Background

Thyroid storm, also referred to as thyrotoxic crisis, is an acute, life-threatening, hypermetabolic state induced by excessive release of thyroid hormones (THs) in individuals with thyrotoxicosis. Thyroid storm may be the initial presentation of thyrotoxicosis in undiagnosed children, particularly in neonates. The clinical presentation includes fever, tachycardia, hypertension, and neurological and GI abnormalities. Hypertension may be followed by congestive heart failure that is associated with hypotension and shock. Because thyroid storm is almost invariably fatal if left untreated, rapid diagnosis and aggressive treatment are critical. Fortunately, this condition is extremely rare in children. Diagnosis is primarily clinical, and no specific laboratory tests are available. Several factors may precipitate the progression of thyrotoxicosis to thyroid storm. In the past, thyroid storm was commonly observed during thyroid surgery, especially in older children and adults, but improved preoperative management has markedly decreased the incidence of this complication. Today, thyroid storm occurs more commonly as a medical crisis rather than a surgical crisis.

Pathophysiology
Thyroid storm is a decompensated state of thyroid hormoneinduced, 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.[1] 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.

Epidemiology
Frequency
United States 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.

Mortality/Morbidity
Thyroid storm is an acute, life-threatening emergency. The adult mortality rate is extremely high (90%) if early diagnosis is not made and the patient is left untreated. With better control of thyrotoxicosis and early management of thyroid storm, adult mortality rates have declined to less than 20%.

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 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.

History
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] o o o o o o o o o o o o 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
Physical findings include the following: o o o o o o o Fever Temperature consistently exceeds 38.5C. Patients may progress to hyperpyrexia. Temperature frequently exceeds 41C. 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

o o o o o o o

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

Causes
The causes of thyroid storm are as follows: o o o o o o o o o o o o o o o o o o o o o o o o Thyroid storm is precipitated by the following factors in individuals with thyrotoxicosis: Sepsis Surgery Anesthesia induction[4] Radioactive iodine (RAI) therapy[5] Drugs (anticholinergic and adrenergic drugs such as pseudoephedrine; salicylates; nonsteroidal antiinflammatory drugs [NSAIDs]; chemotherapy[6] ) Excessive thyroid hormone (TH) ingestion Withdrawal of or noncompliance with antithyroid medications Diabetic ketoacidosis 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 due to 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[7] 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.

o o

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 betaadrenergic 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.

Differentials
Anxiety Disorder: Panic Disorder Heart Failure, Congestive Hypertension Hyperthyroidism Pheochromocytoma Supraventricular Tachycardia, Atrial Ectopic Tachycardia

Laboratory Studies
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.

Thyroid studies Results of thyroid studies are usually consistent with hyperthyroidismand are useful only if the patient has not been previously diagnosed. o Test results may not come back quickly and are usually unhelpful for immediate management. o 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.
o

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.

Imaging Studies
The following imaging studies may be indicated:
o o

Chest radiography 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. CT scanning: 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.

Other Tests
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.

Medical Care
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:

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 h). Promptly administer antiadrenergic drugs (eg, propranolol) to minimize sympathomimetic symptoms. Correct the hyperthyroid state. Administer antithyroid medications to block further synthesis of thyroid hormones (THs). High-dose propylthiouracil (PTU) is preferred because of its early onset of action and capacity to inhibit peripheral conversion of T4 to T3. The US Food and Drug Administration (FDA) had added a boxed warning, the strongest warning issued by the FDA, to the prescribing information for PTU. o 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. o 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. o 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 considered as a second-line drug therapy, except in patients who are allergic or intolerant to methimazole, or for 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.[8] The FDA recommends the following criteria be considered for prescribing PTU: Reserve PTU use during first trimester of pregnancy, or in patients who are allergic to or intolerant of methimazole. Closely monitor 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.

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). 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. Administer glucocorticoids to decrease peripheral conversion of T4 to T3. This may also be useful in preventing relative adrenal insufficiency due to hyperthyroidism. 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.[9] 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.

Surgical Care
Patients with Graves disease who need urgent treatment of hyperthyroidism but have absolute contraindications to thioamides may be managed acutely with beta-blockers, iodine preparations, and glucocorticoids as described. 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.

Consultations
The following consultations are indicated: Endocrinologist Intensivist

Medication Summary
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. [10] 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.

Antithyroids
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.

Iodides
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 iodinecontaining 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.

Beta- blockers
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 betaadrenergic 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 1specific antagonist with a short duration of action.

Glucocorticoids
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.

Further Inpatient Care

A pediatric ICU is the recommended inpatient care setting for patients with thyroid storm. Continue supportive treatment. Appropriately manage the precipitating event. Follow up with laboratory tests to confirm thyrotoxicosis diagnosis, if previously undiagnosed.

Inpatient & Outpatient Medications

Patients may require propranolol and iodides administration for 1 week.

Deterrence/Prevention
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).

Prognosis
If untreated, thyroid storm is almost invariably fatal in adults 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.

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 adult patients, the precipitating factor is often the cause of death.