Becker WK, et al. Inaccuracy of nitrogen balance determinations in thermal injury with calculated total urinary nitrogen. J Burn Care Rehabil.1992;13:254-260.
4. Iapichino G, Radrizzani D, Solca M, et al. The main determinants of nitrogen balance during total parenteral nutrition in critically ill injured patients. Intensive Care Med. 1984;10:251-254.
5. Mancusi-Ungaro HR, Jr., Van Way CW, McCool C. Caloric and nitrogen balances as predictors of nutritional outcome in patients with burns. J Burn Care Rehabil. 1992;13:695-702.
6. Burritt MF, Anderson CF. Laboratory assessment of nutritional status. Hum Pathol.1984;15:130-133.
7. Spiekerman AM. Proteins used in nutritional assessment. Clin Lab Med. 1993;13:353­369.
8. Mattox TW, Teasley-Strausburg KM. Overview of biochemical markers used for nutrition support. Dicp. 1991;25:265-271.
9. Brose L. Prealbumin as a marker of nutritional status. J Burn Care Rehabil. 1990;11:372-375.
10. Boosalis MG, Ott L, Levine AS, et al. Relationship of visceral proteins to nutritional status in chronic and acute stress. Crit Care Med. 1989;17:741-747.
11. Erstad BL, Campbell DJ, Rollins CJ, Rappaport WD. Albumin and prealbumin concentrations in patients receiving postoperative parenteral nutrition. Pharmacotherapy. 1994;14:458-462.
12. Vehe KL, Brown RO, Kuhl DA, Boucher BA, Luther RW, Kudsk KA. The prognostic inflammatory and nutritional index in traumatized patients receiving enteral nutrition support. J Am Coll Nutr. 1991;10:355-363.
13. Carlson DE, Cioffi WG, Jr., Mason AD, Jr., McManus WF, Pruitt BA, Jr. Evaluation of serum visceral protein levels as indicators of nitrogen balance in thermally injured patients. JPEN J Parenter Enteral Nutr. 1991;15:440-444.
14. Bastow MD, Rawlings J, Allison SP. Benefits of supplementary tube feeding after fractured neck of femur: a randomised controlled trial. Br Med J (Clin Res Ed). 1983;287:1589-1592.
15. Nataloni S, Gentili P, Marini B, et al. Nutritional assessment in head injured patients through the study of rapid turnover visceral proteins. Clin Nutr. 1999;18:247-251.
16. Shenkin A, Neuhauser M, Bergstrom J, et al. Biochemical changes associated with severe trauma. Am J Clin Nutr. 1980;33:2119-2127.
17. Lown D. Use and efficacy of a nutrition protocol for patients with burns in intensive care. J Burn Care Rehabil. 1991;12:371-376.
18. Clark MA, Hentzen BT, Plank LD, Hill GI. Sequential changes in insulin-like growth factor 1, plasma proteins, and total body protein in severe sepsis and multiple injury. JPEN J Parenter Enteral Nutr. 1996;20:363-370.
19. Rettmer RL, Williamson JC, Labbe RF, Heimbach DM. Laboratory monitoring of nutritional status in burn patients. Clin Chem. 1992;38:334-337.
20. Waxman K, Rebello T, Pinderski L, et al. Protein loss across burn wounds. J Trauma.1987;27:136-140.
21. Buonpane EA, Brown RO, Boucher BA, Fabian TC, Luther RW. Use of fibronectin and somatomedin-C as nutritional markers in the enteral nutrition support of traumatized patients.Crit Care Med. 1989;17:126-132.
22. Mattox TW, Brown RO, Boucher BA, Buonpane EA, Fabian TC, Luther RW. Use of fibronectin and somatomedin-C as markers of enteral nutrition support in traumatized patients using a modified amino acid formula. JPEN J Parenter Enteral Nutr. 1988;12:592-596.
23. McKone TK, Davis AT, Dean RE. Fibronectin. A new nutritional parameter. Am Surg.1985;51:336-339.
24. Clemmons DR, Underwood LE, Dickerson RN, et al. Use of plasma somatomedin-C/insulin-like growth factor I measurements to monitor the response to nutritional repletion in malnourished patients. Am J Clin Nutr. 1985;41:191-198.
25. Hawker FH, Stewart PM, Baxter RC, et al. Relationship of somatomedin-C/insulin-like growth factor I levels to conventional nutritional indices in critically ill patients. Crit Care Med.1987;15:732-736.
26. Isley WL, Underwood LE, Clemmons DR. Changes in plasma somatomedin-C in response to ingestion of diets with variable protein and energy content. JPEN J Parenter Enteral Nutr.1984;8:407-411.
27. Unterman TG, Vazquez RM, Slas AJ, Martyn PA, Phillips LS. Nutrition and somatomedin. XIII. Usefulness of somatomedin-C in nutritional assessment. Am J Med. 1985;78:228-234.
28. Saffle JR, Medina E, Raymond J, Westenskow D, Kravitz M, Warden GD. Use of indirect calorimetry in the nutritional management of burned patients. J Trauma. 1985;25:32-39.

Table

MONITORING NUTRITIONAL SUPPORT in the TRAUMA PATIENT