e4 136 McCowen KC, Ling PR, Ciccarone A, et al Sustained endotox emia leads to marked down regulation of early steps in the insulin signaling cascade Crit Care Med 2001;29 839 846 137 Mesotten D, Delh[.]
e4 136 McCowen KC, Ling PR, Ciccarone A, et al Sustained endotoxemia leads to marked down-regulation of early steps in the insulinsignaling cascade Crit Care Med 2001;29:839-846 137 Mesotten D, Delhanty PJ, Vanderhoydonc F, et al Regulation of insulin-like growth factor binding protein-1 during protracted critical illness J Clin Endocrinol Metab 2002;87:5516-5523 138 Preissig CM, Rigby MR Hyperglycaemia results from beta-cell dysfunction in critically ill children with respiratory and cardiovascular failure: a prospective observational study Crit Care 2009;13:R27 139 Hacihamdioglu B, Kendirli T, Ocal G, et al Pathophysiology of critical illness hyperglycemia in children J Pediatr Endocrinol Metab 2013;26:715-720 140 Khajavi J, Khademi G, Mehramiz M, et al Association of dysglycemia with mortality in children receiving parenteral nutrition in pediatric intensive care unit Turk J Pediatr 2018;60:134-141 141 Framson CM, LeLeiko NS, Dallal GE, et al Energy expenditure in critically ill children Pediatr Crit Care Med 2007;8:264-267 142 Brownlee M Biochemistry and molecular cell biology of diabetic complications Nature 2001;414:813-820 143 Van den Berghe G How does blood glucose control with insulin save lives in intensive care? J Clin Invest 2004;114:1187-1195 144 Turina M, Fry DE, Polk HC Jr Acute hyperglycemia and the innate immune system: clinical, cellular, and molecular aspects Crit Care Med 2005;33:1624-1633 145 Aljada A, Friedman J, Ghanim H, et al Glucose ingestion induces an increase in intranuclear nuclear factor kappaB, a fall in cellular inhibitor kappaB, and an increase in tumor necrosis factor alpha messenger RNA by mononuclear cells in healthy human subjects Metabolism 2006;55:1177-1185 146 Rao AK, Chouhan V, Chen X, et al Activation of the tissue factor pathway of blood coagulation during prolonged hyperglycemia in young healthy men Diabetes 1999;48:1156-1161 147 Ellger B, Langouche L, Richir M, et al Modulation of regional nitric oxide metabolism: blood glucose control or insulin? Intensive Care Med 2008;34:1525-1533 148 Sonneville R, Vanhorebeek I, den Hertog HM, et al Critical illness-induced dysglycemia and the brain Intensive Care Med 2015;41:192-202 149 van den Berghe G, Wouters P, Weekers F, et al Intensive insulin therapy in the critically ill patients N Engl J Med 2001;345:13591367 150 Kavanagh BP Glucose in the ICU—evidence, guidelines, and outcomes N Engl J Med 2012;367:1259-1260 151 Diabetes AATFoI American College of Endocrinology and American Diabetes Association Consensus statement on inpatient diabetes and glycemic control Diabetes Care 2006;29:1955-1962 152 Dellinger RP, Carlet JM, Masur H, et al Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock Crit Care Med 2004;32:858-873 153 Investigators N-SS, Finfer S, Chittock DR, et al Intensive versus conventional glucose control in critically ill patients N Engl J Med 2009;360:1283-1297 154 Jacobi J, Bircher N, Krinsley J, et al Guidelines for the use of an insulin infusion for the management of hyperglycemia in critically ill patients Crit Care Med 2012;40:3251-3276 155 Preissig CM, Rigby MR A disparity between physician attitudes and practice regarding hyperglycemia in pediatric intensive care units in the United States: a survey on actual practice habits Crit Care 2010;14:R11 156 Beardsall K, Vanhaesebrouck S, Ogilvy-Stuart AL, et al Early insulin therapy in very-low-birth-weight infants N Engl J Med 2008;359:1873-1884 157 Vlasselaers D, Milants I, Desmet L, et al Intensive insulin therapy for patients in paediatric intensive care: a prospective, randomised controlled study Lancet 2009;373:547-556 158 Agus MS, Steil GM, Wypij D, et al Tight glycemic control versus standard care after pediatric cardiac surgery N Engl J Med 2012;367:1208-1219 159 Agus MS, Asaro LA, Steil GM, et al Tight glycemic control after pediatric cardiac surgery in high-risk patient populations: a secondary analysis of the safe pediatric euglycemia after cardiac surgery trial Circulation 2014;129:2297-2304 160 Fisher JG, Sparks