Thyroid Diseases

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Thyroid Crises Laurence A. Gavin, MD, FACP, FRCP*

THYROID STORM

Thyroid storm is a decompensated state of thyrotoxicosis that can be fatal unless recognized and aggressively treated. The diagnosis of thyroid storm is based on a high index of clinical suspicion, and treatment must be instituted on an emergency basis prior to the availability of confirmatory thyroid function tests. Pathophysiology The mechanisms underlying the clinical progression from compensated thyrotoxicosis to storm have not been determined. 42 Laboratory tests generally reveal similar serum total and free thyroxine (T4) and triiodothyronine (T3) levels in compensated thyrotoxicosis and in patients suffering from thyroid storm. However, it has long been recognized that a sudden increase in circulating thyroid hormone levels following the withdrawal of antithyroid drugs, the therapeutic use of iodine-131, or surgery in the thyrotoxic patient may proceed to thyroid storm. Furthermore, plasmapheresis and peritoneal dialysis, which quickly reduce the serum concentration of thyroid hormones, rapidly alleviate thyroid storm. 1. 17 Thus, it seems that an acute elevation of free T3 or T4 in the thyrotoxic patient may produce system decompensation and result in thyroid storm. However, no absolute level of serum T3 or T4 exists, above which thyroid storm inevitably occurs.5 Thyroid storm is a systemic disease, and the effects of excess thyroid hormone result in a spectrum of metabolic responses. Many of these features of thyroid storm seem to stem from sympathetic overactivity. The mechanism for this response has not been established, and serum catecholamine levels are not increased. Recent studies indicate that the enhanced sympathetic activity in thyrotoxicosis (thyroid storm) results partially from an increased number of beta-adrenergic receptors on target organs, such as the myocardium. In addition, imprecisely understood postreceptor *Associate Professor of Medicine. The Medical Center at the University of California; and Staff Physician, Veterans Affairs Medical Center, San Francisco, California

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events may also contribute to the supersensitivity of the thyrotoxic myocardium and other catecholamine-sensitive tissues. 42 The characteristic increase in metabolic rate appears to be due to the induction of key enzymes regulating metabolism. Thyroid hormones potentiate the calorigenic effects of other hormones such as catecholamines, probably by increasing the synthesis of the enzyme Na-K-ATPase. The adenosine diphosphate (ADP) produced by hydrolysis of adenosine triphosphate (ATP) stimulates mitochondria and increases the rate of oxidative phosphorylation. If not adequately dissipated, the excessive thermal energy generated by such enzyme activity results in fever. Unchecked, this process frequently leads to hyperpyrexia and may prove lethal unless the defect that facilitates such uncontrolled heat generation is corrected. Documenting the Presence of Pre-existing Thyrotoxicosis In most patients with thyroid storm, there is a history of thyrotoxicosis either under treatment or recently developed, untreated disease (Table 1).38 This pattern of presentation points to the essentially preventable nature of the condition, as thyroid storm is basically an exaggeration of thyrotoxicosis. However, the clinical features of thyrotoxicosis, which is a systemic disease, are extremely variable. Thus, its presence may be easily overlooked, especially in the absence of the characteristic feature of Graves' disease. The early symptoms of thyrotoxicosis are often missed because they are diverse, nonspecific, and variable. Excessive thyroid hormone may result in restlessness, emotional lability, insomnia, and tremor. Sweating, heat intolerance, and weight loss occur commonly, the latter accompanied by a normal or increased appetite. Less frequently, a proximal muscle myopathy causes difficulty in activities, such as climbing stairs. Symptoms resulting from cardiovascular dysfunction, such as dyspnea and palpitations, are common. Thyrotoxic patients over 40 years may suffer exacerbations of angina pectoris and congestive cardiac failure. However, classic Graves' disease, the most common cause of thyroid storm, especially in younger patients, should rarely be overlooked. The three characteristic features of Graves' disease-ophthalmopathy, diffuse goiter, and dermopathy-present with variable combinations. 43 Thyromegaly is by far the most common of the three and affects about 90% of patients, whereas ocular symptoms occur in over 50% of patients with Graves' disease. Frequent complaints in Graves' disease include protruding eyes, easy tearing, especially on exposure to wind or sunlight, a gritty sensation in the eyes, and, occasionally, diplopia. A few patients may suffer Table 1. Causes of Thyroid Storm Graves' disease Toxic nodular gaiter (Plummer's disease) Toxic adenoma Iodine-induced (Jod-Basedow disease) Factitious thyrotoxicosis Excess TSH

