Chapter 43. Metabolic & Endocrine Emergencies

Most disorders of carbohydrate metabolism are related to diabetes mellitus (DM) and represent a broad category of emergency conditions. Toxin ingestion, medications, multisystem trauma, head injury, cardiovascular disease, cerebrovascular disease, and infection can mimic or exacerbate these conditions. Clinical appearance may vary dramatically. Patients may present with significant mental status changes or appear well while on the brink of metabolic decompensation.

Diabetic Ketoacidosis

Essentials of Diagnosis

• Symptoms and signs include fatigue, tachypnea (Kussmaul's respirations), tachycardia, altered mental status, abdominal pain, vomiting, polyuria, and polydipsia
• Arterial pH < 7.3, serum glucose ≥ 250 mg/dL, and serum bicarbonate ≤ 15 mEq/L

General Considerations

Diabetic ketoacidosis (DKA) is the most common acute life-threatening complication of diabetes. It is more commonly seen in type 1 diabetes but may occur in type 2. Patients with type 1 DM have an absolute insulin deficiency. When the production of insulin in the pancreas fails, the decreased glucose utilization creates a relative state of starvation. Counter-regulatory hormones (cortisol, glucagon, catecholamine, and growth hormone) that help maintain blood glucose levels adequate for cellular function during fasting are stimulated. These hormones promote gluconeogenesis and glycogenolysis, increasing glucose levels, and lipolysis, which converts adipose to free fatty acids. Without insulin to allow cellular absorption of glucose, these mechanisms continue to produce glucose. Severe dehydration and electrolyte losses develop as the kidneys filter the highly osmotic glucose. Furthermore, free fatty acids that cannot enter the citric acid cycle without insulin are oxidized into ketones. These accumulate to cause metabolic acidosis, further electrolyte derangement, and exocrine pancreatic dysfunction.

Clinical Findings

History

If a diabetes history is elicited or known, ascertain potential precipitating causes of DKA:

• Recent or current infection of any type (most common)
• Injury or trauma
• Acute coronary syndrome or myocardial infarction
• Transient ischemic attack or stroke
• Medications (corticosteroids, thiazides, or sympathomimetics)
• Acute or acute-on-chronic pancreatitis
• Ethanol or drug abuse
• Gastroenteritis or GI bleeding
• Psychosocial factors, such as depression or inability to afford medications, limiting compliance
• Noncompliance with insulin regimen due to psychological or physiological reasons

Although noncompliance or misuse of insulin is a frequent cause of DKA, consideration of other causes of decompensation is imperative. Infection or illness may prompt patients to underdose. Up to 25% of DKA admissions results from new-onset diabetes. Alcoholic ketoacidosis (AKA), starvation, lactic acidosis, renal failure, or ingestions such as salicylates, methanol, ethylene glycol, or paraldehyde should be considered in the differential diagnosis of DKA.

Symptoms and Signs

Typical findings include general fatigue and weakness, orthostasis, abdominal pain, and Kussmaul's respirations (rapid deep respirations attempting to compensate for acidosis). A fruity or acetone-like odor is classically described along with historical findings of polyuria, polydipsia, and polyphagia; nausea and vomiting are found in up to 25% of patients. Emesis may have a coffee ground appearance due to hemorrhagic gastritis. Mental status changes ranging from mild confusion to coma may be seen. DKA alone does not cause fever.

Laboratory Findings

Key Findings

Laboratory features include serum glucose ≥ 250 mg/dL, serum ketones or ketonuria, serum bicarbonate ≤ 15 mEq/L, and arterial pH < 7.3. Arterial blood gas (ABG) determination can be limited to patients with an uncertain diagnosis or respiratory concerns. Venous blood is an acceptable alternative. The pH value is usually 0.03 lower than that of arterial blood. This is especially useful for repeated pH determinations. The degree of leukocytosis often correlates with the degree of ketosis.

Serum Potassium

Because the initial serum potassium is unpredictable, the determination of serum potassium should precede insulin therapy. Acidosis drives potassium out of the cells causing a relatively higher serum potassium level despite total body deficits that may be as much as 3–5 mEq/kg. If serum potassium is initially low, insulin administration will exacerbate the situation by facilitating the cellular entry of potassium. The rapid development of severe hypokalemia may cause symptoms such as fatigue and muscle cramps or lead to a lethal arrhythmia.

