Chapter 44: Endocrine Dysfunction Leading to Critical Illness

The endocrine system of extracellular hormone signaling maintains homeostasis via regulation of metabolic pathways and cellular function in multicellular organisms, including humans. During critical illness (CI), the extreme systemic inflammatory response disrupts normal physiology and alters hormone signaling. The immune-neuroendocrine response of CI is marked by hypercatabolism and diminished hypothalamic-pituitary-end-organ function. In some cases, disorders of the endocrine system directly lead to CI. This chapter reviews the endocrine and metabolic physiology and sequelae of CI as well as specific conditions of the endocrine system that can lead to CI.

The pituitary gland, or hypophysis, is located within the sella turcica, inferior to the optic chiasm and is connected to the hypothalamus via the infundibulum. The pituitary is divided functionally and anatomically into anterior and posterior sections. Although much of its function is controlled by the hypothalamus, the pituitary is considered the “master gland” for its role in regulating many of the other endocrine glands.

The anterior pituitary secretes 6 major peptide hormones: growth hormone (GH), prolactin (PRL), thyroid stimulating hormone (TSH), adrenocorticotrophic hormone (ACTH), luteinizing hormone (LH), and follicle stimulating hormone (FSH). The secretion of each of these hormones is pulsatile and follows a circadian rhythm. PRL synthesis is primarily regulated by inhibitory dopaminergic neurons of the hypothalamus. The other peptide hormones of the pituitary are synthesized primarily in response to stimulatory hypothalamic hormones.

Hypothalamic and anterior pituitary function are greatly reduced in CI as a result of high levels of circulating inflammatory cytokines (Table 44–1).¹ In early CI, circulating GH, LH, and FSH levels diminish to negligible levels. TSH production initially rises sharply, but within 6 to 18 hours of CI, TSH secretion is also impaired as part of the nonthyroidal illness phenomenon. ACTH levels also initially increase as part of a generalized stress response of acute CI, but typically decline to below normal levels on day 3 of CI.² Cortisol levels generally remain elevated, even as ACTH levels decline after day 3, suggesting an independent mechanism governing the release of cortisol as patient progress into the prolonged phase of CI.^2,3,4

Despite low-circulating GH levels in CI, the administration of exogenous GH is detrimental. Several large randomized controlled trials have studied the use of GH as an attempt to treat hypercatabolism, that is, commonplace among critically ill patients. Results of these trials consistently show an increase in mortality in the group treated with GH, leading to recommendations against the use of GH in patients with CI.^5,6 In another randomized trial in CI, the administration of insulin-like growth factor-1, an important downstream mediator of GH signaling, also failed to show clinical benefit.⁷

The replacement of testosterone or estrogen, which results from low LH and FSH, and replacement of thyroxine, which results from low TSH, remain controversial.^8,9,10

The posterior pituitary releases 2 peptide hormones: antidiuretic hormone (ADH) and oxytocin. These hormones are synthesized in neuronal cell bodies located in the hypothalamus and transported within vesicles along the axons to the posterior pituitary for release into the bloodstream. Disorders of ADH secretion are discussed in the sections on diabetes insipidus (DI) and syndrome of inappropriate ADH secretion (SIADH).

Aside from the typical neuroendocrine stress response in CI, the loss of normal pituitary function due to direct insults of the hypothalamus or pituitary itself can lead to loss of end-organ gland dysfunction such as secondary hypothyroidism, adrenal insufficiency, or hypogonadism. Clinical scenarios that commonly interfere with normal pituitary function include head trauma, intracranial hemorrhage, and neurosurgery, especially following procedures that involve manipulation within the sella turcica such as resection of a pituitary adenoma, Rathke's cleft cyst, or craniopharyngioma.^11,12 Patients with any of these conditions may be suspected for pituitary insufficiency.

