Thyroid storm

INTRODUCTION — Thyroid storm is a rare, life-threatening condition characterized by severe clinical manifestations of thyrotoxicosis [1]. In national surveys from the United States and Japan, the incidence of thyroid storm was 0.57 to 0.76 and 0.20 per 100,000 persons per year, respectively, and 4.8 to 5.6 per 100,000 hospitalized patients per year [2-4]. In the United States survey, 16 percent of inpatients with thyrotoxicosis were diagnosed with storm [4]. It may be precipitated by abrupt discontinuation of antithyroid drugs or by an acute event such as thyroid or nonthyroidal surgery, trauma, infection, an acute iodine load, or parturition. In addition to specific therapy directed against the thyroid, supportive therapy in an intensive care unit (ICU) and recognition and treatment of any precipitating factors is essential since the mortality rate of thyroid storm is substantial (10 to 30 percent) [2,5-9].

The clinical manifestations, diagnosis, and management of thyroid storm will be reviewed here. The general topic of hyperthyroidism (without thyroid storm), including diagnosis, causes, and treatment, is reviewed separately.

●(See "Overview of the clinical manifestations of hyperthyroidism in adults".)

●(See "Diagnosis of hyperthyroidism".)

●(See "Disorders that cause hyperthyroidism".)

●(See "Graves' hyperthyroidism in nonpregnant adults: Overview of treatment".)

●(See "Treatment of toxic adenoma and toxic multinodular goiter".)

●(See "Hyperthyroidism during pregnancy: Treatment".)

RISK FACTORS — Although thyroid storm can develop in patients with longstanding untreated hyperthyroidism (Graves' disease, toxic multinodular goiter, solitary toxic adenoma), it is often precipitated by an acute event such as thyroid or nonthyroidal surgery, trauma, infection, an acute iodine load (including amiodarone use), or parturition. In addition, irregular use or discontinuation of antithyroid drugs and poor access to health care are commonly reported precipitants of thyroid storm [2-5,8,10,11]. Appropriate preoperative preparation of hyperthyroid patients undergoing nonthyroidal surgery or thyroidectomy for hyperthyroidism has led to a dramatic reduction in the prevalence of surgically induced thyroid storm [12].

It is unclear why certain factors result in the development of thyroid storm. Hypotheses include a rapid rate of increase in serum thyroid hormone levels, increased responsiveness to catecholamines, or enhanced cellular responses to thyroid hormone [1]. The degree of thyroid hormone excess (elevation of thyroxine [T4] and triiodothyronine [T3], suppression of thyroid-stimulating hormone [TSH]) typically is not more profound than that seen in patients with uncomplicated thyrotoxicosis. However, one study found that while the total T4 and T3 levels were similar to those seen in uncomplicated patients, the free T4 and T3 concentrations were higher in patients with thyroid storm [13].

CLINICAL FEATURES — Patients with severe and life-threatening thyrotoxicosis typically have an exaggeration of the usual symptoms of hyperthyroidism. (See "Overview of the clinical manifestations of hyperthyroidism in adults".)

Symptoms and signs — Cardiovascular symptoms in many patients include tachycardia to rates that can exceed 140 beats/minute and congestive heart failure. Hypotension, cardiac arrhythmia, and death from cardiovascular collapse may occur [14]. In one series of 28 cases, cardiac manifestations were predominant, with >60 percent having severe tachycardia and/or atrial fibrillation [5].

Hyperpyrexia to 104 to 106°F is common. Agitation, anxiety, delirium, psychosis, stupor, or coma are also common and are considered by many to be essential to the diagnosis. In one series, altered mentation was the only clinical finding that distinguished "storm" from "compensated" hyperthyroidism [6], and in another series, it was statistically associated with mortality [5]. In a retrospective study from Japan, older age >60 years, central nervous system dysfunction, requirement of mechanical ventilation, and nonuse of antithyroid drugs or beta blockers were associated with higher mortality [7]. Other symptoms may include severe nausea, vomiting, diarrhea, abdominal pain, or hepatic failure with jaundice.