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from malignant exophthalmos, in which marked inflammatory changes may threaten the patients' vision. Pretibial myxedema, found only in Graves' disease, occurs in a mere 1% to 2% of patients. These patients develop a brawny, nontender, and non pitting swelling of the peripheral area. This swelling sometimes extends to the ankles and feet in the form of plaques with a typical peau d'orange appearance. In contrast, "atypical" thyrotoxicosis poses a difficult diagnostic problem. Atypical thyrotoxicosis occurs commonly among elderly patients. It may be due to Graves' disease but more usually results from nodular goiter (see Table 1). Patients with this form of thyroid disease have a remarkable paucity of symptoms. They frequently do not suffer ophthalmopathy and also may not have an obvious goiter. Without timely recognition and management, this condition, traditionally referred to as masked or apathetic thyrotoxicosis, may cause the patient to "quietly and peacefully sink into coma and die an absolutely relaxed death. "35. 40 The clinical differentiation of compensated thyrotoxicosis from storm can be difficult. However, the recognition that thyroid storm is basically an exaggeration of the classical features of thyrotoxicosis, plus a number of cardinal features reflective of decompensation, should facilitate the correct clinical diagnosis (Table 2). The patient in storm frequently exhibits hyperthermia in the absence of an associated infection. Hyperpyrexia (core temperature exceeding 104°F) is even more specific, as it occurs only in a few other conditions. Tachycardia and tachyarrhythmia (usually atrial fibrillation) frequently accompany the high-output cardiac failure of thyroid storm. Most patients have a wide pulse pressure, with elevated systolic blood pressure. g • 10 In contrast, some present with hypotension, which reflects marked cardiac decompensation. Cachexia, dehydration, and icterus are ominous features. Cachexia results from the catabolic effects oflongstanding thyrotoxicosis. Dehydration stems from multiple sources of fluid loss, whereas icterus, although uncommon, signals significant hepatic necrosis. Ocular signs may be absent, mild, and sometimes asymmetric. However, many patients have the typical proptosis and periorbital puffiness. Table 2. Clinical Features of Thyrotoxicosis and Thyroid Storm General Hyperkinesis Heat intolerance Sweating (hyperpyrexia, temperature> 104°F)* Cardiovascular Palpitations Shortness of breath Tachycardia Arrhythmias (new-onset)* Endocrine Goiter Eyes Proptosis Stare *Cardinal features of storm.

Gastrointestinal Diarrhea Weight loss Hepatomegaly Jaundice* Nervous System Restlessness Tremor Psychosis (delirium, dementia)* H yperreflexia Apathy Coma

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Additional ocular signs may include a "staring" look caused by a widened palpebral fissure, with the sclera visible. Inspection of the neck may reveal a diffusely enlarged or multinodular thyroid, with increased vascularity resulting in a bruit or even a palpable thrill. Associated distended neck veins and a raised jugular venous pressure may indicate congestive cardiac failure. The neurologic features may be dramatic and generally provide the most important clinical evidence of progression to thyroid storm. The most frequent relate to personality and mental status changes and range from agitation to delirium, confusion, obtundation, and coma. Systemic examination may reveal spasticity, symmetrically brisk tendon jerk, and, occasionally, bilateral clonus and Babinski signs. Ocular palsy (mainly paralysis of convergence) results from infiltrative ophthalmopathy. Thyrotoxic patients also possess a fine, rapid tremor of their outstretched hands. Finally, some patients present with nausea, vomiting, and severe diarrhea, which may mimic an acute abdominal emergency. In addition, hepatotoxicity may result in clinical jaundice and a metabolic encephalopathy. Further deterioration may progress to obtundation coma and death. 18 Invariably, a precipitating factor can be identified that contributes to the progression of thyrotoxicosis to storm. A spectrum of medical and surgical conditions can precipitate thyroid storm (Table 3). The recognition of the specific precipitant in a given patient assumes great significance because the outcome of thyroid storm depends on effective treatment of that factor. 6, 29, 30, 37 Specific Laboratory Tests The diagnosis and initial treatment of thyroid storm must be based on the clinical evaluation. The thyroid function test provides corroborative, rather than diagnostic, information. 20, 21, 42 Levels of serum total T4 free T4 and T3 as determined by radioimmunoassay (RIA) are elevated' in most patients. A minority of patients may present with an isolated increase in serum T3 (T3 toxicosis). Furthermore, some patients with equivocal hormone levels may require further testing. Newer and more sensitive assays for serum thyroid-stimulating hormone (TSH) can differentiate the suppressed serum TSH characteristic of thyrotoxicosis from normal. In some cases, however, further confirmation of thyrotoxicosis may necessitate an assessment of the serum TSH response to thyrotropin-releasing hormone (TRH). A flat TSH response to TRH given intravenously confirms thyrotoxicosis. 14 Table 3. Precipitating Factors in Thyrotoxicosis Storm MEDICAL

SURGICAL

Infection Pulmonary embolus Diabetic ketoacidosis Thyroid hormone excess Iodine-131 therapy Iodine (drugs and dyes) Cardiovascular accident

Thyroid surgery Major surgery Minor surgery Tooth extraction Childbirth Dilatation and curettage