Pituitary function may be significantly compromised in postpartum women following large amounts of blood loss during delivery (Sheehan's syndrome).¹² Inflammatory conditions, such as lymphocytic hypophysitis, histiocytosis X, or neurosarcoidosis, may involve the pituitary gland and result in hormonal insufficiencies; these conditions are relatively rare but should be considered and then excluded in appropriate at-risk CI patients.¹³ Some malignancies (eg, lymphoma and hypernephroma) can metastasize to the pituitary gland and cause significant endocrinopathy; these conditions should also be included in the differential diagnosis when appropriate.

Pituitary apoplexy, which occurs after hemorrhage of an existing pituitary adenoma, is another possible cause for the sudden loss of pituitary function.¹² Patients typically have a sudden severe headache, nausea, near syncope, or changes in vision if there is any mass effect that compresses the optic chiasm.

Acute manifestations of pituitary insufficiency include hypotension secondary to adrenal insufficiency and either hyponatremia or hypernatremia from changes in ADH secretion. Patients with suspected pituitary insufficiency should be given stress dose corticosteroids and evaluated for the SIADH or DI that may develop acutely in pituitary insufficiency. In some patients, the administration of corticosteroids may unmask underlying DI by impairing the release of ADH by the posterior pituitary and by indirectly attenuating ADH function in the renal collecting ducts.¹⁴

Diagnosing endocrine deficiencies resulting from hypopituitarism includes measurement of the pituitary hormone(s) and end-organ hormone(s), for instance, TSH and thyroxine, or LH, FSH, and either testosterone in men or estradiol in women. In postmenopausal women, pituitary dysfunction may be queried by measuring LH and FSH, which are expected to be elevated 5 to 20 fold.¹⁵

If deficiencies exist, replacement of end-organ hormones, such as treatment with thyroxine, testosterone, or estrogen, can be considered. In general, these treatments should be withheld until the patient has been stabilized. In the case of hypothyroxinemia with suspected or known pituitary dysfunction, it is also critical to initiate stress dose corticosteroid treatment prior to L-thyroxine (T4) treatment. This strategy minimizes the risk of severe adrenal insufficiency because cortisol catabolism (and, therefore, requirement) is enhanced by augmenting thyroid hormone levels, metabolic rate, and energy expenditure.

Insufficient cortisol production by the adrenal cortex is the hallmark of adrenal insufficiency. Primary adrenal insufficiency results when there is adrenal pathology and secondary/tertiary (or “central”) adrenal insufficiency results when there is pituitary/hypothalamic pathology affecting ACTH secretion. Decreased aldosterone reserve, as part of primary adrenal insufficiency, may occur in CI in association with cortisol insufficiency, or more rarely, alone as selective aldosterone deficiency.¹⁶ Underproduction of the weak androgen dehydroepiandrosterone, produced mainly in the zona reticularis of the cortex, or underproduction of adrenal catecholamines, produced in the adrenal medulla generally do not contribute to the clinical scenario of adrenal insufficiency.

Cortisol, the main glucocorticoid hormone, exerts its numerous systemic functions by inducing tissue-specific gene expression. During times of physiologic stress, cortisol secretion increases. Patients with insufficient cortisol production may experience signs and symptoms as mild as headache, malaise, abdominal pain, nausea (generally without vomiting), myalgias, and/or lassitude with adrenal withdrawal (associated with steroid tapering and suppression of the hypothalamic-pituitary-adrenal [HPA] axis), to signs as severe as hypotension, incapacitating fatigue, severe hypoglycemia, hyponatremia (with hyperkalemia if primary adrenal insufficiency), and acidosis with adrenal insufficiency or crisis (associated with either primary or central adrenal insufficiency). Primary adrenal insufficiency can result from autoimmune, infectious, or hemorrhagic processes within the adrenal cortex, for example, Waterhouse–Friderichsen syndrome from meningococcal infection or adrenal vein thrombosis resulting from antiphospholipid antibody syndrome. Central adrenal insufficiency typically results from overly rapid tapering of corticosteroid dosing or increased stress in a patient who was recently tapered off of corticosteroids.

