Welcome to the Society of Critical Care Medicine Pediatric Multiprofessional Critical Care Review Course. My name is Jerry Zimmerman, and I practice pediatric critical care medicine at Seattle Children's Hospital and Harborview Medical Center within the University of Washington School of Medicine in Seattle, Washington. In this lecture, I will be discussing a variety of common endocrine issues encountered in the pediatric intensive care units. My potential conflicts of interest are summarized on this slide. None of them impact my comments on endocrine issues in the ICU. In this lecture, I will discuss six common endocrine issues encountered in the PICU, namely diabetic ketoacidosis, questions surrounding adrenal insufficiency, the renal angiotensin-aldosterone axis, three salt and water syndromes, pheochromocytoma, as well as hypo and hyperthyroidism. To begin the discussion of DKA, here is a review question for your consideration. An eight-year-old with new onset diabetes mellitus and DKA is admitted to the PICU with a Glasgow Coma Scale score of 13, a serum glucose of 470 milligrams per deciliter, beta-hydroxybutyrate eight millimole per liter, and a pH of 7.01. The child's bedside nurse reports new findings of anisocoria and decorticate posturing. So which of the following actions would you prioritize? A, increase the insulin infusion rate, B, undertake immediate CT imaging, C, initiate therapeutic hypothermia, or D, administer a bolus of 3% saline? The correct answer here is D, administer a bolus of 3% saline. This patient is exhibiting clinical evidence of increased intracranial pressure. Imaging can wait. Therapeutic hypothermia has no known benefit and there is no evidence that the patient needs a change in the rate of insulin infusion. Three elements define diabetic ketoacidosis. The first is hyperglycemia with a blood glucose level exceeding 200 milligrams per deciliter. The second is acidosis with a venous pH less than 7.3. And the third is ketosis, currently generally measured as a serum beta-hydroxybutyrate exceeding three millimolar. Diabetic ketoacidosis reflects a deficiency of insulin and there are consequences of insulin deficiency. The first is unrestrained gluconeogenesis. This is exhibited in muscle catabolism in this stress state resulting in mobilization of amino acids that then can undergo gluconeogenesis and contribute towards hyperglycemia. The second consequence of insulin deficiency is a switch to fatty acids as the primary energy substrate. This requires lipolysis in the adipose tissue. Free fatty acids undergo beta-oxidation generating a variety of keto acids, particularly beta-hydroxybutyrate which we monitor clinically during DKA resuscitation. And the third consequence of insulin deficiency is hyperglycemia and associated hyperosmolality which leads to glucosuria and excessive water and electrolyte losses because of osmotic diuresis. And accordingly, DKA patients typically present with an average dehydration of 7% of their body weight. Diabetic ketoacidosis pathogenesis is presented here in a schematic diagram beginning with the importance of insulin deficiency as well as an upregulation of the counterregulatory hormones namely glucagon, epinephrine, cortisol and growth hormone. It is of interest to think about what is happening in three particular tissues or organs, the muscle, the liver and the adipose tissue in relation to DKA pathogenesis. Within muscle, as previously noted, there is a catabolism of lean body muscle resulting in a release of free amino acids. There is a relative decrease in the expression of the GLUT4 receptor that decreases uptake of glucose at the level of the muscle. The liver utilizes free amino acids, particularly their transamination to glutamine and alanine as substrates for gluconeogenesis and in the liver, there is also a breakdown of glycogen, both resulting in increased serum glucose. At the level of the adipose tissue and insulin deficiency, there is increased lipolysis, release of fatty acids in the liver. These fatty acids undergo catabolism generating ketone bodies. So the primary outcomes of all of this are hyperglycemia, leading to the osmotic diuresis and dehydration and electrolyte losses, as well as ketosis, which is the underpinning of the metabolic acidosis in DKA. There are six primary interventions important in DKA treatment. The first is to provide fluid resuscitation and the goal here is to restore renal perfusion. These are not patients with septic shock and for a diagnosis of DKA in terms of initial volume of replacement, less is more. The second intervention, of course, in the setting of insulin deficiency is to