Thyroid Storm

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Background: Thyroid storm is an acute, life-threatening, thyroid hormone–induced hypermetabolic state in patients with thyrotoxicosis. Thyroid storm may be the initial presentation of thyrotoxicosis in undiagnosed children. Common clinical presentation includes fever, tachycardia, neurologic abnormalities, and hypertension, followed by hypotension and shock. Because thyroid storm is 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 precipitating factors can lead to progression of thyrotoxicosis to thyroid storm. In the past, thyroid storm commonly was observed during thyroid surgery, especially in older children and adults, but improved preoperative management has decreased incidence markedly. Today, thyroid storm occurs more commonly as a medical rather than a surgical crisis.


Pathophysiology: Thyroid storm is a decompensated state of thyroid hormone–induced, severe hypermetabolism involving multiple systems. Thyroid storm is the most extreme state of thyrotoxicosis. The clinical picture relates to severely exaggerated effects of thyroid hormones (THs). Heat intolerance and diaphoresis are common in simple thyrotoxicosis but manifest as hyperpyrexia in thyroid storm.

Cardiac findings of mild-to-moderate sinus tachycardia intensify to accelerated tachycardia, hypertension, high-output heart failure, and propensity to develop cardiac arrhythmia. Irritability and restlessness in simple thyrotoxicosis progress to severe agitation, delirium, seizures, and coma.

GI involvement is manifested by diarrhea, vomiting, jaundice, and abdominal pain from mild elevation of transaminases and simple enhancement of intestinal transport in simple thyrotoxicosis. Extremely high metabolism also increases oxygen and energy consumption.

The following factors are known to precipitate thyroid storm:


Infection

Surgery

Trauma

Radioactive iodine treatment

Pregnancy

Anticholinergic and adrenergic drugs

TH ingestion

Diabetic ketoacidosis (DKA)

Frequency:


In the US: The true frequency of thyrotoxicosis and thyroid storm in children is unknown. 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. Adult mortality 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 has declined to less than 20%.

Sex:

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

Because thyrotoxicosis is more likely to occur in adolescents, thyroid storm is more common in this age group, although thyroid storm occurs in patients of all ages.
Infants younger than 1 year constitute only 1% of childhood thyrotoxicosis. More than two thirds of cases occur in children aged 10-15 years. Overall, most thyrotoxicosis occurs during the third and fourth decades of life.
Graves disease presents in 1-2% of neonates born to mothers who have the condition.
CLINICAL Section 3 of 10
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History: Patients may have known thyrotoxicosis. In the absence of previously diagnosed thyrotoxicosis, history may reveal symptoms such as irritability, emotional lability, voracious appetite with poor weight gain, excessive sweating, and poor school performance caused by short attention span.

General symptoms
Fever
Profuse sweating
Poor feeding and weight loss
Respiratory distress

Fatigue (more common in older adolescents)
GI symptoms
Vomiting
Diarrhea
Abdominal pain
Jaundice
Neurologic symptoms
Altered behavior
Seizures, coma
Anxiety (more common in older adolescents)
Physical:

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 congestive heart failure (CHF)
Cardiac arrhythmia (atrial fibrillation)
Neurologic signs
Agitation and confusion
Hyperreflexia and transient pyramidal signs
Tremors, seizures
Coma
Signs of thyrotoxicosis
Orbital signs
Goiter
Causes:

Thyroid storm is precipitated by the following factors in individuals with thyrotoxicosis:
Sepsis
Surgery
Trauma
Drugs (eg, pseudoephedrine, other adrenergic and anticholinergic drugs)
DKA
TH ingestion
Radioiodine therapy
Vigorous palpation of thyroid
Toxemia of pregnancy and labor in older adolescents
Most thyroid storm is associated with Graves disease in childhood. Other reported causes of thyrotoxicosis associated with thyroid storm include the following:
McCune-Albright syndrome with autonomous thyroid function

Hyperfunctioning thyroid nodule

Hyperfunctioning multinodular goiter

Thyroid-stimulating hormone (TSH)-secreting tumor
Graves disease also may occur in association with other autoimmune conditions (and in children with Down or Turner syndromes), including the following:
Juvenile rheumatoid arthritis

Addison disease

Myasthenia gravis

Chronic lymphocytic (Hashimoto) thyroiditis

Systemic lupus erythematosus

Chronic active hepatitis

Nephrotic syndrome
Although thyroid storm's exact pathogenesis is not fully understood, the following theories have been proposed:
TH levels are not increased above levels observed in uncomplicated thyrotoxicosis. Recent studies, however, have demonstrated relatively high levels of free TH in patients with thyroid storm.

