1004 SECTION VII I Pediatric Critical Care Metabolic and Endocrine among healthy (but not critically ill) patients with peak cortisol production typically from 8 am to 9 am and a nadir of cortisol pro[.]
1004 S E C T I O N V I I I Pediatric Critical Care: Metabolic and Endocrine among healthy (but not critically ill) patients with peak cortisol production typically from am to am and a nadir of cortisol production typically around midnight Cortisol exhibits mineralocorticoid activity approximately 1% that of aldosterone Cortisol is transported from the adrenal gland to various tissues via cortisol binding proteins, namely, transcortin with high affinity but low capacity and albumin with low affinity but high capacity.16 Cortisol concentration is locally increased at sites of inflammation through degradation of transcortin by neutrophil elastase, as well as local upregulation of 11b-hydroxysteroid dehydrogenase, an enzyme key to cortisol synthesis.17 Cortisol diffuses through the plasma membrane binding to the glucocorticoid receptor (GCR) Commonly occurring GCR polymorphisms may explain individualized patient responses to corticosteroids.18 Children with septic shock demonstrate a transient depression of GCR messenger ribonucleic acid (mRNA) in their neutrophils19 that may reflect an adaptive cortisol resistance response On the other hand, septic patients may demonstrate a transient increased20 or decreased21 expression of GCR on mononuclear cells GCRs represent a potential drug target for treatment of severe inflammation and the consequences of excess endogenous or exogenous corticosteroid.22 Ultimately, cortisol modulates the transcription of thousands of genes, perhaps 25% of the entire genome.23,24 Although the majority of corticosteroid action is related to changes in gene transcription mediated through chromatin remodeling, corticosteroids also – Hypothalamus (CRH neurons) CRH – IL-1 IL-2 IL-6 TNF-α + + Anterior pituitary (Corticotropes) Adrenal cortex (Fasciculata cells) Actions of Cortisol Cortisol affects three general areas of physiology: immunity, metabolism, and hemodynamics Immunity Much of critical illness may involve disturbance of the balance between systemic inflammatory responses versus compensatory antiinflammatory responses.25,28,31–33 As depicted in Fig 84.2,34 cortisol biochemistry represents a key regulatory mechanism for virtually all aspects of antiinflammation In this respect, cortisol increases the synthesis of IkB, trapping nuclear factor-kB (NF-kB) in the cytoplasm and effectively thwarting synthesis of a variety of proinflammatory mediators In addition, cortisol increases the production of annexin, which inhibits phospholipase A2, resulting in modulation of both cyclooxygenase and lipoxygenase inflammatory lipid pathways Sepsis induces widespread immunosuppression.35,36 Among children with sepsis who receive corticosteroids, further repression of gene networks related to adaptive immunity has been reported.29 Metabolism – ACTH affect protein synthesis by decreasing the stability of mRNA A number of inflammatory proteins appear to be regulated by this posttranscriptional mechanism.23 Even with appropriate cortisol production by the adrenal gland, cortisol resistance can occur by multiple mechanisms, including depletion of corticosteroid-binding globulins, activation of 11b-hydroxysteroid dehydrogenase, decreased glucocorticoid receptor density and activity, and elevated antiglucocorticoid compounds and receptors.25–27 Immune system Lymphocytes Macrophages/ monocytes Neutrophils – Cortisol • Fig 84.1 Signaling for hypothalamic-pituitary-adrenal axis ACTH, Adrenocorticotropic hormone; CRH, corticotropin-releasing hormone; IL, interleukin; TNF, tumor necrosis factor (From Belchetz P, Hammond P Mosby’s Color Atlas and Text of Diabetes and Endocrinology London: Mosby; 2003.) A schematic summary of the effects of cortisol on metabolism is displayed in Fig 84.3.34 As a key mediator of the stress response, cortisol facilitates lean muscle catabolism to provide substrate for hepatic gluconeogenesis, synthesis of acute-phase reactants, and expansion of the immune system.37 Hypercortisolemia represents a key mediator in hyperglycemia of critical illness discussed later.38 Both protein catabolism and hyperglycemia, if prolonged in the ICU, can become maladaptive and associated with increased risk for adverse outcomes, including death Hemodynamics Cortisol’s permissive effects on maintaining a normal hemodynamic status include augmenting cardiac contractility, maintaining TABLE Plasma