1009CHAPTER 84 Endocrine Emergencies receive antifungal and antibiotic medications in large volumes of dextrose containing fluids) Corticosteroids can increase the risk of SHG, especially when given i[.]
CHAPTER 84 Endocrine Emergencies 1009 Alanine Glycolysis ALT Pyruvate LDH Lactate Pyruvate Pyruvate carboxylase Oxaloacetate Malate dehydrogenase Fatty acid oxidation Malate Mitochondria Malate shuttle Cytoplasm GLUCOSE Malate Triglycerides Glucose-6-phosphatase + Fatty acids Glucose 6phosphate Oxaloacetate Epinephrine growth PEPCK hormone Phosphoenolpyruvate Glycerol 3phosphate DHAP Fructose 6phosphate Phosphoenolpyruvate Glyceraldehyde 3-phosphate + Glucagon Fructose 1,6-biphosphatase Fructose 1,6biphosphate – Insulin + Glucagon • Fig 84.4 Schematic overview of gluconeogenesis Pyruvate is generated from glycolysis, lactate, or alanine through pyruvate kinase, lactate dehydrogenase (LDH), and alanine aminotransferase (ALT), respectively Pyruvate enters the mitochondria freely and is converted into oxaloacetate, which is then converted into malate to enter the malate shuttle and cross the mitochondrial membrane into the cytoplasm In the cytoplasm, it is again converted into oxaloacetate and, through phosphoenolpyruvate carboxykinase (PEPCK), is converted into phosphoenolpyruvate that serves as substrate for a series of enzymatic-driven reactions and is finally converted into glucose It should be noted that the rate-limiting step of gluconeogenesis is the conversion of fructose biphosphate into fructose 6-phosphate and is regulated by the actions of glucagon (stimulates) and insulin (inhibits) on fructose 1,6-biphosphatase Triglycerides also contribute to gluconeogenesis by their breakdown into fatty acids and glycerol 3-phosphate The latter is then transformed into dihydroacetone phosphate and then into fructose 1,6-biphosphate to follow the rest of the gluconeogenic pathway and result in the generation of glucose receive antifungal and antibiotic medications in large volumes of dextrose-containing fluids) Corticosteroids can increase the risk of SHG, especially when given in bolus doses Thiazide diuretics are also associated with the occurrence of SHG Calcineurin inhibitors, such as tacrolimus and cyclosporine, can result in SHG and posttransplant diabetes due to decreased insulin biosynthesis and release Nutritional support practices strongly influence SHG Critically ill children are frequently prescribed parenteral nutrition (PN) Provision of excess carbohydrate calories in PN can result in SHG, which has been associated with increased risk of mortality in critically ill pediatric patients.140 Overfeeding is common in critically ill children, regardless of whether PN or enteral nutrition is employed Studies have shown that commonly used predictive equations to calculate caloric needs are inferior to targeted indirect calorimetry and frequently result in overprescription of calories.141 Mechanisms of Stress Hyperglycemia Adverse Outcomes Postulated mechanisms by which SHG causes harm include direct cellular damage and alterations of essential organ function In diabetic patients, four main molecular mechanisms have been identified in glucose-mediated complications: (1) increased polyol pathway flux, (2) increased advanced glycation end-product formation, (3) activation of protein kinase C isoforms, and (4) increased hexosamine pathway flux Each of the four pathogenic mechanisms reflects a hyperglycemia-induced process, namely, overproduction of superoxide anion by the mitochondrial electron-transport chain.142 Diabetes-related injury develops over years, but some common mechanisms parallel acute stress-related hyperglycemia During SHG, overexpression of insulin-independent transporters (glucose transporter types to [GLUT-1 to 1010 S E C T I O N V I I I Pediatric Critical Care: Metabolic and Endocrine GLUT-3]) results in glucose overload and toxicity essentially in every organ.143 Cells damaged by hyperglycemia are primarily those unable to effectively control their intracellular glucose concentration—notably, neuronal, capillary endothelium, and renal mesangial cells Glucose overload results in excessive glycolysis and oxidative phosphorylation with increased production of reactive oxygen species such as superoxide anion, the same toxic end product involved in the injury pathway for diabetic patients Reactive oxygen species cause mitochondrial dysfunction and altered metabolism with subsequent apoptosis and cellular and organ system failure in the critically ill child Glucose overload can also lead to glycation, the reaction of glucose with the amine group of proteins, which may impair the function of these proteins Hyperglycemia is a risk factor