The use of exenatide in severely burned pediatric patients

Gabriel A Mecott, David N Herndon, Gabriela A Kulp, Natasha C Brooks, Ahmed M Al-Mousawi, Robert Kraft, Haidy G Rivero, Felicia N Williams, Ludwik K Branski, Marc G Jeschke, Gabriel A Mecott, David N Herndon, Gabriela A Kulp, Natasha C Brooks, Ahmed M Al-Mousawi, Robert Kraft, Haidy G Rivero, Felicia N Williams, Ludwik K Branski, Marc G Jeschke

Abstract

Introduction: Intensive insulin treatment (IIT) has been shown to improve outcomes post-burn in severely burnt patients. However, it increases the incidence of hypoglycemia and is associated with risks and complications. We hypothesized that exenatide would decrease plasma glucose levels post-burn to levels similar to those achieved with IIT, and reduce the amount of exogenous insulin administered.

Methods: This open-label study included 24 severely burned pediatric patients. Six were randomized to receive exenatide, and 18 received IIT during acute hospitalization (block randomization). Exenatide and insulin were administered to maintain glucose levels between 80 and 140 mg/dl. We determined 6 AM, daily average, maximum and minimum glucose levels. Variability was determined using mean amplitude of glucose excursions (MAGE) and percentage of coefficient of variability. The amount of administered insulin was compared in both groups.

Results: Glucose values and variability were similar in both groups: Daily average was 130 ± 28 mg/dl in the intervention group and 138 ± 25 mg/dl in the control group (P = 0.31), MAGE 41 ± 6 vs. 45 ± 12 (respectively). However, administered insulin was significantly lower in the exenatide group than in the IIT group: 22 ± 14 IU patients/day in the intervention group and 76 ± 11 IU patients/day in the control group (P = 0.01). The incidence rate of hypoglycemia was similar in both groups (0.38 events/patient-month).

Conclusions: Patients receiving exenatide received significantly lower amounts of exogenous insulin to control plasma glucose levels. Exenatide was well tolerated and potentially represents a novel agent to attenuate hyperglycemia in the critical care setting.

Trial registration: NCT00673309.

Figures

Figure 1
Figure 1
CONSORT diagram. Eligibility and enrollment of patients.
Figure 2
Figure 2
Glucose values. Longitudinal analysis of the different glucose values along the 30 days of study. If less than three glucose values were obtained, maximum and minimum values were not calculated (see text for details). (a) Daily average. (b) Maximum. (c) Minimum. (d) Six AM glucose levels. IIT: Intensive insulin treatment. All values are represented as mean ± SEM.
Figure 3
Figure 3
Exogenous insulin administered and insulin plasma levels. (a) Insulin administered per patient per day. (b) Average of administered insulin per patient per acute hospital stay. (c) Mean plasma insulin levels. All values account for first 30 days of hospital stay. Values are represented as mean ± SEM.
Figure 4
Figure 4
MAGE. Mean amplitude of glucose excursion. Expressed as mean ± SEM.
Figure 5
Figure 5
Percentage of coefficient of variance (% CV).
Figure 6
Figure 6
Resting energy expenditure (REE). REE expressed as percentage of predicted. All values are represented as mean ± SEM.
Figure 7
Figure 7
Calories administered. Total amount of calories administered (per Kg) to the patients during the acute stay (first 30 days from admission). Data expressed as mean ± SEM.

