- Typical stigmata of hyperthyroidism, thyromegaly, ophthalmopathy, tremor, stare, diaphoresis, and agitation
- Fever (usually)
- Tachycardia (out of proportion to fever) often with associated atrial arrhythmias
- Mental status changes ranging from confusion to coma
Thyroid storm is a life-threatening disorder that occurs in 1–2% of patients with thyrotoxicosis. A history of previous thyrotoxic symptoms should be sought such as nervousness, restlessness, heat intolerance, sweating, fatigue, muscle cramps, weight loss, tremor, and lighter or less frequent menstrual periods. Thyroid storm should be suspected with a sudden change in mental status (confusion, agitation, delirium more frequent than lethargy or obtundation) with fever and tachycardia out of proportion to fever, and gastrointestinal, cardiac, or central nervous system (CNS) symptoms. Once suspected, treatment should begin immediately and concurrently with treatment for identifiable or suspected precipitating event. Mortality from thyroid storm is high even with proper treatment.
Thyroid storm usually occurs when an already thyrotoxic patient (Graves disease, toxic multinodular goiter, and toxic adenoma are most common) suffers a serious concurrent illness, event, or injury. Common factors that may trigger a thyroid storm include infection, surgery, trauma, pregnancy/preeclampsia, stroke, MI, PE, amiodarone use, DKA, ketosis, radioiodine therapy, drug use (usually stimulants), ETOH, iodine contrast material, or discontinuation of antithyroid medication.
The diagnosis of thyroid storm should be made clinically. Often a history of partially treated hyperthyroidism or signs of thyroid disease such as thyromegaly, proptosis, stare, myopathy, or myxedema can be found. The diagnosis should be made in the patient with a probable history of thyroid disease, which rapidly decompensates in the setting of fever, tachycardia, gastrointestinal symptoms, and mental status change. Elevated thyroid hormone levels are common in significant illness, and there is no significant difference in levels in thyroid storm and thyrotoxicosis. Therefore, no test will confirm this diagnosis.
Fever may exceed 40°C (104°F). This may be due to the catabolic state of thyrotoxicosis or secondary to precipitating infection. Appropriate cultures and broad-spectrum antibiotics are indicated.
Cardiac findings usually include a friction rub or systolic flow murmur, and either sinus or supraventricular tachycardia. The rate is often characterized as out of proportion to fever. Mental status changes are also common. Gastrointestinal symptoms include nausea, vomiting, diarrhea, and abdominal pain—can mimic an acute abdomen. Neuromuscular findings such as agitation, tremor, generalized weakness (especially in the proximal muscles), and periodic paralysis are also seen. Dermatologic findings include warm, moist, smooth skin and palmar erythema.
Findings consistent with prior thyroid disease include thyromegaly with or without a bruit, orbitopathy, tremor, stare, hyperreflexia, pretibial myxedema, and other integumentary changes such as coarse hair and thick, dry skin. Death may occur from hypovolemic shock, coma, congestive heart failure, or tachydysrhythmias.
Apathetic hyperthyroidism is important to consider in the elderly population. With advanced age and other comorbid conditions, the classic symptoms and signs of thyroid storm and thyrotoxicosis may be absent.
Ancillary Diagnostic Findings
Draw blood samples to test for free T4, T3, and TSH (thyroid-stimulating hormone) and serum cortisol levels. A complete blood count, serum electrolytes, glucose, renal and hepatic function tests, and ABG analysis should be performed; obtain cultures of the blood, urine, and possibly sputum; chest X-ray and ECG are indicated to look for precipitating causes or complications. Cranial CT scan is indicated for delirious or comatose patients.
Previous abnormal thyroid function tests may suggest a preexisting thyrotoxicosis. TFTs may be misinterpreted based on levels of thyroid binding globulin. TSH will be markedly low in most patients with thyroid storm or thyrotoxicosis. Free thyroxine (T4) will be elevated, again similar to thyrotoxicosis. Electrolyte and glucose abnormalities may also be present due to gastrointestinal losses, dehydration, physiologic stress, and fever.
The ECG is usually abnormal; common findings are sinus tachycardia, increased QRS interval and P wave voltage, nonspecific ST–T wave changes, and atrial dysrhythmias, usually atrial fibrillation or flutter. Conduction defects, most commonly first-degree AV block and nonspecific intraventricular conduction delay, may occur. Ischemic findings or myocardial infarction may be present, especially in older patients with concurrent illness such as diabetes or hypertension.
Initiate standard resuscitative measures.
Volume replacement is commonly indicated with at least 1 L of normal saline or lactated Ringer's solution in the first hour due to volume depletion from fever. Frequent reassessment is required to prevent fluid overload, especially in patients exhibiting signs of high output cardiac failure (tachycardia, dyspnea, wide pulse pressure). Vasopressors may be required for hypotension not correcting with volume resuscitation. Hypotension, however, may be a sign of another problem such as sepsis or adrenal insufficiency.
Phenobarbital should be considered for sedation since it stimulates the clearance of thyroid hormone by inducing hepatic microsomal enzymes. Fever should be treated aggressively with cool IV fluids, cool mist sprays, cooling blankets, and antipyretics.
Avoid iodinated contrast, amiodarone, NSAIDs, aspirin, pseudoephedrine, and ketamine in these patients.