for infection in acute illness.112 The relative bacterial overgrowth witnessed in hyperglycemia may be partly due to altered host defenses Acute, short-term hyperglycemia impairs macrophage activity, reduces polymorphonuclear leukocyte chemotaxis and bactericidal capacity, and alters complement fixation in critically ill patients.144 SHG affects all major components of innate immunity and impairs the ability of the host to combat infection.144 Furthermore, hyperglycemia is associated with poor gut motility, a factor that may be important in bacterial overgrowth and translocation A raised blood glucose level is also recognized as being proinflammatory and pro-oxidant Mononuclear cells isolated from healthy volunteers exhibited higher levels of NF-kB binding activity, raised reactive oxygen species, and increased levels of TNF-a mRNA following exposure to hyperglycemia.145 Hyperglycemia also results in a hypercoagulable state partly through the increased expression of tissue factor, which is both pro-coagulant and proinflammatory.146 SHG is implicated in other abnormalities, such as endothelial dysfunction and alteration in vascular smooth muscle tone, commonly observed during critical illness.147 Likewise, hyperglycemia has been associated with deleterious effects on the nervous system Underlying mechanisms in critical illness remain largely speculative and are often extrapolated from knowledge in diabetic patients Hyperglycemia-induced blood-brain barrier permeability, oxidative stress, and microglia activation may play a role and compromise neurons and glial cell integrity.148 Clinical Trials Examining Management of Critical Illness Hyperglycemia In 2001, a single-center adult study reported reduction of hospital mortality by more than 30% using a tight glycemic control (TGC) protocol.149 The effect was attributed to the actual glycemic control rather than the infused insulin dose These impressive results brought the issue of SHG to clinical attention and fostered considerable discussion Previously seen as an aspect of a normal stress response, physicians now started viewing SHG differently, considering it to be a major cause or contributor to pathophysiology that must be aggressively addressed and treated The appeal of such straightforward intervention was too great to resist.150 Subsequent studies failed to reproduce these results, yet guidelines generated by professional societies initially recommended TGC for adult critically ill patients.151,152 A large international randomized multicenter study involving more than 6000 adult patients153 and many other smaller studies reported that TGC increased mortality and risk for severe hypoglycemia among adults in the ICU In the setting of such consistent negative results, guidelines were revised and currently recommend using a higher glucose threshold for initiation of insulin therapy at 150 mg/dL, with the goal of keeping blood glucose ,180 mg/dL, focusing on close monitoring and safety margins to avoid hypoglycemia and minimize glucose variability.154 While TGC became the standard of care for adults, the pediatric critical care community was hesitant to adopt any guidelines or consistent standard approach.155 There are, however, several prospective randomized clinical trials to guide practice In very-low-birth-weight neonates, a multicenter trial of insulin with continuous 20% dextrose infusion was terminated prematurely for concerns of futility and potential harm associated with hypoglycemia.156 This study took a proactive approach to glycemic control in that the treatment group received insulin with glucose infusion regardless of their blood glucose level before the intervention Considering the study population and the fact that the study was not designed to treat hyperglycemia, it is difficult to compare the results with any other pediatric study Five randomized prospective studies have examined the association between TGC and clinical outcomes in critically ill children The first study, published in 2009, was derived from a single center in Belgium The study enrolled a mixed medical/surgical patient population, although 75% of the subjects had undergone cardiac surgery.157 The study targeted age-adjusted glycemic range for infants and children, 50 to 80 mg/dL in children less than year old, and 70 to 100 mg/dL in the remainder Results showed improved short-term outcome, including mortality, in the TGC group despite the fact that the TGC group had severe hypoglycemia (,40 mg/dL) at unacceptable rates (25% overall and 44% in neonates) A two-center prospective randomized trial published in 2012 enrolled 980 children below age years who underwent cardiac surgery with cardiopulmonary bypass The authors