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Finally, in patients with thyroid storm, the potential for associated adrenal insufficiency should be evaluated with a serum cortisol measurement. General Laboratory Tests A variety of biochemical abnormalities reflecting hepatic, adrenal, and renal decompensation characterize patients with thyroid storm. Liver function tests often reveal an elevated serum bilirubin, a prolonged prothrombin time, and elevated SCOT and SCPT. Both hypercalcemia and hyperglycemia may occur. Hypoglycemia, an ominous finding, results from depletion of hepatic glycogen, high peripheral utilization of glucose, and decreased gluconeogenesis due to hepatic failure. The presence of an abnormal adrenal status should be prompted by the electrolyte triad of hyperkalemia, hyponatremia, and hypercalcemia. Finally, rising levels of serum blood urea nitrogen (BUN) and creatinine indicate a decreased creatinine clearance and prerenal azotemia secondary to dehydration and obtundation. Management of Thyroid Storm (Table 4) Both specific and supportive therapy for thyroid storm possesses some deficiencies. The efficacy and potential side effects of antithyroid and other drugs differ widely among patients. Supportive therapy is extremely important, as are the detection and treatment of the precipitating disorder. 8, 13, 32, 42 Antithyroid Drugs. Both methimazole and propylthiouracil inhibit hormone production in the thyroid. However, propylthiouracil is the drug of choice in thyroid storm because it also inhibits the monodeiodination of T4 to T3 in peripheral tissues. Thus, administration of propylthiouracil results in a more rapid reduction of circulating thyroid hormone levels. The initial loading dose is 1000 mg, followed by a daily dose of about 600 Table 4. Management of Thyroid Storm 1. Supportive care Adequate hydration with fluid and nutrient support, glucose, and multivitamins Treat fever with external cooling and acetaminophen Digitalis and diuretic therapy for congestive heart failure or tachyrhythmia 2. Inhibition of hormonal biosynthesis: Propylthiouracil, 900-1200 mg PO as a loading dose, then 300-600/day in three divided doses 3. Blockade of hormone release (after step 2) Sodium iodide, 1 g as a slow push (IV) over 30 min; repeat every 8-12 h or Lugol's solution, 20 drops (PO) tid or SSKI, 5 drops (PO) tid 4, Antagonism of peripheral effect of thyroid hormones Beta-adrenergic blockade: Propranolol-Oral dose: 20-80 mg every 6 h. Dose needed may be larger. Intravenous dose: 1-2 mg every 5 min up to 10 mg total. Monitor blood pressure and EKG. Contraindicated in bronchospasm and congestive heart failure. Digitalize patients with congestive heart failure before starting propranolol. 5. Steroids: Hydrocortisone, 100-300 mg as initial IV bolus, then 50-100 mg tid until the patient is stable

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mg to induce an eventual euthyroid status. Propylthiouracil is rarely associated with significant side effects such as agranulocytosis (reverslble) and hepatotoxicity. Iodine treatment yields significant, but temporary, benefit in patients with thyroid storm. Iodine therapy blocks thyroid hormone synthesis (transiently), but more importantly it inhibits the secretion of stored T3 and T 4 • Iodine should not be initiated until 1 to 2 hours after the patient receives the initial dose of propylthiouracil. Failure to block hormone synthesis prior to iodine therapy may paradoxically increase intrathyroidal hormone by providing increased substrate for hormone synthesis. Sodium iodide can be administered (intravenously) in a dose of 1 g every 8 hours or 1 to 2 g in an intravenous drip over 8 to 12 hours. Alternatively, a saturated solution of potassium iodide (SSKI), five drops (orally) three times a day (40 mg of iodide/drop), or Lugol's solution (8 mg of iodide/drop), 20 drops, can be given (orally) three times a day when the patient starts taking fluids by mouth. Sodium ipodate or ipanoic acid, which has the effects of inorganic iodine noted previously as well as blocks the conversion of T4 to T 3. may be administered orally in a dose of 1 g twice daily. Lithium carbonate may be used in patients with a history of iodide allergy. Lithium also causes a reduction in the secretion of thyroid hormones. However, a clinical and biochemical relapse may result on stopping either of these two drugs. Hence, iodine or lithium should be used only as an adjunct to propylthiouracil. Lithium does not yield superior results over iodine because it has even more hazardous side effects. Therefore, most clinicians prefer using iodine in thyrotoxic patients, except for those allergic to iodine. Antiadrenergic Drugs. Propranolol is the drug of choice to counteract some of the peripheral effects of thyroid hormone. Symptoms related to the adverse effects of thyrotoxicosis on the central nervous and cardiovascular systems respond best to propranolol. 25 In addition to blocking the catecholamine-mediated effects, propranolol may also play a secondary role in thyroid storm consequent to the inhibition of monodeiodination of T4 to T 3 . However, antiadrenergic drugs alone do not control thyroid storm. Propranolol therapy usually produces an effect lasting about 3 to 4 hours. Oral therapy may result in an amelioration of symptoms for about an hour. Close clinical and laboratory monitoring of patients given propranolol for thyroid storm is essential. It is routine to administer corticosteroids in thyroid storm, even in patients without definitive signs of adrenal insufficiency. The patient suffering from storm is considered to have a relative deficiency of steroids. The benefits from steroids include inhibition of hormone secretion and T4 conversion to T3. Use hydrocortisone, 100 to 300 mg daily, or dexamethasone, 8 to 10 mg daily, in three divided doses. Dialysis. In some patients with thyroid storm, medical treatment may prove ineffective or cause unacceptable side effects. Plasmapheresis or peritoneal dialysis may control the crisis by removing the excess of circulating thyroid hormone. 1, 17 Surgery. As a last resort in patients with thyroid storm who are not responding adequately to intensive medical therapy, it may be necessary to proceed to surgery and perform a partial or total thyroidectomy.