Hormone Synthesis Blockers
Thionamides are the standard first-line agents to treat thyroid storm. Propylthiouracil (PTU) 600–1000 mg first dose and 200–250 mg PO every 4 hours is the drug of choice. Methimazole 40 mg PO initially and then 25 mg every 6 hours can also be used. PTU has the additional benefit of blocking the peripheral conversion of T4 to the active T3. Neither of the thionamides are available parenterally and must be given PO, via nasogastric tube, or retention enema.
Iodine therapy is an adjunct to the thionamides. It should not be given until at least 1–2 hours after PTU or methimazole is administered. Early administration can promote further hormone production, thus worsening hyperthyroidism.
Several forms are available such as potassium iodide (SSKI, 35 mg/drop) 5 drops PO every 6 hours or Lugol's solution 8 drops every 6 hours. Other forms include contrast agents such as sodium ipodate (Oragrafin) or sodium iopanoate (Telepaque), both of which would be 1 g a day or 500 mg twice a day by mouth. If iodine allergy is a concern, lithium carbonate can be given instead at 300 mg every 6–8 hours to maintain levels of 1.0–1.2 mEq/L.
β-Adrenergic agonists such as propranolol block the peripheral effects of excess thyroid hormone. A typical dose is 0.5–1 mg IV every 10–15 minutes until pulse reduction is achieved and then every 2–3 hours. Caution should be used in patients with bronchospastic disease. Metoprolol can be used at a dose of 50 mg PO every 6 hours. Esmolol with a 250–500 μg/kg IV load and then 50–100 μg/kg/min. Beta blockers are the mainstay for high output cardiac failure. Beta blockers may be especially attractive in cases of atrial fibrillation with rapid ventricular response. Calcium channel blockers have been associated with hypotension, amiodarone is contraindicated, and digoxin is often ineffective.
In very severe cases when thyroid hormone effects are not controlled with the above measures, plasmapheresis, plasma exchange, peritoneal dialysis, or charcoal plasma perfusion may be attempted.
Corticosteroids inhibit peripheral conversion of T4 to T3 and block the release of hormone from the thyroid gland. In addition, they treat the relative adrenal insufficiency that may be present. Intravenous hydrocortisone, 100 mg every 8 hours, is the treatment of choice for concurrent adrenal insufficiency; however, dexamethasone, 0.1 mg/kg intravenously every 8 hours, may be given. The advantage of dexamethasone is that an adrenocorticotropic hormone (ACTH) stimulation test of the adrenocortical axis may still be undertaken by consultants.
Hospitalization in an intensive care unit is indicated for all patients with thyroid storm, having a mortality rate of 20% if treated, and uniformly fatal if untreated. Invasive hemodynamic monitoring may be necessary to facilitate fluid management and assess progress of therapy in cases complicated by cardiac failure.
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- A potentially lethal complication of severe hypothyroidism
- Look for typical stigmata: dry skin, delayed reflex relaxation, generalized weakness, edema, or a transverse scar across the low anterior neck
- Alteration in mental status (although coma is rare).
- Often hypothermic (< 35.5°C[95.9°F])
Myxedema coma is a rare complication of extreme hypothyroidism (most often Hashimoto's thyroiditis). Although it can occur as an initial presentation of hypothyroidism, myxedema coma usually occurs in patients with known hypothyroidism or after surgery or ablative therapy for hyperthyroidism. The incidence mirrors that of hypothyroidism with a 4:1 female predominance. Myxedema coma typically occurs in the winter months after exposure to cold in those 60 years and older.
Other predisposing factors include cerebrovascular accident, CHF exacerbation, anesthesia, GI bleed, cardiac ischemia, surgery, trauma, medications, or infection. The cardinal features are CNS depression with hypothermia and hypothyroidism. Hyporeflexia, generalized swelling, coma, bradycardia, and respiratory depression are also common. Onset is often rapid but can be insidious, especially in the elderly. If untreated, mortality is estimated at up to 60–70%. If recognized and treated appropriately, mortality drops to 15–35%.
The presumptive diagnosis of myxedema coma should be made when clinical manifestations of hypothyroidism are accompanied by disturbances of consciousness, hypothermia, hypoventilation, bradycardia, and hypotension.
Cold intolerance, dry skin, constipation, weight gain, muscle cramps, and general fatigue or weakness are common. Slowing of speech, disorientation, apathy, inappropriate humor (myxedema wit), or psychosis may also occur. Discontinuation of thyroid replacement, previous radioactive iodine treatment, thyroidectomy, or medication administration, such as sedatives, iodides, or amiodarone, is a common historical finding.
These include cold intolerance, dry skin, change in voice, heavier or more frequent menstrual periods, constipation, weight gain, irregular or absent menses, muscle cramps, paresthesias, angina, or seizures. Neurologic complaints such as generalized weakness, slow speech, disorientation, apathy, ataxia, inappropriate humor (myxedema wit), or psychosis are also seen. As hypothyroidism worsens, neurologic symptoms progress to lethargy, disorientation, and coma. Seizures may also occur.
Hypothermia is found in approximately 80% of patients with myxedema coma. Hypoventilation is due to decreased respiratory drive and generalized muscle weakness. Hypotension may be present along with gastrointestinal ileus or urinary retention.