Physical examination may reveal goiter, ophthalmopathy (in the presence of Graves' disease), lid lag, hand tremor, and warm and moist skin.

Laboratory findings — All patients with overt primary hyperthyroidism (including patients with thyroid storm) have low TSH and high free T4 and/or T3 concentrations. The degree of thyroid hormone excess in thyroid storm is typically not more profound than that seen in patients with uncomplicated thyrotoxicosis. Other laboratory findings in patients with thyrotoxicosis (with or without thyroid storm) may include [15]:

●Mild hyperglycemia (secondary to a catecholamine-induced inhibition of insulin release and increased glycogenolysis)

●Mild hypercalcemia (secondary to hemoconcentration and enhanced bone resorption)

●Abnormal liver function tests

●Leukocytosis or leukopenia

DIAGNOSIS — The diagnosis of thyroid storm is based upon the presence of severe and life-threatening symptoms (hyperpyrexia, cardiovascular dysfunction, altered mentation) in a patient with biochemical evidence of hyperthyroidism (elevation of free T4 and/or T3 and suppression of TSH).

There are no universally accepted criteria or validated clinical tools for diagnosing thyroid storm. In 1993, Burch and Wartofsky introduced a scoring system using precise clinical criteria for the identification of thyroid storm (table 1) [16]. A score of 45 or more is highly suggestive of thyroid storm, whereas a score below 25 makes thyroid storm unlikely. A score of 25 to 44 is suggestive of impending storm. While this scoring system is likely sensitive, it is not very specific. For example, a mildly hyperthyroid patient with influenza, a fever, and nausea could score high enough to meet the criteria for storm. Another diagnostic system based upon similar clinical findings (central nervous system manifestations, fever, tachycardia, congestive heart failure, gastrointestinal manifestations) has been proposed [2], but this latter system may have reduced sensitivity for making the diagnosis [6].

●Evaluation

•Thyroid function tests – Thyroid function tests (TSH) should be assessed in all patients in whom there is a clinical suspicion of thyroid storm (hyperpyrexia with temperature >103°F [39.4°C], goiter, cardiovascular dysfunction, altered mentation, atrial fibrillation, history of antithyroid drug therapy for hyperthyroidism, recent thyroid or nonthyroidal surgery, recent exposure to iodine-containing contrast). If the TSH is below normal, free T4 and T3 should be measured. The degree of hyperthyroidism (elevation of T4 and/or T3 and suppression of TSH) in patients with thyroid storm is, in general, comparable with that in patients with uncomplicated overt hyperthyroidism. Thus, the degree of hyperthyroidism is not a criterion for diagnosing thyroid storm. (See "Diagnosis of hyperthyroidism", section on 'Diagnosis'.)

•Determining the etiology – Determining the etiology of thyrotoxicosis in patients with thyroid storm should not delay prompt treatment of patients with clinical manifestations of thyroid storm. (See 'General principles' below.)

Most patients with thyroid storm have Graves' disease, and some have toxic adenoma or toxic multinodular goiter. In a multicenter study from France, amiodarone use was the most common precipitating factor [8]. A destructive thyroiditis associated with the use of checkpoint inhibitors in compromised oncology patients may rarely be associated with thyroid storm [17]. Measuring thyrotropin receptor antibodies (TRAb) or determining a radioiodine uptake can distinguish Graves' disease from other causes of hyperthyroidism. (See "Diagnosis of hyperthyroidism", section on 'Determining the etiology' and "Amiodarone and thyroid dysfunction", section on 'Hyperthyroidism'.)

INITIAL MANAGEMENT — The therapeutic options for thyroid storm are expanded from those used for uncomplicated hyperthyroidism, with additional drugs often used such as glucocorticoids and an iodine solution, and the standard drugs are given in higher doses and with more frequent dosing.

