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CHAPTER 228:  Hypothyroidism and Myxedema Crisis      1447 Phosphate should only be replaced if the phosphate level is <1.0 mil ligram/dL (<1.0 mmol/L). Sodium bicarbonate has been included in American Diabetes Association guidelines if serum pH is <7.0; however, more recent data suggest no benefit and potential harms in the pediatric population. 4,11  INSULIN Begin insulin after initial fluid resuscitation has been completed. If insulin is started too early, intravascular volume may be further depleted by shifting osmotically active glucose and fluids out of the intravascular space. The absorption of insulin by the IM or SC route is unreliable in patients with HHS, and a continuous infusion of insulin is recom mended. Initiation of insulin therapy should begin at 0.1 unit/kg/h. With adequate hydration and insulin therapy, the goal of therapy is to maintain a steady rate of decline in the glucose concentration of 50 to 75 milligrams/dL/h (2.8–4.1 mmol/L/h). With adequate hydra tion, the insulin infusion may be adjusted every hour until a steady glucose decline is achieved. If glucose falls too rapidly, decrease the infusion rate by half, to 0.05 or 0.07 unit/kg/h. Once serum glucose decreases to <300 milligrams/dL (<16.6 mmol/L), change the IV solution to 5% dextrose in half-normal saline, and reduce the insulin infu sion to 0.02 to 0.05 unit/kg/h until serum osmolality is <315 mOsm/ kg and glucose is maintained between 200 and 300 milligrams/dL (11.1–16.6 mmol/L). Once the patient is mentally alert and able to eat and prior to discontinuing parenteral insulin, administration of longacting SC insulin has demonstrated efficacy in preventing rebound hyperglycemia. DISEASE COMPLICATIONS Despite cerebral edema representing >50% of fatalities in children with hyperglycemic emergencies, cerebral edema is an uncommon complication in adults with HHS . There are few data on the inci dence of or clinical indicators that may predispose to cerebral edema in adults. A small case series suggests that rapid changes in osmolality in HHS can predispose to osmotic demyelination syndrome. 13 The current recommendation is to limit the rate of volume repletion dur ing the first 4 hours to <50 mL/kg of normal saline, measure serum osmolality frequently, and monitor the patient’s mental status during treatment. Stat head CT or MRI is indicated, as is early neurosurgi cal consultation, if cognitive deterioration develops. Although there are no evidence-based treatments for cerebral edema, osmotic agents remain the most practical option. Venous and arterial thromboses are a common complication in HHS, and unless contraindicated, all patients should receive prophylactic anticoagulation as part of the management plan. DISPOSITION AND FOLLOW-UP When considering the patient population predisposed to developing HHS (debilitated patients with multiple comorbidities), intensive care unit monitoring for the initial 24 hours of care is usually the most appropriate course of action. Patients without significant comorbid conditions who demonstrate a good response to initial therapy may be considered for monitored step-down or non–intensive care unit admission. Patients with HHS are often chronically debilitated and may present in a pre morbid state often late in the natural history of their disease processes. In this context, the patient’s goals of care should be identified early and remain at the forefront of the ED management plan.

