Tintinalli's Emergency Medicine: A Comprehensive Study Guide, 9e

Chapter 229: Hyperthyroidism and Thyroid Storm Alzamani Mohammad Idrose

FIGURE 229-1.

INTRODUCTION AND EPIDEMIOLOGY

Thyroid hormone a�ects virtually all organ systems and is responsible for increasing metabolic rate, heartrate, and ventricle contractility, as well as muscle and CNS excitability. The thyroid hormones are thyroxine(T4) and triiodothyronine (T3). The ratio of T4 to T3 released in the blood is 10:1. Peripherally, T4 is converted

to the active T3, which is three to four times more potent than T4.

Hyperthyroidism is an excessive amount of thyroid hormones in the body. The terms hyperthyroidism andthyrotoxicosis are o�en used interchangeably. Hyperthyroidism is a clinical syndrome with a variety of signsand symptoms, and thyroid storm is its extreme manifestation.

Thyroid storm is an acute, severe, life-threatening hypermetabolic state caused either by excessive release ofthyroid hormones causing adrenergic hyperactivity or an increased peripheral response to thyroid hormonein response to one or more precipitants. The most common underlying cause is Graves’ disease (85% of allhyperthyroidism cases in the United States). It is caused by thyroid-stimulating hormone (TSH) receptorantibodies that stimulate excess and uncontrolled thyroidal synthesis and secretion of thyroid hormones. Itoccurs most frequently in young women (10 times more common in women compared with men) at any age

group.1 The mortality of thyroid storm is in the range of 8% to 25%.1,2 This chapter will focus primarily on thetreatment of thyroid storm.

HYPERTHYROIDISM

Primary hyperthyroidism is caused by the excess production of thyroid hormones from the thyroid glands orfrom external factors. Secondary hyperthyroidism is caused by the excess production of thyroid-releasinghormones or TSH in the hypothalamus and pituitary, respectively (Tables 229-1 and 229-2).

TABLE 229-1

Common Causes of Primary and Secondary Hyperthyroidism

Primary Hyperthyroidism

Graves’ disease (toxic

di�use goiter)

Most common of all hyperthyroidism (85% of all cases)

Associated with di�use goiter, ophthalmopathy, and local dermopathy

Toxic multinodular goiter Second most common cause of hyperthyroidism

Toxic nodular (adenoma)

goiter

An enlarged thyroid gland that contains a small rounded mass or nodules with

overproduction of thyroid hormone

Thyroiditis Inflammation of the thyroid gland

Hashimoto’s thyroiditis Initially gland is overactive (hyperthyroidism) but is typically followed by a

state of hypothyroidism

Secondary Hyperthyroidism

Thyrotropin-secreting

pituitary adenoma

Thyroid gland stimulated to produce hormones

TABLE 229-2

External Causes of Hyperthyroidism

Nonthyroidal Disease

Ectopic thyroid

tissue (struma

ovarii)/teratoma

A rare form of mature teratoma that contains thyroid tissue

Metastatic

thyroid cancer

Production of extraglandular thyroid hormones

Human

chorionic

gonadotropin

Stimulates thyroid hormone secretion

Drug Induced or Iodine Intake

Iodine Iodine-induced thyrotoxicosis (called Jod-Basedow phenomenon): A�er treatment of

endemic goiter patients with iodine or stimulation of thyroid hormones from use of

iodine-containing agents such as radiographic contrast agents

Amiodarone Contains iodine; may cause either thyrotoxicosis or hypothyroidism

Interferon-α,

interleukin-2

During treatment for other diseases, such as viral hepatitis and human immunodeficiency

virus infection

Thyrotoxicosis

factitia

Accidental or Munchausen-like, whereby thyroid hormone is taken by patient to fake

illness

Ingestion of

meat containing

beef thyroid

tissue

Cow thyroid tissue contains thyroid hormones

Excessive

thyroid

hormone

ingestion

CLINICAL FEATURES

The clinical features of hyperthyroidism are varied. The patient may only complain of constitutionalsymptoms such as generalized weakness and fatigue. Heat intolerance, diaphoresis, fever, voracious appetitebut poor weight gain, anxiety, emotional lability, palpitations, diarrhea, and hair loss are common historicalfeatures. If there is a history of hyperthyroidism, ask about treatment and compliance with medication. Thesigns and symptoms of hyperthyroidism are as shown in Table 229-3. The severity of exophthalmos is notnecessarily parallel with the magnitude of thyroid dysfunction but reflects the autoimmune process takingplace. Not all hyperthyroidism patients present with goiter. A goiter is not present with exogenousadministration of thyroid hormone and apathetic thyrotoxicosis. Likewise, the presence of a goiter does notnecessarily confirm the diagnosis of thyrotoxicosis. Thyroid gland tenderness can be found in inflammatoryconditions such as subacute thyroiditis.

TABLE 229-3

Symptoms and Signs of Hyperthyroidism

A�ected System Symptoms Signs

Constitutional Lethargy

Weakness

Heat intolerance

Diaphoresis

Fever

Weight loss

Neuropsychiatric Emotional lability

Anxiety

Confusion

Coma

Psychosis

Fine tremor

Muscle wasting

Hyperreflexia

Periodic paralysis

Ophthalmologic Diplopia

Eye irritation

Lid lag

Dry eyes

Exophthalmos

Ophthalmoplegia

Conjunctival infection

Endocrine: thyroid gland Neck fullness

Tenderness

Thyroid enlargement

Bruit

Cardiorespiratory Dyspnea

Palpitations

Chest pain

Widened pulse pressure

Systolic hypertension

Sinus tachycardia

Atrial fibrillation or flutter

High-output heart failure

GI Diarrhea

Yellowish sclera

Hyperactive bowel sounds

Jaundice

Reproductive Oligomenorrhea

Decreased libido

Gynecomastia

Telangiectasia

Gynecologic Menorrhagia

Irregularity

Sparse pubic hair

*Pretibial myxedema may be present in 5% of patients with Graves’ disease.

