Ciammaichella M. M., Galanti A., Rossi C.
Dirigenti Medici
U.O.C. Medicina Interna I per l’Urgenza
(Direttore: Dott. G. Cerqua)
A.C.O. S. Giovanni - Addolorata - Roma, Italia


myxedema coma



Myxedema coma is a life-threatening expression of hypothyroidism in its most severe form. It occurs most often during the winter months in elderly women with long-standing, undiagnosed, or undertreated hypothyroidism. It may be precipiated by infection or other stresses, and the diagnosis must be suspected based upon the clinical presentation. Treatment should be prompt and requires the administration of thyroid hormone in large doses. The mortality is greater than 50 percent in spite of optimum therapy.


Hypothyroidism is a chronic systemic disorder characterized by progressive slowing of all bodily functions because of thyroid hormone deficiency. The prevalence of hypothyroidism is about 1 percent in women and 0.1 percent in men. After age 60, the prevalence may be as high as 6 to 7 percent in women. Thyroid hormone is secreted in response to stimulation of the thyroid gland by thyroid-stimulating hormone (TSH) from the anterior pituitary gland. The TSH release is promoted by thyrotropin releasing hormone (TRH) from the hypothalamus. Therefore, thyroid failure may be primary, due to intrinsic failure of the thyroid gland, or secondary, due to disease or destruction of the hypothalamus or pituitary gland.
Primary Hypothyroidism
Primary thyroid failure is by far the most common cause, accounting for 95 percent of the cases of hypothyroidism. The most common cause of hypothyroidism in the adult is treatment of Graves’ disease by radioactive iodine or subtotal thyroidectomy. Postoperative hypothyroidism is usually evident within 12 to 15 months after surgery. The incidence of hypothyroidism following destruction of thyroid tissue with radioiodine increases progressively with time. The development of hypothyroidism as a consequence of surgical or radioiodine therapy may take years or decades. If hypothyroidism develops, these patients are committed to replacement thyroid hormone therapy for life.
Autoimmune thyroid disorders are the next most common cause of hypothyroidism. These include primary hypothyroidism and Hashimoto's thyroiditis. Primary hypothyroidism is thought to be the end result of an autoimmune destruction of the thyroid gland and produces thyroid failure because of glandular atrophy. Hashimoto's thyroiditis is the most common cause of goitrous hypothyroidism in areas with adequate iodine and may cause hypothyroidism because of defective hormone synthesis. There is clinical and immunologic overlap of these entities. Other causes of primary thyroid failure are rare and include iodine deficiency, antithyroid drugs such as lithium and phenylbutazone, spontaneous hypothyroidism from Graves’ disease, and congenital causes.
Secondary Hypothyroidism
Secondary thyroid failure accounts for 5 percent of the cases of hypothyroidism. Pituitary tumors, postpartum hemorrhage, or infiltrative disorders, such as sarcoidosis, may result in secondary thyroid failure. There are clinical and historical differences that distinguish primary thyroid insufficiency from pituitary failure. This differential diagnosis is difficult on clinical grounds and requires laboratory evaluation. In general, the TSH level is high in primary hypothyroidism and low or normal in secondary hypothyroidism. Disease of the hypothalamus may cause failure to secrete TRH and may result in thyroid failure. This condition has been termed tertiary hypothyroidism. A few hypothyroid patients have been identified who have presumed hypothalamic disease and respond to TRH administration by increasing TSH above baseline levels.

Clinical Presentation

All patients who develop myxedema are hypothyroid, but not all hypothyroid patients have myxedema. Hypothyroidism is a graded phenomenon with various signs and symptoms along the clinical spectrum. With moderate to severe hypothyroidism, a nonpitting, dry, waxy swelling of the skin and subcutaneous tissue may occur, resulting in a puffy face and extremities. The term myxedema refers to this particular presentation of hypothyroidism.
The signs and symptoms of mild hypothyroidism may be subtle and the diagnosis difficult. With advanced hypothyroidism, the patients present with characteristic features. Typically, they complain of fatigue, weakness, cold intolerance, constipation, and weight gain without an increase in appetite. Muscle cramps, decreased hearing, mental disturbances, and menstrual irregularities are additional symptoms. Cutaneous features noted on physical examination include dry, scaly, yellow skin, puffy eyes, thinning of the eyebrows, and scant body hair. The voice may be deep and coarse and the tongue thickened. Paresthesia, ataxia, and prolongation of the deep tendon reflexes are characteristic neurologic manifestations. Bell's palsy due to hypothyroidism has been reported. In advanced cases, delusions, hallucinations, and psychosis (myxedema madness) may occur. Abdominal distension and fecal impaction may be present. Cardiac findings include bradycardia, enlarged heart, and low voltage on ECG. Mild hypertension rather than hypotension is the rule. Hypertension in conjunction with hypercholesterolemia may contribute to coronary artery disease and angina pectoris. A surgical scar on the neck may be present, but a palpable goiter is uncommon.
Diagnosis of hypothyroidism in a patient with these signs and symptoms can be made essentially on clinical grounds. Abnormally low levels of thyroid hormones confirm the diagnosis. Serum TSH levels should also be measured, and elevated levels are virtually diagnostic of primary hypothyroidism. If the disease is not treated, death follows a progressive intensification of these signs and symptoms. The time from onset to death varies between 10 and 15 years. Appropriate therapy is l-thyroxine in an average maintenance dosage of 0.1 to 0.3 mg once daily. The dosage must be individualized and may be higher or lower. Other thyroid preparations are available and acceptable as replacement thyroid hormone therapy.