EA, Khan FA, et al Tight glycemic control with insulin does not affect skeletal muscle degradation during the early postoperative period following pediatric cardiac surgery Pediatr Crit Care Med 2015;16:515-521 161 Mesotten D, Gielen M, Sterken C, et al Neurocognitive development of children years after critical illness and treatment with tight glucose control: a randomized controlled trial JAMA 2012;308:1641-1650 162 Faustino EVS, Hirshberg EL, Asaro LA, et al Short-term adverse outcomes associated with hypoglycemia in critically ill children Crit Care Med 2019;47:706-714 163 Macrae D, Grieve R, Allen E, et al A randomized trial of hyperglycemic control in pediatric intensive care N Engl J Med 2014;370:107-118 164 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;182:351-359 165 Le HT, Harris NS, Estilong AJ, et al Blood glucose measurement in the intensive care unit: what is the best method? J Diabetes Sci Technol 2013;7:489-499 166 Boyd JC, Bruns DE Performance requirements for glucose assays in intensive care units Clin Chem 2014;60:1463-1465 167 Krinsley JS, Bruns DE, Boyd JC The impact of measurement frequency on the domains of glycemic control in the critically ill—a Monte Carlo simulation J Diabetes Sci Technol 2015;9: 237-245 168 Klonoff DC, Bergenstal R, Blonde L, et al Consensus report of the coalition for clinical research-self-monitoring of blood glucose J Diabetes Sci Technol 2008;2:1030-1053 169 Thomas F, Signal M, Chase JG Using continuous glucose monitoring data and detrended fluctuation analysis to determine patient condition: a review J Diabetes Sci Technol 2015;9:1327-1335 170 Piper HG, Alexander JL, Shukla A, et al Real-time continuous glucose monitoring in pediatric patients during and after cardiac surgery Pediatrics 2006;118:1176-1184 171 Steil GM, Langer M, Jaeger K, et al Value of continuous glucose monitoring for minimizing severe hypoglycemia during tight glycemic control Pediatr Crit Care Med 2011;12:643-648 172 Welsh JB, Gao P, Derdzinski M, et al Accuracy, utilization, and effectiveness comparisons of different continuous glucose monitoring systems Diabetes Technol Ther 2019;21:128-132 173 Mitrakou A, Ryan C, Veneman T, et al Hierarchy of glycemic thresholds for counterregulatory hormone secretion, symptoms, and cerebral dysfunction Am J Physiol 1991;260:E67-E74 174 Menni F, de Lonlay P, Sevin C, et al Neurologic outcomes of 90 neonates and infants with persistent hyperinsulinemic hypoglycemia Pediatrics 2001;107:476-479 175 Barkovich AJ, Ali FA, Rowley HA, Bass N Imaging patterns of neonatal hypoglycemia AJNR Am J Neuroradiol 1998;19: 523-528 176 Aynsley-Green A Glucose, the brain and the paediatric endocrinologist Horm Res 1996;46:8-25 177 Lteif AN, Schwenk WF Hypoglycemia in infants and children Endocrinol Metab Clin North Am 1999;28:619-646, vii 178 Ulate KP, Lima Falcao GC, Bielefeld MR, et al Strict glycemic targets need not be so strict: a more permissive glycemic range for critically ill children Pediatrics 2008;122:e898-e904 179 Wintergerst KA, Buckingham B, Gandrud L, et al Association of hypoglycemia, hyperglycemia, and glucose variability with morbidity and death in the pediatric intensive care unit Pediatrics 2006;118:173-179 180 Fekete C, Lechan RM Central regulation of hypothalamic-pituitary-thyroid axis under physiological and pathophysiological conditions Endocr Rev 2014;35:159-194 e5 181 Mantzoros CS, Magkos F, Brinkoetter M, et al Leptin in human physiology and pathophysiology Am J Physiol Endocrinol Metab 2011;301:E567-E584 182 Maia AL, Goemann IM, Meyer EL, Wajner SM Deiodinases: the balance of thyroid hormone: type iodothyronine deiodinase in human physiology and disease J Endocrinol 2011;209:283-297 183 Yen PM Physiological and molecular basis of thyroid hormone action Physiol Rev 2001;81:1097-1142 184 Klein I, Ojamaa K Thyroid hormone and the cardiovascular system N Engl J Med 2001;344:501-509 185 Van Vliet G, Deladoey J Diagnosis, treatment and outcome of congenital hypothyroidism Endocr Dev 2014;26:50-59 186 Joseph-Bravo P, Jaimes-Hoy L, Charli JL Regulation of TRH neurons and energy homeostasis-related signals under stress J Endocrinol 2015;224:R139-R159 187 McAninch EA, Bianco AC Thyroid hormone signaling in energy