Cortisol Levels (µg/dL) as Function of Age 84.1 2h 7d wk–3 mo mo–1 y 1–3 y 3–5 y 5–7 y 7–11 y 11–15 y Mean 6.80 1.14 3.34 6.34 7.52 7.37 7.83 7.98 6.41 Range 1.25–29.80 0.13–9.64 0.92–8.68 2.12–17.30 1.71–13.70 3.24–12.98 3.98–12.90 3.54–18.40 2.17–17.40 12 20 11 23 20 17 19 27 25 N A total of 174 normal children were assessed at am to 10 am; unrestrained activity, random diets From Sippell WG, Dörr HG, Bidlingmaier F, et al Plasma levels of aldosterone, corticosterone, 11-deoxycorticosterone, progesterone, 17-hydroxyprogesterone, cortisol, and cortisone during infancy and childhood Pediatr Res 1980;14:39-46 CHAPTER 84 Endocrine Emergencies 1005 vascular tone, promoting endothelial integrity, upregulating vasoactive receptors, and increasing catecholamine synthesis.1,39,40 Specifically, cortisol suppresses inducible nitric oxide synthetase, leading to increased vascular tone and blood pressure Additionally, high intraadrenal concentrations of cortisol during critical illness induce the cascade of enzymatic activity that produces epinephrine via methylation of norepinephrine by phenyl-ethanolamine N-methyltransferase.41–43 I-κB-PO4 I-NF-κB TNF-α NF-κB Tissue insult I-κB Kinase IL-1 Assessing the Cortisol Stress Response I-κB NF-κB GR GR Cortisol GR Prostaglandins Thromboxanes Leukotrienes COX2 NO iNOS PLA2 IL-1 TNF-α Other cytokines • Fig 84.2 Signaling for the antiinflammatory actions of cortisol COX2, cyclo-oxygenase 2; GR, glucocorticoid receptor; IL, interleukin; iNOS, inducible nitric oxide synthase; NF-kB, nuclear factor-kB; NO, nitric oxide; PLA2, phospholipase A2; PO4, phosphate; TNF, tumor necrosis factor (From Goodman HM Adrenal glands In Goodman HM, ed Basic Medical Endocrinology Philadelphia: Elsevier; 2009.) ↑ Protein degradation ↓ Protein synthesis ↓ Glucose utilization ↓ Sensitivity to insulin Amino acids ↑ Glycogen storage ↑ Gluconeogenesis ↑ Activity of enzymes ↑ Amount of enzymes Muscle Cortisol Liver Glucose Free Cortisol Adipose tissue Glycerol ↑ Lipolysis ↓ Glucose utilization ↓ Sensitivity to insulin • Fig 84.3 Schematic Historically, adrenal function during critical illness has been quantified by random total plasma cortisol concentrations or by calculating the difference between a corticotropin-stimulated plasma cortisol concentration minus a baseline cortisol concentration In the latter case, a so-called delta value less than µg/dL was previously considered evidence of adrenal insufficiency (AI) or inadequate adrenal reserve.44 Depending on the cutoff value chosen (10, 15, 18, 20, 25 µg/dL), critically ill patients may demonstrate a wide range of adrenal insufficiency occurrence when random baseline total plasma cortisol concentrations are evaluated.45 A detailed evaluation of critically ill adults with sepsis indicated that those patients with a high baseline plasma cortisol concentration but delta cortisol concentration less than µg/dL exhibited the highest risk for hemodynamic instability and mortality.46 A subsequent interventional trial of adjunctive hydrocortisone for adult septic shock was designed on the basis of these findings.47 However, a confirmatory trial failed to replicate this finding and concluded that corticotropin stimulation testing provided no information regarding which patients with septic shock would benefit from hydrocortisone replacement therapy.48 Serial low-dose corticotropin stimulation testing in addition to comprehensive ACTH, dehydroepiandrosterone, and cytokine measurements in a cohort of critically ill Turkish children revealed that 28% exhibited AI that was largely resolved by weeks.49 Baseline cortisol levels of the patients were significantly higher than those of healthy children Patients with multiple-organ dysfunction syndrome (MODS) had significantly higher concentrations of baseline and stimulated cortisol, as well as higher procalcitonin, TNF-a, and interleukin-6 (IL-6) concentrations compared with those without MODS Cortisol, ACTH, and dehydroepiandrosterone concentrations were higher among the children with AI compared with those without AI Interestingly, sepsis as an antecedent of critical illness was not associated with an increased risk of AI Similarly, among 381 critically ill Canadian children also evaluated by low-dose corticotropin stimulation testing, AI was noted in 30.2%.50 Children with AI exhibited higher baseline cortisol concentrations, were significantly older, and demonstrated an increased need for volume resuscitation and vasoactive-inotropic support overview of metabolic actions of cortisol (From Goodman HM Basic