Medical School · Year 3 · Emergency Medicine · includes a quiz and discussion video

Seminar 11: Endocrine and Metabolic Emergencies

Emergency Medicine Clerkship

Learning Objectives

By the end of this seminar, students will be able to:

1. Diagnose diabetic ketoacidosis using established biochemical criteria and implement a systematic management protocol addressing fluid resuscitation, insulin therapy, and potassium replacement
2. Differentiate hyperosmolar hyperglycemic state from diabetic ketoacidosis based on glucose levels, osmolality, pH, and ketone production, and prioritize fluid therapy in management
3. Recognize the clinical manifestations of hypoglycemia across severity levels, administer appropriate glucose replacement, and identify patients requiring hospital admission
4. Identify the clinical presentation and laboratory findings of adrenal crisis and initiate empiric treatment with hydrocortisone and aggressive fluid resuscitation
5. Diagnose thyroid storm and myxedema coma as life-threatening thyroid emergencies and apply the correct sequencing of pharmacologic interventions
6. Evaluate and manage severe electrolyte derangements including hyperkalemia, hyponatremia, and hypercalcemia with attention to cardiac monitoring and safe correction rates

Seminar Outline

Section 1: Diabetic Ketoacidosis

Diabetic ketoacidosis is a life-threatening metabolic emergency that results from absolute or relative insulin deficiency, leading to unregulated lipolysis, ketogenesis, and metabolic acidosis. The diagnosis requires the simultaneous presence of five biochemical criteria: serum glucose greater than 250 mg/dL, arterial pH less than 7.3, serum bicarbonate less than 18 mEq/L, an elevated anion gap greater than 12, and the presence of serum or urine ketones. While diabetic ketoacidosis is classically associated with type 1 diabetes mellitus, it can occur in type 2 diabetes under conditions of severe physiologic stress, and the increasingly recognized entity of euglycemic diabetic ketoacidosis, associated with SGLT2 inhibitor use, may present with glucose levels below 250 mg/dL, making a high index of suspicion essential.

The identification and treatment of the precipitating factor is as important as the metabolic correction itself. Infection is the most common precipitant, with urinary tract infections and pneumonia being the leading infectious triggers. Insulin omission, whether from non-compliance, insulin pump failure, or financial barriers to medication access, is the second most common cause. New-onset type 1 diabetes presenting with diabetic ketoacidosis as the initial manifestation accounts for a significant portion of cases, particularly in pediatric and young adult populations. Physiologic stress from myocardial infarction, cerebrovascular accident, or trauma can precipitate diabetic ketoacidosis through counterregulatory hormone release. The mnemonic of the "5 I's" provides a useful framework: Infection, Infarction, Intoxication, Iatrogenic causes (including steroids and SGLT2 inhibitors), and Insufficient insulin.

The management protocol for diabetic ketoacidosis follows a systematic, simultaneous approach to fluid resuscitation, insulin administration, and electrolyte correction. Fluid resuscitation begins with normal saline at a rate of 1 to 1.5 liters per hour for the first 1 to 2 hours to restore intravascular volume and improve renal perfusion, followed by a reduced rate of 250 to 500 milliliters per hour. Insulin therapy consists of a 0.1 units per kilogram intravenous bolus followed by a continuous infusion at 0.1 units per kilogram per hour. Potassium management is critical and follows a decision tree based on the serum potassium level: if potassium is below 3.3 mEq/L, insulin must be held and potassium replaced aggressively before initiating insulin; if potassium is between 3.3 and 5.2 mEq/L, potassium is added to each liter of intravenous fluids. Dextrose (D5) is added to the intravenous fluids when the serum glucose decreases to 200 to 250 mg/dL to prevent hypoglycemia while allowing continued insulin infusion to clear ketoacidosis. Sodium bicarbonate administration is reserved for severe acidosis with pH below 6.9.

Monitoring during diabetic ketoacidosis treatment requires frequent reassessment to ensure metabolic improvement and to detect complications. Serum glucose should be checked hourly to guide insulin infusion rate adjustments and to determine when dextrose should be added to intravenous fluids. A basic metabolic panel is repeated every 2 to 4 hours to track electrolyte changes, particularly potassium, which shifts dramatically as acidosis corrects. The anion gap is followed serially as the primary marker of ketoacidosis resolution, with a target of less than 12, and treatment endpoints include an anion gap less than 12, pH greater than 7.3, and serum bicarbonate greater than 18 mEq/L. Transition from intravenous insulin to subcutaneous insulin should occur when the patient is eating, the anion gap has closed, and at least 2 hours of subcutaneous insulin overlap with the intravenous infusion is provided to prevent recurrence of ketosis.

<image>Panel A: Diagnostic criteria diagram for diabetic ketoacidosis showing the five required biochemical parameters (glucose greater than 250, pH less than 7.3, bicarbonate less than 18, anion gap greater than 12, positive ketones) with severity stratification. Panel B: Flowchart of the "5 I's" precipitating factors (Infection, Infarction, Intoxication, Iatrogenic, Insufficient insulin) with the most common triggers highlighted. Panel C: Step-by-step DKA management protocol showing simultaneous fluid resuscitation, insulin infusion, and potassium replacement pathways based on serum potassium levels. Panel D: Monitoring timeline showing hourly glucose checks, 2-4 hour basic metabolic panels, serial anion gap tracking, and transition criteria from intravenous to subcutaneous insulin.</image>

Section 2: Hyperosmolar Hyperglycemic State

Hyperosmolar hyperglycemic state is a severe metabolic derangement characterized by extreme hyperglycemia, hyperosmolality, and dehydration, occurring predominantly in elderly patients with type 2 diabetes mellitus. The diagnostic criteria distinguish it from diabetic ketoacidosis: serum glucose exceeds 600 mg/dL (and frequently exceeds 1,000 mg/dL), serum osmolality surpasses 320 mOsm/kg, and arterial pH remains above 7.3 with only minimal ketone production. The absence of significant ketoacidosis occurs because residual insulin production in type 2 diabetes is sufficient to suppress lipolysis and ketogenesis but insufficient to prevent hyperglycemia. Mental status changes are more prominent in hyperosmolar hyperglycemic state than in diabetic ketoacidosis, correlating with the degree of hyperosmolality, and may range from confusion to coma.