Physical findings including bradycardia; generalized puffiness; periorbital edema; ptosis; cutaneous myxedema; coarse, dry, yellow skin; macroglossia; delayed relaxation phase of deep tendon reflexes; thyroidectomy scar or a goiter; or coarse, sparse hair may be the only clues of this condition in a comatose patient.
Blood glucose should be assessed initially. Thyroid studies are rarely available on an emergency basis. They typically reveal a low serum free T4 and T3. The TSH is usually high in primary hypothyroidism; however, it may be low in secondary and tertiary hypothyroidism. The distinction between hypothyroidism and myxedema coma cannot be made based on TFTs alone.
Blood and urine cultures should be obtained. Arterial blood gases may reveal hypoxemia, hypercapnia, and a respiratory or mixed acidosis. Hyponatremia and hypoglycemia may be potential contributors to CNS depression. Serum creatinine kinase may be elevated. Myocardial pathology or rhabdomyolysis must be excluded as causes. Anemia and hyperlipidemia are common.
Chest radiography may show an enlarged heart (from a pericardial effusion) or other precipitating cause for the myxedema coma, such as pneumonia. Bedside ultrasonography can confirm a pericardial effusion.
The ECG may show bradycardia, low voltage of the QRS complex in all leads, flattening or inversion of the T waves, and conduction abnormalities.
General and Supportive Measures
Patients with myxedema coma will need mechanical ventilation if hypoxemia and hypoventilation are found. Otherwise, supplemental oxygen is indicated. Obtain venous access and blood samples for free T4, free T3, TSH, cortisol, CBC, renal and hepatic function tests, arterial blood gases, cultures, and electrolytes and glucose levels.
Isotonic crystalloid solution (normal saline or lactated Ringer's) should be given for hypotension. Avoid hypotonic solutions because hyponatremia may be present. Watch for the unmasking of congestive heart failure. Treat severe hyponatremia (≤120 mEq/L) with careful administration of 3% saline if mental status is depressed. Thyroid replacement therapy and corticosteroids along with restriction of free water will generally correct mild hyponatremia.
Treatment for Hypothermia
Active rewarming methods are contraindicated due to the risk of cardiovascular collapse. Passive methods of rewarming such as blankets are preferred.
Avoid unnecessary medications that may further depress mental status. Empiric antibiotics are indicated initially in critically ill patients. Hypoglycemia and other electrolyte abnormalities can be treated in the usual manner. Vasopressors are not likely to be effective because of a reduced adrenergic receptor response and may provoke dysrhythmias, especially during intravenous thyroid replacement therapy.
Treatment of Precipitating Causes
Any precipitating cause for myxedema coma must be addressed. Recovery from myxedema coma is slow since reversal of severe metabolic abnormalities is required.
Levothyroxine (T4) is most often recommended for replacement therapy. This form, however, depends on conversion to the active T3 form that may be inhibited by severe illness. Liothyronine (T3) does not require conversion and can also be given, but higher doses have been associated with increased mortality. Combinations of both are also given as a more physiologic replacement. Some of the protocols are as follows:
- Levothyroxine (T4) alone may be considered in geriatric patients or those with cardiac disease. Use an intravenous loading dose of 200–500 μg over the first hour and then 50–100 μg/d, or oral dosing at 50–100 μg/d when tolerated.
- Liothyronine (T3) alone may be used in young, healthy patients. Give a loading dose of 5–20 μg IV or PO and then 5–10 μg/8 h until improvement.
- Levothyroxine (T4) at 200–250 μg bolus and 50 μg PO daily and liothyronine (T3) 10 μg IV or PO load and 10 μg every 8 hours. Maintenance doses are appropriate when the patient is clinically stable.
All three methods may precipitate a cardiac event such as angina, dysrhythmia, or infarction. Lower dosing regimens are recommended in those at increased risk for cardiac events. All patients receiving intravenous thyroid hormone replacement should have continuous cardiac monitoring.
Corticosteroids are also recommended since there is a 5–10% incidence of concurrent adrenal insufficiency. In this situation, thyroid replacement before corticosteroid replacement can cause further deterioration. Therefore, early corticosteroid replacement is indicated. This can be given as intravenous hydrocortisone 100 mg every 8 hours. This is the preferred replacement method due to its action as both a glucocorticoid and a mineralocorticoid. Acutely however, dexamethasone 2–4 mg IV every 6 hours is often used since it will not alter a cosyntropin stimulation test. This will allow consultants to evaluate the need for chronic replacement once the patient has stabilized.
Hospitalization in an intensive care unit is indicated for all patients with myxedema coma.
Benyon J, Akhtar S, Kearney T: Predictors of outcome in myxoedema coma. Crit Care 2008;12(1):111, Epub Jan 23, 2008
Kwaku MP, Burman KD: Myxedema coma. J Intensive Care Med 2007 Jul–Aug;22(4):224–231
Adrenal Insufficiency and Crisis (Addisonian Crisis)
- Consider addisonian crisis in patients with hypotension refractory to intravenous fluids or in acutely ill patients with typical stigmata of chronic glucocorticoid use such as moon facies and buffalo hump
- Common symptoms include orthostasis, weight loss, anorexia, lethargy, abdominal cramps, nausea, vomiting, diarrhea, and mental depression
- Classic electrolyte abnormalities include hyponatremia associated with hyperkalemia
The adrenal glands produce three different groups of hormones: glucocorticoids, mineralocorticoids, and androgenic hormones. These hormones help the body adjust to metabolic stress. Failure results in a chronic disease state while sudden onset or stress may induce a life-threatening emergency resulting in cardiovascular instability, loss of glucose homeostasis, and extracellular fluid and electrolyte imbalance and shock.