homeostasis and energy metabolism Ann N Y Acad Sci 2014; 1311:77-87 188 Leger J Graves’ disease in children Endocr Dev 2014;26:171-182 189 Nayak B, Hodak SP Hyperthyroidism Endocrinol Metab Clin North Am 2007;36:617-656 190 Weetman AP Graves’ disease N Engl J Med 2000;343:1236-1248 191 Pearce EN, Farwell AP, Braverman LE Thyroiditis N Engl J Med 2003;348:2646-2655 192 Radetti G Clinical aspects of Hashimoto’s thyroiditis Endocr Dev 2014;26:158-170 193 Martino E, Bartalena L, Bogazzi F, Braverman LE The effects of amiodarone on the thyroid Endocr Rev 2001;22:240-254 194 Franklyn JA, Boelaert K Thyrotoxicosis Lancet 2012;379:11551166 195 Ezer A, Caliskan K, Parlakgumus A, et al Preoperative therapeutic plasma exchange in patients with thyrotoxicosis J Clin Apher 2009;24:111-114 196 Simsir IY, Ozdemir M, Duman S, et al Therapeutic plasmapheresis in thyrotoxic patients Endocrine 2018;62:144-148 197 Kluijfhout WP, van Beek DJ, Verrijn Stuart AA, et al Postoperative complications after prophylactic thyroidectomy for very young patients with multiple endocrine neoplasia type 2: retrospective cohort analysis Medicine (Baltimore) 2015;94:e1108 198 Zimmermann MB Iodine deficiency Endocr Rev 2009;30:376408 199 DeGroot LJ “Non-thyroidal illness syndrome” is functional central hypothyroidism, and if severe, hormone replacement is appropriate in light of present knowledge J Endocrinol Invest 2003;26:11631170 200 Ross OC, Petros A The sick euthyroid syndrome in paediatric cardiac surgery patients Intensive Care Med 2001;27:1124-1132 201 Michalaki M, Vagenakis AG, Makri M, et al Dissociation of the early decline in serum T(3) concentration and serum IL-6 rise and TNFalpha in nonthyroidal illness syndrome induced by abdominal surgery J Clin Endocrinol Metab 2001;86:4198-4205 202 Peeler KR, Agus MS, The endocrine response to critical illness In: Radovich S, Misra M, eds Pediatric Endocrinology 3rd ed Springer International; 2018:847-861 203 Peeters RP, Wouters PJ, van Toor H, et al Serum 3,39,59-triiodothyronine (rT3) and 3,5,39-triiodothyronine/rT3 are prognostic markers in critically ill patients and are associated with postmortem tissue deiodinase activities J Clin Endocrinol Metab 2005;90:45594565 204 Iervasi G, Pingitore A, Landi P, et al Low-T3 syndrome: a strong prognostic predictor of death in patients with heart disease Circulation 2003;107:708-713 205 Ladenson PW, Sherman SI, Baughman KL, et al Reversible alterations in myocardial gene expression in a young man with dilated cardiomyopathy and hypothyroidism Proc Natl Acad Sci USA 1992;89:5251-5255 206 Pingitore A, Galli E, Barison A, et al Acute effects of triiodothyronine (T3) replacement therapy in patients with chronic heart failure and low-T3 syndrome: a randomized, placebo-controlled study J Clin Endocrinol Metab 2008;93:1351-1358 207 Marks SD, Haines C, Rebeyka IM, Couch RM Hypothalamicpituitary-thyroid axis changes in children after cardiac surgery J Clin Endocrinol Metab 2009;94:2781-2786 208 Bettendorf M, Schmidt KG, Grulich-Henn J, et al Tri-iodothyronine treatment in children after cardiac surgery: a double-blind, randomised, placebo-controlled study Lancet 2000;356:529-534 209 Portman MA, Slee A, Olson AK, et al Triiodothyronine Supplementation in Infants and Children Undergoing Cardiopulmonary Bypass (TRICC): a multicenter placebo-controlled randomized trial: age analysis Circulation 2010;122:S224-233 210 Soto-Rivera CL, Agus MS, Sawyer JE, et al Pediatric Cardiac Intensive Care Society 2014 consensus statement: Pharmacotherapies in cardiac critical care hormone replacement therapy Pediatr Crit Care Med 2016;17:S59-S68 e6 Abstract: Critical illness and its treatment frequently generate unique secondary endocrinopathies affecting multiple endocrine axes The endocrine system is closely aligned with the neurogenic and inflammatory systems, particularly as an aspect of the stress response While these acute responses of the endocrine axes are considered an evolutionarily driven adaptive response to stress, chronic hormonal changes are likely the result of advances in critical care and are the basis of much intensive care unit–related morbidity In this chapter, we review the primary endocrine axes implicated in and affected by