Annals of Burns and Fire Disasters   vol. XI   n. 2   June 1998

VARIATIONS IN NUTRITIONAL PARAMETERS AFTER THERMAL INJURY IN MAN

Bollero D., Giannotti L. Stella M.,Broglio F. Calcagni M., Ghigo E. Magliacani G.

Department of Plastic Surgery, CTO Burn Centre, Turin, Italy
Division of Endocrinology, Department of Internal Medicine, University of Turin

SUMMARY. In spite of optimized artificial nutrition, the development of malnutrition is often rapid in critically ill patients. This particularly applies to  burn patients, in whom dramatic metabolic and hormonal alterations occur. The aim of this study was to define the variations of nutritional parameters, including IGF I levels, in burn patients. To this goal, in 22 burn patients (mean age ± SEM, 46.5 ± 3.4 yr; BMI, 24.9 ± 0.9 M2; % burn surface area 26.0 ± 3.0%; ROI score, 0.22 ± 0. 1) we evaluated prealburnin (pre A), al burnin (A) and transferrin (TRA) as well as IGF I levels on days 1, 3, 7, 14 and 28. On day I post burn, pre A (18.5 ± 2.1 mg/dl), A (3.5 ± 0.2 g1l) and TRA (158.0 ± 13.0 mg/dl) were lower than the normal range, while IGF I levels were still in the low normal range (120.2 ± 11.2 pg/1). Pre A, A and TRA underwent a further decrease, with the lowest point on day 7, for pre A and TRA (7.1 ± 0.6 rng/dI and 103.0 ± 6.5 mg/dI, respectively), and later, on day 14, for A (2.7 ± 0.2 g/dl). A rebound increase was observed from day 7 for pre A and TRA until day 28 (20.3 ± 1.6 mg/dl and 165.5 ± 13.0 mg/dI, respectively), when these parameters were in the normal range. On day 28, A levels persisted lower than the normal range (3.0 ± 0.2 g/dl). IGF I levels showed a progressive decrease until day 14 (86.9 ± 10.9 pg/1), when they were as low as in hypopituitaric patients with severe growth hormone deficiency. IGF I levels then increased and on day 28 (p < .05) they were again in the low normal range (127.4 ± 19.0 pg/1). A levels, but not pre A and TRA levels, showed a negative correlation to burn extent and ROI score (r =  .07; p < .05) on days 3 and 7 only, while IGF I levels were not associated either with other nutritional parameters or with burn extent and ROI score. These findings indicate that in burn patients pre A, A and TRA levels, but not IGF I levels, are reduced within a few hours post  burn. Pre A and TRA show a faster recovery and are normal one month after thermal injury, when A levels still are reduced. IGF I levels show a delayed decrease, which is as marked as in hypopituitaric patients with severe GH deficiency, on day 14 post burn. One month after the burn lGF I levels are normalized. These findings confirm the usefulness of IGF I as a marker of nutritional status, together with al burnin, prealburnin and transferrin as a marker of nutritional status, although only al burnin levels are associated with the severity of the injury and could have prognostic value.

