Chapter 80. Thyroid Disease

• Virtually all patients admitted to an ICU have low levels of serum triiodothyronine (T3), and 30% to 50% have low levels of thyroxine (T4) with normal or low levels of serum thyrotropin (TSH).
• Patients who have a T4 level of less than 3.0 μg/dL despite normal levels of T4-binding proteins have a 68% to 84% mortality rate.
• T3 is the logical choice for critically ill patients requiring thyroid hormone replacement.
• Early intubation and mechanical ventilation are crucial for successful treatment of myxedema coma.
• Management of myxedema coma should include administration of glucocorticoids while the adrenal status is being assessed.
• Alterations in thyroid function change the metabolism of almost all drugs, and the doses need careful adjustment to prevent drug toxicity or decreased efficacy.
• Autonomous hypersecretion and exogenous overdose of thyroid hormone are the most common causes of severe thyrotoxicosis.
• Hyperpyrexia and altered mental status are the hallmarks of thyroid storm.
• Medical treatment of severe hyperthyroidism usually normalizes circulating thyroid hormone levels in 2 to 3 weeks, except under circumstances of iodine overload, in which case hyperthyroxinemia may persist for months.
• Blockade of hormonal secretion is best accomplished by the addition of stable iodine to an antithyroid drug regimen.
• In severe thyrotoxicosis, treatment with iopanoic acid (telepaque) can be lifesaving.
• βBlockers prevent thyroid storm in the thyrotoxic patient undergoing surgery, and they may ameliorate cardiovascular dysfunction in thyroid storm, but their side effects often interfere with therapy in the elderly, in patients with asthma, and in patients with cardiomyopathy.
• Amiodarone-induced thyrotoxicosis in a critically ill patient should be managed with methimazole (30 to 50 mg/d), potassium perchlorate (500 mg twice a day), and prednisone (30 to 40 mg/d).
• After gastric aspiration and lavage, only symptomatic and supportive treatment is needed in cases of levothyroxine overdose.
• Neonatal thyrotoxicosis can be life threatening; it is usually caused by transplacental transfer of thyroid-stimulating antibodies. It is transient and requires only short-term treatment.

Hypothyroidism is a state of tissue deprivation of thyroid hormone. It is manifested by general reduction of the metabolic rate accompanied by specific symptoms and signs. Usually, hypothyroidism is caused by a decreased supply of thyroid hormone due to one of the following: (1) failure of the gland to synthesize and secrete thyroid hormone, (2) failure of the pituitary to secrete thyrotropin (thyroid-stimulating hormone [TSH]), or (3) hypothalamic disease resulting in a deficiency of thyrotropin-releasing hormone (TRH).

Perhaps the most controversial, if not the most challenging, aspects of thyroidology for the intensivist are how to interpret thyroid function tests in critically ill patients and what to do when the test results are abnormal. Clinically important hypothyroidism in its most severe form usually is seen in patients with primary hypothyroidism who then develop some intercurrent illness; it develops over several weeks and culminates in myxedema coma. Equally challenging are the thyroid function abnormalities seen in patients with concurrent severe illness and the assessment of the thyroid hormone status at the tissue level.

Definition of Nonthyroidal Illness Syndrome

Virtually all critically ill patients have reduced serum levels of triiodothyronine (T3), and approximately 30% to 50% also have low levels of thyroxine (T4), both associated with normal or low serum TSH values.1 This phenomenon has been termed low T3syndrome, nonthyroidal illness (NTI), or euthyroid sick syndrome. Each of these descriptive terms assumes a priori that such patients are euthyroid despite reduced thyroid hormone levels. The condition is not limited to acute illness. Patients with chronic hepatic or renal failure, calorie deprivation, and a variety of other illnesses present similar thyroid hormone profiles.2 Serum concentrations of both T3 and T4 also are decreased following nonthyroid surgical procedures.3 In patients with a T4 value of less than 3.0 μg/dL, the mortality rate is 68% to 84%,4 indicating that a low T4 concentration without a corresponding increase in TSH is a marker for a high risk of death in the critically ill population. To understand this phenomenon and develop a rational basis for treatment, it is useful to review the thyroid physiology, with emphasis on processes occurring in NTI.

Thyroid Hormone Physiology in Critical Illness

See Fig. 80-1.

Metabolism of Thyroid Hormone in Peripheral Tissues

Ninety percent of the hormone secreted by the thyroid gland is T4, the remainder being T3. Thyroid hormone is metabolized in peripheral tissues by stepwise monodeiodination until the molecule is completely stripped of iodine. This process uses specific enzymes called deiodinases. The deiodination of T4 can take one of two pathways—removal of the iodine from the outer or phenolic ring (5′ position), resulting in 3,3′, 5-triiodothyronine (T3) or removal of the iodine from the inner or tyrosyl ring (5 position), yielding 3,3′, 5′-triiodothyronine (reverse T3 [rT3]). T3 is the active form of the hormone, whereas rT3 has no biologic activity. The same enzyme that removes iodine from the 5′ position of the T4 molecule also is responsible for deiodination of the 5′ iodine from rT3. Therefore, reduction in the 5′-deiodinase activity, which is invariably associated with severe illness and malnutrition, not only reduces the serum T3 level but also increases that of rT3.

Thyroid Physiology in the Brain in Ntis

The nature of perturbations of the hypothalamic-pituitary-thyroid axis in critically ill patients is beginning to be understood. The basal TSH values in serum of humans with NTIS can be normal or low, but the response of TSH to TRH usually is attenuated.2 Stress and malnutrition may be partly responsible. In rats, starvation reduces hypothalamic messenger ribonucleic acid (mRNA) for TRH, reduces portal serum TRH, and lowers pituitary TSH content.5 Furthermore, low TRH mRNA has been documented in the paraventricular nuclei of patients with NTIS.6 One therefore would predict that if diminished TRH is, at least in part, contributing to NTIS and the low thyroid hormone levels, then treatment with TRH should increase the TSH and therefore increase the thyroid hormone levels. In fact, Van den Berghe and colleagues7 have demonstrated that administration of TRH to patients with NTIS leads to increase in serum TSH, T3, and T4 levels. Critically ill patients who eventually will recover from their illness have, as a rule, less impairment of the TSH response to TRH. The mechanism for the reduced TRH production in NTIS is unknown but may be related to cytokines or glucocorticoids. These factors probably are responsible for suppression not only of TRH but also of other hypothalamic factors that may be decreased in NTIS, such as corticotropin-releasing hormone and gonadotropin-releasing hormone.