Medical Endocrinology Philadelphia: Elsevier; 2009.) Although most cortisol is bound to transcortin or serum albumin, the free fraction comprising 10% to 15% of the total is actually responsible for the protean effects of cortisol Accordingly, it has been suggested that perhaps free cortisol rather than total cortisol concentrations might be more reliable in terms of identifying a population that would most benefit from cortisol replacement therapy.51 For most critically ill patients, cortisol-binding globulin is typically decreased and the percent of cortisol as the free fraction increased Moreover, with corticotropin adrenal stimulation, 1006 S E C T I O N V I I I Pediatric Critical Care: Metabolic and Endocrine free cortisol increases substantially more than total cortisol.52–54 Assessing total cortisol concentrations may be especially problematic in critically ill patients with low albumin In an investigation that measured both total and free cortisol concentrations in a general population of critically ill children, the majority exhibited low total and free cortisol concentrations However, none of these children demonstrated clinical evidence of corticosteroid insufficiency (hypotension, hyponatremia, hypoglycemia).14 These results question the use of current thresholds for assigning diagnoses of AI or critical illness–related corticosteroid insufficiency in critically ill children The results further suggest that clinicians currently are unable to reliably define adequacy of the adrenal response to the stress of critical illness either with total or free cortisol measurements Adrenal Insufficiency in the Intensive Care Unit AI may be classified under two major categories: primary, in which direct malformation or destruction of the adrenal glands occurs, and secondary, in which there is typically loss of HPA axis integrity The latter situation is most often encountered among critically ill patients Primary Adrenal Insufficiency Primary adrenal insufficiency, or Addison disease, is more typically encountered in adult patients and is included in a group of disorders termed autoimmune adrenalitis.55,56 Signs and symptoms of Addisonian crisis include intercurrent illness with a history of chronic weight loss and anorexia, dizziness, lethargy, and chronic pigmentation Symptoms more likely to be associated with admission to the ICU include sudden hypovolemic shock, hyperkalemia, vomiting, diarrhea, abdominal pain, and coma Other causes of primary adrenal failure include congenital adrenal hyperplasia, an autosomal recessive disorder, with approximately 90% of cases secondary to 21 hydroxylase deficiency (CYP21A2 mutation).57,58 Primary congenital adrenal failure can also occur among infants with adrenoleukodystrophy associated with a metabolic defect in metabolism of very-long-chain fatty acids Other causes of congenital adrenal failure include Wolman disease and familial unresponsiveness to ACTH involving altered MC2R, as previously discussed.59 Because of its precarious circulation associated with a subcapsular arteriolar plexus, the adrenal glands are subject to hemorrhage and infarction, particularly in the setting of septic shock Such events, termed the Waterhouse-Friderichsen syndrome, were initially described as adrenal apoplexy.60,61 Although a variety of drugs inhibit the sequential steps in cortisol synthesis, etomidate is particularly notable, as it is increasingly being used as a sedative to facilitate endotracheal intubation without adversely affecting hemodynamics A single bolus of etomidate suppresses 11b-hydroxylase activity, one of the critical enzymes in the cortisol synthetic pathway.62,63 A meta-analysis of seven studies concluded that administration of etomidate for endotracheal intubation was associated with higher rates of AI and mortality among patients with sepsis.64 Further studies, however, have not confirmed consistently worse outcomes with its use.65–67 Given the known effects of etomidate on cortisol production, and until further definitive prospective studies have been performed, the authors recommend empiric administration of stress-dose hydrocortisone for 48 hours after etomidate use in patients with septic shock Secondary Adrenal Insufficiency Secondary AI in the pediatric ICU (PICU) can be seen with pituitary disorders (e.g., among children following surgical resection of a craniopharyngioma).68 In addition, long-term corticosteroid administration among patients with recalcitrant asthma, patients with oncologic or rheumatologic diagnoses, or transplantation patients