Myxedema coma is the extreme expression of severe hypothyroidism and fortunately is rare, with an incidence rate of 0.22 per million per year.¹ The most common presentation of the syndrome is in hospitalized elderly women with long-standing hypothyroidism, with 80% of cases occurring in women older than 60 years. However, myxedema coma occurs in younger patients as well, with 36 documented cases of pregnant women.^2,3

The syndrome will typically present in patients who develop a systemic illness such as pulmonary or urinary infections, congestive heart failure, or cerebrovascular accident (Table 1), superimposed on previously undiagnosed hypothyroidism. Sometimes a history of antecedent thyroid disease, thyroidectomy, treatment with radioactive iodine, or T4 replacement therapy discontinued for no apparent reason can be elicited. A pituitary or hypothalamic basis for hypothyroidism is encountered in about 5% or, according to some studies, in up to 10% to 15% of patients.⁴

Patients with myxedema coma generally present in the winter months, suggesting that external cold may be an aggravating factor.⁵ Some abnormalities such as hypoglycemia, hypercalcemia, hyponatremia, hypercapnia, and hypoxemia, may be either precipitating factors or secondary consequences of myxedema coma. Moreover, the comatose state is associated with the risk of aspiration pneumonia and sepsis. In hospitalized patients, drugs such as anesthetics, narcotics, sedatives, antidepressants, and tranquilizers may depress respiratory drive and thereby either cause or compound the deterioration of the hypothyroid patient into coma.^6,7 The effect of these drugs should be taken into consideration as a potential causative mechanism. In fact, Church and Callen⁸ described a 41-year-old male patient without any history of thyroid disease who developed myxedema coma after being administered combined therapy with aripiprazole and sertraline.

There is also a report of myxedema coma induced by chronic ingestion of large amounts of raw bok choy. This Chinese white cabbage contains glucosinolates, which break down products such as thiocyanates, nitriles, and oxazolidines, and inhibit iodine uptake and production of thyroid hormones by the thyroid gland. When eaten raw, digestion of the vegetable releases the enzyme myrosinase, which accelerates production of the aforementioned thyroid disruptors.⁹

Hypothermia (often profound to 80°F [26.7°C]) and unconsciousness constitute 2 of the cardinal features of myxedema coma.¹⁰ Of importance is that coincident infection may be masked by hypothyroidism, with a patient presenting as afebrile despite an underlying severe infection. In view of the latter and the fact that undiagnosed infection might lead inexorably to vascular collapse and death, some authorities have advocated the routine use of antibiotics in patients with myxedema coma. Underlying hypoglycemia may further compound the decrement in body temperature.

Although coma is the predominant clinical presentation, a history of disorientation, depression, paranoia, or hallucinations (myxedema madness) may often be elicited. The neurologic findings may also include cerebellar signs (poorly coordinated purposeful movements of the hands and feet, ataxia, adiadochokinesia), poor memory and recall, or even frank amnesia, and abnormal findings on electroencephalography (low amplitude and a decreased rate of α-wave activity). Status epilepticus has been also described¹¹ and up to 25% of patients may experience seizures possibly related to hyponatremia, hypoglycemia, or hypoxemia.

The mechanism for hypoventilation in profound myxedema is a combination of a depressed hypoxic respiratory drive and a depressed ventilatory response to hypercapnia.^12,13 Partial obstruction of the upper airway caused by edema of the tongue or vocal cords may also play a role. Hypothyroid patients may be predisposed to increased airway hyperresponsiveness and chronic inflammation.¹⁴ Tidal volume may be additionally reduced by other factors such as pleural effusion or ascites. to achieve appropriately effective pulmonary function in myxedema coma, prolonged mechanically assisted ventilation is usually required.

Patients diagnosed with myxedema coma are at increased risk for shock and potentially fatal arrhythmias. Typical electrocardiographic (ECG) findings include bradycardia, varying degrees of block, low voltage, flattened or inverted T waves, and prolonged Q-T interval, which can result in torsades de pointes ventricular tachycardia.¹⁵ Myocardial infarction should also be ruled out by the usual diagnostic procedures, because aggressive or injudicious T4 replacement may increase the risk of myocardial infarction. Moreover, cardiac contractility is impaired, leading to reduced stroke volume and cardiac output. Reduced stroke volume in severe cases may also be due to the cardiac tamponade caused by the accumulation of fluid rich in mucopolysaccharides within the pericardial sac.