The fluid deficit in hyperosmolar hyperglycemic state is profound, typically ranging from 8 to 10 liters, as the osmotic diuresis from sustained extreme hyperglycemia produces massive free water and electrolyte losses over days to weeks. Initial fluid resuscitation begins with isotonic normal saline at a rate of 1 to 1.5 liters per hour for the first 1 to 2 hours to restore intravascular volume and improve end-organ perfusion. The corrected sodium should be calculated by adding 1.6 mEq/L for each 100 mg/dL of glucose above 100 mg/dL. Once the corrected sodium is normal or elevated, the intravenous fluid should be switched to half-normal saline (0.45 percent sodium chloride) to provide free water replacement. The overall goal is gradual replacement of the fluid deficit over 24 to 48 hours to avoid the complications of overly rapid correction.

Insulin management in hyperosmolar hyperglycemic state differs from that in diabetic ketoacidosis in both priority and dosing. Fluid resuscitation takes precedence over insulin administration because aggressive insulin therapy before adequate volume repletion can cause precipitous drops in serum glucose and osmolality, triggering hemodynamic collapse and cerebral edema. When insulin is initiated, it is typically given at a lower rate of 0.05 to 0.1 units per kilogram per hour. The target rate of glucose decline is 50 to 70 mg/dL per hour; more rapid correction increases the risk of cerebral edema, particularly in elderly patients. Dextrose is added to intravenous fluids when the serum glucose decreases to approximately 300 mg/dL, higher than the threshold in diabetic ketoacidosis because the primary goal is gradual osmolality correction rather than clearance of ketoacidosis.

The complications of hyperosmolar hyperglycemic state are serious and contribute to a mortality rate that exceeds that of diabetic ketoacidosis, ranging from 5 to 20 percent. Cerebral edema, though rare in adults, can occur with overly aggressive fluid administration or too-rapid correction of osmolality and carries a high mortality rate. The hyperviscosity of blood resulting from severe dehydration and hyperosmolality creates a markedly prothrombotic state, placing patients at high risk for deep vein thrombosis, pulmonary embolism, and arterial thrombosis; prophylactic anticoagulation should be considered. Rhabdomyolysis may develop from hyperosmolality-induced muscle injury and contributes to acute kidney injury. The overall higher mortality compared to diabetic ketoacidosis reflects the advanced age and multiple comorbidities of the typical patient population as well as the severity of the metabolic derangement.

<image>Panel A: Side-by-side comparison of diabetic ketoacidosis and hyperosmolar hyperglycemic state showing differences in glucose levels, pH, osmolality, ketone production, typical patient population, and mental status changes. Panel B: Fluid resuscitation algorithm showing initial normal saline bolus, corrected sodium calculation formula, decision point for switching to half-normal saline, and 24-48 hour deficit replacement timeline. Panel C: Insulin dosing comparison between DKA and HHS showing the lower insulin rates in HHS, glucose decline target of 50-70 mg/dL per hour, and the higher dextrose addition threshold of 300 mg/dL. Panel D: Complications diagram showing cerebral edema from rapid correction, venous and arterial thrombosis from hyperviscosity, rhabdomyolysis, and the overall higher mortality rate of HHS compared to DKA.</image>

Section 3: Hypoglycemia

Hypoglycemia is the most common endocrine emergency encountered in the emergency department and is defined biochemically by a serum glucose level below 70 mg/dL. The clinical manifestations follow a predictable pattern based on the degree of hypoglycemia. At glucose levels below 70 mg/dL, adrenergic symptoms predominate, including tremor, diaphoresis, palpitations, anxiety, and hunger, as the sympathetic nervous system activates counterregulatory mechanisms. When glucose falls below 54 mg/dL, neuroglycopenic symptoms emerge because the brain is unable to meet its metabolic demands, manifesting as confusion, weakness, visual disturbances, bizarre behavior, and difficulty concentrating. Severe hypoglycemia may produce seizures and coma. Hypoglycemia unawareness, a phenomenon in which patients lose the ability to perceive adrenergic warning symptoms due to autonomic failure from recurrent hypoglycemic episodes, is particularly dangerous because neuroglycopenic symptoms may be the first clinical manifestation.

The causes of hypoglycemia span a broad differential diagnosis. In diabetic patients, the most common causes are exogenous insulin administration and sulfonylurea medications, which stimulate endogenous insulin secretion independent of glucose levels. In non-diabetic patients, insulinoma (a pancreatic beta-cell tumor) and adrenal insufficiency should be considered. Medications beyond diabetes drugs can contribute to hypoglycemia, including quinine and beta-blockers, the latter of which may mask the adrenergic symptoms of hypoglycemia and delay recognition. Alcohol consumption inhibits hepatic gluconeogenesis and is a particularly common cause of hypoglycemia in the emergency department. Critical illness, including sepsis and hepatic failure, impairs glucose homeostasis through multiple mechanisms. Factitious hypoglycemia from surreptitious exogenous insulin administration is identified by the pattern of elevated insulin levels with low C-peptide levels, since exogenous insulin suppresses endogenous production.

