Thyroid Emergency: Are You Prepared?

Deteriorating thyroid function may progress to the extreme of either thyrotoxic storm or myxedema coma. The authors detail signs, symptoms, diagnostic considerations, and a rescue plan for each of these emergencies.

By Nikolaos Stathatos, MD, and Leonard Wartofsky, MD

Thyroid disease is commonly encountered in clinical practice and has a wide spectrum of presentations. At either end of this spectrum are thyrotoxic storm and myxedema coma, both of which are medical emergencies. Although these conditions are relatively rare, their life-threatening potential mandates that every clinician be able to recognize their signs and symptoms and intervene promptly and appropriately.

In this article, we will discuss the key clinical features of thyrotoxic storm and myxedema coma. We will also discuss pertinent diagnostic considerations and various treatment regimens.
 

PRESENTATION OF THYROTOXIC STORM

Thyrotoxic storm usually develops after some specific precipitating event such as infection, sepsis, trauma, cerebrovascular accident, or radioactive iodine therapy. Most patients will have obvious signs and symptoms of thyrotoxicosis, such as goiter and Graves' ophthalmopathy. In older patients, however, particularly those who have an underlying toxic multinodular goiter rather than Graves' disease, thyrotoxic storm may present as so-called masked or apathetic thyrotoxicosis, in which case signs and symptoms may be subtle.

The differential diagnosis between true storm and an otherwise uncomplicated infection in a thyrotoxic patient may be difficult, because tachycardia and fever are often present in both. But a very high fever that seems out of proportion to an infection, along with extreme diaphoresis, could be a clue to impending thyrotoxic storm. In such a case, intervention with a vigorous treatment plan should be considered, for no other clue may be present prior to a potentially dramatic decline in the patient's condition.

As thyrotoxic storm progresses, signs of central nervous system (CNS) dysfunction develop, such as increasing agitation, emotional lability, confusion, paranoia, psychosis, and finally frank coma. The longer a patient goes untreated, the greater the likelihood of irreversible progression to death. For this reason, prudent management dictates that therapy should be initiated immediately as soon as the diagnosis of thyrotoxic storm is considered. Treatment should never be delayed until the diagnosis has been confirmed.

Tachyarrhythmias other than sinus tachycardia as well as signs and symptoms of heart failure may be present. Cardiac decompensation may be seen in relatively young or middle-aged patients without a known history of cardiac disease. Most patients will have systolic hypertension, with a widened pulse pressure, at least initially. Postural hypotension due to volume depletion from vomiting or diarrhea may progress to vascular collapse, shock, and death.

Gastrointestinal manifestations of thyrotoxic storm may include acute abdomen, intestinal obstruction, diffuse abdominal pain, hepatomegaly, splenomegaly, and liver function test abnormalities. Tender hepatomegaly may be present due to heart failure or hepatic necrosis; jaundice is a poor prognostic sign.

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LABORATORY FINDINGS

Extremely high elevations in serum thyroid hormone levels should not be expected in thyrotoxic storm. Indeed, levels of total thyroxine (T4) may be similar to those found in uncomplicated thyrotoxicosis. Serum total triiodothyronine (T3) levels may actually be within normal limits because of the inhibition of T3 generation from T4 in acute illness (the so-called euthyroid sick syndrome), thereby complicating the diagnosis of thyrotoxicosis. In patients who can be transported to the nuclear medicine department, the presence of previously undiagnosed thyrotoxicosis can be quickly confirmed by a two-hour radioiodine uptake. However, most hospital laboratories can determine serum T4 and thyroid-stimulating hormone levels within an hour to a few hours on an emergency basis. It bears repeating, though, that given the poor prognosis of untreated thyrotoxic storm, treatment should not be postponed until confirmation of the diagnosis.

Other laboratory abnormalities may include mild hyperglycemia in the absence of diabetes mellitus. While most hematologic values tend to be normal, a moderate leukocytosis with a mild shift to the left is common even in the absence of infection. Increased serum calcium levels may be seen, perhaps due to both hemoconcentration and the known resorptive effects of thyroid hormone on bone, but sodium, potassium, and chloride levels are usually normal.