Hyponatremia is a common finding observed in patients with myxedema coma. The mechanism accounting for the hyponatremia is associated with increased serum anti-diuretic hormone¹⁶ and impaired water diuresis caused by reduced delivery of water to the distal nephron.¹⁷ Depending on its duration and severity, hyponatremia will add to altered mental status, and when severe may be largely responsible for precipitating the comatose state. Alterations in renal function observed in myxedema coma include decreases in glomerular filtration rate and renal plasma flow, and increases in total body water. Atony of the urinary bladder with retention of large residual urine volumes is commonly seen. Renal failure may occur as a result of underlying rhabdomyolysis with extremely high levels of creatine kinase.^18–21

The gastrointestinal tract in myxedema may be marked by mucopolysaccharide infiltration and edema of the muscularis, as well as neuropathic changes leading to gastric atony, impaired peristalsis, and even paralytic ileus. Ascites may occur, and has been documented in one report of 51 cases.²² Another potential complication is gastrointestinal bleeding secondary to an associated coagulopathy.²³ It is important to recognize the underlying mechanisms of these acute gastrointestinal complications so as to avoid unnecessary surgery for an apparent acute abdomen.²⁴

In contrast to the tendency to thrombosis seen in mild hypothyroidism, severe hypothyroidism is associated with a higher risk of bleeding caused by coagulopathy related to an acquired von Willebrand syndrome (type 1) and decreases in factors V, VII, VIII, IX, and X.²⁵ The von Willebrand syndrome is reversible with T4 therapy.²⁶ Another cause of bleeding may be disseminated intravascular coagulation associated with sepsis. Patients with myxedema coma have increased preponderance to severe infections, including sepsis, because of granulocytopenia and a decreased cell-mediated immunologic response. Such patients may also present with a microcytic anemia secondary to hemorrhage, or a macrocytic anemia caused by vitamin B₁₂ deficiency, which may also worsen the neurologic state.

To summarize the aforementioned clinical manifestations, the typical patient presenting with myxedema coma is a woman in the later decades of life who may have a history of thyroid disease and who is admitted to hospital, typically in winter, with pneumonia. Physical findings could include bradycardia, macroglossia, hoarseness, delayed reflexes, dry skin, general cachexia, hypoventilation, and hypothermia, commonly without shivering. Laboratory evaluation may indicate hypoxemia, hypercapnia, anemia, hyponatremia, hypercholesterolemia, and increased serum lactate dehydrogenase and creatine kinase. On lumbar puncture there is increased pressure and the cerebrospinal fluid has high protein content.

Although an elevated serum thyrotropin (TSH) concentration is the most important laboratory evidence for the diagnosis, the presence of severe complicating systemic illness or treatment with drugs such as dopamine, dobutamine, or corticosteroids may serve to reduce the elevation in TSH levels.^27,28 There may also be a pituitary cause for the hypothyroidism, in which case an increased TSH would not be found.

Myxedema coma as a true medical emergency requires a multifaceted approach to treatment in a critical care setting.

Even with this vigorous therapy, the prognosis for myxedema coma remains grim, and patients with severe hypothermia and hypotension seem to do the worst. In the past the mortality rate was as high as 60% to 70%, but this has now been reduced to 20%–25% with the advances in intensive care management.⁴⁴ Several prognostic factors may be associated with a fatal outcome,^1,5,32,35,45 and include older age, persistent hypothermia or bradycardia, lower degree of consciousness by Glasgow Coma Scale, multiorgan impairment indicated by an APACHE II score (Acute Physiology and Chronic Health Evaluation) of more than 20, or SOFA score (Sequential Organ Failure Assessment) of more than 6. The most common causes of death are respiratory failure, sepsis, and gastrointestinal bleeding. Early diagnosis and prompt treatment, with meticulous attention to the details of management during the first 48 hours, remain critical for effective therapy.