The preceding, however, does not rule out an effect of NTIS directly on the pituitary. For example, why is serum TSH not elevated when the thyroid hormone levels are low? There is experimental evidence that the pituitary may be “euthyroid” owing to increased pituitary conversion of T4 to T3, unlike other tissues.8

In addition, drugs commonly administered to ICU patients have inhibitory effects on the hypothalamic and pituitary function. Dopamine is one such drug; it inhibits TSH even when infused at low doses.9,10

Other Actions of Thyroid Hormone on Physiology in Ntis

Type II pneumocytes, which have been shown to be involved in regulation of lung function, express thyroid hormone receptors on their surfaces.11 Furthermore, T3 has been shown to modulate surfactant function during sepsis.12–14

Sepsis and multisystem organ failure often are associated with disseminated intravascular coagulation (DIC) and consumption of coagulation inhibitiors such as antithrombin III. Treatment of rats with experimentally induced NTIS with T3 reduced the sepsis-induced decrease in antithrombin III levels.15

Interpretation of Thyroid Function Studies

(Table 80-1) The levels of thyroid hormone and TSH are measured in many critically ill patients at some point during the course of hospitalization. Low concentrations of thyroid hormone without an appropriate increase in serum TSH level would, under normal conditions, raise the suspicion of pituitary (secondary) or hypothalamic (tertiary) hypothyroidism. However, in a critically ill patient, the diagnosis of primary hypothyroidism with inadequate pituitary response needs consideration. A modest elevation of serum TSH level without an increase in rT3 concentration is a strong indicator of primary hypothyroidism. Except in the presence of renal failure, a decreased rT3 level raises the possibility of hypothyroidism and should prompt a search for the etiology. While these possible diagnoses are being investigated, thyroid hormone replacement and glucocorticoid treatment are indicated. Since results of rT3 measurement often are not obtained readily, this test is useful in retrospect for ruling out primary endocrine dysfunction and adds little to the decision of initial management of patients. Since only severe primary hypothyroidism requires emergency treatment, its recognition is usually simple because of persistent TSH elevation, a prior history of thyroid disease, and physical findings compatible with hypothyroidism.

To Treat or Not to Treat

Should patients with low serum levels of thyroid hormone in the face of catastrophic NTIS receive hormonal replacement? In order to answer this question, several issues need to be determined: (1) Is the serum TSH level an accurate reflection of the thyroid status of all body tissues, or does it only reflect the status of the pituitary? (2) Are the tissues of the body functionally hypothyroid? and (3) Is the low serum T3 level an adaptive mechanism for conservation of energy during critical illness? Unfortunately, these questions remain relatively unanswered. In a randomized, prospective study to determine the effect of T4 treatment in NTIS, 11 patients admitted to an ICU with reduced thyroid hormone levels were treated with intravenous T4, and 12 served as controls.16 The study indicated an earlier mortality in the treated group, although the number of survivors was not significantly different between the groups. It was concluded that T4 therapy was not beneficial, and inhibition of TSH secretion by the administration of T4 may be detrimental to the recovery of thyroid function. These results have been confirmed in a similar study carried out in an ICU setting.17 Nevertheless, many physicians understandably find it difficult to withhold treatment in a dying patient with virtually undetectable thyroid hormone levels.

Not only are data on the benefit of thyroid hormone treatment limited, but it is unlikely that an answer regarding the efficacy of this treatment will be forthcoming, given multiple-organ involvement in serious illness and the difficulty of interpreting the effect of thyroid hormone replacement in individuals receiving multiple drugs. Thus the argument centers not only on the question of whether such patients are truly hypothyroid (hence the bias of the term euthyroidsick) but also on whether this temporary hypothyroidism may not, in fact, be beneficial. Inhibition of the type I 5′-deiodinase is the principal mechanism that reduces the supply of biologically active thyroid hormone, T3, to peripheral tissues in the severely ill. Experimental work in a rat model indicates that peripheral tissue hypothyroidism is maintained by an inhibition of the usual compensatory increase in TSH level. This inhibition occurs because normal levels of T3 are generated in the pituitary gland, which uses a different form of 5′-deiodinase, the type II enzyme, that is actually more active in severe illness.8,18 Teleologists argue that this mechanism to reduce the delivery of thyroid hormone to peripheral tissues is not accidental and, therefore, that reduced metabolic activity may be beneficial in the face of the increased catabolism characteristic of severe illness. The question is, Does the physician or nature know best? At our institution there is no consensus on this subject.

Recent studies have shown decreased serum T3 concentrations in patients undergoing cardiopulmonary bypass surgery. T3 treatment can normalize the serum levels and may increase cardiac output and lower systemic vascular resistance19; however, these effects may be negligible.20

Table 80-2 may serve as a bedside guide to the intensivist for the selection of patients for thyroid hormone treatment.

What to Treat with

If the decision is made to treat a sick patient who has reduced thyroid hormone levels, the logical choice is T3. Administration of T4 does not change the serum T3 concentration significantly—it only increases the level of the biologically inactive rT3. The problem with T3 treatment is its potential cardiac “toxicity.” One possible problem is the proarrhythmogenic effect of T3 in anesthetized patients; another possible problem is that T3 may increase the oxygen demand of a myocardium with a fixed coronary artery lesion. T3 is now available as the product TRIOSTAT; however, the cost of a single day's treatment for myxedema would be in excess of US$3500! Alternatively, a solution of T3 for intravenous use can be prepared by the hospital pharmacist by dissolving l-T3 in 0.1 N NaOH, followed by a 10-fold dilution in normal saline containing 2% albumin to a final concentration of 25 μg T3 per milliliter. The solution is sterilized by a single passage through a 0.22-μm Millipore filter and is stored, for no longer than 1 week, at 4° C, protected from light. The materials for this preparation cost about US$1.

Diagnosis

Myxedema coma is caused by marked and prolonged depletion of thyroid hormone. The cardinal features of myxedema coma are (1) defective thermoregulation to the point of hypothermia, (2) altered mental status to the point of coma, (3) a history or sign (such as a neck scar) of ablative thyroid treatment, and (4) an identifiable precipitating event. The condition is a medical emergency because it is fatal in approximately one-half of cases.21 This rare entity occurs typically in elderly women with long-standing hypothyroidism who develop an intercurrent illness and lapse into coma or in hypothyroid persons exposed to cold or given tranquilizers, narcotics, or sedatives sufficient to push them to the brink of myxedema coma. Table 80-3 lists events likely to precipitate myxedema coma. The usual features of severe hypothyroidism (myxedema) include dry, coarse skin, scaly elbows and knees, yellowness in the skin without scleral icterus, coarse hair, thinning of the lateral aspect of eyebrows, macroglossia and hoarseness, obtundation, delayed deep tendon reflexes, and hypothermia. When a markedly reduced serum T4 level and an elevated TSH concentration accompany these signs, the diagnosis is obvious. However, as for thyrotoxic crisis, initiation of treatment should not be delayed until the results of the thyroid function studies are available. Furthermore, because of intercurrent illness, TSH values may not be elevated in proportion to the severity of hypothyroidism. A high index of suspicion in a patient presenting as just described should prompt immediate treatment after a blood sample is taken for laboratory confirmation of the diagnosis.