Hepatic dysfunction in thyroid storm will result in elevated levels of serum lactate dehydrogenase, glutamic oxaloacetate transaminase (aspartate aminotransferase), and bilirubin. Because serum cortisol levels should be elevated in thyrotoxic storm, as in any other acute stressful situation, a normal value may be interpreted as inappropriately low. In view of the association of adrenal insufficiency with Graves' disease, a reasonably high index of suspicion should be maintained for adrenal hypofunction, particularly in the presence of hypotension and electrolyte abnormalities such as azotemia, hyponatremia, hyperkalemia, and hypercalcemia. A serum sample for determination of cortisol and adrenocorticotropin levels should be obtained prior to the administration of a corticosteroid. Even in the absence of adrenal insufficiency, adrenal reserve may be inadequate to meet the increased demand from the accelerated disposal of glucocorticoids that occurs in thyrotoxicosis.

There are several factors involved in the decompensation of thyrotoxicosis into thyrotoxic storm, and the precise underlying pathogenesis is likely to differ among patients. Elevation of serum hormone levels does not appear to be critical. However, the acute discharge of a hormone, resulting in a sudden change in its concentration, might trigger a crisis. This has been reported to have occurred, for example, after vigorous palpation of the thyroid, 131-I therapy, or withdrawal of propylthiouracil (PTU) therapy, or after administration of lithium, stable iodine, or iodinated contrast dyes.

Another key factor is the interaction between the effects of high thyroid hormone levels and circulating catecholamines. Support for this is inferred from the dramatic clinical improvement that follows the use of agents that either deplete thyroid hormone and catecholamine tissue levels, such as reserpine, or block adrenergic receptors, such as propranolol. While adrenergic receptor blockers are an important mainstay of treatment at our institution, use of these agents as monotherapy has not prevented thyrotoxic storm from occurring.
 

FOUR-PRONGED APPROACH TO TREATMENT

To avoid a disastrous outcome, we advocate a four-pronged approach to management of thyrotoxic storm. First, specific antithyroid drugs of the thiourea type must be used to reduce thyroid hormone production, and the ongoing release of T4 and T3 must be blocked by agents such as iodine or lithium carbonate. The second goal is to block the effects of excessive circulating concentrations of T4 and T3. The third arm of therapy is directed against systemic decompensation, as reflected by fever, heart failure, and shock, for example. Finally, any underlying precipitating illness such as infection or ketoacidosis must be addressed or thyrotoxic storm will recur. For therapy to be successful, no one component of this four-pronged approach, which we will now review in detail, should be neglected.

Therapy directed against the thyroid gland. Inhibition of newly synthesized thyroid hormones is achieved by administration of thionamide antithyroid drugs, such as PTU or methimazole. These drugs can only be given orally or rectally or by nasogastric tube; there are no available parenteral preparations. Standard dosing for PTU is 1200 to 1500 mg daily, given as 200 to 250 mg every 4 hours; for methimazole, 120 mg daily, given as 20 mg every 4 hours. Unlike methimazole, PTU inhibits conversion of T4 to T3, thereby more rapidly reducing serum T3 levels.

Since the thionamides reduce new hormone synthesis but not the continued secretion of preformed glandular stores of hormone, separate treatment must be administered to address this goal. Either inorganic iodine (Lugol's solution or a saturated solution of potassium iodide, six to eight drops every six hours) or lithium may be used for this purpose. Iodine should not be used without prior PTU or methimazole administration, because without the thionamide block on new hormone synthesis, the iodine will enrich hormone stores and possibly exacerbate the crisis. On the other hand, dramatic decreases in serum T4 levels are seen within four to five days when iodine is administered after full doses of a thionamide have been given.

In patients who may be allergic to iodine, lithium may be used to inhibit hormonal release, although some concerns have been raised with regard to its use in thyrotoxic storm. This drug may also be used in thyrotoxic patients who are known to have had a serious reaction to a thionamide. The standard dose is 300 mg three to four times daily, with daily monitoring of serum lithium levels to achieve a concentration of 1.0 to 1.2 mEq/L.