A�ected System Symptoms Signs

Hematologic Pale skin Anemia

Leukocytosis

Dermatologic Hair loss Pretibial myxedema*

Warm, moist skin

Palmar erythema

Onycholysis

LABORATORY TESTING

Obtain a CBC, electrolytes, glucose, serum cortisol, renal and liver function tests, ECG, and chest radiograph.Obtain a pregnancy test in women of child-bearing age. Other general studies depend on clinical evaluation,comorbidities, and the di�erential diagnosis.

Serum TSH Level

In primary hyperthyroidism, the TSH level is low as a result of the negative feedback mechanism toward ahigh thyroid hormone level. Nevertheless, a low TSH level by itself is not diagnostic, as serum TSH may bereduced as a result of chronic liver or renal disease or the e�ect of certain drugs such as glucocorticoids,which reduce TSH secretion.

In secondary hyperthyroidism, TSH is increased because of increased production in the pituitary.

Free Thyroid Hormone Levels: Free T4 and Free T3

A low TSH with an elevated free T4 confirms primary hyperthyroidism. A high TSH with high free T4 denotes

secondary causes of hyperthyroidism. On the other hand, a low TSH with a normal free T4 but elevated free

T3 is diagnostic of T3 thyrotoxicosis. T3 thyrotoxicosis occurs in <5% of patients who have thyrotoxicosis in

North America. Thyroid hormone levels are not necessarily acutely elevated when the transition fromuncomplicated thyrotoxicosis to thyroid storm occurs.

Total Thyroid Hormone Level of T4 and T3

Total serum T4 and T3 (bound and unbound) are increased in thyrotoxicosis. Eighty percent of circulating T3

is derived from monodeiodination of T4 in peripheral tissues, whereas 20% emanates from direct thyroidal

secretion. Both T4 and T3 are then bound to proteins in the form of thyroxine-binding globulin, transthyretin,

and albumin. Only a small fraction of the hormones are free and unbound. Laboratory measurement of totalT3 and total T4 measures mainly protein-bound hormone concentrations. In thyroid storm, total thyroid

hormone level may or may not be increased. Results also may be a�ected by conditions that a�ect proteinbinding. With the improved assays for free T4 and free T3, there is now little indication to measure total T3

and total T4.

Thyroid Antibody Titers

Thyroid-stimulating antibodies are detected in Graves’ disease. Thyroid antibody titers (to thyroidperoxidase or thyroglobulin) will help determine diagnosis.

TREATMENT AND DISPOSITION OF UNCOMPLICATED HYPERTHYROIDISM

Further evaluation, treatment, and disposition of patients with uncomplicated hyperthyroidism depend onthe patient’s age, comorbidities, disease severity, and identification of the underlying cause.

A thyroid sonogram with Doppler flow can be done to assess thyroid gland size, vascularity, and the presenceof nodules. Typically, a thyroid gland secreting excessive hormones would be enlarged. However, in thesetting of subacute postpartum thyroiditis, silent thyroiditis, or exogenous causes of hyperthyroidism, thethyroid gland is not expected to be enlarged. Nuclear medicine imaging with iodine-131 would reveal agreatly increased uptake of radioiodine as early as 1 or 2 hours a�er administration of the agent.

Ambulatory evaluation is usually appropriate for most patients. Consult with an endocrinologist or thepatient’s primary care physician about the next diagnostic and therapeutic steps.

For patients with features suggesting impending thyroid storm, see discussion below on thyroid storm.

THYROID STORM

Thyroid storm is a clinical diagnosis for patients with preexisting hyperthyroidism. Do not rely on lab resultsfor diagnosis or to start treatment. In determining whether or not a patient has thyroid storm, the mainsystems to concentrate on are the thermoregulatory system (rise in temperature), cardiovascular system(ranging from tachycardia to atrial fibrillation and congestive cardiac failure), CNS (ranging from beingagitated to seizure), and the GI-hepatic system (ranging from nausea to vomiting and jaundice) (Figure 229-1). Search for a precipitating event (Table 229-4).

TABLE 229-4

Precipitants of Thyroid Storm

Systemic insult

Infection

Trauma

General surgery

Endocrinal insult

Diabetic ketoacidosis

Hyperosmolar coma

Drug or hormone related

Withdrawal of antithyroid medication

Iodine administration

Thyroid gland palpation

Ingestion of thyroid hormone

Unknown cause in up to 25% of cases

Cardiovascular insult

Myocardial infarction

Cerebrovascular accidents

Pulmonary embolism

Obstetrics related

Labor and delivery

Eclampsia

Radioactive iodine therapy

FIGURE 229-1.

Clinical features of thyroid storm.

PATHOPHYSIOLOGY

The pathophysiologic mechanisms underlying the shi� from uncomplicated hyperthyroidism to thyroidstorm are not entirely clear. However, they involve adrenergic hyperactivity either by increased release ofthyroid hormones or increased receptor sensitivity. Many of the signs and symptoms are related toadrenergic hyperactivity. Patients with thyroid storm have relatively higher levels of free thyroid hormones asopposed to those with uncomplicated hyperthyroidism. The total thyroid hormone level may or may not beincreased in those with uncomplicated hyperthyroidism.