Serum Sodium

Significant diuresis and emesis frequently lower serum sodium. Osmotic shifts from hyperglycemia also dilute the serum and fictitiously lower the reported sodium value. This effect can be corrected by adding 1.8 mEq/L to the serum sodium concentration for each 100 mg/dL above normal.

Sodium deficits may approach 7–10 mEq/kg; however, rapid correction with increasing osmolality may precipitate cerebral edema, especially in children.

Serum Phosphate

Serum phosphate values may be normal or elevated despite deficits approaching 1 mmol/kg body weight. Routine phosphate repletion does not improve outcome in DKA and is generally not indicated in the emergency department (ED). Severe hypophosphatemia (<1 mg/dL), however, may cause skeletal, cardiac, and respiratory muscle depression. Phosphate should be replaced in this circumstance. This can be done by using potassium phosphate as 1/3 of potassium replacement.

Other Important Laboratory Findings

Anion Gap

The anion gap is useful to assess severity of acidosis and to follow progress of therapy. The anion gap is obtained from the formula:

Anion Gap = [Na] - ([Cl] + [HCO3])

Normal values are 8–16.

Serum Osmolality

Serum osmolality values above 340 mOsm/kg usually result in mental status changes. Below this value, other causes for lethargy or coma should be investigated. This value may also be used to diagnose hyperosmolar hyperglycemic state (HHS) and ingestions of ethanol, ethylene glycol, or other alcohols. Effective serum osmolality can be estimated by the formula:

Serum osmolality = 2[Na] + (glucose/18) + (blood urea nitrogen/2.8).

Serum Ketones

The laboratory determination of serum ketones is not always reliable as a diagnostic test. The primary ketone body formed in DKA initially is β-hydroxybutyrate. However, standard ketone assays measure only acetoacetate. Since insulin is required for the conversion of β-hydroxybutyrate to acetoacetate, these assays may be reassuringly negative even in a severely ill patient. Due to insulin's effect, in most cases serum ketone values will initially increase as the patient improves before resolving.

Blood Urea Nitrogen and Creatinine

These levels may be elevated because of severe dehydration, acute tubular necrosis, or renal failure. In these circumstances, establish urine output prior to initiating potassium repletion.

Amylase/Lipase

Levels of both enzymes can be elevated in DKA in the absence of pancreatic pathology.

Treatment

See below.

Hyperosmolar Hyperglycemic State

Essentials of Diagnosis

• Most symptoms relate to severe dehydration
• Absence of acidosis, small or absent serum ketones, and hyperglycemia usually ≥ 600 mg/dL
• Kussmaul's respirations and abdominal pain are unusual findings

General Considerations

In contrast to DKA, patients with HHS have sufficient insulin activity to prevent lipolysis and ketogenesis. HHS results from gradual diuresis, resulting in severe dehydration and electrolyte depletion without significant early symptoms. This leads to profound electrolyte deficiencies and eventually mental status changes. In contrast, DKA often manifests symptoms more suddenly over hours to a few days due to acidosis.

HHS is often caused by physiologic stressors such as infection, myocardial infarction, cerebrovascular accident, trauma, decreased access to water, and medication effects or interactions.

Clinical Findings

History

Risk factors for HHS include age greater than 65, residence in a chronic care facility or nursing home, change in diabetes regimen, addition of medications that may elevate glucose levels (e.g., corticosteroids, thiazides, anticonvulsants, immunosuppressants, sympathomimetics), recent or current infection, and dementia. Other factors include myocardial infarction, Cushing's syndrome, intracranial hemorrhage, cerebrovascular accident, Down's syndrome, trauma/burns, hemodialysis, and hyperalimentation.

Symptoms and Signs

These include polydipsia, polyuria, or polyphagia; generalized weakness; altered mental status (clouded thinking to confusion to lethargy or coma); dry mucous membranes; poor skin turgor; and delayed capillary refill. Since the average fluid deficit is 9 L, tachycardia and orthostatic hypotension are common.

Abdominal pain is not a typical finding in HHS (in contrast to DKA); its presence merits aggressive investigation for a precipitating cause. Acute cholecystitis and appendicitis may be insidious and have an atypical presentation in elderly patients.

