Thyroid Storm

Thyroid storm is a decompensated state of thyroid hormone–induced, severe hypermetabolism involving multiple systems and is the most extreme state of thyrotoxicosis. The clinical picture relates to severely exaggerated effects of THs due to increased release (with or without increased synthesis) or, rarely, increased intake of TH.

Heat intolerance and diaphoresis are common in simple thyrotoxicosis but manifest as hyperpyrexia in thyroid storm. Extremely high metabolism also increases oxygen and energy consumption. Cardiac findings of mild-to-moderate sinus tachycardia in thyrotoxicosis intensify to accelerated tachycardia, hypertension, high-output cardiac failure, and a propensity to develop cardiac arrhythmias. Similarly, irritability and restlessness in thyrotoxicosis progress to severe agitation, delirium, seizures, and coma.[4] GI manifestations of thyroid storm include diarrhea, vomiting, jaundice, and abdominal pain, in contrast to only mild elevations of transaminases and simple enhancement of intestinal transport in thyrotoxicosis.

Thyroid storm is precipitated by the following factors in individuals with thyrotoxicosis:

• Sepsis
• Surgery
• Anesthesia induction ^[5]
• Radioactive iodine (RAI) therapy ^[6]
• Drugs (anticholinergic and adrenergic drugs, eg, pseudoephedrine; salicylates; nonsteroidal anti-inflammatory drugs [NSAIDs]; chemotherapy ^[7]
• Excessive thyroid hormone (TH) ingestion
• Withdrawal of or noncompliance with antithyroid medications
• Diabetic ketoacidosis ^[8]
• Direct trauma to the thyroid gland
• Vigorous palpation of an enlarged thyroid
• Toxemia of pregnancy and labor in older adolescents; molar pregnancy

Thyroid storm can occur in children with thyrotoxicosis from any cause but is most commonly associated with Graves disease. Other reported causes of thyrotoxicosis associated with thyroid storm include the following:

• Transplacental passage of maternal thyroid-stimulating immunoglobulins in neonates
• McCune-Albright syndrome with autonomous thyroid function ^[9]
• Hyperfunctioning thyroid nodule
• Hyperfunctioning multinodular goiter
• Thyroid-stimulating hormone (TSH)-secreting tumor

Graves disease may also occur in children with Down syndrome or Turner syndrome and in association with other autoimmune conditions, including the following:

• Juvenile rheumatoid arthritis
• Addison disease
• Type I diabetes
• Myasthenia gravis
• Chronic lymphocytic (Hashimoto) thyroiditis
• Systemic lupus erythematosus
• Chronic active hepatitis
• Nephrotic syndrome

The pathophysiologic mechanisms of Graves disease are shown in the image below.

Pathophysiologic mechanisms of Graves disease relating thyroid-stimulating immunoglobulins to hyperthyroidism and ophthalmopathy. T4 is levothyroxine. T3 is triiodothyronine.

Although the exact pathogenesis of thyroid storm is not fully understood, the following theories have been proposed:

• Patients with thyroid storm reportedly have relatively higher levels of free THs than patients with uncomplicated thyrotoxicosis, although total TH levels may not be increased.
• Adrenergic receptor activation is another hypothesis. Sympathetic nerves innervate the thyroid gland, and catecholamines stimulate TH synthesis. In turn, increased THs increase the density of beta-adrenergic receptors, thereby enhancing the effect of catecholamines. The dramatic response of thyroid storm to beta-blockers and the precipitation of thyroid storm after accidental ingestion of adrenergic drugs such as pseudoephedrine support this theory. This theory also explains normal or low plasma levels and urinary excretion rates of catecholamines. However, it does not explain why beta-blockers fail to decrease TH levels in thyrotoxicosis.
• Another theory suggests a rapid rise of hormone levels as the pathogenic source. A drop in binding protein levels, which may occur postoperatively, might cause a sudden rise in free hormone levels. In addition, hormone levels may rise rapidly when the gland is manipulated during surgery, during vigorous palpation during examination, or from damaged follicles following RAI therapy.
• Other proposed theories include alterations in tissue tolerance to THs, the presence of a unique catecholaminelike substance in thyrotoxicosis, and a direct sympathomimetic effect of TH as a result of its structural similarity to catecholamines.