Treatment of hypoglycemia is straightforward but must be matched to the patient's clinical status and ability to take oral intake. Alert patients who can safely swallow should receive oral glucose, typically 15 to 20 grams of fast-acting carbohydrate such as glucose tablets or juice. Patients who are unable to swallow or who are obtunded should receive glucagon at a dose of 1 milligram intramuscularly or subcutaneously, which stimulates hepatic glycogenolysis and typically raises glucose within 10 to 15 minutes. When intravenous access is available, dextrose is the preferred treatment, with D50W (50 percent dextrose in water) given as 25 to 50 milliliters, providing 12.5 to 25 grams of glucose; D10W is increasingly preferred as it allows for more controlled dosing and reduces the risk of phlebitis and tissue necrosis from extravasation. Sulfonylurea-induced hypoglycemia presents a unique challenge because these medications have prolonged durations of action, and dextrose boluses may paradoxically stimulate additional insulin release; octreotide, a somatostatin analog at a dose of 50 to 100 micrograms subcutaneously, inhibits insulin secretion and is a valuable adjunct. Glucose should be rechecked at 15-minute intervals and treatment repeated until the glucose normalizes.

Disposition decisions in hypoglycemia depend critically on the underlying cause and risk of recurrence. Patients with hypoglycemia from short-acting insulin whose glucose has normalized and who are eating and asymptomatic may be safely discharged with appropriate follow-up and education. Patients with sulfonylurea-induced hypoglycemia must be admitted to the hospital for observation, typically for at least 24 hours, because the prolonged duration of action of these medications creates a high risk for recurrent hypoglycemia requiring ongoing dextrose infusion and monitoring. Patients with hypoglycemia of unknown cause should be admitted for a comprehensive workup including insulin levels, C-peptide, proinsulin, and cortisol levels to identify the underlying etiology. Patients with recurrent hypoglycemic episodes require investigation into potential causes including changes in medication, dietary habits, renal function, and the possibility of an insulin-secreting tumor.

<image>Panel A: Glucose threshold diagram showing the progressive symptoms of hypoglycemia from adrenergic symptoms below 70 mg/dL through neuroglycopenic symptoms below 54 mg/dL to seizures and coma in severe hypoglycemia. Panel B: Differential diagnosis flowchart for hypoglycemia separating diabetic causes (insulin, sulfonylureas) from non-diabetic causes (insulinoma, adrenal insufficiency, alcohol, critical illness) with laboratory distinguishing features. Panel C: Treatment algorithm showing oral glucose for alert patients, glucagon for those without IV access, D50W or D10W for IV access, and the special role of octreotide in sulfonylurea-induced hypoglycemia. Panel D: Disposition decision tree based on cause of hypoglycemia showing discharge criteria for short-acting insulin, mandatory admission for sulfonylureas, and workup pathway for unknown causes.</image>

Section 4: Adrenal Crisis

Adrenal crisis is an acute, life-threatening manifestation of adrenal insufficiency characterized by hemodynamic collapse that is refractory to standard fluid resuscitation and vasopressor therapy. The most common risk factor is chronic exogenous glucocorticoid use, which suppresses the hypothalamic-pituitary-adrenal axis, rendering the patient unable to mount an appropriate cortisol response to physiologic stress. Primary adrenal insufficiency (Addison disease) results from destruction of the adrenal cortex, most commonly from autoimmune adrenalitis in developed countries. Secondary adrenal insufficiency from hypothalamic-pituitary pathology or, most commonly, from chronic steroid suppression may be precipitated by abrupt glucocorticoid withdrawal without tapering. Bilateral adrenal hemorrhage, though rare, may occur in the setting of anticoagulation therapy, severe sepsis (Waterhouse-Friderichsen syndrome), or the antiphospholipid syndrome.

The clinical presentation of adrenal crisis reflects the combined deficiency of cortisol and, in primary adrenal insufficiency, aldosterone. The hallmark finding is hypotension that is disproportionately severe and refractory to both fluid resuscitation and vasopressor administration, a clinical scenario that should always prompt consideration of adrenal insufficiency. Electrolyte abnormalities provide important diagnostic clues: hyponatremia results from impaired free water excretion due to both cortisol and aldosterone deficiency, while hyperkalemia is a feature of primary adrenal insufficiency where aldosterone deficiency leads to impaired renal potassium excretion. Hypoglycemia occurs because cortisol is essential for gluconeogenesis. Nonspecific symptoms including nausea, vomiting, abdominal pain, and altered mental status are common but may be attributed to the underlying stressor, delaying recognition of the adrenal crisis.

The diagnosis of adrenal crisis should be suspected on clinical grounds and treatment initiated empirically without waiting for confirmatory laboratory results. A random cortisol level drawn before treatment may support the diagnosis if it is inappropriately low (typically less than 15 micrograms per deciliter), but a normal random level does not exclude the diagnosis if drawn during a period of physiologic stress when cortisol should be elevated. The ACTH stimulation test, in which synthetic ACTH is administered and cortisol is measured at 30 and 60 minutes, is the definitive diagnostic test for adrenal insufficiency but should not delay treatment in an acutely ill patient. Serum electrolytes demonstrating the combination of hyponatremia and hyperkalemia, along with hypoglycemia, should raise suspicion for adrenal crisis in the appropriate clinical context.

Treatment of adrenal crisis must be initiated immediately and consists of three concurrent interventions. Aggressive intravenous fluid resuscitation with normal saline is the first priority, as these patients are typically severely volume depleted and the cortisol deficiency impairs the vascular response to catecholamines. Hydrocortisone at a dose of 100 milligrams is administered as an intravenous bolus, followed by 50 to 100 milligrams every 6 to 8 hours, providing both glucocorticoid and mineralocorticoid replacement. Dextrose-containing fluids are added if the patient is hypoglycemic. The precipitating factor, most commonly infection, must be identified and treated aggressively. Notably, separate mineralocorticoid replacement with fludrocortisone is not needed in the acute setting because hydrocortisone at stress doses possesses sufficient mineralocorticoid activity. Patients with known adrenal insufficiency should receive education about stress dosing of glucocorticoids and should carry injectable hydrocortisone for emergency self-administration.