administer insulin. As DKA epitomizes insulin deficiency, this is commonly provided as a continuous infusion of insulin. Practitioners should plan a rehydration, generally around 7% to correct over approximately 48 hours. There's no rush to fix the dehydration immediately. Close monitoring and management of electrolytes with appropriate replacement is the next important intervention. In terms of initial workup, investigation for potential precipitants for the episode of DKA should be pursued and corrected as identified. And then lastly, it is important to avoid complications that can occur during a treatment and probably the two most common are hypoglycemia during the transition from a continuous infusion of insulin to intermittent subcutaneous dosing as well as hypokalemia. For just a moment, let's consider in a little more detail this question of volume administration for children presenting with DKA. In here, there is a nice evidence recently generated in a multi-center randomized controlled trial within the PCARN Emergency Medicine Research Network. In this trial, investigators utilize the two by two factorial design, either not normal saline or half normal saline. As well as either a more rapid or a slower rate of fluid administration. The outcomes were centered around changes in neurologic status with a primary outcome as a proportion of patients with a decline in mental status that is a Glasgow Coma Score less than 14. Well, here is a summary of that important study. Investigators reported 1,389 episodes of DKA in 1,255 children. In this descriptive study, a decline in Glasgow Coma Score occurred in 48 DKA episodes or three and a half percent with a clinically apparent brain injury in 12 of these DKA episodes, just under 1%. When examining this outcome in relation to sodium content and rate of volume resuscitation, these investigators reported no significant differences in terms of the percent of episodes in which the Glasgow Coma Score declined to less than 14, the magnitude of declination of the Glasgow Coma Score, the duration of the Coma Score less than 14, subsequent test of short-term memory, clinical apparent brain injury during treatment for DKA, as well as memory and IQ scores. So the take home message here is that in this study at least, sodium concentration and rate of fluid administration did not significantly impact declination in Glasgow Coma Score as a surrogate for neurologic injury during DKA treatment. All of that being said, as a general rule of thumb, to ensure a slow fall in effective osmolasticity, the plasma sodium concentration will need to rise by approximately one millimolar for every two millimolar decreased in the plasma glucose concentration in order to maintain a relatively stable serum osmolality. Of course, the most dreaded complication for patients presenting with DKA is cerebral edema. This adverse event is primarily seen in children and usually occurs during the first day of therapy. Initially, it typically manifests as headache, deterioration of consciousness, and may proceed to papilledema, seizures, and even coma based on several imaging study. It is likely that there are many asymptomatic cases of cerebral edema during treatment of DKA. Based on a variety of descriptive studies examining risk factors for DKA cerebral edema, the following have really stood the test of time. These risk factors are a lower PCO2, likely reflecting the degree of metabolic acidosis and attempted respiratory compensation, a higher serum BUN, likely reflecting the degree of dehydration, treatment with bicarbonate, as well as bolus insulin dosing. The pathogenesis of DKA cerebral edema continues to be a topic of discussion as well as investigation. Currently, the leading theories surrounding pathogenesis of DKA cerebral edema include paradoxical central nervous system acidosis, hypercoagulation, osmotic disequilibrium, loss of cerebral autoregulation, alterations in the cerebral blood-brain barrier, as well as ischemia reperfusion injury. Changes in blood-brain barrier permeability during DKA treatment has been examined in a series of patients utilizing paired contrast-enhanced MRI perfusion scans. An example of a pair of scans is shown on this slide. With T0 representing the time of initiation of insulin. For most patients, there was an increase in permeability during treatment for diabetic ketoacidosis as shown here. Similarly, in a separate investigation, employing MRI imaging focused on fractional anisotropy, most patients with DKA increased fractional anisotropy during treatment for diabetic ketoacidosis. These changes are best explained by vasogenic edema that was initially