Pulmonary and Cardiovascular Complications

Alveolar hypoventilation is known to occur in myxedema.22 It is thus not surprising that patients with underlying lung pathology experience worsening of gas exchange. It has been demonstrated that the hypoxic ventilatory drive is depressed in patients with myxedema and that it responds to hormone replacement.23 The hypercapnic ventilatory response is also significantly depressed, but it does not change with replacement of thyroid hormone. Therefore, a reduced central nervous system (CNS) drive to breathe and decreased respiratory muscle activity are the main reasons for respiratory depression in myxedema coma. Secondary aspiration pneumonia, laryngeal obstruction, and reduced surfactant contribute to lung dysfunction. It is important to be alert to the potential for subtle but progressive aspiration and ventilatory failure.

The cardiovascular complications in myxedema coma are caused by the combination of hypothyroid cardiomyopathy, hypothermia, and hypoxia. Pericardial effusion is almost a constant finding, but it rarely leads to tamponade. It is best demonstrated by echocardiography. In patients with long-standing hypothyroidism, hypercholesterolemia may accelerate the progress of atherosclerosis, leading to ischemic heart disease. The reader is referred to the discussion of hypothermia and its cardiovascular complications (see Chap. 110).

The intercurrent illness and decreased food intake caused by the mental obtundation of myxedema may reduce the serum levels of cholesterol and TSH, diminishing their value as indicators of the severity of the myxedema. Patients presenting with a more profound hypothermia have a poor prognosis. The laboratory findings in patients with myxedema coma are listed in Table 80-4.

Treatment

Thyroid Hormone

Although severe hypothyroidism, especially in elderly patients, should be treated cautiously, with gradual increments of small doses of thyroid hormone, myxedema coma is an exception to this rule. The immediate threat to life takes precedence over the risks of rapid hormone replacement. The advantage of treating critically ill patients with T3 as opposed to T4 was discussed earlier. In hypothyroid patients without major intercurrent illness, T4 therapy alone may be sufficient to increase the serum T3 level to normal in 2 to 3 days. This is unlikely to be true in ICU patients with multiple-organ-system failure. The principle of hormonal treatment is to rapidly replenish the extrathyroid pool of thyroid hormone, which consists mainly of hormone bound to serum proteins, and to provide the tissues with their daily requirement of the biologically active hormone. Replenishment is best achieved by the immediate administration of T4, a hormone with a considerably longer half-life (7 days) and higher affinity for serum proteins than T3.22–24 The active form of the hormone, T3, then can be provided because it is readily available to tissues and carries a smaller risk of accumulating to excessive amounts (owing to a half-life of approximately 1 day).

The average size of the extrathyroid T4 pool is approximately 800 μg/1.73 m2.24–27 On the basis of this estimate and the normal turnover rate of 10% per day, the daily T4 requirement can be calculated to be, on average, 80 μg (possibly 50 μg in hypothyroidism, owing to a reduced rate of hormone degradation). Intensivists using only T4 for treatment should give initially 500 μg l-T4, followed by 50 to 100 μg daily. The serum T4 concentration should be in the normal range within 24 to 48 hours. Daily electrocardiographic (ECG) monitoring for ischemic changes and continuous monitoring of rhythm are essential.

We prefer a regimen that uses both T4 and T3. Following the intravenous loading dose of 500 μg T4, 25 μg T3 is given every 6 hours through a nasogastric tube until improvement is noted, and provided the diagnosis has been confirmed by laboratory tests. The dose is then reduced to maintenance level, and the agent is changed to T4 only after recovery from intercurrent illness.

Use of Steroids

The rate of metabolism of most drugs and natural compounds is markedly reduced in patients with myxedema coma. Therefore, the absolute requirement for steroids is reduced. However, because of the 5% to 10% incidence of associated primary hypoadrenalism, glucocorticoids should be given until evidence for intact adrenal function is secured by the cortisol measurement on the blood sample obtained on admission. The usual dose of hydrocortisone is 50 mg intravenously every 6 hours. The steroid dose then can be tapered rapidly after confirmation of a normal pituitary-adrenal axis. Alternatively, the initial dose can be 2 mg dexamethasone, and a 1-hour adrenocorticotropin hormone (ACTH, cosyntropin) stimulation test can be done on the spot to assess adrenocortical function26 (see Chap. 79).

Supportive Care

Early intubation and mechanical ventilation are believed to be central for the successful treatment of myxedema coma. Severe hemodynamic collapse in the presence of a large pericardial effusion may necessitate immediate pericardiocentesis. Because hypothyroidism can cause an elevation of the serum creatine phosphokinase (CPK) level, obtaining a baseline value is helpful for follow-up, particularly if a myocardial infarction is later suspected. Moderate elevations of the blood urea nitrogen (BUN) and creatinine levels are not uncommon and are not necessarily indicative of chronic renal failure.

Hypothermia is treated with blankets, letting internal heat generation slowly warm the body.21 External warming runs the risk of initiating shock by producing peripheral vasodilation in a patient with already reduced cardiac output. Measurement of central venous pressure is useful to guide therapy. Patients with myxedema are rarely volume overloaded, and the use of diuretics runs the risk of further reducing cardiac output. Hyponatremia is best treated by water restriction because the total body sodium content is increased owing to the storage of sodium in glycosaminoglycan, forming the myxedematous accumulation that becomes mobilized with thyroid hormone treatment. Antiulcer prophylaxis is recommended. More important, it should be remembered that hypothyroidism reduces the metabolism of all drugs, and their dosing needs careful adjustment to prevent drug toxicity. Diligent investigation into the precipitating causes should include blood, urine, and sputum cultures, and empirical treatment with antibiotics should be given.

If severe anemia is present, it should be corrected with blood transfusion to increase the oxygen-carrying capacity of the blood. Use of α-adrenergic agents should be avoided because patients are already vasoconstricted.

Efficacy of Treatment

Assuming that an accurate diagnosis has been made and that proper therapeutic measures have been carried out, how are the patient's progress and the efficacy of treatment followed? The physician is committed to treat the patient for several days or as long as the serum TSH concentration remains elevated. Reduction of the TSH level is the earliest indicator of a response to thyroid hormone therapy. Irreversible damage to the respiratory centers has been observed, with failure of spontaneous respiration, despite full repletion of thyroid hormone. No laboratory measurements are helpful in assessing the peripheral tissue responses to thyroid hormone in the critical care setting. The ultimate gauge of successful treatment is complete clinical recovery.