Therapy directed against the effects of thyroid hormones. Peritoneal dialysis and plasmapheresis have been used to reduce the high levels of circulating T4 and T3 in thyrotoxic storm, as has experimental hemoperfusion through a resin bed or charcoal columns. Such aggressive management is normally feasible in a large general hospital and should be considered in severe cases.

Beta blockers are an important part of this arm of therapy, with propranolol being the agent most commonly used. Large oral doses of as much as 60 to 120 mg intravenously (IV) every six hours are often required, with continuous cardiac monitoring. The more rapid-acting agent esmolol may also be considered. Additional benefits seen with beta blockers in these patients include improvement in agitation, convulsions, psychotic behavior, tremor, diarrhea, fever, and diaphoresis.

Therapy directed against systemic decompensation. Fluid depletion caused by fever, diaphoresis, vomiting, or diarrhea must be vigorously corrected to avoid vascular collapse. (Judicious fluid replacement would be necessary, of course, in elderly patients with heart failure or other cardiac conditions.) Intravenous fluids containing 10% dextrose and electrolytes will restore depleted hepatic glycogen. For fever, acetaminophen rather than a salicylate is preferred, because salicylates inhibit thyroid hormone binding and could increase free hormone levels, potentially worsening the crisis.

Hypotension that is not readily reversed by adequate hydration may require pressor therapy temporarily. Stress-dose glucocorticoids have been given empirically for suspected relative adrenal insufficiency. The ability of steroids to inhibit conversion of T4 to T3, while a relatively minor effect, is additional justification for their use.

Therapy directed against the precipitating illness. Many patients in thyrotoxic storm most likely have had untreated or incompletely treated thyrotoxicosis, which then flared into thyrotoxic storm as a result of some precipitating event such as infection. Thus, therapy is not considered complete until a diagnosis of the precipitating event has been made and treatment for that condition has been implemented.

In the obtunded or psychotic patient, the presence of conditions such as ketoacidosis, pulmonary thromboembolism, or stroke should be considered a likely precipitating event for thyrotoxic storm and appropriate treatment should be initiated. If no such relatively obvious underlying condition is apparent, a diligent search for some focus of infection must be conducted. Broad-spectrum antibiotic coverage on an empirical basis may be necessary initially until the results of culture tests become available.

After implementation of this four-pronged approach to management of thyrotoxic storm, dramatic clinical improvement is usually seen within 12 to 24 hours in most patients who survive.

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PRESENTATION OF MYXEDEMA COMA

Myxedema coma is a severe, life-threatening sequela of profound hypothyroidism. The textbook case is an elderly woman with a long-standing history of hypothyroidism and classic signs and symptoms of the disease who presents with stupor or coma.

Myxedema coma often occurs during the winter months, which suggests that significant environmental factors such as low temperatures may precipitate decompensation of underlying hypothyroidism. Several other factors such as hypoglycemia and hyponatremia have been associated with myxedema coma (see table below). All are thought to contribute to the presentation of the disease, but it is often difficult to determine whether they are precipitating factors or consequences of myxedema coma.
 

The disease usually evolves from a state of uncomplicated hypothyroidism into CNS depression with lethargy, then stupor, and even coma. The patient may have a history of using a CNS depressant, narcotic, or sedative. About 25% of patients with myxedema coma have focal or generalized seizures. Hallmark signs of hypothyroidism will be present—dry, coarse, scaly skin; sparse or coarse hair; nonpitting edema of the periorbital regions, hands, and feet; macroglossia; hoarseness; and delayed deep tendon reflexes.

Decreased respiratory drive, together with decreased ventilatory response to hypercapnia, can cause respiratory depression. This can lead to carbon dioxide narcosis and worsening CNS depression. Depressed function of the respiratory muscles will also exacerbate hypoventilation, and the presence of pleural effusions or ascites will further diminish respiratory function by reducing lung volumes.

