Myxedema Coma

• Severe thyroid hormone deficiency and metabolic collapse: Profound reduction in circulating T3 and T4 (typically TSH >100 mIU/L, free T4 often <0.5 ng/dL) leads to dramatically decreased metabolic rate (up to 40% reduction) affecting all tissues. Thyroid hormones normally bind to nuclear receptors in virtually all cells to regulate gene transcription controlling thermogenesis, oxygen consumption, and substrate utilization. Without adequate hormone, cells cannot maintain ATP production at physiologic rates, leading to global cellular energy depletion, impaired Na-K-ATPase function, and accumulation of intracellular sodium and fluid. This profound metabolic depression affects thermogenesis through reduced brown adipose tissue activation and decreased sympathetic nervous system responsiveness, resulting in hypothermia that can be profound (temperature <30°C).

• Loss of adrenergic responsiveness and cardiovascular collapse: Chronic thyroid hormone deficiency causes reduced expression of β-adrenergic receptors throughout the cardiovascular system and impaired coupling of remaining receptors to G-protein signaling pathways. Myocardial contractility decreases due to reduced expression of contractile proteins and impaired calcium handling in the sarcoplasmic reticulum. Intracardiac fluid accumulation (myxedematous infiltration of myocardium) physically reduces ventricular compliance. Peripheral vascular resistance increases due to reduced sympathetic tone yet paradoxical increased responsiveness to circulating catecholamines, creating a mismatch between metabolic demand and delivery. The combination produces a "shock-like" state with bradycardia, hypotension, narrow pulse pressure, and severely reduced cardiac output despite elevated peripheral resistance. Coronary perfusion becomes inadequate, increasing risk of acute coronary syndromes and arrhythmias.

• Cerebral dysfunction and altered mental status through multiple mechanisms: Thyroid hormones regulate cerebral blood flow, glucose metabolism in the brain, myelin formation, and neurotransmitter synthesis. Severely deficient hormone levels cause decreased cerebral metabolic rate, impaired cerebrovascular autoregulation, and reduced responsiveness to hypercapnia/hypoxia. Central hypoventilation develops through multiple mechanisms: reduced sensitivity of respiratory centers to CO2 (medullary chemoreceptor dysfunction), skeletal muscle weakness from myopathy, reduced chest wall compliance from myxedematous infiltration, and altered consciousness reducing respiratory drive. CO2 retention produces respiratory acidosis which, combined with metabolic acidosis from tissue hypoxia and lactate accumulation, severely impairs consciousness. Myxedematous infiltration of the brain parenchyma (actual polysaccharide deposition in neural tissue and perivascular spaces) contributes to encephalopathy independent of metabolic factors. Hyponatremia develops through inappropriate vasopressin secretion and impaired free water clearance, further worsening consciousness.

• Impaired thermoregulation and profound hypothermia: Hypothalamic temperature regulation is directly dependent on thyroid hormone. Sustained hormone deficiency impairs the hypothalamic set point for body temperature and reduces thermogenic responses to cold exposure. Shivering is absent or greatly diminished in myxedema coma due to profound metabolic depression and myopathy. Brown adipose tissue activation is severely blunted due to loss of sympathetic responsiveness. Patients become profoundly poikilothermic, unable to regulate temperature in response to environmental exposure. Severe hypothermia (<30°C) itself worsens all other pathophysiologic derangements through reduced enzyme kinetics, impaired oxygen delivery, increased arrhythmia risk, and increased metabolic acidosis.

• Gastrointestinal dysmotility, ileus, and multi-organ edema: Reduced intestinal smooth muscle contractility and myenteric plexus dysfunction produce severe constipation, fecal impaction, and ileus. Myxedematous infiltration of the intestinal wall reduces compliance and increases perforation risk. Mucosal atrophy and reduced blood flow impair barrier function, increasing bacterial translocation risk. Widespread myxedematous infiltration affects all tissues—cardiac (reduced contractility and compliance), renal (reduced filtration and glomerulosclerosis), hepatic (hepatic dysfunction with reduced synthetic capacity and impaired drug metabolism), and CNS (brain edema, impaired CSF flow). Accumulation of hyaluronic acid and other glycosaminoglycans in interstitial spaces produces the characteristic "myxedema" (mucin infiltration) that gives the condition its name, manifesting clinically as periorbital puffiness, facial edema, and skin thickening.

