Abstract
Abnormalities in glucose metabolism and stress hyperglycemia (SH) are commonly seen in critically ill children. While SH may represent an adaptive stress response as a source of fuel for the body during the “fight or flight response” of critical illness, several studies have observed the association of SH with worse outcomes in different disease states. In addition to alterations in glucose metabolism and acquired insulin resistance from inflammation and organ dysfunction, specific intensive care unit (ICU) interventions can also affect glucose homeostasis and SH during critical illness. Common ICU interventions can mediate the development of SH in critical illness. The strategy of tight glucose control combined with intensive insulin therapy (TGC-IIT) has been well studied to improve outcomes in both adult and pediatric critical illness. Though early single-center studies of TGC-IIT observed benefits with better outcomes albeit with greater incidence of hypoglycemia, subsequent larger multicenter studies in both children and adults have not conclusively demonstrated benefits and have even observed harm. Several possible reasons for these contrasting results include differences in patient populations, glycemic control targets, and glucose control protocols including nutrition support, and variability in achieving these targets, measurement methods, and expertise in protocol implementation. Future studies may need to individualize management of SH in critically ill children with improved monitoring of indices of glycemia utilizing continuous sensors and closed-loop insulin administration.
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References
Srinivasan V, Spinella PC, Drott HR, Roth CL, Helfaer MA, Nadkarni V. Association of timing, duration, and intensity of hyperglycemia with intensive care unit mortality in critically ill children. Pediatr Crit Care Med. 2004;5:329–36.
Faustino EV, Apkon M. Persistent hyperglycemia in critically ill children. J Pediatr. 2005;146:30–4.
Wintergerst KA, Buckingham B, Gandrud L, Wong BJ, Kache S, Wilson DM. Association of hypoglycemia, hyperglycemia, and glucose variability with morbidity and death in the pediatric intensive care unit. Pediatrics. 2006;118:173–9.
Yung M, Wilkins B, Norton L, Slater A; Paediatric Study Group; Australian and New Zealand Intensive Care Society. Glucose control, organ failure, and mortality in pediatric intensive care. Pediatr Crit Care Med. 2008;9:147–52.
Hirshberg E, Larsen G, Van Duker H. Alterations in glucose homeostasis in the pediatric intensive care unit: Hyperglycemia and glucose variability are associated with increased mortality and morbidity. Pediatr Crit Care Med. 2008;9:361–6.
Li Y, Bai Z, Li M, et al. U-shaped relationship between early blood glucose and mortality in critically ill children. BMC Pediatr. 2015;15:88.
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;51:540–4.
Michaud LJ, Rivara FP, Longstreth WT Jr, Grady MS. Elevated initial blood glucose levels and poor outcome following severe brain injuries in children. J Trauma. 1991;31:1356–62.
Branco RG, Garcia PC, Piva JP, Casartelli CH, Seibel V, Tasker RC. Glucose level and risk of mortality in pediatric septic shock. Pediatr Crit Care Med. 2005;6:470–2.
Yates AR, Dyke PC 2nd, Taeed R, et al. Hyperglycemia is a marker for poor outcome in the postoperative pediatric cardiac patient. Pediatr Crit Care Med. 2006;7:351–5.
Jeschke MG, Kulp GA, Kraft R, et al. Intensive insulin therapy in severely burned pediatric patients: a prospective randomized trial. Am J Respir Crit Care Med. 2010;182:351–9.
Beardsall K, Vanhaesebrouck S, Ogilvy-Stuart AL, et al. Early insulin therapy in very-low-birth-weight infants. N Engl J Med. 2008;359:1873–84.
Vlasselaers D, Milants I, Desmet L, et al. Intensive insulin therapy for patients in paediatric intensive care: a prospective, randomised controlled study. Lancet. 2009;373:547–56.
Agus MS, Steil GM, Wypij D, et al; SPECS Study Investigators. Tight glycemic control versus standard care after pediatric cardiac surgery. N Engl J Med. 2012;367:1208–19.
Macrae D, Grieve R, Allen E, et al; CHiP Investigators. A randomized trial of hyperglycemic control in pediatric intensive care. N Engl J Med. 2014;370:107–18.
Agus MS, Wypij D, Hirshberg EL, et al; HALF-PINT Study Investigators and the PALISI Network. Tight glycemic control in critically ill children. N Engl J Med. 2017;376:729–41.
Mechanick JI. Metabolic mechanisms of stress hyperglycemia. JPEN J Parenter Enteral Nutr. 2006;30:157–63.
Dufour S, Lebon V, Shulman GI, Petersen KF. Regulation of net hepatic glycogenolysis and gluconeogenesis by epinephrine in humans. Am J Physiol Endocrinol Metab. 2009;297:E231–5.
Mizock BA. Alterations in fuel metabolism in critical illness: hyperglycaemia. Best Pract Res Clin Endocrinol Metab. 2001;15:533–51.
Shamoon H, Hendler R, Sherwin RS. Synergistic interactions among antiinsulin hormones in the pathogenesis of stress hyperglycemia in humans. J Clin Endocrinol Metab. 1981;52:1235–41.
Gardelis JG, Hatzis TD, Stamogiannou LN, et al. Activity of the growth hormone/insulin-like growth factor-I axis in critically ill children. J Pediatr Endocrinol Metab. 2005;18:363–72.
Dimitriadis G, Leighton B, Parry-Billings M, et al. Effects of glucocorticoid excess on the sensitivity of glucose transport and metabolism to insulin in rat skeletal muscle. Biochem J. 1997;321 (Pt 3)(Pt 3):707–12.