General principles — The principles of treatment outlined below are based upon clinical experience and case studies since there are no prospective studies. They are frequently also applied to patients with severe hyperthyroidism who do not fully meet the criteria for thyroid storm. The therapeutic regimen typically consists of multiple medications, each of which has a different mechanism of action [15,18,19]:

●A beta blocker (if not contraindicated) to control the symptoms and signs induced by increased adrenergic tone

●A thionamide to block new hormone synthesis

●An iodine solution to block the release of thyroid hormone

●An iodinated radiocontrast agent (not available in the United States) to inhibit the peripheral conversion of T4 to T3

●Glucocorticoids to reduce T4-to-T3 conversion, promote vasomotor stability, possibly reduce the autoimmune process in Graves' disease, and possibly treat an associated relative adrenal insufficiency

●Bile acid sequestrants may also be of benefit in severe cases to decrease enterohepatic recycling of thyroid hormones

Full support of the patient in an intensive care unit (ICU) is essential since the mortality rate of thyroid storm is substantial [2,5-8]. In two series of patients with thyroid storm (patients seen between 2006 and 2013), mortality was 8 percent in a Los Angeles hospital and 25 percent in a Singapore hospital [5,6]. In a French series (patients seen between 2000 and 2017), mortality was 17 percent in the ICU and 22 percent six months after hospital admission [8].

Recognition and treatment of any precipitating factors (eg, infection), in addition to specific therapy directed against the thyroid, may be critical to the final outcome. Many patients require substantial amounts of fluid (eg, 3 to 5 liters a day), while others may require diuresis because of congestive heart failure. Medication requirements (eg, beta blocker, digoxin) may be quite high because of increased drug metabolism as a result of hyperthyroidism. Infection needs to be identified and treated, and hyperpyrexia should be aggressively corrected. Acetaminophen should be used instead of aspirin since the latter can increase serum free T4 and T3 concentrations by interfering with their protein binding. The use of cooling blankets and ice packs should be considered in patients with persistent fever.

For most patients with clinical features of thyroid storm or with impending storm (ie, severe thyrotoxicosis that does not fully meet the criteria for thyroid storm), we begin immediate treatment with:

●Beta blocker – Propranolol preferred. (See 'Beta blockers' below.)

●Thionamide – Propylthiouracil (PTU) preferred. (See 'Thionamides' below.)

●Iodine – Saturated solution of potassium iodide (SSKI) or Lugol's solution. (See 'Iodine' below.)

For patients with clinical features of thyroid storm, we also administer:

●Hydrocortisone – (See 'Glucocorticoids' below.)

Cholestyramine is an additional adjunctive therapy, especially if the patient is allergic to thionamides. (See 'Other therapies' below.)

Initial therapy is adjusted after there is evidence of clinical improvement. (See 'Subsequent management' below.)

Beta blockers — For most patients with thyroid storm or severe thyrotoxicosis, we begin immediate treatment with a beta blocker (typically propranolol) in a dose to achieve adequate control of heart rate and blood pressure.

Although control of tachycardia may lead to improvement in cardiac function (if heart rate is an exacerbating factor), beta blockers (oral or intravenous) are contraindicated in patients with acute decompensated heart failure with systolic dysfunction. The hyperadrenergic state is important for maintaining cardiac output. In this setting, a beta blocker-induced reduction in heart rate could lead to profound hypotension [20,21]. (See "Treatment of acute decompensated heart failure: General considerations", section on 'Treatment goals for acute versus chronic HF'.)

Beta blockers should be used with caution in patients who have asthma, chronic obstructive pulmonary disease, or severe peripheral vascular disease. In patients with reactive airways disease, cardioselective beta blockers such as metoprolol or atenolol could be considered, but this should be done carefully. In some patients with severe asthma in whom beta blockers might be contraindicated, rate control can be achieved with calcium channel blockers such as diltiazem [22]. (See "Beta blockers in the treatment of hyperthyroidism".)