During CI, a form of central adrenal insufficiency (also termed “relative adrenal insufficiency” or “adrenal exhaustion” in the medical literature) may develop due to higher systemic cortisol requirements, effects of certain medications that inhibit cortisol synthesis, such as etomidate, and/or an impaired HPA axis during CI. The incidence of this form of central adrenal insufficiency has been reported between 10% and 30% of patients admitted with septic shock.¹⁷ Note that this entity, though real and relevant, is still the subject of great interest among intensivists and changes in definitions and management are likely to change in the near future.

Adrenal insufficiency should be suspected in patients with unexplained or persistent hypotension, hypoglycemia, hyponatremia, or hyperkalemia. An absence of hyperglycemia, that is, expected as a stress response to CI may also be an indication of adrenal insufficiency.³ The diagnosis is made by cosyntropin (250 mcg) stimulation testing that includes 2 criteria to confirm normal adrenal function: (1) plasma cortisol levels should reach 18 µg/dL/h after administering recombinant ACTH; (2) plasma cortisol levels should increase by at least 9 µg/dL from baseline. If both of these criteria are met, patients should be considered to have normal adrenal function. Patients with severe adrenal insufficiency fail to meet either of these criteria. If only 1 of the 2 criteria is met, adrenal insufficiency may still be suspected based on clinical impression.¹⁷ Unfortunately, there are several legitimate caveats to this approach that account for overdiagnosis and underdiagnosis: (1) measured total cortisol levels may be falsely low due to typically suppressed levels of cortisol-bind globulin (generally paralleling suppressing of albumin), (2) inadequate normative data for different CI patient subsets, and (3) the appearance of cortisol resistance. Consequently, a free cortisol level may be helpful, but this test usually requires several days to obtain a result, rendering the test moot for emergent decision making. Thus, a clinical diagnosis is still paramount to guide management.¹⁸

Treatment of adrenal insufficiency in CI includes stress-dose corticosteroids, usually hydrocortisone at doses of 50 to 100 mg every 6 to 8 hours. In patients with suspected adrenal insufficiency, corticosteroid treatment should be empirically initiated, and may be discontinued later in the subgroup of patients that do not meet criteria after the results of cosyntropin stimulation or free cortisol testing become available. In the cases of septic shock refractory to fluid resuscitation, and in patients with acute respiratory distress syndrome, several studies demonstrate improvement in clinical outcomes with glucocorticoid therapy regardless of cosyntropin stimulation testing.¹⁸ Treatment with stress dose glucocorticoid therapy is currently recommended in these groups of patients.¹⁸ Another approach that is more clinically oriented is to provide a lower dose of hydrocortisone (50 mg q 12) to patients suspected of relative adrenal insufficiency (pressor dependence without clear reason), while deferring specific adrenal biochemical testing and then taper empirically.¹⁸

Patients with adrenal insufficiency should continue to receive steroid treatment until hemodynamically stable. As the patient improves, the corticosteroid dose should be tapered over days to weeks based on clinical judgment, taking into account initial dosing level, dosing chronicity, and setting.

The administration of fludrocortisone, a pure mineralocorticoid, in conjunction with glucocorticoid therapy in patients with septic shock and adrenal insufficiency, was suggested by the results of 1 clinical trial.¹⁹ However, a subsequent study failed to show any benefit with the use of fludrocortisone in this population.²⁰

Several conditions that may mimic adrenal insufficiency should be considered if patients do not respond to corticosteroid therapy. Dysautonomia may occur in patients with chronic underlying neurologic disease, such as parkinsonism, which reduces sympathetic control of blood pressure and may lead to hypotension despite fluid resuscitation.²¹ Autonomic dysfunction may also be suspected and responsive to midodrine in patients on renal replacement therapy.²² Cortisol resistance, which may occur in preterminal patients or those with hepatic disease, may also lead to hypotension, but cortisol levels are often extremely high.²³

Insulin signaling modulates a number of metabolic and growth pathways on the cellular level. In addition to the well-known function of insulin to stimulate glucose uptake in endothelial, muscle, and adipose tissues, a low level of basal insulin regulates β-oxidation of fatty acids. In patients with negligible insulin secretion, uncontrolled fatty acid β-oxidation leads to the generation of acidic ketone bodies, including acetone, acetoacetate, and β-hydroxybutyrate. Overproduction and accumulation of ketone bodies, especially β-hydroxybutyrate and acetoacetate that release hydrogen ions in circulation, are the main causes of diabetic ketoacidosis (DKA).