When there is excess of thyroid hormones, circulating T4 and T3 are taken into the cytoplasm of cells. T4 is

converted to its active form, T3. Within the cytoplasm, the T3 then exerts its e�ect by passing into the nucleus

and binding to thyroid hormone receptors or thyroid hormone–responsive elements to induce gene

activation and transcription.3,4 The receptors receiving the hormone will stimulate changes specific to thetissue.

In the pituitary gland, thyroid hormones exert negative regulation, resulting in TSH suppression.

During thyroid storm, precipitants such as infection, stress, myocardial infarction, or trauma will multiply thee�ect of thyroid hormones by freeing thyroid hormones from their binding sites or increasing receptorsensitivity.

PRECIPITANTS OF THYROID STORM

The precipitants of thyroid storm are as shown in Table 229-4. In some patients undergoing radioactiveiodine therapy for hyperthyroidism, thyroid storm may ironically occur following treatment due towithdrawal of antithyroid drugs, release of thyroid hormones from damaged thyroid follicles, or the e�ect ofradioactive iodine itself.

CLINICAL FEATURES OF THYROID STORM

The additional signs and symptoms of thyroid storm, apart from those evident in hyperthyroidism, are asshown in Figure 229-1. Fever is o�en present in thyroid storm. It may herald the onset of thyrotoxic crisis inpreviously uncomplicated disease. Palpitations, tachycardia, and dyspnea are common. A pleuropericardialrub may be heard. The direct inotropic and chronotropic e�ects of thyroid hormone on the heart causeincreased stroke volume, contractility, and cardiac output. Enhanced contractility produces elevations insystolic blood pressure. Thyroid storm may also cause widened pulse pressure due to high cardiac output

and reduced peripheral vascular resistance. Atrial fibrillation occurs in 10% to 35%.4

Table 229-5 provides the Burch and Wartofsky Point Scale (BWPS) for thyroid storm diagnosis. The system ispractical because it is based on clinical and physical criteria and it is sensitive for thyroid storm, but it is notvery specific.

TABLE 229-5

Burch and Wartofsky Diagnostic Parameters and Scoring Points for Thyroid Storm

Diagnostic Parameters Scoring Points

1. Thermoregulatory dysfunction

Temperature °C (°F)

37.2–37.7 (99–99.9)

37.7–38.3 (100–100.9)

38.3–38.8 (101–101.9)

38.9–39.4 (102–102.9)

39.4–39.9 (103–103.9)

≥40 (≥104.0)

 

 

5

10

15

20

25

30

2. CNS e�ects

Absent

Mild (agitation)

Moderate (delirium, psychosis, extreme lethargy)

Severe (seizures, coma)

 

0

10

20

30

3. GI-hepatic dysfunction

Absent

Moderate (diarrhea, nausea/vomiting, abdominal pain)

Severe (unexplained jaundice)

 

0

10

20

4. Cardiovascular dysfunction

Tachycardia (beats/min)

90–109

110–119

120–129

≥140

 

 

5

10

15

25

5. Congestive heart failure

Absent

Mild (pedal edema)

Moderate (bibasilar rales)

Severe (pulmonary edema)

 

0

5

10

15

*See Table 229-3.

Scoring system: Score of ≥45: highly suggestive of thyroid storm. Score of 25–44: suggestive of impending storm. Score

of <25: unlikely to represent thyroid storm.

Source: Reproduced with permission from Burch HB, Wartofsky L. Life-threatening thyrotoxicosis. Thyroid storm.

Endocrinol Metab Clin North Am 22: 263, 1993.3,5

Diagnostic Parameters Scoring Points

6. Atrial fibrillation

Absent

Present

 

0

10

7. Precipitating event*

Absent

Present

 

0

10

Apart from this scoring system, in 2012, Akamizu et al1 formulated diagnostic criteria for thyroid storm andclarified its clinical features, prognosis, and incidence based on nationwide surveys in Japan. A�er this, theJapanese Thyroid Association proposed diagnostic criteria of TS1 and TS2 for thyroid storm, taking intoaccount laboratory evidence of increased free thyroid hormones with any CNS symptoms and non-CNS

symptoms such as fever, tachycardia, heart failure presentation, or GI–hepatic derangement manifestations.1

Nevertheless, a Burch and Wartofsky Point Scale score ≥45 appears more sensitive than a Japanese Thyroid

Association classification of TS1 or TS2 in detecting patients with a clinical symptoms.5-7

The major di�erential diagnoses of thyroid storm are shown in Table 229-6.

TABLE 229-6

Di�erential Diagnosis of Thyroid Storm

Infection and sepsis

Sympathomimetic ingestion (e.g., cocaine, amphetamine, ketamine drug use)

Heat exhaustion

Heat stroke

Delirium tremens

Malignant hyperthermia

Malignant neuroleptic syndrome

Hypothalamic stroke

Pheochromocytoma

Medication withdrawal (e.g., cocaine, opioids)

Psychosis

Organophosphate poisoning

LABORATORY TESTING, IMAGING, AND ECG

Obtain a CBC, electrolytes, glucose, and renal and liver function tests to identify comorbidities. Obtain apregnancy test in women of child-bearing age. Except for pregnancy testing (see later treatment section,“Inhibition of New Thyroid Hormone Synthesis,” below), start treatment upon suspicion of the diagnosiswithout waiting for laboratory results. In thyroid storm, CBC typically shows leukocytosis with shi� to thele�. Hyperglycemia tends to occur because of a catecholamine-induced inhibition of insulin release andincreased glycogenolysis and rapid intestinal absorption of glucose. Mild hypercalcemia and elevatedalkaline phosphatase can occur because of hemoconcentration and enhanced thyroid hormone–stimulated

bone resorption.8

Thyroid storm also induces liver enzyme metabolism, causing raised liver enzymes, so obtain baselinevalues. In 30% of patients, treatment with an antithyroid drug such as propylthiouracil can cause transient

elevation of liver enzymes.6 A high serum cortisol value is an expected finding. This should be the normalreaction of an adrenal gland to a body under stress. The finding of an abnormally low cortisol level shouldraise suspicion of coincidental adrenal insu�iciency.