●Propranolol – We use propranolol for initial therapy because in high doses it inhibits the conversion of T4 to T3 by inhibiting the type 1 deiodinase [23]. The dose of propranolol is titrated to achieve adequate control of heart rate, typically 60 to 80 mg orally every four to six hours, with appropriate adjustment for heart rate and blood pressure. It can also be given intravenously or via a nasogastric tube. Intravenous administration should only be done in a setting where hemodynamics can be monitored. The intravenous dose of propranolol is 0.5 to 1 mg over 10 minutes followed by 1 to 2 mg over 10 minutes every few hours [16,24]. Higher doses may occasionally be required, but care should be taken to avoid hypotension and aggravation of existing heart failure.

When transitioning from intravenous to oral/nasogastric treatment, intravenous therapy may need to be continued until adequate effectiveness of the oral/nasogastric treatment is ascertained.

●Esmolol – The Japanese guidelines recommend the short-acting intravenous beta blocker (eg, esmolol) over propranolol because of increased mortality in patients with heart failure treated with propranolol [25]. Esmolol may be a reasonable option if it is uncertain that a beta blocker will be tolerated since after discontinuation, duration of action is very short. It must be administered in a monitored setting.

Recommended published doses include a loading dose of 250 to 500 mcg/kg, followed by an infusion at 50 to 100 mcg/kg per minute [26], or, in the Japanese guidelines, a loading dose of 1 mg/kg over 30 seconds followed by approximately 150 mcg/kg/minute [25]. The dose is adjusted based on the heart rate. These regimens permit rapid up- or down-titration of the drug to achieve adequate beta blockade while minimizing adverse reactions. (See "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy".)

Thionamides — For patients with thyroid storm or severe thyrotoxicosis, we begin immediate treatment with either PTU or methimazole [27]. Carbimazole, a third drug that is metabolized to methimazole, is available in many countries but not in North America. Thionamides block de novo thyroid hormone synthesis within one to two hours after administration. However, they have no effect on the release of preformed hormone from the thyroid gland. (See "Thionamides in the treatment of Graves' disease".)

Choice of thionamide

●We suggest PTU for the acute treatment of life-threatening thyroid storm in an ICU setting, where it can be administered regularly every four hours. PTU is favored over methimazole because of PTU's effect to decrease T4-to-T3 conversion. T3 levels drop by approximately 45 percent within 24 hours after PTU but only 10 to 15 percent within 24 hours after methimazole [28,29].

Patients started on PTU in the ICU should be transitioned to methimazole before discharge from the hospital. (See 'Subsequent management' below.)

●Methimazole may be preferred for severe (but not life-threatening) hyperthyroidism because methimazole has a longer duration of action and, after weeks of treatment, results in more rapid normalization of serum T3 compared with PTU. In addition, the frequency of hepatotoxicity may be less with methimazole. (See "Thionamides: Side effects and toxicities".)

In Japan, methimazole is preferred over PTU, and in a retrospective study of 356 patients, there was no difference in mortality or disease severity in patients receiving methimazole or PTU [25,30].

Initial dosing and administration

●PTU – The dose of PTU is 200 to 250 mg every four hours. We do not typically administer a loading dose of PTU since the initial dose is generally adequate to block thyroid hormone synthesis. The American Thyroid Association (ATA) guidelines suggest a loading dose of 500 to 1000 mg [19].

●Methimazole – The dose of methimazole is 20 mg orally every four to six hours.

The dose of thionamide given to patients with thyroid storm is likely higher than that required to completely block thyroid hormone synthesis. Both the substantial mortality associated with thyroid storm and the possibility of poor absorption because of concurrent gastrointestinal dysfunction have been used to justify the higher dose. Lower doses are used in patients with severe thyrotoxicosis who do not meet criteria for thyroid storm. (See "Thionamides in the treatment of Graves' disease", section on 'Dosing'.)

Both drugs are administered orally or, if need be, can be given via a nasogastric tube. The drugs can also be suspended in liquid or made up as a suppository or retention enema for rectal administration, which should be ordered well in advance from the pharmacy (table 2) [15,31-34]. In one study comparing the use of an enema versus a suppository preparation of PTU, 15 patients with newly diagnosed hyperthyroidism were randomly assigned to a PTU enema (eight 50 mg tablets of PTU were dissolved in 90 mL of sterile water) versus two PTU suppositories (200 mg of PTU were dissolved in a polyethylene glycol base and put into each suppository) [34]. The enema form provided better bioavailability than the suppository form (time to peak level 85 versus 172 minutes, maximum peak level 3.89 versus 2.01 mcg/mL). However, both preparations proved to have comparable therapeutic effect, as measured by a significant decrease in serum free T3 levels.