Adrenergic receptor activation is another hypothesis. In this theory, sympathetic nerves innervate the thyroid gland, and catecholamines can stimulate TH synthesis. This increased TH then increases the density of beta-adrenergic receptors, thereby enhancing the effect of catecholamines. Supporting this theory is the dramatic response of thyroid storm to beta-blockers and the precipitation of thyroid storm after accidental ingestion of adrenergic drugs such as pseudoephedrine. This theory also explains normal or low plasma and urinary excretion rates of catecholamines; 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 proteins, which might occur postoperatively, might cause a sudden rise in free hormone levels. A rapid rise in hormone levels also may occur when the gland is manipulated during surgery or by vigorous palpation during examination.

Other proposed theories include tissue tolerance to THs, 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 Section 4 of 10
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Anxiety Disorder: Panic Disorder
Heart Failure, Congestive
Hypertension
Hyperthyroidism
Pheochromocytoma
Supraventricular Tachycardia, Atrial Ectopic Tachycardia



Other Problems to be Considered:

Anticholinergic or adrenergic drug intoxication
CNS infections
Hypertensive encephalopathy
Malignant hyperthermia
Septic shock

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Related Articles
Anxiety Disorder: Panic Disorder

Heart Failure, Congestive

Hypertension

Hyperthyroidism

Pheochromocytoma

Supraventricular Tachycardia, Atrial Ectopic Tachycardia




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WORKUP Section 5 of 10
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Lab Studies:


Never forget that the diagnosis for thyroid storm is clinically based; no laboratory tests are diagnostic.

If the patient’s clinical picture is consistent with thyroid storm, never delay treatment to await laboratory confirmation of thyrotoxicosis.
Thyroid studies
Results of thyroid studies usually are consistent with hyperthyroidism and are useful only if the patient has not been diagnosed previously.

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

Usual findings include elevated triiodothyronine (T3) and thyroxine (T4), elevated free T4, increased T3 resin uptake, suppressed TSH, and an elevated 24-hour iodine uptake. TSH is not suppressed if the etiology is excess TSH secretion.
CBC reveals mild leukocytosis, with a shift to the left.
LFTs commonly show nonspecific abnormalities such as elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), creatinine kinase, alkaline phosphatase, and serum bilirubin.
Blood gases, electrolytes, and urinalysis testing may be performed to assess and monitor short-term management.
Imaging Studies:


Chest radiography
Chest radiography may show cardiac enlargement due to CHF.

Radiography may also reveal pulmonary edema caused by heart failure and/or evidence of pulmonary infection.
Perform a head CT to exclude other neurologic conditions if diagnosis is uncertain after initial stabilization of a patient presenting with altered mental status.
Other Tests:


ECG is used to reveal atrial fibrillation, the most common cardiac arrhythmia associated with tyroid storm.
TREATMENT Section 6 of 10
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Medical Care:

If needed, immediately provide supplemental oxygen, ventilatory support, and IV fluids. Dextrose solutions are preferred to cope with continuous high metabolic demand. Appropriately treat cardiac arrhythmia, if it occurs.
Control hyperthermia by applying ice packs and cooling blankets and by administering acetaminophen (15 mg/kg PO/PR q4h).
Promptly administer antiadrenergic drugs (eg, propranolol) to minimize sympathomimetic symptoms.
Administer antithyroid medications to block further synthesis of THs.
Administer PO iodine compounds to block release of THs after starting antithyroid drug therapy.
Administer glucocorticoids to decrease peripheral conversion of T4 to T3.
Consultations:

Endocrinologist
Intensivist

MEDICATION Section 7 of 10
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Therapy is aimed at (1) ameliorating hyperadrenergic effects of TH on peripheral tissues with use of beta-blockers (eg, propranolol, labetalol); (2) decreasing production of TH with antithyroid medications (eg, propylthiouracil [PTU], methimazole), thereby blocking further synthesis of THs; (3) decreasing hormonal secretion from the thyroid, using iodides; and (4) preventing further TH secretion and peripheral conversion of T4 to T3, using glucocorticoids.