results in suppression of ACTH release, occasionally leading to adrenal atrophy.69,70 Probably the most controversial cause of secondary adrenal failure seen in the ICU is so-called relative adrenal insufficiency or critical illness–related corticosteroid insufficiency (CIRCI).71 A seemingly inadequate adrenal response relative to the magnitude of stress characterizes CIRCI This situation is a dynamic, typically reversible state that is thought to be secondary to both decreased cortisol production and tissue resistance to cortisol, as discussed previously Multiple pediatric observational studies, most associated with sepsis, have examined associations with random baseline serum cortisol concentrations with various outcomes.62,72–75 These studies ascertain cortisol circadian rhythm among children with sepsis As sepsis severity increased (e.g., sepsis n septic shock n sepsis death), proinflammatory mediator concentrations (e.g., IL-6, TNF-a) and ACTH increased, while cortisol concentrations decreased Both serum cortisol and ACTH concentrations correlated with illness severity per the Pediatric Risk of Mortality study, organ dysfunction scores, lactate, and C-reactive protein Pediatric observational studies have also examined corticotropin stimulation testing among children with severe sepsis.76–80 These studies in general demonstrated that, like adults, low delta cortisol is common among children with sepsis Among children with a low delta cortisol, illness severity was higher, as was requirement for vasoactive-inotropic resuscitation Such children also more frequently demonstrate vasoactive-inotropic resistance shock and MODS Chronic illness and the degree of organ dysfunction at presentation, as well as low delta cortisol concentration, predicted risk of mortality Treatment of Adrenal Insufficiency Guidelines for steroid replacement in the acute and long-term management of primary AI are well established with utilization of stress-dose hydrocortisone during times of illness and replacement of maintenance glucocorticoids and mineralocorticoids when well.81,82 The 2017 American College of Critical Care Medicine Clinical Practice Parameters for Hemodynamic Support of Pediatric and Neonatal Septic Shock additionally recommend use of hydrocortisone in children with catecholamine-resistant septic shock at risk for absolute AI, such as those with purpura fulminans, chronic steroid exposure, sedation with etomidate, and congenital adrenal hyperplasia.83 The same group did not make recommendations for how or when to treat CIRCI Treatment of CIRCI remains controversial, as the diagnosis of CIRCI remains controversial Two recent adult randomized controlled trials again looked at mortality outcomes after use of steroids in adult patients with septic shock The ADRENAL study found no difference in mortality among intubated adults with septic shock treated with a continuous infusion of hydrocortisone compared with those who did not received hydrocortisone.84 The APROCCHSS trial reported lower 90-day mortality in adults with septic shock who received hydrocortisone plus fludrocortisone compared with those who received placebo.85 Multiple pediatric observational cohort CHAPTER 84 Endocrine Emergencies 1007 studies have shown no benefit or possible harm with adjunctive corticosteroids used in pediatric septic shock.86–92 No large prospective pediatric randomized clinical trial has yet to examine this issue, although one is currently underway at the time of publication of this chapter Corticosteroid Side Effects Main side effects of corticosteroid administration include immunosuppression and subsequent increased risk for secondary infection,93 protein catabolism with resultant myopathy, hyperglycemia, and hypernatremia Corticosteroid therapy has been associated with increased risk for hospital-acquired infection among a general population of critically ill children94 and in children following surgery for congenital heart disease.95 In the latter investigation, children who received hydrocortisone were nearly 30 times more likely to develop a central catheter–associated infection as compared with children who did not receive hydrocortisone With increasing recognition of the key role of immunosuppression in the pathogenesis of sepsis, it is noteworthy that children with sepsis demonstrate widespread repression of gene programs associated with adaptive immunity and that this gene repression is further enhanced with concurrent corticosteroid administration.29 Even if administering only a single dose of a corticosteroid, it