For patients intolerant of oral or rectal thionamides, intravenous methimazole is available in some countries (eg, Japan) but not in the United States. In a case study, United States Pharmacopeia (USP) methimazole powder was prepared for intravenous administration (using aseptic technique) for two patients intolerant of oral or rectal administration [35]. In this setting, routine pharmacologic sterility tests are required as dictated by individual hospitals.

Patients unable to take a thionamide — Although thionamide toxicity is uncommon, some patients are unable to continue thionamides because of rare side effects (such as agranulocytosis or hepatotoxicity) or because of allergy. Thyroid storm has been reported in patients with Graves' disease after discontinuation of thionamides (due to agranulocytosis or hepatotoxicity) [36,37]. In such patients who require urgent treatment of hyperthyroidism, thyroidectomy is the treatment of choice (see "Surgical management of hyperthyroidism", section on 'Preoperative preparation'). However, in a critically ill patient with a history of a severe reaction to one thionamide (eg, agranulocytosis or hepatotoxicity), who is too unstable for urgent thyroidectomy, cautious use of the alternate drug could be considered for one to two weeks with close monitoring of granulocyte counts/hepatic function tests.

Patients who are to undergo surgery require preoperative treatment of thyrotoxicosis. We typically treat with beta blockers (if not contraindicated, propranolol in a dose to achieve adequate control of heart rate, typically 60 to 80 mg every four to six hours), glucocorticoids to inhibit conversion of T4 to T3 (eg, dexamethasone, 1 to 2 mg every six hours), bile acid sequestrants (eg, cholestyramine 4 g orally four times daily) to reduce enterohepatic circulation of thyroid hormone, and, in patients with Graves' disease, iodine (SSKI, 5 drops [20 drops/mL, 50 mg iodide/drop] orally every six hours or Lugol's solution, 10 drops [20 drops/mL, 6.25 mg iodine/drop] every eight hours) [38,39].

Optimum preoperative treatment with iodine is approximately 10 days; however, depending upon the clinical status of the patient and surgical availability, preoperative treatment for 5 to 14 days is reasonable. Surgery should not be delayed longer, because of a phenomenon called escape from the Wolff-Chaikoff effect. Large doses of exogenous iodine inhibit the organification of iodine in the thyroid gland (the Wolff-Chaikoff effect). However, this effect is transient. The iodide transport system is able to adapt to higher concentrations of iodine, allowing thyroid hormone synthesis to proceed, with potential exacerbation of thyrotoxicosis. (See "Iodine-induced thyroid dysfunction".)

In case reports, when traditional therapy has not been successful, plasmapheresis has been used to prepare patients with thyroid storm for thyroid surgery (see 'Other therapies' below). Iodinated contrast agents have also been used to prepare hyperthyroid patients for urgent surgery, but they are no longer available in most countries. (See "Surgical management of hyperthyroidism", section on 'Preoperative preparation'.)

Iodine — For patients with thyroid storm or severe thyrotoxicosis, we administer SSKI or potassium iodide and iodine (Lugol's solution) one hour after the first dose of thionamide is taken. The administration of iodine should be delayed for at least one hour after thionamide administration to prevent the iodine from being used as substrate for new hormone synthesis in patients with toxic adenoma or toxic multinodular goiter (since the etiology of the thyrotoxicosis is frequently uncertain at the time of admission) [15]. When the etiology of thyroid storm is known to be toxic adenoma or toxic multinodular goiter, iodine should be used cautiously since the use of iodine can exacerbate hyperthyroidism if thionamide treatment is interrupted.