Frequency

In the US, the true frequency of thyrotoxicosis and thyroid storm in children is unknown. The incidence of thyrotoxicosis increases with age. Thyrotoxicosis may affect as many as 2% of older women. Children constitute less than 5% of all thyrotoxicosis cases. Graves disease is the most common cause of childhood thyrotoxicosis and, in a possibly high estimate, reportedly affects 0.2-0.4% of the pediatric and adolescent population. About 1-2% of neonates born to mothers with Graves disease manifest thyrotoxicosis.

Based on nationwide surveys conducted between 2004 and 2008, the incidence of thyroid storm in Japan has been estimated to be 0.2 persons per 100,000 population, with the rate of thyroid storm in all thyrotoxic patients being 0.22%, and in hospitalized thyrotoxic patients, 5.4%.[10]

Sex

Thyrotoxicosis is 3-5 times more common in females than in males, especially among pubertal children. Thyroid storm affects a small percentage of patients with thyrotoxicosis. The incidence is presumed to be higher in females; however, no specific data regarding sex-specific incidence are available.

Age

Neonatal thyrotoxicosis occurs in 1-2% of neonates born to mothers with Graves disease. Infants younger than 1 year constitute only 1% of cases of childhood thyrotoxicosis. More than two thirds of all cases of thyrotoxicosis occur in children aged 10-15 years. Overall, thyrotoxicosis occurs most commonly during the third and fourth decades of life. Because childhood thyrotoxicosis is more likely to occur in adolescents, thyroid storm is more common in this age group, although it can occur in patients of all ages.

Thyroid storm is an acute, life-threatening emergency. If untreated, thyroid storm is almost invariably fatal in adults (90% mortality rate) and is likely to cause a similarly severe outcome in children, although the condition is so rare in children that these data are not available. Death from thyroid storm may be a consequence of cardiac arrhythmia, congestive heart failure, hyperthermia, multiple organ failure, or other factors,[11] though the precipitating factor is often the cause of death.

With adequate thyroid-suppressive therapy and sympathetic blockade, clinical improvement should occur within 24 hours. Adequate therapy should resolve the crisis within a week. Treatment for adults has reduced mortality to less than 20%. In one retrospective study from Japan of 1324 patients who were diagnosed with thyroid storm, the overall mortality was 10%.[12]  In the same study, the following factors were associated with increased mortality risk in thyroid storm[12] :

• Age 60 years or older
• Central nervous system (CNS) dysfunction at admission
• Lack of antithyroid drug and beta-blockade use
• Need for mechanical ventilation and plasma exchange along with hemodialysis

In addition, a study by Swee et al of 28 patients with thyroid storm reported that CNS dysfunction of greater than mild severity appeared to be a risk factor for mortality.[13]

Using the National (Nationwide) Inpatient Sample database, a study by Waqar et al indicated that in hospitalized patients with thyroid storm, the inhospital mortality rate is higher in those with cardiovascular events than in persons without (3.5% vs 0.2%, respectively). The cardiovascular events that were most frequently associated with thyroid storm in hospitalized patients were arrhythmia (96.8%), acute heart failure (14.2%), and ischemic events (3.9%). Of patients with an ischemic event, 16.7% suffered inhospital mortality, compared with 3.6% and 3.2% of those with acute heart failure or arrhythmia, respectively.[14]

A retrospective study by Bourcier et al of 31 French intensive care units (ICUs) found that in ICU patients with thyroid storm, multiple organ failure (as evaluated using the Sequential Organ Failure Assessement [SOFA] score, absent the cardiovascular component), and the occurrence, within 48 hours following ICU admission, of cardiogenic shock are independent risk factors for mortality in the ICU.[15]

A study by Burmeister reported a mortality rate of 38% in patients with thyroid storm–related coma, including 70% between 1935 and 1977, and 11% between 1978 and 2019. The investigator found that there was a greater tendency for patients to awaken from their coma when total and free T4 values, and possibly the total T3 value as well, was reduced. Moreover, the employment of antithyroid drugs, corticosteroids, beta blockers, and intubation correlated positively with lower death rates. Although plasmapheresis-related awakenings occurred in 67% of patients in which plasmapheresis was used, the procedure was not linked to a reduction in the death rate.[16]

For excellent patient education resources, visit eMedicineHealth's Thyroid and Metabolism Center. Also, see eMedicineHealth's patient education articles Thyroid Problems and Thyroid Storm.