Large goiters, weighing 150 g or more, can cause some degree of tracheal obstruction, especially if they are substernal in location. In a series of 2908 goiters, only 58 (2.0%) caused tracheal obstruction at presentation. Tracheal compression obstructing up to 75% of the tracheal lumen often remains asymptomatic.28 Although dyspnea on exertion has been attributed to goiter, the symptoms are often only nocturnal, manifesting as stridor or, when more severe, as sleep apnea. This problem can be confirmed by x-ray views of the trachea at rest and during a reverse Valsalva maneuver and by sleep studies.29

Growth of the goiter would have to be extensive to cause direct tracheal compression. In Riedel's struma, there is tracheal cartilage destruction by fibrous invasion, which also can cause bilateral vocal cord paralysis. Several case reports have been published describing the acute presentation of tracheal obstruction associated with goiter.30,31 Management of these patients is somewhat difficult because emergency tracheostomy may be difficult to perform owing to interference by the thyroid gland. The use of small endotracheal tubes and immediate subtotal thyroidectomy should reduce the need for tracheostomy. It should be noted that subtotal thyroidectomy may not be successful in the presence of tracheomalacia, which may necessitate prosthetic supports.32 In some instances, a simple division of the thyroid isthmus may be sufficient to relieve the symptoms. Although not particularly useful in the acute care setting, 131I therapy can be effective in the long term in elderly patients with large, compressive goiters.33

Thyrotoxicosis occurs when the supply of thyroid hormone exceeds the amount needed for normal tissue function. The source of thyroid hormone may be (1) excessive synthesis and secretion of hormone from the thyroid gland in response to either TSH or abnormal thyroid-stimulating substances (usually immunoglobulins), (2) autonomous hormone hypersecretion or abnormal release of preformed hormone, or (3) production of the hormone by an exogenous or ectopic source.34 Manifestations can be mild or severe depending on the degree of hormone excess and its duration, as well as the presence of intercurrent illness. Aspects related to thyrotoxicosis in the severely ill patient will be the focus of this section.

A few basic facts about thyroid physiology are important for understanding the therapeutic approach to thyroid disorders. Iodine is actively transported into the thyroid gland, where it is covalently bound to tyrosines within the thyroglobulin molecule. The iodinated tyrosines are coupled to form mainly T4 as well as some T3. It is in the form of thyroglobulin that the hormone is stored in the colloid of the thyroid follicles. In response to TSH or an abnormal stimulator, thyroglobulin is digested by proteolysis, and the liberated hormone—predominantly T4—is secreted into the circulation. In the blood, T4 is transported bound to specific serum proteins. In virtually all peripheral tissues, T4 derived from blood is converted into the active hormone, T3, by removal of a single iodine atom from the 5′ position in the outer ring of the molecule. This reaction is mediated by a tissue-specific 5′-deiodinase. Removal of iodine from the inner ring yields the inactive form rT3. Intracellular T3 binds to nuclear receptors, through which it exerts its effects.

Diagnosis in the ICU

Thyrotoxicosis may be manifested by adverse changes in every organ system. Pyrexia, tachycardia, congestive heart failure, oxyhemoglobin desaturation, and hypertension are the hallmarks of thyrotoxic crisis.35 There also may be involvement of the CNS, ranging from tremulousness to seizures and coma, or involvement of the respiratory system, with tachypnea and respiratory muscle fatigue. Goiter and exophthalmos are as likely to be absent as present. Unfortunately, at the time of presentation in the ICU, most patients with these characteristics have only modest elevations of thyroid hormone concentration in serum (see above). Failure to recognize these symptoms as manifestations of thyrotoxicosis may result in nonspecific treatment, with a resulting risk of morbidity or even death. On the other hand, failure to treat pyrexia as a sign of sepsis or tachycardia as a sign of ischemia or hypoxia could be equally devastating. Stat laboratory measurement of thyroid hormone levels is not always available to provide firm laboratory support for the diagnosis. A 2-hour radioiodine uptake test conceivably could be done at the bedside using a portable gamma counter probe, but it is not practical. Therefore, the preliminary diagnosis of thyrotoxicosis usually is based on a careful history and physical examination. Useful findings are (1) a previous diagnosis and treatment of thyrotoxicosis, (2) presence of exophthalmos, (3) goiter, (4) a history of thyroid hormone ingestion, (5) evidence of previous thyroid surgery, including an anterior neck surgical scar, and (6) recent use of iodine-containing radiologic contrast agents. Such information only supports the possibility that suggestive physical signs may be due to thyrotoxicosis.

Physiologic Consequences and Cardiovascular Complications

Thyroid hormone exerts its tissue effect both directly by interaction with specific nuclear receptors and indirectly through activation of the sympathoadrenal system. Each of these actions causes unique effects on various tissues. The physiologic basis of the sympathomimetic effect of thyroid hormone is unknown. Table 80-5 summarizes the cardiopulmonary complications of thyrotoxicosis.

Perhaps the most detrimental effect of thyrotoxicosis, which clearly is evident in the more severe state of thyroid storm (see below), is pyrexia. Increased body temperature may be secondary to the increased basal metabolic rate or to actual resetting of hypothalamic thermoregulation. Pyrexia further increases cardiovascular stress; therefore, reduction of body temperature is an important goal of therapy.

Neurologic complications of severe thyrotoxicosis include neuromuscular disorders of myopathy (present in over 50% of all hyperthyroid patients and classified as severe in 4%),36 exophthalmic ophthalmoplegia, aggravation of myasthenia gravis, and thyrotoxic periodic paralysis (primarily in Asian men). Except for irritability and tremulousness, the delirium, stupor, coma, and convulsions may be related to the direct action of thyroid hormone on the brain.37 Thyroid hormone can affect the concentrations and distributions of various neurotransmitters.38 Hematologic manifestations of thyrotoxicosis39 are rarely life threatening. It is useful for the intensivist to be aware that hyperthyroidism can cause slight anemia. Anemia may be secondary to hemodilution caused by increased blood volume, but true reduction of red blood cell mass may be caused by reduced iron absorption and vitamin B12 deficiency associated with autoimmune reduction of gastric acidity and intrinsic factor. Minimal thrombocytopenia, with rare instances of idiopathic thrombocytopenic purpura, has been reported.40 Moderate eosinophilia may occur and has been attributed to relative or absolute hypoadrenalism. A variable relative or absolute lymphocytosis may be associated with hyperthyroidism. These manifestations may cloud the picture of a critically ill patient who may have other hematologic perturbations for different reasons.