An accurate estimation of the incidence of thyroid storm is impossible to determine because of the considerable variability in the criteria for its diagnosis. The syndrome does appear to be less common today than in the past, perhaps because of earlier diagnosis and treatment of thyrotoxicosis, thereby precluding its progression to the stage of crisis. Nevertheless, it may occur in 1% to 2% of hospital admissions for thyrotoxicosis.⁴⁸ Thyrotoxic storm is rarely seen after thyroid surgery, because of the routine preparation of patients for elective thyroidectomy by treatment with antithyroid drugs. However, several types of nonthyroidal surgeries or other traumas have precipitated surgical thyrotoxic storm in patients with previously undiagnosed thyrotoxicosis. The crisis may be related to perioperative events, such as anesthesia, stress, and volume depletion, because these conditions are associated with increases in the concentration of free thyroid hormone. Thyroid storm has been seen in pregnancy, during labor, and in complicated deliveries such as those with placenta previa.⁴⁹ An acute discharge of hormones in the appropriate clinical setting may trigger a crisis, and cases have been reported following vigorous palpation of the thyroid, radioactive iodine therapy,⁵⁰ withdrawal of propylthiouracil therapy, or after administration of lithium, stable iodine, or iodinated contrast dyes. The other conditions known to be associated with increased free fraction of T4 and T3 include stress, infections, burns, cytotoxic chemotherapy for acute leukemia, aspirin overdose, ketoacidosis, or organophosphate intoxication (see Table 1).^45,51–55 Amiodarone, an antiarrhythmic and antianginal drug that is also rich in iodine, may cause either an iodine-induced thyrotoxicosis (type 1) or a destructive thyroiditis (type 2); the latter has been reported as a cause of thyroid storm refractory to the usual treatment.⁵⁶ There is also a case report of thyrotoxic storm precipitated by food poisoning with marine neurotoxin after ingestion of seafood.⁵⁷ Notwithstanding the multiplicity of precipitating factors, in hospitalized patients the most common event associated with thyrotoxic storm is some type of infection.

The clinical diagnosis is based on the identification of signs and symptoms that suggest decompensation of several organ systems. Some of these cardinal manifestations include fever out of proportion to an apparent infection and dramatic diaphoresis. Hyperthermia in thyroid crisis can represent defective thermoregulation by the hypothalamus and/or increased basal metabolic rate, increased oxidation of lipids being responsible for more than 60% of the resting energy expenditure.⁵⁸ The other key components of thyrotoxic storm include tachycardia out of proportion to the fever, and gastrointestinal dysfunction, which can include nausea, vomiting, diarrhea and, in severe cases, jaundice. As the storm progresses, symptoms of central nervous system dysfunction simulating an encephalopathic picture will appear, which may include increasing agitation and emotional lability, confusion, paranoia, psychosis, and coma.⁵⁹ Patients have been reported who presented with thyroid storm associated with status epilepticus and stroke and with bilateral basal ganglia infarction.⁶⁰ In patients with neurologic symptoms, a high index of suspicion for cerebral sinus thrombosis should be considered, because of the higher prevalence of this condition in severe hyperthyroidism.⁶¹ Paralysis observed in thyroid crisis might be due to not only the cerebrovascular accident but also thyrotoxic periodic paralysis with hypokalemia, as frequently may present in Asian men.⁶² In older patients, the thyrotoxic storm may present as so-called masked or apathetic thyrotoxicosis.⁶³

The most common cardiovascular manifestations are rhythm disturbances such as sinus tachycardia, atrial fibrillation, or other supraventricular tachyarrhythmias, and rarely, ventricular tachyarrhythmias, which can be observed even in patients without previous heart disease.⁶⁴ Congestive heart failure or a reversible dilated cardiomyopathy⁶⁵ also may be present even in young or middle-aged patients without known antecedent cardiac disease. A high-output state is present, attributable to the increased preload secondary to activation of the renin-angiotensin-aldosterone axis and to decreased afterload secondary to a direct relaxing effect of thyroid hormones on vascular muscle cells. Therefore, most patients present with systolic hypertension with widened pulse pressure. The hyperthyroid heart is characterized by higher than usual oxygen demands and hence myocardial infarction can be observed, even in young patients.^66,67 A relatively rare complication of severe hyperthyroidism is pulmonary hypertension, which is presumed to be on an autoimmune basis when associated with Graves disease, but which also may be secondary to an augmented blood volume, cardiac output, and sympathetic tone, leading to pulmonary vasoconstriction and increased pulmonary arterial pressure. This condition is usually reversible after treatment with antithyroid drugs. The other possible reason for pulmonary hypertension is pulmonary embolism caused by the thrombotic or hypercoagulable state that has been observed in severe hyperthyroidism.

The main pulmonary symptom is dyspnea and tachypnea related to an increased oxygen demand. The excessive work of the respiratory muscles may eventually lead to diaphragmatic dysfunction.⁶⁸ Respiratory failure may result from the hyperdynamic cardiomyopathy but also from preexistent underlying pulmonary disease.^69,70

The most common symptoms are diarrhea and vomiting, which can aggravate volume depletion, postural hypotension, and shock with vascular collapse. The diffuse abdominal pain, possibly caused by impaired neurohormonal regulation of gastric myoelectrical activity with delayed gastric emptying,⁷¹ may even lead to a presentation such as acute abdomen⁷² or intestinal obstruction.⁷³ The liver function abnormalities and presence of jaundice warrant immediate and vigorous therapy. Although most presentations of an acute abdomen in thyrotoxicosis are medical in nature, surgical conditions may also occur.⁷⁴

Increased serum calcium levels, caused by both hemoconcentration and known effects of thyroid hormone on bone resorption, may be seen. The sodium, potassium, and chloride levels are usually normal. Because of the augmented lipolysis and ketogenesis, and the basal metabolic demands that exceed oxygen delivery, ketoacidosis and lactic acidosis are observed.

