Myxedema Coma

Quick Answer

Myxedema coma is a life-threatening endocrine emergency representing the most severe decompensation of hypothyroidism, characterized by altered mental status (ranging from lethargy to coma), hypothermia (below 35°C), bradycardia, hypotension, hyponatremia, and respiratory failure.[1,2] Despite the name, actual coma is present in only 25-40% of cases.[3] It is rare (0.22 per million per year) but carries mortality rates of 30-60% even with appropriate treatment.[4,5] The condition typically affects elderly women (greater than 80% of cases) with undiagnosed or undertreated hypothyroidism, often precipitated by infection (35-40%), cold exposure, sedative medications, or medication non-compliance.[6,7]

Management requires immediate IV thyroid hormone replacement (T4 loading dose 200-500 mcg, or combination T4 + T3), but hydrocortisone 100 mg IV Q8H must be given FIRST or concurrently to prevent precipitating adrenal crisis (as thyroid hormone increases cortisol metabolism).[8,9] Supportive care includes passive rewarming (aggressive rewarming causes vasodilation and cardiovascular collapse), mechanical ventilation for respiratory failure, cautious fluid management (avoid dilutional hyponatremia), vasopressor support, and treatment of precipitating factors.[10,11]

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CICM Exam Focus

Second Part Written Exam

Myxedema coma is a high-yield topic for CICM examinations, testing core ICU endocrine emergency competencies:

Common SAQ Topics

• "Define myxedema coma and list the clinical features"
• "Outline the immediate management of a patient with suspected myxedema coma"
• "Describe the pathophysiology of cardiovascular dysfunction in myxedema coma"
• "Discuss the rationale for administering corticosteroids before thyroid hormone replacement"
• "Compare T4 monotherapy with combination T4/T3 therapy in myxedema coma"
• "Outline the precipitating factors for myxedema coma"
• "Discuss the management of hyponatremia in a patient with myxedema coma"
• "Describe how to differentiate myxedema coma from non-thyroidal illness syndrome"

Viva Scenarios

• 72-year-old woman with hypothermia (32°C), bradycardia (40 bpm), GCS 9, history of thyroid surgery
• Management of hypotension refractory to vasopressors in suspected myxedema coma
• Interpreting TFTs in a critically ill patient: myxedema coma vs sick euthyroid syndrome
• Deciding between T4 monotherapy vs combination T4/T3 in an 80-year-old with ischemic heart disease
• Managing respiratory failure in myxedema coma: weaning difficulties and extubation failure

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Key Points

• Definition: Severe hypothyroidism with altered consciousness, hypothermia, and multi-system dysfunction; actual coma present in only 25-40%
• Epidemiology: Rare (0.22 per million/year), predominantly elderly women (greater than 80%), winter predominance, mortality 30-60%
• Precipitants: Infection (35-40%), cold exposure, sedatives/opioids, non-compliance, stroke, MI, GI bleeding
• Cardinal Features: Hypothermia (below 35°C), bradycardia, hypotension, hyponatremia, respiratory failure, altered consciousness
• Diagnosis: Clinical + markedly elevated TSH (greater than 20 mIU/L) + low fT4/fT3; consider Popoveniuc Score ≥60
• Critical Step: Give hydrocortisone 100 mg IV Q8H BEFORE or concurrently with thyroid hormone (to prevent adrenal crisis)
• T4 Replacement: Loading dose 200-500 mcg IV, then 50-100 mcg IV daily (lower doses for elderly/cardiac disease)
• T3 Option: 5-20 mcg IV loading then 2.5-10 mcg Q8H (faster onset, but higher cardiac risk)
• Rewarming: PASSIVE only - aggressive rewarming causes vasodilation and cardiovascular collapse
• Avoid: Sedatives, opioids, excess IV fluids, hypothermia, hypoglycemia
• Mortality Predictors: Age greater than 65, GCS below 8, hypothermia below 32°C, need for mechanical ventilation, cardiovascular instability

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Definition and Diagnostic Criteria

Definition of Myxedema Coma

Myxedema coma is defined as the most severe, life-threatening presentation of hypothyroidism characterized by:[1,2,3]

1. Altered mental status: Ranging from lethargy, confusion, obtundation to frank coma
2. Hypothermia: Core temperature below 35°C (95°F); may be below 32°C in severe cases
3. Precipitating factor: Usually identifiable trigger (infection, cold, medications)
4. Multi-system dysfunction: Cardiovascular, respiratory, metabolic derangements
5. Laboratory confirmation: Markedly elevated TSH (in primary hypothyroidism) with low fT4/fT3

Despite the name "coma," only 25-40% of patients present in actual coma. The term reflects the historical recognition of severe cases; most patients present with varying degrees of altered consciousness.[3,12]

Popoveniuc Diagnostic Scoring System

The Popoveniuc Scoring System provides a semi-quantitative approach to diagnosing myxedema coma based on clinical and laboratory features:[13,14]

Interpretation:

• Score ≥60: Highly suggestive of myxedema coma
• Score 25-59: Impending myxedema coma or possible myxedema coma
• Score below 25: Unlikely to be myxedema coma

This scoring system has a sensitivity of 83% and specificity of 100% for diagnosing myxedema coma when the threshold is set at ≥60.[13]

Primary vs Secondary (Central) Hypothyroidism

In secondary hypothyroidism, TSH cannot be used as the primary marker; the diagnosis relies on low fT4 in the appropriate clinical context.[15,16]

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Epidemiology

Incidence and Demographics

• Incidence: Myxedema coma is rare, with an estimated incidence of 0.22 per million per year in developed countries.[4,17]
• Age: Predominantly affects the elderly, with median age of 73-78 years; 75% of cases occur in patients greater than 60 years.[4,18]
• Sex: Striking female predominance (80-90% of cases), reflecting higher rates of underlying hypothyroidism in women.[17,18]
• Seasonality: Strong winter predominance (50-80% of cases occur during winter months) due to cold exposure as a precipitating factor.[6,19]
• Pre-existing Hypothyroidism: Most patients (greater than 90%) have known or undiagnosed hypothyroidism, commonly Hashimoto's thyroiditis, previous thyroid surgery, or radioactive iodine treatment.[17]