<image>Panel A: Diagram of the hypothalamic-pituitary-adrenal axis showing the sites of disruption in primary adrenal insufficiency (adrenal cortex), secondary adrenal insufficiency (pituitary), and iatrogenic suppression from chronic exogenous glucocorticoids. Panel B: Clinical presentation infographic showing the constellation of refractory hypotension, hyponatremia, hyperkalemia, hypoglycemia, and nonspecific gastrointestinal symptoms that characterize adrenal crisis. Panel C: Laboratory findings including random cortisol levels, ACTH stimulation test protocol, and electrolyte patterns distinguishing primary from secondary adrenal insufficiency. Panel D: Treatment protocol showing simultaneous aggressive fluid resuscitation with normal saline, hydrocortisone 100 mg IV bolus followed by 50-100 mg every 6-8 hours, dextrose supplementation, and identification of the precipitating factor.</image>

Section 5: Thyroid Storm

Thyroid storm is a life-threatening exacerbation of hyperthyroidism characterized by multi-organ dysfunction driven by excessive thyroid hormone activity. The clinical presentation involves multiple organ systems simultaneously. Cardiovascular manifestations are prominent and include severe tachycardia, often with heart rates exceeding 140 beats per minute, atrial fibrillation (which occurs in up to 15 percent of thyrotoxic patients), and high-output heart failure. Central nervous system manifestations range from marked agitation, delirium, and psychosis to obtundation and coma in severe cases. Gastrointestinal symptoms include nausea, vomiting, diarrhea, and jaundice from hepatic dysfunction. Fever exceeding 38.5 degrees Celsius is a cardinal feature, and its absence should prompt reconsideration of the diagnosis. Common precipitants include infection, surgery, iodinated contrast administration, trauma, and acute cessation of antithyroid medications.

The diagnosis of thyroid storm is fundamentally clinical because laboratory values alone cannot distinguish thyroid storm from uncomplicated thyrotoxicosis. Thyroid function tests typically reveal a suppressed TSH and elevated free T4 and total T3, though the degree of elevation may not be markedly different from that seen in compensated thyrotoxicosis. The Burch-Wartofsky Point Scale is a clinical scoring system that incorporates temperature, central nervous system effects, gastrointestinal-hepatic dysfunction, cardiovascular parameters including heart rate and the presence of heart failure or atrial fibrillation, and the presence of a precipitating event, with a score of 45 or greater being highly suggestive of thyroid storm. The differential diagnosis includes sepsis, drug toxicity (particularly sympathomimetic or anticholinergic poisoning), malignant hyperthermia, and neuroleptic malignant syndrome.

The pharmacologic treatment of thyroid storm follows a specific sequence that is critical for optimal outcomes, as the order of medication administration matters significantly. The first step is administration of a beta-blocker, with propranolol preferred at a dose of 60 to 80 milligrams orally or 1 to 2 milligrams intravenously every 10 to 15 minutes, to block the peripheral adrenergic effects of thyroid hormone excess. Propranolol has the additional benefit of inhibiting peripheral conversion of T4 to the more metabolically active T3. The second step is a thionamide, with propylthiouracil at 200 milligrams orally or via nasogastric tube every 4 hours being preferred in thyroid storm because, unlike methimazole, it also inhibits peripheral T4-to-T3 conversion. The third step, which must be delayed at least 1 hour after thionamide administration, is iodine (SSKI 5 drops every 6 hours), which blocks release of preformed thyroid hormone from the gland. Iodine given before a thionamide would provide substrate for new hormone synthesis, potentially worsening the crisis. The fourth step is hydrocortisone 100 milligrams intravenously every 8 hours, which blocks T4-to-T3 conversion and addresses the possibility of concurrent adrenal insufficiency from accelerated cortisol metabolism. Active cooling and aggressive supportive care with fluids and electrolyte management complete the treatment approach.

Monitoring in thyroid storm requires intensive care unit admission for all patients, with frequent reassessment of multiple clinical parameters. Heart rate response to beta-blockade is the most immediately useful clinical marker, with a target of less than 100 beats per minute. Temperature should be monitored continuously with active cooling measures employed as needed. Mental status should be reassessed frequently, as improvement correlates with therapeutic response and declining thyroid hormone levels. The precipitating event must be identified and treated concurrently, as thyroid storm will not resolve if the underlying trigger persists. Patients who fail to respond to maximal medical therapy may require plasmapheresis or emergent thyroidectomy as salvage interventions.

<image>Panel A: Multi-system presentation of thyroid storm showing cardiovascular (tachycardia, atrial fibrillation, heart failure), neurologic (agitation, delirium, coma), gastrointestinal (nausea, vomiting, diarrhea, jaundice), and thermoregulatory (fever exceeding 38.5 degrees Celsius) manifestations. Panel B: The Burch-Wartofsky Point Scale scoring system showing the categories of thermoregulatory, central nervous system, gastrointestinal-hepatic, and cardiovascular dysfunction with corresponding point values. Panel C: Sequential pharmacologic treatment diagram emphasizing the critical order: (1) propranolol for beta-blockade, (2) PTU or methimazole to block synthesis, (3) iodine after 1-hour delay to block release, (4) hydrocortisone to block peripheral conversion and prevent adrenal insufficiency. Panel D: ICU monitoring parameters including heart rate target below 100, continuous temperature monitoring, serial mental status assessments, and thyroid function test trends.</image>

Section 6: Myxedema Coma

Myxedema coma is the most severe and life-threatening manifestation of hypothyroidism, representing the decompensated state of longstanding, untreated or undertreated hypothyroidism, most commonly in elderly women. Despite its name, frank coma is not required for the diagnosis; rather, the term encompasses a spectrum of severely depressed mental status from confusion and obtundation to unresponsive coma. Hypothermia is a cardinal feature, with core temperatures often below 35.5 degrees Celsius, and these patients characteristically fail to mount a febrile response even in the presence of serious infection, making fever an unreliable indicator of sepsis. Additional features include bradycardia, hypotension that may be refractory to vasopressors, hypoventilation with carbon dioxide retention, and hyponatremia resulting from impaired free water excretion through a mechanism similar to the syndrome of inappropriate antidiuretic hormone secretion.