Laboratory Findings

Key Laboratory Findings

Key findings to diagnose HHS and differentiate it from DKA are as follows:

• HHS typically is associated with a greater fluid deficit (9 L vs. 3–5 L).
• Serum glucose ≥ 600 mg/dL.
• Urine or serum ketones are small or absent (a small amount of ketone may be detected secondary to starvation).
• Glucosuria is prominent.
• Serum bicarbonate is usually >15 mEq/L.
• pH is usually >7.30, but the patient can have acidemia from lactate, starvation ketosis, or renal insufficiency.
• The anion gap may be variable depending on precipitating cause but is usually ≤10.
• Serum osmolality is 320–380 mOsm/kg.

Serum Sodium

In the early stages of HHS, serum sodium findings are similar to those in patients with DKA. Urinary losses and fluid shifts out of the cell and into the extracellular compartment create hyponatremia usually 125–130 mg/dL. Correct for hyperglycemia with the addition of 1.8–2.4 mg/dL sodium per 100 mg/dL of glucose.

Serum Potassium

Serum potassium levels will most commonly be normal or low, unless renal failure is present. Total body deficits are often 4–6 mEq/L, which is as much as 500 mEq total.

Blood Urea Nitrogen and Creatinine

Blood urea nitrogen (BUN) is often markedly elevated. Gastrointestinal bleeding may also elevate BUN and is a possible precipitating cause of HHS in elderly patients.

Other Studies

Ancillary diagnostic testing should also be considered including serial ECGs and cardiac enzymes, cranial and abdominal tomography, and evaluation for gastrointestinal hemorrhage. Bedside ultrasonography may also be useful.

Treatment

Treatment of DKA and HHS is very similar. Continuous monitoring of vital signs, mental status, and laboratory parameters is essential. A flow sheet may be helpful during resuscitation due to the complexity of treatment and need for frequent therapeutic changes.

Resuscitation Issues

Standard airway management is indicated. If tracheal intubation is required, avoid succinylcholine unless hyperkalemia is excluded. Hypoxia should trigger an investigation for aspiration, pneumonia, or pulmonary edema. Maintain oxygen saturation above 96% or Po2 ≥70 mm Hg for all DKA or HHS patients.

Fluid Therapy

Fluid therapy is dictated by three parameters: vital signs, corrected serum sodium, and serum glucose. Overall fluid deficits approach 6–10 L in most patients. Large-bore (≥18-gauge) intravenous lines are essential. Central venous access may be indicated. Hypotension should prompt a bolus of 1–2 L of 0.9% NaCl solution to restore blood pressure to at least 90 mm Hg.

Caution: Decreased cardiac systolic function and renal failure complicate crystalloid resuscitation. Reassess patients frequently for adequate urine output and signs of pulmonary edema or congestive heart failure. Invasive hemodynamic monitoring may be indicated in very select cases to facilitate fluid management if cardiogenic shock is present.

Serum electrolytes including potassium, bicarbonate, and sodium should be monitored every hour along with hourly glucose determination. The calculated serum osmolality should not decrease more than ∼3 mOsm/kg/h due to increased risk of cerebral edema.

• Usually 1–1.5 L of 0.9% saline is infused over the first hour while initial laboratory values are determined. Subsequent infusion can be decreased to 500 mL/h, then 250–500 mL/h, and then 150–300 mL/h as the hydration status improves. Correct one-half of the fluid deficit over the initial 8 hours, and the other half over the following 24 hours.

If the serum sodium is high normal or high, 0.45% saline is recommended after initial fluid boluses to avoid severe hypernatremia. If serum sodium is low or low normal, 0.9% saline should be continued.

• Once serum glucose reaches approximately 250 mg/dL, 5% dextrose in 0.45% NaCl is the fluid of choice at a rate of 250 mL/h; alternatively, use 5% dextrose in normal saline if the corrected serum sodium remains low.

The clinical relevance of the urine output is unreliable while glucose levels remain high due to osmotic diuresis. Once glucose levels approach normal, urine output may be used to guide therapy; 30–50 cc/h is considered adequate.

Cerebral edema may occur in the following cases: correcting acidosis too rapidly, correcting glucose too rapidly, overaggressive IV fluid resuscitation.

