|TABLE 140.2 Commonly Used Drugs that Affect Thyroid Function|
In the ICU, patients with thyrotoxicosis may have an atypical presentation, with tachyarrhythmias or central nervous system disturbance as the primary sign. It is important for the intensivist to consider thyroid dysfunction in the differential diagnosis of such patients, since treatment with beta blockers and antithyroid medications can rapidly improve the clinical course (10). The diagnosis may need to be a clinical one, however, as the laboratory testing can take days to return. Table 140.3 lists the symptoms and signs that may be seen in a patient with thyrotoxicosis.
Sinus tachycardia and atrial fibrillation are the most commonly seen cardiovascular disorders in hyperthyroidism. Since atrial fibrillation may be the only indication of thyrotoxicosis, it is important to screen such patients with a TSH and FT4. Congestive heart failure typically occurs only in patients with underlying heart disease, but may also manifest as a result of chronic tachycardia-induced cardiomyopathy (11). Physical examination findings in a thyrotoxic patient include widened pulse pressure, hyperdynamic precordium, tachycardia, and systolic ejection murmur. The pathogenesis of cardiovascular diseases from exposure to excessive thyroid hormone is not entirely understood. Thyroid hormone has both indirect and direct effects on vascular smooth muscle tone and increases cardiac output. Thyroxine also regulates expression of myocardial genes involved in the handling of calcium (12).
The typical electrocardiographic changes seen in thyrotoxicosis are sinus tachycardia and atrial fibrillation (11). Patients may also present with complete heart block, and cases have been reported which showed reversal of the cardiac dysfunction with treatment of the underlying thyroid disorder (13–16).
|TABLE 140.3 Symptoms and Signs of Thyrotoxicosis|
Dyspnea on exertion is a common presenting symptom of patients with hyperthyroidism. Respiratory muscle strength is significantly reduced in thyrotoxicosis, and improves with reduction of thyroid hormone levels (17). Several studies also have shown that thyrotoxicosis is a risk factor for the development of pulmonary hypertension (18-20). Pulmonary emboli may be seen in patients with atrial fibrillation not on anticoagulation therapy (21). Further, pulmonary edema has been described in uncontrolled thyrotoxic patients (22–24).
The laboratory findings in hyperthyroidism are the combination of a low TSH and a high FT4 (see Table 140.1) (25). If the FT4 is normal and TSH suppressed in a patient suspected of having thyrotoxicosis, it is important to check a T3 level, as this may be elevated in early Graves’ disease or in T3-secreting toxic adenomas. In the event that the patient presents with an elevated T4 or T3 and a detectable or “normal” TSH, the clinician should consider the effects of nonthyroidal illness (see below) or drugs (see Table 140.2) on thyroid function testing. Rarely, the patient may have a TSH-secreting pituitary tumor or thyroid hormone resistance (25). Consultation with an endocrinologist may be warranted if the pattern of thyroid function tests cannot be readily corroborated with the entire clinical picture.
The two most common causes of thyrotoxicosis in the outpatient setting are Graves disease and toxic multinodular goiter. Elderly patients tend to have a solitary or multiple nodules which become autonomously functioning and lead to hypersecretion of thyroid hormone. The goiter may not always be palpable if the offending nodule is small or if the patient has a substernal goiter. Tracheal deviation on chest x-ray may be the only finding to alert the physician of the underlying disease process. By way of contrast, young women are more likely to present with the classic stigmata of Graves disease—thyroid bruit, ophthalmopathy, and diffuse goiter. In the ICU, however, it is important to consider other causes of hyperthyroidism. Factitious thyrotoxicosis is rare but should be considered in a patient with a history of taking herbal supplements or over-the-counter weight-loss medications (26). Surreptitious use of thyroid hormone may be diagnosed by measurement of serum thyroglobulin levels. If low, this would indicate that the patient is self-medicating (27). Typically, the thyroglobulin levels are high in patients with endogenous thyroid disorders. Two additional clues may be a low uptake on radioiodine scanning (if done) and absence of a goiter on physical examination. Iodinated contrast media as used with computed tomography or cardiac catheterization may also cause hyperthyroidism because these agents contain free iodine (28). Generally, patients with normal thyroid function are not at risk of this complication. Patients with a history of Graves disease, multinodular goiter, or even subclinical hyperthyroidism, however, may develop frank thyrotoxicosis several days after the administration of contrast media (see Contrast Media subsection in Drug-Induced Alterations in Thyroid Function Section) (28,29).
