Thyroid storm is a rare complication of hyperthyroidism in which the manifestations of thyrotoxicosis are exaggerated to life-threatening proportions. Thyroid storm is most often seen in a patient with moderate to severe antecedent Graves’ disease and is usually precipitated by a stressful event. It must be suspected and treated based upon a clinical impression, as there are no pathognomonic findings or confirmatory tests.
Hyperthyroid patients who are undiagnosed or undertreated are at risk for this complication. The duration of uncomplicated thyrotoxicosis preceding the onset of storm varies from months to years. A majority of the patients have had symptoms of hyperthyroidism for fewer than 24 months. It is not possible to predict accurately which thyrotoxic patient will develop storm as there is no predisposition by age, sex, or race.

PRECIPITATING FACTORS

A wide variety of factors have been reported as precipitating events. Thyroid surgery for treatment of hyperthyroidism used to be the most common cause of storm. Medically identified causes of thyroid storm are numerous and now predominate over surgical ones. Infection, especially pulmonary infection, is the most common precipitating event. In diabetic patients, ketoacidosis, hyperosmolar coma, and insulin-induced hypoglycemia have provoked storm. Events known to increase the levels of circulating thyroid hormones and initiate storm in susceptible persons, include premature withdrawal of antithyroid drugs, administration of radioactive iodide, use of an iodinated contrast medium during x-ray study, thyroid hormone overdose, administration of a saturated solution of potassium iodide to patients with nontoxic goiters, and vigorous palpation of the thyroid gland in thyrotoxic patients. Additional events implicated as causes of storm include vascular accidents, pulmonary emboli, toxemia of pregnancy, and emotional stress. Finally, hospitalization may lead to storm because of the rigors of diagnostic procedures.

PATHOPHYSIOLOGY

The exact pathogenesis of thyroid storm has not been defined. It is attractive to attribute storm to excess thyroid hormone production or secretion. The results of thyroid function studies are elevated in the vast majority of patients during storm, but the values are not significantly different from those found in uncomplicated thyrotoxicosis. An increase in free triiodothyronine (T3) or free thyroxine (T4) levels has been suggested as causative of storm. But storm has occurred in the absence of elevated free T3 or T4 levels. Something in addition to excess amounts or forms of thyroid hormones must occur during storm.
Adrenergic hyperreactivity due to either patient sensitization by thyroid hormones or altered interaction between thyroid hormones and catecholamines has been suggested. Plasma levels of epinephrine and norepinephrine are not increased during thyroid storm. The exact role of catecholamines in storm awaits further study.
Altered peripheral response to thyroid hormone, causing increased lipolysis and overproduction of heat, is another theory. This theory maintains that excessive lipolysis due to catecholamine-thyroid hormone interaction results in excessive thermal energy and fever. Finally, exhaustion of the body's tolerance to the action of thyroid hormones, leading to decompensated thyrotoxicosis, is a long-standing viewpoint. This implies an altered response to thyroid hormones rather than a sudden increase in their concentration.

CLINICAL PRESENTATION

Thyroid storm is a clinical diagnosis as there are no laboratory studies that distinguish it from thyrotoxicosis. Although the clinical presentation is extremely variable, there are clues to diagnosis. A history of hyperthyroidism, eye signs of Graves’ disease, widened pulse pressure, and a palpable goiter are present in most patients who develop thyroid storm. However, the history may be unobtainable and the usual features of Graves’ disease absent, including no obvious goiter in up to 9 percent of patients with Graves’ disease.

Diagnostic Criteria

The generally accepted diagnostic criteria for thyroid storm are a temperature higher than 37.8?C (100?F); marked tachycardia out of proportion to the fever; dysfunction of the CNS, cardiovascular system or gastrointestinal (GI) system; and exaggerated peripheral manifestations of thyrotoxicosis.
The signs and symptoms of storm usually occur suddenly, but there may be a prodromal period with subtle increases in the manifestations of thyrotoxicosis.