Introduction

Malnutrition rapidly occurs in critically ill patients with sepsis and severe trauma and particularly following  burns when dramatic metabolic and hormonal alterations are present. In burn patients hypermetabolism associated with protein and fat catabolism, negative nitrogen balance, hyperglycaemia and insulin resistance is a frequent occurrence` and the response to nutritional support is only slight. The increase in capillary permeability due to an extensive  burn, particularly when associated with sepsis, further impairs the degree of hypoproteinemia. As a result, in burned patients, the progressive loss of body cell mass, particularly of muscle mass, is a common development ......
The monitoring of nutritional status is thus of major importance in order to provide adequate support. Preal burnin (pre A) is a sensitive marker of protein deficiency, as it is a rapid turnover protein and its synthesis in the liver promptly reflects protein deficiency and refeeding. 
Serum al burnin (A) and transferrin (TRA) are other markers of nutritional status. However, A is an insufficiently sensitive marker of rapid change in protein metabolism, particularly when compared with pre A and TRA; in fact, both TRA and pre A reliably reflect rapid changes in protein balance while A levels do not show significant variations, even after prolonged protein restriction.
More recently, the evaluation of IG17 1 levels has received great attention as another marker of nutritional status." IGF 1 is a hormone endowed with endocrine and paracrine/autocrine action and its synthesis and release depend on growth hormone (GH) secretion` and nutritional factors, mainly amino acids and glucose ...... Other hormones, such as insulin, glucocorticoids, thyroid hormones and gonadal steroids, also influence IGF 1.
Evidence that amino acids and glucose play a critical role in IG17 1 synthesis favoured the hypothesis that this hormone could be a sensitive marker of nutritional status. 20 This hypothesis has been demonstrated` and IG17 1 is clearly reduced in malnourished, diabetic and critically ill patients In cases of malnutrition, reduced IG17 1 synthesis reflects peripheral resistance to the bioactivity of GH, the secretion of which is frequently enhanced. 26 On the basis of these premises, this study defines variations in nutritional parameters following thermal injury until day 28 post burn in patients admitted to a burn unit receiving artificial nutrition in order to cover their caloric and protein needs.

Patients and methods

The study was conducted in the CTO Hospital Burn Centre in Turin on adult patients after thermal injury.
From July to December 1996, 22 subjects admitted to our burn centre following a major thermal injury were considered for enrolment in the study. Patients considered eligible for inclusion in the study were 20 60 yr of age and 80 110% of ideal weight, had no history of hepatic, renal or cardiac failure or severe chronic disease, cancer disease, diabetes mellitus or pre existing metabolic disorders, and were free of glucocorticoid therapy and recent chemotherapy. The patients arrived at the burn unit within 24 h of their burn injury. The ROI score 2 and burn surface area were determined on admission. The initial treatment was intravenous rehydration therapy following the Parkland formula, using lactated Ringers solution, after which artificial nutrition (entero parenteral) commenced (40% carbohydrates, 35% fat and 10% protein: 8 10 g N). The patients received insulin in order to maintain glucose levels lower than 180 mg/dl.
The total amount of calories was calculated following the Curreri formula (approximately 25 kcal/kg + 40 kcal/% burn).
Enteral nutrition with Osmolyte was initiated 6 8 h after admission to the burn unit. After the second 24 h parenteral nutrition began via a central vein.
Blood and plasma products, al burnin, antibiotics and analgesics were administered when needed. Of the 22 patients, 18 developed sepsis within the first 10 days post­burn. Clinical details of the patients are given in Table I.
Patients were studied for 28 days after admission to the burn centre: observations were recorded at five different times: within 24 h of admission (day 1) and on days 3, 7, 14 and 28 of burn unit stay.
On day 1 patients underwent the following:

• physical examination, including determination of body mass index (BMI) and evaluation of protocol inclusion/exclusion criteria
• calculation of ROI score
• laboratory tests, as reported below

All laboratory tests were repeated on days 3, 7, 14 and 28. Blood samples were collected through a central venous access; in all patients the lines were prepared for clinical utilization, independently of the study. The determinations included routine tests, such as complete blood count, platelets and electrolytes, and nutritional parameters such as insulin like growth factor 1 (IGF 1), al burnin (A), preal burnin (pre A) and transferrin (TRA). The normal range levels for pre A, TRA and A were 21 42 mg/dl, 168 302 mg/dl and 3.6 5.2 g/dl, respectively, while the normal range levels for IGF 1, calculated in a population of 256 normal adults aged 20 60 yr, were 76­320 pg/1. The values are expressed as mean ± SEM. The statistical analysis of the data was carried out using the Kruskall Wallis ANOVA test and the Mann Whitney U test where appropriate.