Myxedema coma is almost always triggered by an identifiable precipitating event in a patient with pre-existing hypothyroidism. Infection is the most common trigger, and its detection may be challenging because the typical signs of infection including fever, tachycardia, and leukocytosis may be blunted or absent in the severely hypothyroid patient. Medications that depress central nervous system function, including sedatives, opioids, and lithium, may tip a chronically hypothyroid patient into myxedema coma. Cold exposure compounds the already impaired thermoregulatory capacity of hypothyroid patients. Non-compliance with prescribed thyroid hormone replacement is a common contributing factor. Other physiologic stressors including myocardial infarction, cerebrovascular accident, and surgery may precipitate decompensation.

Treatment of myxedema coma requires aggressive thyroid hormone replacement alongside supportive care. Intravenous levothyroxine (T4) is the mainstay of treatment, given as a loading dose of 200 to 400 micrograms followed by 50 to 100 micrograms daily; the intravenous route is essential because gastrointestinal absorption is unreliable in critically ill patients with myxedema ileus. The addition of liothyronine (T3), given as 5 to 20 micrograms intravenously every 8 hours, remains controversial but may be considered because T3 is the metabolically active hormone and peripheral conversion of T4 to T3 may be impaired in critical illness. Hydrocortisone at 100 milligrams intravenously every 8 hours must be administered concurrently until adrenal insufficiency has been excluded, because thyroid hormone replacement without adequate cortisol can precipitate adrenal crisis by increasing cortisol metabolism. Passive rewarming with blankets and a warm environment is preferred over active rewarming, which can cause peripheral vasodilation and hemodynamic deterioration. Mechanical ventilation may be required for hypoventilation and carbon dioxide retention. Intravenous fluids should be administered cautiously, as overly aggressive hydration may worsen hyponatremia.

The diagnosis is supported by laboratory findings that demonstrate the underlying hypothyroidism and its metabolic consequences. In primary hypothyroidism, which accounts for the vast majority of cases, TSH is markedly elevated and free T4 is low. In the less common secondary (central) hypothyroidism, TSH may be low or inappropriately normal in the setting of low free T4. A cortisol level should be obtained because concurrent adrenal insufficiency is possible and empiric hydrocortisone should be initiated pending results. Arterial blood gas analysis typically reveals hypercapnia and hypoxia from hypoventilation. Additional laboratory abnormalities may include anemia, elevated creatine kinase from hypothyroid myopathy, hypoglycemia, and elevated cholesterol. The clinical context of an elderly patient with altered mental status, hypothermia, and characteristic laboratory findings should prompt immediate treatment, as mortality approaches 25 to 50 percent even with appropriate therapy.

<image>Panel A: Clinical presentation of myxedema coma showing the constellation of hypothermia, altered mental status, bradycardia, hypotension, hypoventilation, and characteristic facial and skin changes of severe hypothyroidism. Panel B: Precipitating factors diagram showing infection as the most common trigger, along with sedative medications, cold exposure, thyroid hormone non-compliance, and physiologic stressors. Panel C: Treatment protocol showing concurrent intravenous levothyroxine loading and maintenance, optional liothyronine (T3), mandatory empiric hydrocortisone, passive rewarming technique, and ventilatory support. Panel D: Laboratory findings in myxedema coma including elevated TSH and low free T4 in primary hypothyroidism, arterial blood gas demonstrating hypercapnia and hypoxia, and additional findings of anemia, elevated CK, and hyponatremia.</image>

Section 7: Hyperkalemia

Hyperkalemia is among the most dangerous electrolyte emergencies because of its potential to cause fatal cardiac arrhythmias. The severity is classified by serum potassium level: mild hyperkalemia ranges from 5.5 to 6.0 mEq/L, moderate from 6.0 to 7.0 mEq/L, and severe is defined as greater than 7.0 mEq/L. However, the clinical significance depends not only on the absolute potassium level but also on the rate of rise, the presence of concurrent metabolic abnormalities (particularly acidosis, which shifts potassium extracellularly), and the presence of electrocardiographic changes, which indicate cardiac membrane instability regardless of the serum level. Common causes include renal failure, medications (ACE inhibitors, ARBs, potassium-sparing diuretics, NSAIDs), rhabdomyolysis, tumor lysis syndrome, and metabolic acidosis.

The electrocardiographic changes of hyperkalemia follow a characteristic progression that correlates roughly with increasing serum potassium levels and represents worsening cardiac conduction disturbance. The earliest change is peaked, narrow-based T waves, reflecting accelerated repolarization. As potassium continues to rise, the PR interval prolongs and the P wave flattens as atrial conduction is impaired. Progressive widening of the QRS complex follows as ventricular conduction slows. At critically elevated levels, the widened QRS merges with the T wave to form a sinusoidal (sine wave) pattern, which is a pre-arrest rhythm. The terminal event is either ventricular fibrillation or asystole. It is essential to recognize that electrocardiographic changes may not follow this orderly progression, and patients may progress from minimal changes to a lethal arrhythmia without warning, making any electrocardiographic abnormality in the setting of hyperkalemia an indication for emergent treatment.