Electrolyte Replacement

Potassium

Potassium repletion may begin once continuous urine output is confirmed and an initial potassium level is determined. With target levels of 4.0–5.0 mEq/L, the following algorithm is useful:

• If the serum potassium is 3.3 mEq/L or less, withhold insulin therapy and give potassium replacement. Give 40 mEq potassium chloride intravenously or a mixture of two-thirds potassium chloride and one-third potassium phosphate (∼5 mmol) if serum phosphate is less than 1 mmol/L. Potassium chloride, 40 mEq, may also be given orally or by nasogastric tube. This method allows for safer administration of larger doses of potassium and is the preferred replacement method if oral dosage is tolerated. Assume a deficit of about 100 mEq potassium for each 1 mEq/L below normal.
• If the serum potassium is 3.3–5.0 mEq/L, give 20–30 mEq potassium chloride in each liter of intravenous fluid.
• If the serum potassium is 5.0 mEq/L or more, hold potassium repletion and recheck the serum potassium in 1 hour. If levels remain significantly elevated (above 6 mEq/L) or ECG changes are noted, a regular insulin bolus of 8–12 units can be given along with other standard treatments for hyperkalemia.
• Magnesium is often deficient due to diuresis, and may worsen vomiting.

Insulin Therapy

Intravenous regular insulin is used for initial therapy. Subcutaneous insulin may be absorbed erratically in volume-depleted patients. A continuous infusion of regular insulin at 0.1 units/kg body weight per hour is the treatment of choice. Historically, after the serum potassium determination, a bolus of 0.1–0.15 units/kg body weight of regular insulin was considered (not recommended in pediatric patients). Due to the risk of cerebral edema, one should avoid insulin boluses even in adult patients; continuous infusion of insulin is optimal. If glucose is not decreasing by at least 50–70 mg/dL/h, the insulin dosage should be doubled until this rate of decline is achieved. Decrease insulin infusion by 25–75% if the decline in serum glucose is more than 100 mg/dL/h since this results in rapid shifts in serum osmolality.

Insulin therapy should be delayed if the potassium level is less than 3.3 mEq/L until the potassium level is rising.

Sodium Bicarbonate Therapy

Sodium bicarbonate therapy is generally not indicated except for unstable patients with severe acidosis such as an arterial pH < 6.9. Bicarbonate therapy is rarely indicated for HHS patients. The incidence of cerebral edema increases with aggressive bicarbonate use (particularly in children). There is no proven impact on outcome in controlled trials when bicarbonate therapy was used for severe acidosis. However, due to the catastrophic potential of severe acidosis, bicarbonate therapy may be considered in these patients. NaHCO3 (50 mmol) is diluted in 200 mL sterile water and infused at 200 mL/h. This may be repeated every 2 hours until the venous pH is greater than 7.

Treatment of Precipitants

Infection is the most common pathological precipitant of DKA and HHS. The patient's entire skin surface should be examined for wounds and cellulitis. A pelvic examination may be indicated to rule out infection. Analysis and cultures of all appropriate body fluids (blood, sputum, urine, cerebrospinal fluid) should be obtained. The empiric administration of broad-spectrum antibiotics should be considered until culture results are available.

Disposition

Patients with all but very mild cases of DKA and all patients with HHS should have cardiac monitoring and a higher level of nursing care for at least 24 hours. Whether the patient goes to an intermediate care, telemetry unit, or the intensive care unit is based on severity of the case and response to initial therapy as judged by the treating physician.

Hyperglycemia

Hyperglycemia in the absence of metabolic decompensation (DKA or HHS) is a common finding in the ED. Patients with either known or undiagnosed diabetes may present with symptoms due to hyperglycemia, complications of untreated diabetes, or numerous unrelated conditions that incidentally have high blood glucose levels.

Clinical Findings

History

Age greater than 45, obesity, physical inactivity, and family history are risk factors for insulin resistance. Personal history of gestational diabetes, impaired glucose tolerance, hypertension, dyslipidemia, vascular disease, or polycystic ovary disease also increases risk.

Symptoms and Signs

Symptoms of hyperglycemia may include polydipsia, polyuria, polyphagia, weakness, fatigue, headache, blurred vision, dehydration, lightheadedness, or dizziness.

Infections are much more common in poorly controlled diabetics. Superficial skin infections such as cellulitis, furuncles, abscesses, nonhealing wounds, and ulcers are very common complaints. Urinary tract infections and candidal infections, malignant otitis externa, and rhinocerebral mucormycosis all have epidemiologic associations with hyperglycemia.

Laboratory Findings

A random serum glucose greater than 200 mg/dL with symptoms of hyperglycemia or metabolic decompensation (DKA or HHS) or a fasting serum glucose greater than 126 mg/dL on repeat occasions is diagnostic of diabetes. Impaired fasting glucose is defined as a fasting plasma glucose of 110–126 mg/dL. Glycosylated hemoglobin, or HbA1C, can facilitate the diagnosis of diabetes, and is becoming more valued as a screening test. Levels of 7% or more are nearly always consistent with diabetes.