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Supportive Therapy. Fluid and electrolyte imbalances are severe and frequently underestimated in these hypermetabolic patients. Adequate replacement with dextrose or dextrose-saline is mandatory, especially in the dehydrated patient with evidence for prerenal azotemia and hypoglycemia. B-complex vitamins should be added to the infused fluids, because large amounts are utilized in association with the hypermetabolism associated with thyroid storm. Cooling blankets and antipyretics are adequate in most cases to reduce the hyperthermia associated with thyroid storm. Psychotropic drugs may be needed to treat agitation. Congestive heart failure during thyroid storm usually does not respond well to conventional measures such as cardiotonic drugs and oxygen. However, once the hyperthyroidism is controlled it is generally easier to ameliorate cardiac failure. Because propranolol may exacerbate cardiac failure, it should be initiated after prescribing digitalis and diuretics. 9 Thus, in the setting of characteristic features of thyrotoxicosis, the diagnosis and aggressive management of thyroid storm should result in a successful outcome. However, severe storm may lead to irreversible cardiovascular collapse, especially in the older patient who may have atypical features of thyrotoxicosis. The fundamental feature is prompt and optimal treatment in the emergency department once the presenting clinical features suggest its presence. Delay in the introduction of therapy while awaiting laboratory confirmation may result in further decompensation and death. MYXEDEMA COMA Patients suffering from myxedema coma, the endpoint of chronic thyroid hormone deficiency, exhibit widespread organ dysfunction. Myxedema coma adversely affects vital functions such as respiration, cardiac performance, mental status, and thermoregulation. In addition myxedema is associated with a spectrum ofhematologic, biochemical, and immunologic derangements. Pathophysiology This condition is seen most often in elderly women who have chronic hypothyroidism from a spectrum of causes (Table 5).2, 4, 11 The classic features of hypothyroidism are generally present. However, less severe forms of hypothyroidism may also be associated with coma when vital organ function is compromised by a precipitating or aggravating factor. Myxedema coma is complex, because apart from thyroid hormone deficiency, the syndrome is frequently associated with cardiorespiratory dysfunction (hypoxemia, hypercapnia), hyponatremia, hypoglycemia, and hypothermia. The mortality rate remains high (50%) despite optimal therapy. Respiratory System. Myxedema causes respiratory decompensation due to a complex interaction of factors affecting both the peripheral and central control of breathing. Macroglossia, together with upper airway edema, may reduce the diameter of the upper respiratory tract. 33 M yxede-

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Table 5. Causes of Hypothyroidism Thyroid Insufficiency (Primary) Autoimmune: Hashimoto's thyroiditis and atrophic hypothyroidism Iatrogenic: Radioactive iodine or surgical therapy for hyperthyroidism, thyroidectomy for thyroid carcinoma, radiation for head and neck tumors Drugs: Iodine excess or deficiency, amiodarone, lithium, and antithyroid medications Congenital: Defects in thyroid hormone biosynthesis, thyroid gland dysgenesis or agenesis Pituitary or Hypothalamic Insufficiency (Secondary or Tertiary) Radiation Tumors Infiltrative disease (sarcoidoses) Surgery Apoplexy

matous infiltration of respiratory muscles and concomitant pleural effusion may cause restrictive breathing. However, the major cause for abnormal ventilation is a depression of the hypoxia-mediated respiratory response. This may also be accompanied by a reduced response to hypercapnia. The consequent alveolar hypoventilation leads to progressive carbon dioxide narcosis and coma. 27, 45 Cardiovascular Manifestations. Myxedema heart disease is characterized by pericardial effusion, bradycardia, hypotension, and variable degrees of congestive heart failure. The pericardial effusion arises from a transudative process. However, cardiac tamponade occurs infrequently, because the effusion generally develops gradually.28 The hypothyroid state per se may further decompensate cardiac function by reducing intrinsic myocardial contractility, leading to a diminished stroke volume and a low cardiac output. 9 Despite the increase in total body water, myxedema patients have a reduced effective intravascular volume and a propensity for hypotension, cardiovascular collapse, and shock. Impaired Thermoregulation. Hypothermia «90°F) occurs in many (75%) patients in myxedema coma. Hypothermia most likely results from a decrease in the basal metabolic rate as well as dysfunction of the thermoregulatory center, with a consequent reduction in heat generation by the body. Patients with core temperature less than 90°F tend to have the worst prognosis. Renal and Electrolyte Alterations. Hyponatremia is a frequent finding and is reflective of the increase in total body water (dilutional). The hyponatremia results from a combination of events: diminished glomerular filtration, decreased delivery of water to the distal tubule, and a consequent impaired water diuresis. Patients with hypothyroid coma may suffer from the syndrome of inappropriate ADH (SIADH) secretion and a deficiency of atrial natriuretic factor (ANF). Both defects aggravate the salt and water abnormalities. 24, 26, 44 The hyponatremia will compound the patient's mental confusion and, when severe, may be responsible for the eventual decompensation into coma. Gastrointestinal Alterations. Paralytic ileus occurs frequently in myxedema coma, Impaired motility is due to both thyroid hormone deficiency and gut wall edema. Reversal of the hypothyroid state will eliminate this