Hypercalcemia is the most common life-threatening electrolyte abnormality seen in thyrotoxicosis.39 Severe hypercalcemia (11.8 to 19.2 mg/dL) has been reported in several patients with thyrotoxicosis.41

The most notable effect of thyrotoxicosis on the gastrointestinal system is hypermotility with malabsorption.42 The myopathy of hyperthyroidism may cause weakness of the striated muscles of the pharynx and, perhaps, the smooth muscle of the esophagus. Such patients could have dysphagia and then could aspirate and develop pneumonia.43 Patients with hyperthyroidism appear to have a higher incidence of gastritis.44 This association is consistent with the hypergastrinemia seen in thyrotoxic patients.45 Treatment with H2 blockers or proton pump inhibitors is indicated.

Rarely, fulminant hepatic necrosis or less severe hepatic injury occurs. Although thyroid hormone has no direct toxic effect on the liver, hyperthermia can result in hepatic failure. In patients receiving propylthiouracil (PTU), drug toxicity is more likely the cause of fulminant hepatic necrosis.46 Any thyrotoxic patient who presents with jaundice or other signs of hepatic injury should have a thorough evaluation for possible alternative causes of liver damage.

Thyroid storm, or thyrotoxic crisis, is a life-threatening though rare complication of severe thyrotoxicosis. The diagnosis is clinical, bearing no direct relation to the absolute levels of thyroid hormones in serum. The cardinal features of thyroid storm are marked tachycardia, hypertension, and widened pulse pressure; hyperpyrexia (usually greater than 38.5° C [101° F]); and altered mental status. In extreme cases, cardiovascular collapse and shock may be seen. Some investigators contend that abnormal mentation is the most important diagnostic component of thyroid storm.26 Of course, these clinical features can occur with a multitude of illnesses in the absence of thyrotoxicosis. Some authors propose a “point system” for determining whether a patient's condition represents true storm or severe thyrotoxicosis, but the distinction between these two entities is not useful clinically.47 A blood sample for measurement of the levels of T4 or free T4, or the free T4 index (FT4I), and TSH, by a sensitive method, should be obtained immediately in all individuals suspected of having this disorder. Empirical treatment then should begin. It is prudent to obtain a blood sample for cortisol determination before “stress doses” of steroids are administered for use later in deciding later whether long-term therapy is necessary. Laboratory findings in thyroid storm are listed in Table 80-6.

Precipitating Factors

Patients who develop thyroid storm usually have poorly controlled thyrotoxicosis; often there is an identifiable precipitating factor26,48 (Table 80-7). In many cases it is difficult to determine whether the intercurrent illness is the cause or the consequence of the thyroid storm.

Treatment

To prevent irreversible cardiovascular collapse, the treatment of thyroid storm should take a four-pronged approach: (1) therapy to reduce the serum thyroid hormone levels, (2) therapy to reduce the action of the thyroid hormones on peripheral tissues, (3) therapy to prevent cardiovascular decompensation and to maintain normal homeostasis, and (4) treatment of the precipitating event(s).

Therapy to Reduce Thyroid Hormone Levels

An antithyroid drug, either PTU or methimazole (MMI), is given to prevent further synthesis of thyroid hormone. These drugs are not available in parenteral form; they can only be given orally or by nasogastric tube. Instances may arise in which these drugs cannot be given even by nasogastric tube—such as, for example, in patients with infarcted bowel. PTU offers a slight advantage over MMI in that, in addition to its inhibitory effect on hormone synthesis, it decreases the conversion of T4 to T3 in peripheral tissue. PTU should be given in a dose of 200 to 250 mg every 6 hours, and MMI should be given in a dose of 25 mg every 6 hours. Some authors recommend giving an initial PTU loading dose of 600 to 1000 mg, but this strategy has not been proved to be advantageous. Another regimen that has been reported consists of one 600-mg loading dose of PTU (12 tablets suspended in 90 mL of water) given as a retention enema, followed by 250 mg of PTU every 4 hours plus potassium iodide, 1 g diluted in 60 mL of water, given after the second PTU dose.49 PTU has an immediate onset of action for blocking the synthesis of thyroid hormone, but serum levels of thyroid hormone may take several weeks to normalize because of continuing secretion of stored hormone. In severe thyrotoxicosis with a decreased glandular content of hormone, a significant decline in serum levels may be observed in a matter of a few days. We usually repeat thyroid function tests every other day while the patient is acutely ill to help guide management.

Blockade of hormonal secretion usually is best accomplished by the addition of stable iodine to the antithyroid drug regimen. Iodine can be administered as Lugol's solution or as a saturated solution of potassium iodide (ssKI) (2 drops every 12 hours) or given by intravenous drip as sodium iodide (0.5 mg every 12 hours). It is important not to give iodide prior to antithyroid drug blockade because new hormone synthesis may occur and result in delayed release of hormone. There have been several cases where the use of iodine alone triggered thyroid storm. Administration of antithyroid drugs 1 hour before iodine is given is sufficient to establish blockade of hormone synthesis. A combination of antithyroid drugs and ssKI should decrease the serum T3 level to the normal range in 1 to 5 days; however, the metabolic response may lag behind by 2 to 3 days.50 Corticosteroids and propranolol, which also decrease the peripheral conversion of T4 to T3, can be used to further reduce the serum T3 concentration (Tables 80-8 and 80-9).

In the event that antithyroid drugs cannot be used because of a previous history of reactions, such as agranulocytosis or hepatotoxicity, iodine and oral cholecystographic agents may have to be used alone—the latter in the form of ipodate or iopanoate (iopanoic acid). These agents are strong inhibitors of the 5′ deiodination of thyroid hormones; thus they decrease serum levels of T3 and increase those of rT3.51 They also bind to the thyroid hormone receptor, but it is unclear whether this results in competitive inhibition of T3 action.52 These agents have a high iodine content (approximately 60% by weight) and thus also act by releasing iodine in the course of their degradation. As in the case of iodine treatment, their administration in the absence of antithyroid drugs requires careful monitoring of the clinical status. Iopanoic acid telepaque) may be given in amounts of 1 to 3 g daily. We have found that 3 g/d often causes diarrhea; this effect can be prevented with no reduction of the drug's therapeutic efficacy by giving 0.5 g three times a day. Alternatively, sodium ipodate oragrafin) may be used at a dose of 0.5 mg/d, which can reduce serum T3 by 62% in 1 day.53,54

For the rare patient with allergic reactions to both antithyroid drugs and to iodine-containing contrast media, lithium carbonate and perchlorate are alternative drugs. Lithium carbonate can be given in doses of 300 mg every 6 hours, with subsequent adjustments to maintain a serum lithium level of 0.7 to 1.4 mEq/L. Caution should be exercised in patients over 60 years of age. This drug acts by blocking iodide uptake and hormone release by the thyroid gland. Sodium or potassium perchlorate (ClO4) competes with iodide for uptake by the thyroid gland, ultimately reducing the production of T4. These compounds are not readily available in the United States. Serious side effects, including aplastic anemia and nephrotic syndrome, occur rarely.