Drug Category: Antithyroids -- Of the thiourylene (thionamide) class, these agents inhibit synthesis of THs.Drug Name
Propylthiouracil (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.
Adult Dose Initial: 300-400 mg PO q4-8h
Maintenance: 100-150 mg PO q8-12h
Comatose patients may require administration via NG tube, since agent is available solely as PO preparation
Pediatric Dose Neonate dose: 5-10 mg/kg/d PO divided q8h
Children, initial dose: 15-20 mg/kg/d PO divided q6-8h; higher doses as much as 30-40 mg/kg/d have been used successfully; not to exceed 1200 mg/d
Children, maintenance dose: 1/3-2/3 of initial dose q8-12h
Comatose patients may require administration via NG tube, since agent is available solely as PO preparation; has been administered successfully PR
Contraindications Documented hypersensitivity
Interactions Concurrent use with other drugs known to cause bone marrow suppression may cause agranulocytosis; may cause hypothyroidism if used with lithium or potassium iodide; may cause bleeding diathesis if used with anticoagulants (warfarin)
Pregnancy D - Unsafe in pregnancy
Precautions Adverse effects higher in children; aplastic anemia has been described, but leukopenia more often observed; dermatitis, especially urticarial rash; arthritis, arthralgia; lupuslike syndrome; idiosyncratic reactions (eg, hepatitis, hepatic failure) may occur; discontinue immediately if neutropenia or abnormal LFT results present; administer with food to minimize adverse GI effects
Drug Name
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.
Adult Dose Initial dose: 15-60 mg/d PO divided q8h
Maintenance dose: 10-20 mg/d PO q4-8h
Pediatric Dose Initial dose: 0.5–1.0 mg/kg/d PO tid
Maintenance dose: 1/2-1/3 of initial dose in 2-3 divided doses; not to exceed 30 mg/d; comatose patients may require administration via NG tube, since agent is available solely as PO preparation
Contraindications Documented hypersensitivity
Interactions Concurrent use with lithium or potassium iodide may cause hypothyroidism; concurrent use with anticoagulants (warfarin) may cause bleeding diathesis
Pregnancy X - Contraindicated in pregnancy
Precautions Adverse effects higher in children; aplastic anemia has been described, but leukopenia observed more often; dermatitis, especially urticarial rash; arthritis, arthralgias; lupuslike syndrome; idiosyncratic reactions (eg, cholestatic jaundice) may occur; liver failure has not been identified; immediately discontinue if neutropenia or abnormal LFT results present; administer with food to minimize adverse GI effects; infants born to mothers receiving methimazole have suffered from aplasia cutis
Drug Category: Iodides -- Iodides inhibit the release of TH from the thyroid gland. Precede iodide administration with thionamides to prevent increased intrathyroidal hormone stores. Radiographic contrast dyes, which contain iodinelike ipodate (Oragrafin) and iopanoic acid (Telepaque) also have been used, but their utility in childhood thyroid storm is untested. Lithium carbonate also can be used if patient is hypersensitive to iodine.Drug Name
Saturated solution of potassium iodide (Pima, SSKI, Thyro-Block) -- Used to inhibit TH release from thyroid gland.
Adult Dose 5 gtt q6h PO or sodium iodide 0.25 g IV q6h
Pediatric Dose Neonates: 0.1 mL (100 mg) PO q6-8h
Children: 0.3-0.5 mL (300-500 mg) PO q6-8h
Contraindications Documented hypersensitivity; hyperkalemia; pregnant adolescent mothers; impaired renal function, Addison disease
Interactions Use with other potassium-containing agents, potassium-sparing diuretics, and ACE inhibitors may result in hyperkalemia; use with lithium or potassium iodide may precipitate hypothyroidism
Pregnancy D - Unsafe in pregnancy
Precautions Hypersensitivity reactions; arrhythmias; GI bleeding; angioedema; administer PO after meals with food or milk or dilute with large quantity of juice, water, or milk
Drug Category: Beta-blockers -- 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.Drug Name
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 necessary to control thyroid storm symptoms.
Adult Dose 10-40 mg/dose PO q6h
1-3 mg/dose slow IVP as a single dose; not to exceed 1 mg/min
1-3 mg slow IVP; not to exceed 1 mg/min; repeat in 2 min, if necessary
Pediatric Dose Neonates: 2 mg/kg/d PO divided q6h
Children: 0.5-4 mg/kg/d PO divided q6h; not to exceed 60 mg/d
0.025 mg/kg IV over 10 min; may be repeated q10min until hyperdynamic cardiovascular state is improved; not to exceed 5 mg