present with a subsequent resolution during follow-up. In discussing diabetic ketoacidosis and its initial resuscitation, it is also important to comment on an alternative diagnosis for some patients, namely the hyperglycemia hyperosmolar syndrome. This disease most commonly occurs in patients with existing type two diabetes mellitus. It is characterized by higher intraportal insulin and a lower, less elevated concentration of the counter regulatory hormones. There is thought to be inhibition of lipolysis in adipose tissue because of the hyperosmolality. And particularly in terms of clinical presentation, these patients are often severely dehydrated with a concomitant higher risk for seizures, coma, and death. A comparison of the characteristics of patients presenting with DKA and hyperglycemia hyperosmolar syndrome are summarized in this table. In general, patients presenting with HHS have higher serum glucose concentrations and accordingly higher serum osmolality. Patients with HHS in general have less severe metabolic acidosis characterized by a higher serum bicarbonate and higher pH as compared to patients who present with DKA. Similarly, both serum and urine ketones are less pronounced among patients presenting with HHS. Moving on to the next subject of issues around adrenal sufficiency. Here is a relevant board review question. Which of the following would be augmented as opposed to inhibited in a child administered hydrocortisone in the setting of fluid and vasoactive inotropic refractory septic shock? Which would be augmented? A, acute phase protein synthesis, B, cyclooxygenase enzyme activity, C, endothelial adhesion molecule expression, or D, NADPH oxidoreductase superoxide anion production? Well, the answer is A, corticosteroids actually increase synthesis and release of acute phase proteins cyclooxygenase, endothelial adhesion molecule expression, and NADPH oxidoreductase are all inhibited with corticosteroids. This figure summarizes signaling mechanisms involved in cortisol synthesis and release. Following a variety of stresses, signals in the hypothalamus result in production and release of corticotropin releasing factor that makes its way down the pituitary stalk to the anterior pituitary gland and signals production and release of ACTH. This hormone in turn binds to the MC2R receptor within the zona fasciculata adrenal cells in the adrenal cortex, ultimately resulting in increased synthesis and a release of cortisol. The two primary anti-inflammatory mechanisms of action of corticosteroids are illustrated in this figure. Corticosteroids may bind to glucocorticoid receptors, translocate to the nucleus where the corticosteroid is, where this complex binds to DNA glucocorticoid responsive elements, having the general effect of reducing actions involved in a pro-inflammatory response. Glucocorticoids, corticosteroids may also inhibit the assembly of the nuclear transcription factor NF-kappa-B and its translocation into the nucleus and binding to DNA with the same anti-inflammatory effects. As shown in this figure, glucocorticoids, corticosteroids have a wide ranging anti-inflammatory effects which can involve chemokines, adhesion molecules, inducible nitric oxide synthase, NADPH oxygenase, as well as cyclooxygenase. It is important to note that all of these actions are inhibitory in nature, but it's also important to remember that glucocorticoids can also positively affect the production of a number of mediators, including lipocortin, which in turn inhibits the NADPH oxidase or cyclooxygenase. There's increased production via interleukin-6 of acute phase proteins, increased production of i-kappa-B, which would provide a counter feedback mechanism for inhibition of action of glucocorticoids. There's increased production of interleukin-10, an anti-inflammatory molecule, as well as increased production of macrophage inhibition factor, which would inhibit the anti-inflammatory mechanisms of glucocorticoids in terms of inhibition of pro-inflammatory mediators. So even in this single figure, you can see that there are intricate feedback mechanisms on many levels to finally tune corticosteroids production and effect. In discussing adrenal insufficiency, generally it can be seen as a primary entity in which there is impaired development or destruction of the adrenal glands. This can occur with hemorrhage or thrombosis or trauma, for example. Much more common is secondary adrenal insufficiency, which occurs as a result of loss of the integrity of the hypothalamic pituitary adrenal axis. This type of adrenal insufficiency is commonly encountered among critically ill patients. Particularly