Signs and Symptoms

The earliest signs are fever, tachycardia, diaphoresis, increased CNS activity, and emotional lability. If the condition is untreated, a hyperkinetic toxic state ensues in which the symptoms are intensified. Progression to congestive heart failure, refractory pulmonary edema, circulatory collapse, coma, and death may occur within 72 h.
Fever ranges from 38?C (100.4?F) to 41?C (105.8?F). The pulse rate may range between 120 and 200 beats per minute but has been reported as high as 300 beats per minute. Sweating may be profuse, leading to dehydration from insensible fluid loss.
Central nervous system disturbance occurs in 90 percent of patients with thyroid storm. Symptoms vary from restlessness, anxiety, and emotional lability, manic behavior, agitation, and psychosis, to mental confusion, obtundation, and coma. Extreme muscle weakness can occur. Thyrotoxic myopathy can occur and usually involves the proximal muscles. In severe forms, muscles of the more distal extremities and muscles of the trunk and face may be involved. About 1 percent of patients with Graves’ disease develop myasthenia gravis, producing an occasional confusing clinical situation. The response of thyrotoxic myopathy to edrophonium (Tensilon test) is incomplete, unlike the complete response that occurs with myasthenia gravis. Hypokalemic periodic paralysis may also occur in patients with thyrotoxicosis.
Cardiovascular abnormalities are present in 50 percent of the patients regardless of underlying heart disease. Sinus tachycardia is usual. Arrhythmias, especially atrial fibrillation, but also including premature ventricular contractions and, rarely, complete heart block, may be present. In addition to increased heart rate, there is increased stroke volume, cardiac output, and myocardial oxygen consumption. Pulse pressure is characteristically widened. Congestive heart failure, pulmonary edema, and circulatory collapse may be terminal events.
Gastrointestinal symptoms develop in most patients in storm. Before the onset of storm, a history of severe weight loss is usual. Diarrhea and hyperdefecation seem to herald impending storm and can be severe, contributing to dehydration. During storm, anorexia, nausea, vomiting, and crampy abdominal pain may occur. Jaundice and tender hepatomegaly due to passive congestion of the liver, or even hepatic necrosis, have been reported. Jaundice is a poor prognostic sign.

LABORATORY

There are no laboratory tests that confirm thyroid storm. The combination of free T4 assay and a sensitive TSH assay are the primary means of assessing thyroid status in all patients. Some authors feel a single TSH assay is an appropriate screening tool. Both tests are needed in an emergency setting. When the clinical impression is thyrotoxicosis, an elevated free T4 and a suppressed unmeasurable TSH confirms the diagnosis.
In an emergency setting rarely would additional thyroid tests be necessary to establish a diagnosis of thyrotoxicosis. The uncommon T3 thyrotoxicosis would present with a suppressed TSH and a normal or low free T4. With this entity, the total T3 or free T3 would be required to accurately make the diagnosis.
Routine laboratory data during thyroid storm show wide variation. Nonspecific abnormalities in the complete blood cell count, electrolyte levels, and liver function studies may be found. Bacterial infection may be reflected only by a leftward shift in the differential white count without elevation in the total white cell count. Hyperglycemia (?120 mg/dL) is common, and hypercalcemia is occasionally present. One series reported all patients to have low cholesterol levels with a mean value of 117 mg/dL. Plasma cortisol levels have been observed to be inappropriately low for the degree of stress, suggesting a lack of adrenal reserve.