Contraindications Documented hypersensitivity; uncompensated CHF, cardiogenic shock, bradycardia, heart block; pulmonary edema, severe hyperactive airway disease, chronic obstructive pulmonary disease; Raynaud disease
Interactions Aluminum salts, barbiturates, calcium salts, NSAIDs, penicillins, rifampin, salicylates, and sulfinpyrazone decrease effects; CCBs, contraceptives, cimetidine, loop diuretics, and THs all potentially can increase effect/toxicity
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Most common adverse drug reactions include hypotension, CHF, bradycardia, heart block, CNS depression; nausea, vomiting, constipation, hypoglycemia agranulocytosis; do not administer IV dose faster than 1 mg/min; gradually taper dose over 1-2 wk when discontinuing; administer at same time each day; advise patient to inform physician if using concurrently with other adrenergic agonists
Drug Name
Esmolol (Brevibloc Injection) -- A beta-1-specific antagonist with a shorter duration of action.
Adult Dose 500 mcg/kg/min IV for 1 min, then 50-100 mcg/kg/min for 4 min; repeat until desired effect; not to exceed 200 mcg/kg/min
Pediatric Dose Bolus dose: 250-500 mcg/kg IV; repeat frequently until desired effect'
Maintenance dose: 50-100 mcg/kg/min IV infusion
Contraindications Documented hypersensitivity; uncompensated CHF, cardiogenic shock, bradycardia, heart block; Raynaud disease
Interactions May increase blood concentrations of digoxin and theophylline
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Common adverse cardiovascular reactions include hypotension, CHF, bradycardia, and heart block; use with caution in patients with diabetes as drug can cause hypoglycemia and mask signs and symptoms; bronchospasm; infusion site reactions (eg, phlebitis, skin necrosis) upon extravasation
Drug Category: Glucocorticoids -- Block conversion of T4 to T3. Use of steroids has been associated with improved survival. Stress doses are required to replace accelerated production and degradation of cortisol induced by TH. If steroids are not administered, acute glucocorticoid deficiency hypothetically could occur because demand may outpace production.Drug Name
Hydrocortisone hemisuccinate
Adult Dose 100-500 mg IV q8-12h
Pediatric Dose 5-7 mg/kg IV q6-8h
Contraindications Documented hypersensitivity; serious infections (excluding meningitis, septic shock), fungal infections, varicella infections
Interactions Barbiturates, diuretics
Pregnancy B - Usually safe but benefits must outweigh the risks.
Precautions May suppress immune function, but benefits outweigh risks in serious conditions such as thyroid storm; if PO, administer with meals to decrease GI upset; early-onset adverse effects include glucose intolerance, hypertension, agitation, indigestion; late-onset adverse effects include immune suppression, increased susceptibility to sepsis, adrenal suppression, hypertension, urinary calcium loss, osteopenia, and gastric irritation and bleeding
Drug Name
Dexamethasone (AK-Dex, Dexone)
Adult Dose 2 mg PO q6h
Pediatric Dose 0.1-0.2 mg/kg/d PO q6-8h
Contraindications Documented hypersensitivity; serious infections (excluding meningitis, septic shock), fungal infections, varicella infections
Interactions Concurrent use of barbiturates, phenytoin, and rifampin can decrease effects; conversely, dexamethasone decreases effect of salicylates and immunization vaccines
Pregnancy B - Usually safe but benefits must outweigh the risks.
Precautions May suppress immune function, but benefits outweigh risks in serious conditions such as thyroid storm; administer with meals to decrease GI upset; early-onset adverse effects include glucose intolerance, hypertension, agitation, indigestion; late-onset adverse effects include immune suppression, increased susceptibility to sepsis, adrenal suppression, hypertension, urinary calcium loss, osteopenia, and gastric irritation and bleeding
FOLLOW-UP Section 8 of 10
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Further Inpatient Care:


A pediatric ICU is the recommended inpatient care setting.
Continue supportive treatment.
Appropriately manage the precipitating event.
Follow up laboratory tests to confirm thyrotoxicosis diagnosis, if previously undiagnosed.
In/Out Patient Meds:


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.
Prognosis:


If untreated, thyroid storm almost invariably is 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 unavailable.
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
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