those with sepsis and those who have required a previous prescription of corticosteroids. Causes of primary adrenal insufficiency are summarized here. Congenital adrenal hyperplasia can result secondary to a variety of enzyme deficiencies along the cortisol anabolic pathway, but 25-hydroxylase deficiency is the most common and there is almost universal neonatal screening for this deficiency in resource-rich settings. Other causes of primary adrenal insufficiency include Addison's disease, Wollman's disease, adrenal leukodystrophy, familial glucocorticoid deficiency involves a mutation in the ACTH receptor in the adrenal gland, and then of course, Waterhouse-Frederickson syndrome, or adrenal apoplexy was more common in the past with a greater prevalence of meningococcal and haemophilus influenza septic shock, but still is a constant worry for most critical care providers. This syndrome is characterized by hemorrhage of the adrenal gland with loss of functional activity. Another board review question for your consideration, which of the following actions of angiotensin II would augment a pro-inflammatory state? A, ADH, ACTH, and norepinephrine release. B, aldosterone synthesis. C, NF kappa B activation, or D, renal vasoconstriction. The answer here is C, angiotensin II indeed activates the nuclear transcription factor NF kappa B, which in general has activity in terms of reducing multiple elements of pro-inflammation. Initiation of the renin-angiotensin-aldosterone axis begins in the kidney at the juxtaglomerular apparatus shown here. Cellular elements that are important include, first of all, modified distal tubular cells with chemoreceptors for sodium and chloride. These cells are called the macula densa. Adjacent are mesangial cells of the glomerulus with contractile properties that can alter blood flow of the afferent and efferent glomerular blood vessels. And then thirdly, modified fenestrated endothelial cells of the afferent arterioles that produce and release renin. It's also important to note that sympathetic adrenergic stimulation can activate a direct release of renin from the juxtaglomerular apparatus. Shown here is an overview of signaling and revolved in the renin-angiotensin-aldosterone axis. Begin by focusing on the juxtaglomerular apparatus in the kidney. As just discussed, the JGA can be activated by beta-1 adrenergic activities. There are nerve endings that terminate at the juxtaglomerular apparatus. In addition, the apparatus can be activated by increases in sodium chloride concentration in the collecting tubule, as well as by decreases in renal perfusion. The net effect is release of renin from the kidney arteriole. Renin metabolizes angiotensin to angiotensin-1 with its proteolytic activity. Subsequently, angiotensin-1 is converted to angiotensin-2 by another protease, angiotensin converting enzyme that is found in all endothelial cells, but particularly pulmonary endothelial cells. Angiotensin-2 releases aldosterone from the adrenal cortex, which in turn has an effect in terms of sodium reclamation at the kidney distal convoluted tubule. Angiotensin-2 is probably underappreciated in terms of its wide array of activities. Certainly most people are familiar with its actions on inducing an increase in systemic vascular resistance and blood pressure. This can actually be deleterious long-term. Obviously, it also ultimately stimulates the release of aldosterone. But angiotensin-2 has an interesting activity in terms of promoting a pro-inflammatory state including release of plasminogen activator inhibitor type-1, increasing the production of NF kappa B, which in turn stimulates release of multiple pro-inflammatory cytokines. Angiotensin-2 also increases release of antidiuretic hormone, ACTH, as well as norepinephrine. It enhances thirst and salt craving and long-term if continuously elevated can mediate cardiomyocyte hypertrophy and contribute to clinical hypertension. The actions of aldosterone like angiotensin-2 are also multiple. Of course, it has important activity in terms of facilitating sodium reabsorption and potassium excretion. But it also is important in terms of promoting insulin resistance as well as hypertension. Like angiotensin-2, it activates NF kappa B and promotes a pro-inflammatory state. It facilitates antidiuretic hormone or arginine vasopressin release. And also, similar to potassium, induces the secretion of hydrogen cation. Another board review course question for your consideration. A preschooler with a history of asthma remains in the PICU receiving mechanical ventilation for influenza-associated bronchiolitis and secondary MRSA pneumonia. She is receiving