critical illness, treatment of such derangements, and the latest studies pertaining to these endocrinopathies Key Words: endocrine, cortisol, critical illness–related corticosteroid insufficiency, tight glucose control, thyroid, euthyroid sick syndrome 85 Diabetic Ketoacidosis ILDIKO H KOVES AND NICOLE GLASER • Etiology, Definition, and Presentation Diabetic ketoacidosis (DKA) occurs when serum insulin concentrations are very low in relation to concentrations of glucagon and other counterregulatory hormones (epinephrine, norepinephrine, cortisol, and growth hormone) This situation occurs most commonly in new-onset type diabetes mellitus (T1DM) and in patients with known diabetes during infections or other intercurrent illnesses or with insulin omission (discussed later) In the setting of low insulin concentrations in relation to counterregulatory hormone concentrations, the normal physiologic mechanisms responsible for maintaining adequate energy substrate during fasting and physiologic stress are exaggerated, resulting in hyperglycemia, ketosis, and acidosis A diagnosis of DKA can be made when the serum glucose concentration is greater than 200 mg/dL (.11 mmol/L) and venous pH is less than 7.30 (or the serum bicarbonate concentration is less than 15 mmol/L) in the presence of ketosis (“moderate” or “large” ketonuria or serum b-hydroxybutyrate mmol/L).1 In a child with new onset of T1DM, declining insulin production results from autoimmune destruction of pancreatic b-cells The concentration of insulin is decreased relative to glucagon, causing excess hepatic glucose production and decreased peripheral glucose uptake in muscle and adipose tissue.2,3 When the serum glucose concentration rises above approximately 180 to 200 mg/dL, the renal threshold for glucose reabsorption is exceeded This causes glycosuria, which leads to osmotic diuresis and compensatory polydipsia Low insulin concentrations also stimulate the release of free fatty acids (FFAs) from adipose tissue to fuel ketogenesis.4 This, in combination with activation of the hepatic b-oxidative enzyme sequence resulting from relative excess of glucagon in relation to insulin, results in markedly increased hepatic ketone production.3–5 1016 • Diabetic ketoacidosis (DKA) results either from absolute insulin deficiency or from relative insulin deficiency in the setting of high levels of counterregulatory hormones stimulated by infection or other illness DKA is characterized by hyperglycemia, ketosis, and acidosis • • PEARLS Treatment of pediatric DKA involves intravenous insulin administration, intravenous fluid administration to correct dehydration, and replacement of electrolyte deficits Cerebral injury is the most frequent serious complication of DKA in children and is the most frequent cause of morbidity and mortality resulting from DKA Progressive dehydration and increasing acidosis eventually stimulate release of the counterregulatory (“stress”) hormones— cortisol, catecholamines, and growth hormone—which accelerate hepatic glucose output and ketone production.6,7 Infection or other illness or injury can likewise contribute to this process by stimulating release of counterregulatory hormones Elevated cortisol concentrations augment FFA release from adipose tissue and decrease peripheral glucose uptake Increased epinephrine concentrations directly increase glycogenolysis and stimulate the release of gluconeogenic precursors from muscle.8,9 Both epinephrine and norepinephrine also stimulate lipolysis and b-oxidation of FFAs.10,11 Catecholamines may also directly inhibit insulin secretion, thereby accelerating DKA in patients with endogenous insulin capacity, such as those with a new diagnosis of T1DM or with type diabetes.12,13 Growth hormone also decreases peripheral glucose uptake and enhances ketone production by increasing FFA release.14 Elevated concentrations of counterregulatory hormones thus facilitate increased acidosis, hyperglycemia, and dehydration This, in turn, stimulates further counterregulatory hormone release, creating a vicious cycle resulting in rapid worsening of DKA During DKA, intestinal ileus results from potassium depletion, acidosis, and diminished splanchnic perfusion, causing abdominal pain and