Imaging

Chest radiograph should be done to rule out infection as a precipitant for thyroid storm. Bedsideechocardiography would typically show tachycardia, enhanced le� ventricular contractility, and a dilatedinferior vena cava in the presence of high-output cardiac failure. CT of the brain may be necessary to exclude

neurologic conditions if diagnosis is uncertain, because CNS abnormalities causing altered mental statusmay precipitate thyroid storm.

ECG

ECG findings most commonly include sinus tachycardia and atrial fibrillation. Sinus tachycardia occurs in

approximately 40% of cases.4 Atrial fibrillation occurs in 10% to 35% of patients and more commonly in

patients >60 years old with underlying structural heart disease.4 Premature ventricular contractions andheart blocks may be present. Atrial premature contractions and atrial flutter may also occur. Institute cardiacmonitoring.

TREATMENT OF THYROID STORM

The order of therapy in treating thyroid storm is very important with regard to the use of thionamide andiodine therapy. Obtain pregnancy testing before beginning ED treatment, and obtain consultation fortreatment if the patient is pregnant or breastfeeding. If the patient is not pregnant, inhibit thyroid glandsynthesis of new thyroid hormone with a thionamide (methimazole and propylthiouracil are thionamidedrugs available in the United States) before iodine therapy is begun to prevent the stimulation of new thyroidhormone synthesis that can occur if iodine is given too soon.

Treatment aims are as follows:

Supportive care

Inhibition of peripheral adrenergic e�ects

Inhibition of new hormone synthesis

Inhibition of thyroid hormone release

Preventing peripheral conversion of T4 to T3

Preventing free thyroid hormone reabsorption

Treating the precipitant

Definitive care

The treatment recommendations are shown in Table 229-7, with specific comments in the following sections.

TABLE 229-7

Treatment for Thyroid Storm

1. Supportive care

General: oxygen, cardiac monitoring

Fever: external cooling with ice packs or cooling blankets; acetaminophen 325–650 milligrams PO/PR

every 4–6 h (aspirin is contraindicated because it may increase free thyroid hormone)

Dehydration: IV fluids, IV saline with 5% dextrose may be used to replace glycogen depletion if blood

sugar is low

Nutrition: glucose, multivitamins, thiamine, and folate can be considered (deficient secondary to

hypermetabolism)

2. Inhibition of peripheral adrenergic e�ects

Propranolol 0.5–1 milligrams IV over 10 minutes, then 1–2 milligrams every few hours adjusted to vital

signs. For the less toxic patient, PO dose of 60–80 milligrams every 4 h (for reactive airway diseases,

cardioselective β-blockers, such as atenolol or metoprolol, or calcium channel blockers can be

considered)

or

Esmolol 250–500 micrograms/kg IV load, then 50–100 micrograms/kg/min titrated doses to vital signs

or

Reserpine 2.5–5.0 milligrams IM every 4–6 h, preceded by 1-milligram test dose while monitoring blood

pressure (may consider if β-blocker is contraindicated but avoid in congestive heart failure or hypotension

and cardiac shock)

or

Guanethidine 30–40 milligrams PO every 6 h (may consider if β-blocker is contraindicated but avoid in

congestive heart failure, hypotension, and cardiac shock)

3. Inhibition of new thyroid hormone synthesis

Methimazole 20 milligrams every 6 h PO

(Avoid methimazole in pregnant women. Teratogenic risk is highest in first trimester. Methimazole is Food

and Drug Administration pregnancy category D. Obtain consultation if patient is breastfeeding.)

or

PTU, a loading dose of 500–1000 milligrams given PO and followed by 250 milligrams every 4 h

(PTU is used for pregnant women in first trimester. PTU also has a boxed warning issued by the U.S. Food

and Drug Administration in 2010 regarding rare but severe hepatic dysfunction. There are case reports of

hepatic failure in mother/fetus.) Obtain consultation if the patient is breastfeeding.

4. Inhibition of thyroid hormone release (at least 1 h a�er step 3)

Lugol solution 8–10 drops PO every 6–8 h

or

Potassium iodide (SSKI) five drops (0.25 mL or 250 milligrams) PO every 6 h

or

Note: Replacement therapy: dialysis and plasmapheresis are last resorts for patients who do not respond to treatments

1–5.

Abbreviation: PTU = propylthiouracil.

IV iopanoic acid (Telepaque®), 1 gram every 8 h for first 24 h, then 500 milligrams twice a day (Food and

Drug Administration pregnancy category C)

or

Ipodate (Oragrafin®), 0.5–3 grams/d PO (especially useful with thyroiditis or thyroid hormone overdose)

or

Lithium carbonate (if allergic to iodine or agranulocytosis occurs with thionamides), 300 milligrams PO

every 6 h (1200 milligrams/d) and subsequently to maintain serum lithium at 1 mEq/L

(Lithium is contraindicated for use in pregnant mothers; e�ects in breastfeeding uncertain, so obtain

consultation.)