Hyperthyroidism is often associated with an accelerated glomerular filtration rate, which may progress to glomerulosclerosis and excessive proteinuria. There are case reports of renal failure caused by rhabdomyolysis,⁷⁵ urinary retention associated with dyssynergy of the detrusor muscle and bladder dysfunction,⁷⁶ and an autoimmune complex–mediated nephritis concomitant with Graves disease.⁷⁷

A moderate leukocytosis with a mild shift to the left is a common finding, even in the absence of infection. Hyperthyroidism may be associated with hypercoagulability caused by increased concentrations of fibrinogen, factors VIII and IX, tissue plasminogen activator inhibitor 1, von Willebrand factor, increase in red blood cell mass secondary to erythropoietin upregulation, and a tendency to augmented platelet plug formation.⁷⁸ Major thromboembolic complications are responsible for 18% of deaths caused by thyrotoxicosis.^79–83

Diagnosis can be established predominantly on the basis of clinical presentation, because the laboratory findings may not be much different than those observed in uncomplicated hyperthyroidism. Indeed, serum total T3 levels may be even within normal limits, as these patients may have some underlying precipitating illness that reduces T4 to T3 conversion as is seen in the euthyroid sick syndrome.⁸⁴ Therefore, a semiquantitative scale (Table 2) assessing the presence and severity of the most common signs and symptoms has been developed to aid in the diagnosis.⁸⁵

Other laboratory abnormalities may include a modest hyperglycemia in the absence of diabetes mellitus, probably as a result of augmented glycogenolysis and catecholamine-mediated inhibition of insulin release, as well as increased insulin clearance and insulin resistance. When thyrotoxicosis is prolonged, leading to the depletion of glycogen deposits, hypoglycemia may occur, particularly in older people when aggravated by malnutrition secondary to emesis or abdominal pain.⁸⁶ Hepatic dysfunction in thyroid storm results in elevated levels of serum lactate dehydrogenase, aspartate aminotransferase, and bilirubin. Increased levels of serum alkaline phosphatase are also observed, predominantly because of increased osteoblastic bone activity in response to the augmentation of bone resorption.

Of importance, adrenal reserve may be exceeded in thyrotoxic crisis because of the inability of the adrenal gland to meet the metabolic demands and accelerated turnover of glucocorticoids. Moreover, there is known coincidence of adrenal insufficiency with Graves disease. This diagnosis should be considered when there is hypotension and suggestive electrolyte abnormalities.

To avoid a disastrous outcome, a complex approach to management is recommended.⁸⁷ First, specific antithyroid drugs must be used to reduce the increased thyroid production and release of T4 and T3. The second approach comprises treatment intended to block the effects of the remaining but excessive circulating concentrations of free T4 and T3 in blood. The third arm involves treatment of any systemic decompensation, for example, congestive heart failure, and shock. The final component addresses any underlying precipitating illness such as infection or ketoacidosis.

Even with early diagnosis, death can occur, and reported mortality rates have ranged from 10% to 75% in hospitalized patients.^85,116,117 In most patients who survive thyrotoxic crisis, clinical improvement is dramatic and demonstrable within the first 24 hours. During the recovery period of the next few days, supportive therapy such as corticosteroids, antipyretics, and intravenous fluids may be tapered and gradually withdrawn, based on patient status, oral intake of calories and fluids, vasomotor stability, and continuing improvement. After the crisis has been resolved, attention may be turned to consideration of the definitive treatment of thyrotoxicosis. Should thyroidectomy be considered, thyrotoxicosis will need to have been adequately treated preoperatively, to obviate any likelihood of another episode of crisis during the surgery. Total thyroidectomy is the procedure of choice, in view of reports of recurrent severe thyrotoxicosis and thyroid crisis after less than total thyroidectomy.¹¹⁸

Radioactive iodine as definitive treatment is often precluded by the recent use of inorganic iodine in virtually all cases of storm, but it could be considered at a later date, in which case antithyroid thionamide therapy is continued to restore and maintain euthyroidism until such a time as ablative therapy can be administered. Continuing treatment with antithyroid drugs alone, in the hope of the patient’s sustaining a spontaneous remission, is also possible.