1014 SECTION VII I Pediatric Critical Care Metabolic and Endocrine regions of genes that they regulate whether the thyroid hormone is present Presence or absence of T3 on the thyroid receptor dic tate[.]
1014 S E C T I O N V I I I Pediatric Critical Care: Metabolic and Endocrine • BOX 84.1 Thyroid Effects on Metabolism • • • • • • • • • Increased oxygen consumption Enhanced thermogenesis Accelerated amino acid and lipid metabolism Facilitated water and ion transport Enhanced tissue growth and development Altered cortisol and insulin catabolism Modulated growth hormone and parathormone activity Enhanced respiratory response to hypoxia and hypercarbia Increased b-adrenergic receptor affinity and responsiveness to catecholamines • BOX 84.2 Signs and Symptoms of Thyrotoxicosis • Hyperactivity, tremor, agitation, hyperreflexia • Sinus tachycardia, palpitations, arrhythmias, systolic hypertension, heart failure • Perspiration • Abdominal pain, diarrhea • Bulging eyes (exophthalmos) • Thirst • Proximal myopathy • Apathy, stupor, coma Thyroid Hormone Actions Box 84.1 summarizes the effects of thyroid hormone on metabolism 184 Thyroid hormone significantly affects skeletal and central nervous system growth and maturation Unrecognized hypothyroidism in infancy results in marked physical, motor, and mental delay.185 Hemodynamically, thyroid hormone is known to increase b-adrenergic receptor density and activity; it also upregulates genes encoding calcium channels (ryanodine receptor) and sodium potassium adenosine triphosphatase Through its effects on uncoupling of adenosine triphosphate production, thyroid hormone can significantly affect energy metabolism and homeostasis, as well as heat production.186,187 mellitus, and McCune-Albright syndrome Signs and symptoms of thyrotoxicosis are summarized in Box 84.2 Treatment of thyroid storm involves a four-pronged approach: (1) controlling thyroid gland production of T4 using a thionamide such as methimazole, which interferes with thyroid peroxidase iodination; (2) blocking T3 activity in peripheral tissues using thionamides, iopanoic acid, b-adrenergic blockage, and corticosteroids; (3) providing supportive measures such as antipyretics, anxiolytics, and volume resuscitation as needed; and (4) identifying and treating identifiable precipitating antecedents In severe cases of recalcitrant thyroid storm, plasmapheresis with charcoal hemoperfusion has been used to reduce circulating thyroxine.195,196 Occasionally, subtotal thyroidectomy may be required for chronic thyrotoxicosis Postsurgical complications in such patients that intensivists should anticipate include recurrent laryngeal nerve damage, hypocalcemia with tetany secondary to inadvertent parathyroid gland resection or injury, and hypothyroidism.197 Hyperthyroidism Hypothyroidism Manifestations of thyrotoxicosis reflect increased thyroid hormone concentration; thyroid storm represents the most severe manifestation of hyperthyroidism Graves disease is probably the best-known example of hyperthyroidism It is classically associated with a diffusely enlarged thyroid gland (goiter), exophthalmos, and cardiac palpitations Pathophysiology of Graves disease involves thyroid-stimulating autoantibodies that bind to TSH receptors.188 Hypertrophy and hyperplasia of the thyroid accompanying Graves disease are associated with lymphocytic infiltration.189 Graves disease more commonly occurs in adults but can be seen in the neonate (due to maternal antibodies that have crossed the placenta into the newborn) and in the child It is chronically associated with nervousness, fatigue, tremor, heat intolerance, and weight loss.190 Clinical hyperthyroidism can rarely occur via increased production of TSH secondary to a pituitary adenoma Painful thyroiditis (de Quervain thyroiditis) can occur following a viral illness and can be associated with hyperthyroidism.191 A more common presentation of hyperthyroidism in a teenager is caused by Hashimoto thyroiditis.192 Amiodarone with a structure similar to thyroxine can be associated with either hyperthyroidism or hypothyroidism.193 Patients admitted to the ICU with exaggerated hyperthyroidism (thyrotoxicosis) will typically exhibit either sinus tachycardia or supraventricular tachycardia, nausea, vomiting and diarrhea, weakness, as well as confusion, delirium, or even coma.194 Classic findings of a diffusely enlarged thyroid with an overlying bruit or murmur may not be present Thyrotoxicosis pathophysiology is more common among patients with Down syndrome, diabetes The most common cause of hypothyroidism is iodine deficiency, affecting approximately 800 million people worldwide.198 As noted previously, unrecognized neonatal hypothyroidism is of particular concern given the consequences if appropriate intervention is not initiated In the PICU, Down syndrome children with unstable hemodynamics following cardiovascular surgery should be particularly suspect for hypothyroidism Signs and symptoms of neonatal hyperthyroidism include prolonged neonatal jaundice, coarse features, protruding tongue, apathy, poor feeding, and umbilical hernia True hypothyroidism secondary to thyroid gland failure or maldevelopment will manifest with an elevated TSH concentration, although this response may be blunted in the ICU by malnutrition and administration of dopamine and corticosteroids regions of genes that they regulate whether the thyroid hormone is present Presence or absence of T3 on the thyroid receptor dictates a corepressor or coactivator activity.183 Euthyroid Sick Syndrome in Critical Illness As previously noted, monodeiodination of the inner tyrosine residue of T4 leads to production of rT3 Euthyroid sick syndrome is characterized by a rapid decrease in T3 and variable increase in rT3 that appears to be proportional to the intensity of illness severity and concentration of TNF-a.199 In addition, a decline in various thyroid hormone-binding proteins is evident Conversion of T4 to T3 is suppressed secondary to decreased 59-deiodinase activity Because of decreased thyroid-releasing hormone (TRH) gene