Patients may have a known history of thyrotoxicosis. In the absence of previously diagnosed thyrotoxicosis, the history may include symptoms such as irritability, agitation, emotional lability, a voracious appetite with poor weight gain, excessive sweating and heat intolerance, and poor school performance caused by decreased attention span. Burch and Wartofsky have published precise criteria and a scoring system for the diagnosis of thyroid storm based on clinical features.[2]

• General symptoms

  • Fever

  • Profuse sweating

  • Poor feeding and weight loss

  • Respiratory distress

  • Fatigue (more common in older adolescents)

• GI symptoms

  • Nausea and vomiting

  • Diarrhea

  • Abdominal pain

  • Jaundice[3]

• Neurologic symptoms

  • Anxiety (more common in older adolescents)

  • Altered behavior

  • Seizures, coma

Physical findings include the following:

• Fever

  • Temperature consistently exceeds 38.5°C.

  • Patients may progress to hyperpyrexia.

  • Temperature frequently exceeds 41°C.

• Excessive sweating

• Cardiovascular signs

  • Hypertension with wide pulse pressure

  • Hypotension in later stages with shock

  • Tachycardia disproportionate to fever

  • Signs of high-output heart failure

  • Cardiac arrhythmia (Supraventricular arrhythmias are more common, [eg, atrial flutter and fibrillation], but ventricular tachycardia may also occur.)

• Neurologic signs

  • Agitation and confusion

  • Hyperreflexia and transient pyramidal signs

  • Tremors, seizures

  • Coma

• Signs of thyrotoxicosis

  • Orbital signs

  • Goiter

• Rhabdomyolysis - Rare cases have been reported following a diagnosis of thyroid storm in adults[17]

Complications of thyroid storm include:

• High output cardiac failure
• Cardiac arrhythmias
• Delirium, seizures, coma
• Abdominal pain, diarrhea, vomiting, jaundice
• Elevation of transaminases

A study by Mohananey et al found that out of 41,835 US patients with thyroid storm, 1% developed cardiogenic shock, with the incidence of this complication in these patients rising between 2003 and 2011 from 0.5% to 3%. However, during this same period the mortality rate from cardiogenic shock in patients with thyroid storm decreased from 60.5% to 20.9%. The highest likelihood of cardiogenic shock was in male patients with preexisting atherosclerotic or structural heart disease.[18]

Thyroid storm diagnosis is based on clinical features, not on laboratory test findings. If the patient's clinical picture is consistent with thyroid storm, do not delay treatment pending laboratory confirmation of thyrotoxicosis.

Results of thyroid studies are usually consistent with hyperthyroidism and are useful only if the patient has not been previously diagnosed.

• Test results may not come back quickly and are usually unhelpful for immediate management.

• Usual findings include elevated triiodothyronine (T3), thyroxine (T4), and free T4 levels; increased T3 resin uptake; suppressed thyroid-stimulating hormone (TSH) levels; and an elevated 24-hour iodine uptake. TSH levels are not suppressed in the rare instances of excess TSH secretion.

• CBC count: CBC count reveals mild leukocytosis, with a shift to the left.

• Liver function tests (LFTs): LFTs commonly reveal nonspecific abnormalities such as elevated levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), creatinine kinase, alkaline phosphatase, and serum bilirubin.

• ABG and urinalysis: Measurement of blood gas and electrolyte levels and urinalysis testing may be performed to assess and monitor short-term management.

• Hypercalcemia may occur from thyrotoxicosis.

Chest radiography may reveal cardiac enlargement due to congestive heart failure. Radiography may also reveal pulmonary edema caused by heart failure and/or evidence of pulmonary infection.

Head CT scanning may be necessary to exclude other neurologic conditions if diagnosis is uncertain after the initial stabilization of a patient who presents with altered mental status.

ECG is useful in monitoring for cardiac arrhythmias. Atrial fibrillation is the most common cardiac arrhythmia associated with thyroid storm. Other arrhythmias such as atrial flutter and, less commonly, ventricular tachycardia may also occur.

The approach to treatment of thyroid storm includes the following:

• Supportive measures
• Antiadrenergic drugs
• Thionamides
• Iodine preparations
• Glucocorticoids
• Bile acid sequestrants
• Treatment of the underlying condition
• Rarely plasmapheresis

Patients with contraindications to thionamides need to be managed with supportive measures, aggressive beta blockade, iodine preparations, glucocorticoids, and bile acid sequestrants for about a week in preparation for a thyroidectomy. Plasmapheresis may be attempted if other measures are not effective. 