Severe hyperglycemia (≥400 mg/dL) may foreshadow impending decompensation. An underlying cause should be sought aggressively such as infection, cardiac ischemia, or myocardial infarction. White blood cell count, blood cultures, and ECG with cardiac enzymes may be helpful. Lack of compliance with antidiabetic regimen or diet should always be exclusionary. In this setting evaluate electrolytes, BUN, creatinine, and serum bicarbonate to screen for metabolic decompensation.

Treatment

If diabetes was previously undiagnosed and insulin deficiency (type 1) cannot be excluded, then the patient should be admitted. Insulin resistance (type 2) is much more common. If hyperglycemia is mild (<250–350 mg/dL) with no signs of decompensation, no specific treatment is required if primary care follow-up is readily available. Newly diagnosed patients should also be counseled on diet and the importance of follow-up. If the serum glucose is greater than 300 mg/dL, treatment is as follows:

Fluids

Normal saline 1 L given over 1 hour may be adequate monotherapy for hyperglycemia.

Insulin

Usually 0.1–0.15 units/kg regular insulin, insulin lispro (Humalog), or insulin aspart (NovoLog) can be given subcutaneously or intravenously. Insulin may be rebolused intravenously if glucose does not decline by 50–75 mg/dL in the first hour.

Oral Hypoglycemic Agents

Oral hypoglycemic agents are generally not indicated for acute therapy of severe hyperglycemia. Oral agents may, however, be initiated or continued by emergency physicians when follow-up is available.

Metformin inhibits fasting hepatic glucose production and promotes weight loss. It is an attractive option that should only be prescribed if follow-up is possible, since it is the least likely to cause hypoglycemia. Metformin can be safely started at 500 mg orally once per day; the dosage can be increased by 500 mg/d each week until 1000 mg twice a day is reached. It should not be given if serum creatinine levels are above 1.4 mg/dL, due to the risk of developing lactic acidosis. Metformin should also be avoided in the following circumstances: risk of hypoxemia, CHF, hepatic impairment, renal insufficiency, acute infection, age >80 or <17, alcoholic, exposure to contrast in the past 48 hours, or planned exposure to contrast.

Initial treatment with sulfonylurea, thiazolidinediones, and α-glucosidase inhibitors is best withheld until the patient has received diabetes education. If education can be provided along with supplies such as glucometer and test strips, these agents can be started in conjunction with consultation and close follow-up. When adjusting an existing oral agent or insulin dosage, do not increase insulin dosages by more than 10% or sulfonylurea dosage by more than about 20%.

Disposition

Most patients with blood glucose less than 250–350 mg/dL in the absence of metabolic decompensation can be safely discharged with follow-up after a thorough evaluation for underlying illness. Patients with serious underlying precipitants or in whom hyperglycemia is resistant to treatment should be hospitalized.

Hypoglycemia

Essentials of Diagnosis

• Common symptoms and signs include irritability, diaphoresis, and tachycardia related to increased circulating catecholamines
• As hypoglycemia progresses, neuroglycopenic effects range from focal neurologic deficits such as diplopia and paresthesias to coma
• Always check the fingerstick blood glucose on every patient presenting with altered mental status or who appears to be acutely ill

Background

Symptoms can include altered mental status, focal neurologic deficits, and coma. Even mild, treated episodes can exacerbate preexisting microvascular disease and lead to cumulative brain damage.

Causes

Hypoglycemia is commonly defined as serum glucose of <50 mg/dL. Less than 30 mg/dL is considered severe hypoglycemia. This most commonly occurs in diabetics on exogenous insulin therapy. Changes in daily activities such as diet, exercise, or dosage changes may result in hypoglycemia. Many other factors, however, may result in hypoglycemia such as infection, endocrine disorders, drugs or alcohol, liver failure, intentional overdose of insulin, tumors or malnutrition in both diabetics and nondiabetics.

Other causes of hypoglycemia include glycogen storage disease (esp von Gierke's), carnitine deficiency, sepsis, Addisonion crisis, beta blocker overdose, pregnancy, salicylate toxicity.