expression in the hypothalamus, TRH is decreased with a resultant reduced TSH mRNA Euthyroid sick syndrome (nonthyroidal illness syndrome) has been detailed among pediatric CHAPTER 84 Endocrine Emergencies cardiac surgery patients.200 Laboratory finding characteristics of euthyroid sick syndrome are summarized in Table 84.2.201,202 Significance of euthyroid sick syndrome in critical illness remains controversial Evidence indicating overt pathology in this setting is sparse Some argue that this scenario reflects an effort of the body to conserve energy expenditure as one aspect of the stress response Thyroid hormone alterations characteristic of euthyroid sick syndrome would also be expected to modulate protein catabolism.203 Euthyroid sick syndrome should be differentiated from true hypothyroidism The latter can occasionally occur among patients administered dopamine and high-dose corticosteroids, both secondary to inhibition of TSH Various drug effects on thyroid hormone metabolism are summarized in Table 84.3 Thyroid Hormone Supplementation in the PICU Patients with true hypothyroidism should obviously receive replacement T4 Treatment of euthyroid sick syndrome is more controversial Although the basis for the observation is not clear, adult investigators have previously demonstrated that low serum T3 levels represent the single most significant predictor of cardiovascular and all-cause mortality among adults with heart disease.204 T3 replacement in adults with impaired left ventricular function resulted in improved left ventricular function and restored cardiomyocyte gene expression to euthyroid levels.205 Among adult patients with heart failure, infusion of T3 for 72 hours resulted in normalization of serum T3 levels with TABLE 84.2 Euthyroid Sick Syndrome Laboratory Data Variable Value Free T4 Low or normal T4 n T3 conversion Decreased T3 Markedly decreased rT3 Variable TSH Normal rT3, Reverse triiodothyronine; T3, triiodothyronine; T4, thyroxine; TSH, thyroid-stimulating hormone TABLE Effects of Various Drugs on Thyroid Hormone 84.3 Metabolism Drug Effect Dopamine Blunts TSH response to TRH Corticosteroids Suppresses basal and TRH-stimulated TSH release Iodinated contrast agents Decreases hepatic conversion of T4 to T3 Amiodarone Decreases hepatic conversion of T4 to T3 and decreases servo feedback T3 binding at the pituitary Phenytoin Enhances T4 to T3 conversion (low free T4 and low total T4) T3, Triiodothyronine; T4, thyroxine; TRH, thyroid-releasing hormone; TSH, thyroid-stimulating hormone 1015 concomitant improvement in stroke volume and left ventricular end-diastolic volume.206 Such findings have stimulated interest in thyroid hormone pathophysiology among children with cardiovascular disease Thyroid function and clinical outcomes were assessed serially among children undergoing cardiac bypass surgery All subjects demonstrated euthyroid sick syndrome characterized by reduced TSH, total T3, free T3 index, and T3 uptake These changes were correlated with prolonged need for mechanical ventilation, degree of organ dysfunction, and vasoactive-inotropic scores.207 One interventional trial reported the effect of T3 supplementation among children undergoing cardiovascular surgery In this investigation, replacement dosing of T3 following cardiopulmonary bypass resulted in increases in plasma T3 concomitant with measures of improved myocardial performance, particularly among those children exhibiting low postoperative cardiac output.208 A subsequent multicenter, double-blind, randomized placebo-controlled trial enrolling children younger than years undergoing cardiac surgery requiring cardiopulmonary bypass examined the effect of IV T3 (n 98) or placebo (n 95).209 Overall, the primary outcome, time to tracheal extubation, was similar between groups However, for patients younger than months, the hazard ratio (chance of extubation) for extubation was 1.72 (P 0216), with median time to extubation in the T3 group being 55 hours compared with 98 hours in the placebo group Shorter duration of mechanical ventilation corresponded to a reduction in inotropic agent use and improvement in cardiac function There were no differences in adverse event rates, including arrhythmia, between groups More recently, however, the consensus statement by the Pediatric Cardiac Intensive Care Society (PCICS) on pharmacotherapies in cardiac critical care hormone replacement therapy found the evidence equivocal Thus, the PCICS does not recommend routine use of thyroid replacement therapies after cardiac surgery unless dictated by specific patient circumstances.210 Key References Boonen E, Van den Berghe G Endocrine responses to critical illness: novel insights and therapeutic implications J Clin Endocrinol Metab 2014;99:1569-1582 Venet F, Monneret G Advances in the understanding and treatment of sepsis-induced immunosuppression Nat Rev Nephrol 2018;14:121-137 Marik PE Critical illness-related corticosteroid insufficiency Chest 2009;135:181-193 Bruder EA, Ball IM, Ridi S, Pickett W, Hohl C Single 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J Diabetes Sci Technol 2012;6:37-47 134 Ognibene KL, Vawdrey DK, Biagas KV The association of age, illness severity, and glycemic status in a pediatric intensive care unit Pediatr Crit Care Med 2011;12:e386-e390 135 Stumvoll M, Chintalapudi U, Perriello G, et al Uptake and release of glucose by the human kidney Postabsorptive rates and responses to epinephrine J Clin Invest 1995;96:2528-2533 ... critical illness remains controversial Evidence indicating overt pathology in this setting is sparse Some argue that this scenario reflects an effort of the body to conserve energy expenditure... trial reported the effect of T3 supplementation among children undergoing cardiovascular surgery In this investigation, replacement dosing of T3 following cardiopulmonary bypass resulted in increases... care hormone replacement therapy Pediatr Crit Care Med 2016;17:S59-S68 The full reference list for this chapter is available at ExpertConsult.com e1 References Boonen E, Van den Berghe G Endocrine