Patients with thyroid storm should be treated in an ICU setting for close monitoring of vital signs and for access to invasive monitoring and inotropic support, if necessary. Initial stabilization and management of systemic decompensation is as follows:

• Supportive measures

  • If needed, immediately provide supplemental oxygen, ventilatory support, and intravenous fluids. Dextrose solutions are the preferred intravenous fluids to cope with continuously high metabolic demand.

  • Correct electrolyte abnormalities.

  • Treat cardiac arrhythmia, if necessary.

  • Aggressively control hyperthermia by applying ice packs and cooling blankets and by administering acetaminophen (15 mg/kg orally or rectally every 4 hours).

• Antiadrenergic drugs

  • Promptly administer antiadrenergic drugs (eg, propranolol) to minimize sympathomimetic symptoms. Propranolol is administered orally or via nasogastric tube at a dose of 60-80 mg every 4-6 hours and the dose adjusted based on heart rate and blood pressure. It may also be given intravenously when necessary for rapid onset of action (0.5-1 mg over 10 min followed by 1-2 mg over 10 min every few hours, adjusted based on vital signs). It is important to avoid propranolol in conditions such as asthma, chronic obstructive pulmonary disease, peripheral vascular disease, or decompensated heart failure. Cardioselective beta blockers such as atenolol or metoprolol may be administered in patients with reactive airway disease, and calcium channel blockers may be used when beta blockers are contraindicated. The use of intravenous short acting beta-1 blockers, such as esmolol (loading dose of 250-500 mcg/kg, followed by an infusion of 50-100 mcg/kg per minute), allows quick dose titration with minimization of side effects.

  • Dosing of beta blockers for thyroid storm in a pediatric population:

    • Propranolol: Neonates: 2 mg/kg per day PO/NGT divided every 6-12 hours; Children: 0.5-4 mg/kg per day PO/NGT divided every 6 hours (not to exceed 60 mg per day) or 0.01-0.02 mg/kg IV over 10 minutes (may repeat over 10’ every few hours to a maximum cumulative dose of 5 mg)
    • Esmolol: Loading dose: 250-500 mcg/kg over 1 minute, repeat as needed, maintenance dose: 50-100 mcg/kg per minute IV infusion

• Thionamides: Correct the hyperthyroid state. Administer antithyroid medications to block further synthesis of thyroid hormones (THs).

  • High-dose propylthiouracil (PTU) or methimazole may be used for treatment of thyroid storm. PTU has a theoretical advantage in severe thyroid storm because of its early onset of action and capacity to inhibit peripheral conversion of T4 to T3. However, a study by the taskforce committee of the Japan Thyroid Association (JTA) and the Japan Endocrine Society (JES) found evidence that in severe thyroid storm, T4-to-T3 conversion may already be reduced. The taskforce also found that disease severity and mortality did not significantly differ between thyroid storm patients in the study who were managed with methimazole or PTU.[19]

  • Dosing for thyroid storm in adults is as follows: PTU 200 mg every 4 hours or methimazole 20 mg orally every 4-6 hours; these drugs may need to be administered through a nasogastric tube. Guidelines released in 2016 by the JTA/JES recommended the use of intravenous methimazole in severe cases of thyroid storm; however, intravenous methimazole is not currently available in the United States.[19, 20]

  • Dosing for thyroid storm in children is as follows: PTU in neonates: 5-10 mg/kg per day PO/NGT divided every 6-8 hours; PTU in children: 15-20 mg/kg per day PO/NGT divided every 6-8 hours (up to 40 mg/kg per day has been used; not to exceed 1200 mg per day); recommendations for methimazole dosing are variable (a reasonable starting dose is about one tenth of the PTU dose given every 6-8 hours).

  • Of note, the US Food and Drug Administration (FDA) has added a boxed warning, the strongest warning issued by the FDA, to the prescribing information for PTU.

    • The boxed warning emphasizes the risk for severe liver injury and acute liver failure, some of which have been fatal. The boxed warning also states that PTU should be reserved for use in those who cannot tolerate other treatments such as methimazole, radioactive iodine, or surgery.

    • The decision to include a boxed warning was based on the FDA's review of postmarketing safety reports and meetings held with the American Thyroid Association, the National Institute of Child Health and Human Development, and the pediatric endocrine clinical community.