own or non–intensive care unit admission. Patients with HHS are often chronically debilitated and may present in a pre morbid state often late in the natural history of their disease processes. In this context, the patient’s goals of care should be identified early and remain at the forefront of the ED management plan. In a retrospective study that looked at predictors of recurrent hospitalization for patients with DKA and HHS, age <35 years, history of depression or substance abuse, self-pay or publicly funded insurance, and HbA 1c level >10.6% were associated with higher odds of readmission.15 REFERENCES The complete reference list is available online at www.TintinalliEM.com. Hypothyroidism and Myxedema Crisis Alzamani Mohammad Idrose INTRODUCTION AND EPIDEMIOLOGY Hypothyroidism is a clinical syndrome caused by insufficient thyroid hormone production, which slows cell metabolism. The prevalence of overt hypothyroidism in the general population varies between 0.3% and 3.7% in the United States, and between 0.2% and 5.3% in Europe. 1-4 The prevalence of hypothyroidism increases with age (>65 years) and is higher among white individuals and women. 5 The disorder is nearly 10 times more common in females than in males. On the other hand, subclinical hypothyroidism is more prevalent than overt hypothyroid ism in all age groups and can be seen in 4% to 15% of women, especially the elderly. 6 Myxedema coma mortality rates with current treatments are between 30% and 60%.6 PATHOPHYSIOLOGY Thyroxine (T 4) and triiodothyronine (T 3) are the thyroid hormones. The ratio of thyroxine T 4 to triiodothyronine T 3 released in the blood is about 10:1. Peripherally, thyroxine T 4 is converted to the active triiodothyronine T 3, which is three to four times more potent than thyroxine T4. The half-life of thyroxine T 4 is 7 days, and the half-life of triiodothyronine T3 is about 1 day. Primary hypothyroidism is caused by the intrinsic dysfunction of the thyroid gland. The most common cause is Hashimoto’s thyroiditis. Primary hypothyroidism is also caused by surgical removal or radioactive ablation and can be a result of some drug effects. 7 Drugs such as lithium, α-interferon, interleukin, and tyrosine kinase inhibitors (e.g., sunitinib) can cause hypothyroidism. Amiodarone can cause hypothy roidism in up to 14% of patients. 8-10 Secondary hypothyroidism is caused by a deficiency of thyroidstimulating hormone (TSH) from the pituitary gland or deficiency of thyrotropin-releasing hormone from the hypothalamus. Some literature specifically refers to hypothalamic causes as tertiary hypothyroidism. 11,12 Nevertheless, both are central causes of hypothyroidism involving the hypothalamic-pituitary axis and shall be referred to as secondary hypo thyroidism in this chapter. Euthyroid sick syndrome is associated with low triiodothyronine T or thyroxine T4 levels and a normal or low TSH level in a patient who is clinically euthyroid. This condition is found in critically ill patients or those with severe systemic illness. Table 228-1 lists common causes of hypothyroidism. CLINICAL FEATURES OF HYPOTHYROIDISM The common clinical features of hypothyroidism are listed in Figure 228-1. Additional cardiopulmonary findings include angina, bradycardia, distant heart sounds from pericardial effusion, low voltage on the ECG, pleural effusions, cardiomyopathy, or hypoventilation. 13 Figure 228-2 shows an example of severe pretibial myxedema. Table 228-2 describes the clinical differences between primary and secondary hypothyroidism. CLINICAL FEATURES OF MYXEDEMA CRISIS Myxedema crisis is a state of metabolic and multiorgan decompensation characterized by uncorrected hypothyroidism, mental status changes or coma, and hypothermia (usually <35.5°C [95.9°F]).