reported that TGC (target range, 80–110 mg/dL) could be achieved with a low hypoglycemia rate However, the study found no clinical benefit for TGC in terms of infection rate, mortality, LOS, or measures of organ failure when compared with standard care.158 A post hoc analysis of this study demonstrated that TGC may, in fact, lower the rate of infection in children older than 60 days of age at the time of cardiac surgery when compared with standard care.159 In a secondary analysis of this trial, insulin appeared to have no discernible impact on skeletal muscle degradation.160 The concern for the impact of hypoglycemia on neurocognitive long-term outcome was addressed by both investigator teams Four-year neurocognitive follow-up in the single-center study ascertained that insulin-induced hypoglycemia caused by TGC was not associated with worse neurocognitive outcome.161 However, the outcomes of both treatment groups were similar to the few patients who developed moderate or severe hypoglycemia in the two-center, cardiac-only trial The group that had no hypoglycemia, as reported by continuous glucose monitoring, had a markedly better neurocognitive outcome than the other three groups, raising the possibility that the group in the first trial with no hypoglycemia detected may have had undetected hypoglycemia leading to the moderately impaired outcomes Subsequent studies have confirmed the dangers of hypoglycemia in this population.162 Taken together, these data suggest that, in order to ensure optimal outcome, hypoglycemia should be assiduously avoided In 2014, a large multicenter randomized trial involving 13 centers in the United Kingdom reported that TGC in critically ill children had no significant effect on major clinical outcomes (number of days alive and free from mechanical ventilation at 30 days after enrollment), but patients in the TGC arm had lower CHAPTER 84 Endocrine Emergencies need for renal replacement therapy and reduced 12-month health care costs These effects were mostly notable in the noncardiac patient population.163 In 2010, a single-center study focusing on pediatric patients with severe burns concluded that intensive insulin therapy significantly decreased infections and sepsis and improved organ function by decreasing inflammation.164 After five randomized clinical trials of TGC to low versus high target ranges, this area of critical care therapeutics has become one of the most well studied in the field The end result in general pediatric ICU and cardiac ICU patients, although initial promising findings were noted in the original single-center trial, is that low targets produce little to no benefit yet increase hypoglycemia, which is becoming increasingly associated with harm Consensus has evolved that insulin infusion should be initiated when glucose levels reach 150 mg/dL, with the goal of keeping blood glucose less than 180 mg/dL In the burn population, which has repeatedly been shown to be physiologically different from other critically ill children, the single-center study that has been completed stands in support of targeting a low range of 80 to 110 mg/dL Glucose Measurement Until recently, intermittent blood glucose levels (using point of care, blood gas analyzer, or central laboratory measurement) were the only means of blood glucose monitoring Accuracy is probably the most important metric in selecting the best glycemic management device for critically ill children, but rapidity/turnaround time, cost, and sample volume are also important factors.165 Intermittent measurements are limited by the workload associated with the sampling process and with the potential that “between measurements” events will be missed A simulation study modeling adult patients on TGC protocol demonstrated that increasing the frequency of glucose measurements reduced the adverse impact of glucose measurement imprecision on glycemic control.166 A mathematical simulation in a cohort of critically ill patients suggested that glycemic control is more optimal with a blood glucose measurement interval of no longer than hour, with further benefit obtained with use of a measurement interval of 15 minutes These findings have important implications for the development of glycemic control standards and future studies.167 With growing interest in glycemic control and the possible beneficial effect of frequent glucose measurements, continuous glucose monitoring systems have been developed Although termed continuous, current systems still sample glucose intermittently with a measurement interval of a few milliseconds up to 15 minutes The Clinical and Laboratory Standard Institute uses 15 minutes as the cutoff for definition of continuous measurement.168 One