Results

On post  burn day 1, pre A, A and TRA were lower than the normal range (18.5 ± 2.1 mg/dI, 3.5 ± 0.2 g/l and 158.0 ± 13.0 mg/dl, respectively), while IGF I levels were still in the low normal range (120.2 ± 11.2 pg/1).
Pre A, A and TRA underwent a further decrease, with a low point on day 7 for pre A and TRA (7.1 ± 0.6 mg/dl and 103.0 ± 6.5 mg/dI, respectively) and on day 14 for A (2.7 ± 0.2 g/dl).
A rebound increase was observed from day 7 for pre­A and TRA until to day 28 (20.3 ± 1.6 mg/dI and 165.5 ± 13.0 mg/dI, respectively), when these parameters were in the normal range. A levels remained lower than the normal range (3.0 0.2 mg/dl).
IGF I levels showed a progressive decrease up to day 14 (86.9 ± 10.9 pg/1), when they were as low as in hypopituitaric patients with severe GH deficiency. IGF I levels then increased and on day 28 (p < .05) they were again in the low normal range (127.4 ± 19.0 pg/1). The results are summarized in Fig. 1.
A levels (but not pre A and TRA levels), showed a negative correlation to  burn extent and ROI score (r =  .07; p < .05) on days 3 and 7 (Fig. 2) only, while IGF I levels were not associated either with either other nutritional parameters or with  burn extent and the ROI score.

Discussion
Our findings indicate that in the  burn patients we treated preal burnin, al burnin and transferrin levels (but not IGF 1 levels) were reduced within a few hours of the trauma. Preal burnin and transferrin showed a more rapid return to normal, within a month of the thermal injury, when al burnin levels were still reduced. IGF 1 levels showed a delayed decrease which was as marked as that observed in hypopituitaric patients with severe GH deficiency on day 14 post burn. IGF 1 levels were normalized one month post burn. According to other studies, preal burnin, al burnin and transferrin levels show a prompt reduction (within 24 h) after a thermal injury and present a further reduction in the first week after admission to the  burn unit.

This progressive reduction of classical nutritional parameters is concomitant with the prompt development of the hypercatabolism that characterizes the first week after thermal injury.2,4,2 As widely demonstrated by previous studies, this first phase of the disease is characterized by a marked impairment of nutrient uptake and utilization, leading to progressive loss of muscle and 2 adipose mass. The loss of muscle mass occurs in spite of optimized and enriched nutrition which normally prevent the loss of fat mass.
The monitoring of classical protein markers, such as al burnin and, in particular, prealburnin and transferrin, is of major importance for the evaluation of nutritional status. It also helps in the prediction of the outcome and in decisions regarding therapeutical support.
Confirming evidence that metabolic status improves by the second week after  burn unit admission, 2 prealburnin and transferrin levels showed a progressive increase and reached normal levels on day 28. This means that an optimized artificial nutrition had been provided, preventing prolonged protein catabolism. In the present study, parameters of energy expenditure, such as indirect calorimetry and the measurement of nitrogen balance, were not evaluated, and we were thus unable to demonstrate a direct association between the progressive reduction of hypermetabolism and protein marker improvement.
In agreement with evidence that al burnin is not a sensitive and prompt marker of changes in protein metabolism, al burnin levels persisted below normal limits after 28 days and in presence of normal preal burnin and transferrin levels. Al burnin levels are strongly influenced by skin loss and infection and nearly all burn patients suffer sepsis.
The prognostic value of al burnin has been pointed out, mainly on the evidence that it shows a close negative association with burn extent and the ROI score, at least in the first week post burn. This evidence is clearly confirmed in the present study (Fig. 2), in which no association was found with any other biochemical or hormonal parameter.
In the present study, it is interesting to note that a slight IGF 1 reduction was already apparent on day 1, i.e. within 12 24 h of thermal injury, indicating IG17 1 as a sensitive marker of rapid variation in nutritional balance, in agreement with other studies .4,12 IGF 1 progressively decreased until day 14, when the values were comparable with those of hypopituitaric patients with severe GH deficiency, suggesting severe impairment of IGF 1 synthesis and release.

Fig. 1   Variation of pre A, TRA, A and lGF-l from day 1 to day 28.