Iodine-containing solutions have traditionally been utilized for the treatment of thyroid storm since iodine blocks the release of T4 and T3 from the gland within hours. (See "Iodine in the treatment of hyperthyroidism".)

Either SSKI or Lugol's solution maybe be administered [19,33]. These solutions can be irritating to the gastrointestinal tract and should be diluted in 240 mL or more of beverage or taken with food.

●SSKI – 5 drops (50 mg iodide/drop [0.05 mL]) orally every six hours

●Lugol's solution – 10 drops (6.25 mg iodide/iodine per drop [0.05 mL]) orally three times daily

There is no standard intravenous iodide preparation. The iodine solution can be given rectally [33].  

Although iodine is typically well tolerated, local esophageal or duodenal mucosal injury and hemorrhage have been reported after oral administration of Lugol's solution (960 mg iodine/day) for the treatment of thyroid storm [40,41].

Glucocorticoids — For patients with clinical features of thyroid storm, we administer glucocorticoids (300 mg loading dose, then hydrocortisone, 100 mg intravenously every eight hours; dexamethasone can be used as an alternative). In contrast, we do not routinely use glucocorticoids in patients with moderate to severe, but otherwise uncomplicated, hyperthyroidism.

Glucocorticoids reduce T4-to-T3 conversion. They may have a direct effect on the underlying autoimmune process (if the thyroid storm is due to Graves' disease) and in addition, treat potentially associated limited adrenal reserve [42]. Because of the high mortality rate of thyroid storm, their use is commonly recommended by experts, although data are limited, and there are no randomized trials comparing management of thyroid storm with or without glucocorticoids [43,44]. In a retrospective study based on a claims database (811 ICU admissions for thyroid storm between 2013 and 2017), 600 patients received glucocorticoids and 211 did not [44]. There was no change in hospital mortality or mortality 30 days after discharge. Glucocorticoid use was associated with increased use of insulin.

Tapering and discontinuing glucocorticoids after improvement is reviewed below. (See 'Subsequent management' below.)

Other therapies

●Cholestyramine – Thyroid hormones are metabolized in the liver, where they are conjugated with glucuronide and sulfate, and the conjugation products are excreted in the bile. Free thyroid hormones are released in the intestine and are reabsorbed. Bile acid sequestrants (eg, cholestyramine 4 g orally four times daily) have been found to reduce thyroid hormone levels in thyrotoxic patients by interfering with enterohepatic circulation and recycling of thyroid hormone [45-47].

Cholestyramine can be a useful adjunctive therapy in patients with thyroid storm, particularly in patients who are intolerant of thionamides. Since cholestyramine can interfere with the absorption of oral medications, other drugs given orally should be given two hours before or two hours after cholestyramine administration [45]. Cholestyramine may be discontinued when clinical status improves.

●Iodinated radiocontrast agents – Iodinated contrast agents previously used to treat hyperthyroidism are currently not available in the United States or in most other countries.

Iopanoic acid and other iodinated radiocontrast agents used for oral cholecystography have been used to treat hyperthyroidism, but there are little published data on their efficacy in thyroid storm (see "Iodinated radiocontrast agents in the treatment of hyperthyroidism"). They are, however, potent inhibitors of T4-to-T3 conversion, and the release of iodine in pharmacologic quantities from these agents has the additional benefit of blocking thyroid hormone release. They have been extremely useful in treating severe hyperthyroidism and in preparing hyperthyroid patients for urgent surgery [48,49]. If available, these agents can be given to patients with severe hyperthyroidism at a dose of 0.5 to 1 g once daily.

Because they are iodinated, they should be given at least one hour after the thionamide to prevent the iodine from being used as substrate for new hormone synthesis.

●Plasmapheresis – Plasmapheresis has been tried when traditional therapy has not been successful [37,50-54]. It is an option for patients who cannot tolerate thionamides and in patients who are being prepared for urgent thyroidectomy. Plasmapheresis removes cytokines, antibodies, and thyroid hormones from plasma [52]. In one case report, a woman with Graves' disease and methimazole-induced agranulocytosis developed thyroid storm after methimazole was discontinued. Treatment with plasmapheresis resulted in marked improvement in thyrotoxicosis within three days, allowing thyroidectomy for definitive therapy [37].