References

    1. Gore DC, Chinkes D, Heggers J, Herndon DN, Wolf SE, Desai M. Association of hyperglycemia with increased mortality after severe burn injury. J Trauma. 2001;51:540–544. doi: 10.1097/00005373-200109000-00021.
    1. Gore DC, Chinkes DL, Hart DW, Wolf SE, Herndon DN, Sanford AP. Hyperglycemia exacerbates muscle protein catabolism in burn-injured patients. Crit Care Med. 2002;30:2438–2442. doi: 10.1097/00003246-200211000-00006.
    1. Hemmila MR, Taddonio MA, Arbabi S, Maggio PM, Wahl WL. Intensive insulin therapy is associated with reduced infectious complications in burn patients. Surgery. 2008;144:629–637. doi: 10.1016/j.surg.2008.07.001.
    1. Pham TN, Warren AJ, Phan HH, Molitor F, Greenhalgh DG, Palmieri TL. Impact of tight glycemic control in severely burned children. J Trauma. 2005;59:1148–1154. doi: 10.1097/01.ta.0000188933.16637.68.
    1. Jeschke MG, Kulp GA, Kraft R, Finnerty CC, Mlcak R, Lee JO, Herndon DN. Intensive insulin therapy in severely burned pediatric patients: A prospective randomized trial. Am J Respir Crit Care Med. 2010. in press .
    1. Finfer S, Chittock DR, Su SY, Blair D, Foster D, Dhingra V, Bellomo R, Cook D, Dodek P, Henderson WR, Hebert PC, Heritier S, Heyland DK, McArthur C, McDonald E, Mitchell I, Myburgh JA, Norton R, Potter J, Robinson BG, Ronco JJ. Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 2009;360:1283–1297. doi: 10.1056/NEJMoa0810625.
    1. Griesdale DE, de Souza RJ, van Dam RM, Heyland DK, Cook DJ, Malhotra A, Dhaliwal R, Henderson WR, Chittock DR, Finfer S, Talmor D. Intensive insulin therapy and mortality among critically ill patients: a meta-analysis including NICE-SUGAR study data. CMAJ. 2009;180:821–827.
    1. Mecott GA, Al-Mousawi AM, Gauglitz GG, Herndon DN, Jeschke MG. The role of hyperglycemia in burned patients: Evidence-based studies. Shock. 2010;33:5–13. doi: 10.1097/SHK.0b013e3181af0494.
    1. Kendall DM, Cuddihy RM, Bergenstal RM. Clinical application of incretin-based therapy: therapeutic potential, patient selection and clinical use. Am J Med. 2009;122(6 Suppl):S37–50. doi: 10.1016/j.amjmed.2009.03.015.
    1. Nauck MA, Homberger E, Siegel EG, Allen RC, Eaton RP, Ebert R, Creutzfeldt W. Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses. J Clin Endocrinol Metab. 1986;63:492–498. doi: 10.1210/jcem-63-2-492.
    1. Meier JJ, Weyhe D, Michaely M, Senkal M, Zumtobel V, Nauck MA, Holst JJ, Schmidt WE, Gallwitz B. Intravenous glucagon-like peptide 1 normalizes blood glucose after major surgery in patients with type 2 diabetes. Crit Care Med. 2004;32:848–851. doi: 10.1097/01.CCM.0000114811.60629.B5.
    1. Deane AM, Chapman MJ, Fraser RJ, Burgstad CM, Besanko LK, Horowitz M. The effect of exogenous glucagon-like peptide-1 on the glycaemic response to small intestinal nutrient in the critically ill: a randomised double-blind placebo-controlled cross over study. Crit Care. 2009;13:R67. doi: 10.1186/cc7874.
    1. Drucker DJ, Philippe J, Mojsov S, Chick WL, Habener JF. Glucagon-like peptide I stimulates insulin gene expression and increases cyclic AMP levels in a rat islet cell line. Proc Natl Acad Sci USA. 1987;84:3434–3438. doi: 10.1073/pnas.84.10.3434.
    1. Pratley RE, Gilbert M. Targeting Incretins in Type 2 Diabetes: Role of GLP-1 receptor agonists and DPP-4 inhibitors. Rev Diabet Stud. 2008;5:73–94. doi: 10.1900/RDS.2008.5.73.
    1. Eng J, Kleinman WA, Singh L, Singh G, Raufman JP. Isolation and characterization of exendin-4, an exendin-3 analogue, from Heloderma suspectum venom. Further evidence for an exendin receptor on dispersed acini from guinea pig pancreas. J Biol Chem. 1992;267:7402–7405.