The treatment of hyperkalemia employs three mechanistic categories that should be initiated simultaneously in severe cases. Membrane stabilization with calcium gluconate is the first and most urgent intervention, given as 10 milliliters of 10 percent solution intravenously over 2 to 3 minutes. Calcium does not lower the serum potassium level but rather antagonizes the effect of potassium on cardiac membrane potential, providing immediate but temporary cardioprotection with an onset of action within minutes and a duration of approximately 30 to 60 minutes. The dose may be repeated in 5 minutes if electrocardiographic changes persist. The second category involves transcellular shift of potassium from the extracellular to the intracellular space. Regular insulin at 10 units intravenously, co-administered with dextrose (25 grams of D50W) to prevent hypoglycemia, shifts potassium intracellularly within 15 to 30 minutes. High-dose albuterol (10 to 20 milligrams nebulized) provides an additive shift effect within 30 minutes. Sodium bicarbonate shifts potassium in the setting of concurrent metabolic acidosis but is less effective in non-acidotic patients. The third category involves actual removal of potassium from the body through furosemide (promoting renal excretion), sodium polystyrene sulfonate (kayexalate, promoting gastrointestinal excretion over hours), and dialysis as the definitive removal method for refractory hyperkalemia or renal failure.

The calcium administration protocol requires careful attention to avoid complications. Calcium gluconate at 10 milliliters of 10 percent solution is the preferred formulation for peripheral intravenous administration, as calcium chloride, while containing three times the elemental calcium, is highly caustic and can cause tissue necrosis if it extravasates from a peripheral line. The dose may be repeated in 5 minutes if electrocardiographic changes persist after the initial administration. A critical precaution is that calcium must never be administered through the same intravenous line as sodium bicarbonate, as the two precipitate to form insoluble calcium carbonate, rendering both medications ineffective. The protective effect of calcium is temporary, lasting only 30 to 60 minutes, which provides a window to implement the shift and removal strategies that will actually lower the serum potassium concentration.

<image>Panel A: Severity classification of hyperkalemia with corresponding serum potassium ranges and associated clinical risk, highlighting that ECG changes are the critical determinant of urgency regardless of the absolute potassium level. Panel B: Sequential ECG strip progression showing peaked T waves, PR prolongation with P wave flattening, QRS widening, sine wave pattern, and terminal ventricular fibrillation or asystole. Panel C: Three-category treatment framework showing membrane stabilization (calcium gluconate), transcellular shift (insulin plus glucose, albuterol, bicarbonate), and potassium removal (furosemide, kayexalate, dialysis) with onset times for each intervention. Panel D: Calcium gluconate administration protocol showing dose, rate, repeat criteria, the prohibition against co-administration with bicarbonate, and the distinction between calcium gluconate for peripheral IV and calcium chloride for central lines only.</image>

Section 8: Hyponatremia

Hyponatremia, defined as a serum sodium concentration below 135 mEq/L, is the most common electrolyte abnormality encountered in clinical practice. The initial classification is based on serum osmolality, which determines the underlying mechanism. Hypertonic hyponatremia (osmolality greater than 295 mOsm/kg) is a dilutional phenomenon caused by the presence of osmotically active solutes such as glucose or mannitol that draw water into the extracellular space, diluting sodium; this is the hyponatremia seen in diabetic ketoacidosis and hyperosmolar hyperglycemic state. Isotonic hyponatremia (osmolality 280 to 295 mOsm/kg) represents pseudohyponatremia, an artifact of older laboratory techniques when hyperlipidemia or hyperproteinemia displaces the aqueous fraction of plasma. True hypotonic hyponatremia (osmolality less than 280 mOsm/kg) is the clinically significant category and requires further evaluation.

The evaluation of true hypotonic hyponatremia requires assessment of the patient's volume status, as this determines the underlying mechanism and guides treatment. Hypovolemic hyponatremia occurs when both sodium and water are lost but sodium losses are proportionally greater, as seen with diuretic use, vomiting, diarrhea, and third-spacing. Euvolemic hyponatremia is the most common category in hospitalized patients and is most frequently caused by the syndrome of inappropriate antidiuretic hormone secretion (SIADH), hypothyroidism, and adrenal insufficiency. Hypervolemic hyponatremia occurs in edematous states where total body water is increased to a greater degree than total body sodium, as seen in congestive heart failure, cirrhosis, and nephrotic syndrome. Careful clinical assessment of volume status through vital signs, skin turgor, mucous membrane moisture, jugular venous pressure, and the presence of edema or ascites is essential for accurate classification.

The clinical manifestations of hyponatremia depend on both the severity of the sodium deficit and the rate at which it developed. Chronic hyponatremia (developing over more than 48 hours) may be remarkably well tolerated, with patients remaining asymptomatic at sodium levels that would produce severe symptoms if they developed acutely. At mildly reduced levels of 125 to 135 mEq/L, patients may experience nausea, malaise, and subtle cognitive impairment. Moderate hyponatremia between 120 and 125 mEq/L produces headache, confusion, and lethargy. Severe hyponatremia below 120 mEq/L, particularly when acute in onset, may cause seizures, coma, respiratory arrest, and brain herniation. The rate of development is a more important determinant of symptoms than the absolute sodium level, as the brain can adapt to gradual changes in osmolality through compensatory loss of intracellular organic osmolytes.

Treatment of hyponatremia is guided by the severity of symptoms and the chronicity of the condition, with the overriding principle that correction must occur at a controlled rate to avoid osmotic demyelination syndrome. For severe symptomatic hyponatremia with seizures or coma, 3 percent hypertonic saline is administered as a 100 to 150 milliliter bolus over 10 minutes, which may be repeated two to three times for persistent symptoms. The critical safety limit is a maximum correction rate of 8 to 10 mEq/L in the first 24 hours, as more rapid correction, particularly in chronic hyponatremia, creates an osmotic gradient that can cause osmotic demyelination syndrome (formerly known as central pontine myelinolysis), a devastating neurologic condition producing quadriparesis, dysphagia, dysarthria, and locked-in syndrome. If inadvertent overcorrection occurs, it can be reversed with administration of desmopressin (DDAVP) and 5 percent dextrose in water. SIADH is treated with fluid restriction. Hypovolemic hyponatremia is treated with isotonic normal saline.