The effects of plasmapheresis are transient, lasting 24 to 48 hours [37]. In a series of three patients who had therapeutic plasma exchange for thyroid storm preoperatively, free T4 levels were reduced on average by 21 percent after each treatment and by 55 percent after four treatments [54].

●Lithium – Lithium has also been given to acutely block the release of thyroid hormone. However, its renal and neurologic toxicity limit its utility. (See "Lithium and the thyroid", section on 'Hyperthyroidism'.)

SUBSEQUENT MANAGEMENT — After there is evidence of clinical improvement (defervescence, resolution of central nervous system and cardiovascular manifestations), some medications can be discontinued and others reduced.

●Iodine therapy can be discontinued (unless a thyroidectomy is planned in the next 10 to 14 days).

●Beta blockers can be withdrawn, but only after thyroid function tests have returned to normal.

●Glucocorticoids are tapered and discontinued. The pace of the glucocorticoid taper depends upon the clinical course of the patient; a slower taper is necessary in patients who had a prolonged intensive care unit (ICU) stay with longer duration of glucocorticoid treatment. Some patients may need testing of adrenal function prior to discontinuing glucocorticoids. (See "Diagnosis of adrenal insufficiency in adults".)

●Propylthiouracil (PTU), if given, should be switched to methimazole once the T3 is declining and hospital discharge is anticipated. Methimazole is preferred because of its better safety profile and better compliance rates. When switching to methimazole, the initial dose is generally high, 30 to 40 mg daily in divided doses, depending on the patient's clinical status. The dose is then titrated down to maintain euthyroidism. It is important to provide patient education about the risk of abruptly discontinuing treatment. Monitoring, dosing, and duration of thionamide therapy are reviewed in detail separately. (See "Thionamides in the treatment of Graves' disease", section on 'Monitoring'.)

In patients with Graves' disease, definitive therapy with radioiodine or thyroidectomy is important to prevent a recurrence of severe thyrotoxicosis. Individual patient factors may influence the choice of definitive therapy, and the selection of therapy should involve discussion of the values and preferences of the patient. (See "Graves' hyperthyroidism in nonpregnant adults: Overview of treatment" and "Radioiodine in the treatment of hyperthyroidism", section on 'Approach to treatment' and "Surgical management of hyperthyroidism", section on 'Preoperative preparation' and "Thionamides in the treatment of Graves' disease", section on 'Clinical use'.)

SUMMARY AND RECOMMENDATIONS

●Definition and risk factors – Thyroid storm is a rare, life-threatening condition characterized by severe or exaggerated clinical manifestations of thyrotoxicosis. Although thyroid storm can develop in patients with longstanding untreated hyperthyroidism (Graves' disease, toxic multinodular goiter, solitary toxic adenoma), it is often precipitated by an acute event such as thyroid or nonthyroidal surgery, trauma, infection, an acute iodine load, or parturition. (See 'Introduction' above and 'Risk factors' above.)

●Clinical features – Patients with thyroid storm typically have an exaggeration of the usual symptoms of hyperthyroidism. The classical symptoms of thyroid storm include tachycardia, hyperpyrexia, central nervous system dysfunction (agitation, delirium, psychosis, stupor, or coma), and gastrointestinal symptoms (nausea, vomiting, abdominal pain). Physical examination may reveal goiter, ophthalmopathy (in the presence of Graves' disease), lid lag, hand tremor, and warm and moist skin. Thyroid function tests show hyperthyroidism (suppressed thyroid-stimulating hormone [TSH], elevated free thyroxine [T4] and triiodothyronine [T3]) generally comparable with that in patients with uncomplicated overt hyperthyroidism. (See 'Clinical features' above.)