Primary Adrenocortical Insufficiency
Primary adrenocortical insufficiency (Addison's disease) results from primary destruction or inhibition of the adrenal glands. There are several known causes such as autoimmune insults (most common), infection (tuberculosis is most common worldwide while AIDS is most common in the United States), systemic inflammatory response, congenital, trauma, hemorrhage, metastatic carcinoma, and medications.
Bilateral adrenal hemorrhage may occur due to infections such as Neisseria meningitidis or pneumococcal septicemia (Waterhouse–Friderichsen syndrome). Patients with coagulopathy, thromboembolic disease, or those taking anticoagulants are also at increased risk.
Secondary Adrenocortical Insufficiency
Secondary adrenocortical insufficiency results from pathology of the hypothalamus and pituitary. Corticotropin-releasing hormone and ACTH release are impaired, causing dysfunction along the hypothalamus–pituitary–adrenal axis. Chronic steroid use resulting in ACTH suppression and adrenal hypoplasia is the most common cause of adrenocortical insufficiency. A primary pituitary or hypothalamic mass must also be considered. Traumatic brain injury is becoming a more common cause of secondary or tertiary insufficiency, occurring from 1 day to 6 months after trauma.
The most common presentation of adrenal crisis is shock, often refractory to fluids and vasopressors. Adrenal insufficiency presents with symptoms such as fatigue, anorexia, generalized aches, and abdominal pain, which are common with low cortisol levels, while hypotension, hyponatremia, hyperkalemia, metabolic acidosis, and orthostasis are seen with low aldosterone production. ACTH is cleaved with melanocyte-stimulating hormone (MSH), which upregulates melanocytes and causes hyperpigmentation of the axillae and other skin folds in primary adrenal insufficiency. Low androgen levels cause decreased body hair. Amenorrhea develops commonly in women.
Mineralocorticoid deficiency causes a classic hyponatremia and hyperkalemia. The finding of the two together in symptomatic patients should suggest the diagnosis of primary adrenal insufficiency.
Other findings may include anemia of chronic disease, elevated BUN, hypoglycemia, hypocalcemia, lymphocytosis, and eosinophilia. Hyperkalemia is typically not seen in secondary adrenal insufficiency because aldosterone production is usually preserved.
Calcification of the adrenals may be present as a result of tuberculosis, histoplasmosis, or other disseminated fungal disease. Cranial magnetic resonance imaging (MRI) is usually the test of choice for secondary adrenal insufficiency to reveal sellar and hypothalamic–pituitary tumors, and abdominal CT is the test of choice in primary adrenal insufficiency to image the adrenal glands. Enlarged adrenal glands suggest tuberculosis, fungal disease, cancer, hemorrhage, or AIDS. Small adrenal glands suggest autoimmune disease, chronic infection, exogenous corticosteroids, or chronic vascular abnormalities.
The ECG may reveal low voltage in all leads and changes characteristic of electrolyte abnormalities such as hyperkalemia with peaked T waves, prolongation of QRS interval, and loss of P waves in severe cases.
Draw blood for serum cortisol level. A serum cortisol exceeding 20 μg/dL at any time of the day makes the diagnosis of adrenal insufficiency unlikely. A level less than 3 μg/dL is confirmatory. Ideally the blood is drawn when the patient is under duress.
An ACTH stimulation test, however, is the study of choice. After the initial serum cortisol is drawn, 250 μg of synthetic ACTH (cosyntropin) is given. Serum cortisol levels are drawn 30 and 60 minutes later. Failure of the adrenals to produce cortisol to levels of 25–30 μg/dL or an increase of less than 9 μg/dL suggests primary adrenal insufficiency. Administration of hydrocortisone will alter the results of this test. Dexamethasone is an alternative that will not interfere with the diagnosis. This should not, however, be allowed to cause a delay in treatment. A random cortisol sample in an unstable patient should be helpful in making the diagnosis.
General and Supportive Measures
After standard stabilization, draw blood to test for CBC, electrolytes, glucose, renal and hepatic functions, and random serum cortisol. ACTH stimulation test may be done later by a consultant.
Monitor fluid intake and urine output. Monitor potassium levels carefully. Even though potassium levels may be high initially, total body deficits often exist. Replace fluid volume and correct electrolyte abnormalities as appropriate.
Hydrocortisone, 100 mg intravenously every 8 hours, is the mainstay for treating adrenal insufficiency. Alternatively, dexamethasone, 0.1 mg/kg every 8 hours, may be used without disruption of diagnostic testing, although it supports only glucocorticoid function. Once diagnostic testing has been done, hydrocortisone is the drug of choice because it has both glucocorticoid and mineralocorticoid functions. Once patients are stable, the dose may be tapered gradually over 1–2 weeks.
Patients receiving less than 50 mg/d of hydrocortisone will likely need mineralocorticoid support as well. Fludrocortisone, 0.05–0.2 mg/d, is the drug of choice. Fludrocortisone therapy is necessary as transition to oral therapy begins.