5. Preventing peripheral conversion of T4 to T3

Hydrocortisone 300 milligrams IV initially, then 100 milligrams every 8 h until stable (also for adrenal

replacement due to hypermetabolism)

or

Dexamethasone 2 milligrams IV every 6 h

6. Prevention of free thyroid hormones reabsorption

Cholestyramine 4 grams every 6 h

7. Treat precipitating event

All triggers of thyroid storm should be searched and treated accordingly (e.g., infection, myocardial

infarct, diabetic ketoacidosis)

8. Definitive therapy

Radioactive iodine ablation therapy or surgery may be necessary.

TREATMENT AIM 1: SUPPORTIVE CARE

Fluid losses could result from the combination of fever, diaphoresis, vomiting, and diarrhea. With highmetabolic rate in thyroid storm, check blood glucose, and if blood sugar is relatively low, IV fluids withdextrose (isotonic saline with 5% or 10% dextrose) may be given to replenish glycogen stores.

TREATMENT AIM 2: INHIBITION OF PERIPHERAL ADRENERGIC EFFECTS

Thyroid storm is a hyperadrenergic state with the risk of high-output cardiac failure. Therefore, reducinga�erload and heart rate with a β-blocker is essential. Inotropic agents may have to be considered carefully asthey may worsen the hyperadrenergic state.

Propranolol can be given IV in slow 1- to 2-milligram boluses, which may be repeated every 10 to 15 minutesuntil the desired e�ect is achieved (i.e., clinical improvement or heart rate <100 beats/min). Orally,propranolol therapy usually begins at 20 to 120 milligrams per dose or 160 to 320 milligrams/d in divided

doses.6,9

Propranolol can be given IV at 0.5 to 1 milligram over 10 minutes. This can then be increased to 1 to 2

milligrams over 10 minutes each time, adjusting the dose every few hours to the patient’s vital signs.9 For theless toxic patient, a PO dose of 60 to 80 milligrams every 4 hours can be given.

Alternatively, a short acting β-blocker such as esmolol may be used by administering an IV load of 250 to 500micrograms/kg, a�er which 50 to 100 micrograms/kg/min are given in a titrated dose based on the vitalsigns. A short-acting β-blocker is preferable for patients with cardiac failure because the drug’s action could

be curtailed if the patient deteriorates. Alternatively, IV landiolol or oral bisoprolol can be also be used.9

Propranolol seems to be better than esmolol, because propranolol has the beneficial e�ect of preventing T4

to T3 conversion as well as being a nonselective β-blocker. Nevertheless, a recent study found evidence that,

in severe thyroid storm, T4 to T3 conversion may already be reduced.9

For other conditions contraindicated to β-blockers such as reactive airway diseases, cardioselective β-blockers, such as atenolol or metoprolol, or calcium channel blockers can also be considered.

Alternatively, reserpine 2.5 to 5.0 milligrams IM can be given every 4 to 6 hours, preceded by 1-milligram testdose while monitoring blood pressure. Reserpine is an alkaloid agent that depletes catecholamine stores insympathetic nerve terminals and the CNS. It can have CNS depressant e�ects. In severe asthmatics, IMreserpine, 2.5 milligrams every 4 hours, may be considered in lieu of peripheral blockade. Guanethidine, 30to 40 milligrams PO every 6 hours, may also be an option. Guanethidine inhibits the release ofcatecholamines. These agents would be indicated only in rare situations in which β-adrenergic receptorantagonists are contraindicated and when there is no hypotension or evidence of CNS-associated mental

status changes.3 Side e�ects of both medications include hypotension and diarrhea. Avoid their use incongestive heart failure, hypotension, and cardiac shock as the blood pressure may drop.

The contraindications to peripheral blockade are the same as those for other medical conditions. Exercisecaution in patients with congestive cardiac failure and thyrotoxic cardiomyopathy. Complicated patients withboth a tachydysrhythmia and congestive heart failure can be managed first with rate control.

TREATMENT AIM 3: INHIBITION OF NEW THYROID HORMONE SYNTHESIS

Thionamides

Thionamides used for the treatment of thyrotoxicosis are either methimazole or propylthiouracil (PTU).Thionamide therapy decreases the synthesis of new hormone production but also has immunosuppressive

e�ects.10 Thionamides inhibit synthesis of thyroid hormones by preventing organification and trapping ofiodide to iodine and by inhibiting coupling of iodotyrosines.

Methimazole has a longer half-life than propylthiouracil, permitting less frequent dosing. It presents in free

form in the serum, whereas 80% to 90% of propylthiouracil is bound to albumin.10 Methimazole is U.S. Foodand Drug Administration pregnancy category D and is especially teratogenic in the first trimester ofpregnancy.

The dose for methimazole is 20 milligrams given PO every 6 hours.6,9 The total daily dose that should begiven is 60 to 80 milligrams/d. If given PR, similar dose can be crushed in aqueous solution. Although thereare no commercially available parenteral formulations of the thionamides, there are case reports ofmethimazole being administered IV in circumstances in which the PO and PR routes of administration could

not be used.8 Methimazole was shown to have similar pharmacokinetics for both PO and IV use in normalsubjects and in subjects with hyperthyroidism. In some centers, only carbimazole (which is the prodrug of

methimazole) is available. If methimazole is not available, carbimazole can be used with the same potency.9

The initial dose is 40 to 60 milligrams, followed by a maintenance dose of between 5 and 20 milligrams daily.