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problem. 4 , 39 Thus, conservative care should be followed to assess the response, as surgical intervention can be fatal under these conditions. Infection. Myxedema patients are susceptible to infection, especially if they are in myxedema coma. Hypothyroidism is associated with an impaired leukocyte response to infective organisms. Therefore, leukocytosis, an otherwise characteristic indicator of infection, may not develop in such patients. Respiratory tract infection may be more common because of the risk of aspiration in a stuporous patient, especially when associated with seizures. Diagnosis. The diagnosis of myxedema coma is based on a detailed clinical evaluation. Historical details should be obtained from family members and associates. One should obtain information pertinent to previous thyroid disease, such as recent symptoms of hypothyroidism and features that may indicate a precipitating event, Patients treated in the past for hyperthyroidism with surgery or radioactive iodine may develop occult hypothyroidism. Relevant treatment, such as antithyroid drugs or exposure to iodine, lithium, or amiodarone, should be determined. 29 , 31 Typically, myxedema coma occurs in elderly women, an association linked to the higher incidence of autoimmune hypothyroidism in women. A history of classic symptoms is generally available from family members. The history may indicate a progressive mental status dysfunction that had been attributed to "old age." Observers may detail cold intolerance, fatigue, somnolence, lethargy, and a memory deficit. In addition, a history of confusion, paranoia, psychotic behavior (myxedema madness), apathy, negligence, and antisocial tendencies may be obtained,32, 39 Although spontaneous coma can complicate chronic hypothyroidism, a specific precipitating event or intercurrent illness most often leads to coma. Aggravating factors may range from cold exposure and alcohol use to infection, gastrointestinal bleeding, cardiovascular events, injuries, and surgery. Special attention must be given to possible iatrogenic precipitants. Improperly treated hypothyroid patients exhibit an exquisite sensitivity to the respiratory depressant effects of numerous medications, such as sleep medications, phenothiazines, narcotics, and general anesthesia. Hypothyroid patients may lose consciousness with otherwise normal doses of such medications. Physical Findings The typical features of myxedema may include a dry, rough skin, generalized yellowish discoloration (due to carotenoid deposition), and hyperkeratosis around the elbows and knees. A puffy face and eyelids, with loss of the outer third of eyebrows, is classic. Diffuse alopecia may also occur, and the nails may be ridged, brittle, and thickened. Vitiligo may provide a clue to a clustering of autoimmune diseases. The neck may reveal a goiter or a barely visible scar consistent with previous thyroid surgery. Hypoventilation in the cyanotic patient should suggest a depressed respiratory center and associated carbon dioxide retention. Further examination may reveal signs of a pleural effusion as well as increased heart size due to

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pericardial effusion. The apex beat may be impalpable, and heart sounds may be faint, with marked bradycardia. A special thermometer should be used to detect hypothermia. Examination of the alimentary system may reveal the characteristic macroglossia of myxedema, which could predispose to upper airway occlusion and necessitate an oropharyngeal airway. Reduced or absent bowel sounds should suggest paralytic ileus. A palpable urinary bladder should indicate urinary retention. The patient in myxedema coma (metabolic encephalopathy) usually has no cranial nerve deficit; however, examination of the motor system may reveal bulky muscles with diminished power and myotonia-like contractions. An additional characteristic feature is myoedema, a transient local swelling after tapping a muscle that persists for a short period of time. Finally, myxedema coma is classically associated with reflexes that are diminished, absent, or have a prolonged recovery phase. Specific Laboratory Tests (Table 6) In the florid case of myxedema coma, measurement of thyroid function tests may be only necessary for confirmation. It must be re-emphasized that once the clinical suspicion of myxedema is suggested, it is essential that treatment be promptly instituted prior to the availability of the results. Serum total T4 and free T4 are generally in the low hypothyroid range. Serum total and free T3 values may, however, be normal or only marginally decreased. Thus, T3 measurement is not a useful test in suspected hypothyroidism. Invariably, serum TSH is elevated (> 60 f1U1mL) in primary thyroid failure. 20 Note that in coma associated with secondary (pituitary or hypothalamic) hypothyroidism, the serum TSH will be normal or low. In the latter state, the clinical features are generally less pronounced and facial periorbital and peripheral edema are usually absent. Loss of total body hair is more pronounced, and the hair texture is thinner compared to the coarseness in primary hypothyroidism. The history and examination should reveal additional features of hypogonadism and hypoadrenalism. Table 6. Laboratory Tests in Myxedema Coma Specific Diagnostic Tests Serum TSH (>60 fLU/mL) Serum total T4 and free T4 (Iow) Serum total T3 and free T3 (normal or Iow) Nonspecific Tests EKC: Bradycardia, Iow-voltage, prolonged QT interval Radiographs: Chest: Pleural effusion, cardiomegaly Skull: Enlarged sella (secondary hypothyroidism) Arterial blood gases: Hypoxia, hypercapnia Complete blood count: Anemia SCOT, CPK, LDH: Abnormal Lipids: Cholesterol and triglycerides (elevated) Hypoglycemia Hyponatremia H ypercalcemia Cortisol (normal or low)