Admission is indicated if an addisonian crisis is suspected or confirmed. Intensive care unit admission is warranted for hemodynamically unstable patients. Adrenal insufficiency will require close follow-up and instructions on stress dosing of adrenal supplementation.
Taub YR, Wolford RW: Adrenal insufficiency and other adrenal oncologic emergencies. Emerg Med Clin North Am 2009 May;27(2):271–282.
Bornstein SR: Predisposing factors for adrenal insufficiency. N Engl J Med 2009 May 28;360(22):2328–2339. Review
Pheochromocytoma (Catecholamine Crisis)
- Symptoms of catecholamine crisis are headache, palpitations, flushing, ordiaphoresis associated with hypertension
- Symptoms associated with pheochromocytoma are often intermittent (with asymptomatic periods in between episodes), whereas those of a monoamine oxidase inhibitor (MAOI) crisis or of sympathomimetic intoxication are not
A catecholamine crisis is typically caused by one of three entities: (1) a pheochromocytoma, (2) a monoamine oxidase inhibitor (MAOI) crisis, or (3) intoxication from cocaine or other similar sympathomimetics. Occasionally, a catecholamine crisis may also be induced by sudden cessation of clonidine therapy. Catecholamines bind to α-1 and β-receptors and in excess may cause various symptoms and signs such as headache, palpitations, diaphoresis, and often severe hypertension. A thorough history will usually lead to the cause of catecholamine crisis, except in the case of pheochromocytoma, which often remains elusive since the symptoms are nonspecific and often intermittent.
Classic manifestations include hypertension, headache, diaphoresis, pallor, palpitations, nervousness, apprehension, nausea, vomiting, and abdominal pain. Labile hypertension is the hallmark of a pheochromocytoma. Severe hypertension (≥120 mm Hg diastolic) often prompts the clinician to include catecholamine crisis in the differential diagnosis. It is frequently intermittent, however, and may not always be present at the time of examination. Only half of these patients will have sustained hypertension.
Complications that occur late in the course of the disease may be dramatic and often obscure the diagnosis. Abdominal or chest pain, aortic dissection, encephalopathy, cardiomyopathy, pulmonary edema, fever, and anion gap metabolic acidosis are often distracting presentations.
Neurocutaneous syndromes such as neurofibromatosis, von Hippel–Lindau disease, ataxia-telangiectasia, tuberous sclerosis, and Sturge–Weber syndrome are sometimes associated with pheochromocytoma. Cutaneous findings (ie, café-au-lait spots, telangiectasias) may provide clues to the diagnosis.
Mucosal neuromas and a marfanoid appearance suggest multiple endocrine neoplasia type IIB. Other findings include weight loss, heat intolerance, hyperglycemia, and tachycardia.
Laboratory Findings and Special Tests
The diagnosis of pheochromocytoma is made along two pathways. First, a biochemical diagnosis must be made. Second, the tumor must be defined by radiologic studies for possible surgical excision.
The initial traditional biochemical test of choice is a 24-hour urine collection for metanephrines and catecholamines. Challenging this tradition, some endocrinologists have advocated plasma fractionated metanephrines as the initial screening test based on high sensitivity of the test (96–100%) and ease of obtaining the specimen. Because of the intermittent nature of secretion, however, 24-hour urine evaluations often produce more consistent results and greater sensitivity (fewer false positives that lead to expensive radiographic testing and sometimes surgery) than with plasma fractionated metanephrine testing.
After positive biochemical tests, localization of the tumor is performed by CT scan, MRI, or isotope scanning with metaiodobenzylguanidine (MUGA). Ninety percent of pheochromocytomas arise from the adrenal glands, however, 10% are found in extra-adrenal sites.
Cardiac Effects of a Catecholamine Crisis
In addition to tachydysrhythmias, a prolonged QT interval, which can predispose the patient to lethal arrhythmias, may be present on the ECG. Findings of cardiac ischemia and coronary artery disease also complicate the diagnostic picture. Many of these findings resolve after tumor removal.
General and Supportive Measures
Obtain blood for routine studies (CBC, serum electrolytes, glucose, hepatic and renal function). Replace volume deficits, and correct electrolyte abnormalities. Avoid drugs or procedures that may exacerbate a catecholamine crisis. Obtain a serum metanephrine specimen or begin 24-hour urine collection for fractionated catecholamines, metanephrine, and vanillylmandelic acid (VMA).
α-Adrenergic blockade with phentolamine is the traditional cornerstone of acute therapy for pheochromocytoma. The dose is 1–2 mg intravenously every 5 minutes. Caution: Higher initial doses may cause sudden severe hypotension. If no response is seen, increase the dose to 5 mg intravenously every 5 minutes until adequate blood pressure control occurs. Orthostatic hypotension is a common side effect and can be managed by ensuring adequate hydration and keeping the patient recumbent.
Intravenous sodium nitroprusside has classically been the treatment for hypertensive crisis associated with pheochromocytoma. It is still recommended in presentations with a clinical picture of congestive heart failure or myocardial infarction. Newer agents such as nicardipine, labetalol, and fenoldopam are now commonly recommended due to risks of cyanide toxicity with prolonged therapy associated with nitroprusside.