The ultimate treatment of thyrotoxicosis is based upon the underlying pathophysiology. Patients with Graves disease, toxic multinodular goiter, or toxic adenoma initially should be started on a thionamide, such as methimazole (MMI) or propylthiouracil (PTU). MMI is the preferred agent in nearly all patients with thyrotoxicosis because PTU can cause fulminant hepatic necrosis that can be fatal. Routine monitoring of liver function tests has not been shown to prevent severe hepatotoxicity. The three indications for the use of PTU are during the first trimester of pregnancy, in thyroid storm, and in a patient who has minor reactions to MMI and refuses RAI or surgery (30). The dosage of antithyroid medication should be tailored to the degree of thyrotoxicosis; hence consultation with an endocrinologist may be advisable. Patients with peripheral manifestations of hyperthyroidism may also benefit from the addition of a beta-adrenergic antagonist. This agent will assist with the symptoms of agitation, tremor, palpitations, and diarrhea. Propranolol is the drug most commonly used in the United States. Patients who have overdosed on thyroid hormone or are taking a supplement with thyroid hormone extract should be counseled regarding the complications of taking thyroid hormone supplements in excess and the offending agent should be discontinued. If the patient requires treatment, beta-adrenergic antagonists and bile acid sequestrants—for example, cholestyramine—may be used (31).
Thyroid storm is a rare, but life-threatening syndrome of exaggerated clinical manifestations of thyrotoxicosis. It is a medical emergency typically caused by exacerbation of hyperthyroidism following a precipitating event or illness; Table 140.4 lists the precipitants of thyroid storm. The clinical picture is one of decompensation of one or more organ systems (32). There are four main features noted in thyroid storm: tachycardia, fever, central nervous system disturbances, and gastrointestinal symptoms. The CNS symptoms vary from marked hyperirritability and anxiety, to confusion and coma. Mortality rates range from 20% to 100%, so prompt diagnosis and treatment are essential (33). The Burch–Wartofsky scoring system is readily available on the Internet and provides an objective set of criteria for diagnosis of thyroid storm (33). This system assigns points for the degree of derangements seen, assessing temperature, heart rate, CNS alterations, congestive heart failure, atrial fibrillation, and gastrointestinal symptoms. A score greater than 45 indicates thyroid storm, a score between 25 and 45 suggests thyroid storm, and a score less than 25 indicates that thyroid storm is unlikely (33).
|TABLE 140.4 Precipitants of Thyroid Storm|
|TABLE 140.5 Summary of Treatment for Thyroid Storm|
The treatment of thyroid storm takes a four-pronged approach (Table 140.5). First, an antithyroid drug must be given to reduce thyroid hormone production and peripheral conversion of T4 to T3. Second, supportive care must be administered against the systemic disturbances of fever, hypovolemia, and cardiovascular compromise. Third, the peripheral actions of thyroid hormone should be blocked. And finally, any precipitating factors should be addressed.
A thionamide is given to block synthesis of T3 and T4. PTU is the favored agent because it also inhibits peripheral conversion of T4 to T3. By reducing T3 concentrations in the serum, it is postulated that the manifestations of thyrotoxicosis are more rapidly improved with PTU than with MMI (33). Neither of these drugs is available parenterally, so administration is typically by mouth or nasogastric (NG) tube. In patients with altered mental status, or in whom an NG cannot be placed, rectal administration of PTU has been reported in a few patients (34,35). It is conventional to use high doses of antithyroid drugs, such as 200 to 400 mg PTU every 4 hours or 20 mg MMI every 4 hours.