is important to recognize that such a dose alters the expression of about 25% of the human genome.96,97 Dissolution of lean body mass mediated by both endogenous and exogenous98 corticosteroids represents a key element of the stress response.99 Although this may be beneficial in the short term, prolonged corticosteroid-mediated muscle catabolism can be associated with ICU weakness (including the diaphragm) and hyperglycemia Muscle weakness has been associated with prolonged mechanical ventilation weaning.37,100–102 Hyperglycemia has been associated with a variety of adverse events in the PICU, as detailed later.38 Additional important clinical consequences of protein catabolism that may be exaggerated by exogenous corticosteroid administration include impaired wound healing, hypoalbuminemia, disordered coagulation, and impaired gut function with bacterial translocation.103 In the CORTICUS sepsis interventional trial,48 transient hypernatremia was also noted among patients receiving hydrocortisone Although gastrointestinal hemorrhage represented an important side effect in previous clinical trials examining the potential utility of high-dose methylprednisolone as adjunctive therapy in sepsis, this side effect has not been problematic in later investigations using low-dose hydrocortisone Among adult critically ill patients with acute lung injury, corticosteroid administration is associated with transition to delirium.104 However, among critically ill adults with mixed diagnoses in a separate large prospective study, systemic corticosteroid use was not associated with transition to delirium.105 Several important clinical differences in patient characteristics between the two studies may explain the opposing findings Further research is needed to elucidate the relationship between exogenous steroid administration and ICU delirium.106 Long-term exposure to corticosteroids results in characteristic cushingoid side effects (e.g., as manifested in children with bronchopulmonary dysplasia).107 In the absence of obvious exogenous steroid administration, Cushing disease is diagnosed as a high 24-hour urine-free cortisol concentration that is not suppressed by administration of dexamethasone.108 Clinical characteristics of Cushing syndrome include hypertension, hypokalemic alkalosis, proximal myopathy, hyperglycemia, osteoporosis, opportunistic infections, psychiatric problems, and central obesity with characteristic striae Alterations of Glucose Homeostasis Glucose Homeostasis in Health Under normal conditions, glucose concentration is tightly regulated by the neuroendocrine system Control of blood glucose is complex, involving interaction among the liver, pancreas, muscle, adipose tissue, pituitary, adrenals, and bone The brain and periphery conduct a constant biochemical conversation by which the periphery informs the brain about its metabolic needs and the brain addresses these needs through its control of somatomotor, autonomic, and neurohumoral pathways involved in energy intake, expenditure, and storage.109,110 Glucose is obtained from three sources: intestinal absorption of food, glycogenolysis, and gluconeogenesis Once transported into cells, glucose can be stored as glycogen or it can undergo glycolysis to pyruvate Pyruvate can be reduced to lactate, transaminated to form alanine, or converted to acetyl coenzyme A (CoA) Acetyl CoA can be oxidized in the mitochondrial tricarboxylic acid cycle to carbon dioxide and water, converted to fatty acids for storage as triglyceride, or serve as substrate for ketone body or cholesterol synthesis Although glycogenolysis can occur in most tissues in the body, only the liver and kidneys express the enzyme glucose-6-phosphatase, which is required for release of cellular glucose into the bloodstream The liver and kidneys also contain the enzymes required for gluconeogenesis Of the two organs, the liver is responsible for the bulk of glucose output; the kidney supplies only 10% to 20% of glucose production during fasting Glucose homeostasis is centered on glucose-induced secretion of insulin from pancreatic b cells and insulin effect on glucose metabolism in peripheral tissues The switch from glycogen synthesis during and immediately after meals to glycogen breakdown and gluconeogenesis is orchestrated by hormones, of which insulin is centrally important Plasma insulin concentrations peak after meals This surge in insulin activates glycogen synthesis, enhances peripheral glucose uptake, and inhibits glucose production In addition, lipogenesis is stimulated while