INTRODUCTION — Myxedema coma is defined as severe hypothyroidism leading to decreased mental status, hypothermia, and other symptoms related to slowing of function in multiple organs. It is a medical emergency with a high mortality rate. Fortunately, it is now a rare presentation of hypothyroidism, likely due to earlier diagnosis as a result of the widespread availability of thyroid-stimulating hormone (TSH) assays.
Early recognition and therapy of myxedema coma are essential. Treatment should be initiated on the basis of clinical suspicion without waiting for laboratory results. Important clues to the possible presence of myxedema coma in a poorly responsive patient are the presence of a thyroidectomy scar or a history of radioiodine therapy or hypothyroidism. A history obtained from family members often reveals antecedent symptoms of thyroid dysfunction followed by progressive lethargy, stupor, and coma.
The clinical presentation, diagnosis, and treatment of myxedema coma will be reviewed here. The diagnosis and treatment of hypothyroidism are reviewed separately.
●(See "Disorders that cause hypothyroidism".)
●(See "Clinical manifestations of hypothyroidism".)
●(See "Diagnosis of and screening for hypothyroidism in nonpregnant adults".)
●(See "Treatment of primary hypothyroidism in adults".)
EPIDEMIOLOGY AND RISK FACTORS — The demographics of patients who develop myxedema coma are those of hypothyroidism in general, with older women being most often affected [1].
Myxedema coma can occur as the culmination of severe, longstanding hypothyroidism or be precipitated by an acute event in a poorly controlled hypothyroid patient, such as infection, myocardial infarction, cold exposure, surgery [2], or the administration of sedative drugs, especially opioids. It can occur in patients who have any of the usual causes of hypothyroidism, particularly chronic autoimmune thyroiditis, because its insidious course may lead the diagnosis to be overlooked, compared with postsurgical or postablative hypothyroidism (see "Disorders that cause hypothyroidism"). Myxedema coma can occur in patients with central hypothyroidism, lithium-induced hypothyroidism [3,4], or checkpoint inhibitor (pembrolizumab)-induced hypothyroidism [5], and there are a dozen case reports of myxedema coma in patients taking amiodarone [6].
CLINICAL PRESENTATION — The hallmarks of myxedema coma are decreased mental status and hypothermia, but hypotension, bradycardia, hyponatremia, hypoglycemia, and hypoventilation are often present as well (table 1). Puffiness of the hands and face, a thickened nose, swollen lips, and an enlarged tongue may occur secondary to nonpitting edema with abnormal deposits of albumin and mucin in the skin and other tissues (myxedema).
The possibility of a precipitating infection or other acute illness should always be considered; it is important to appreciate, however, that the patient may not have a febrile response to infection.
Neurologic manifestations — Despite the name myxedema coma, patients frequently do not present in coma but do manifest lesser degrees of altered consciousness [7]. This usually takes the form of confusion with lethargy and obtundation. Alternatively, a more activated presentation may occur with prominent psychotic features, so-called myxedema madness [8,9]. Untreated, patients will progress to coma.
Focal or generalized seizures may occur, sometimes due to concomitant hyponatremia, and status epilepticus has been reported [10,11]. In the absence of seizures, electroencephalogram (EEG) findings are nonspecific with slowing and decreased amplitude, rarely with triphasic waves [12]. When cerebrospinal fluid is obtained (usually to rule out infection in a patient with fever and mental status changes), modest elevation of protein levels (<100 mg/dL) may be seen [12].
Hyponatremia — Hyponatremia is present in approximately one-half of patients with myxedema coma. It can be severe and may contribute to the decrease in mental status. Most, but not all, patients have an impairment in free water excretion due to inappropriate excess vasopressin secretion or impaired renal function [13]. In addition, some patients may have concomitant adrenal insufficiency. (See 'Laboratory evaluation' below and 'Glucocorticoids' below.)
The low serum sodium concentration is reversible after treatment of the hypothyroidism. (See "Causes of hypotonic hyponatremia in adults", section on 'Hypothyroidism'.)
Hypothermia — Hypothermia is present in many patients with myxedema coma (table 1). It is due to the decrease in thermogenesis that accompanies the decrease in metabolism.
The low body temperature may not be recognized initially, because many automatic thermometers do not register frankly hypothermic body temperatures. If a low temperature is found, the thermometer itself should be checked to avoid an incorrect measurement. The severity of the hypothermia is related to mortality in severe hypothyroidism; the lower the temperature, the more likely a patient is to die.
Hypoventilation — Hypoventilation with respiratory acidosis results primarily from central depression of ventilatory drive with decreased responsiveness to hypoxia and hypercapnia [14]. Other contributing factors include respiratory muscle weakness, mechanical obstruction by a large tongue, and sleep apnea. (See "Respiratory function in thyroid disease", section on 'Hypothyroidism'.)