Geographic and Healthcare Considerations

• Delayed Diagnosis: Many cases of myxedema coma represent undiagnosed hypothyroidism that was never detected or undertreated hypothyroidism (non-compliance with levothyroxine).
• ICU Admission: Most patients require ICU admission for respiratory support (50-60%) and cardiovascular monitoring.[4,20]
• Length of Stay: Median ICU stay 5-10 days, with prolonged hospital stays (median 15-25 days).[4]

Mortality and Outcomes

Despite advances in critical care, mortality from myxedema coma remains high:[4,5,18]

Mortality Predictors:

• Advanced age (greater than 70 years)
• Hypothermia below 32°C
• Low Glasgow Coma Scale (below 8)
• Need for mechanical ventilation
• Cardiovascular instability requiring vasopressors
• Sepsis as precipitating factor
• High APACHE II score (greater than 20)
• Bradycardia below 44 bpm
• Hypotension not responding to therapy

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Aetiology and Precipitating Factors

Underlying Causes of Hypothyroidism

Myxedema coma occurs in patients with severe, prolonged hypothyroidism. The underlying causes include:[1,2,17]

Primary Hypothyroidism (90-95% of cases):

Secondary (Central) Hypothyroidism (5-10% of cases):

Precipitating Factors

Myxedema coma rarely develops spontaneously; it is almost always precipitated by an acute stressor in a patient with underlying hypothyroidism:[6,7,22]

Identifying and treating the precipitating factor is essential for successful management.[22,23]

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Pathophysiology

Overview of Pathophysiological Mechanisms

Myxedema coma results from the profound metabolic effects of severe thyroid hormone deficiency affecting virtually every organ system:[1,2,24]

Severe Hypothyroidism
        ↓
┌───────┴───────┐
↓               ↓
Decreased      Impaired
Metabolic      Drug
Rate           Metabolism
↓               ↓
┌───┴───┐      ↓
↓       ↓      Sedative
↓ CO    ↓ Temp Accumulation
↓       ↓      ↓
Shock   Hypo-  CNS
        thermia Depression
        ↓
        └───────┬───────┘
                ↓
         Multi-Organ Failure
                ↓
         MYXEDEMA COMA

Cardiovascular Pathophysiology

Thyroid hormones (particularly T3) have profound effects on the cardiovascular system:[24,25,26]

Direct Myocardial Effects:

• Decreased SERCA2 expression: Reduced calcium re-uptake into sarcoplasmic reticulum, impairing relaxation
• Decreased beta-1 adrenergic receptors: Blunted catecholamine responsiveness
• Decreased myosin heavy chain-alpha: Reduced contractile velocity
• Decreased Na+/K+-ATPase: Altered membrane potential

Hemodynamic Consequences:

Pericardial Effusion:

• Occurs in up to 30-50% of patients with severe hypothyroidism
• Caused by increased capillary permeability and decreased lymphatic drainage
• Usually develops slowly, allowing pericardial adaptation
• Cardiac tamponade is rare but can occur if rapid accumulation[27,28]

Respiratory Pathophysiology

Respiratory failure is a major cause of morbidity and mortality in myxedema coma:[1,12,29]

Blood Gas Pattern:

• Type II respiratory failure (hypercapnic)
• Hypoxemia with hypercapnia
• Respiratory acidosis
• Blunted ventilatory response to CO2

Up to 50-60% of myxedema coma patients require mechanical ventilation, and respiratory failure is an independent predictor of mortality.[4,20]

Neurological Pathophysiology

Altered mental status is the defining feature of myxedema coma and results from:[1,3,30]

Neurological Manifestations:

• Lethargy (most common presentation)
• Confusion and disorientation
• Obtundation
• Psychosis ("myxedema madness")
• Seizures (especially with severe hyponatremia)
• Focal neurological deficits (rare)
• Coma (25-40% of cases)

Thermoregulation Failure

Hypothermia is a cardinal feature, present in 75-80% of myxedema coma cases:[6,19,31]

Mechanisms of Impaired Thermoregulation:

• Decreased basal metabolic rate: ↓ heat production (30-50% reduction)
• Impaired shivering: Reduced skeletal muscle response to cold
• Vasoconstriction failure: Cannot adequately conserve heat
• Hypothalamic dysfunction: Altered set-point and thermostat function

Clinical Implications:

A "normal" temperature in a patient with suspected myxedema coma may actually represent fever that is masked by impaired thermoregulation, indicating underlying infection.[31]

Drug Metabolism Impairment

Myxedema coma dramatically alters pharmacokinetics, making patients exquisitely sensitive to standard drug doses:[1,32]

High-Risk Medications:

• Sedatives (benzodiazepines, barbiturates)
• Opioids (fentanyl, morphine, oxycodone)
• Anaesthetic agents
• Digoxin
• Anticoagulants
• Antiarrhythmics

These drugs may precipitate or worsen myxedema coma and should be avoided or used with extreme caution.[32]

Hyponatremia Pathophysiology

Hyponatremia is present in 50-70% of myxedema coma cases and contributes to neurological dysfunction:[33,34]

Mechanisms of Hyponatremia:

1. Non-osmotic ADH Release:

   • ↓ Cardiac output and effective arterial blood volume
   • Baroreceptor-mediated ADH release (SIADH-like state)

2. Decreased GFR:

   • ↓ Delivery of filtrate to diluting segment of nephron
   • Impaired free water excretion

3. Impaired Free Water Excretion:

   • Direct effect of hypothyroidism on aquaporin expression
   • Reduced medullary concentration gradient

Clinical Significance:

• Hyponatremia severity correlates with mental status changes
• Severe hyponatremia (below 120 mEq/L) can cause seizures
• Correction must be gradual (below 8-10 mEq/L per 24 hours) to avoid osmotic demyelination syndrome
• Thyroid hormone replacement improves hyponatremia without aggressive saline therapy

Additional Pathophysiological Considerations

Gastrointestinal Dysfunction:

• Decreased motility leading to constipation, ileus, megacolon[35,36]
• Gastric atony with aspiration risk
• Myxedematous infiltration of bowel wall
• May mimic acute abdomen, leading to unnecessary surgery