• Primary hypothyroidism with longstanding duration (>90% of cases): Chronic Hashimoto's thyroiditis (autoimmune destruction of thyroid tissue) is the most common cause of myxedema coma in iodine-sufficient regions. Patients frequently have a long history of progressive symptoms that went unrecognized or were undertreated with inadequate levothyroxine dosing. Prior radioactive iodine ablation for Graves' disease or thyroidectomy for any indication can lead to myxedema coma if subsequent hypothyroidism develops and is not appropriately managed. Regional iodine deficiency remains a significant cause globally, though rare in North America. The critical factor is not merely the diagnosis of hypothyroidism but the chronicity and severity of hormone deficiency combined with loss of physiologic compensation.

• Acute decompensation in previously stable hypothyroid patients: Patients with known hypothyroidism on replacement therapy can develop myxedema coma when exposed to severe precipitating stressors that unmask inadequate thyroid hormone reserve. Infection (particularly pneumonia, urinary tract infection, or any severe sepsis) is the most common precipitant, likely through multiple mechanisms including increased metabolic demand, impaired immune response, and systemic inflammatory mediators. Cold exposure (accidental hypothermia, living in inadequate shelter, winter hospitalization) is a classic precipitant that overwhelms impaired thermoregulation. Medications reducing thyroid hormone absorption or metabolism worsen decompensation: amiodarone (antiarrhythmic causing both direct thyroid injury and altered T4-T3 conversion), contrast agents (iodine-containing), lithium (interferes with thyroid peroxidase), interferon-alpha, and thiopurines. Non-compliance with levothyroxine replacement is underappreciated as a precipitant. Acute illness from myocardial infarction, stroke, trauma, or surgery induces metabolic stress requiring increased thyroid hormone availability. Anesthesia and sedating medications (benzodiazepines, opioids) can precipitate coma in borderline-compensated patients by depressing respiratory drive.

• Advanced age and female predominance: Myxedema coma occurs predominantly in elderly patients (peak incidence >60 years) due to cumulative effects of chronic hypothyroidism and reduced physiologic reserve. Autoimmune thyroid disease, the predominant cause, affects women 5-10 times more frequently than men, explaining the female predominance in myxedema coma (though mortality is higher in males). Comorbid conditions in elderly patients—cardiovascular disease, renal insufficiency, respiratory compromise, dementia—reduce capacity to compensate for metabolic derangement.

• Profound altered mental status progressing to coma: Lethargy, confusion, and disorientation develop insidiously, often attributed to other causes (dementia, delirium) until critical illness develops. Patients manifest psychomotor slowing, flat affect, apathy, and apparent depression with severe cognitive impairment. Speech becomes slow, thick, and dysarthric. Seizures can occur due to profound hypoglycemia, hyponatremia, hypercapnia with respiratory acidosis, or cerebral edema. Complete unconsciousness may be present on presentation, with patients unresponsive to verbal stimuli and displaying minimal responsiveness to pain. The altered consciousness is multifactorial: reduced cerebral metabolic rate, increased intracranial pressure from brain edema, hyponatremia-induced cellular edema, respiratory acidosis from hypoventilation, and hypoxia.

• Severe, often profound hypothermia: Core body temperature frequently drops to 30-35°C (86-95°F), but can fall below 30°C in severe cases. Importantly, standard thermometers may not register temperatures below 35°C—core temperature must be measured with low-reading thermometers, esophageal probes, or bladder catheters in suspected myxedema coma. Patients appear "dead" (the aphorism "no one is dead until they're warm and dead" applies to myxedema coma patients with severe hypothermia). Peripheral vasoconstriction is marked, making patients appear pale or cyanotic with cold extremities. Shivering is typically absent (characteristic finding—"no shivering in myxedema coma" due to severely impaired thermogenic response). Skin develops the characteristic myxedematous appearance: cool, dry, thick, with reduced elasticity ("doughy" consistency). Periorbital puffiness and facial edema are often striking.