APATHETIC THYROTOXICOSIS

Apathetic thyrotoxicosis is a rare, distinct form that usually occurs in the elderly and is frequently misdiagnosed. These patients may develop thyroid storm without the usual hyperkinetic manifestations and may quietly lapse into coma and die. There are some salient clinical characteristics which are helpful in establishing this diagnosis. The patient is generally in the seventh decade or older, with lethargy, slowed mentation, and placid apathetic facies. Goiter is usually present but may be small and multinodular. The usual eye signs of exophthalmos, stare, and lid lag are absent, but blepharoptosis (drooping upper eye lid) is common. Excessive weight loss and proximal muscle weakness are usual. These patients generally have had symptoms longer than nonapathetic thyrotoxic patients.
“Masked” thyrotoxicosis occurs when signs and symptoms referable to dysfunction of one organ system dominate and obscure the underlying thyrotoxicosis. Signs and symptoms referable to the cardiovascular system tend to mask thyrotoxicosis in apathetic patients. These patients frequently present with atrial fibrillation and congestive heart failure. In one series of nine patients, the diagnosis of hyperthyroidism was unsuspected in each case because of the predominance of cardiovascular symptoms. Congestive heart failure in this setting may be refractory to the usual therapy unless the underlying hyperthyroidism is diagnosed and treated.
The pathogenesis of an apathetic response to thyrotoxicosis is not understood. Age alone is not the determining factor, as apathetic thyrotoxicosis has been described in the pediatric age group. A high index of suspicion must be maintained for this diagnosis.

TREATMENT

The importance of early treatment of thyroid storm based upon the clinical impression cannot be overemphasized. Before the therapy is begun, blood should be drawn for sensitive TSH assay, free T4 index or free T4 assay and free T3 and cortisol levels, a complete blood cell count, and routine chemistries. Appropriate cultures in search of infection are indicated.
Specific therapeutic goals can be divided into five areas; general supportive care, inhibition of thyroid hormone synthesis, retardation of thyroid hormone release, blockade of peripheral thyroid hormone effects, and identification and treatment of precipitating events. Each of these goals must be pursued concurrently.

General Supportive Care

Adequate hydration with intravenous fluids and electrolytes to replace insensible and GI losses is indicated. Supplemental oxygen is needed because of increased oxygen consumption. Hyperglycemia and hypercalcemia usually improve with fluid administration but occasionally require specific therapy. Fever should be controlled through the use of antipyretics and a cooling blanket. Aspirin should be used with caution or not at all during storm because salicylates increase free T3 and T4 levels because of decreased protein binding. This objection to the use of aspirin is theoretical, as no untoward clinical effect from aspirin use has been demonstrated. Caution should also be exercised in the use of sedatives during thyroid storm. Sedation depresses the level of consciousness and reduces the value of this parameter as an indicator of clinical improvement. Sedation may also cause hypoventilation.
Congestive heart failure should be treated with digitalis and diuretics even though congestive failure due to hyperthyroidism may be refractory to digitalis. Cardiac arrhythmias are treated with the usual antiarrhythmic agents. Atropine should be avoided, as its parasympatholytic effect may accelerate the heart rate. Atropine also may counteract the effect of propranolol.
Intravenous glucocorticoids equivalent to 300 mg of hydrocortisone per day should be given. The role of the adrenal glands in the pathogenesis of thyroid storm is uncertain, but the use of hydrocortisone has been reported to increase the rate of survival. Dexamethasone offers an advantage over other glucocorticoids as it decreases the peripheral conversion of T4 to T3.

Inhibition of Thyroid Hormone Synthesis

The antithyroid drugs propylthiouracil (PTU) and methimazole act to block the synthesis of thyroid hormone by inhibiting the organification of tyrosine residues. This action begins within 1 h after administration, but a full therapeutic effect is not achieved for weeks. An initial loading dose of PTU, 900 to 1200 mg, should be given, followed by 300 to 600 mg daily for 3 to 6 weeks or until the thyrotoxicosis comes under control. Methimazole, 90 to 120 mg initially followed by 30 to 60 mg daily, is an acceptable alternative. Both preparations must be given orally or via a nasogastric tube, as no parenteral form is available. The PTU has an advantage over methimazole because it inhibits the peripheral conversion of T4 to T3 and produces a more rapid clinical response. Although these drugs inhibit the synthesis of new thyroid hormone, they do not affect the release of stored hormone.