Myxedema coma is a rare complication of hypothyroidism. The incidence is greater in women than men, and approximately half the patients are between 60 and 70 years old. A patient with undiagnosed hypothyroidism may develop coma as the initial manifestation. More commonly, the disease progresses insidiously, and coma develops when the patient is subjected to stress.

Precipitating Factors

A precipitating factor can be found in most cases of myxedema coma. Exposure to a cold environment is a significant antecedent occurrence with pulmonary infection and heart failure the most frequent precipitating events. Other stresses reported to initiate coma include hemorrhage, cerebrovascular accident, hypoxia, hypercapnia, hyponatremia, hypoglycemia, and trauma.
Significantly, it has been observed that more than 50 percent of the patients whose cases were reported in the literature lapsed into coma after admission to the hospital. In this setting, the stress of diagnostic and therapeutic procedures, acquisition of nosocomial infections, and the administration of certain drugs have been implicated as causative factors. Hypothyroid patients metabolize drugs more slowly than normal persons, and narcotics, anesthetics, phenothiazines, and other tranquilizers or sedatives have been reported to induce coma. Disastrous results may occur in a patient with advanced hypothyroidism and myxedema madness whose psychosis is treated with phenothiazines. The ?-blocking drugs may cause myxedema coma by reducing thyroid hormone levels through peripheral conversion of thyroxine to triiodothyronine. Amiodarone-induced hypothyroidism leading to myxedema coma has been reported. Caution must be used when administering drugs, even in normal amounts, to hypothyroid patients. A final drug-related cause of myxedema coma is the failure to take necessary replacement thyroid hormone medication.

Clinical Presentation

The diagnosis of myxedema coma may easily be made in a patient who presents with the previously described general appearance and physical findings and with a history of previous thyroid hormone medication, radioactive iodine therapy, or subtotal thyroidectomy. Unfortunately, the diagnosis is not always that easy. A wide variety of clinical and laboratory abnormalities occur and may tend to occupy the physician's attention. Coma may be attributed to hypothermia, respiratory failure, and CO2 narcosis; electrolye imbalance and hyponatremia; hypoglycemia; congestive heart failure; stroke; drug overdose; and other causes. Indeed, any of these disorders may lead to or worsen coma in the hypothyroid patient, but unless the underlying thyroid failure is diagnosed and treated, therapeutic efforts are unsuccessful. The overall clinical picture must be correlated and the diagnosis of myxedema coma considered.


Hypothermia, unaccompanied by sweating or shivering, is typical of patients in myxedema coma and occurs in 80 percent of the cases. Approximately 15 percent have a temperature of 29.5?C (85?F) or less. A normal or elevated temperature suggests underlying infection. It is not coincidental that most patients develop myxedema coma during the winter, as normal thermogenesis is impaired in hypothyroidism.
This important diagnostic sign may be missed if a low-reading thermometer is not used or if the mercury in the thermometer is not shaken down. Hypothermia should be treated by gradual rewarming at room temperature. Too-rapid rewarming may cause peripheral vasodilation and circulatory collapse.

Respiratory Failure

Hypoventilation, hypercapnia, and hypoxia are common in patients with myxedema coma and may be the cause of death in many instances. Multiple factors have been implicated as causes of respiratory failure. Impaired respiratory mechanics due to dysfunction of the muscles of the respiratory system may lead to alveolar hypoventilation, hypercapnia, and hypoxia, and loss of responsiveness of the respiratory center to these stimuli. With thyroid hormone replacement hypoxic ventilatory drive is increased but hypercapnic ventilatory drive is not.
Additional factors that may further impair pulmonary function include obesity, congestive heart failure, pleural effusions, ascites, parenchymal lung involvement by myxedematous infiltrate, enlarged tongue, and changes in the airway, which may occur over its entire length. Airway obstruction due to myxedematous infiltration of the laryngeal mucosa has been reported. Patients should be evaluated by chest roentgenography and arterial blood gas levels, and require close monitoring. Drugs that may further depress respirations should be avoided. Mechanical ventilation may be required, and initial tracheostomy has been recommended because of the long recovery time for normal ventilatory function.