• Cardiovascular collapse with bradycardia, hypotension, and reduced cardiac output: Severe bradycardia is nearly universal, with heart rates often 30-50 bpm or lower. Hypotension is present with systolic pressures frequently <90 mmHg. Narrow pulse pressure reflects reduced cardiac output and increased peripheral resistance. Atrial fibrillation with a slow ventricular response is common and often attributed to other causes until thyroid function is checked. The cardiac examination reveals distant, muffled heart sounds (due to pericardial effusion with myxedematous fluid accumulation). Pericardial effusion is present in the majority of cases, occasionally producing tamponade physiology. Jugular venous pressure may be elevated if right heart failure develops. Acute coronary syndrome can occur as myxedema coma uncovers underlying coronary disease or creates supply-demand mismatch with severe bradycardia, hypotension, and hypoxia.

• Severe hypoventilation with respiratory depression: Respiratory rate may be dangerously low (8-12 breaths/min or lower). Central hypoventilation is the primary mechanism—medullary chemoreceptors lose responsiveness to rising CO2. Patients fail to increase ventilation appropriately in response to hypercapnia or hypoxia. Severe hypercapnia develops (CO2 often 60-100 mmHg or higher) producing CO2 narcosis and respiratory acidosis that directly contributes to altered consciousness. Sleep apnea is severe and often unrecognized. Respiratory muscles are weak and myxedematous infiltration reduces chest wall compliance. Aspiration risk is markedly elevated due to decreased consciousness and loss of protective airway reflexes.

• Other constitutional and systemic findings: Severe constipation with fecal impaction is nearly universal and can precipitate the acute crisis. Abdominal distention may be marked, and bowel perforation is a serious complication risk. Ascites accumulates due to reduced serum oncotic pressure (decreased synthetic protein production) and third-spacing from myxedematous infiltration. Weight gain is paradoxical despite often reduced oral intake, due to fluid retention and reduced metabolic rate. Hair loss and brittle nails reflect chronic deficiency. Delayed relaxation of deep tendon reflexes is characteristic (prolonged relaxation phase, best appreciated in Achilles reflex with slowed return to baseline—"hung-up" reflexes). Hearing loss may be present. Amenorrhea or menorrhagia reflects hormonal imbalances. Patients often appear much older than their stated age due to myxedematous infiltration and cutaneous changes. Psychotic features ("myxedema madness") with paranoid delusions or visual hallucinations can occur as an atypical presentation.

• Thyroid function tests (TSH and free T4): TSH is markedly elevated (typically >100 mIU/L, often >500 mIU/L) and free T4 is severely reduced (<0.4 ng/dL, often <0.1 ng/dL in myxedema coma compared to overt hypothyroidism where TSH >10 mIU/L but free T4 may be low-normal). These laboratory findings confirm primary hypothyroidism of severe degree. TSH measurement alone may be falsely reassuring early in central hypothyroidism, so free T4 must be measured. Patients presenting with coma and severe hypothermia should have thyroid studies sent immediately even if hypothyroidism is not clinically suspected. Delayed treatment while awaiting lab confirmation is inappropriate—treatment should begin based on clinical suspicion in patients with the classic triad of altered mental status, hypothermia, and cardiovascular instability.

• Electrolyte abnormalities: Hyponatremia is present in >80% of myxedema coma cases, typically moderate (sodium 115-130 mEq/L) and due to inappropriate ADH secretion combined with impaired free water clearance. Severe hyponatremia (<115 mEq/L) contributes significantly to altered consciousness and seizure risk. Hypoglycemia may occur due to reduced hepatic glycogenolysis and impaired counterregulatory hormone response. Hypercarbia (CO2 >60 mmHg) is present on blood gas due to hypoventilation. Respiratory and metabolic acidosis are typical with pH often <7.30. Arterial blood gas analysis reveals the combination: elevated pCO2 (respiratory acidosis from hypoventilation), elevated lactate (metabolic acidosis from tissue hypoperfusion), and low pH.