Some patients require mechanical ventilation (see "Control of ventilation"). Airway management may be complicated by myxedematous infiltration of the pharynx [15]. Recovery from ventilatory depression may take as long as three to six months after treatment of hypothyroidism [7].
Hypoglycemia — Hypoglycemia may be caused by hypothyroidism alone or, more often, by concurrent adrenal insufficiency due to autoimmune adrenal disease or hypothalamic-pituitary disease. The presumed mechanism is decreased gluconeogenesis, but starvation and infection can contribute. (See "Clinical manifestations of adrenal insufficiency in adults".)
Cardiovascular abnormalities — Thyroid hormone plays a role in blood pressure homeostasis. Hypothyroid patients have diastolic hypertension, even though cardiac output is reduced, and a narrowed pulse pressure. Severe hypothyroidism is associated with bradycardia, decreased myocardial contractility, a low cardiac output, and sometimes hypotension [16]. Overt congestive heart failure is quite rare in the absence of preexisting cardiac disease. This is probably due to the lower tissue demands for oxygenation and cardiac output in hypothyroidism. (See "Cardiovascular effects of hypothyroidism".)
Pericardial effusion may be present. Its clinical manifestations include diminished heart sounds, low voltage on electrocardiogram (ECG), and a large cardiac silhouette on chest radiograph; however, ventricular function is rarely compromised. (See "Diagnosis and treatment of pericardial effusion", section on 'Clinical presentation'.)
All of the cardiac abnormalities are reversible with thyroid hormone therapy [17].
DIAGNOSIS — The diagnosis of myxedema coma is initially based upon the history, physical examination, and exclusion of other causes of coma (see "Stupor and coma in adults", section on 'Evaluation'). In patients in whom the diagnosis is suspected, thyroid function tests confirm the diagnosis.
When to suspect the diagnosis — The diagnosis of myxedema coma should be considered in any patient with coma or depressed mental status who also has hypothermia, hyponatremia, and/or hypercapnia [7]. Important clues to the possible presence of myxedema coma in a poorly responsive patient are the presence of a thyroidectomy scar or a history of radioiodine therapy or hypothyroidism. A history obtained from family members often reveals antecedent symptoms of thyroid dysfunction followed by progressive lethargy, stupor, and coma.
Laboratory evaluation — If the diagnosis of myxedema coma is suspected, a blood sample should be drawn prior to treatment for measurement of:
●TSH
●Free thyroxine (T4)
●Cortisol
The serum T4 concentration is usually very low. The serum TSH concentration may be high, indicating primary hypothyroidism, or it may be low, normal, or slightly high, indicating central hypothyroidism. Most patients with myxedema coma have primary hypothyroidism. (See "Diagnosis of and screening for hypothyroidism in nonpregnant adults", section on 'Diagnosis' and "Central hypothyroidism", section on 'Diagnosis'.)
Patients with central hypothyroidism may have associated hypopituitarism and secondary adrenal insufficiency. Furthermore, the pituitary corticotropin (ACTH) response to stress may be impaired in severe hypothyroidism [18]. In addition, patients with autoimmune-mediated primary hypothyroidism may have concomitant primary adrenal insufficiency. Ideally, cortisol should be measured before and after cosyntropin administration. (See "Diagnosis of adrenal insufficiency in adults".)
A diagnostic scoring system for myxedema coma has been proposed based on 21 patients diagnosed with myxedema coma [19]. The scoring system gives points for the degree of hypothermia; lethargy, obtundation, stupor, or coma; anorexia, reduced intestinal mobility, or paralytic ileus; the presence of a precipitating event; the degree of bradycardia, electrocardiogram (ECG) changes, pericardial or pleural effusions, cardiomegaly or hypertension; and hyponatremia, hypoglycemia, hypoxemia, hypercapnia, or reduced glomerular filtration rate (GFR). Although some clinicians may find this scoring system useful, it is limited by the small number of patients from which it was derived.
TREATMENT — If myxedema coma is suspected, treatment should be instituted without waiting for laboratory confirmation. Myxedema coma is an endocrine emergency that should be managed aggressively as the mortality rate remains high, even with treatment. (See 'Prognosis' below.)
Treatment consists of (table 2):
●Thyroid hormone
●Glucocorticoids (until the possibility of coexisting adrenal insufficiency has been excluded)
●Supportive measures
●Appropriate management of coexisting problems (eg, infection)
Thyroid hormone
Choice of therapy — For patients with myxedema coma, we suggest combined therapy with T4 (levothyroxine) and T3 (liothyronine) rather than T4 alone (table 2).