lipolysis and ketogenesis are suppressed During fasting, the plasma insulin level falls to less than or equal to mU/mL Hormones—including glucagon, catecholamines, cortisol, and growth hormone (GH)—counteract the effects of insulin and promote glycogenolysis, gluconeogenesis, lipolysis, and ketogenesis Currently, obesity is an increasingly prevalent disease in the pediatric population Glucose metabolism in patients with obesity is altered in health with chronic inflammation and dysregulated immune pathways, leading to impaired glucose metabolism.111 This subset of patients may require special attention when dealing with stress hyperglycemia Hyperglycemia Hyperglycemia has been defined by the World Health Organization as blood glucose levels greater than 126 mg/dL when fasting There are no specific age-adjusted levels for infants and children No guidelines specifically define stress hyperglycemia, although a common definition describes it as transient hyperglycemia resolving 1008 S E C T I O N V I I I Pediatric Critical Care: Metabolic and Endocrine spontaneously after dissipation of acute severe illness Stress hyperglycemia (SHG) was first described by Thomas Willis in the seventeenth century Initially identified as an appropriate adaptive harmless or even beneficial short-term physiologic response to critical illness, it is now considered a risk factor, especially because advanced critical care has improved survival and extended ICU length of stay (LOS).112 Hyperglycemia is common in nondiabetic critically ill children and occurs in up to 86% of patients.113 Stress Hyperglycemia and Outcomes Studies in children have challenged the assertion that hyperglycemia is beneficial or inconsequential by observing that SHG is associated with worse clinical outcomes A retrospective study from a single PICU examined 1173 admissions Hyperglycemia was prevalent and associated with increased morbidity, as characterized by increased LOS and mortality.114 Association between hyperglycemia and worse outcome in children was also demonstrated in specific disease processes, such as traumatic brain injury,115 general trauma,116 severe burns,117 septic shock,118 meningococcal sepsis,119 and postoperative congenital heart disease.120,121 Hyperglycemia is common in infants with necrotizing enterocolitis admitted to the neonatal ICU (NICU) and is associated with increased late mortality and NICU LOS.122 SHG is also associated with specific complications, such as increased risk of venous thromboembolism in nondiabetic children,123 increased risk of mortality from central catheter–associated bloodstream infections,124 and more frequent nosocomial infections, including surgical site infection.125 While clearly prevalent in critically ill children, some studies were unable to show a clear association between hyperglycemia and worse outcomes One retrospective study found that hyperglycemia within 24 hours of PICU admission was associated with increased rate of mechanical ventilation, ICU LOS, and mortality, but when controlled for disease severity, it was not independently associated with increased morbidity or mortality.126 Another retrospective study evaluated the association between blood glucose level and duration of mechanical ventilation and ICU LOS in mechanically ventilated patients with bronchiolitis Hyperglycemia was a frequent event in this patient population, yet results failed to show an independent association with worse outcomes.127 Such studies support the notion that hyperglycemia may be a marker of severity of illness rather than a cause Preexisting nutritional status may also impact outcomes associated with hyperglycemia in the critically ill child A prospective study from Brazil reported that malnourished patients with hyperglycemia were at greater risk of mortality independent of severity of illness.128 Obesity is prevalent among critically ill pediatric patients, but the available literature on the relationship between obesity and clinical outcome is limited and conflicting.129 A systematic review of recent observational studies showed increased mortality in obese critically ill pediatric patients,130 while two separate retrospective single-center analyses revealed no difference in mortality by weight status.131,132 With current knowledge, it is clear that hyperglycemia is prevalent in critically ill children and is associated with worse outcome in some disease processes but not in others Many studies are not controlled for severity of illness, making it difficult to interpret results Different definitions