DKA typically occurs in patients with type 1 diabetes that are newly diagnosed, acutely ill, or resulting from missed scheduled insulin doses.²⁴ Other patients at risk for DKA include those that have undergone surgical pancreatic resection, have pancreatic failure following episodes of pancreatitis, or patients with type 2 diabetes that have severely reduced pancreatic β-cell function during periods of extreme hyperglycemia (atypical or “Flatbush” diabetes).²⁵

Patients that develop DKA present with an anion gap acidosis, mental status changes, hyperglycemia, dehydration, and electrolyte abnormalities that commonly include hyponatremia, and initially, hyperkalemia. As DKA is treated with insulin, hypophosphatemia may develop, which can lead to muscle weakness and in extreme cases, respiratory failure. Without appropriate supportive treatments, severe neurologic deficits and death may occur in patients that develop DKA.²⁴

Treatment of DKA includes administration of insulin, intravenous fluids, and supportive measures. Additionally, an underlying cause for DKA should be investigated, which may include urinary tract infections or pneumonia, gastroenteritis, myocardial infarction, or simply nonadherence to insulin dosing.

Patients are stabilized with intravenous administration of regular insulin. A loading dose of 0.05 to 0.1 units/kg is recommended, followed by a continuous rate of 0.025 to 0.05 units/kg/h.²⁶ Normal saline is infused at the rate of 100 to 200 mL/h after a 1.5 to 2 L bolus. Electrolytes should be monitored at regular intervals, every 1 to 2 hours at first, then with declining frequency as the patient stabilizes. Potassium levels are typically elevated initially, but can decline to severely low serum levels as potassium shifts intracellularly with insulin and fluids treatment. Magnesium levels may also decline through a similar mechanism. As insulin drives cellular glucose uptake, glucose-6-phosphate is formed, consuming intracellular phosphate, and leading to passive inward diffusion of free phosphate and hypophosphatemia. Supplementation with potassium, phosphorus, and magnesium may need to be aggressive and should be administered to compensate for these changes.²⁶

Capillary blood glucose levels should also be monitored frequently, with adjustment of the insulin infusion as needed. If blood glucose levels normalize but the serum anion gap remains above 16 mEq/L, the insulin infusion should be continued, and a 5% to 10% dextrose infusion should be started. The overall strategy is to render patients as anabolic, thus the provision of dextrose in addition to insulin can help drive a positive nutritional balance in cellular metabolic pathways.

As the anion gap declines to levels consistently less than 16 mEq/L and arterial pH is greater than 7.30, patients should be considered for transition to subcutaneous insulin.²⁶ In many cases, the home insulin regimen can be restarted. For newly diagnosed type 1 diabetics, a good rule of thumb is to give 0.2 units/kg of long-acting insulin, such as glargine or detemir, and another 0.2 units/kg of rapid-acting insulin, divided into 3 premeal treatments daily. For patients with Flatbush diabetes, a combination of insulin and antihyperglycemic oral medication may be appropriate. Consultation with an endocrinologist can assist in determining the medication regimen for each individual patient.

In contrast to DKA, which primarily occurs in type 1 diabetes, hyperglycemic hyperosmolar state (HHS), previously known as nonketotic coma, is more commonly seen in patients with type 2 diabetes.²⁴ Patients with type 2 diabetes have both systemic insulin resistance and impaired β-cell function, which, if not adequately treated, may lead to severely elevated blood glucose levels. HHS usually occurs during a period in which medication adherence has lapsed and uncontrolled blood glucose levels that reach extreme heights, often greater than 600 mg/dL, persist. These concentrations overwhelm renal glucose resorption, leading to hyperglycosuria and an osmotic diuresis occurs. Patients present with severe dehydration, with hyponatremia, polyuria, blurred vision, and acute weight loss. There may be a minimal production of ketones owing to a shift to lipid consumption for energy utilization, but this is generally not sufficient to cause acidosis. If the dehydration and hyponatremia are severe enough, mental status changes may occur, necessitating admission to a closely monitored setting.