Successful reduction of the serum concentration of thyroid hormones by means of plasma exchange has been reported in three patients (two of whom were pregnant).55,56 Filtration through a resin bed that removes T3 and T4 has been used occasionally.57 Intravenous administration of thyroxine-binding globulin has been shown experimentally to decrease the transfer of thyroid hormone from blood to tissues.58

Prevention of Systemic Decompensation

Reduction of the body temperature decreases the demands on the cardiovascular system. Body temperature can be reduced by cooling and by pharmacologic blockade of the thermoregulatory centers. Use of a cooling blanket and ice packs alone will induce shivering; treatment with chlorpromazine, 25 to 50 mg, and meperidine, 25 to 50 mg, intravenously every 4 to 6 hours will decrease the severe shivering and limit further heat generation.21

Patients in thyroid storm lose excessive amounts of fluid because of (1) increased insensible water loss associated with hyperthermia and tachypnea, (2) decreased levels of antidiuretic hormone, and (3) vomiting and diarrhea associated with increased intestinal motility. Thus patients may present with either high- or low-output failure, and fluid management may necessitate central venous catheterization to determine filling pressures and guide management. Solutions containing crystalloid (for volume replacement) and dextrose (to replenish hepatic glycogen stores and minimize the breakdown of body protein) are used. Treatment with high doses of propranolol, as discussed below, can make it necessary to use 5% to 10% dextrose solutions. Multivitamins often are administered to replenish the B-complex vitamins.

Treatment of congestive heart failure usually is supportive. While reduction of the high body temperature should be attempted before specific treatment is instituted, the judicious use of inotropic agents and diuretics also should be considered. Since patients are often volume depleted, diuretics should be used carefully and always with meticulous monitoring of intravascular volume. Impending shock should be treated with rapid correction of volume and with inotropic agents, as indicated. Atrial fibrillation is a known complication of thyrotoxicosis. Control of ventricular response can be achieved with β blockers, but conversion to sinus rhythm can be achieved only after the patient is made euthyroid.

Since relative hypoadrenalism is thought to occur in thyroid storm because of accelerated metabolism of glucocorticoids, it is prudent to give 300 mg hydrocortisone intravenously, followed by 100 mg every 8 hours to provide adequate stress levels. In addition, glucocorticoids can be beneficial for their effect in reducing the conversion of T4 to T3 in peripheral tissue. Use of parenteral H2 blockers is indicated to reduce the likelihood of ulcer formation. In thyrotoxicosis, there is rapid clearance of drugs. Therefore, doses of digitalis, insulin, and antibiotics need to be increased to be effective. Two exceptions are adrenergic drugs and anticoagulants.59 It is necessary to remember to reduce drug doses as the thyrotoxicosis resolves.

Reduction of Thyroid Hormone Action on Body Tissues

The effects of thyroid hormone can be reduced by (1) decreasing its conversion to the active form, T3, (2) counteracting its sympathomimetic effects, (3) displacing it from its receptor, and (4) reducing its transport to tissues.

The oral cholecystographic agents, as discussed earlier, may act in part by displacing T3 from its site of action at the receptor in cell nuclei. Other analogs of thyroid hormone with reduced thyromimetic activity, which nevertheless compete with thyroid hormone at its site of action, deserve theoretical consideration.60 The activity of 5′-deiodinase is regulated by the concentration of T4, as well as by catecholamines and other factors. PTU, glucocorticoids, propranolol, oral cholecystographic agents, and amiodarone also reduce the activity of this enzyme and thus decrease the generation of T3, resulting in reduction of serum T3 concentration. Severe acute or chronic nonthyroidal illness also suppresses T3 generation in peripheral tissues.

β Blockers, which are useful in the preparation of thyrotoxic patients for surgery, should be used with caution in thyroid storm. Whereas surgical stress clearly is related to increased catecholamine levels, and thyroid storm can be prevented by the use of propranolol, it is unclear whether thyroid storm induced by other mechanisms is equally responsive to β blockers. However, when there is evidence of increased adrenergic activity short of thyroid storm (i.e., no evidence of hyperpyrexia or mental status changes), 1 mg propranolol can be administered by slow intravenous push every 5 minutes until an effect on pulse rate is seen. Usually a total daily dose of 300 to 400 mg oral propranolol is required to achieve effective β blockade in the severely thyrotoxic patient. It appears that younger patients are more susceptible to hyperadrenergic states with more labile courses and do better with β blockers.21 By contrast, elderly patients may present with “apathetic” thyrotoxicosis without elevation in body temperature and without severe tachycardia. These elderly patients more often experience cardiotoxic effects in response to β blockers. Therefore, β blockers should be used with caution in thyroid storm and in severe thyrotoxicosis, except in the elderly, in asthmatics, and in patients with evidence of dilated cardiomyopathy. When surgery is indicated in such patients, careful titration of the adverse adrenergic cardiovascular effects (tachycardia, large pulse pressure) can be implemented with shorter-duration β blockers (esmolol) preceded by maximal bronchodilator therapy in asthmatic patients or right-sided heart catheterization in elderly patients and those with prior heart failure.

Treatment of Precipitating Events

Without an antecedent history of surgery, any patient with thyroid storm should be suspected of being septic until proven otherwise. Blood, urine, and other body secretions (i.e., ascites or pleural fluid and sputum) should be Gram stained and cultured. Empirical use of broad-spectrum antibiotics is recommended.

In a seriously ill patient in whom an infection or other precipitating cause, such as diabetic ketoacidosis, cannot be identified, pulmonary thromboembolism61,62 or bowel infarction should be considered.

Thyroid Storm in Pregnancy

The approach to treatment of thyroid storm in pregnant patients is similar to that outlined earlier. Thyroid storm is clearly a life-threatening condition for the mother. The basic approach to prevent decompensation is aggressive fluid replacement along with treatment of the precipitating event and antithyroid therapy. Because β blockers may have deleterious effects on the fetus at all stages of fetal development, their use must be weighed against maternal safety. While administration of iodide often results in the development of massive fetal goiter, PTU can be given to the toxic pregnant patient with only a small likelihood of adverse effects on the fetus.