Fig. 2   Correlation al burnin/R01 score and al burnin/ burned surface area on day 3.

This finding implies that IGF 1 synthesis and release reflect an improvement in protein metabolism later than pre A and TRA and that they depend on some other regulation mechanism.` This could be due to the persistence of peripheral GH resistance" and/or to the marked impact of sepsis on IGF 1 synthesis In effect, some relationships between IGF 1 and cytokines such as interleukins and TNF, which are strongly elevated during sepsis, have been reported ......IGF-I levels progressively increased between days 14 and 28; IGF 1 levels on day 28 were in the low normal range, at variance with A levels which were persistently reduced. This means that adequate nutritional support had been provided and that GH secretion and sensitivity were almost completely restored.
In conclusion, these findings confirm the usefulness of IGF 1, together with al burnin, preal burnin and transferrin, as markers of nutritional status, although only A levels are associated with the severity of the injury and could have prognostic value.

RESUME. La clinique des Brûlures et de Chirurgie Plastique du Centre Hospitalier Universitaire de Tirana en Albanie soccupe dun large éventail de maladies chirurgicales. Une grande partie de cette activité concerne les séquelles des brûlures. Les Auteurs présentent une description générale de cette activité pendant 1996, suivie par des observations sur le traitement chirurgical des séquelles des brûlures. Après une comparaison entre les divers groups des pathologies traitées avec des interventions chirurgicales, ils présentent limage chirurgicale de leur clinique et discutent les conceptions médicales à la base dune clinique de ce type. Les données statistiques indiquent clairement que la propagande médicale, les recherches et le contrôle à long terme sont les moyens les plus efficaces pour prévenir les brûlures et leur séquelles.