Fenoldopam, a dopamine-1 receptor agonist, is an alternative to nitroprusside. An intravenous infusion beginning at 0.1 μg/kg/min vasodilates the renal, splanchnic, and coronary circulation. Improved renal blood flow, lack of a toxic metabolite, and a short half-life of 7–9 minutes are its major advantages.
Calcium channel blockers such as nicardipine are commonly used in the treatment of hypertension associated with pheochromocytoma. Both oral and intravenous administrations are very effective in controlling fluctuating pressures. They are also helpful in preventing coronary vasospasm precipitated by catecholamine release.
β-Adrenergic blockade is contraindicated until sufficient α-blockade is initiated due to unopposed α-stimulation, which can precipitate a hypertensive crisis. β-Blockers are usually reserved for patients with severe tachydysrhythmias. Esmolol 50–200 μg/kg/min after a 500 μg/kg loading dose can be used. A mixed α–β-receptor antagonist such as labetalol has a slightly decreased risk of unopposed alpha effects. However, α-blockade is still required since hypertensive crisis has been reported. Labetalol may be given in 10–20 mg intravenous boluses every 10 minutes until the desired blood pressure is achieved with maintenance intravenous infusion of 0.5–2.0 mg/min.
Benzodiazepines may also be useful in blunting the body's sympathetic response to excess catecholamines. Lorazepam, 1–2 mg intravenously, and diazepam, 5–10 mg intravenously, are common starting doses. Administer these drugs judiciously to avoid oversedation and hypotension, particularly if the patient is volume depleted.
Hospitalization in an intensive care unit is indicated in all patients with pheochromocytoma.
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- Rare event with variable presentation
- Patients often have a sudden onset of headache
- Neurologic deficits including hemiparesis; cranial nerve defects including ophthalmoplegia and bitemporal hemianopsia
Pituitary apoplexy is an infarction or hemorrhage of the pituitary gland. This often occurs in the setting of a preexisting pituitary tumor such as an adenoma. The symptoms seen in pituitary apoplexy result from (1) leakage of blood and necrotic material into the subarachnoid space, (2) development of a rapidly expanding hemorrhagic intrasellar mass lesion compressing the optic chiasm, cavernous sinuses, cranial nerves, and adjacent structures (hypothalamus and internal carotid arteries), and (3) acute hypopituitarism.
Risk factors for pituitary apoplexy include head trauma, irradiation, estrogen, anticoagulation use, DKA, hypertension, diuretics, and use of bromocriptine. Sheehan's syndrome most commonly occurs in the postpartum period, causing hemorrhage and vasospastic necrosis of the pituitary.
The diagnosis is challenging, because pituitary apoplexy is a rare disease with variable presentation. Onset is usually acute and dramatic; however, it can rarely be insidious. A headache, often described as a severe sudden-onset retro-orbital or bifrontal, is nearly always present. It is also associated with nausea and vomiting and symptoms of meningeal irritation due to blood in the subarachnoid space. Fever may also be present due to blood or disruption of hypothalamic structures. Neurologic symptoms that are most commonly associated with pituitary apoplexy are ophthalmologic symptoms, including decreased visual acuity, visual field defects, classically bitemporal hemianopia, and opthalmoplegia, due to encroachment of cranial nerves III, IV, and VI. Compression of the internal carotid artery or decreased blood flow from increased intracranial pressure or vascular spasm can lead to mental status changes or stroke-like symptoms caused by hemispheric ischemia. Blood in the subarachnoid space can also cause seizures.
Pituitary hypofunction is seen on presentation in most patients. A history of pituitary hormone dysfunction may be helpful in the diagnosis. Although several hormone deficiencies are often present, adrenal insufficiency is the most life-threatening complication and requires immediate attention. Respiratory failure may also occur from hypothalamic compression or increased intracranial pressure.
Global pituitary function should be assessed by thyroid function tests, cortisol levels, growth hormone levels, and prolactin levels. A basic metabolic panel may reveal hyper- or hyponatremia. Cerebrospinal fluid may be xanthochromic or grossly bloody, with an elevated opening pressure.
MRI is the imaging study of choice for diagnosis of pituitary apoplexy. MRI is superior to cranial CT because it allows differentiation of hemorrhagic and necrotic tissues, as well as abnormalities of the surrounding areas; MRI is up to 50% more sensitive for the detection of pituitary apoplexy than CT. However, these patients are often unstable, which may prohibit the use of MRI. CT is a reasonable alternative in unstable patients and will detect most abnormalities in unstable patients.
After initial resuscitation, hydrocortisone 100 mg intravenously should be given to all patients suspected of having pituitary apoplexy to treat frequently concurrent and potentially lethal acute adrenal insufficiency.
Definitive treatment for pituitary apoplexy is usually neurosurgical decompression. Indications for immediate surgery are decreasing consciousness, progressive vision loss, or increasing extraocular motor palsy indicating cavernous sinus compression.
Immediate neurosurgical consultation is indicated. Surgery is the definitive treatment, but not every patient will require an operation. Some patients recover without sequelae with conservative management alone.