• Additional supporting laboratory findings: Elevated creatine kinase (CK) may be present due to myopathy and reduced muscle perfusion. Elevated liver enzymes (AST, ALT) reflect hepatic dysfunction. Elevated lipids (cholesterol, triglycerides) due to impaired metabolism. Hypercholesterolemia is characteristic of chronic hypothyroidism. Anemia may be present (hypothyroidism-associated macrocytic anemia or anemia of chronic disease). Hypoalbuminemia reflects impaired hepatic synthetic function. Elevated amylase can occur without pancreatitis. Complete blood count may show normocytic or macrocytic anemia. Urinalysis typically shows concentrated urine due to reduced renal perfusion and prerenal azotemia.

• Electrocardiographic findings: Sinus bradycardia is nearly universal. Atrial fibrillation with slow ventricular response is common. Low-voltage QRS complexes are characteristic, reflecting pericardial effusion and myxedematous infiltration of myocardium. Prolonged PR interval and widened QRS may be seen. T-wave flattening or inversion is typical. Prolonged QT interval increases arrhythmia risk. The combination of these findings in a patient with bradycardia and hypothermia should raise suspicion for myxedema coma.

• Chest X-ray findings: Cardiomegaly is typical due to pericardial effusion and myocardial dysfunction. Pericardial effusion is visible as widened cardiac silhouette with loss of the normal cardiac waist. Pulmonary edema may be present due to heart failure or aspiration. Pleural effusions (typically bilateral) occur due to reduced plasma oncotic pressure. Absence of infiltrates despite respiratory symptoms should raise suspicion for myxedema-associated respiratory failure rather than infection.

• Diagnostic criteria and diagnostic approach: No validated scoring system exists for myxedema coma, but the diagnosis is established by combining three elements: (1) severe hypothyroidism confirmed by markedly elevated TSH and low free T4; (2)

Immediate stabilisation (before any laboratory confirmation)

• Airway and ventilation: intubation with mechanical ventilation for CO2 narcosis, obtundation, or loss of airway reflexes. Hypercapnia will not correct with hormone alone in the first hours.
• Passive rewarming: blankets and a warm environment. Aggressive active external rewarming is discouraged because cutaneous vasodilation in a patient with a fixed low cardiac output precipitates rewarming shock.
• Correct hypoglycaemia and hypotonic hyponatraemia: dextrose as needed; free-water restriction, with hypertonic saline reserved for seizures or profound symptomatic hyponatraemia, correcting slowly to avoid osmotic demyelination.
• Search for and treat the precipitant: empiric antibiotics are reasonable for suspected sepsis, since hypothyroid patients characteristically fail to mount fever or leukocytosis.

Hormonal therapy (American Thyroid Association 2014 hypothyroidism guideline)

• Glucocorticoid first: a stress-dose corticosteroid, typically hydrocortisone 100 mg IV every 8 hours, given before thyroid hormone. Coexisting adrenal insufficiency (autoimmune polyglandular disease or central hypothyroidism with ACTH deficiency) is common, and restoring metabolic rate accelerates cortisol clearance, which can precipitate adrenal crisis. Draw a random cortisol first if it does not delay treatment.
• Thyroid hormone, intravenous: levothyroxine (T4) given as an IV loading dose followed by a daily maintenance dose; the ATA notes IV dosing must be lower than oral because enteral absorption is bypassed. The oral route is unreliable — gut wall oedema and ileus impair absorption.
• Adjunctive liothyronine (T3): the ATA considers combined T4 plus low-dose IV T3 reasonable in the sickest patients, because peripheral 5'-deiodinase conversion of T4 to T3 is impaired in critical illness. T3 is more arrhythmogenic, so use the lowest effective dose in elderly patients with coronary disease.

Escalation and what to avoid

• Vasopressors are often refractory until thyroid hormone restores beta-adrenergic receptor expression; they are a bridge, not the fix.
• Contraindicated/avoid: sedatives, opioids, and benzodiazepines (impaired hepatic clearance, respiratory depression); oral levothyroxine; and reflexive fluid boluses, which worsen dilutional hyponatraemia.
• Manage in an ICU with continuous telemetry; hemodynamically significant pericardial effusion requires pericardiocentesis.