Table 228-2 describes the clinical differences between primary and secondary hypothyroidism. CLINICAL FEATURES OF MYXEDEMA CRISIS Myxedema crisis is a state of metabolic and multiorgan decompensation characterized by uncorrected hypothyroidism, mental status changes or coma, and hypothermia (usually <35.5°C [95.9°F]). In hypothyroid patients, myxedema crisis can be precipitated by a number of condi tions, including infection, anesthetic agents, cold exposure, trauma, myocardial infarction or congestive heart failure, stroke, GI hemorrhage, surgery, burns, medications (e.g., β-blockers, sedatives, narcotics, phe nothiazine, amiodarone), or thyroid medication noncompliance. CHAPTER Tintinalli_Sec17_p1419-1460.indd 1447 8/2/19 12:23 PM

ection, anesthetic agents, cold exposure, trauma, myocardial infarction or congestive heart failure, stroke, GI hemorrhage, surgery, burns, medications (e.g., β-blockers, sedatives, narcotics, phe nothiazine, amiodarone), or thyroid medication noncompliance. CHAPTER Tintinalli_Sec17_p1419-1460.indd 1447 8/2/19 12:23 PM 1448 SECTION 17: Endocrine Disorders The characteristic hypothyroid habitus is evident (Figure 228-1), as well as bradycardia, hypotension, hypothermia, hypoventilation, and altered mental status or coma. Blood pressure is quite variable, but of patients in full myxedema crisis, half initially exhibit clinical shock with systolic blood pressure <100 mm Hg. The capillaries are “leaky, ” and this may contribute to hypotension. Infection may be present even though fever, tachycardia and sweating may not be evident, because bradycardia and hypothermia mask these signs. Altered mental status can result from CO 2 narcosis or hypoglycemia. Pleural effusions are frequently demonstrable. Other potential respiratory problems include upper air way obstruction from glottic edema, vocal cord edema, and macroglossia. Metabolism of tranquilizers, sedatives, and anesthetics is reduced in hypothyroidism, and the exaggerated effects of such medications can also contribute to altered mental status. Hypothermia is so common in myxedema crisis that a normal temperature should suggest an underlying infection. Hypothyroid habitus, absence of shivering, and pseudomyotonic reflexes (prolonged relaxation phase of deep tendon reflexes—at least twice as long as the contraction phase) may help dis tinguish myxedema crisis from accidental hypothermia. TABLE 228-2 Clinical Differentiation of Primary and Secondary Hypothyroidism Features Primary Hypothyroidism Secondary Hypothyroidism Previous thyroid operation Yes None Obese More obese Less obese Hypothermia More common Less common Voice Coarse Less coarse Pubic hair Present Absent Skin Dry and coarse Fine and soft Heart size Increased Normal Menses and lactation Normal No lactation, amenorrhea Sella turcica size Normal May be increased Serum TSH Increased Decreased Plasma cortisol Normal Decreased Response to TSH None Good Response to levothyroxine without steroids Good Poor response Abbreviation: TSH = thyroid-stimulating hormone. FIGURE 228-2. Mysedema  (non-pitting  edema)  in  a  patient  with  hypothyroidism. (Image courtesy of Dr. Zanariah Hussein.) TABLE 228-1 Common Causes Primary and Secondary of Hypothyroidism Primary Hypothyroidism (disorders of thyroid gland) Secondary Hypothyroidism (disorders of hypothalamic-pituitary axis) Autoimmune disease (e.g., Hashimoto’s thyroiditis) Panhypopituitarism Pituitary adenoma, hypothalamic tumor Infiltrative disorders (hemochromatosis, sarcoidosis) Brain irradiation CNS infection Thyroiditis Iodine deficiency After ablation (surgery, radioiodine) Infiltrative thyroid disease (lymphoma, sarcoid, tuberculosis) Drugs directly affecting thyroid function •  Valproate •  Potassium  perchlorate •  Iodine •  α-Interferon •  Interleukin-2 •  Amiodarone •  Lithium •  Sunitinib •   Antituberculosis drugs (ethionamide and para-aminosalicylic acid [PAS]) •  Retroviral  agents Signs Periorbital puffiness Loss of outer third of eyebrow Pallor Macroglossia Hoarseness Bradycardia Hypoventilation Absent or decreased bowel sounds Nonpitting edema Delayed relaxation of ankle jerks Peripheral neuropathy Cool, rough, dry skin Hypothermia Symptoms Hair loss Fatigue Depression Shortness of breath Weight gain Constipation Menstrual irregularities Infertility Muscle cramps Joint pain Cold intolerance FIGURE 228-1. Signs and symptoms of hypothyroidism. Tintinalli_Sec17_p1419-1460.indd 1448 8/2/19 12:24 PM