    • The FDA has identified 32 cases (22 adult and 10 pediatric) of serious liver injury associated with PTU. Among adults, 12 deaths and 5 liver transplants occurred; among the pediatric patients, 1 death and 6 liver transplants occurred. PTU is indicated for hyperthyroidism due to Graves disease. These reports suggest an increased risk for liver toxicity with PTU compared with methimazole. Serious liver injury has been identified with methimazole in 5 cases (3 resulting in death).

    • PTU is now considered as a second-line drug therapy for treatment of hyperthyroidism in general (though not thyroid storm), except in patients who are allergic or intolerant to methimazole, or women who are in the first trimester of pregnancy. Rare cases of embryopathy, including aplasia cutis, have been reported with methimazole during pregnancy. For more information, see the FDA Safety Alert.[21] The FDA recommends the following criteria be considered for prescribing PTU.

    • Reserve PTU use for during first trimester of pregnancy or for patients who are allergic to or intolerant of methimazole.
    • Closely monitor patients undergoing PTU therapy for signs and symptoms of liver injury, especially during the first 6 months after initiation of therapy.
    • For suspected liver injury, promptly discontinue PTU therapy and evaluate for evidence of liver injury and provide supportive care.
    • PTU should not be used in pediatric patients unless the patient is allergic to or intolerant of methimazole and no other treatment options are available.
    • Counsel patients to promptly contact their health care provider for the following signs or symptoms: fatigue, weakness, vague abdominal pain, loss of appetite, itching, easy bruising, or yellowing of the eyes or skin.

  • If the patient is given PTU during treatment of thyroid storm, this should be switched to methimazole at the time of discharge unless methimazole is contraindicated. If methimazole is contraindicated, alternative methods to treat hyperthyroidism should be considered after discharge, such as radioactive iodine or surgery.

  • One retrospective review found no difference in mortality rates in patients with thyroid storm treated with PTU vs. methimazole.[22]

• Iodine compounds:

  • Administer iodine compounds (Lugol iodine or potassium iodide) orally or via a nasogastric tube to block the release of THs (at least 1 h after starting antithyroid drug therapy). In adults, SSKI is a given at a dose of 5 drops every 6 hours, or Lugol's iodine at a dose of 10 drops every 8 hours. If available, intravenous radiocontrast dyes such as ipodate and iopanoate can be effective in this regard. These agents are particularly effective at preventing peripheral conversion of T4 to T3.

  • Dosing of iodine compounds for thyroid storm in children:

    • SSKI (50 mg iodide per drop): Neonates: 2 drops PO/NGT every 6-8 hours; Children: 2-5 drops PO/NGT every 6 hours

    • Lugol's iodine (8 mg iodine/drop): 10 drops PO/NGT every 8 hours

• Glucocorticoids

  • Administer glucocorticoids to decrease peripheral conversion of T4 to T3. This may also be useful in preventing relative adrenal insufficiency due to hyperthyroidism and improving vasomotor symptoms. Hydrocortisone is administered intravenously at a dose of 100 mg every 8 hours or dexamethasone at a dose of 1-2 mg every 6 hours. 

  • Dosing of glucocorticoids for thyroid storm in children:

    • Hydrocortisone: 5 mg/kg (up to 100 mg) intravenously every 6-8 hours

    • Dexamethasone: 0.1-0.2 mg/kg per day divided every 6-8 hours

• Bile acid sequestrants prevent reabsorption of free THs in the gut (released from conjugated TH metabolites secreted into bile through the enterohepatic circulation). A recommended dose is 4 g of cholestyramine every 6 hours via a nasogastric tube. Another option is 20-30 g/day of Colestipol-HCl.[11]

• Treat the underlying condition, if any, that precipitated thyroid storm and exclude comorbidities such as diabetic ketoacidosis and adrenal insufficiency. Infection should be treated with antibiotics.

• Rarely, as a life-saving measure, plasmapheresis has been used to treat thyroid storm in adults.[23]

Iodine preparations should be discontinued once the acute phase resolves and the patient becomes afebrile with normalization of cardiac and neurological status. Glucocorticoids should be weaned and stopped and the dose of thioamides adjusted to maintain thyroid function in the normal range. Beta-blockers may be discontinued once thyroid function normalizes.

If the patient is given PTU during treatment of thyroid storm, this should be switched to methimazole at the time of discharge unless methimazole is contraindicated. If there is a contraindication for the use of methimazole, alternative methods to treat hyperthyroidism should be considered after discharge, such as radioactive iodine or surgery.