Exogenous Insulin

In patients with known diabetes, hypoglycemia may occur as a result of the following:

• Delay in eating after taking insulin, general malnutrition, or inadequate caloric intake due to nausea and vomiting or gastroparesis.
• Increased physical activity.
• Increased physiologic stress resulting from infection or injury.
• Excessive dose of exogenous insulin (Note: Remember to check the patient's vision and confirm that he or she can read the syringe appropriately.).
• Variable absorption from injection sites.
• Impaired counter-regulatory hormone axis.
• Excessive insulin release produced by sulfonylurea drugs, especially in the presence of renal insufficiency.
• Alterations in therapeutic regimen, particularly increases in insulin or oral agent dosages or the addition of new oral agents such as thiazolidinediones (also known as glitazones), which may reduce insulin resistance and improve therapeutic action of endogenous or exogenous insulin.
• Intentional hypoglycemia may result from insulin or antihyperglycemic agents such as sulfonylurea that may be taken by, or given to, the patients. C-peptide is naturally secreted along with insulin by the pancreas and is not present in manufactured insulin. A high insulin level without a correspondingly high C-peptide level is diagnostic of exogenous insulin.

Pancreatic β-Cell Tumor

Tumor of the insulin-secreting β-cells in the islets of Langerhans may cause refractory hypoglycemia and even coma. C-peptide levels will elevate concurrently with insulin levels.

ETOH

Acute or chronic excessive ethanol intake, especially without adequate caloric intake, may cause severe hypoglycemia (especially in children). Chronic abuse reduces NADH-mediated gluconeogenesis and depletes hepatic glycogen production and storage.

Caution: Administer thiamine, 100 mg, to alcoholic patients with hypoglycemia to avoid Wernicke's encephalopathy.

Postprandial or Reactive Hypoglycemia

The intake of large amounts of concentrated calories in nondiabetics may produce enough excess insulin to induce mildly symptomatic hypoglycemia. Rarely, hypoglycemia may be severe enough to cause briefly decreased level of consciousness.

Clinical Findings

History

Try to obtain a history of diabetes from emergency medical services, family, Medic Alert bracelet, necklace, or wallet card. Emergency medical services or family may also be helpful in disclosing alcohol use, recent caloric intake, alterations of medication regimen, and recent illness or injury.

Symptoms and Signs

Most early symptoms and signs are the result of increased catecholamine release: tachycardia, irritability, diaphoresis, paresthesias, hunger, and decreased concentration are common. With more severe or prolonged hypoglycemia, symptoms and signs of neuroglycopenia result in mental status changes including confusion or bizarre behavior, lethargy, or coma; visual disturbances such as blurred vision, diplopia, hallucinations; seizures or seizure-like activity or focal neurologic deficits similar to Todd's paralysis that resolves with glucose administration.

Laboratory Findings

The capillary or fingerstick glucose is a rapid screen to determine blood glucose levels. Glucometers become unreliable at readings less than 40 mg/dL. Obtain a sample for laboratory determination.

Search for ancillary causes of hypoglycemia such as infection or sepsis, myocardial infarction, cerebrovascular accident, renal insufficiency or failure, alcohol use, pregnancy, drug use (particularly stimulants), occult trauma, depression (poor caloric intake or insulin or oral agent overdose), and other endocrinopathies (Addison's disease, myxedema, thyrotoxicosis, pituitary insufficiency).

Treatment

Emergency Therapeutic Measures

Intravenous Glucose

If intravenous access is readily obtainable, administer 50 cc of 50% dextrose in water (containing approximately 25 g of glucose, which is enough to resolve most hypoglycemic episodes). Caution: Remember to give thiamine, 100 mg intravenously or intramuscularly, to alcoholic patients to prevent Wernicke's encephalopathy. Monitor the patient's mental status and recheck capillary blood glucose 15–30 minutes after glucose administration. Repeat dosages of 50% dextrose or infusion of glucose-containing intravenous fluids (5–10%) may be necessary to maintain adequate blood glucose levels. Neuroglycopenia (altered level of consciousness, seizure-like activity, focal neurologic deficits) may take time to resolve completely. If abnormalities persist longer than 30 minutes after glucose administration and hypoglycemia has not recurred, other causes should be investigated with a cranial CT scan and appropriate laboratory studies.

Oral Feeding

As soon as the patient regains consciousness (or in an already conscious patient), clear fruit juice (eg, apple, grape; 6 oz ≅ 15 g glucose) is a good choice to maintain glucose levels, a snack or meal is appropriate.

Glucagon

If intravenous access is not readily available, 1 mg of glucagon may be given intramuscularly. The response time is typically 10–15 minutes, and nausea and vomiting along with overcorrection of glucose levels are common. Since glucagon can be given intramuscularly, all patients with insulin-treated diabetes (or their families) should carry and be familiar with the use of glucagon emergency kits.