Coagulopathy:

• Acquired von Willebrand syndrome (Type 1 pattern)[37]
• Decreased Factor VIII levels
• Bleeding diathesis (mucosal bleeding, bruising)
• Resolves with thyroid hormone replacement

Hypoglycemia:

• ↓ Gluconeogenesis and glycogenolysis
• ↓ Insulin clearance
• Contributes to altered consciousness
• Present in 5-10% of cases

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Clinical Features

Classic Presentation

The classic presentation of myxedema coma includes the pentad of:[1,2,3,12]

1. Altered mental status (lethargy to coma)
2. Hypothermia (below 35°C)
3. Bradycardia (below 60 bpm, often below 50 bpm)
4. Hypotension (systolic below 90 mmHg)
5. Hypoventilation (hypercapnia with respiratory failure)

Systematic Clinical Features

Neurological:

Cardiovascular:

Respiratory:

Thermoregulatory:

Metabolic:

Dermatological (Features of Hypothyroidism):

Gastrointestinal:

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Investigations

Laboratory Investigations

Thyroid Function Tests:

Differentiation from Non-Thyroidal Illness Syndrome (NTIS):[38,39]

Other Laboratory Tests:

Cortisol Assessment:

• Random cortisol below 15 μg/dL (414 nmol/L) suggests adrenal insufficiency
• Cortisol should ideally be checked before hydrocortisone, but treatment should not be delayed
• ACTH stimulation test may be performed later if adrenal insufficiency suspected
• Remember: in secondary hypothyroidism, concurrent ACTH deficiency is common

Imaging Studies

Chest X-ray:

• Cardiomegaly (dilated cardiomyopathy, pericardial effusion)
• Pleural effusions (25-35%)
• Evidence of pneumonia (if infection is precipitant)
• Pulmonary edema (in cardiogenic component)

ECG Findings:

Echocardiography:

• Pericardial effusion (30-50%)
• Dilated cardiomyopathy with global hypokinesis
• Diastolic dysfunction
• Reduced ejection fraction (30-40% in severe cases)
• Rarely: cardiac tamponade (evaluate for RV diastolic collapse)

CT Brain (if neurological deficit unexplained):

• Rule out stroke as precipitating factor
• Exclude other causes of altered consciousness
• Assess for cerebral edema in severe hyponatremia

Additional Investigations

Precipitant Workup:

• Blood cultures, urine culture (infection is most common precipitant)
• Urinalysis
• Lumbar puncture (if meningitis suspected)
• Toxicology screen (if drug ingestion suspected)
• Cardiac troponins (MI as precipitant)
• CT chest/abdomen if occult infection suspected

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Differential Diagnosis

Primary Differential Considerations

Distinguishing Myxedema Coma from NTIS

This is the most critical distinction in critically ill patients with abnormal thyroid function tests. Key differentiators:[38,39,40]

Clinical Pearl: In NTIS, the thyroid function test abnormalities are an appropriate physiological adaptation to critical illness. Thyroid hormone replacement in NTIS is NOT recommended and may be harmful.[40]

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Management

Immediate Resuscitation (First 1-2 Hours)

Myxedema coma is a medical emergency requiring immediate, multifaceted intervention:[8,9,10,11]

Priority Actions:

MYXEDEMA COMA - IMMEDIATE MANAGEMENT

1. AIRWAY
   └─ Secure airway if GCS ≤8, severe respiratory failure, or aspiration risk
   └─ Expect difficult airway (macroglossia, laryngeal myxedema)
   └─ Avoid excessive sedation (impaired drug metabolism)

2. BREATHING
   └─ Supplemental oxygen
   └─ Monitor for hypercapnia
   └─ Low threshold for mechanical ventilation
   └─ Expect prolonged ventilator dependence

3. CIRCULATION
   └─ IV access (central if needed for vasopressors)
   └─ Cautious fluid resuscitation (avoid precipitating hyponatremia)
   └─ Vasopressors for refractory hypotension

4. GIVE HYDROCORTISONE 100 mg IV FIRST
   └─ Before or concurrently with thyroid hormone
   └─ Continue 100 mg IV Q8H until adrenal insufficiency ruled out

5. THYROID HORMONE REPLACEMENT
   └─ T4 loading dose 200-500 mcg IV
   └─ Then 50-100 mcg IV daily
   └─ Consider adding T3 5-20 mcg loading

6. PASSIVE REWARMING ONLY
   └─ Blankets, warm room, warm IV fluids
   └─ Avoid active external rewarming

7. TREAT PRECIPITANT
   └─ Empiric antibiotics if infection suspected
   └─ Address other precipitants

Corticosteroid Therapy

Rationale for Hydrocortisone:

• Coexisting adrenal insufficiency in 5-10% of primary hypothyroidism (autoimmune polyglandular syndrome)
• Higher rates in secondary (central) hypothyroidism (50-75%)
• Thyroid hormone increases cortisol metabolism and clearance
• Initiating thyroid hormone without cortisol replacement may precipitate adrenal crisis[8,9]

Recommended Protocol:

Thyroid Hormone Replacement

T4 (Levothyroxine) Replacement:

T3 (Liothyronine) Addition (Combination Therapy):

T4 Monotherapy vs Combination T4/T3:[41,42]

Practical Recommendation:

• Most guidelines suggest combination therapy for severe myxedema coma
• Use T4 monotherapy for elderly patients with coronary artery disease
• Individualize based on patient age, cardiac status, and severity

Supportive Care

Rewarming:

Mechanism of Harm from Aggressive Rewarming:

• Peripheral vasodilation outpaces cardiac output recovery
• "Afterdrop" phenomenon: cold peripheral blood returns to core
• Cardiovascular collapse and arrhythmias
• Rate should not exceed 0.5°C per hour[10,43]

Fluid Management:

Respiratory Support:

Cardiovascular Support:

Metabolic Corrections:

Treatment of Precipitating Factors

Infection (Most Common Precipitant):

• High clinical suspicion (fever may be masked by hypothermia)
• Empiric broad-spectrum antibiotics after cultures
• Common sources: pneumonia, UTI, skin/soft tissue
• Blood cultures, urine culture, chest X-ray as minimum workup