Treatment of HHS is generally supportive in nature. Intravenous fluids are given generously. Insulin should be administered, which may be given as an intravenous infusion or as subcutaneous basal/bolus injections. In patients admitted to the intensive care unit with mental status changes, an intravenous infusion of regular insulin is preferred.

As blood glucose normalizes and patients are able to take meals regularly, the insulin regimen should be converted to a combination of long-acting insulin with rapid acting bolus insulin administered with each meal. As a rule of thumb, 80% of the previous 24 hours intravenous insulin given can be used as a total daily subcutaneous insulin dose. This may be divided in half, and given as basal insulin; the remaining half can be divided into thirds and given as premeal rapid-acting insulin. This basal-bolus insulin administration strategy mimics normal pancreatic function and should be considered for optimal glycemic control in patients tolerating an oral diet, or for those on bolused tube feeding.²⁷ For patients on continuous enteral feeding, long-acting insulin, given 1 to 3 times per day is more suitable to match the infusion and absorption rate of dietary carbohydrates.

In addition, a multidisciplinary approach to the continued care of the patient may involve consultation with nutrition and diabetes educators and close follow up with the patient's diabetes specialist after hospital discharge.

The vast majority of thyroid hormone produced by the thyroid gland is released into circulation as T4 and is converted to triiodothyronine (T3) or reverse T3 (rT3) by deiodinase enzymes in the liver and other target tissues. T3, the active form of thyroid hormone, functions as a general regulatory signal of metabolism, whereas rT3 is generally inactive metabolite of T4. Nearly all cells and tissues contain thyroid hormone receptors that modulate gene expression and cellular metabolic function in response to T3.

The controlled release of thyroid hormone occurs in several steps, which includes the secretion of TSH by the anterior pituitary and the secretion of thyrotropin releasing hormone from the hypothalamus. Thyroid hormone activity is further modulated through control of the deiodination process during the systemic conversion of T4 to either T3 or rT3.

In addition to the metabolic state of the individual, certain medications may influence the regulation of thyroid hormone function. Lithium affects T4 synthesis and release, and deiodination.²⁸ Corticosteroids and β-adrenergic antagonists alter deiodination.²⁹ Amiodarone has several effects on thyroid function and is reviewed as follows.

Both the hypothalamus activity and pituitary gland function are affected in CI. Patients commonly demonstrate a typical pattern of thyroid function blood tests that are associated with severity of CI rather than alteration in thyroid function. This phenomenon is known as nonthyroidal illness, or previously the “sick-euthyroid” syndrome.¹⁰ In this condition, TSH levels often decrease. T4 levels may remain normal, but are usually decreased. T3 levels decrease as conversion of T4 to rT3 increases. As a patient recovers, the TSH levels begin to rise and can become elevated above the normal range, as high as 15 to 20 mIU/L (milli-international units per liter). Consequently, thyroid function tests can be difficult to interpret in the setting of acute illness or hospitalization. Treatment of nonthyroidal illness with thyroid hormone replacement remains controversial and has not been shown to affect overall outcome.^30,31

In conditions that lead to excessive thyroid hormone production, hyperthyroidism or thyrotoxicosis develops. Patients may experience excessive warmth, diaphoresis, tachycardia, hyperreflexia, weight loss, hair loss, fine tremor and loose bowel movements. TSH levels are low, with normal to elevated free T4 and T3 levels.

In severe cases, thyrotoxic crisis may be classified under the Burch–Wartofsky scoring system (Table 44–2) as “Thyroid Storm.”³² In addition to the classic symptoms of hyperthyroidism, patients may exhibit altered mental status, psychosis, fevers, nausea, vomiting, high-output heart failure, and unstable blood pressure. This may be precipitated by a large physiologic stressor, such as a myocardial infarction, surgery or other CI in a patient with long-standing, inadequately treated thyrotoxicosis.