●Diagnosis – The diagnosis of thyroid storm is based upon the presence of severe and life-threatening symptoms (hyperpyrexia, cardiovascular dysfunction, altered mentation) in a patient with biochemical evidence of hyperthyroidism (elevation of free T4 and/or T3 and suppression of TSH). There are no universally accepted criteria or validated clinical tools for diagnosing thyroid storm. In one scoring system (table 1), a score of 45 or more is highly suggestive of thyroid storm, whereas a score below 25 makes thyroid storm unlikely. (See 'Diagnosis' above.)

●Treatment

•General principles – The therapeutic options for thyroid storm are expanded from those used for uncomplicated hyperthyroidism, with additional drugs typically used, such as glucocorticoids and iodine solution (eg, saturated solution of potassium iodide [SSKI]), and standard drugs are given in higher doses and more frequently. In addition to specific therapy directed against the thyroid, supportive therapy in an intensive care unit (ICU) and recognition and treatment of any precipitating factors is essential since the mortality rate of thyroid storm is substantial (10 to 30 percent). (See 'General principles' above.)

•Medical therapy – For most patients with clinical features of thyroid storm, we begin immediate treatment with:

-Beta blocker (if not contraindicated, propranolol in a dose to achieve adequate control of heart rate, typically 60 to 80 mg orally every four to six hours)

-Thionamide

-Glucocorticoids (eg, hydrocortisone intravenously, 300 mg loading dose, then 100 mg every eight hours)

One hour after a thionamide is given, we administer iodine (SSKI, 5 drops [20 drops/mL, 50 mg iodide/drop] orally every six hours; or Lugol's solution, 10 drops [20 drops/mL, 6.25 mg iodine/drop] every eight hours). Bile acid sequestrants (cholestyramine, 4 g orally four times daily) may also be of benefit in severe cases, especially if the patient is allergic to thionamides, to decrease enterohepatic recycling of thyroid hormones. (See 'General principles' above.)

•Choice of thionamide – For patients with life-threatening thyroid storm admitted to an ICU, we suggest propylthiouracil (PTU; 200 to 250 mg orally every four hours) rather than methimazole as initial therapy (Grade 2C). PTU blocks T4-to-T3 conversion and results in lower serum T3 levels for the first several days of treatment. However, for severe, but not life-threatening, hyperthyroidism, methimazole (20 mg every four to six hours) may be preferred because of its longer half-life, lower frequency of hepatic toxicity, and because it ultimately restores euthyroidism more quickly than PTU. Patients initially treated with PTU should be transitioned to methimazole before discharge from the hospital. (See 'Thionamides' above and "Thionamides: Side effects and toxicities" and 'Subsequent management' above.)

•Thionamide intolerance – For patients with contraindications to thionamides who require urgent correction of hyperthyroidism, surgery is the treatment of choice. Patients who are to undergo surgery require preoperative treatment of thyrotoxicosis. We typically treat with beta blockers (if not contraindicated, propranolol 60 to 80 mg every four to six hours), glucocorticoids to inhibit conversion of T4 to T3 (eg, dexamethasone, 1 to 2 mg every six hours), bile acid sequestrants (eg, cholestyramine 4 g orally four times daily), and, in patients with Graves' disease, iodine (SSKI, 5 drops [50 mg iodide/drop] orally every six hours; or Lugol's solution, 10 drops [6.25 mg iodide/iodine per drop] every eight hours). Optimal preoperative treatment is approximately 10 days, but depending upon clinical considerations and surgical availability, 5 to 14 days of treatment with iodine preoperatively is reasonable. (See 'Thionamides' above and "Surgical management of hyperthyroidism", section on 'Patients unable to take a thionamide drug'.)

•Subsequent management – After there is evidence of clinical improvement (eg, defervescence, resolution of central nervous system and cardiovascular manifestations), some medications can be discontinued and others reduced. Long-term antithyroid therapy is required to prevent a recurrence of severe thyrotoxicosis. Individual patient factors may influence the choice of definitive therapy, and the selection of therapy should involve discussion of the values and preferences of the patient. (See 'Subsequent management' above and "Graves' hyperthyroidism in nonpregnant adults: Overview of treatment" and "Treatment of toxic adenoma and toxic multinodular goiter".)