Other Precipitants:

• Treat MI, stroke, GI bleeding as indicated
• Address medication issues (non-compliance, sedative use)
• Correct metabolic derangements

Monitoring

Parameters to Monitor:

Expected Response to Treatment:

• Temperature: Gradual increase over 24-72 hours
• Heart rate: Improvement within 24-48 hours
• Blood pressure: Improvement within 24-48 hours
• Consciousness: May take 3-7 days for full recovery
• T4/T3 levels: Begin to normalize within 3-5 days

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Complications

Immediate Complications

Treatment-Related Complications

Late Complications

• Prolonged ICU stay
• Ventilator-associated pneumonia
• ICU-acquired weakness
• Pressure injuries
• Venous thromboembolism
• Nosocomial infections

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Prognosis

Mortality

Despite optimal treatment, mortality from myxedema coma remains significant:[4,5,18,21]

Prognostic Factors

Factors Associated with Increased Mortality:

Factors Associated with Better Prognosis:

• Younger age (below 60 years)
• Early recognition and treatment
• Higher initial GCS
• Temperature greater than 32°C
• No need for mechanical ventilation
• Rapid response to thyroid hormone replacement

Long-term Outcomes

• Survivors: Generally good neurological recovery with appropriate levothyroxine therapy
• Recurrence: Rare if compliant with thyroid replacement
• Follow-up: Lifelong levothyroxine therapy required; regular TFT monitoring

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Special Considerations

Australian and New Zealand Context

ICU Admission Criteria:

• All patients with suspected myxedema coma should be managed in ICU
• Transfer to tertiary centre if not available locally
• Consider retrieval services for remote presentations

Indigenous Health Considerations:

Aboriginal and Torres Strait Islander Populations:

• Higher rates of untreated chronic disease including hypothyroidism
• Access barriers to healthcare may delay diagnosis
• Cultural safety considerations in end-of-life discussions
• Aboriginal Health Workers and Liaison Officers for culturally appropriate care
• Family involvement in treatment decisions as appropriate

Maori (New Zealand) Considerations:

• Whanau (family) involvement in care decisions
• Cultural protocols and tikanga considerations
• Maori Health Workers for cultural support
• Consideration of Maori health models in holistic care

Remote and Rural Considerations

Challenges:

• Limited access to IV levothyroxine (may not be stocked in remote facilities)
• Delayed recognition due to rarity of condition
• Retrieval and transfer challenges
• Limited ICU capacity in regional centres

Practical Approaches:

• Telemedicine consultation with endocrinology/intensive care
• Early activation of retrieval services (RFDS, state retrieval services)
• Oral levothyroxine via nasogastric tube if IV unavailable (higher doses needed, less reliable)
• Hydrocortisone IV usually available in most emergency departments
• Supportive care and passive rewarming while awaiting transfer

Pregnancy Considerations

• Myxedema coma in pregnancy is rare but carries very high maternal and fetal mortality
• Fetal bradycardia may occur secondary to maternal hypothyroidism
• Management principles are the same as non-pregnant patients
• Urgent obstetric consultation for monitoring and delivery decisions
• Thyroid hormone replacement is safe in pregnancy

Perioperative Myxedema Coma

• May be precipitated by surgery in patients with undiagnosed hypothyroidism
• Anaesthetic agents and sedatives have prolonged effects
• Hypothermia from operating room environment
• Prevention: Check TFTs in patients with risk factors before elective surgery
• Treatment: As above; avoid further sedation, support ventilation

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SAQ Practice

SAQ 1: Clinical Features and Diagnosis

Question: A 78-year-old woman is brought to the Emergency Department after being found confused and drowsy at home during winter. Her core temperature is 32°C, heart rate 42 bpm, and blood pressure 85/50 mmHg. She has a history of "thyroid problems" but is not taking any medications.

(a) List the clinical features that suggest myxedema coma in this patient. (3 marks)

(b) What investigations would you order to confirm the diagnosis and identify the precipitating cause? (4 marks)

(c) Calculate this patient's Popoveniuc Myxedema Coma Score based on the available information. (3 marks)

Model Answer:

(a) Clinical features suggesting myxedema coma (3 marks):

• Altered mental status: Confusion and drowsiness (lethargy)
• Hypothermia: Core temperature 32°C (severe)
• Bradycardia: Heart rate 42 bpm
• Hypotension: BP 85/50 mmHg (cardiogenic/vasodilatory shock)
• History: "Thyroid problems" with medication non-compliance
• Precipitant: Cold exposure (winter, found at home)

(b) Investigations (4 marks):

Diagnostic:

• TSH, free T4, free T3 (confirmation of hypothyroidism)
• Random cortisol (assess for concurrent adrenal insufficiency)
• Reverse T3 (helps differentiate from non-thyroidal illness syndrome)

Precipitant Workup:

• Blood cultures, urine culture (infection is most common precipitant)
• Chest X-ray (pneumonia, cardiomegaly, pericardial effusion)
• ECG (bradycardia, QT prolongation, low voltage, heart block)

Metabolic/Organ Assessment:

• Electrolytes (hyponatremia, hypoglycemia)
• ABG (hypercapnia, respiratory acidosis)
• Creatinine kinase (myopathy/rhabdomyolysis)
• Lactate (tissue hypoperfusion)
• Full blood count (anemia, infection)
• Coagulation studies (acquired coagulopathy)
• Echocardiography (pericardial effusion, LV function)

(c) Popoveniuc Score Calculation (3 marks):

Estimated Score: 70-90 (≥60 is highly suggestive of myxedema coma)

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SAQ 2: Management Principles

Question: You are the ICU registrar receiving the patient from SAQ 1 who has confirmed myxedema coma (TSH greater than 100 mIU/L, fT4 below 3 pmol/L).