so-called maintenance fluids with normal saline. Her current serum sodium is 133. And overall, she has a positive fluid balance of approximately two liters, but in the setting of a declining urine output over the past day. Clinically, this child appears euvolemic. What is the most likely underlying cause of this clinical scenario? A, inadequate sodium intake. B, antibiotic-induced cerebral salt wasting. C, diabetes insipidus. Or D, elevated serum vasopressin. The answer to this question is choice D, elevated serum vasopressin. This child demonstrates the syndrome of seemingly inappropriate antidiuretic hormone. The other choices illustrate other saltwater syndromes that we will now consider. So here are the three common saltwater syndromes commonly encountered in the critical care setting. The first is cerebral salt wasting. The second, syndrome of inappropriate antidiuretic hormone excess, or SIADH. And third, diabetes insipidus. Cerebral salt wasting may occur after a variety of types of central nervous system insults. In general, it is characterized by a negative salt balance and associated negative fluid balance and hyponatremia. This actually can result in volume This actually can result in volume contraction to the point of hypotension. This syndrome is treated with volume and salt replacement. The pathogenesis remains somewhat unclear, but is thought to involve the action of natriuretic peptides and or olivine-like compounds or direct neural effects of the brain on the renal collecting system. Actions of vasopressin at the kidney are summarized in this figure. Vasopressin from the hypothalamus binds to V2 receptors in the kidney, resulting in signaling that ultimately enhances phosphorylation of aquaporin 2. This change in biochemistry enhances the translocation of aquaporin to the cell membrane of the collecting duct cell, which ultimately enhances the reabsorption of water. With the absence of vasopressin or altered abnormal binding of vasopressin, water is not reabsorbed and rather secreted, sometimes in large volume, clinically characterized as diabetes insipidus. Probably the most common saltwater syndrome encountered in the intensive care unit is SIADH. It is characterized by hyponatremia and a hyper-hypoosmolar serum. These patients are typically euvolemic and have absence of edema. But in this setting, demonstrate a seemingly inappropriately concentrated urine with urine sodium typically exceeding 20 milliequivalents per liter. These patients with corresponding hyponatremia do not have a deficiency of sodium, but rather an excess of water. This slide summarizes the various antecedents associated with SIADH. These include central nervous system disorders of many kinds, neoplasms that are notable for ectopic production of antidiuretic hormone, pulmonary disease, for example, pneumonia or asthma, endocrine disorders like hypothyroidism and adrenal insufficiency, positive pressure ventilation, and many, many drugs. For critically ill patients, any lung disease can be associated with SIADH. Here, the mechanism of action is thought to be increased intrathoracic pressure with a relative impairment of blood flow into the lungs and relative decreased delivery back to the left atrium. Stretched receptors in the left atrium, in this case, a smaller left atrium because of decreased left atrial return signal the hypothalamus to reduce release of antidiuretic hormone. So such patients and others with SIADH are not characterized by insufficient total body sodium, but rather by excess of total body water. Both cerebral salt wasting and SIADH may produce hyponatremia, but for very different reasons. As previously discussed, cerebral salt wasting induces negative salt balance, negative water balance, decreased plasma volume because of a high urine output with a characteristic high sodium concentration, sometimes exceeding 150 milliequivalents per liter of urine. On the other hand, SIADH, which can also produce hyponatremia, is associated with a low urine output and a positive or no change in overall water balance. These patients are definitely not edematous. The urine sodium is increased, but not nearly to the extent of that of cerebral salt wasting. Cerebral salt wasting requires replacement of water and sodium, but it's important to note that this syndrome typically lasts only hours or a few days. At some point, clinicians will need to bite the bullet and stop the replacement, or you will begin chasing your tail in terms of replacing normal urine output associated with a salt and water load. SIADH requires an intervention of decreasing overall water intake, not providing more sodium. When