As for propylthiouracil, the dose for thyroid storm is 500 to 1000 milligrams given PO as a loading dose

followed by 250 milligrams every 4 hours.6 The drug can be given by nasogastric tube or PR. Outside thethyroid gland, only PTU, not methimazole, can inhibit conversion of T4 to T3, and this is the advantage of

PTU.

Precautions on Use of PTU

In 2009, the Food and Drug Administration notified healthcare professionals of the risk of serious liver injury,including liver failure and death, with the use of PTU in adults and children. There is an increased risk ofhepatotoxicity with PTU when compared with methimazole. Since 2010, the Food and Drug Administrationadded a boxed warning to the prescribing information of PTU to include information about case reports of

severe liver injury and acute liver failure, some of which had been fatal.11 The Food and Drug Administrationrecommends that PTU be reserved for patients who cannot tolerate methimazole.

PTU is currently used as a second-line drug therapy for hyperthyroidism in general. Its use as a first-line agentis still considered in thyroid storm in view of its advantage of blocking T4 to T3 conversion. Nevertheless,

there is recent evidence that this conversion may already be reduced in thyroid storm.6 PTU is strictlypreferred only in the case of pregnant patients during the first trimester, as methimazole use during this

period had been associated with teratogenicity.12 Nevertheless, methimazole is again suggested for useduring the second and third trimesters of pregnancy.

If PTU is used, signs and symptoms of liver injury should be closely monitored, especially in the first 6months of therapy initiation. PTU medication may cause increased liver enzyme levels. It should not be used

as therapy if transaminase levels reach more than three times the upper limit of normal or if the levels are

elevated at the onset of therapy.6 PTU should not be used in children unless the patient is allergic to or

intolerant of methimazole and no other treatment options are available.6

TREATMENT AIM 4: INHIBITION OF HORMONE RELEASE

Iodine Lugol solution, potassium iodide, ipodate (Oragrafin®), or lithium carbonate can be given to stopthyroid hormone release. Thionamide therapy must be instituted first with these drugs only given at least 1hour later. Iodine therapy blocks the release of prestored hormone and decreases iodide transport andoxidation in follicular cells.

Lugol solution can be given as 8 to 10 drops PO initially and then every 6 to 8 hours. Lugol solution provides 8milligrams of iodide per drop.

Iodinated radiographic contrast dyes that contain ipodate (Oragrafin®) 0.5 to 3 grams/d orally or IV iopanoicacid (Telepaque®) 1 gram every 8 hours for the first 24 hours followed by 500 milligrams twice a day have alsobeen used to inhibit hormone release, and they also have the added property to e�ectively preventconversion of T4 to T3 (Food and Drug Administration pregnancy category C).

All of the iodine-containing agents listed here lead to rapid decreases in both T4 and T3 levels.13

Nevertheless, iodine-containing solution should not be given to patients with iodine hypersensitivity, iodineoverload, or iodine-induced hyperthyroidism or to those with amiodarone-induced thyrotoxicosis.

Alternative Drugs if Iodine Intake Is Contraindicated

Potassium Perchlorate

Potassium perchlorate blocks thyroid uptake of iodine and thus interferes with the production of new

hormones. The perchlorate anion, ClO4–, is a competitive inhibitor of iodide transport. The recommended

dose is 0.5 gram of potassium perchlorate per day. It is used in amiodarone-induced thyrotoxicosis for whichiodine replacement is contraindicated. However, it has side e�ects of aplastic anemia and nephroticsyndrome.

Lithium

In severe thyroid storm conditions, lithium can also be used in combination with PTU or methimazole.Lithium inhibits thyroid hormone release from thyroid gland. Lithium also has added e�ects on the thyroidgland that decrease thyroid hormone synthesis, thereby increasing intrathyroidal iodine content andinhibiting coupling of iodotyrosine residues that form T4 and T3. In thyroid storm, the dosing for lithium is

300 milligrams every 8 hours. To avoid lithium toxicity, lithium level should be monitored regularly every dayto maintain a concentration of approximately 0.6 to 1.0 mEq/L (0.6–1.0 mmol/L). Frequent monitoring of

serum lithium levels is mandatory, especially because the serum lithium concentrations may change as the

patient is rendered more euthyroid. Avoid lithium in pregnancy as it has teratogenic e�ects.14

TREATMENT AIM 5: PREVENTING PERIPHERAL CONVERSION OF THYROXINE TOTRIIODOTHYRONINE

The peripheral conversion of T4 to T3, which is responsible for 85% of T3 present in the circulation, is blocked

by PTU, propranolol, and glucocorticoid. Nevertheless, for PTU and propranolol, this e�ect is notquantitatively significant. Therefore, glucocorticoids such as hydrocortisone or dexamethasone are essential

in treatment. Glucocorticoid use in thyroid storm also improves survival rates.3 In patients who have severethyrotoxicosis, especially in conjunction with hypotension, treatment with glucocorticoids is a standardpractice because of the possibility of relative adrenal insu�iciency. Hydrocortisone 300 milligrams IV is giveninitially, followed by 100 milligrams every 8 hours until stable. Alternatively, dexamethasone 2 milligrams IV

can be given every 6 hours.9

TREATMENT AIM 6: PREVENTING REABSORPTION OR REMOVAL OF THYROID HORMONES

Cholestyramine is used to inhibit thyroid hormone reabsorption. Thyroid hormone is metabolized mainly inthe liver, where it is conjugated to glucuronides and sulfates. These conjugation products are then excretedin the bile. Free hormones are released in the intestine and finally reabsorbed, completing the enterohepaticcirculation of thyroid hormone. In states of thyrotoxicosis, there is increased enterohepatic circulation ofthyroid hormone. Cholestyramine is an anion exchange resin that decreases reabsorption of thyroidhormone from the enterohepatic circulation. Cholestyramine in combination with methimazole or PTU

causes a more rapid decline in thyroid hormone levels than standard therapy with thionamides alone.15 Itsdosage is 4 grams every 6 hours.