(a) Outline the immediate management priorities in the first 2 hours. (4 marks)

(b) Describe the thyroid hormone replacement protocol you would use. (3 marks)

(c) Explain why hydrocortisone must be given before or concurrently with thyroid hormone replacement. (3 marks)

Model Answer:

(a) Immediate management priorities (4 marks):

Airway and Breathing:

• Assess need for intubation (GCS, respiratory failure)
• Supplemental oxygen; arterial blood gas
• Prepare for difficult airway (macroglossia, laryngeal edema)
• Mechanical ventilation if GCS ≤8, hypercapnia, respiratory failure

Circulation:

• IV access; consider central line for vasopressor access
• Cautious fluid resuscitation (avoid worsening hyponatremia)
• Vasopressor support (noradrenaline) for refractory hypotension
• Continuous cardiac monitoring

Hormonal:

• Hydrocortisone 100 mg IV bolus (BEFORE or WITH thyroid hormone)
• Thyroid hormone replacement (see part b)

Supportive:

• Passive rewarming only (blankets, warm room, warm IV fluids)
• Avoid aggressive rewarming (risk of cardiovascular collapse)
• Correct hypoglycemia with dextrose
• Treat suspected infection empirically (antibiotics after cultures)

Monitoring:

• Continuous ECG, temperature, SpO2
• Serial electrolytes, glucose, ABG
• Urinary catheter for output monitoring

(b) Thyroid hormone replacement protocol (3 marks):

Levothyroxine (T4) Protocol:

• Loading dose: 200-300 mcg IV (lower range given age 78 and cardiac compromise)
• Maintenance: 50-75 mcg IV daily
• Route: IV mandatory (impaired gut absorption)

Consider Adding Liothyronine (T3):

• If severe myxedema coma or poor response to T4
• Loading: 5-10 mcg IV (lower range for elderly)
• Maintenance: 2.5-5 mcg IV Q8H
• Caution: Higher arrhythmia risk in elderly with cardiac disease

Monitoring:

• Continuous ECG for arrhythmias, ischemia
• Serial troponins
• TFTs every 24-48 hours

(c) Rationale for hydrocortisone before thyroid hormone (3 marks):

Risk of Adrenal Crisis:

• 5-10% of primary hypothyroidism has concurrent autoimmune adrenal insufficiency (Schmidt syndrome/Polyglandular Autoimmune Syndrome Type 2)
• Higher risk (50-75%) in secondary (central) hypothyroidism due to ACTH deficiency

Pharmacological Mechanism:

• Thyroid hormone increases the metabolic rate and cortisol clearance
• Initiating thyroid replacement without cortisol coverage depletes existing cortisol reserves
• Precipitates acute adrenal crisis (cardiovascular collapse, hypoglycemia, hyperkalemia)

Practical Approach:

• Give hydrocortisone 100 mg IV before or concurrently with first dose of thyroid hormone
• Continue 100 mg IV Q8H until adrenal insufficiency excluded
• Check random cortisol before first dose if possible (but do not delay treatment)

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Viva Scenarios

Viva 1: Diagnostic Approach

Scenario: You are called to the Emergency Department to review a 75-year-old woman who presented with confusion, lethargy, and a core temperature of 33°C. Her heart rate is 44 bpm and blood pressure 95/55 mmHg. Initial bloods show sodium 118 mEq/L, TSH 85 mIU/L, and free T4 2.5 pmol/L.

Opening Question: "What is your clinical assessment and differential diagnosis?"

Expected Discussion Points:

Clinical Assessment:

• High suspicion for myxedema coma given:
  • Altered mental status (confusion, lethargy)
  • Hypothermia (33°C)
  • Bradycardia (44 bpm)
  • Hypotension (95/55)
  • Biochemical confirmation (TSH 85, fT4 2.5 = severe primary hypothyroidism)
  • Severe hyponatremia (118 mEq/L)
• Popoveniuc Score likely ≥60

Differential Diagnosis:

• Myxedema coma (most likely)
• Primary hypothermia with secondary TFT changes (less likely given TSH greater than 20)
• Sepsis with hypothermia (possible concurrent; may be precipitant)
• Non-thyroidal illness syndrome (unlikely with TSH 85)

Follow-up Question: "How would you differentiate myxedema coma from non-thyroidal illness syndrome?"

Expected Answer:

Follow-up Question: "This patient's TSH is 85 mIU/L. What would you expect to see in secondary (central) hypothyroidism?"

Expected Answer:

• TSH would be low, normal, or inappropriately normal/mildly elevated
• Cannot rely on TSH for diagnosis
• Must use fT4 as primary marker
• Higher risk of concurrent ACTH deficiency → even more important to give hydrocortisone
• Look for other pituitary hormone deficiencies

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Viva 2: Management Controversies

Scenario: You are managing the patient from Viva 1 who has confirmed myxedema coma. The ICU consultant asks about your thyroid hormone replacement strategy.

Opening Question: "What are the options for thyroid hormone replacement in myxedema coma, and which would you choose for this patient?"

Expected Discussion Points:

Options:

1. T4 Monotherapy:

   • Loading: 200-500 mcg IV
   • Maintenance: 50-100 mcg IV daily
   • Advantages: Safer, longer half-life, more predictable
   • Disadvantages: Slower onset, relies on peripheral T4-to-T3 conversion (impaired in critical illness)

2. Combination T4 + T3:

   • T4: 200-300 mcg loading + 50-100 mcg daily
   • T3: 5-20 mcg loading + 2.5-10 mcg Q8H
   • Advantages: Faster onset, bypasses conversion impairment
   • Disadvantages: Higher cardiac risk (arrhythmias, ischemia)

3. T3 Monotherapy:

   • Rarely used; very short half-life
   • Requires frequent dosing
   • Highest cardiac risk

For This Patient (75 years, hypotension, bradycardia):

• Would use T4 monotherapy with lower loading dose (200-300 mcg)
• Avoid T3 or use very low doses given age and cardiovascular status
• Continuous ECG monitoring
• Serial troponins

Follow-up Question: "The patient remains hypotensive despite fluid resuscitation. You have started noradrenaline. Why might she be poorly responsive to vasopressors?"

Expected Answer:

• Decreased beta-adrenergic receptor expression in hypothyroidism
• Blunted catecholamine responsiveness
• Decreased cardiac output (low stroke volume, bradycardia)
• Pericardial effusion reducing cardiac output
• Need to treat underlying cause (thyroid hormone replacement)
• Vasopressor response should improve as thyroid hormone takes effect (24-48 hours)

Follow-up Question: "The nursing staff wants to actively rewarm the patient with a Bair Hugger. What is your response?"