serum sodium falls to less than 125, expected clinical signs and symptoms include lethargy, fatigue, anorexia, nausea, and muscle cramps. With serum sodium less than 115, these patients can exhibit hypothermia, outright delirium and seizures, that may progress to coma, and even a chain stokes breathing pattern. For patients with hyponatremia, true hyponatremia in this sense, treatment involves infusion of 2% or 3% sodium chloride until the clinical sign resolves or serum sodium exceeds 135. Clinicians should be aware of conavaptin, which is a vasopressin 1A2 receptor antagonist. This drug has been approved by the FDA for treating uvolemic and hypervolemic and is a very effective antiviral. This drug has been approved by the FDA for treating uvolemic and hypervolemic hyponatremia. Small clinical case reports, clinical series have been described for children. However, the data and efficacy, as well as safety, have not been adequately studied in children. Many of the endocrine issues that we are discussing today involve communication between the hypothalamus and pituitary, nicely illustrated on the image on the left. As you know, the hypothalamus is a site of synthesis for the releasing hormones that subsequently are transported via veno-venous connections to the pituitary with then synthesis and release of hormones such as thyroid-releasing hormone, ACTH, and growth hormones. The hypothalamus is also the site of synthesis of antidiuretic hormone that is subsequently transferred via the pituitary as stock to the posterior pituitary, where it is released as needed. The point of these paired images is just to point out the vulnerability of this pituitary stock, particularly in the setting of closed head trauma. And the message here is that it is a good idea to assess for hormone production by both the hypothalamus and pituitary after a severe head trauma that could injure the pituitary stock and hence impair this communication between the hypothalamus and pituitary. Previously, we reviewed the actions of vasopressin at the kidney. When vasopressin is absent or unable to elicit binding at the kidney, diabetes insipidus occurs. It is characterized by a large volume, dilute urine, thirst, and a hyperosmotic serum. Unlike cerebral salt wasting, diabetes insipidus results in a high output of urine with low osmolality, essentially water, as compared to cerebral salt wasting, where the urine sodium concentration is very high. Central diabetes insipidus can occur because of a damaged hypothalamic posterior pituitary functionality that will ultimately result in insufficient or absent storage and release of antidiuretic hormone. So things typically related to critically ill patients include neurosurgical procedures, trauma, supercellular tumors, particularly craniopharyngioma and infiltrative disease. On the other hand, there may be adequate vasopressin antidiuretic hormone. But if there is a failure or inability of vasopressin to bind to V2 receptors in the kidney, the effect will be the same. But this is termed nephrogenic diabetes insipidus. This MRI image highlights a craniopharyngioma that postoperatively can be associated with cerebral salt wasting, SIADH, and diabetes insipidus, and may provide a particular challenge for critical care providers in terms of maintaining appropriate electrolyte and fluid balance. Pheochromocytoma is thought to develop because of extra adrenal neuroectodermal chromaffin tissue that is present in fetal and infant life and typically involutes. This tumor usually involves the adrenal medulla but actually can occur anywhere along the sympathetic chain. It is more common in males. And it is typically diagnosed between 9 and 12 years of age. And it is important to realize that pheochromocytoma may present as one aspect of multiple endocrine neoplasia. Children presenting with pheochromocytoma typically exhibit hypertension. But other signs include tachycardia, diaphoresis, headache, palpitations, flushing, emotional liability, and in older children, maybe a sense of impending doom from excess of catecholamine circulating. These patients may exhibit acrocyanosis, which is a result of chronic peripheral vasoconstriction. It's important to realize or think of neuroblastoma as an alternative diagnosis as the workup for both may involve serum and urine analysis of catecholamine metabolites. Ultimate genetic testing may identify a specific treatment mechanism as family genetic mutations are common for pheochromocytoma. Usual treatments for patients with pheochromocytoma may begin in an outpatient setting and continue preoperatively in the intensive care unit. This intervention typically