Thyroid Hormone Removal

In patients who have contraindications to PTU and methimazole, such as a prior severe reaction, directremoval of thyroid hormone has been described. Plasmapheresis, charcoal hemoperfusion, resinhemoperfusion, and plasma exchange may be e�ectively used to rapidly reduce thyroid hormone levels in

thyroid storm patients who respond poorly to traditional therapeutic measures.16

TREATMENT AIM 7: IDENTIFY PRECIPITATING FACTORS

Search for infection in febrile thyrotoxic patients. Obtain an ECG to identify myocardial infarction, ischemia,or arrhythmia.

In cases of thyroid storm precipitated by DKA, myocardial infarction, pulmonary embolism, or other acuteprocesses, appropriate management of the specific underlying problem should proceed along with the

treatment of the thyrotoxicosis.3

TREATMENT AIM 8: DEFINITIVE THERAPY

Definitive therapy with radioactive iodine ablation or surgery may not be able to be done for several weeks ormonths a�er treatment with iodine for thyroid storm. Close follow-up and monitoring should continue, with

plans for definitive therapy to prevent a future recurrence of life-threatening thyrotoxicosis.2

RAPID PREPARATION OF THYROTOXIC PATIENTS FOR EMERGENCYSURGERY

In the event that a patient has thyrotoxicosis and requires emergent surgery, the recommendation of drugsupplementation is as shown in Table 229-8. The supplementation is important because surgery in a patient

with hyperthyroidism may precipitate thyroid storm.17,18

TABLE 229-8

Rapid Preparation of Thyrotoxic Patients for Emergent Surgery

Drug ClassRecommended

DrugDosage Mechanism of Action

Continue

Postoperatively?

β-Adrenergic

blockade

Propranolol 40–80 milligrams

PO 3 to 4 times a

day

β-Adrenergic

blockade; decreased

thyroxine-to-

triiodothyronine

conversion (high

dose)

Yes

or      

Esmolol 50–100

micrograms/kg/min

β-Adrenergic

blockade

Change to PO

propranolol

Thionamide Propylthiouracil 200 milligrams PO

every 4 h

Inhibition of new

thyroid hormone

synthesis; decreased

thyroxine-to-

triiodothyronine

conversion

Stop immediately

a�er near-total

thyroidectomy;

continue a�er

nonthyroidal

surgery

or      

Methimazole 20 milligrams PO

every 4 h

Inhibition of new

thyroid hormone

synthesis

Stop immediately

a�er near-total

thyroidectomy;

continue a�er

nonthyroidal

surgery

Oral

cholecystographic

agent

Iopanoic acid 500 milligrams PO

twice a day

Decreased release of

thyroid hormone;

decreased thyroxine-

to-triiodothyronine

conversion

Stop immediately

a�er surgery

Source: Reproduced with permission from Langley RW, Burch HB: Perioperative management of the thyrotoxic patient.

Endocrinol Metab Clin of North Am 32: 519, 2003. Copyright Elsevier.

Drug ClassRecommended

DrugDosage Mechanism of Action

Continue

Postoperatively?

Corticosteroid Hydrocortisone 100 milligrams PO

or IV every 8 h

Vasomotor stability;

decreased thyroxine-

to-triiodothyronine

conversion

Taper over first 72

h

or      

Dexamethasone 2 milligrams PO or

IV every 6 h

Vasomotor stability;

decreased thyroxine-

to-triiodothyronine

conversion

Taper over first 72

h

or      

Betamethasone 0.5 milligram PO

every 6 h, IM or IV

Vasomotor stability;

decreased thyroxine-

to-triiodothyronine

conversion

Taper over first 72

h

DISPOSITION AND FOLLOW-UP

Thyroid storm patients typically require admission to the intensive care unit. Patients with thyroid stormo�en have concomitant diseases precipitating the attack and require close monitoring. Complete recoverymay take 1 week until circulating levels of thyroid hormones are depleted. Stable hyperthyroid patients withminimal symptoms can only be discharged for follow-up either by an endocrinologist or primary carephysician, if the patient is already on medication with a clear plan of follow-up.

SPECIAL SITUATIONS

PREGNANCY AND LACTATION

Avoid methimazole during the first trimester of pregnancy in thyrotoxic patients in view of its teratogenice�ects. PTU should be used during the first trimester. This can be converted back to methimazole from the

1. 

2. 

second trimester onward. Lithium is contraindicated in pregnancy. E�ects on breastfeeding infants are notwell documented. Obtain consultation.

ELDERLY PATIENTS

Older patients may present with “apathetic” thyrotoxicosis (i.e., with some atypical symptoms, includingweight loss, palpitations, weakness, dizziness, syncope, memory loss, and physical findings of sinustachycardia or atrial fibrillation). Signs and symptoms of this condition are few and subtle, and the initialappearance of disease may be single-organ failure (e.g., congestive heart failure), producing diagnosticconfusion by pointing to diagnoses other than thyrotoxicosis.