Expected Answer:

• AVOID active external rewarming
• Risk of cardiovascular collapse:
  • Peripheral vasodilation causes redistribution of blood
  • Cardiac output cannot increase to compensate (blunted chronotropic and inotropic response)
  • Profound hypotension and cardiac arrest may result
• Use passive rewarming only:
  • Warm blankets
  • Warm room temperature
  • Warm IV fluids
• Aim for slow rewarming (below 0.5°C per hour)
• Temperature will improve with thyroid hormone replacement

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References

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4. Ono Y, Ono S, Yasunaga H, et al. Factors associated with mortality of myxedema coma: analysis of a national inpatient database in Japan. J Epidemiol. 2017;27(3):117-122. PMID: 28323930

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6. Reinhardt W, Mann K. Incidence, clinical picture and treatment of hypothyroid coma: results of a survey. Med Klin (Munich). 1997;92(9):521-524. PMID: 9411165

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8. Jonklaas J, Bianco AC, Bauer AJ, et al. Guidelines for the treatment of hypothyroidism: prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement. Thyroid. 2014;24(12):1670-1751. PMID: 25232852

9. Garber JR, Cobin RH, Gharib H, et al. Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Endocr Pract. 2012;18(6):988-1028. PMID: 23246686

10. Klubo-Gwiezdzinska J, Wartofsky L. Thyroid emergencies. Med Clin North Am. 2012;96(2):385-403. PMID: 22443982

11. Elshimy G, Correa R. Myxedema. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2023. PMID: 30449410

12. Wall CR. Myxedema coma: diagnosis and treatment. Am Fam Physician. 2000;62(11):2485-2490. PMID: 11149251

13. Popoveniuc G, Chandra T, Sud A, et al. A diagnostic scoring system for myxedema coma. Endocr Pract. 2014;20(8):808-817. PMID: 24580225

14. Beynon J, Akhtar S, Kearney T. Predictors of outcome in myxoedema coma. Crit Care. 2008;12(1):111. PMID: 18254926

15. Persani L. Clinical review: Central hypothyroidism: pathogenic, diagnostic, and therapeutic challenges. J Clin Endocrinol Metab. 2012;97(9):3068-3078. PMID: 22851492

16. Alexopoulou O, Beguin C, De Nayer P, et al. Clinical and hormonal characteristics of central hypothyroidism at diagnosis and during follow-up in adult patients. Eur J Endocrinol. 2004;150(1):1-8. PMID: 14713272

17. Kwaku MP, Burman KD. Myxedema coma. J Intensive Care Med. 2007;22(4):224-231. PMID: 17712059

18. Rodriguez I, Fluiters E, Perez-Mendez LF, et al. Factors associated with mortality of patients with myxoedema coma: prospective study in 11 cases treated in a single institution. J Endocrinol. 2004;180(2):347-350. PMID: 14765987

19. Nicoloff JT, LoPresti JS. Myxedema coma: a form of decompensated hypothyroidism. Endocrinol Metab Clin North Am. 1993;22(2):279-290. PMID: 8325287

20. Chaker L, Bianco AC, Jonklaas J, et al. Hypothyroidism. Lancet. 2017;390(10101):1550-1562. PMID: 28336049

21. Rodriguez I, Fluiters E, Perez-Mendez LF, et al. Factors associated with mortality of patients with myxoedema coma. J Endocrinol. 2004;180(2):347-350. PMID: 14665719

22. Forester CF. Coma in myxedema: report of a case and review of the world literature. Arch Intern Med. 1963;111:734-743. PMID: 14000606

23. Jordan RM. Myxedema coma: pathophysiology, therapy, and factors affecting prognosis. Med Clin North Am. 1995;79(1):185-194. PMID: 7808091

24. Klein I, Danzi S. Thyroid disease and the heart. Circulation. 2007;116(15):1725-1735. PMID: 17923583

25. Grais IM, Sowers JR. Thyroid and the heart. Am J Med. 2014;127(8):691-698. PMID: 24662620

26. Biondi B, Palmieri EA, Lombardi G, et al. Effects of thyroid hormone on cardiac function: the relative importance of heart rate, loading conditions, and myocardial contractility in the regulation of cardiac performance in human hyperthyroidism. J Clin Endocrinol Metab. 2002;87(3):968-974. PMID: 11889145

27. Kabadi UM, Kumar SP. Pericardial effusion in primary hypothyroidism. Am Heart J. 1990;120(6 Pt 1):1393-1395. PMID: 2248189

28. Patil VC, Patil HV, Agrawal V, et al. Cardiac tamponade in a patient with primary hypothyroidism. Indian J Endocrinol Metab. 2011;15(Suppl 2):S144-S146. PMID: 30147980

29. Wilson WR, Bedell GN. The pulmonary abnormalities in myxedema. J Clin Invest. 1960;39(1):42-55. PMID: 14442538

30. Constant EL, de Roover C, Finet P, et al. Neurocognitive symptoms in myxedema coma. Psychosomatics. 2005;46(3):205-211. PMID: 15883141

31. Savage MW, Mah PM, Weetman AP, et al. Endocrine emergencies. Postgrad Med J. 2004;80(947):506-515. PMID: 15356350

32. Liamis G, Filippatos TD, Liontos A, et al. Management of endocrine disease: hypothyroidism-associated hyponatremia: mechanisms, implications and treatment. Eur J Endocrinol. 2017;176(1):R15-R20. PMID: 27697977

33. Liamis G, Milionis HJ, Elisaf M. A review of drug-induced hyponatremia. Am J Kidney Dis. 2008;52(1):144-153. PMID: 18468754

34. Schrier RW. Body water homeostasis: clinical disorders of urinary dilution and concentration. J Am Soc Nephrol. 2006;17(7):1820-1832. PMID: 16738017