The optimal mode of thyroid hormone therapy in patients with myxedema coma is controversial, largely because the condition is so rare that there are no clinical trials comparing the efficacy of different treatment regimens. Whether patients with myxedema coma should be treated with T4, T3, or both is uncertain [7]. Some experts favor administration of T3, while others favor T4, preferring that T3 production be governed by the activity of 5'-deiodinase in the patient, while others prefer a combination of T4 and T3 [7,20-24].
We prefer to give both hormones because the biologic activity of T3 is greater and its onset of action is more rapid than T4. An additional consideration is that the conversion of T4 to T3 is impaired due to both hypothyroidism and any concurrent nonthyroidal illness. The decrease in T4 to T3 conversion may be a protective adaptation in the face of severe illness. Therefore, proper dosing of T3, avoiding high concentrations, is important.
Dosing — T4 and T3 should be given intravenously as a slow bolus, when available, because gastrointestinal absorption may be impaired [20,21].
●We typically administer an initial dose of 200 to 400 mcg T4 intravenously, followed by daily intravenous doses of 50 to 100 mcg until the patient can take T4 orally. The lower end of the dosing range is preferred in lighter and older patients and in those at risk for cardiac complications (myocardial infarction, arrhythmia). This regimen should raise the total serum T4 level by 2 to 4 mcg/dL.
●T3 is given intravenously at the same time; the initial dose is 5 to 20 mcg, followed by 2.5 to 10 mcg every eight hours, with lower doses chosen for older patients and those with coexisting cardiovascular disease. T3 is continued until there is clinical improvement and the patient is stable.
The optimal dose of thyroid hormone therapy in patients with myxedema coma is uncertain. Both very high (T4 >500 mcg, T3 ≥75 mcg) and very low doses seem less effective than intermediate doses [25]. Excessive replacement of T3 should be avoided. In one small study, high serum T3 levels during therapy were associated with mortality [26]. (See 'Potential risks' below.)
Monitoring — Serum T4 (or free T4) and T3 should be measured every one to two days to confirm that the therapy is working and that very high levels of T3 are avoided. Due to its pharmacokinetics, serum T3 levels may be above the reference range if measured within an hour after intravenous administration. Therefore, in patients receiving parenteral T3 therapy, serum T3 should be measured at least one hour after dosing [27,28].
Clinical and biochemical improvement are typically evident within a week. Serum TSH typically falls at a rate of approximately 50 percent per week in hypothyroid patients receiving a full replacement dose of thyroid hormone. Therefore, failure of the serum TSH to fall is an indication of inadequate therapy.
Once there is improvement (regained consciousness, improved mental status, improved pulmonary and cardiac function), the patient can be treated with oral T4 alone. The initial oral T4 dose should be determined based on body weight, age, coexistent cardiovascular disease, and the recent intravenous dose (note that only 75 to 80 percent of an oral dose is absorbed when converting from an intravenous to an oral dose under steady state conditions, but the intravenous dose given in the early treatment of myxedema coma is unlikely to reflect steady state conditions).
Chronic therapy of hypothyroidism is discussed elsewhere. (See "Treatment of primary hypothyroidism in adults" and "Central hypothyroidism", section on 'Treatment'.)
Potential risks — While increasing serum thyroid hormone concentrations rapidly carries some risk of precipitating myocardial infarction or atrial arrhythmias, this risk must be accepted because of the high mortality of untreated myxedema coma. In one randomized trial of 11 patients, those who received a 500 mcg loading dose of T4, followed by 100 mcg daily, had a lower mortality than those treated with 100 mcg daily without a loading dose (one of six died compared with three of five who did not receive the loading dose); however, the difference did not reach statistical significance [29].
If T3 is administered, it is important to avoid excessive replacement. In a retrospective study of 11 patients with myxedema coma, high serum T3 concentrations during treatment were correlated with mortality [26].
Glucocorticoids — Until the possibility of coexisting adrenal insufficiency has been excluded, the patient must be treated with glucocorticoids in stress doses (eg, hydrocortisone given intravenously, 100 mg every eight hours). (See "Diagnosis of adrenal insufficiency in adults" and "Treatment of adrenal insufficiency in adults".)
Patients with central hypothyroidism may have associated hypopituitarism and secondary adrenal insufficiency. In addition, patients with autoimmune-mediated primary hypothyroidism may have concomitant primary adrenal insufficiency. Also, pituitary corticotropin (ACTH) secretion may be blunted in severe hypothyroidism, resulting in subnormal cortisol response to stress [18]. (See "Diagnostic testing for hypopituitarism" and "Causes of primary adrenal insufficiency (Addison's disease)", section on 'Autoimmune adrenalitis'.)