THYROTOXIC PATIENTS WITH ATRIAL FIBRILLATION

β-Blockers can provide rate control. Propranolol can be used if the patient is not in failure. Esmolol, withshort-acting e�ect, is a safer choice. If β-blockers are contraindicated, digoxin can be used. Calcium channelblockers can also be cautiously considered but can induce severe hypotension and reduce systemic vascularresistance. Amiodarone can be considered, but note that it has 37% organic iodine in weight. Ensurethionamides have been given to avoid synthesis of new thyroid hormones. As in any atrial fibrillation,thrombosis may ensue and heparinization should be instituted. Thyrotoxic patients may require a lowermaintenance dose of warfarin than euthyroid patients because of increased clearance of vitamin K–dependent clotting factors.

CONGESTIVE CARDIAC FAILURE IN THYROID STORM

Avoid vasodilators such as nitrates because thyrotoxicosis is associated with vasodilatation and decreasedsystemic vascular resistance. Avoid β-blockers when the cardiac failure is associated with underlyingischemic, hypertensive, or valvular heart disease. A short-acting β-blocker such as esmolol is a safer choice.

DRUG INTERACTIONS IN THYROTOXIC PATIENTS

Many drugs interfere with protein binding, including heparin, furosemide, phenytoin, carbamazepine,diazepam, salicylates, opiates, estrogens, and NSAIDs. Because of this interference with total thyroid

hormone levels, free hormone concentrations are preferable in the diagnosis of thyrotoxicosis.8

REFERENCES

Akamizu  T, Satoh  T, Isozaki  O,  et al: Diagnostic criteria, clinical features, and incidence of thyroid stormbased on nationwide surveys. Thyroid 22: 661, 2012. [PubMed: 22690898]  

Angell  TE, Lechner  MG, Nguyen  CT, Salvato  VL, Nicolo�  JT, LoPresti  JS: Clinical features and hospitaloutcomes in thyroid storm: a retrospective cohort study. J Clin Endocrinol Metab 100: 451, 2015.

3. 

4. 

5. 

6. 

7. 

8. 

9. 

10. 

11. 

12. 

[PubMed: 25343237]  

Burch  HB, Wartofsky  L: Life-threatening thyrotoxicosis. Thyroid storm. Endocrinol Metab Clin North Am22: 263, 1993. [PubMed: 8325286]  

Wald  D: ECG manifestations of selected metabolic and endocrine disorders. Emerg Med Clin North Am 24:145, 2006. [PubMed: 16308117]  

Angell  TE, Lechner  MG, Nguyen  CT, Salvato  VL, Nicolo�  JT, LoPresti  JS: Clinical features and hospitaloutcomes in thyroid storm: a retrospective cohort study. J Clin Endocrinol Metab 100: 451, 2015. [PubMed: 25343237]  

Ross  DS, Burch  HB, Cooper  DS,  et al: 2016 American Thyroid Association guidelines for diagnosis andmanagement of hyperthyroidism and other causes of thyrotoxicosis. Thyroid 26: 1343, 2016. [PubMed: 27521067]  

Idrose  AM: Acute and emergency care for thyrotoxicosis and thyroid storm. Acute Med Surg 147:10.1002/ams2.104, 2015. [PubMed: 29123713]

Pimental  L, Hansen  K: Thyroid disease in the emergency department: a clinical and laboratory review. JEmerg Med 28: 201, 2005. [PubMed: 15707817]  

Satoh  T, Isozaki  O, Suzuki  A,  et al: 2016 guidelines for the management of thyroid storm from the JapanThyroid Association and Japan Endocrine Society (First edition). Endocr J 63 (12): 1025, 2016. [PubMed: 27746415]  

Cooper  DS: Antithyroid drugs. N Engl J Med 352: 905, 2005. [PubMed: 15745981]  

https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm209023.htm (U.S. Food and Drug Administration: FDA MedWatch Safety Alerts for HumanMedical Products. Propylthiouracil [PTU]). Accessed July 31, 2017.

American College of Obstetricians and Gynecologists: Practice Bulletin No. 148: thyroid disease inpregnancy. Obstet Gynecol 125(4): 996, 2015. [PubMed: 25798985]  

13. 

14. 

15. 

16. 

17. 

18. 

Tyer  NM, Kim  TY, Martinez  DS: Review of oral cholecystographic agents for the management ofhyperthyroidism. Endocr Pract 20: 1084, 2014. [PubMed: 25100369]  

Diav-Citrin  O, Shechtman  S, Tahover  E,  et al: Pregnancy outcome following in utero exposure to lithium:a prospective, comparative, observational study. Am J Psychiatry 171: 785, 2014. [PubMed: 24781368]  

Nayak  B, Burman  K: Thyrotoxicosis and thyroid storm. Endocrinol Metab Clin North Am 35: 663, 2006. [PubMed: 17127140]  

Muller  C, Perrin  P, Faller  B, Richter  S, Chantrel  F: Role of plasma exchange in the thyroid storm. TherApher Dial 15: 522, 2011. [PubMed: 22107688]  

Langley  RW, Burch  HB: Perioperative management of the thyrotoxic patient. Endocrinol Metab ClinNorth Am 32: 519, 2003. [PubMed: 12800544]  

Pagsisihan  DA, Andag-Silva  A, Piores-Roderos  O, Escobin  MA: Rapid preoperative preparation forthyroidectomy of a severely hyperthyroid patient with Graves’ disease who developed agranulocytosis. JASEAN Fed Endocrin Soc 30: 48, 2015.

McGraw HillCopyright © McGraw-Hill EducationAll rights reserved.Your IP address is 75.148.241.33 Terms of Use   •  Privacy Policy   •  Notice   •  Accessibility

Access Provided by: HCA HealthcareSilverchair