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Inappropriate Secretion of Antidiuretic Hormone
- Hyponatremia in the setting of a reduced plasma osmolality, persistent urinary secretion of sodium (>20 mEq/L), and urine osmolality that is inappropriately high for the degree of hyponatremia and hypo-osmolality found
- Mental status changes ranging from mild to severe dependent on the degree of hyponatremia and the rate of decline
Arginine vasopressin (AVP), also known as antidiuretic hormone (ADH), is secreted from the posterior pituitary in response primarily to hyperosmolality and decreased circulating volume. AVP acts on the collecting ducts in the nephrons to allow water reabsorption. Inappropriate secretion of antidiuretic hormone (SIADH) is a state of pathological hormone excess in the presence of hyponatremia and hypoosmolality. Classic diagnostic criteria include (1) euvolemic hyponatremia and low plasma osmolality, (2) failure of the kidney to dilute the urine in the presence of reduced serum osmolality (urine osmolality is frequently >300 mOsm/kg), (3) continued sodium excretion (usually >20 mEq/L) despite hyponatremia, and (4) absence of other conditions such as hypothyroidism, adrenal insufficiency, congestive heart failure, cirrhosis, or renal disease, which can cause hyponatremia.
Numerous diseases and drugs can cause SIADH. See Table 43–1.
Table 43–1. Causes of SIADH. |Favorite Table|Download (.pdf)
Table 43–1. Causes of SIADH.
- Small cell carcinoma of the lung
- Pancreatic carcinoma
- Hodgkin disease
- CNS disorder
- ACE inhibitors
- MDMA (Ecstasy)
- Antineoplastic agents
- Pulmonary disorders
- Mechanical ventilation
The elderly are at higher risk for SIADH because several physiologic effects of aging contribute to its pathogenesis, including an increased ADH response to osmotic stimulation, declining renal function, and decreased renin, angiotensin, and aldosterone production.
The clinical presentation of SIADH depends on the level of hyponatremia and water intoxication:
- In mild cases (serum sodium ≥ 120 mEq/L), patients are usually asymptomatic.
- When serum sodium reaches 105–120 mEq/L, patients begin to experience neurologic manifestations such as anorexia, nausea, vomiting, personality changes, depressed tendon reflexes, and muscle weakness.
- With severe hyponatremia (≤105 mEq/L), coma, seizures, delirium, cranial nerve palsies, hypothermia, and altered patterns of respiration (Cheyne–Stokes) may be evident.
Because SIADH can be caused by various pathologic conditions, patients will also present with symptoms or signs of their underlying disease (eg, malignancy, CNS or pulmonary disease). Edema and other signs of volume overload are highly unusual even with severe hyponatremia and water intoxication. Signs of volume overload indicate an alternative diagnosis.
Hyponatremia along with reduced plasma osmolality, persistent urinary secretion of sodium (>20 mEq/L), and urine osmolality that is inappropriately high for the degree of hyponatremia and hypo-osmolality is found.
General and Supportive Measures
Draw blood for measurement of serum sodium and other electrolytes, creatinine, BUN, osmolality, cortisol levels, and thyroid function studies (TSH and free T4). Send urine for urinalysis and measurement of urinary osmolality, electrolytes, and specific gravity.
Measure serum and urine electrolytes and osmolality every 1–2 hours during the acute phase if receiving 3% NaCl, and then 1–4 times daily until the patient's condition has stabilized. Assess the patient for evidence of renal, hepatic, or cardiac dysfunction. Obtain a history of drugs and medications used by the patient. Imaging may be indicated for evaluation of causes of SIADH, and evaluate for cancer, CNS disease, or pulmonary disease.
Fluid restriction is the treatment of choice for the correction of euvolemic (SIADH) or hypervolemic (CHF, cirrhosis) hyponatremia.
Mild SIADH (Serum Sodium ≥ 120 Meq/L)
Restrict fluids to 800–1000 mL per 24 hours.
Moderate SIADH (Serum Sodium 105–120 Meq/L)
Restrict fluids to 500 mL per 24 hour.
Severe SIADH (Serum Sodium < 105 Meq/L or at Any Level If the Patient Develops Neurologic Complications Such as Coma or Seizures)
This is a medical emergency. Treatment is as follows:
- Administer hypertonic saline, 3% solution, at 1–2 mL/kg/h for the first 3–4 hours.
- Use intravenous furosemide, 1 mg/kg, to counteract volume overload.
- Monitor sodium and potassium every 1–2 hours and adjust fluids and replace as needed.
- Correct to a serum sodium level of 125 mEq/L or until CNS involvement resolves, and then resume fluid restriction therapy as described previously.
Serum sodium correction should average 0.5–2 mEq/L/h and no more than 10 mEq/L in the first 24 hours. Faster rates of sodium correction and longer duration of hyponatremia increase the risk for central pontine myelinolysis. Symptoms of quadripareis and bulbar palsy are seen. Once central pontine myelinolysis occurs as a complication, there is no proven treatment.
Responsible patients with mild SIADH without any neurologic symptoms may be managed on an outpatient basis with fluid restriction and close follow-up. Patients with more severe symptoms of SIADH and those who may not follow treatment recommendations should be hospitalized. Patients receiving hypertonic saline should be admitted to the intensive care unit.
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- Symptoms and signs include lethargy, altered mental status, irritability, hyperreflexia, and spasticity
- Urine osmolality of <150 mOsm/kg in the setting of serum hypertonicity and polyuria is generally diagnostic of diabetes insipidus
Patients with diabetes insipidus have an abnormal excretion of large amounts of hypotonic urine. Urine volumes often reach over 3–4 L a day. Most patients will have an intact thirst mechanism and thus may present with only polydipsia and polyuria. Fluid intake >3.5 L/d occurs in an attempt to maintain adequate hydration. If water intake does not keep up with urinary losses, extracellular volume depletion and hypernatremia soon develop.