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From a clinical perspective, secondary hypothyroidism is rare, and few patients develop myxedema coma. 15 Be aware that the finding of low serum total and free T4 levels in the critically ill patient may indicate the euthyroid sick syndrome and should not be considered or treated as hypothyroidism. Such patients will have normal or slightly elevated serum TSH « 15 f.L UlmL). 7, 14, 21 Finally, the use of pressor agents (dopamine) in the obtunded shocked patient may normalize an elevated TSH, and the true diagnosis of hypothyroidism may be overlooked, General Laboratory Tests A skull radiograph will detect an enlarged or eroded sella turcica due to a pituitary tumor causing secondary hypothyroidism, The chest radiograph may confirm an increase in cardiac size due to pericardial effusion, and the lung fields may show an infiltrate (pneumonia), which could be the precipitating cause of the coma, Abdominal radiograph may show ascites or ileus. Characteristic electrocardiographic (EKC) changes include brachycardia, various degrees of heart block, prolonged QT interval, and lowvoltage QRS complexes. Arterial blood gas analysis will confirm the presence of respiratory acidosis, hypoxemia, and hypercapnia. Chemistries may detect hyponatremia, hypoglycemia, and hypercalcemia, In secondary hypothyroidism, hyperkalemia may reflect adrenal insuffiCiency, Liver enzymes (SCOT, SCPT, and LDH) may be abnormal, and a modest increase in CPK MB has been described. The absence of EKC changes and the rapid reversal with therapy should exclude the presence of a myocardial infarction. 16 Many patients with myxedema coma demonstrate elevated subarachnoid pressure and increased cerebrospinal fluid protein. The cerebrospinal fluid is otherwise normal, a feature that serves to exclude intracranial disease such as tumor, meningitis, or encephalitis, Management of Myxedema Coma (Table 7) A comprehensive approach is needed for effective therapy and should include aggressive management of any precipitating factor, supportive therapy, and thyroid hormone replacement. Myxedema coma is a true medical emergency, and meticulous care in a critical care setting with monitoring is essential. 12, 19, 32 Thyroid Hormone Replacement. To minimize chances of a delayed response in myxedema coma, T4 is administered parenterally. Following the initial loading dose, maintenance T4 may be given intravenously or orally. 12, 19, 22, 32 Subsequent to hormonal replacement, a rising body temperature and heart rate constitute early signs of recovery. These signs should be evident within 8 to 12 hours. In most cases, the patients should recover consciousness within 24 hours after initiating specific treatment. Serum TSH generally decreases slowly over 24 to 48 hours. The other biochemical signs of thyroid dysfunction will, however, persist for about a week to 10 days. Supportive Measures. A number of the systemic complications of myxedema coma may not respond rapidly. It is necessary to manage

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Table 7. Treatment of Myxedema Coma Detection of Precipitating Factor Carefully search for an associated intercurrent illness as an aggravating condition. Note that the normal temperature and leukocyte count may be inappropriate in the myxedema coma patient with associated infection. Thyroid Hormone Replacement: L-Thyroxine (T4) 500 f,Lg IV as a single dose, followed by 50-100 f,Lg IV or 100-200 f,Lg PO daily. Respiratory Failure Monitor arterial blood gases. Use mechanical ventilation if necessary. Hyponatremia: Fluid restriction is appropriate for hyponatremia, but cautious volume expansion may be necessary in the hypotensive patient. Hypoglycemia: 050 (acute), 05 (maintenance) Hypotension This usually responds to thyroid hormone replacement. If needed, use vasopressor agents, and closely monitor cardiovascular system. Hypothermia Avoid external heat sources; do not actively rewarm. Cover with blankets; use passive care. Steroids: Hydrocortisone (Solucortef), 100 mg IV and 50-100 mg tid daily.