Supportive measures — Supportive measures are extremely important in the treatment of patients with myxedema coma and, in the first day or so, may make the difference between survival and death. These measures include treatment in an intensive care unit, mechanical ventilation if necessary, judicious administration of intravenous fluids including electrolytes and glucose, correction of hypothermia, and treatment of any underlying infection. (See 'Clinical presentation' above.)
●Dilute fluids should be avoided in hyponatremic patients to prevent a further reduction in the plasma sodium concentration. (See "Overview of the treatment of hyponatremia in adults".)
●Hypotension, if present and not caused by volume depletion, will be corrected by thyroid hormone therapy over a period of hours to days. Severe hypotension that does not respond to fluids should be treated with a vasopressor drug until the T4 has had time to act. (See "Evaluation of and initial approach to the adult patient with undifferentiated hypotension and shock", section on 'Initial approach'.)
●Passive rewarming with a blanket is preferred for correction of hypothermia. Active rewarming carries a risk of vasodilatation and worsening hypotension. (See "Hypothermia in children: Management" and "Accidental hypothermia in adults", section on 'Management'.)
●As with any critically ill, comatose patient, empiric administration of antibiotics should be considered until appropriate cultures are proven negative.
PROGNOSIS — Myxedema coma is an endocrine emergency that should be managed aggressively as the mortality rate is high, ranging from 30 to 50 percent [1,26,30,31]. In a report of 149 Japanese patients with myxedema coma, the mortality rate was 30 percent [1]. Older age, cardiac complications, reduced consciousness, need for mechanical ventilation, persistent hypothermia, and sepsis were predictive of mortality [1,25,30]. Some patients have a complete recovery [11,32].
SUMMARY AND RECOMMENDATIONS
●Definition – Myxedema coma is defined as severe hypothyroidism leading to slowing of function in multiple organs. It is a medical emergency with a high mortality rate. Fortunately, it is now a rare presentation of hypothyroidism, likely due to earlier diagnosis, as a result of the widespread availability of thyroid-stimulating hormone (TSH) assays. (See 'Introduction' above.)
●Clinical presentation – The hallmarks of myxedema coma are decreased mental status and hypothermia, but hypotension, bradycardia, hyponatremia, hypoglycemia, and hypoventilation are often present as well (table 1). (See 'Clinical presentation' above.)
●Diagnosis – If the diagnosis of myxedema coma is suspected, a blood sample should be drawn for measurement of serum T4 (thyroxine), TSH, and cortisol (ideally before and after cosyntropin administration) before therapy with a glucocorticoid and thyroid hormone is initiated. The serum T4 concentration is usually very low. The serum TSH concentration may be high, indicating primary hypothyroidism, or it may be low, normal, or slightly high, indicating central hypothyroidism. (See 'Diagnosis' above and "Diagnosis of and screening for hypothyroidism in nonpregnant adults" and "Central hypothyroidism".)
●Treatment – Patients with myxedema coma should be treated aggressively (table 2) because the mortality rate approaches 40 percent. In circumstances where laboratory confirmation of hypothyroidism is delayed, treatment with thyroid hormone and glucocorticoids should be instituted without waiting for laboratory confirmation. (See 'Treatment' above.)
•Thyroid hormone – For patients with myxedema coma, we suggest combined therapy with T4 (levothyroxine) and T3 (liothyronine) rather than T4 alone (Grade 2C). We suggest an initial dose of 200 to 400 mcg T4 intravenously, followed by daily intravenous doses of 50 to 100 mcg until the patient can take T4 orally. T3 is given intravenously at the same time; the initial dose is 5 to 20 mcg, followed by 2.5 to 10 mcg every eight hours, depending upon the patient's age and coexisting cardiovascular disease. T3 is continued until there is clinical improvement and the patient is stable. (See 'Treatment' above.)
•Glucocorticoids – Until coexisting adrenal insufficiency can be excluded, the patient should be given high-dose glucocorticoid therapy (hydrocortisone 100 mg intravenously every eight hours for two days, then lower doses). (See 'Glucocorticoids' above.)
•Supportive measures – Supportive measures are extremely important, including mechanical ventilation, appropriate fluid replacement, and correction of hyponatremia and hypothermia. In addition, there is often an associated illness that must be treated, such as infection or gastrointestinal bleeding. (See 'Supportive measures' above.)
●Prognosis – Myxedema coma is associated with a high mortality rate (30 to 50 percent). Older age, cardiac complications, reduced consciousness, need for mechanical ventilation, persistent hypothermia, and sepsis are predictive of mortality. (See 'Prognosis' above.)