Monitoring

Consider the duration of action of the insulin or oral agents taken by the patient. Hourly capillary glucose checks should be taken until glucose levels are stable. Generally the patient should be observed through the peak time of the longest-acting insulin, typically 30 minutes to 1–2 hours after the dose with insulin lispro or insulin aspart, 2–4 hours with regular insulin, or 6–8 hours with NPH. Insulin glargine has no peak activity and does not generally cause hypoglycemia by itself. Patients taking long-acting insulins with peak activity, such as lente or ultralente, or patients taking sulfonylurea oral agents should generally be observed in the hospital.

Disposition

Indications for admission include persistent or recurrent hypoglycemia despite appropriate therapy, hypoglycemia related to an oral agent or long-acting insulin, and unknown cause of hypoglycemia or serious ancillary cause (eg, severe infection, persistent nausea, and vomiting).

Conditions for discharge include well-understood cause of hypoglycemia, easily reversible episode, availability of responsible adult to observe the patient for next 8–12 hours; ability to take oral fluids and food; medical follow-up available within 24–48 hours; and ability to check blood glucose levels.

Advances

With advances in the treatment of insulin-dependent diabetes mellitus, more ED physicians will encounter patients who have insulin pumps. These devices come in various brands. The pump consists of a device worn by the patient, which has a reservoir for fast-acting insulin. Tubing connects the reservoir to a subcutaneous site implanted on the trunk or thigh of the patient. Insulin is administered as a continuous basal rate with the addition of bolus therapy with carbohydrate intake. Although associated with iatrogenic hypoglycemia, insulin pumps help the motivated/educated patient achieve tight glycemic control.

Lactic Acidosis

General Considerations

Lactic acidosis is a common complication of critical illness. It is defined as serum lactic acid concentration greater than 5 mmol/L and arterial pH less than 7.35. Lactic acid is measured as the L isomer; however, the D isomer is being increasingly noticed due to rates of small bowel resection and gastric bypass surgery. Typically lactic acidosis results from the metabolism of glucose under anaerobic conditions or inadequate breakdown of lactic acid by the liver.

Severe acidosis can lead to impairment of cardiac contractility, increased pulmonary vascular resistance, sensitization of the myocardium to dysrhythmias, hyperkalemia, and inhibition of metabolism at the cellular or molecular level. The mortality rate is high, approaching 40–60%.

Causes

Lactic acidosis may occur in any severe illness with a combination of inadequate tissue oxygenation, tissue perfusion, and lactic acid clearance. Common underlying causes include:

• respiratory, hepatic, renal, or heart failure
• sepsis
• shock
• cancer, especially leukemias
• acute infarction of lung, bowel, or extremities
• severe abdominal or multisystem trauma
• ETOH, methanol, ethylene glycol, or cyanide poisoning
• drugs (cocaine, metformin, isoniazid, NRTI HIV medications).

Clinical Findings

Diagnostic efforts should focus on finding the underlying cause of the lactic acidosis. Treatment of the underlying cause is crucial to recovery.

Symptoms and Signs

The clinical presentation varies according to the underlying illness or injury. Symptoms may be minimal initially and then progress to include hyperventilation, generalized weakness, abdominal pain, or hypotension.

Laboratory Findings

Laboratory findings include pH less than 7.35 and often less than 7.2; anion gap greater than 15 mEq/L; and lack of explanation of acidosis by other causes—such as salicylates; ETOH, methanol, or ethylene glycol poisoning; or diabetic or alcoholic ketoacidosis. Hyperphosphatemia is a common finding secondary to anaerobic glycolysis or cellular disruption.

Samples collected for lactate should be chilled immediately and centrifuged promptly to avoid continued lactic acid production by red and white blood cells.

Treatment

Basic treatment of lactic acidosis is medical resuscitation for improvement of oxygenation and perfusion of tissues along with treatment of the underlying cause of decompensation.

Oxygen

High flow rates are indicated. Consider rapid-sequence intubation, mechanical ventilation, or noninvasive ventilation when indicated by blood gas analysis and overall clinical picture.

Fluids

Rapid infusion of 1 L of 0.9% saline is indicated to restore intravascular volume. The patient should be frequently reassessed to avoid volume overload in the setting of acute renal failure or cardiogenic shock and circulatory failure.