cardiorespiratory dysfunction, hypothermia, hyponatremia, and possible adrenal insufficiency on an individual basis. Mechanical ventilation may prove life-saving in myxedema coma. Many patients require assisted ventilation for prolonged periods. Early weaning of the myxedema coma patient from the ventilator should be avoided, because the patient frequently needs respiratory support for a protracted period. 27 Hypotension may prove particularly difficult to manage, especially until adequate levels of circulating thyroid hormone are achieved. Because this may take several days, it may be necessary to administer fluids (D5! 0.5 N-saline) carefully to expand the effective intravascular volume. Keep a close clinical watch for the potential development of congestive cardiac failure. This approach should also correct the associated hyponatremia and hypo glycemia. A rare patient may need pressor agents (dopamine) to sustain adequate perfusion. In addition, steroid therapy should be continued until hemodynamic and electrolyte stability is achieved. Aggressive treatment of hypothermia may prove hazardous consequent to the increased oxygen demands and metabolism. This may lead to peripheral vasodilatation, circulatory collapse, and even death. To prevent this, ensure heat preservation by cautious utilization of passive methods, such as external rewarming with blankets. Ultimately, it is thyroid hormone replacement that restores temperature to normal. Adrenal insufficiency may co-exist with myxedema coma on the basis of either hypopituitarism or primary autoimmune adrenal failure. In addition, it is believed that the ATCH response to stress is relatively deficient in the setting of myxedema coma and hypothermia. Thus, one should not be reluctant to give steroids as a component of care until the patient has

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stabilized. Administer hydrocortisone, 100 mg intravenously initially, followed by 50 to 100 mg every 6 hours, to a total of 500 mg in the first 24 hours. Reduce the dose to 50 to 100 mg every 8 hours during the first 7 to 10 days of management. Subsequently, taper the dose on the basis of the clinical response and eventually discontinue once adrenal insufficiency has been excluded. Prophylaxis The prevention of myxedema coma entails paying special attention to certain high-risk patient groups. These groups include older women with a history of Hashimoto's thyroiditis, or previous irradiation or thyroid surgery for hyperthyroidism. Inform such patients of the symptoms and signs of hypothyroidism, and perform annual thyroid function tests, such as a serum TSH, in order to provide early, adequate treatment once the test becomes positive. SUMMARY In the setting of characteristic features of thyrotoxicosis, the timely diagnosis and aggressive management of thyroid storm should result in a successful outcome. However, severe storm may lead to irreversible cardiovascular collapse, especially in the older patient who may have atypical features of thyrotoxicosis. The fundamental approach is prompt and optimal treatment in the emergency department once the presenting clinical features suggest its presence. Delay in the introduction of therapy while awaiting laboratory confirmation may result in further decompensation and death. The prevention of myxedema coma entails paying special attention to certain high-risk patient groups. These groups include older women with a history of Hashimoto's thyroiditis, or previous irradiation or thyroid surgery for hyperthyroidism. Inform such patients of the symptoms and signs of hypothyroidism, and perform annual thyroid function tests, such as a serum TSH, in order to provide early, adequate treatment once the test becomes positive.

REFERENCES 1. Ashkar F, Katims RB, Smoak WM Ill, et al: Thyroid storm treatment with blood exchange and plasmapheresis. JAM A 214:1275, 1970 2. Bastenie PA, Bonnyns M, Vanhaelst L: Natural history of primary myxedema. Am J Med 79:91, 1985 3. Berkowitz I, Di Bisceglie AM: Hyponatremia complicating the treatment of myxedema coma. S Afr Med J 69(2):136, 1986 4. Borrie MJ, Cape RDT, Troster MM, et al: Myxedema megacolon after external neck irradiation. J Am Geriatr Soc 31:228, 1983 5. Brooks MH, Waldstein ss: Free thyroxine concentration in thyroid storm. Ann Intern Med 93:694, 1980 6. Brennan MD, van Heeden JA: Amiodarone associated thyrotoxicosis: Experience with surgical management. Surgery 102:1062, 1987