Patients with severe thyrotoxicosis should be kept in a closely monitored setting and treated with stress-dose corticosteroids, β-adrenergic receptor blocking agents, and propylthiouracil (PTU) or methimazole, which prevent thyroidal synthesis and release of thyroid hormone. In this setting, PTU is given as a loading dose of 500 to 1000 mg orally or via nasogastric tube, followed by 200 to 250 mg every 4 hours. As an alternative to PTU, methimazole is given as 60 to 80 mg daily.^33,34

The use of other agents such as lithium to prevent thyroid hormone release or cholestyramine to sequester T4 and T3 from portal circulation may be considered. Lithium may be given at doses of 300 mg every 6 hours.³³ Large amounts of potassium iodine may also be administered orally as 3 to 5 drops every 6 hours, which temporarily down regulates thyroid hormone synthesis and release, known as the Wolff–Chaikoff phenomenon.³³ In the case of a patient with a nodular goiter, the administration of iodine should be omitted. This may lead to the undesired Jod–Basedow phenomenon, a condition in which exogenous iodine induces a surge in thyroxine production by an enlarged, nodular thyroid, that is, typically iodine avid.

Surgical resection of the thyroid gland may also be considered in several conditions such as if the patient remains hemodynamically unstable despite medical treatment, if any of the mentioned medical therapies are contraindicated, during pregnancy or other medical conditions that warrant rapid reversal of thyrotoxicosis. In such patients, plasmapheresis has also been suggested as a means of rapidly lowering circulating T4 and T3.³³ In severely thyrotoxic patients, medication half-lives can be affected; higher doses of medications, such as corticosteroids, antihypertensives, or antiseizure medications, may be required.

With supportive care, mortality rates between 10% and 75% have been reported after thyrotoxic crisis. Patients that survive often show marked improvement within 24 hours of hospitalization.³³ After stabilization, treatment of the underlying cause of thyrotoxicosis should be initiated. The most common cause is Graves' disease, in which autoantibodies activate the TSH receptor on thyrocytes.

Amiodarone toxicity may also induce thyrotoxic crisis though 1 of 2 mechanisms. In type 1 amiodarone-induced thyrotoxicosis, the high iodine content of the amiodarone preparation causes a Jod–Basedow phenomenon in patients with a nodular goiter. In type 2 amiodarone-induced thyrotoxicosis, the direct toxicity of amiodarone to thyrocytes induces subacute thyroiditis. Differentiating these 2 responses in the setting of severe thyrotoxicosis can be difficult because diagnostic testing with radioiodine thyroid uptake and scan can take several days to complete and the initiation of treatment may be more urgent. Often both types of amiodarone-induced thyrotoxicosis are addressed with an empiric medical-treatment strategy that includes either methimazole or PTU, and a 2 to 3 months course of corticosteroids.

Other causes of thyrotoxicosis, which include subacute thyroiditis, a hot thyroid nodule, toxic multinodular goiter, and surreptitious use of T4 are less likely to induce thyrotoxic crisis. A thyroid uptake and scan can help to differentiate these conditions if the diagnosis is not clear.

In patients with less than the required thyroxine production, hypothyroidism ensues. Rarely, if left untreated for a prolonged timeframe, severe hypothyroidism may develop, leading to myxedema coma. These patients generally are unresponsive or have severely altered mental status, with cool, clammy skin, decreased body temperature, nonpitting edema, depressed respiratory drive and hypercapnia, bradycardia, and hypotension. A prolonged Q-T interval may increase risk of Torsades de pointes ventricular tachycardia.