Patients with contraindications to thionamides need to be managed with supportive measures, aggressive beta blockade, iodine preparations, glucocorticoids and bile acid sequestrants for about a week in preparation for a thyroidectomy. Plasmapheresis may be attempted if other measures are not effective. 

Patients with Graves disease who need urgent treatment of hyperthyroidism but have absolute contraindications to thioamides may be treated acutely with beta-blockers, iodine preparations, glucocorticoids, and bile acid sequestrants as described. Plasmapheresis is sometimes used as a last resort if other measures are not effective. Subsequently, thyroidectomy may be performed after about 7 days of iodine administration. Iodine reduces the vascularity of the gland and the risk for thyroid storm.

In rare patients with hyperthyroidism, thyroid artery embolization has been used as adjuntive therapy[24, 25, 26] .  In one case series, this strategy caused an increase in thyroid hormone levels over the first three days following embolization followed by a subsequent reduction in levels (with normalization in nine out of twelve patients by 12 weeks), but the majority did not achieve permanent remission[26] .  In one reported case of a 64 year old man in whom thyroid hormone levels remained elevated and the patient remained unstable despite steroids, a thionamide, beta blockers and plasmapheresis, thyroid artery embolization was performed as the patient had contraindications to radioactive iodine and surgery[25] . Thyroid hormone levels increased over the first 2-3 days, but decreased from baseline after a week of the procedure. The goal of embolization in this patient was to cause atrophy, but not acute necrosis of the gland given the risk of thyroid storm with the latter. Subsequently, the patient's clinical condition improved and he was able to undergo a thyroidectomy.

The following consultations are indicated:

• Endocrinologist

• Intensivist

Promptly and appropriately treat thyrotoxicosis after diagnosis. Perform surgery in thyrotoxic patients only after appropriate thyroid and/or beta-adrenergic blockade.

Thyroid storm following radioactive iodine (RAI) therapy for hyperthyroidism may be related to (1) withdrawal of antithyroid medications for RAI administration (usually withdrawn 5-7 d before administration of RAI and held until 5-7 d after RAI therapy), (2) release of large amounts of thyroid hormone from damaged follicles, and (3) RAI itself. Because TH levels are often higher immediately before RAI treatment than they are afterward, many endocrinologists believe that withdrawal of antithyroid drugs is the cause of thyroid storm. One option is to stop antithyroid drugs (including methimazole) only 3 days (rather than 5-7 d) before RAI therapy and to restart antithyroid drugs 3 days after RAI administration. Early institution of antithyroid drugs after RAI therapy may decrease the efficacy of treatment, requiring a second dose.

Consider testing thyroid function before operative procedures in children at high risk for hyperthyroidism (eg, patients with McCune-Albright syndrome).

In 2016, the Japan Thyroid Association and Japan Endocrine Society released guidelines for the management of thyroid storm. Recommendations include the following[20] :