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7. Cavalieri RR: Thyroid dysfunction in the ICU patient. Hosp Physician 5:18, 1990 8. Cooper DS, Ridgeway EC: Clinical management of patients with hyperthyroidism. Med Clin North Am 69:953, 1985 9. Dillman WH: Thyroid hormone and the heart. Thyroid Today 6:1, 1983 10. Fofar JC, Muir AJ, Sawer SA, et al: Abnormal left ventricular function in hypothyroidism. N Engl J Med 207:1165, 1982 11. Forester CF: Coma in myxedema. Arch Intern Med 111:734, 1963 12. Gavin LA, Bosker G: Reversing hypothyroid coma. Emerg Med Reports 6(19):145, 1985 13. Gavin LA, Hamburger S: Thyroid storm. Emerg Med Reports 6:137, 1985 14. Gavin LA: The diagnostic dilemma of hyperthyroxinemia and hypothyroxinemia. Adv Intern Med 33:185, 1988 15. Gharib H, Abboud CF: Primary idiopathic hypothalamic hypothyroidism. Am J Med 83:171, 1987 16. Goldman J, Matz R, Mortimer R, et al: High elevations of creatinine phosphokinase in hypothyroidism: Isoenzyme analysis. JAMA 238:325, 1977 17. Herman J, Schmidt HJ, Kruskemper HL: Thyroxine elimination by peritoneal dialysis in experimental thyrotoxicosis. Horm Metab Res 5:180, 1973 18. Howton JC: Thyroid storm presenting as coma. Ann Emerg Med 17:343, 1988 19. Hylander B, Rosenqvist U: Treatment of myxedema coma: Factors associated with fatal outcome. Acta Endocrinol 108:65, 1985 20. Kaplan MM: Clinical and laboratory assessment of thyroid abnormalities. Med Clin North Am 69(5):863, 1985 21. Kaptein EM: Interpretation and use of thyroid function tests in nonthyroidal disease. Intern Med Spec 3(7):102, 1982 22. Kaptein EM, Quion-Verde H, Swinney RS, et al: Acute hemodynamic effect of levothyroxine loading in critically ill hypothyroid patients. Arch Intern Med 146:662, 1986 23. Klein I, Levey GS: Unusual manifestations of hypothyroidism. Arch Intern Med 144:123, 1984 24. Kiode Y, Oda K, Shimizu K, et al: Hyponatremia without inappropriate secretion of vasopressin in case of myxedema coma. Endocrinol Jpn 29(3):363, 1982 25. Levey GS: Beta-adrenergic blocking drugs in the treatment of hyperthyroidism. Hosp Form 14:45, 1979 26. Ladenson PW, Langevin H, Michener M: Plasma atriopeptin in hyperthyroidism and hypothyroidism. J Clin Endocrinol Metab 65: 1172, 1987 27. Ladenson PW, Goldenheim PD, Ridgeway EC: Prediction and reversal of blunted ventilatory responsiveness in patients with hypothyroidism. Am J Med 84(50):877, 1988 28. Manolis AS, Varriable P, Ostrowski RM: Hypothyroid cardiac tamponade. Arch Intern Med 147(6):1167, 1987 29. Martino E, Safran M, Aghini-Lombardi F, et al: Environmental iodine intake and thyroid dysfunction during chronic amiodarone therapy. Ann Intern Med 101:28, 1984 30. Martino E, Safran M, Aghini-Lombardi F, et al: Amiodarone: A common source of iodineinduced thyrotoxicosis. Horm Res 25:158, 1987 31. Manzonson PD, William MI, Cantley LK, et al: Myxedema coma during long-term amiodarone therapy. Am J Med 77:751, 1984 32. Nicoloff JT: Thyroid storm and myxedema coma. Med Clin North Am 69:1005, 1985 33. Orr WC, Males JL, Imes NK: Myxedema and obstructive sleep apnea. Am J Med 70:1061, 1981 34. Ridgeway EC, McCammon JA, Bnotti J, et al: Acute metabolic responses in myxedema to large doses of intravenous L-thyroxine. Ann Intern Med 77:549, 1972 35. Serri 0, Gagnon R, Goulet Y, et al: Coma secondary to apathetic thyrotoxicosis. Can Med Assoc J 119:605, 1978 36. Skowsky WR, Kiluchi TA: The role of vasopressin in the impaired water secretion of myxedema. Ann J Med 64:613, 1978 37. Smyrk TC, Goellner JR, Brennan MD: Pathology of the thyroid in amiodarone associated thyrotoxicosis. Am J Surg Pathol11:197, 1987 38. Spaulding SW, Lippes H: Hyperthyroidism: Causes, clinical features and diagnosis. Med Clin North Am 69:937, 1985 39. Tachman ML, Guthrie GP: Hypothyroidism: Diversity of presentation. Endocr Rev 5(3):456, 1984

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40. Thomas FB, Mazzaferri EL, Skillman TG: Apathetic thyrotoxicosis. Ann Intern Med 72:679, 1970 41. Tunbridge WMG: The epidemiology of hypothyroidism. J Clin Endocrinol Metab 8:21, 1979 42. Wartofsky L: Thyroid storm. In Ingbar SH, Braverman LE (eds): Werner's The Thyroid: A Fundamental and Clinical Test. Philadelphia, JB Lippincott, 1986, pp 974-986 43. Woeber KA: Graves' disease general considerations. In Ingbar SH, Braverman LE (eds): Werner's The Thyroid: A Fundamental and Clinical Test. Philadelphia, JB Lippincott, 1986, pp 982-985 44. Zimmerman RS, Gharib H, Zimmerman 0, et al: Atrial natriuretic peptide in hypothyroidism. J Clin Endocrinol Metab 64(2):353, 1987 45. Zwillich CW, Pierson DJ, Hofeldt FD, et al: Ventilatory control in myxedema and hypothyroidism. N Engl J Med 292:662, 1975

Address reprint requests to Laurence A. Gavin, MD, FACP, FRCP Department of Medicine Veterans Administration Medical Center BUilding 203, GB5 4150 Clements Street San Francisco, CA 94121