Thionamides do not inhibit release of preformed T3 and T4 from the thyroid. Inorganic iodide, however, can accomplish this goal. It may be administered orally as Lugol’s solution (10 drops every 8 hours) or as saturated solution of potassium iodide (SSKI, five drops every 6 hours). Oral radiographic contrast agents, such as sodium ipodate or iopanoic acid, may be substituted for iodine. These drugs block the release of preformed thyroid hormone from the gland and inhibit the extrathyroidal conversion of T4 to T3 (36). It is critical to give the thionamide therapy at least an hour before the iodide or contrast agent is administered, because the sudden influx of iodide into the thyroid can lead to increased thyroid hormone production and can thereby exacerbate the thyrotoxicosis (37). However, when the iodide or contrast agent is given after the antithyroid drug, serum T3 and T4 levels are substantially reduced in 2 to 3 days and may reach the normal range in 5 to 7 days (33,38).
If the patient has an allergy to iodide or cannot tolerate thionamides, lithium may be substituted to inhibit T3 and T4 synthesis (39). It may be given initially at a dose of 300 mg every 6 hours and is titrated to maintain serum lithium concentrations around 1 mEq/L.
Supportive care should also be provided. Fever is preferentially treated with acetaminophen. Salicylates should not be used as they competitively inhibit T3 and T4 binding to serum proteins and thus increase serum-free T3 and T4 levels (40). The patient’s fluid losses should be appropriately replaced, bearing in mind the insensible losses from high fever and, if present, diarrhea. Hypercalcemia, if present, will usually be reversed by adequate hydration. High-dose glucocorticoids have been given historically for empiric treatment of relative adrenal insufficiency. Such treatment also has the added benefit of inhibition of peripheral conversion of T4 to T3. In patients with Graves disease, glucocorticoids also directly inhibit secretion of thyroid hormone. A loading dose of hydrocortisone 200 mg may be given initially followed by 100 mg every 8 hours; this therapy can be tapered rapidly after 2 to 3 days. Dexamethasone or methylprednisolone at equivalent doses may be substituted for hydrocortisone if preferred.
Therapy directed against the peripheral actions of thyroid hormone should be administered as well. Beta-adrenergic antagonist drugs can provide rapid amelioration of many of the symptoms of thyroid storm and should be dispensed immediately. Propranolol is the most commonly used agent, and may be given intravenously or orally depending upon the clinical setting. It is important to consider that in the thyrotoxic state, drug clearance is increased and higher than usual doses may be necessary to achieve the desired effect. If rapid beta-blockade is necessary to reduce the heart rate or if the patient’s mental status precludes oral drugs, intravenous administration is preferred. Propranolol attenuates the effects of catecholamines and weakly inhibits peripheral conversion of T4 to T3. This inhibition occurs over a period of a week, however, and thus does not solely account for the beneficial effects of propranolol in the thyrotoxic patient.
In extreme cases, it may be beneficial to utilize a method to remove T3 and T4 from the patient’s serum. The simplest approach is to administer oral cholestyramine. This drug binds the hormones in the GI tract, interrupting the enterohepatic circulation (31). Plasmapheresis (41–45) and charcoal hemoperfusion (46,47) also have been used successfully to lower T3 and T4 levels in patients who were unable to tolerate thionamides.
Finally, it is important to search for and treat underlying illnesses, which may have precipitated the thyroid storm. This process can be difficult in obtunded patients, but a systematic approach is usually successful in uncovering the cause.
Patients treated with the above regimen may clinically improve within 12 to 24 hours of starting therapy if the syndrome is recognized and treated in a timely fashion. As the patient’s condition stabilizes, it is important to wean the glucocorticoids, switch to oral rehydration, and taper the beta-blocking drugs. Long-term treatment of the hyperthyroidism is required if the patient has Graves disease or toxic multinodular goiter. In patients with Graves, it may be preferable to treat with thionamides, as there is a chance of remission of the autoimmune condition. Others advocate total thyroidectomy if a patient’s disease is severe enough to lead to thyroid storm; a highly skilled surgeon is required, however (30,48). Radioiodine ablation is not an option for several months because the inorganic iodide used in the treatment of the thyroid storm saturates the gland and precludes further uptake of iodide.