starts with alpha-adrenergic blockade to address hypertension, often with fentolamine, followed by beta-adrenergic blockade with agents such as Esmolol. When both hypertension and tachycardia are under adequate control, the patient may be transitioned to combined alpha and beta blockade, utilizing an agent such as lobetalol. Inhibition of tyrosine hydroxylase, the initial step in catecholamine metabolism may be achieved with metyrosine, and ultimately these patients undergo surgical resection, typically with postoperative close monitoring in the intensive care unit, where hemodynamics may initially be unstable. One final board review question. A child with Down syndrome is being managed in the CICU following repair of an AV canal defect. Because of persistent hypotension, despite an epinephrine infusion of 0.15 micrograms per kilogram per minute, the child is initiated on stress dose hydrocortisone, but still continues with unstable hemodynamics. At this time, the serum sodium and glucose are 145 and 110, respectively. Increase in which of the following laboratory findings is most consistent with this clinical scenario? A, free thyroxine, B, triiodothyronine, C, reverse triiodothyronine, or D, thyroid stimulating hormone. The correct answer is D, thyroid stimulating hormone, this is a patient with Down syndrome at higher risk of hypothyroidism, and an increase in thyroid stimulating hormone would differentiate true hypothyroidism from CICU thyroid syndrome. An overview of thyroid metabolism is shown in this figure. Iodide is transported into the thyroid gland. Subsequently, thyroid peroxidase facilitates iodination of tyrosine residues within thyroglobulin, which ultimately undergoes proteolysis under the stimulation of thyroid stimulating hormone to generate and release thyroxine, or T4. Thyroxine is metabolized in peripheral tissues by an iodothyronine 5-deiodinase to yield T3, or triiodothyronine, period. This molecule binds to appropriate sense receptors and is transported to the nucleus at DNA binding sites where it exerts alterations and transcription affecting multiple aspects of metabolism. Thyroid hormone affects virtually every aspect of metabolism, period. Well-known are its effects on oxygen consumption as well as thermal regulation. Thyroid hormone affects all aspects of energy substrate metabolism as well as water and electrolyte transport. It is essential for normal growth and development. With cortisol and insulin, it is involved in the regulation of catabolism. In addition, it affects the activity of other hormones, particularly growth hormone, and is known to exert a effect on respiration in response to hypoxia and hypercarbia. And with its beta receptor affinity, can affect responsiveness to catecholamines and hence be a valuable addition to a vasoactive inotropic regimen. This figure summarizes normal and stress thyroid hormone metabolism with the thyroid product being byroxin or T4. Under normal circumstances, a peripheral tissue five prime deiodinase can clip off one iodide resulting in triiodothyronine or T3. An alternative enzyme five deiodinase is responsible for an alternative metabolic route involving removal of a different enzyme iodide molecule resulting in reverse T3. Multiple adult and pediatric studies substantiate the so-called sick U thyroid syndrome that is very prevalent in critically ill patients. This syndrome includes rapid decrease in T3 that is proportional to measures of illness severity and inversely related to the concentration of TNF alpha. It is also associated with a decrease in thyroid hormone binding proteins. There is suppression of the peripheral conversion of T4 to T3 and at the same time, a variable increase in the production of reverse T3. There is a decrease in thyroid releasing hormone gene expression in the hypothalamus and reduced thyroid stimulating hormone messenger RNA as well. Accordingly, the biochemical description of sick U thyroid syndrome is summarized here. Free T4 is typically normal. The conversion of T4 to T3 is decreased secondary to a decrease in the five deiodinase activity. So T3 is markedly decreased. The increase in reversed T3 is variable but thyroid stimulating hormone, the measure of true hypothyroidism remains normal. The clinical significance of sick U thyroid syndrome, I believe it is fair to say remains controversial. It may represent a pathologic response or a normal response to stress. For example, it potentially could represent an attempt at conservation of energy expenditure in a highly stressed patient. It may represent a mechanism for modulation of catabolism. And at this point in time, it remains unclear