The Swiss surgeon Emil Theodor Kocher (1841–1917), who was the first to operate on hyperthyroid patients, was also among the first to recognize that thyroidectomy carried a high rate of mortality in “unprepared” thyrotoxic patients. The stress of any form of surgery or anesthesia alone could push a mildly decompensated thyrotoxic patient into a thyroid crisis, a life-threatening condition (see above). Therefore, it is important to control thyrotoxicosis prior to surgery. Ideally, the FT4I should be below the upper limit of normal. Unfortunately, even in the presence of a rapid turnover rate, thyroxine has a half-life of at least 72 hours, and frequently it takes more than 1 week to achieve a normal FT4I—an unacceptable wait, especially when the need for surgery is urgent. In such instances, the preoperative therapeutic goal is to prevent the occurrence of thyroid storm. Blocking the effect of thyroid hormone on the sympathetic nervous system, particularly on the heart, is an alternative (if not an ideal) approach to therapy.63 An arbitrary goal of maintaining a heart rate below 90 beats per minute may not always be achieved in patients who have a pulse rate of 200 beats per minute at the outset. In fact, there are no strict criteria for the response to therapy prior to surgery. Propranolol is the most widely used drug64–66; other parenteral preparations are now available, but there is no clear evidence that any of them has advantages over any other. Propranolol, however, has the added effect of decreasing the conversion of T4 to T3 in peripheral tissues. This effect may not be shared by other β blockers, such as atenolol. By and large, β blockers have little effect on the serum concentration of T4 or on the metabolic status of the patient. The combined use of an antithyroid drug (PTU or MMI) and iodide provides the most rapid means of reducing the serum level of thyroid hormone; the antithyroid drug blocks the synthesis of the hormone, and iodide blocks its release. Although the results of determinations of serum thyroid hormone concentrations may not be available on a stat basis, it is important to obtain a blood sample before treatment is initiated.

We would like to discuss three scenarios for the preoperative treatment of thyrotoxic patients. First, consider an ICU patient who is in a septic condition with severe cholecystitis. The presence of thyrotoxicosis has been confirmed by an FT4I of 21 (normal range = 6 to 10.5) and a TSH level below 0.01 mU/L. A cholecystectomy is planned as the definitive treatment, to take place in approximately 1 week. In this instance, the physician has time to institute therapy aimed at reducing the thyroid hormone concentration and to follow serum hormone levels as guides of therapeutic response. Initiation of PTU, 200 mg every 8 hours given orally or by nasogastric tube, followed by 1 or 2 drops of ssKI twice daily, is the suggested treatment for this patient's thyrotoxicosis. The reason for starting PTU before iodide is to prevent the gland from being flooded with iodide, which has been shown to produce, on occasion, a later exacerbation of thyrotoxicosis. A full discussion of these drugs appears under Thyroid Storm above and in Table 80-4. Thyroid function tests should be performed every 2 days.

Second, consider a 65-year-old woman admitted for semiemergent aortic valvuloplasty for severe aortic stenosis due to rheumatic carditis. She has been noted to be thyrotoxic; recent thyroid function tests revealed an FT4I of 19 and a TSH level of less than 0.01 mU/L. The valvuloplasty is scheduled for the next morning. While antithyroid drugs and ssKI should be given at the onset, in this case there is little chance for this treatment to reduce the thyroid hormone levels in 24 hours. Propranolol can provide a rapid and effective preparation for surgery.66 An initial dose of 40 mg every 6 hours is appropriate, to be followed by increments of 20 mg every 6 hours, depending on the response, as judged by the heart rate. Although the usual dose is approximately 40 mg every 6 hours, doses of up to 320 mg/d may be required. Symptoms of tachycardia, anxiety, and sweating should be relieved within 12 hours. Intraoperative propranolol may be administered for tachycardia as needed. Propranolol treatment should be resumed within 4 to 6 hours after surgery and maintained for 48 hours. If the patient is unable to take oral medications perioperatively, then propranolol can be administered as a 1.0- to 2.0-mg slow intravenous bolus. On postoperative day 3, the dose of propranolol can be halved; it can be halved again on day 4, and the drug can be discontinued completely on day 5, 6, or 7 depending on the symptoms and the response to continuing antithyroid drug therapy. Propranolol is not indicated in patients with bronchial asthma, advanced grades of heart block, or unstable insulin-dependent diabetes nor in patients taking quinidine or psychotropic drugs that augment adrenergic activity. β Blockers generally are safe and effective in congestive heart failure, when administered with caution, and are useful in correcting the high-output failure of thyrotoxicosis. Three cases have been reported in which thyroid storm followed surgery for which the patient had been prepared with propranolol alone.67–69

Third, consider a 25-year-old 38-week primigravida who must undergo emergent cesarean section for fetal distress. The patient is known to have active Graves' disease. She has not been compliant in taking the prescribed PTU and is febrile, tachycardic, and hallucinating. Appropriate preparation for this patient prior to general anesthesia and emergency cesarean section would be intravenous propranolol, 1.0 to 2.0 mg as a slow intravenous bolus. Then 10 to 15 mg propranolol can be added to 500 mL 5% dextrose and infused while the patient's and fetus's heart rates are monitored. Continuation of the propranolol after surgery would be indicated, as discussed earlier. The use of atropine to control bronchial secretions during surgery should be avoided in thyrotoxic patients because of possible exacerbation of the sympathomimetic activity. There are reports of the use of plasma exchange in severe thyrotoxicosis of pregnancy.54 In summary, euthyroidism can be rapidly accomplished with iopanoic acid and dexamethasone, β-blockers, and, when possible, antithyroid drugs.69a

Amiodarone is an iodine-rich antiarrhythmic (37% of its weight is organic iodine). Because of its efficacy, it has become widely used. This has resulted in a significant increase in side effects associated with the drug, such as thyrotoxicosis. Given the patient's underlying cardiac problem that necessitated the use of this drug, the thyrotoxicosis, when it occurs, results in a worsening of the problem. The incidence of amiodarone-induced thyrotoxicosis (AIT) is thought to be higher in individuals with low dietary iodine. Amiodarone also can cause hypothyroidism but usually in populations with relatively high dietary iodine.

The mechanism of AIT is unknown but undoubtedly involves thyroid iodine dysautoregulation and destruction and/or inflammation of the thyroid gland. AIT is classified as types I and II. Type I occurs in structurally abnormal thyroid glands (such as a nodular goiter), and type II occurs in a structurally normal gland.70 Type I is caused by iodine-induced thyroid hormone synthesis, and type II is believed to be due to a destructive thyroiditis. Treatment of type I and type II AIT in critically ill patients can be a challenge, and often the type of AIT is not apparent at the time of presentation.