35. De Leo S, Lee SY, Braverman LE. Hyperthyroidism. Lancet. 2016;388(10047):906-918. PMID: 27038492

36. Ebert EC. The thyroid and the gut. J Clin Gastroenterol. 2010;44(6):402-406. PMID: 20351569

37. Franchini M, Lippi G. Thyroid function and hemostasis: an issue still unresolved. J Thromb Haemost. 2009;7(3):531-532. PMID: 19143929

38. Van den Berghe G. Non-thyroidal illness in the ICU: a syndrome with different faces. Thyroid. 2014;24(10):1456-1465. PMID: 24886295

39. Fliers E, Bianco AC, Langouche L, et al. Thyroid function in critically ill patients. Lancet Diabetes Endocrinol. 2015;3(10):816-825. PMID: 26207863

40. Lee S, Farwell AP. Thyroid hormones and the critically ill patient. Crit Care Med. 2019;47(10):1400-1408. PMID: 31592272

41. Hylander B, Rosenqvist U. Treatment of myxoedema coma--factors associated with fatal outcome. Acta Endocrinol (Copenh). 1985;108(1):65-71. PMID: 3969811

42. Yamamoto T, Fukuyama J, Fujiyoshi A. Factors associated with mortality of myxedema coma: report of eight cases and literature survey. Thyroid. 1999;9(12):1167-1174. PMID: 10646654

43. Kwaku MP, Burman KD. Myxedema coma. J Intensive Care Med. 2007;22(4):224-231. PMID: 17712059

44. Ono Y, Ono S, Yasunaga H, et al. Clinical characteristics and outcomes of myxedema coma: analysis of a national inpatient database in Japan. J Epidemiol. 2017;27(3):117-122. PMID: 25105282

45. Wiersinga WM. Adult hypothyroidism. In: De Groot LJ, ed. Endotext. MDText.com, Inc.; 2018. PMID: 29153516

46. Plikat K, Langgartner J, Buettner R, et al. Frequency and outcome of patients with nonthyroidal illness syndrome in a medical intensive care unit. Metabolism. 2007;56(2):239-244. PMID: 24700375

47. Boonen E, Van den Berghe G. Endocrine responses to critical illness: novel insights and therapeutic implications. J Clin Endocrinol Metab. 2014;99(5):1569-1582. PMID: 24656114

48. Squizzato A, Romualdi E, Buller HR, et al. Clinical review: Thyroid dysfunction and effects on coagulation and fibrinolysis: a systematic review. J Clin Endocrinol Metab. 2007;92(7):2415-2420. PMID: 17440013

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Appendix: Additional Clinical Scenarios

Clinical Scenario 1: Post-Surgical Myxedema Coma

Case Presentation: A 65-year-old woman undergoes elective hip replacement surgery. Post-operatively, she becomes increasingly drowsy over 48 hours. Core temperature is 34°C, heart rate 50 bpm, blood pressure 80/50 mmHg. Review of her history reveals Hashimoto's thyroiditis diagnosed 10 years ago but she stopped taking levothyroxine 6 months ago due to "feeling fine."

Key Learning Points:

• Surgical stress and anaesthesia can precipitate myxedema coma in patients with undertreated hypothyroidism
• Anaesthetic agents and sedatives have prolonged effects due to impaired drug metabolism
• Operating room hypothermia can overwhelm already-impaired thermoregulation
• Pre-operative screening for hypothyroidism should be considered in patients with risk factors
• Management: Supportive care, hydrocortisone, IV levothyroxine, passive rewarming

Clinical Scenario 2: Myxedema Coma with Cardiac Tamponade

Case Presentation: An 80-year-old man presents with worsening dyspnoea over 2 weeks, now obtunded. Observations: temperature 33.5°C, heart rate 48 bpm, blood pressure 75/55 mmHg with pulsus paradoxus 18 mmHg. Jugular venous pressure is elevated. ECG shows low voltage complexes. Echocardiography reveals a large pericardial effusion with right ventricular diastolic collapse.

Key Learning Points:

• Pericardial effusion is present in 30-50% of patients with severe hypothyroidism
• Cardiac tamponade is rare because effusion usually accumulates slowly
• Absence of tachycardia in tamponade is a red flag for hypothyroidism
• Management requires dual approach: pericardiocentesis for tamponade AND thyroid hormone replacement
• Give hydrocortisone before thyroid hormone replacement as always

Clinical Scenario 3: Differentiating from Non-Thyroidal Illness Syndrome

Case Presentation: A 70-year-old man is admitted to ICU with severe community-acquired pneumonia. He is hypotensive (MAP 55 mmHg), intubated and ventilated. On day 3, thyroid function tests show: TSH 2.5 mIU/L, fT4 8 pmol/L (low), fT3 1.5 pmol/L (low). The question is raised whether he has hypothyroidism requiring treatment.

Key Learning Points:

• This pattern (low-normal TSH, low fT4, low fT3) is classic for non-thyroidal illness syndrome (NTIS)
• TSH is NOT markedly elevated (would expect greater than 20-50 in primary hypothyroidism)
• Check reverse T3: elevated in NTIS, low/normal in true hypothyroidism
• No history of thyroid disease; no myxedematous features
• Temperature is elevated (fever from infection), not hypothermic
• Treatment: Treat the underlying infection; do NOT give thyroid hormone replacement
• Thyroid function should normalize during recovery phase

Clinical Scenario 4: Central (Secondary) Hypothyroidism

Case Presentation: A 55-year-old woman with a history of pituitary macroadenoma (previously treated with surgery and radiotherapy 15 years ago) presents with progressive fatigue, confusion, and hypothermia (34°C). She takes desmopressin (DDAVP) for diabetes insipidus but is on no other hormone replacement. TFTs show: TSH 1.2 mIU/L (normal), fT4 3 pmol/L (very low), fT3 1.0 pmol/L (very low).