• A multimodality approach with antithyroid drugs, inorganic iodide, corticosteroids, beta-adrenergic receptor antagonists, and antipyretic agents should be used to ameliorate thyrotoxicosis and its adverse effects on multiple organ systems
• Antithyroid drugs, either methimazole or propylthiouracil, should be administered for the treatment of hyperthyroidism in thyroid storm
• Intravenous administration of methimazole is recommended in severely ill patients with consciousness disturbances or impaired gastrointestinal tract function
• Inorganic iodide should be administered simultaneously with antithyroid drugs to patients with thyroid storm caused by thyrotoxic diseases associated with hyperthyroidism
• Corticosteroids (300 mg/day hydrocortisone or 8 mg/day dexamethasone) should be administered to patients with thyroid storm regardless of its origin
• Aggressive cooling with acetaminophen and mechanical cooling with cooling blankets or ice packs should be performed for thyroid storm patients with high fever
• The focus of infection should be investigated in patients with high fever and accompanying infection should be treated
• In addition to prompt treatment of thyrotoxicosis, differential diagnosis and treatment of acute disturbances of consciousness, psychosis, and convulsion in thyroid storm should be performed based on established guidelines in consultation with a psychiatrist or neurologist
• Since thyrotoxicosis and dysfunction of multiple organs such as the liver and kidney can affect pharmacokinetics in thyroid storm patients, the condition of each patient should be considered individually when selecting and adjusting doses of psychotropic medications
• Beta1-selective adrenergic receptor antagonists (landiolol, esmolol [intravenous], or bisoprolol [oral]) should be selected as the first choice of treatment for tachycardia in thyroid storm; other beta1-selective oral drugs are also recommended; although the nonselective beta-adrenergic receptor antagonist propranolol is not contraindicated, it is not recommended for the treatment of tachycardia in thyroid storm
• When atrial fibrillation occurs, digitalis is used in patients without severe renal dysfunction (it is given intravenously at an initial dose of 0.125 to 0.25 mg, followed by an appropriate maintenance dose with careful monitoring for signs and symptoms of digitalis toxicity); when hemodynamics are impaired rapidly because of atrial fibrillation, cardioversion is recommended when left atrial thrombus has been ruled out; class Ia and Ic antiarrhythmics are recommended to maintain sinus rhythm after cardioversion (amiodarone may be considered for patients with impaired left ventricular systolic function)
• Anticoagulation should be used for persistent atrial fibrillation based on the CHADS2 (congestive heart failure, hypertension, age ≥75, diabetes mellitus, stroke [doubled]) score, which has been used to evaluate the risk of stroke onset
• Gastrointestinal symptoms, including diarrhea, nausea, and vomiting, are associated with thyrotoxicosis, heart failure, neurologic disorders, and gastrointestinal infection; treatment for gastrointestinal infection should be performed in parallel with that for thyrotoxicosis to improve gastrointestinal symptoms
• Administration of large doses of corticosteroids, coagulopathy associated with thyroid storm, and intensive care unit (ICU) stay with prolonged mechanical ventilation may be risk factors for gastrointestinal hemorrhage and mortality; acid-suppressive drugs such as proton pump inhibitors or histamine-2 receptor antagonists are recommended for patients in these instances
• Hepatotoxicity with or without jaundice in thyroid storm can be caused by hepatocyte damage due to thyrotoxicosis, heart failure, precipitating hepatic-biliary infection, or drug-induced liver damage; nationwide surveys showed that patient prognosis is worse when total bilirubin levels are ≥3.0 mg/dL; differential diagnosis for the origin of hepatic dysfunction and appropriate treatment based on its origin should be performed, including therapeutic plasmapheresis for acute hepatic failure
• ICU admission should be recommended for all thyroid storm patients; patients with potentially fatal conditions such as shock, disseminated intravascular coagulation (DIC), and multiple organ failure should immediately be admitted to the ICU
• Based on nationwide survey analyses, it is strongly recommended that patients with APACHE II (Acute Physiologic Assessment and Chronic Health Evaluation II) scores above 9 be admitted to the ICU
• DIC, which is often complicated with thyroid storm, should be intensively treated because DIC was shown to be associated with high mortality in the Japan Thyroid Association nationwide surveys
• The APACHE II score or Sequential Organ Failure Assessment score can be used for the prognostic prediction of thyroid storm
• Care should be taken to prevent thyroid storm in patients with poor adherence who are undergoing antithyroid drug treatment
• Definitive treatment of Graves disease, either by radioiodine treatment or thyroidectomy, should be considered to prevent recurrent thyroid storm in patients successfully managed during the acute stage of thyroid storm
• When patients with high fever (≥38°C), marked tachycardia (≥130 bpm), and symptoms originating from multiple organ systems such as the central nervous system, cardiovascular system, and gastrointestinal tract present, it is important to consider the possibility of thyroid storm

Therapy is aimed at (1) ameliorating hyperadrenergic effects of thyroid hormone (TH) on peripheral tissues with use of beta-blockers (eg, propranolol, labetalol); (2) decreasing further synthesis of THs with antithyroid medications (eg, propylthiouracil [PTU], methimazole); (3) decreasing hormonal release from the thyroid, using iodides; and (4) preventing further TH secretion and peripheral conversion of T4 to T3, using glucocorticoids or iodinated radiocontrast dyes when available.

Based on evidence and frequency estimates, Rivkees and Mattison have raised significant concerns regarding the potential for severe liver disease in children due to PTU.[27] This side effect is not seen with methimazole, and current recommendations (endorsed by the Endocrine Society) are to preferentially use methimazole in the pediatric population for treatment of Graves disease. The use of PTU in conditions of thyroid storm was not specifically addressed; however, the use of PTU may be preferred in this setting because of the ability of this drug to inhibit conversion of T4 to T3.