vomiting, thereby limiting fluid intake Progressive dehydration eventually leads to diminished tissue perfusion sufficient to cause accumulation of lactic acid, which further contributes to metabolic acidosis.15 In addition, poor perfusion may result in diminished renal function, limiting the capacity for clearance of glucose and ketones Ongoing osmotic diuresis and ketonuria in the setting of acidosis also results in urinary losses of electrolytes (potassium, sodium, chloride, calcium, phosphate, and magnesium) Classical symptoms of DKA include polyuria, polydipsia, polyphagia, weight loss, abdominal pain, nausea, and vomiting CHAPTER 85 Diabetic Ketoacidosis Abdominal tenderness, absence of bowel sounds, and guarding are frequent and may even mimic an acute abdomen.16 Tachycardia and signs of hypoperfusion, such as delayed capillary refill time and cool extremities, are also common, as well as dry mucous membranes, absence of tears, and poor skin turgor Despite substantial volume depletion, however, hypotension is unusual in children with DKA Instead, studies have shown that hypertension occurs frequently in children with DKA and that children with more severe dehydration and acidosis are more likely to be hypertensive during DKA.17,18 The cause of hypertension in children with DKA is unknown Kussmaul breathing and tachypnea are the result of metabolic acidosis and respiratory compensatory mechanisms Fruity breath odor (acetone) may be present Hypothermia has also been described.19 Although hyperglycemia is part of the definition of DKA, in rare cases, the serum glucose concentration may be nearly normal, so-called euglycemic DKA This was previously reported mainly in pregnant women,20–22 but has recently been documented in patients with T1DM taking sodium-glucose transporter (SGLT2) inhibitor medications.23 Normal glucose concentrations or even hypoglycemia despite ketosis may also occur in children with known diabetes who administer insulin to treat DKA prior to arrival in the emergency department In general, however, the persistence and severity of hyperglycemia reflect the severity of dehydration In the absence of preexisting renal disease or unusually high carbohydrate intake just prior to presentation, blood glucose concentrations in excess of 500 to 600 mg/dL imply that dehydration is of sufficient severity to diminish the glomerular filtration rate and thereby diminish the capacity for renal clearance of excess glucose.24 Concentrations of ketone bodies (b-hydroxybutyrate [bOHB] and acetoacetate [AcAc]) are elevated in DKA, resulting in acidosis Hyperchloremic acidosis frequently coexists with increased anion-gap acidosis; the anion gap reflects the combination of these processes.25 The ratio of bOHB:AcAc (typically 1:1 in the normal state) is increased during DKA and may be as high as 10:1.26 During treatment, this ratio returns to normal The nitroprusside reaction used to test urine ketone concentrations detects only AcAc and not bOHB As a result, urine testing cannot be relied on to determine DKA severity or treatment response Bedside blood ketone meters provide a rapid means for measuring bOHB and may be useful in place of or in addition to urine testing, particularly in patients with anuria or oliguria who produce insufficient amounts of urine for ketone testing.27 Blood ketone measurements are also useful for determining the timing of transition from continuous intravenous (IV) to intermittent subcutaneous insulin administration Urine ketones may be present even when blood ketones have normalized as a result of urine stagnating in the bladder Hyperglycemia results in fluid shifts from the extravascular to intravascular space and a decrease in serum sodium concentration This decrease can be calculated as an approximately 1.6 mEq/L decrease in sodium concentration for every 100 mg/dL increase in serum glucose above 100 mg/dL (Nacorrected Naactual [glucose – 5.5 mmol/L]).28,29 Hyperlipidemia may also contribute to a decrease in measured serum sodium concentrations as a result of a laboratory artifact.30 However, with modern laboratory techniques, these erroneous measurements are uncommon Typically, serum potassium concentrations at presentation are in the highnormal