ipheral neuropathy Cool, rough, dry skin Hypothermia Symptoms Hair loss Fatigue Depression Shortness of breath Weight gain Constipation Menstrual irregularities Infertility Muscle cramps Joint pain Cold intolerance FIGURE 228-1. Signs and symptoms of hypothyroidism. Tintinalli_Sec17_p1419-1460.indd 1448 8/2/19 12:24 PM CHAPTER 228:  Hypothyroidism and Myxedema Crisis      1449 DIAGNOSIS The diagnosis of hypothyroidism is based on laboratory testing. The diagnosis of myxedema crisis is clinical . The differential diagnoses include sepsis, depression, adrenal crisis, congestive heart failure, hypoglycemia, stroke, hypothermia, drug overdose, and meningitis.  LABORATORY EVALUATION AND IMAGING Obtain baseline levels of TSH, thyroxine T 4, triiodothyronine T 3, and cortisol before initiating treatment. This facilitates eventual diagnosis as well as response to treatment. High TSH, with low total or free thyroxine T 4 and triiodothyronine T3, confirm primary hypothyroidism. Low TSH with low total or free thyroxine T 4 and triiodothyronine T3 points toward secondary hypothyroidism (hypothalamic–pituitary etiology). The assays of free thyroxine T4 and triiodothyronine T 3 are preferable to total thyroxine T 4 and triiodothyronine T 3, as results are more accurate and not affected by protein binding. Thyroid hormone levels may also be altered as a result of drug inter actions (Table 228-1), but thyroid function usually normalizes after discontinuation of these drugs. Ideally, thyroid function tests should be obtained before initiating therapy with these agents and periodically thereafter. Menorrhagia can be a sign of hypothyroidism, and if menorrhagia is severe, microcytic anemia due to iron loss can develop. Hyponatremia due to increased antidiuretic hormone and impaired free water clearance is common. Hypoglycemia may be present due to decreased gluconeogenesis, decreased insulin clearance, and concomitant adre nal insufficiency or growth hormone deficiency. Arterial blood gases typically show hypoxemia, hypercapnia, metabolic acidosis from tissue hypoxia, and respiratory acidosis from hypoventilation due to muscle weakness. Further laboratory assessment depends on the differential diagnosis, comorbidities, and search for precipitating factors. Obtain an ECG to identify myocardial infarction or heart block. Chest radiograph is needed to identify pneumonia, pleural effusion, or cardiomegaly. Bed side ultrasound can detect pericardial and pleural effusions. TREATMENT OF SYMPTOMATIC HYPOTHYROIDISM If a hypothyroid patient has symptoms of hypothyroidism and has been noncompliant with thyroid medication, or a newly diagnosed hypo thyroid patient is confirmed by thyroid function tests done in the ED, oral levothyroxine may be started. The average starting dose for healthy adults younger than age 50 is 50 micrograms of oral levothyroxine once a day. 14 For those older than 50 years or with cardiac disease, the initial dose is lower, 12.5 to 25 micrograms once a day. For all adults, the dose is adjusted by 12.5- to 25-microgram increments at 4- to 6-week inter vals. Instruct the patient to follow up with the primary care physician or endocrinologist for monitoring and further dose adjustments in a month. TREATMENT OF MYXEDEMA CRISIS Myxedema crisis treatment consists of supportive care, thyroid hormone replacement (supplementing with thyroxine T 4, triiodothyronine T3, or a combination of both), and identification and treatment of precipitating factors (Table 228-3).  THYROID HORMONE REPLACEMENT FOR MYXEDEMA CRISIS Administer thyroid hormone upon clinical suspicion of myxedema crisis, as confirmatory laboratory thyroid hormone levels will not be available initially. IV thyroxine (T 4) in the form of levothyroxine should be started as replacement.