Although frank heart failure is rare, cardiomegaly, bradycardia, and decreased cardiac contractility are common features of cardiovascular involvement in myxedema coma. Satisfactory management of cardiovascular collapse usually requires vasopressors and thyroid hormone replacement.

Gastrointestinal tract involvement in myxedema coma may result in decreased intestinal motility, paralytic ileus, or megacolon, causing patients to present with abdominal pain, constipation, and nausea. Oral medications may be ineffective because of these problems. Hyponatremia and decreased glomerular filtration rate occur, and the kidneys lose their ability to excrete a water load because of decreased delivery of water to the distal nephron, as well as increased production of antidiuretic hormone.

Pulmonary infections will exacerbate any respiratory dysfunction. Unfortunately, the patient with myxedema coma typically is more vulnerable to such infections because of hypoventilation and obtundation. Early detection of pulmonary or other infections may be complicated by the fact that the hypothermia and bradycardia that accompany myxedema coma may mask classic signs of infection such as fever and tachycardia.
 

PROMPT TREATMENT NECESSARY

Given the high mortality associated with myxedema coma, we recommend that treatment be initiated as soon as the diagnosis is suspected. Ventilatory support is often required and helps prevent respiratory failure, a common cause of death in these patients. Management in an intensive care unit is strongly recommended. Frequent assessment of blood gases and mechanical ventilation, together with antibiotic therapy, is usually required, sometimes for a prolonged period of time.

Correction of hyponatremia, especially if the patient's serum sodium concentration is less than 120 mEq/L, is essential because of its role in the altered mental status of patients with myxedema coma. Intravenous saline and dextrose are used to correct any volume depletion and to provide minimal nutritional support. If the sodium concentration is less than 120 mEq/L, small amounts of hypertonic saline may be used, but this requires cautious administration with very close monitoring of sodium concentration changes to avoid central pontine myelinolysis. Intravenous fluids may be warmed to help correct hypothermia. Thyroid hormone will ultimately restore normal body temperature. Applying external heat with warming blankets requires extreme caution because it may cause vasodilation and too precipitous a fall in peripheral vascular resistance. It would be safer to use ordinary blankets or increase the room temperature.

If there is any suspicion of adrenal insufficiency, stress-dose steroids should be given after a baseline cortisol level has been determined. The presence of hallmark signs of adrenal insufficiency like hypoglycemia, hyponatremia, hyperkalemia, and hypotension are highly suggestive for this diagnosis. Vasopressor support may be required for hemodynamic stability. Recognizing adrenal insufficiency in patients with myxedema coma can be extremely significant, because correcting the hypothyroidism without correcting adrenal insufficiency might precipitate an acute adrenal crisis.

While it is important to address all of the therapeutic issues discussed here, the mainstay of therapy in myxedema coma is clearly the correction of the thyroid hormone deficiency. Which regimen to institute remains controversial, largely because no one center has enough experience with myxedema coma to have conducted a controlled trial.

Theoretically, the administration of T4 alone may result in insufficient levels of T3 because of failure to convert T4 to T3. On the other hand, such a regimen would provide a smooth rise in the T3 level and avoid any adverse effects of excessive hormone levels. A commonly used dosing regimen involves administration of a single initial high dose of T4 (300 to 600 µg) IV the first day, followed by 50 to 100 µg IV or orally daily. Administering T3 has the advantage of a much faster onset of action than T4, which could increase survival in profound coma. A drawback of a T3-only regimen is the risk of complications such as arrhythmias or myocardial ischemia. Intravenous preparations of T3 are available; an appropriate dose for myxedema coma would be 10 to 20 µg IV every four hours for the first day, then 10 µg every six hours for one to two days, after which oral administration of T3 or T4 is usually possible.

Our approach is to administer both T3 and T4 initially. T4 is given at a dose of 4 µg/kg lean body weight (about 200 to 300 µg) IV, followed by 100 µg 24 hours later and then 50 µg daily either IV or orally as tolerated. Simultaneously with the T4, an initial T3 dose of 10 µg is given IV every 8 to 12 hours until the patient is able to tolerate oral intake.

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