range as a result of the redistribution of potassium ions from the intracellular to extracellular space Several processes are responsible for intracellular potassium depletion, including direct 1017 effects of low insulin concentrations, intracellular protein and phosphate depletion, and buffering of hydrogen ions in the intracellular compartment.31 Intracellular potassium stores may be profoundly depleted, and the serum potassium concentration typically declines rapidly with insulin treatment Serum phosphate concentrations similarly decrease during treatment Leukocytosis is frequent in children with DKA, likely resulting from elevated concentrations of catecholamines and proinflammatory cytokines In children, new onset of T1DM or insulin omission is a far more common cause of DKA than infection.32 Therefore, an elevated or left-shifted white blood cell count need not prompt a search for an infectious process in the absence of fever or other symptoms or signs of infection However, in the presence of fever, careful history, physical examination, and laboratory evaluation to assess for infection are prudent (eTable 85.1) Epidemiology Frequency of Diabetic Ketoacidosis at Diagnosis The frequency of DKA at diagnosis varies widely by geographic region, with an overall estimated frequency of approximately 20% to 67% In the population-based US study SEARCH for Diabetes in Youth, data were collected from self-reported health questionnaires and medical record review In this study, 36.4% of children and adolescents presented with DKA at the onset of diabetes.33,34 As mentioned, frequency of DKA varies depending on regions: in a collaborative cohort in Germany and Austria, 26.3% and 21.1%, respectively35; in a Swedish data report, 16.9%; and in a Finnish register report, 18.7%.36 Younger age (,5 years) and female sex were associated with higher likelihood of presenting with DKA.37,38 A delay in diagnosis is associated with a higher likelihood of DKA; two factors contributing to this result are patient age and provider experience Regions with a higher prevalence of T1DM generally have a lower frequency of DKA,39 attributed to heightened awareness in providers and thus earlier detection Interestingly, however, three of The Environmental Determinant of Diabetes in the Young (TEDDY) study participant families who were counseled on diabetes symptoms nonetheless presented with DKA.40 The nonspecific nature of individual symptoms, such as polyuria, tachypnea, and altered mental status, may cause such symptoms to be misconstrued as urinary tract infection, pneumonia, or meningitis, respectively.41 Mallare et al reported a frequency of DKA of 33% in children and adolescents at the initial visit and almost double (59%) in those for whom the diagnosis of diabetes was missed at the initial visit The diagnosis of diabetes was more likely to be missed in very young children (34% of children #5 years compared with 8.5% in those older than 10 years),42 particularly when these very young children are evaluated by family practitioners rather than pediatricians.43 Usher-Smith et al found protective diagnostic factors of a first-degree relative with T1DM, higher parental education, and higher background incidence of T1DM in a systemic review of 46 studies involving 24,000 children from 31 countries.44 Frequency of Diabetic Ketoacidosis in Children and Adolescents After Diagnosis More data are becoming available describing the incidence of DKA in children and adolescents with established diabetes Reported frequencies range from to 10 per 100 patient-years.45 In the Diabetes Control and Complications Trial, the incidence of ... In this chapter, we review the primary endocrine axes implicated in and affected by critical illness, treatment of such derangements, and the latest studies pertaining to these endocrinopathies... e6 Abstract: Critical illness and its treatment frequently generate unique secondary endocrinopathies affecting multiple endocrine axes The endocrine system is closely aligned with the neurogenic... and other counterregulatory hormones (epinephrine, norepinephrine, cortisol, and growth hormone) This situation occurs most commonly in new-onset type diabetes mellitus (T1DM) and in patients with