Retardation of Thyroid Hormone Release

Iodide administration promptly retards thyroidal release of stored hormones. Iodide can be provided by various preparations. It can be given as strong iodine solution, 1 mL 3 times daily, as potassium iodide, 10 drops of a solution containing 1 g/mL every 4 to 6 h, or as sodium iodide, 1 g every 8 to 12 h by slow intravenous infusion. Caution should be used in those patients taking potassium-sparing diuretics or potassium-containing drugs as potassium iodide preparations will add to the potassium load. Concomitant use of iodides and lithium salts may result in an additive hypothyroid effect. Iodide should be administered 1 h after the loading dose of antithyroid medication to prevent utilization of the iodide by the thyroid in the synthesis of new hormone.

Blockade of Peripheral Thyroid Hormone Effects

Adrenergic blockade is a maintstay of therapy for thyroid storm. Currently, the ?-adrenergic blocking agent propranolol is the drug of choice. In addition to reducing sympathetic hyperactivity, propranolol also partially blocks the peripheral conversion of T4 to T3.
Propranolol can be given intravenously at a rate of 1 mg/min with cautious incremental increases of 1 mg every 10 to 15 min to a total dose of 10 mg. The effects of the drug in controlling cardiac and psychomotor manifestations of storm should be seen in 10 min. The lowest possible dose required to control thyrotoxic symptoms should be used, and this dose can be repeated every 3 to 4 h as needed. The oral dose of propranolol is 20 to 120 mg every 4 to 6 h. When given by mouth, propranolol is effective in about 1 h. Propranolol has been used successfully in treatment of thyroid storm in childhood. Younger patients may require a dosage as high as 240 to 320 mg/day orally.
The usual precaution of avoiding propranolol in patients with bronchospastic disease and heart block should be observed. Electrocardiographic evaluation for conduction disturbance should occur before the administration of propranolol. In patients with congestive heart failure, the benefit of slowing the heart rate and controlling certain arrhythmias must be weighed against the risk of depressing myocardial contractility with ?-adrenergic blockade. Urbanic believes the benefit outweighs the risk in this situation but recommends administration of digitalis before propranolol.
Guanethidine and reserpine also provide effective autonomic blockade and are alternatives to propranolol. Guanethidine depletes catecholamine stores and blocks their release. When given 1 to 2 mg/kg per day orally (50 to 150 mg), it is effective in 24 h, but it may not have its maximum effect for several days. Toxic reactions are cumulative and include postural hypotension, myocardial decompensation and diarrhea. It has an advantage over reserpine because it does not cause the pronounced sedation observed with that drug.
Reserpine acts to deplete catecholamine stores. As the initial dose, 1 to 5 mg is given intramuscularly, followed by 1 to 2.5 mg every 4 to 6 h. Improvement may be seen within 4 to 8 h. Side effects include sedation; psychic depression, which can be severe; abdominal cramping; and diarrhea.
Finally, a thorough evaluation for a precipitating cause of thyroid storm should be made. The treatment of thyroid storm should not be delayed by this evaluation, which may have to wait until the patient is at least partially stabilized.
Following the initiation of therapy, symptomatic improvement should occur within a few hours, primarily due to adrenergic blockade. Resolution of thyroid storm requires degradation of the already-circulating thyroid hormones, whose biological half-life is 6 days for T4 and 22 h for T3. Storm may last from 1 to 8 days, with an average duration of 3 days. If conventional therapy is not successful in controlling storm, alternative therapeutic modalities include peritoneal dialysis, plasmapheresis, and charcoal hemoperfusion to remove circulating thyroid hormone. Following recovery from thyroid storm, radioactive iodine therapy is the treatment of choice for hyperthyroidism. The mortality in untreated thyroid storm approaches 100 percent. Decreased mortality has occurred with the use of antithyroid drugs. Underlying illness is the cause of death in many cases. Prevention of thyroid storm is the ultimate solution to reduce mortality.

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