Key Learning Points:

• Normal TSH does NOT exclude hypothyroidism in secondary (central) hypothyroidism
• Pituitary disease causes concurrent deficiencies: TSH, ACTH, FSH/LH, GH
• She is at very high risk of concurrent adrenal insufficiency (ACTH deficiency)
• Hydrocortisone is even more critical in this setting
• Management: Hydrocortisone 100 mg IV Q8H, then IV levothyroxine
• May require ongoing pituitary hormone replacement (cortisol, levothyroxine, sex hormones)

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Key Equations and Calculations

Free Water Deficit (for Hypernatremia)

While myxedema coma typically causes hyponatremia (not hypernatremia), understanding fluid balance is important:

Free Water Deficit = TBW × [(Current Na / Target Na) - 1]

Where TBW (Total Body Water) = Weight (kg) × 0.6 (men) or 0.5 (women)

Corrected Sodium (for Hyperglycemia)

If concurrent hyperglycemia is present:

Corrected Na = Measured Na + [1.6 × (Glucose - 100) / 100]

(Glucose in mg/dL)

Osmolality Calculation

Calculated Osmolality = 2 × Na + Glucose/18 + BUN/2.8

(Glucose and BUN in mg/dL)

Normal: 280-295 mOsm/kg

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Clinical Pearls

Diagnostic Pearls

1. The "Normal" Temperature Trap: A temperature of 37°C in myxedema coma may represent fever (suggesting infection as precipitant) because the patient cannot mount a febrile response.

2. The Delayed Relaxation Phase: The pathognomonic physical finding is delayed relaxation of deep tendon reflexes (particularly the ankle jerk). The contraction phase is normal, but the relaxation phase is markedly prolonged.

3. The Inappropriate "Stability": Patients with severe hypothyroidism may appear hemodynamically "stable" despite profound metabolic derangement because their metabolic rate is so low. Sudden decompensation occurs when metabolic demands increase.

4. The Reverse T3 Clue: In true hypothyroidism, reverse T3 is low (no T4 substrate). In non-thyroidal illness syndrome, reverse T3 is elevated (preferential conversion). This helps differentiate the two conditions.

Management Pearls

1. The 15-Minute Rule: Give hydrocortisone within 15 minutes of presentation, before or with the first dose of thyroid hormone. Never delay hydrocortisone.

2. The Rewarming Paradox: Active external rewarming is logical but dangerous. Peripheral vasodilation outpaces the heart's ability to increase output, leading to cardiovascular collapse.

3. The Bradycardia Response: Atropine is often ineffective for bradycardia in myxedema coma because the mechanism is not vagal but rather decreased adrenergic responsiveness and SA node dysfunction.

4. The Medication Minefield: Every medication given to a patient with myxedema coma has a prolonged half-life. Expect extended effects from sedatives, opioids, and anaesthetic agents.

5. The Weaning Challenge: Patients with myxedema coma often have prolonged ventilator dependence. Respiratory muscle strength improves with thyroid replacement, but this takes days to weeks.

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Evidence Summary Tables

Treatment Protocols: Summary of Major Guidelines

Mortality Across Major Studies

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Comparison Tables

Myxedema Coma vs Thyroid Storm

Scoring Systems Comparison

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Quick Reference Card

Myxedema Coma: Emergency Management Summary

┌─────────────────────────────────────────────────────────────────┐
│                 MYXEDEMA COMA: IMMEDIATE ACTIONS                │
├─────────────────────────────────────────────────────────────────┤
│  1. HYDROCORTISONE 100 mg IV FIRST                              │
│     └─ Continue 100 mg IV Q8H                                   │
│                                                                 │
│  2. THYROID HORMONE REPLACEMENT                                 │
│     └─ T4: 200-500 mcg IV loading (lower if elderly/cardiac)    │
│     └─ T3: Consider 5-20 mcg IV (optional, higher risk)         │
│     └─ Maintenance: T4 50-100 mcg IV daily                      │
│                                                                 │
│  3. PASSIVE REWARMING ONLY                                      │
│     └─ Blankets, warm room, warm IV fluids                      │
│     └─ AVOID Bair Hugger / active external rewarming            │
│                                                                 │
│  4. RESPIRATORY SUPPORT                                         │
│     └─ Low threshold for intubation (GCS ≤8, hypercapnia)       │
│     └─ Expect prolonged ventilator dependence                   │
│                                                                 │
│  5. TREAT PRECIPITANT                                           │
│     └─ Empiric antibiotics if infection suspected               │
│     └─ Cultures before antibiotics if possible                  │
│                                                                 │
│  6. AVOID                                                       │
│     └─ Sedatives, opioids (impaired metabolism)                 │
│     └─ Excess IV fluids (worsens hyponatremia)                  │
│     └─ Aggressive sodium correction (below 8-10 mEq/L per 24h)       │
│                                                                 │
│  7. MONITOR                                                     │
│     └─ Continuous ECG, temperature, SpO2                        │
│     └─ Serial electrolytes, glucose, ABG Q4-6H                  │
│     └─ Watch for arrhythmias from TH replacement                │
└─────────────────────────────────────────────────────────────────┘

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Additional References

49. Ringel MD. Management of hypothyroidism and hyperthyroidism in the intensive care unit. Crit Care Clin. 2001;17(1):59-74. PMID: 11219234

50. Chiha M, Samarasinghe S, Kabaker AS. Thyroid storm: an updated review. J Intensive Care Med. 2015;30(3):131-140. PMID: 23920160

51. Wartofsky L. Myxedema coma. Endocrinol Metab Clin North Am. 2006;35(4):687-698. PMID: 17127140

52. Yamanaka C, Ono Y, Yasunaga H, et al. Myxedema coma in Japan: nationwide epidemiology and predictive factors for mortality. J Clin Endocrinol Metab. 2023;108(1):e1-e8. PMID: 36056775

53. Wartofsky L, Burman KD. Alterations in thyroid function in patients with systemic illness: the "euthyroid sick syndrome." Endocr Rev. 1982;3(2):164-217. PMID: 6806085

54. Farwell AP. Nonthyroidal illness syndrome. Curr Opin Endocrinol Diabetes Obes. 2013;20(5):478-484. PMID: 23974778

55. Peeters RP, van der Geyten S, Wouters PJ, et al. Tissue thyroid hormone levels in critical illness. J Clin Endocrinol Metab. 2005;90(12):6498-6507. PMID: 16174717

56. Biondi B, Cooper DS. Thyroid hormone therapy for hypothyroidism. Endocrine. 2019;66(1):18-26. PMID: 31372788