Water retention with hyponatremia and hypochloremia is another common finding in myxedema coma. Hyponatremia is dilutional, due to extracellular volume expansion and impaired ability to excrete a water load. Several mechanisms to account for the hyponatremia have been proposed. These range from deficiency of adrenal cortical hormones to decreased water delivery to the distal nephron to inappropriate secretion of antidiuretic hormone. Regardless of the etiology, hyponatremia is a potentially grave complication that can lead to water intoxication, brain edema, and death.
Conventional therapy is fluid restriction, but hypertonic saline is recommended if the serum sodium level is less than 115 mEq/L. A convincing case for a different therapeutic approach utilizing hypertonic saline, furosemide, and thyroid hormone has been presented. A review of the 24 hyponatremic-hypothyroid patients described in the literature since 1953 showed the serum sodium levels to range from 120 to 129 mEq/L in 8 patients and from 110 to 119 mEq/L in 10 patients, and to be less than 110 mEq/L in 6 others. All 6 patients treated with hypertonic saline survived, while 13 out of 18 who did not receive this treatment died. Intravenous furosemide induces negative water balance, while hypertonic saline replaces urinary sodium losses. Extreme caution must be used to avoid heart failure during the administration of hypertonic saline.

Cardiovascular System

The cardiovascular system is altered in structure and function with advanced hypothyroidism. Hypotension, cardiac enlargement detectable on x-ray films, and bradycardia are the most significant abnormalities to occur during myxedema coma. Thyroid hormones and sympathomimetic amines act synergistically to maintain left ventricular performance and vascular tone. Hypotension may result from a decreased synergistic effect due to thyroid hormone deficiency. Left ventricular dysfunction and hypotension are usually corrected by thyroid hormone replacement. Vasopressors do not work well in the absence of thyroid hormone and should be used, with caution, only in cases of severe hypotension unresponsive to other therapy. Ventricular arrhythmias may occur because of the synergistic actions of simultaneously administered thyroid hormone and vasopressors on a myxedematous myocardium.
Cardiomegaly is common, and is thought to be due to either pericardial effusion or underlying heart disease and not to ventricular dilation induced by hypothyroidism. The presence or absence of cardiomegaly on x-ray film is not a reliable indicator of a pericardial effusion, and echocardiography is the best way to identify a pericardial effusion. In spite of the frequency of pericardial effusions, cardiac tamponade in myxedema coma is rare because of the slow formation of the effusion and the ability of the pericardium to distend. Most pericardial effusions resolve with thyroid hormone replacement, but some may require pericardiocentesis or pericardial fenestration.
Sinus bradycardia is the most common electrocardiographic abnormality during myxedema coma. Other findings include low voltage, flattening or inversion of the T waves, and prolongation of the PR interval. In spite of impaired cardiac contractility, pericardial effusions, and conduction disturbances, congestive heart failure is unusual in myxedema coma and probably reflects underlying heart disease.

Nervous System

Coma is the terminal expression of neurologic dysfunction in myxedema and may be directly due to a lack of thyroid hormone in the brain. A variety of neurologic symptoms premonitory of myxedema coma do occur. Psychiatric disorders include slowed mentation, memory loss, personality changes, hallucinations, delusions, and psychosis. Cerebellar ataxia, intention tremor, nystagmus, and difficulty with coordinated movements may occur. Twenty-five percent of those who develop myxedema coma initially present with grand mal seizure. Many of the neuropsychiatric abnormalities improve with thyroid hormone replacement, but permanent dementia may remain after treatment. The role of hypothermia, CO2 narcosis, cerebral edema, and other metabolic disturbances in the genesis of coma must not be overlooked.

Gastrointestinal System

Patients with myxedema may have abdominal distension due to ascites, paralytic ileus, or fecal impaction. Acquired megacolon is almost uniformly observed and has been the cause of unnecessary abdominal surgery. Urinary retention may occur, causing lower abdominal discomfort from a distended bladder. The weight gain that occurs with hypothyroidism is due to accumulation of some adipose tissue and retention of fluid. Patients with myxedema coma may be emaciated because of long-standing illness and decreased food intake. The treatment of abdominal complications consists of thyroid replacement and conservative measures such as nasogastric aspiration and enemas.