Complications of the disease

• Hypoventilatory respiratory failure with CO2 narcosis — emergency. Blunted medullary chemoreceptor response plus respiratory myopathy; signalled by a rising pCO2 with falling pH and worsening obtundation despite hormone therapy. Requires intubation, not supplemental oxygen alone (oxygen may mask the hypercapnia).
• Cardiogenic shock and bradyarrhythmia — emergency. Loss of beta-receptor expression and myxedematous myocardial infiltration; signalled by narrow pulse pressure, pressor-refractory hypotension, and heart block on telemetry.
• Pericardial tamponade — emergency. Mucin-rich effusion accumulating slowly; signalled by pulsus paradoxus, muffled sounds, and electrical alternans or low voltage on ECG, confirmed by bedside echocardiography.
• Hyponatraemic seizures: inappropriate vasopressin release plus impaired free-water excretion; signalled by sodium falling into the low 110s with new seizure activity.
• Ileus with megacolon or perforation: myenteric hypomotility; signalled by rising abdominal distension, absent bowel sounds, and free air on imaging.
• Ventricular fibrillation from severe hypothermia — emergency. Core temperature below roughly 28–30°C makes the myocardium exquisitely irritable; rough handling or central line placement can trigger it, and defibrillation is often ineffective until rewarming occurs.

Complications of treatment

• Precipitated adrenal crisis: thyroid hormone given before glucocorticoid accelerates cortisol metabolism; signalled by refractory hypotension, hyponatraemia with hyperkalaemia, and hypoglycaemia. Emergency — treat with IV hydrocortisone.
• Myocardial ischaemia, atrial fibrillation, or ventricular arrhythmia from thyroid hormone, particularly liothyronine: abrupt restoration of chronotropy and inotropy raises myocardial oxygen demand in a patient with fixed coronary supply; signalled by new chest pain, ST-segment change, or tachyarrhythmia on telemetry.
• Osmotic demyelination syndrome: over-rapid sodium correction; signalled by delayed pseudobulbar palsy and quadriparesis days after apparent improvement.
• Rewarming shock: active external rewarming causes peripheral vasodilation into an underfilled circuit, signalled by an abrupt blood-pressure drop as skin warms.
• Aspiration pneumonia and drug accumulation (sedatives, digoxin) from delayed hepatic and renal clearance.

• The classic stem: an elderly woman, in winter, found obtunded at home with hypothermia without shivering, bradycardia, hypotension, and a thyroidectomy scar or a bottle of levothyroxine she stopped taking. Look for non-pitting periorbital and facial oedema, a doughy skin texture, and "hung-up" (delayed-relaxation) ankle reflexes.
• Single best next step: give IV hydrocortisone first, then IV levothyroxine — empirically, before TSH and free T4 return. Waiting for confirmatory labs is the most commonly selected wrong answer. Steroid-before-hormone sequencing exists to prevent precipitating adrenal crisis.
• The association examiners test: an identifiable precipitant is nearly always in the stem — infection, cold exposure, or a sedating drug (opioid, benzodiazepine) or amiodarone. Hypothyroid patients with sepsis are typically afebrile with a normal white count, so absence of fever does not exclude infection.
• Route matters: levothyroxine must be intravenous. "Give oral levothyroxine via NG tube" is a distractor — gut wall oedema and ileus make absorption unreliable.
• ECG buzzwords: sinus bradycardia with low-voltage QRS, flat T waves, and prolonged QT. Low voltage plus an enlarged cardiac silhouette on chest film means pericardial effusion, not cardiomegaly from systolic failure — echocardiography is the confirming test.
• Do not actively rewarm aggressively: passive rewarming only, because cutaneous vasodilation in a low-output state causes rewarming shock and hypotension.
• Labs to expect: markedly elevated TSH, very low free T4, hyponatraemia, hypoglycaemia, hypercapnic respiratory acidosis, and elevated CK. Correct the sodium slowly to avoid osmotic demyelination.
• Common distractor: euthyroid sick (non-thyroidal illness) syndrome — low T3 with normal or low TSH in an ICU patient — does not cause myxedema coma and does not warrant hormone replacement. Central hypothyroidism is the other trap: TSH may be low or normal, so a low free T4 is what drives the diagnosis.