Of note, one retrospective chart review from Japan has reported a higher risk of mortality in patients receiving non-selective bea-blockers compared with selective beta-blockers[22] .

Class Summary

These agents belong to the thioureylene (thionamide) class and inhibit synthesis of THs within 1-2 hours. They have no effect on decreasing the release of preformed THs.

Propylthiouracil (PTU, Propyl-Thyracil)

DOC that inhibits synthesis of TH by preventing organification and trapping of iodide to iodine and by inhibiting coupling of iodotyrosines; also inhibits peripheral conversion of T4 to T3, an important component of management.

Comatose patients may require administration via NG tube because the agent is available solely as PO preparation; has been successfully administered PR as an enema or suppository. Very rarely, in patients who cannot take the medication PO, via NG, or PR, IV administration has been described. The IV preparation should be made by the hospital pharmacy by dissolving tablets in normal saline rendered alkaline by adding sodium hydroxide to obtain a pH of 9.25; it is essential to ensure sterility.

Methimazole (Tapazole)

Inhibits synthesis of TH by preventing organification of iodide to iodine and coupling of iodotyrosines. Although at least 10 times more potent than PTU on a weight basis, it does not inhibit peripheral conversion of T4 to T3. May be used instead of PTU in thyroid storm if iodinated radiocontrast agents are used in conjunction to prevent the conversion of T4 to T3 or if the condition is not life-threatening.

Comatose patients may require administration via NG tube because agent is available only as a PO preparation. In rare instances, it may be necessary to administer methimazole PR as an enema or suppository or IV after dissolving tablets in normal saline at a neutral pH and filtering the solution through a fine filter. PR and IV preparations should be made by the hospital pharmacy; it is essential to ensure sterility of IV preparations.

Class Summary

Iodides inhibit the release of TH from the thyroid gland. Precede iodide administration with thionamides by at least 1 hour to prevent increased intrathyroidal TH synthesis. Iodinated radiographic contrast dyes that contain ipodate (Oragrafin) or iopanoic acid (Telepaque) have also been used and effectively prevent conversion of T4 to T3. However, their utility in childhood thyroid storm is untested. Another benefit of these radiocontrast agents is the once-daily dosing regimen, as opposed to 3-4 daily doses with iodine-containing oral solutions. Currently, these radiocontrast agents are no longer available in the United States. Lithium carbonate may be used if the patient is hypersensitive to iodine.

Potassium iodide, saturated solution (Pima, SSKI, Thyro-Block)

This agent is used to inhibit TH release from the thyroid gland. One mL of SSKI contains 1 g of potassium iodide or 750 mg of iodide (ie, approximately 50 mg iodide/drop and 15 drops per mL). Because of the viscosity, SSKI comes as 15 drops per mL rather than the usual 20 drops per mL.

Strong iodine (Lugol Solution)

Contains 100 mg potassium iodide and 50 mg iodine; provided 8 mg iodide/drop, 20 drops per ml.

Class Summary

These agents are used as the mainstay therapy to control autonomic effects of TH. Beta-blockers also block peripheral conversion of T4 to T3. Esmolol, a short-acting selective beta 1-antagonist, has been used successfully in children, as has labetalol in adults. Beta-blockers should be used with caution in congestive cardiac failure and thyrotoxic cardiomyopathy. In the latter case, they have been known to precipitate cardiac arrest.

Propranolol (Inderal)

DOC most widely used in this group; is a nonselective beta–adrenergic antagonist. Decreases heart rate, myocardial contractility, BP, and myocardial oxygen demand. Often the only adjunctive drug needed to control thyroid storm symptoms.

Esmolol (Brevibloc)

Beta 1–specific antagonist with a short duration of action.

Class Summary

These agents block conversion of T4 to T3. The use of corticosteroids has been associated with improved survival. Stress doses are required to replace accelerated production and degradation of cortisol induced by TH. If corticosteroids are not administered, acute glucocorticoid deficiency hypothetically could occur because demand may outpace production.

Hydrocortisone (Solu-Cortef)

Hydrocortisone provides mineralocorticoid activity and glucocorticoid effects and may help ameliorate decreased adrenal reserve. It reduces the conversion of T4 to T3.

Dexamethasone (Decadron)

Dexamethasone elicits glucocorticoid effects; however, hydrocortisone is preferred in thyroid storm.