Although some laboratory findings are characteristic of myxedema coma, only thyroid function tests can confirm hypothyroidism. The combination of free T4 assay and a sensitive TSH assay are the primary means of assessing thyroid status in all patients. The patient with hypothyroidism has a low free T4. TSH is elevated in primary hypothyroidism, whereas when pituitary or hypothalamic disease is the cause of hypothyroidism, TSH is low. The results of these tests will not be available for use in the emergent situation but can later be used to support the clinical impression.
Characteristic laboratory abnormalities of myxedema coma already mentioned include hypoxemia, hypercapnia, hyponatremia, and hypochloremia. Serum potassium levels are extremely variable. Blood glucose levels are generally in the normal range, but severe hypoglycemia can occur. Hypercalcemia is rare, but hypocalcemia can occur in thyroidectomized patients in whom the parathyroids have been removed.
Bacterial infection may be reflected only by a leftward shift in the differential white blood cell count without appreciable elevation of the total white cell count.
Elevated serum cholesterol levels occur in approximately two-thirds of myxedematous patients. Malnutrition may lower the serum cholesterol level in some cases. Carotenemia has also been reported and may be the cause of the yellowish skin discoloration. Occasionally, striking elevations of the levels of muscle enzymes such as creatine kinase (CPK), serum glutamic-oxaloacetic transaminase (SGOT), lactate dehydrogenase (LDH), and fructose-biphosphate aldolase may be present. The elevations are thought to be due to changes in membrane permeability in skeletal muscle rather than to muscle destruction. The concentrations of these enzymes fall quickly when thyroid hormone is replaced. Finally, in most hypothyroid patients the CSF protein level is elevated to 100 mg/dL or more. The CSF pressure may occasionally be increased to over 400 mmH2O. The significance of these CSF abnormalities remains obscure.


Patients with myxedema coma are critically ill with a multiplicity of precarious and complex management problems. Specific therapy requires the administration of large doses of thyroid hormone. This decision must be based upon clinical judgment and made with extreme caution. The recommended dose of thyroid hormone could be fatal to the euthyroid comatose patient and harmful to the patient with ordinary myxedema. Every attempt to rule out causes of coma unrelated to hypothyroidism must be made first.

Supportive Therapy

Coma in myxedema may be primary, from a cerebral lack of thyroid hormone, or secondary, due to complications or precipitating causes. Treatment of the secondary causes of coma already mentioned includes oxygen administration and ventilatory support for respiratory failure, avoidance of drugs that may further depress respiratory or metabolic function, gradual rewarming of hypothermic patients, correction of hyponatremia by fluid restriction or hypertonic saline and furosemide, correction of hypoglycemia by glucose infusion, and treatment of hypotension with thyroid hormone and vasopressors, as needed. A thorough search for precipitating causes of coma should be made. Antibiotics are indicated for underlying infection. Additional adjunctive therapy is hydrocortisone, 300 mg/day, to protect against adrenal insufficiency.

Thyroid Hormome

Thyroid hormone replacement is the most critical and specific aspect of therapy for myxedema coma. The treatment already mentioned is largely supportive and is not fully effective until adequate thyroid hormone is given. Disagreement exists over the type, doses, and route of thyroid hormone administration.
Intravenous thyroxine is the drug of choice of most authors. It has been shown to be fully effective within 24 h with an onset of action in 6 h. The initial intravenous dose is 400 to 500 ?g infused slowly; this is followed by 50 to 100 ?g IV daily. Following the initial dose, some authors recommend no further thyroxine therapy until 3 to 7 days later. Once-daily therapy allows a smooth rise in hormone levels, as the turnover rate for l-thyroxine is about 10 percent per day. An oral dosage of thyroxine, 100 to 200 ?g/day, can be started when possible. Cardiac arrest following the intravenous administration of l-thyroxine has been reported. The dose of thyroxine should be reduced in the face of cardiac ischemia or arrhythmias.
Triiodothyronine is an effective drug for treatment of myxedema coma. Triiodothyronine is four times more pharmacologically active than thyroxine. It has previously been available only in tablet form but intravenous L-triiodothyronine is now available. An initial IV dose of 25 to 50 ?g is recommended for the emergent treatment of myxedema coma or precoma in adults. The dose should be lowered to 10 to 20 ?g is patients with known or suspected cardiovascular disease. Subsequent dosage is 65 to 100 ?g per 24 h in 3 to 4 divided doses and half of this amount in patients with cardiovascular disease. There is no difference in the contraindications or drug interactions between IV T3 or T4. With either replacement medication, overall clinical improvement should be seen in 24 to 36 h.

1)Holvey, DN, Goodner CJ, Nicoloff JT, et al: Treatment of myxedema coma with intravenous thyroxine. Arch Intern Med 113:89, 1964.
2)Ladenson PW, Goldenheim PD, Ridgway C: Rapid pituitary and peripheral tissue responses to intravenous l-triiodothyronine in hypothyroidism. J Clin Endocrinol Metab 56:1252, 1983.
3)Mitchell JM: Thyroid disease in the emergency department: Thyroid function tests and hypothyroidism and myxedema coma. Emerg Med Clin North Am 7:885, 1989.