The diagnosis is made in a patient who presents with the typical laboratory findings of thyrotoxicosis and a history of being on or recently having been on amiodarone. Owing to accumulation of the drug in fat tissue, it has a long half-life in the body. Laboratory tests such as an elevated spot urinary iodine determination and an 123I uptake test (although the latter is rarely practical in the ICU setting) can be helpful to confirm the diagnosis in a patient who is thyrotoxic and on amiodarone.

The most appropriate treatment of AIT is still to be determined. All agree that amiodarone should be discontinued immediately in all patients, where possible. Two recent investigations have demonstrated that treatment with prednisone or prednisolone was advantageous in resolution of the hyperthyroidism.71,72 The mechanism of how steroids help may be related to their anti-inflammatory effect during a destructive type II AIT or to the effect on reduction of conversion of T4 to T3. A protocol for the treatment of AIT in the ICU is outlined in Fig. 80-2. Briefly, the critically ill patient should be placed on prednisone 30 mg daily, along with an antithyroid drug, PTU 200 mg three times daily or MMI 20 mg twice daily, and potassium perchlorate, 500 mg twice daily. This regimen should continue for 2 weeks, at which time repeat serum FT4I and FT3I and urine iodine level should be measured. If the FT4I and FT3I both are normal, a rapid taper of the steroid and discontinuation of the potassium perchlorate (because of its poor gastrointestinal tolerance) should be initiated, and management of the antithyroid drug should be as in anyone with hyperthyroidism. If the FT4I and/or FT3I are elevated, then the same course of medications should be continued for 2 more weeks, and then remeasurement of the serum thyroid hormone and urine iodine levels would be indicated. In circumstances where medication is not an option and the severity of the thyrotoxicosis is causing cardiovascular collapse, patients should be stabilized as much as possible, and emergent thyroidectomy should be considered. Radioactive iodine ablation is rarely an option given the low thyroidal uptake of the isotope.

Levothyroxine (l-T4) is dispensed commonly and, in the United States, is the fourth most frequently prescribed drug in the 3.05 billion prescriptions written in 2002 (http://www.rxlist.com/top200.htm). This wide availability leads to frequent overdoses, with reports of 2000 to 5000 acute toxic exposures annually in this country.73–75 Despite the high frequency of overdosage, with documented blood levels of T4 up to 16 times normal, there have been no reported deaths from l-T4 ingestion.74 Clearly, patients do become symptomatic, with tachycardia, nervousness, diarrhea, and even seizures, but these symptoms generally are self-limited. In patients suspected (but denying) of having ingested thyroid hormone, the finding of a suppressed serum thyroglobulin level in the presence of a high serum T4 and/or T3 level is diagnostic.76

The most commonly used thyroid preparation today is synthetic l-T4, which contains no T3, in contrast to the thyroid preparations of 20 years ago, which consisted of thyroid gland extracts containing 20% to 30% T3. Therefore, ingestion of a large quantity of l-T4 does not cause immediate toxic effects. Symptoms occur after a significant amount of T4 has been converted to T3, usually about 24 hours after ingestion. After gastrointestinal decontamination, by induction of vomiting with syrup of ipecac and gastric lavage using charcoal, only symptomatic and supportive treatment is indicated. Recommendations by Lehrner and Weir,77 based on experience with two patients and review of the literature, are aggressive treatment with (1) gastrointestinal decontamination, (2) cholestyramine to increase fecal elimination of the hormone, (3) prednisone and propylthiouracil, and (4) propranolol. Recently, Gorman and colleagues74 recommended only gastrointestinal decontamination and propranolol if the patient is markedly symptomatic. They suggested home gastrointestinal decontamination when 0.5 mg l-T4 has been ingested and determination of the serum T4 level for ingestions of roughly 2.0 to 4.0 mg. When we give 1 mg T4 for an absorption test, the serum T4 level increases by only about 2 μg/dL in 8 hours. Therefore, the former guidelines are a bit conservative, and we would recommend that ingestion of over 10 mg in an adult is cause for aggressive treatment. Elderly patients and persons with underlying cardiac disease should be hospitalized for observation if the serum T4 level is high or the patient is symptomatic. Cholestyramine has been used in treating iatrogenic thyrotoxicosis and may shorten the time it takes for the thyroid hormone concentration to normalize.78 The use of other medical therapy should await the onset of symptoms.

Neonatal thyrotoxicosis is a rare emergency that is treatable but nevertheless is associated with a 12% to 16% mortality.79,80 A neonate can present signs of thyrotoxicosis within the first 24 hours of life but usually later if the mother was receiving thyroid-suppressive therapy and when blocking as well as stimulating antibodies are present. Physical findings are goiter, tachypnea, tachycardia, cardiomegaly, hyperkinesis, restlessness, diarrhea, and poor weight gain. Flushing, periorbital edema, and exophthalmos also may be present.

Most infants with neonatal thyrotoxicosis are born to mothers with hyperthyroidism. Neonatal thyrotoxicosis also can occur with no documented maternal thyroid disease and even in the presence of maternal hypothyroidism. In most cases, this disease is caused by transplacental transfer of thyroid-stimulating immunoglobulin.81 In others, where such a substance cannot be demonstrated in the mother's serum, there may be de novo formation of thyroid-stimulating immunoglobulins in the fetus due to neonatal Graves' disease or autonomous hyperfunction due to an activating mutation in the TSH receptor.82

Treatment of neonatal thyrotoxicosis is short term until the placentally transferred immunoglobulins have disappeared. PTU is given at doses of 5 to 10 mg/kg per day in three divided daily doses. Iodide solutions (10% potassium iodide, 76.6 mg/mL) may be given in a dose of 1 drop, or about 4 mg, every 8 hours. High-output congestive heart failure and other sympathomimetic effects can be treated with propranolol, 2 mg/kg per day in two or three divided doses. Caution should be exercised in the use of propranolol because severe bradycardia and hypoglycemia may result.83 Surgery and radioiodine treatment are required after the initial drug control of thyrotoxicosis in infants with nonautoimmune hyperthyroidism.

Iodide, in the form of dietary supplements or medication (e.g., antitussive agents, amiodarone, or contrast agents), can induce thyrotoxicosis, especially in patients who are relatively iodide deficient. Treatment requires special considerations because antithyroid drugs alone are slow to act because of a flooded iodine pool. To deplete the gland of iodine, perchlorate must be added to the therapeutic regimen—particularly in amiodarone-induced thyrotoxicosis.84 Naturally, iodide treatment is not indicated.

This work was supported by U.S. Public Health Service Grants DK-02081, DK-15070, and RR-00055.