Diabetes insipidus occurs in two basic forms. Central diabetes insipidus results from inadequate secretion of AVP (arginine vasopressin or antidiuretic hormone) and nephrogenic diabetes insipidus results from decreased responsiveness of the kidneys to vasopressin.
Central diabetes insipidus may be caused by trauma, neurosurgery, neoplasm, granulomatous infiltration, or autoimmune destruction of cells. Nephrogenic diabetes insipidus is often congenital; however, acquired forms are seen especially in the elderly. Severe forms are more likely to result from renal disease, drug-induced damage to the kidneys (most commonly lithium or demeclocycline), or electrolyte disturbances such as hypokalemia or hypercalcemia.
Profound polydipsia and polyuria may be present. Polyuria may lead to associated nocturia, incontinence, or enuresis. Urine osmolality is typically less than 300 mOsm/kg.
Hypernatremia and Hyperosmolality
Hypernatremia and hyperosmolality may be absent in an awake patient with unrestricted availability of hypotonic fluids. If this supply is restricted for any reason, however, hypernatremia and intracellular dehydration will occur. The organ most susceptible to these effects is the brain, resulting in lethargy, altered mental status, irritability, hyperreflexia, and spasticity. Acute changes result in a more symptomatic presentation. Gradual changes can result in adaptation and few symptoms.
Intracranial hemorrhage may occur as the brain shrinks and mechanical tension is placed on dural veins and venous sinuses. Patients with marked volume deficits typically have hypotension, tachypnea, tachycardia, and decreased level of consciousness. Visual field defects and anterior pituitary insufficiency may be present when diabetes insipidus is caused by intracranial neoplasm.
A urine osmolality of less than 150 mOsm/kg or specific gravity less than 1.005 in the setting of hypertonicity and polyuria is diagnostic of diabetes insipidus. A trial of 1 μg DDAVP (1-deamino-8-D-arginine vasopressin; exogenous vasopressin) subcutaneously or IV will distinguish central from nephrogenic diabetes insipidus. Urine osmolality will increase and volume will decrease with DDAVP administration in central but not nephrogenic diabetes insipidus.
Hypernatremia and hyperosmolality are found in uncompensated patients. Serum sodium may be greater than 160 mEq/L in severe cases, and prerenal azotemia is common in these patients. Specific gravity and osmolality of urine are low in proportion to serum osmolality. Glycosuria is another cause of polyuria.
If the diagnosis is unclear, a water deprivation test can be performed under controlled conditions by a consultant.
CT scanning may help exclude some CNS lesions; however in select cases, urgent MRI of the brain is indicated to search for a mass, or hemorrhage, in the region of the hypothalamus or pituitary gland.
General and Supportive Measures
Provide supplemental oxygen as needed. Draw blood samples for measurement of electrolytes, osmolality, glucose, calcium, and serum cortisol levels and for renal and thyroid function tests. Measure plasma ADH; if very low, this may be diagnostic.
Obtain urine specimens for routine urinalysis and specific gravity and osmolality measurements. Monitor volume status, body weight, fluid intake, and urine output and specific gravity.
Volume and Electrolyte Deficits
Water administration whether orally, by nasogastric tube, or intravenously is the treatment for hypernatremia. Whenever possible, the oral or nasogastric route is preferred because water absorption and the decline in serum sodium concentrations are more gradual.
Awake patients will often maintain equilibrium when given free access to water. In patients with altered mental status, the onset of hypernatremia can be catastrophic. The free water deficit should be corrected and fluid balance maintained. The free water deficit can be calculated by the following equation:
Free water deficit = 0.6 × Premorbid body weight (in kg) × [1 – (140/plasma sodium in mmol/L)]
Hypotonic saline (0.45% normal saline) or 5% dextrose in water may be given. The latter is given to patients who show severe signs of neurologic compromise from hypernatremia. Avoid iatrogenic hyperglycemia when using dextrose-containing solutions; it may cause an osmotic diuresis and worsen the hypernatremia.
Replace half the free water deficit within the first 12–24 hours. When serum sodium decreases to less than 150 mEq/L, 0.45% or 0.9% saline should be used. Decreasing the serum sodium greater than 1–2 mEq/L/h can cause fluid shifts back into the intracellular compartment causing cerebral edema. Neurologic deterioration after hydration therapy should raise serious concern and prompt action. Idiogenic osmoles found in chronic hypernatremia are thought to cause decompensation; therefore, levels should be corrected over 48 hours.
Desmopressin acetate or DDAVP is a synthetic vasopressin analogue. A dose of 1–2 μg every 12–24 hours subcutaneously or intravenously or 5–20 μg every 12 hours intranasally is the drug of choice when treating central diabetes insipidus. It is preferred over other vasopressin preparations because it has a longer half-life and has almost no pressor effect.
Nephrogenic diabetes insipidus is more difficult to treat. Thiazide diuretics and sodium restriction are the mainstays of treatment.
Patients with diabetes insipidus should be hospitalized for definitive diagnosis and initiation of treatment. Patients who are severely hypernatremic or who present in hypovolemic shock merit intensive care unit admission for at least the first 24 hours of treatment.
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