    1. Linnebjerg H, Park S, Kothare PA, Trautmann ME, Mace K, Fineman M, Wilding I, Nauck M, Horowitz M. Effect of exenatide on gastric emptying and relationship to postprandial glycemia in type 2 diabetes. Regul Pept. 2008;151:123–129. doi: 10.1016/j.regpep.2008.07.003.
    1. Goke R, Fehmann HC, Linn T, Schmidt H, Krause M, Eng J, Goke B. Exendin-4 is a high potency agonist and truncated exendin-(9-39)-amide an antagonist at the glucagon-like peptide 1-(7-36)-amide receptor of insulin-secreting beta-cells. J Biol Chem. 1993;268:19650–19655.
    1. Pereira C, Murphy K, Jeschke M, Herndon DN. Post burn muscle wasting and the effects of treatments. Int J Biochem Cell Biol. 2005;37:1948–1961. doi: 10.1016/j.biocel.2005.05.009.
    1. Mlcak RP, Jeschke MG, Barrow RE, Herndon DN. The influence of age and gender on resting energy expenditure in severely burned children. Ann Surg. 2006;244:121–130. doi: 10.1097/01.sla.0000217678.78472.d3.
    1. Weir JB. New methods for calculating metabolic rate with special reference to protein metabolism. J Physiol. 1949;109:1–9.
    1. Harris JA, Benedict FG. A Biometric Study of Human Basal Metabolism. Proc Natl Acad Sci USA. 1918;4:370–373. doi: 10.1073/pnas.4.12.370.
    1. Service FJ, Molnar GD, Rosevear JW, Ackerman E, Gatewood LC, Taylor WF. Mean amplitude of glycemic excursions, a measure of diabetic instability. Diabetes. 1970;19:644–655.
    1. Rodbard D. Interpretation of continuous glucose monitoring data: glycemic variability and quality of glycemic control. Diabetes Technol Ther. 2009;11(Suppl 1):S55–67.
    1. Perley MJ, Kipnis DM. Plasma insulin responses to oral and intravenous glucose: studies in normal and diabetic sujbjects. J Clin Invest. 1967;46:1954–1962. doi: 10.1172/JCI105685.
    1. Gromada J, Holst JJ, Rorsman P. Cellular regulation of islet hormone secretion by the incretin hormone glucagon-like peptide 1. Pflugers Arch. 1998;435:583–594. doi: 10.1007/s004240050558.
    1. Nauck MA, Heimesaat MM, Behle K, Holst JJ, Nauck MS, Ritzel R, Hufner M, Schmiegel WH. Effects of glucagon-like peptide 1 on counterregulatory hormone responses, cognitive functions, and insulin secretion during hyperinsulinemic, stepped hypoglycemic clamp experiments in healthy volunteers. J Clin Endocrinol Metab. 2002;87:1239–1246. doi: 10.1210/jc.87.3.1239.
    1. Nielsen LL, Young AA, Parkes DG. Pharmacology of exenatide (synthetic exendin-4): a potential therapeutic for improved glycemic control of type 2 diabetes. Regul Pept. 2004;117:77–88. doi: 10.1016/j.regpep.2003.10.028.
    1. Idris I, Patiag D, Gray S, Donnelly R. Exendin-4 increases insulin sensitivity via a PI-3-kinase-dependent mechanism: contrasting effects of GLP-1. Biochem Pharmacol. 2002;63:993–996. doi: 10.1016/S0006-2952(01)00924-8.
    1. Egi M, Bellomo R, Reade MC. Is reducing variability of blood glucose the real but hidden target of intensive insulin therapy? Crit Care. 2009;13:302. doi: 10.1186/cc7755.
    1. Jeha GS, Heptulla RA. Newer therapeutic options for children with diabetes mellitus: theoretical and practical considerations. Pediatr Diabetes. 2006;7:122–138. doi: 10.1111/j.1399-543X.2006.00159.x.
    1. Raman VS, Heptulla RA. New potential adjuncts to treatment of children with type 1 diabetes mellitus. Pediatr Res. 2009;65:370–374. doi: 10.1203/PDR.0b013e3181975ee4.
    1. Srinivasan BT, Jarvis J, Khunti K, Davies MJ. Recent advances in the management of type 2 diabetes mellitus: a review. Postgrad Med J. 2008;84:524–531. doi: 10.1136/pgmj.2008.067918.
    1. Greenfield JR, Farooqi IS, Keogh JM, Henning E, Habib AM, Blackwood A, Reimann F, Holst JJ, Gribble FM. Oral glutamine increases circulating glucagon-like peptide 1, glucagon, and insulin concentrations in lean, obese, and type 2 diabetic subjects. Am J Clin Nutr. 2009;89:106–113. doi: 10.3945/ajcn.2008.26362.

Source: PubMed

赞助者和合作者

医疗条件

药物干预

3
订阅