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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]

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

o Fatigue (more common in older adolescents)

GI symptoms
o Nausea and vomiting
o Diarrhea
o Abdominal pain
o Jaundice[3]

Neurologic symptoms
o Anxiety (more common in older adolescents)
o Altered behavior
o Seizures, coma

Physical
Physical findings include the following:

Fever
o Temperature consistently exceeds 38.5C.
o Patients may progress to hyperpyrexia.
o Temperature frequently exceeds 41C.

Excessive sweating

Cardiovascular signs
o Hypertension with wide pulse pressure
o Hypotension in later stages with shock
o Tachycardia disproportionate to fever
o Signs of high-output heart failure

o Cardiac arrhythmia (Supraventricular arrhythmias are more common, [eg, atrial


flutter and fibrillation], but ventricular tachycardia may also occur.)

Neurologic signs
o Agitation and confusion
o Hyperreflexia and transient pyramidal signs
o Tremors, seizures
o Coma

Signs of thyrotoxicosis
o Orbital signs
o Goiter

Causes
The causes of thyroid storm are as follows:

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


o Sepsis
o Surgery
o Anesthesia induction[4]
o Radioactive iodine (RAI) therapy[5]
o Drugs (anticholinergic and adrenergic drugs such as pseudoephedrine; salicylates;
nonsteroidal anti-inflammatory drugs [NSAIDs]; chemotherapy[6] )
o Excessive thyroid hormone (TH) ingestion
o Withdrawal of or noncompliance with antithyroid medications
o Diabetic ketoacidosis
o Direct trauma to the thyroid gland

o Vigorous palpation of an enlarged thyroid


o 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:
o Transplacental passage of maternal thyroid-stimulating immunoglobulins in
neonates
o McCune-Albright syndrome with autonomous thyroid function[7]
o Hyperfunctioning thyroid nodule
o Hyperfunctioning multinodular goiter
o 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:
o Juvenile rheumatoid arthritis
o Addison disease
o Type I diabetes
o Myasthenia gravis
o Chronic lymphocytic (Hashimoto) thyroiditis
o Systemic lupus erythematosus
o Chronic active hepatitis
o 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:
o 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.
o 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.
o 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.
o 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
o Results of thyroid studies are usually consistent with hyperthyroidism and 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.

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:

Chest radiography
o Chest radiography may reveal cardiac enlargement due to congestive heart failure.

o 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).
o 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]

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.
View full drug information

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.
View full drug information

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. Comatose patients may require administration via NG tube because agent is
available solely as PO preparation.

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
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.
View full drug information

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

Used to inhibit TH release from thyroid gland. 1 mL of SSKI contains 1 g of potassium


iodide (ie, approximately 50 mg/drop). In adults, sodium iodide 0.25 g IV q6h or 0.5 g IV
q12h has also been used successfully.

Strong iodine (Lugol Solution)

Contains 100 mg potassium iodide and 50 mg iodine; provided 8 mg iodide/drop.

Beta- blockers
Class Summary

These agents are used as the mainstay therapy to control autonomic effects of TH. Betablockers 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. Betablockers should be used with caution in congestive cardiac failure and thyrotoxic
cardiomyopathy. In the latter case, they have been known to precipitate cardiac arrest.
View full drug information

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.
View full drug information

Beta 1specific antagonist with a short duration of action.

Esmolol (Brevibloc)

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.
View full drug information

Hydrocortisone (Solu-Cortef)

Provides mineralocorticoid activity and glucocorticoid effects.


View full drug information

Elicits glucocorticoid effects.

Dexamethasone (Decadron)

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.

Patient Education
For excellent patient education resources, visit eMedicine's Endocrine System Center. Also, see
eMedicine's patient education articles Thyroid Problems and Thyroid Storm.