<image>Panel A: Classification algorithm for hyponatremia based on serum osmolality, separating hypertonic (dilutional), isotonic (pseudo), and hypotonic (true) hyponatremia with underlying causes for each category. Panel B: Volume status assessment diagram showing the clinical features and causes of hypovolemic, euvolemic, and hypervolemic hypotonic hyponatremia. Panel C: Symptom severity spectrum showing neurologic manifestations at different sodium levels from mild (125-135 mEq/L) through moderate (120-125 mEq/L) to severe (below 120 mEq/L) with emphasis on acute versus chronic onset. Panel D: Treatment protocol showing 3 percent hypertonic saline bolus for severe symptoms, the maximum correction rate of 8-10 mEq/L in 24 hours, and the risk and MRI appearance of osmotic demyelination syndrome from overcorrection.</image>

Section 9: Hypercalcemia

Hypercalcemia is defined as a serum calcium level above 10.5 mg/dL (corrected for albumin) and has two predominant causes that account for the vast majority of cases. Primary hyperparathyroidism, in which autonomous parathyroid hormone secretion increases bone resorption, renal calcium reabsorption, and intestinal calcium absorption, is the most common cause in the outpatient setting. Malignancy-associated hypercalcemia is the most common cause in hospitalized patients and occurs through several mechanisms including parathyroid hormone-related peptide (PTHrP) secretion by tumors (humoral hypercalcemia of malignancy), direct osteolytic bone destruction from metastatic disease, and increased calcitriol production by lymphomas. Less common causes include granulomatous diseases (sarcoidosis, tuberculosis) where activated macrophages produce excess calcitriol, medications including thiazide diuretics and lithium, immobilization-induced bone resorption, and endocrine disorders such as hyperthyroidism and adrenal insufficiency.

The clinical manifestations of hypercalcemia follow the classic mnemonic "stones, bones, groans, and psychiatric moans." Stones refers to nephrolithiasis and nephrocalcinosis from calcium deposition in the renal parenchyma. Bones encompasses bone pain, pathologic fractures, and osteoporosis from excessive osteoclastic bone resorption. Groans refers to gastrointestinal symptoms including nausea, vomiting, constipation, anorexia, and pancreatitis. Psychiatric moans includes fatigue, depression, confusion, and in severe cases, obtundation and coma. The severity of symptoms generally correlates with the calcium level: mild hypercalcemia (10.5 to 12 mg/dL) is often asymptomatic, moderate hypercalcemia (12 to 14 mg/dL) produces constitutional and gastrointestinal symptoms, and severe hypercalcemia (above 14 mg/dL) may cause altered mental status, polyuria from nephrogenic diabetes insipidus, shortened QT interval on electrocardiogram, and cardiac arrhythmias. Hypercalcemic crisis, typically at levels exceeding 15 to 16 mg/dL, is a medical emergency.

Treatment of symptomatic or severe hypercalcemia addresses both the immediate calcium level and the underlying cause. Intravenous fluid resuscitation with normal saline is the cornerstone of initial management, administered at rates of 200 to 500 milliliters per hour, as these patients are invariably volume depleted from the renal concentrating defect and resultant polyuria. Calcitonin at a dose of 4 international units per kilogram administered intramuscularly or subcutaneously is the fastest-acting pharmacologic agent, reducing calcium within hours, though its effect is modest and subject to tachyphylaxis within 48 hours. Bisphosphonates, with zoledronic acid being the preferred agent, provide more potent and sustained calcium reduction but have a delayed onset of 2 to 4 days; they act by inhibiting osteoclast-mediated bone resorption. Dialysis is reserved for severe, refractory hypercalcemia or for patients with renal failure who cannot tolerate the volume load of saline hydration. Loop diuretics (furosemide) should only be administered after the patient has been adequately volume resuscitated, as premature diuresis may worsen dehydration and exacerbate hypercalcemia.

The diagnostic workup to determine the underlying cause of hypercalcemia centers on the parathyroid hormone level, which provides the critical branch point in the differential diagnosis. An elevated or inappropriately normal PTH in the setting of hypercalcemia indicates primary hyperparathyroidism. A suppressed PTH directs the workup toward non-PTH-mediated causes, with malignancy being the most important consideration; PTHrP should be measured, as it is elevated in humoral hypercalcemia of malignancy. Vitamin D levels (both 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D) should be assessed, as elevated calcitriol is seen in granulomatous diseases and some lymphomas. Cross-sectional imaging with computed tomography should be pursued when malignancy is suspected. Additional laboratory evaluation includes serum protein electrophoresis to evaluate for multiple myeloma and thyroid function tests to exclude hyperthyroidism.

<image>Panel A: Differential diagnosis branching diagram showing primary hyperparathyroidism versus malignancy as the predominant causes, with secondary categories including granulomatous disease, medications, immobilization, and endocrine causes. Panel B: Clinical manifestations illustration organized by the "stones, bones, groans, psychiatric moans" mnemonic showing nephrolithiasis, bone resorption, gastrointestinal symptoms, and neuropsychiatric effects at different calcium levels. Panel C: Stepwise treatment algorithm showing initial saline hydration, calcitonin for rapid onset, bisphosphonate for sustained effect, and dialysis for refractory cases, with timing of loop diuretic use after volume repletion. Panel D: Diagnostic workup flowchart centered on PTH measurement, with elevated PTH leading to hyperparathyroidism evaluation and suppressed PTH leading to PTHrP, vitamin D levels, imaging, and protein electrophoresis.</image>

Section 10: Other Electrolyte Emergencies

Hypokalemia becomes clinically significant below 3.0 mEq/L and life-threatening below 2.5 mEq/L. Mild hypokalemia between 3.0 and 3.5 mEq/L is usually well tolerated in otherwise healthy individuals. Moderate hypokalemia between 2.5 and 3.0 mEq/L produces skeletal muscle weakness, myalgias, and electrocardiographic changes including T wave flattening, U wave formation, and QT prolongation. Severe hypokalemia below 2.5 mEq/L can cause paralysis, respiratory failure from diaphragmatic weakness, rhabdomyolysis, and fatal cardiac arrhythmias including torsades de pointes, ventricular tachycardia, and ventricular fibrillation. Treatment involves potassium replacement, with the intravenous route preferred for severe hypokalemia using potassium chloride at a rate of 10 to 20 mEq per hour through a peripheral line or up to 40 mEq per hour through a central line with continuous cardiac monitoring. Concurrent hypomagnesemia must be identified and corrected because magnesium depletion causes renal potassium wasting, making hypokalemia refractory to potassium replacement alone.