of the key advantages of continuous glucose monitoring is the ability to identify and display trends in blood glucose measurements High-quality continuous glucose monitoring devices enable clinicians to assess the complexity of the glycemic signal—how one point in time changes relative to neighboring measurements.169 Continuous glucose monitoring using subcutaneous sensors measuring interstitial fluid has been validated in the pediatric population,170,171 and sensor performance has improved exponentially over the past decade.172 Although not yet approved by the US Food and Drug Administration for use in the inpatient setting, we expect such approvals to be forthcoming 1011 Hypoglycemia Although the determination of which glucose levels represent hypoglycemia is controversial, a glucose level less than 40 mg/dL is generally accepted to represent severe hypoglycemia However, this concentration is well below the level at which counterregulatory responses occur As plasma glucose levels reach 80 to 85 mg/dL, insulin secretion decreases, and as levels approximate 65 mg/dL, glucagon, epinephrine, cortisol, and GH are released.173 In addition, a decrease in mental efficiency may be seen when levels fall below 50 to 60 mg/dL Because a delay in the recognition and management of hypoglycemia may lead to long-term neurologic sequelae,174 it is important to make a distinction between the laboratory diagnosis of hypoglycemia (,40 to 50 mg/dL) and an interventional threshold at which therapies to raise serum glucose should be applied Setting the interventional threshold at a level similar to that which elicits counterregulatory responses seems appropriate; as such, treatment should be offered for hypoglycemia when levels fall below 60 mg/dL to prevent complications, especially in young children An even higher interventional threshold (,70 mg/dL) is warranted for children who are at increased risk of hypoglycemia Clinical Manifestations Diaphoresis, tremor, tachycardia, anxiety, weakness, hunger, nausea, and vomiting are all autonomic manifestations caused by the adrenergic stress response that occurs with a rapid decline in blood glucose levels Other symptoms associated with hypoglycemia are a result of a deficiency of the brain’s primary energy substrate, which are known as neuroglycopenic symptoms These symptoms include headache, visual disturbances, lethargy, restlessness, irritability, dysarthria, confusion, somnolence, stupor, coma, hypothermia, seizures, and motor and sensory disturbances The glycemic ranges at which these symptoms manifest vary, as critically ill patients cannot recognize or communicate symptoms The picture is further masked by sedation and analgesia Pathogenesis Imaging studies of infants who sustained neonatal hypoglycemic brain injury display diffuse cortical and subcortical white matter damage that is most prominent in the parietal and occipital lobes This pattern differs from the neuroimaging features of other neonatal insults, including hypoxic-ischemic encephalopathy.175 Interestingly, this pattern does not resemble the glucose uptake pattern of neonatal brains by positron emission tomography, which may indicate that neuronal damage is not simply due to cerebral deprivation of its primary substrate for energy production Evidence indicates that hypoglycemia activates receptors for excitatory amino acids within the brain and causes cell depolarization, with subsequent cellular edema and apoptosis.176 Fasting Adaptation Consumption of glucose is largely dependent on the brain-tobody ratio This phenomenon explains the reduced fasting tolerance of infants whose glucose utilization rate (approximately mg/kg per minute) is significantly higher than that of older children and adults (1 to mg/kg per minute) This reality places younger patients at increased risk of hypoglycemia In addition, 1012 S E C T I O N V I I I Pediatric Critical Care: Metabolic and Endocrine their ability to maintain euglycemia through glycogenolysis and gluconeogenesis is reduced because glycogen stores and muscle bulk are small, thus reducing the pool of available gluconeogenic substrates Within the brain, astrocytes, but not neurons, are capable of storing glycogen The brain contains less than mmol/ kg of free glucose reserve Fasting tolerance increases rapidly in the first days of life Neonates may fast up to 18 hours after week of age By year, a 24-hour fast is tolerated; by years, a child may fast for up to 36 hours without experiencing hypoglycemia Understanding fasting physiology is crucial to the logic and methodologic approach required for diagnosing the etiology of hypoglycemia Normally in the postabsorptive state, metabolism is governed primarily by