Li L, Thompson LH, Zhao L, Messina JL. Tissue-specific difference in the molecular mechanisms for the development of acute insulin resistance after injury. Endocrinology. 2009;150:24–32.
Gauglitz GG, Herndon DN, Kulp GA, Meyer WJ 3rd, Jeschke MG. Abnormal insulin sensitivity persists up to three years in pediatric patients post-burn. J Clin Endocrinol Metab. 2009;94:1656–64.
Van den Berghe G. How does blood glucose control with insulin save lives in intensive care? J Clin Invest. 2004;114:1187–95.
Turina M, Fry DE, Polk HC Jr. Acute hyperglycemia and the innate immune system: clinical, cellular, and molecular aspects. Crit Care Med. 2005;33:1624–33.
Langouche L, Vanhorebeek I, Vlasselaers D, et al. Intensive insulin therapy protects the endothelium of critically ill patients. J Clin Invest. 2005;115:2277–86.
Srinivasan V. Stress hyperglycemia in pediatric critical illness: the intensive care unit adds to the stress! J Diabetes Sci Technol. 2012;6:37–47.
Ranieri VM, Suter PM, Tortorella C, et al. Effect of mechanical ventilation on inflammatory mediators in patients with acute respiratory distress syndrome: a randomized controlled trial. JAMA. 1999;282:54–61.
Barth E, Albuszies G, Baumgart K, et al. Glucose metabolism and catecholamines. Crit Care Med. 2007;35(9 Suppl):S508–18.
Selby NM, Fialova J, Burton JO, McIntyre CW. The haemodynamic and metabolic effects of hypertonic-glucose and amino-acid-based peritoneal dialysis fluids. Nephrol Dial Transplant. 2007;22:870–9.
Verhoeven JJ, Hokken-Koelega AC, den Brinker M, et al. Disturbance of glucose homeostasis after pediatric cardiac surgery. Pediatr Cardiol. 2011;32:131–8.
Thomas Z, Bandali F, McCowen K, Malhotra A. Drug-induced endocrine disorders in the intensive care unit. Crit Care Med. 2010;38(6 Suppl):S219–30.
Bier DM, Leake RD, Haymond MW, et al. Measurement of “true” glucose production rates in infancy and childhood with 6,6-dideuteroglucose. Diabetes. 1977;26:1016–23.
Sheridan RL, Yu YM, Prelack K, Young VR, Burke JF, Tompkins RG. Maximal parenteral glucose oxidation in hypermetabolic young children: a stable isotope study. JPEN J Parenter Enteral Nutr. 1998;22:212–6.
Lienhardt A, Rakotoambinina B, Colomb V, et al. Insulin secretion and sensitivity in children on cyclic total parenteral nutrition. JPEN J Parenter Enteral Nutr. 1998;22:382–6.
Grau T, Bonet A, Minambres E, et al. Metabolism, Nutrition Working Group, SEMICYUC, Spain. The effect of L-alanyl-L-glutamine dipeptide supplemented total parenteral nutrition on infectious morbidity and insulin sensitivity in critically ill patients. Crit Care Med. 2011;39:1263–8.
Nguyen N, Ching K, Fraser R, Chapman M, Holloway R. The relationship between blood glucose control and intolerance to enteral feeding during critical illness. Intensive Care Med. 2007;33:2085–92.
Bhisitkul DM, Morrow AL, Vinik AI, Shults J, Layland JC, Rohn R. Prevalence of stress hyperglycemia among patients attending a pediatric emergency department. J Pediatr. 1994;124:547–51.
Ulate KP, Lima Falcao GC, Bielefeld MR, Morales JM, Rotta AT. Strict glycemic targets need not be so strict: a more permissive glycemic range for critically ill children. Pediatrics. 2008;122:e898–904.
de Ferranti S, Gauvreau K, Hickey PR, et al. Intraoperative hyperglycemia during infant cardiac surgery is not associated with adverse neurodevelopmental outcomes at 1, 4, and 8 years. Anesthesiology. 2004;100:1345–52.
Ballweg JA, Wernovsky G, Ittenbach RF, et al. Hyperglycemia after infant cardiac surgery does not adversely impact neurodevelopmental outcome. Ann Thorac Surg. 2007;84:2052–8.
Ballweg JA, Ittenbach RF, Bernbaum J, et al. Hyperglycaemia after Stage I palliation does not adversely affect neurodevelopmental outcome at 1 year of age in patients with single-ventricle physiology. Eur J Cardiothorac Surg. 2009;36:688–93.
Krueger JJ, Brotschi B, Balmer C, Bernet V, Latal B. Postoperative hyperglycemia and 4-year neurodevelopmental outcome in children operated for congenital heart disease. J Pediatr. 2015;167:1253–8.e1.
Srinivasan V, Agus MS. Tight glucose control in critically ill children–a systematic review and meta-analysis. Pediatr Diabetes. 2014;15:75–83.
Zhao Y, Wu Y, Xiang B. Tight glycemic control in critically ill pediatric patients: a meta-analysis and systematic review of randomized controlled trials. Pediatr Res. 2018;84:22–7.
Chen L, Li T, Fang F, Zhang Y, Faramand A. Tight glycemic control in critically ill pediatric patients: a systematic review and meta-analysis. Crit Care. 2018;22:57.
Srinivasan V. Nutrition support and tight glucose control in critically ill children: food for thought! Front Pediatr. 2018;6:340.
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Srinivasan, V. Glucose Metabolism and Stress Hyperglycemia in Critically Ill Children. Indian J Pediatr 90, 272–279 (2023). https://doi.org/10.1007/s12098-022-04439-y
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DOI: https://doi.org/10.1007/s12098-022-04439-y