Hypocalcemia produces clinical manifestations primarily through increased neuromuscular excitability. The hallmark features are tetany, Chvostek sign (twitching of the facial muscles when the facial nerve is tapped anterior to the ear), and Trousseau sign (carpal spasm induced by inflating a blood pressure cuff above systolic pressure for 3 minutes). Prolongation of the QT interval on electrocardiogram increases the risk of torsades de pointes and cardiac arrest. Severe hypocalcemia may cause seizures. The most common causes include hypoparathyroidism (often post-surgical), vitamin D deficiency, chronic kidney disease, and acute pancreatitis. Treatment of symptomatic hypocalcemia consists of intravenous calcium gluconate, 1 to 2 grams infused over 10 to 20 minutes, followed by a continuous infusion if necessary. Concurrent magnesium deficiency must be corrected because magnesium is required for appropriate parathyroid hormone secretion and end-organ response.

Hypomagnesemia is critically important not only for its own clinical effects but because it renders both hypokalemia and hypocalcemia refractory to replacement therapy. The serum magnesium level must be checked and corrected whenever hypokalemia or hypocalcemia fails to respond to standard replacement, as magnesium is essential for the function of the sodium-potassium ATPase (renal potassium conservation) and for parathyroid hormone secretion and action (calcium homeostasis). The primary cardiac manifestation of hypomagnesemia is predisposition to torsades de pointes, for which intravenous magnesium sulfate 2 grams is both the treatment and prophylaxis. Other manifestations include weakness, tremor, hyperreflexia, and seizures. Treatment of hypomagnesemia consists of magnesium sulfate 2 grams administered intravenously over 15 to 30 minutes in emergent situations, with additional repletion as guided by serum levels.

Severe metabolic acidosis is a common finding in critically ill patients and requires treatment directed at the underlying cause rather than empiric bicarbonate administration. Metabolic acidosis from diabetic ketoacidosis, lactic acidosis, and toxic ingestions each requires specific treatment targeting the underlying mechanism. Lactic acidosis, the most common cause of anion gap metabolic acidosis in the emergency department, is most frequently produced by tissue hypoperfusion in shock, and treatment focuses on volume resuscitation, vasopressor support, and treatment of the underlying cause of shock; metformin should be discontinued in these patients due to the risk of exacerbating lactic acidosis. Sodium bicarbonate administration is generally reserved for severe acidosis with pH below 7.1 and should be viewed as a temporizing measure rather than definitive treatment. Toxic acidosis from methanol, ethylene glycol, or salicylate ingestion requires specific antidotes and often hemodialysis. Respiratory acidosis is managed by improving ventilation through treatment of the underlying respiratory pathology and, when necessary, mechanical ventilation.

<image>Panel A: Hypokalemia severity spectrum showing ECG changes at different potassium levels including T wave flattening, U wave appearance, QT prolongation, and the progression to ventricular arrhythmias, with corresponding replacement protocols for peripheral and central intravenous administration. Panel B: Clinical examination findings in hypocalcemia demonstrating Chvostek sign (facial nerve tapping producing ipsilateral facial muscle contraction) and Trousseau sign (carpal spasm with blood pressure cuff inflation). Panel C: The interconnected relationship between magnesium, potassium, and calcium homeostasis showing how hypomagnesemia causes renal potassium wasting and impaired PTH secretion, rendering both hypokalemia and hypocalcemia refractory to replacement. Panel D: Approach to severe metabolic acidosis showing the anion gap calculation, common causes (DKA, lactic acidosis, toxic ingestions), specific treatments for each etiology, and the limited role of sodium bicarbonate administration.</image>

Summary

• DKA is diagnosed by glucose greater than 250, pH less than 7.3, anion gap greater than 12, and positive ketones; management requires simultaneous fluids, insulin, and potassium replacement guided by serum potassium level
• HHS is distinguished from DKA by glucose greater than 600, osmolality greater than 320, and minimal ketones; treatment prioritizes aggressive fluid resuscitation with a lower insulin infusion rate
• Hypoglycemia is treated with D50W or glucagon; sulfonylurea-induced hypoglycemia requires hospital admission due to prolonged duration and may benefit from octreotide
• Adrenal crisis presents with refractory hypotension plus hyponatremia; treatment is hydrocortisone 100 mg IV with aggressive fluid resuscitation
• Thyroid storm treatment follows a critical sequence: beta-blocker, then PTU, then iodine after a 1-hour delay, then hydrocortisone
• Myxedema coma presents with hypothermia and altered mental status; treatment requires IV levothyroxine plus empiric hydrocortisone until adrenal insufficiency is excluded
• Hyperkalemia is treated with calcium gluconate for membrane stabilization, insulin plus glucose for intracellular shift, and dialysis for definitive removal
• Hyponatremia correction must not exceed 8 to 10 mEq/L in 24 hours to prevent osmotic demyelination syndrome; 3 percent saline is used for severe symptoms
• Hypercalcemia treatment begins with saline hydration; calcitonin provides rapid but temporary effect while bisphosphonates provide sustained reduction over days
• Hypomagnesemia must be corrected when hypokalemia or hypocalcemia is refractory to standard replacement therapy

Key Terms

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