The TSH is elevated, with low T3 and T4 levels. Supportive treatment should include the administration of intravenous fluids. Stress dose corticosteroids should also be given to anticipate a temporary adrenal insufficiency that develops as normal thyroid function is restored. After corticosteroids have been started, T4 may be administered. Initial doses should be given intravenously. Some authors favor giving a loading dose of 300 to 600 mcg T4, followed by a maintenance dose of 100 mcg daily.³⁵ Comparison studies show no difference in outcome, if lower doses are initiated.³⁶ The administration of T3 has also been suggested on the theoretical basis that conversion of T4 to T3 is impaired in severe illness. T3 may be given at a dose of 10 mcg every 8 to 12 hours, until consciousness is restored.³³ Once able to take medications orally, T4 may be given as an oral preparation during periods of fasting, separated by other medications that may impair absorption by at least 3 to 4 hours. Oral iron supplements, calcium supplements, and soy products can severely impair the absorption of T4.

Despite intensive supportive measures, mortality for myxedema coma remains at 20% to 25%.³³

The loss of ADH function either through impaired central production or by a lack of renal response to ADH signaling results in DI. Without ADH function, the distal collection tubules of the nephron are unable to adequately concentrate the urine that is produced. The dilute urine output often exceeds 300 mL/h and has an osmolality below 200 mOsm (Table 44–3). Consequently, patients lose a substantial amount of free water and experience an increased thirst sensation. Many patients with DI are able to compensate for renal losses by consuming adequate fluids, leading to the classic symptoms of polydipsia and polyuria. However, if a patient either does not have access to water or if their thirst mechanism is impaired, such as during CI, hypernatremia and dehydration may develop.

Common causes of DI include pituitary or other brain surgery, brain tumors, Sheehan's syndrome, neurosarcoid, histiocytosis X, and head trauma. DI can also result if the cells of the renal collecting ducts do not respond to circulating ADH, a condition known as nephrogenic DI.

DI is treated with desmopressin (DDAVP), a synthetic analogue of ADH which preferentially targets the renal vasopressin receptors. DDAVP may be given as oral, inhaled, and intravenous forms. During administration, plasma sodium levels and urine output should be closely monitored. The dose of DDAVP should be slowly titrated to avoid hyponatremia and to maintain a normal urine output.

A disproportionate release of ADH by the posterior pituitary can lead to SIADH, causing an inappropriate retention of free water and hyponatremia as the most common presenting finding. Patients with SIADH also exhibit highly concentrated urine and mildly elevated urine sodium levels ranging from 40 to 70 mmol/L (see Table 44–3). Common etiologies of SIADH include: pain, nausea, head trauma, meningitis, encephalitis, brain tumors, intracranial hemorrhage, pituitary, or other brain surgery as well as certain medications (selective serotonin uptake inhibitors, carbamazepine among others). ADH may also be synthesized ectopically in lung tumors, lymphomas, gastrointestinal tumors, and in association with pulmonary infections.

The mainstay of treatment for SIADH includes restriction of free water intake by the patient while the underlying cause is addressed. Daily weights and total volume taken in and put out should be recorded. ADH receptor blockers such as tolvaptan can also be given when fluid restriction fails to raise the plasma sodium adequately. The use of demeclocycline has fallen out of favor with the availability of ADH receptor blockers. In severe cases and in closely monitored settings, hypertonic saline can be administered.

In some patients at risk for SIADH with conditions affecting the central nervous system, cerebral salt wasting may develop. In this condition, high amounts of brain natriuretic peptide and possibly other factors are released from the CNS lead to excessive renal sodium losses and hyponatremia. Cerebral salt wasting may rarely be seen following head trauma, meningitis, encephalitis, and intracranial hemorrhage.³⁷ To differentiate from SIADH, urine sodium levels are inappropriately elevated. Treatment is with replacement of salt given either orally as sodium chloride tablets or intravenously as hypertonic saline.

In addition to the immune-neuroendocrine response, which is generally observed in all forms of CI, the specific disorders of pituitary insufficiency, adrenal insufficiency, DKA, HHS, thyrotoxic crisis, myxedema coma, DI, and syndrome of inappropriate ADH response represent severe conditions of the endocrine system that can lead to CI. Patients with any of these conditions must be monitored closely, treated appropriately, with continued adjustment to the treatment regimen. Understanding the pathophysiology of each of these disorders allows for the anticipation of treatment strategies and improved and patient outcomes.