for SHG used by different authors (range of 126–250 mg/dL in nine key pediatric studies of association of SHG and mortality)133 make it even harder to compare results and create thresholds for treatment Moreover, thus far, all studies have failed to establish cause-and-effect relationships, yet many suggest that aggressive maneuvers should be used to normalize plasma glucose levels Younger patients (,1 year) are at higher risk for spontaneous hypoglycemia and require special consideration when treating hyperglycemia with insulin.134 Pathophysiology of Stress Hyperglycemia During stress, the normal mechanisms that counteract hyperglycemia are overwhelmed, causing a persistent unchecked state of high glucose blood levels These changes help the body provide glucose to meet increased metabolic demands SHG results from increased levels of counterregulatory hormones (epinephrine and norepinephrine, glucagon, cortisol, and GH) and proinflammatory cytokines (TNF-a, IL-1, and IL-6) The overall effect is increased hepatic and renal glucose production Peripheral and hepatic insulin resistance is a well-recognized phenomenon in critically ill patients It is characterized by organ-specific alteration in glucose utilization/ production and impaired insulin-mediated uptake.112 Insulin concentrations may be elevated or decreased Use of carbohydratebased feeds, glucose-containing fluids, and drugs such as epinephrine and corticosteroids may exacerbate the situation High hepatic output of glucose, especially through gluconeogenesis, is the most important contributor to SHG Glycogen stores are limited and rapidly depleted during stress Lactate, pyruvate, and alanine are the main precursors used by the liver for gluconeogenesis Often overlooked, renal-derived gluconeogenesis is a significant contributor (up to 40%) of glucose production during stress, mostly in response to epinephrine.135 The principal precursors for renal gluconeogenesis are lactate and glycerol (Fig 84.4) Mechanisms underlying insulin resistance occur at several levels Insulin receptor levels are unchanged in most short-term animal models of sepsis However, reduction in insulin receptors is seen in longer-term models.136 One known mechanism for hepatic insulin resistance is associated with an increase in GH and reduction in insulin growth factor-1 (IGF-1) During critical illness, GH levels increase significantly, but there is a fall in hepatic GH receptors with disruption of downstream signaling IGF-1 levels drop in response to proinflammatory cytokines, especially TNF-a with decreased IGF-1 synthesis In addition, low IGF-1 may result from upregulation and increased affinity of its binding protein IGFBP-3, reducing the free active protein.137 Elevated insulin levels are common in critically ill adults The critically ill child may present with insulin deficiency due to b-cell dysfunction and impaired insulin production (direct effect of proinflammatory cytokines), which contributes to SHG.138,139 Insulin resistance ultimately promotes a catabolic state in which lipolysis is activated Lipotoxicity, glucotoxicity, and inflammation are key components of global SHG Hyperglycemia itself further exacerbates the inflammatory and oxidative stress response and proinflammatory cytokine storming, promoting a vicious cycle whereby SHG leads to further SHG During critical illness, specific interventions can mediate development of SHG Use of vasoactive-inotropic drugs—such as epinephrine, norepinephrine, and dopamine—is frequently associated with SHG Epinephrine stimulates b2-receptors, promoting glycogenolysis and gluconeogenesis, and increases insulin resistance by release of glucagon and cortisol It also reduces insulin secretion via stimulation of a2-receptors Effects of dopamine and norepinephrine are less prominent due to lesser activity at the b2receptors Several medications commonly used in the ICU setting may result in development of SHG (e.g., patients frequently ... prospective pediatric randomized clinical trial has yet to examine this issue, although one is currently underway at the time of publication of this chapter Corticosteroid Side Effects Main side effects... A seemingly inadequate adrenal response relative to the magnitude of stress characterizes CIRCI This situation is a dynamic, typically reversible state that is thought to be secondary to both... was designed on the basis of these findings.47 However, a confirmatory trial failed to replicate this finding and concluded that corticotropin stimulation testing provided no information regarding