counterregulatory hormones In the first hours of a fast in infants or in the first hours in older children, glucagon is released and euglycemia is maintained primarily by glycogenolysis Following glycogen store depletion, gluconeogenesis gains importance in the maintenance of normal glucose levels (see Fig 84.4) Muscle provides amino acids, particularly alanine and glutamine, as gluconeogenic substrates Glycerol 3-phosphate derived from triglyceride hydrolysis is also a gluconeogenic precursor Fatty acids resulting from triglyceride hydrolysis are transported to the liver, where they are oxidized to generate acetyl CoA and ketones The latter may then be used as alternative fuel by skeletal and cardiac muscle to help ensure availability of glucose to the brain and to erythrocytes that are strictly dependent on glucose for energy production The brain may also use ketones as an alternative fuel source, but it does so only during a prolonged fast Hypoglycemia that occurs early during fasting may indicate hormonal imbalance or a primary disorder of glycogenolysis Disorders of gluconeogenesis (see also Chapter 81) will not manifest during early fast They become apparent only after glycogen stores have been depleted; hence, typically, they present later in infancy once feeding intervals become increasingly prolonged The same is true for fatty oxidation disorders These disorders generally require a more prolonged fast to manifest, nearing 12 to 18 hours in infants and 18 to 24 hours in older children However, the most common cause of childhood hypoglycemia is ketotic hypoglycemia.177 This illness most frequently occurs in toddlers and preschoolers and is uncommon after to years It is typically triggered by intercurrent infection and caloric restriction, both common events in the PICU A defect in protein catabolism, transamination, or amino acid efflux from skeletal muscle, as well as impaired autonomic regulation of epinephrine secretion, has been postulated Hypoglycemia has been observed in association with a variety of critical illness diagnoses, including sepsis, congestive heart failure, renal failure, liver failure, and pancreatitis, and it has been associated with increased mortality among critically ill children.178,179 Critically ill patients are at risk of hypoglycemia not only because of their underlying illness but also because of factors unique to their hospitalization, such as muscular atrophy from prolonged immobilization and gluconeogenic substrate depletion, undernutrition often resulting from the limitation of caloric intake because of fluid restriction, increased glucose consumption, AI, loss of IV access or inadvertent disconnection of infusion lines, or iatrogenic factors related to drugs and therapies, including the practice of TGC Hypoglycemia Treatment After obtaining the “critical” blood/urine samples, administration of mL/kg of 10% dextrose water solution (or an equivalent dose of dextrose) is indicated for patients with hypoglycemia Subsequently, an IV maintenance fluid regimen should be considered to provide a glucose infusion rate of to mg/kg per minute Serum glucose should be rechecked 15 minutes after the initial bolus; if hypoglycemia persists, a repeat bolus of to mL/kg of 10% dextrose water (or an equivalent dose of dextrose) should be administered and the glucose infusion rate increased by 25% to 50% If the volume of fluid required to maintain glucose concentrations greater than 70 mg/dL is excessive, a higher dextrose concentration should be used Glucagon (0.03 mg/kg for patients ,30 kg, or mg for patients 30 kg) can reverse hypoglycemia in patients with adequate glycogen stores and normal glycogenolytic pathways Definitive treatment will depend on the underlying etiology In summary, hypoglycemia is a manifestation of iatrogenic, intentional, or accidental drug ingestion or administration or the manifestation of an underlying disorder All critically ill patients with hypoglycemia should raise a high index of suspicion because many defects that cause hypoglycemia remain silent until an intercurrent illness or stress overwhelms the compensatory capacity of the individual Unless certitude of the etiology of the hypoglycemia exists before therapy, a “critical” blood/urine sample should be obtained to guide diagnosis and further management Prompt recognition and treatment are necessary to prevent neurologic injury A multidisciplinary approach, including endocrine and/or metabolism consultation, is often necessary Alterations of Thyroid Hormone In Critical Illness Thyroid Biochemistry Thyroid-stimulating hormone (TSH) derived from the anterior pituitary is a pleotropic hormone that modulates all aspects of thyroid hormone synthesis.180 