if in the setting of sick U thyroid syndrome that T3 or T4 should or should not be replaced. Acquired true hypothyroidism can be represented by many clinical conditions, but most commonly could include Hashimoto thyroiditis, post thyroid ablation, secondary to a radiation of the neck, perhaps in the setting of malignancy, effects of various medications. Hypothyroidism can occur in the setting of iodine deficiency formerly very common, but less so now. And there is also described late onset congenital hypothyroidism. The true marker of hypothyroidism as opposed to the sick U thyroid syndrome, the marker for hypothyroidism is elevation of thyroid stimulating hormone. However, this response can be blunted and could occur commonly in the intensive care unit in the setting of malnutrition, dopamine and corticosteroid administration. Common causes of hyperthyroidism are displayed here. Graves disease, toxic multinodular goiter, iodine overload, autoimmune thyroiditis presenting as hyperthyroidism, also eventually associated with hypothyroidism and quite common amiodarone associated hyperthyroidism. For a patient, particularly with hyperthyroidism, thyroid storm can evolve and be triggered by factors such as amiodarone, discontinuation of antithyroid drugs, concurrent infection, exogenous excess of thyroid hormone or with no triggering factors. Identifiable. Features of thyroid storm typically occur in patients with ongoing hypothyroidism such as Graves disease or Hashimoto's thyroiditis. Here, immunoglobulin with thyroid stimulating activity is typically present. And in a similar fashion, neonatal thyrotoxicosis can occur in infants where there is transplacental passage of thyroid stimulating activity from a mother, for example, with Graves disease. Thyroid storm is most common in patients with Down syndrome, diabetes mellitus and McKeown-Albright syndrome. The pathophysiology of thyroid storm involves dysfunction of thermoregulatory systems resulting in hyperthermia. Gastrointestinal and hepatic disorders are common. CNS impairment is also frequent and manifested by confusion that may evolve into overt delirium and coma. A condition termed cardiothyrosis involves atrial and ventricular arrhythmias, heart failure and even cardiac arrest. So thyroid storm can be deadly. In this regard, patients with hypothyroidism who evolve into thyroid storm can exhibit deterioration into a cardiogenic shock. And in this setting, these patients are at significant risk for mortality. Treatment of patients with thyroid storm involve interventions that are specific to the thyroid and its hormonal output as well as the immune system. The thyroid and its hormonal output as well as general supportive interventions. Inhibition of thyroid hormone secretion and synthesis typically are involved in all treatment regimens. Blockage of thyroid hormone in peripheral tissues is an adjunct intervention. Typically using propothiouracil beta blockers and corticosteroids. It is important to identify and treat the precipitating event and manage any systemic decompensation with the particular focus on potential evolution into cardiogenic shock. Provide appropriate supportive measures including veno-arterial extracorporeal life support in the setting of cardiogenic shock. Plasmapheresis may be helpful in removing immunoglobulin with thyroid stimulating activity. And ultimately these patients may require thyroid ablation with radioiodine or surgery. A multitude of drugs that are commonly utilized in the intensive care setting can affect thyroid hormone metabolism and critical care practitioners should be aware of these drug effects. For example, dopamine blunts, thyroid stimulating hormone response to thyroid releasing hormone. Glucocorticoids can suppress basal and TRH stimulated TSH release. Iodinated contrast agents can decrease hepatic conversion of T4 to T3. Amiodarone has a variety of effects but is known to decrease conversion also of T4 to T3 as well as binding of T3 to pituitary receptors. Phenytoin can enhance metabolism of T4 to T3 and result in a low free T4 and total T4. Thank you for your attention during this overview of common endocrine issues encountered in critically ill children. If you have any comments or questions regarding this presentation, please feel free to contact me at the email address below. Your constructive criticism, anything would be most welcome. Enjoy the rest of the review course.

endocrine issues

pediatric intensive care unit

diabetic ketoacidosis

adrenal insufficiency

salt and water syndromes

pheochromocytoma

hypo and hyperthyroidism

SIADH

pathophysiology

clinical features

treatment options