DRUG-INDUCED ALTERATIONS IN THYROID FUNCTION
Amiodarone and Thyroid Function
Amiodarone is a lipophilic drug that contains 75 mg iodine per 200-mg tablet. The drug has a half-life of several months and during that time it releases approximately 6 mg of inorganic iodine per day (49). In euthyroid patients, chronic administration of the drug results in increased serum TT4 (see the above section on thyroid function tests), FT4, and rT3 levels, lower T3 concentrations, and normal TSH (50). The reason for these changes is the drug’s strong inhibition of 5′-deiodinase, the enzyme responsible for conversion of T4 to T3 and rT3 to T2. Most patients remain euthyroid while on amiodarone, despite the hormonal derangements that may be seen. However, about 14% to 18% of patients develop either hypothyroidism or hyperthyroidism while on amiodarone (51). Hypothyroidism is more commonly encountered in iodine-replete areas, such as the United States (52). Treatment is aimed at normalization of the TSH with levothyroxine replacement while the amiodarone therapy is continued. Upon discontinuation of the amiodarone, most patients return to euthyroidism though it may take several months because of the prolonged half-life of the drug.
In iodine-deficient regions, it is more common to see hyperthyroidism as a result of amiodarone therapy (52). There are two mechanisms (Table 140.6) of amiodarone-induced thyrotoxicosis (AIT) and distinction of these two disorders is relevant because their treatment differs. Type I AIT occurs in glands with an underlying anatomic abnormality. Areas of autonomous thyroid tissue such as a toxic nodule or autoimmune disease in the thyroid produce increased the levels of hormone in response to the excess iodine released from the amiodarone (51). Type II AIT develops as a result of a direct cytotoxic effect of amiodarone on the thyrocyte (53). Treatment of type I AIT can be difficult because most patients do not respond to thionamides as these drugs have decreased efficacy in states of iodine excess (54). Use of potassium perchlorate (KClO4) blocks further iodine entry into the thyrocyte and may enhance the efficacy of thionamides (50). It is important to note that both thionamides and KClO4 may cause agranulocytosis, so serial monitoring of blood counts is advisable (30). The treatment of type II AIT is primarily with glucocorticoids (55). Whether it is advisable to stop the amiodarone with either form of AIT is a controversial issue particularly because the long half-life of the drug indicates that its effects may persist for many months even after discontinuation. Additionally, amiodarone may be the only effective treatment for the arrhythmia. Consequently, a careful discussion with the cardiologist is warranted to aid in the decision of whether to discontinue the medication. For patients in whom chronic therapy with amiodarone is essential, thyroidectomy is a potential treatment for AIT (50). Radioiodine ablation, however, is not an immediate option given the low iodine uptake as a result of the iodine excess from the amiodarone.
Another potential source of excess iodine is radiographic contrast media. As noted in the section about the management of thyroid storm, the oral cholecystographic agents, iopanoic acid and sodium ipodate, may be used short-term in thyrotoxic patients for their side effect of decreasing peripheral conversion of T4 to T3 and blocking hormone secretion from the thyroid. Such agents used over a longer period of time, however, can exacerbate the underlying hyperthyroidism (36). There are a multitude of other agents available which have variable effects on the thyroid gland. Typically, patients with no underlying thyroid disease will not be affected by the use of these agents (56). Patients with Graves disease, multinodular goiter, or the elderly, are at risk to develop thyrotoxicosis after the use of these contrast agents (28). The lipid-soluble agents used for myelography, bronchography, and uterosalpingography are cleared slowly and release inorganic iodine for months to years. Newer, water-soluble preparations used in arteriography and computed tomography are cleared from the plasma more quickly but the iodine they release during these procedures can still have an effect on thyroid function. The degree of thyroid dysfunction can range from mild, transient subclinical hyperthyroidism to thyroid storm (57–61). The majority of patients experience only transient thyrotoxicosis and the syndrome resolves when the excess iodine is cleared. If treatment is required, thionamides and beta-adrenergic blockade may be used until the thyrotoxicosis resolves (59).