TSH action within the thyroid follicular cells facilitates the sodium iodide symporter, resulting in (1) enhanced iodine concentration in the thyroid gland; (2) increased synthesis of thyroglobulin, the site of tyrosine residues destined for iodination; and (3) activated thyroid peroxidase, which catalyzes iodination of tyrosine residues as well as tyrosine coupling It is important to note that autoantibodies may bind to TSH receptors and stimulate a response similar to TSH, resulting in a hyperthyroid state Leptin is likely to mediate an important role in the regulation of the thyroid axis, as suggested by the close correlation between the circadian rhythm of leptin secretion and TSH.181 An overview of thyroid hormone biosynthesis and secretion is provided in Fig 84.5.34 In this schematic diagram, iodide is transported into the thyroid follicular cell by the action of the sodiumiodide symporter (NIS) Subsequently, this iodide diffuses passively through the iodide channel termed pendrin (P) Thyroglobulin (TG) is synthesized within the rough endoplasmic reticulum (ER) and subsequently packaged by the Golgi apparatus into thyroglobulin secretory vesicles that are released into the follicular cell lumen Thyroid oxidase (TO) produces hydrogen peroxide that is subsequently used by thyroid peroxidase (TPO) to oxidize iodide to iodine, which subsequently reacts with the tyrosine residues within thyroglobulin to produce monoiodotyrosine (MIT) and diiodotyrosine (DIT) residues within the thyroglobulin peptide Thyroid peroxidase also catalyzes coupling of adjacent iodotyrosines to form thyroxine (T4) and lesser amounts of triiodothyronine (T3) Secretion of thyroxine from the thyroid follicular cell CHAPTER 84 Endocrine Emergencies DIT DIT DIT 1013 Follicular lumen DIT MIT MIT DIT TG H2O2 T4 P TO T4 DIT TPO TG vesicle DIT MIT T4 Endosome E.R Golgi MIT PF DIT T4 MIT Nucleus DIT Lysosome T4 ITDI I– 3Na+ NIS I– 2Na+ ATP 2K+ T4 • Fig 84.5 Thyroid hormone biosynthesis and secretion ATP, Adenosine triphosphate; DIT, diiodotyrosine; ER, endoplasmic reticulum; H2O2, hydrogen peroxide; I2, iodide ion; ITDI, iodotyrosine deiodinase; MIT, monoiodotyrosine; Na1, sodium ion; NIS, sodium-iodide symporter; P, pendrin; P1, potassium ion; PF, peptide fragments; T3, triiodothyronine; T4, thyroxine; TG, thyroglobulin; TO, thyroid oxidase; TPO, thyroid peroxidase (From Goodman HM Basic Medical Endocrinology Philadelphia: Elsevier; 2009.) begins with thyroglobulin phagocytosis with a subsequent fusion of thyroglobulin endosomes containing proteolytic enzymes capable of digesting thyroglobulin to peptide fragments (PF), as well as MIT, DIT, and T4 While T4 is released from the cell at the basal membrane, both MIT and DIT are deiodinated by iodotyrosine deiodinase (ITDI) and subsequently recycled (Fig 84.6) T4 is transported to peripheral tissues via transport hormones T4-binding globulin, transthyretin, and albumin Because all the T4 transport proteins are moderately sized, T4 is not filtered by the kidney In peripheral tissues, T4 is metabolized to T3 and reverse T3 (rT3) by the action of various isoforms of iodothyrosine deiodinases.182 Transcription and translation of this enzyme are highly dependent on cytokine stimulation Selenocysteine residues characterize the active site of this iodine cleavage enzyme As indicated in Fig 84.6, if monodeiodination occurs on the outer tyrosine ring, the product is T3, and if the monodeiodination occurs on the inner tyrosine ring, the resultant product is rT3.34 In peripheral tissues, T3 binds to thyroid hormone receptors that subsequently undergo homodimerization with other thyroid hormone receptors or heterodimerization with retinoid receptors Thyroid hormone receptors can bind to specific nucleotide sequences termed thyroid responsive elements within promoter O HO C C COOH NH2 Thyroxine 3,5,3´,5´-Tetraiodothyronine (T4) O HO C C COOH NH2 3,5,3´-Triiodothyronine (T3) O HO C C COOH NH2 3,5´,3´-Triiodothyronine reverse T3 (rT3) • Fig 84.6 Thyroid hormone chemical structures (From Goodman HM Basic Medical Endocrinology Philadelphia: Elsevier; 2009.) ... parietal and occipital lobes This pattern differs from the neuroimaging features of other neonatal insults, including hypoxic-ischemic encephalopathy.175 Interestingly, this pattern does not resemble... acids within the brain and causes cell depolarization, with subsequent cellular edema and apoptosis.176 Fasting Adaptation Consumption of glucose is largely dependent on the brain-tobody ratio This... provided in Fig 84.5.34 In this schematic diagram, iodide is transported into the thyroid follicular cell by the action of the sodiumiodide symporter (NIS) Subsequently, this iodide diffuses passively