BIBLIOGRAPHY

1. Meguin M.M., Brennan M.F., Aoki T.T. et al.: Hormone substrate interrelationships following trauma. Arch. Surg., 109: 776 83, 1974.
2. Frayn K.N.: Hormonal control of metabolism in trauma and sepsis. Clin. Endocrinol., 24: 577 99, 1986.
3. Voerman H.J., Greneveld A.B.J., de Boer H. et al.: Time course and variability of the endocrine and metabolic response to severe sepsis. Surgery, 114: 951 9, 1993.
4. Nygren J., Sammann M., Malm M. et al.: Distributed anabolic hormonal patterns in burned patients: the relation to glucagon. Clin. Endocr., 43: 49t 500, 1995.
5. Nordestrom J., Carpentier Y.A., Askanazi J. et al.: Free fatty acid mobilization and oxidation during total parenteral nutrition in trauma and infection. Ann. Surg., 198: 725 35, 1983.
6. Ming Yu Y., Young VR., Castillo L. et al.: Plasma arginine and leucine kinetics and urea production rates in  burn patients. Metabolism, 44: 659 66, 1995.
7. Nguyen T.T., Gilpin D.A., Meyer N., Hemdon D.N.: Current treatment of severely burned patients. Ann. Surg., 223: 14 25, 1996.
8. Pereira JL., Garrido M., Gomez Cia T. et al.: Enteral nutrition in  burn patients. Nutr. Hosp., 7: 340 5, 1992.
9. Golden M.H.N.: Transport proteins as indices of protein status. Am. J. Clin. Nutf., 35: 1159 65, 1982.
10. Wolfe R.R.: Nutrition and metabolism in  burns. Critical care, 7: 19­23, 1986.
11. Hemdon D.N., Curreri R.W., Abston S. et al.: Treatment of burns. Current problems in surgery, 2: 347 73, 1987.
12. Abribat T., Brazeau P., Davignon I., Garret D.R.: Insulin like growth factor I blood levels in severely burned patients: effects of time post injury, age of patient and severity of  burn. Clin. Endocrinol., 39: 583 9, 1993.
13. Jeejebhoy K.N., Baker J.P., Wolman S.L. et al.: Critical evaluation of the role of clinical assessment and body composition studies in patients with malnutrition and after total parenteral nutrition. Am. J. Clin. Nutr.: 1117 27, May 1982.
14. Ingenbleek Y., De Visscher M., De Nayer P.: Measurement of preal burnin as index of protein calorie malnutrition. Lancet, 106 9: July 15, 1972.
15. Clemmons D.R., Klibanski A., Underwood L.E. et al.: Reduction of plasma immunoreactive somatomedin C during fasting in humans. J. Clin. Endocrinol. Metab., 53: 1247 51, 1981.
16. Isley W.L., Underwood L.E., Clemmons D.R.: Dietary components that regulate serum somatomedin C concentrations in humans. J. Clin. Invest., 71: 175 82, 1983.
17. Donahue S.P., Phillips L.S.: Response of IGF I to nutritional support in malnourished hospital patients: a possible indicator of short tenil changes in nutritional status. Am. J. Clin. Nutr., 52: 39 44, 1990.
18. Jacob V., Le Carpentier J.E., Salzano S. et a].: IGF 1, a marker of undemutrition in haemodialysis patients. Am. J. Clin. Nutr., 52: 39­44, 1990.
19. Minuto F., Barreca A.., Adami G.F. et al.: IGF I in human malnutrition: relationship with some body composition and nutritional parameters. J. Parent. Ent. Nutr., 13: 392 6, 1989.
20. Thissen J.P., Ketelstegers J.M., Underwood L.F.: Nutritional regulation of insulin like growth factors. Endocr. Rev., 15: 80 5, 1994.
21. Furlanetto R.W.: Insulin like growth factor measurements in the evaluation of growth hormone secretion. Horm. Res., 33: 25 30, 1990.
22. Clemmons D.R., Underwood L.E.: Nutritional regulation of IGF I and IGF I binding protein. Ann. Rev. Nutr., 11: 393 412, 1991.
23. Jones J.1., Clemmons D.R.: Insulin like growth factors and their binding proteins: biological actions. Endocr. Rev., 16: 3 34, 1995.
24. Phillips L.S., Unterman T.G.: Somatomedin activity in disorders of nutrition and metabolism. Clin. Endocrinol. Metab., 13: 145 80, 1995.
25. Donaghy A., Ross R., Gimson A. et al.: Growth hormone, insulin­like growth factor 1, and insulin like growth factor binding protein­I e 3 in chronic liver disease. Hepatology, 21: 680 8, 1995.
26. Jenkins R.C., Ross R.J.M.: The endocrinology of the critically ill. Current opinion in endocrinology and diabetes, 3: 138 45, 1996.
27. Ross R.J.M.: Acquired growth hormone resistance. Eur. J. Endo­crinol., 132: 655 60, 1995.
28. Roi L.D., Flora J.D., Davis T.M. et al.: Two new  burn severity indices. J. Trauma, 23: 1023 30, 1983.
29. Tredget E.E., Yu Y.M.: The metabolic effects of thermal injury. World J. Surgery, 16: 68 79, 1992.
30. Cammani F., Aimaretti G.L., Gianotti L. et al.: New approach to the diagnosis of GH deficiency in adults. Fur. J. Endocrinology, 5: 122 34, 1996.
31. Bentham J., Rodriguez Amao J., Ross R.J.M.: Acquired growth hormone resistance in patients with hypercatabolism. Horm. Res., 40: 87 91, 1993.
32. Dahn M.S., Lange M.P., Jacobs L.A.: Insulin like growth factor I production is inhibited in human sepsis. 123: 1409 14, 1988.
33. Peisen J.N., McDonnel K.J., Mulroney S.E., Lumpkin M.D.: Endotoxin induced suppression of the somatotropic axis is mediated by interleukin I and corticotropin releasing factor in the juvenile rat. Endocrinology, 136: 3378 90, 1995.
34. Spath Schwalbe E., Schrezenmeier H., Bornstein S. et al.: Endocrine effects of recombinant interleukin 6 in man. Neuro­endocrinology, 63: 237 43, 1996.