|TABLE 140.6 Features of Amiodarone-Induced Thyrotoxicosis|
THYROTOXIC PERIODIC PARALYSIS
Thyrotoxic periodic paralysis (TPP) is a complication of hyperthyroidism characterized by localized or generalized attacks of weakness or flaccid paralysis and hypokalemia (62). Although it has been reported in Western countries and in women, it is more common in Asian men, where the incidence is 1.9% in thyrotoxic patients (63). The clinical presentation is identical to familial hypokalemic periodic paralysis but the pathophysiology is distinct. Though the mechanism of the syndrome is not clearly defined, hypokalemia alone is not enough to elicit the paralysis. Hypokalemia sufficient to create the paralysis in a hyperthyroid patient has no effect on the same patient when euthyroid (64). This finding points to the importance of thyroid hormone excess in the pathophysiology of this process. It is most commonly associated with Graves disease but may be seen with any form of thyrotoxicosis (65).
The clinical presentation is one of symmetrical flaccid weakness with lower extremities generally affected more than upper extremities (64). Breathing may be impaired if the patient has a more generalized weakness. The onset of the attacks is usually sudden and may be preceded by cramping. Ingestion of alcohol or carbohydrates and strenuous physical exercise commonly precipitate the episodes of weakness (64). Patients have decreased or absent deep tendon reflexes. The symptoms may last from a few hours to several days (64).
Treatment of TPP is aimed at correction of the hyperthyroidism. If hypokalemia is present, replacement should be given. Some patients are given a potassium-sparing diuretic in addition to the potassium supplementation until euthyroidism is achieved. Beta-adrenergic antagonists also decrease the frequency of attacks in these patients (63).
Preoperative Management of Hyperthyroidism
Adequate preparation for surgery in thyrotoxic patients is critical to the successful outcome of the procedure. Surgery in a hyperthyroid patient can precipitate thyroid storm, with high morbidity and mortality if preoperative care is inadequate. The type of treatment will depend upon the amount of time before the surgery. Elective procedures should be postponed until the T3 and T4 levels are normalized with thionamides and beta-adrenergic blockade (30). This can usually be achieved within approximately 2 weeks. It is important to note that a suppressed TSH may not normalize for months and this value should not be used as the criteria to assess the thyroid status. Urgent or emergent procedures may be safely done after initiation of a thionamide and a beta-adrenergic antagonist. Iodide, as either SSKI, Lugol’s solution, or an oral radiographic contrast agent—sodium ipodate or iopanoic acid—should also be administered to block the release of thyroid hormone and decrease peripheral conversion of T4 to T3 (66). Finally, a glucocorticoid, such as hydrocortisone or dexamethasone, should also be used if the patient is suspected of having concomitant adrenal insufficiency or additional inhibition of extrathyroidal conversion of T4 to T3 is needed (67). Considerable lowering of T3 and T4 levels can be achieved within 1 to 3 days and normalization within 3 to 5 days (67,68).
Hypothyroidism is a common clinical problem, affecting approximately 4.6% of the population in the United States (69). It is important to recognize the clinical features and potential complications of a patient with hypothyroidism. Nonthyroidal illness, surgery, or diagnostic testing can lead to metabolic decompensation in patients with undiagnosed or untreated hypothyroidism. Additionally, it is important to note that untreated hypothyroidism may slow the metabolism of certain drugs, thereby increasing the risk of problematic side effects. Hypothyroidism is most often caused by autoimmune thyroiditis, also known as Hashimoto’s thyroiditis. Other common causes of hypothyroidism are noted in Table 140.7.
The clinical manifestations of hypothyroidism are manifold. A majority of the symptoms are nonspecific which can lead to a delay in the diagnosis. In elderly patients, the diagnosis may be missed because the patient may be asymptomatic or the signs attributed to aging (70). Patients in the ICU may present with severe CNS disturbances, cardiovascular derangements, hyponatremia, or respiratory failure. Table 140.8 notes the signs and symptoms of hypothyroidism.
|TABLE 140.7 Causes of Hypothyroidism|