ecipitating factors (Table 228-3).  THYROID HORMONE REPLACEMENT FOR MYXEDEMA CRISIS Administer thyroid hormone upon clinical suspicion of myxedema crisis, as confirmatory laboratory thyroid hormone levels will not be available initially. IV thyroxine (T 4) in the form of levothyroxine should be started as replacement. Alternatively, IV triiodothyronine (T3) in the form of liothyronine (synthetic triiodothyronine T3) can be given if it is avail able, but should be cautiously used in the elderly or those with cardiac disease as it is more potent. IV thyroxine T4 and IV triiodothyronine T3 can be given together if the patient has persistent hemodynamic instability or poor respiratory effort. Thyroid hormone replacement should initially be given IV because severe or even mild hypothyroidism results in decreased intestinal motility and GI absorption. Once intestinal motility recovers, oral medication can be given. Replacement with Intravenous Thyroxine (Levothyroxine) Levothyroxine is the synthetic form of thyroxine. The initial dose for myx edema crisis is 4 micrograms/kg IV , with the usual starting dose from 200 to 400 micrograms IV . 15 This is followed in 24 hours by 100 micrograms IV , then 50 micrograms IV until oral medication is tolerated. Starting dose in the elderly is lower at 100 micrograms IV . The advantages of levothyroxine are smooth, slow, and steady onset of action and its widespread availability. Disadvantages include the fact that extrathyroidal conversion of thyroxine T 4 to triiodothyronine T 3 may be reduced in myxedema crisis. The onset of action of thyroxine T4 is longer than that of triiodothyronine T3. Replacement with Intravenous Triiodothyronine (Liothyronine) Liothyronine is the synthetic form of triiodothyronine T3. In myxedema crisis, the loading dose of 20 micrograms can be given, followed by a maintenance dose of 10 micrograms every 8 hours until oral medication can be given. 15 The advantage of triiodothyronine T 3 over thyroxine T 4 is that the deiodinase conversion of thyroxine T 4 to the active hormone triiodothyronine T3 is reduced in myxedema crisis. IV triiodothyronine T3 also has a rapid onset of action, between 2 and 4 hours. triiodothyronine T3 crosses the blood–brain barrier more readily than thyroxine T4. However, TABLE 228-3 ED Treatment for Myxedema Crisis Supportive care •  Airway, breathing, and circulation: airway control, oxygen, IV access, and cardiac monitoring •  IV therapy: dextrose for hypoglycemia; water restriction for hyponatremia •  Vasopressors: if indicated (ineffective without thyroid hormone replacement) •  Hypothermia: treated with passive rewarming •  Steroids: hydrocortisone (due to increased metabolic stress; start with 100–200 milligrams IV) Thyroid replacement therapy (see discussion of thyroid hormone replacement in text) •  IV thyroxine (levothyroxine) at 4 micrograms/kg (typically between 200 and 400 micrograms as initial dose), followed in 24 h by 100 micrograms IV, then 50 micrograms IV until oral medication is tolerated. Starting dose of thyroxine in the elderly is 100 micrograms IV. •  IV triiodothyronine (liothyronine) at a dose of 20 micrograms IV followed by 10 micrograms IV every 8 h until the patient is conscious. Start with no more than 10 micrograms IV for the elderly or those with coronary artery disease. (Triiodothyronine is less preferred in patients with cardiac disease, as its potency could precipitate cardiac arrhythmias or infarction.) Note: Start with IV levothyroxine first. IV liothyronine can be added if treatment with IV levothyroxine alone is not effective or in patients with persistent hemodynamic instability or poor respiratory effort.

ferred in patients with cardiac disease, as its potency could precipitate cardiac arrhythmias or infarction.) Note: Start with IV levothyroxine first. IV liothyronine can be added if treatment with IV levothyroxine alone is not effective or in patients with persistent hemodynamic instability or poor respiratory effort. Identify and treat precipitating and comorbid factors •  Infections •  Sedatives •  Cold exposure •  Trauma •  Myocardial infarction or congestive heart failure •  Cerebrovascular accident •  GI hemorrhage •  Hypoxia •  Hypercapnia •  Hyponatremia •  Hypoglycemia Tintinalli_Sec17_p1419-1460.indd 1449 8/2/19 12:24 PM