Pressors

Vasoactive pressors such as epinephrine, norepinephrine, and dopamine may be required to support systemic blood pressure and improve overall perfusion in patients with lactic acidosis. One must remember, however, that these agents can increase vasoconstriction to already-hypoxic tissues and increase the metabolic demands of organs such as the heart. For a more detailed discussion of vasopressors use in shock, see Chapter 11.

Sodium Bicarbonate

The use of sodium bicarbonate is one of the most controversial issues in the treatment of metabolic acidosis. The majority of data available suggest that no benefit is seen at pH levels greater than 6.9 in the clinical settings of severe metabolic acidosis resulting from DKA and sepsis. Significant risks of administering bicarbonate include hypernatremia, hyperosmolality, volume overload, paradoxical increase of intracellular acidosis secondary to excess carbon dioxide from bicarbonate metabolism, and cerebral edema. If pH is less than 6.9 and the patient exhibits one or more complications of severe acidosis, administration of sodium bicarbonate can be considered using 2–3 ampules (44 mEq/ampule) diluted in 1 L of 5% dextrose in water infused over 2 hours. Reassess pH after allowing at least 2 hours for equilibration. Some experts do not recommend bicarbonate administration at any pH.

Treatment of Underlying Causes

Treatment of the underlying cause is the most effective treatment for lactic acidosis. This may include revascularization therapy or balloon pump support in patients with cardiogenic shock, antibiotics for suspected sepsis with appropriate cultures, amputation or revascularization of ischemic extremities, removal or revascularization of ischemic bowel, hemodialysis for renal failure, or removal of toxic components such as ethylene glycol or methanol.

Thiamine should be considered since thiamine deficiency can result from many insults and can produce substantial lactic acidosis.

Disposition

Since the prognosis is grim, prompt identification and treatment of the underlying cause of lactic acidosis remains the best chance for recovery.

Alcoholic Ketoacidosis

Essentials of Diagnosis

• Signs include tachypnea (Kussmaul's respirations are common), tachycardia, abdominal tenderness, poor skin turgor, and delayed capillary refill
• In general, serum glucose < 250 mg/dL distinguishes alcoholic ketoacidosis from DKA

General Considerations

Alcoholic ketoacidosis is a complex metabolic condition usually developing in chronic alcoholics, but it can also be seen in binge drinkers. It usually develops 24–48 hours after abstinence. Patients are usually either unable or unwilling to consume calories due to abdominal pain, nausea, vomiting, or secondary conditions such as gastritis, pancreatitis, infection, trauma, ingestion, and hepatic or renal failure. Starvation and volume depletion along with depletion of enzymes required for alcohol metabolism inhibit aerobic metabolism. This promotes lipolysis and the release of counter-regulatory hormones as in DKA. A mixed acid–base disturbance from metabolic acidosis results with coinciding volume depletion alkalosis and respiratory alkalosis.

Clinical Findings

History

History usually includes chronic alcohol consumption or a recent binge. In either case there is a history of poor food intake, nausea, vomiting, and abdominal pain prior to presentation.

Symptoms and Signs

Symptoms are nonspecific and include nausea, vomiting, and abdominal pain. Patients can also present with hematemesis, tremulousness, shortness of air, and dizziness. Common signs are tachypnea (Kussmaul's respiration), tachycardia, and abdominal tenderness.

Differential Diagnosis

Because of its vague symptoms the differential diagnosis is quite broad. Most causes of wide anion gap acidosis can present similar to those in AKA. Ingestions of various alcohols, lactic acidosis, infection, DKA, starvation, and renal failure should be considered.

Laboratory Findings

Metabolic Acidosis with a Wide Anion Gap

Serum pH is often <7.2 with a low bicarbonate value.

Plasma or Urine Ketones

The depletion of nicotinamide adenosine dinucleotide by ethanol metabolism slows the conversion of β-hydroxybutyrate to acetoacetate. Since the most common laboratory assessment of ketones is the nitroprusside test, which detects acetoacetate only, initial ketone values may be low or negative. Therefore, negative ketones do not exclude AKA. With treatment, ketone levels may initially rise as the conversion of β-hydroxybutyrate to acetoacetate occurs. They should then fall as ketoacidosis resolves. Of note, the ratio of β-hydroxybutyrate to acetoacetate is usually 6–10:1 in AKA and 3–4:1 in DKA.

Electrolyte Disorders

Hyponatremia, hyperkalemia, hypokalemia, hypophosphatemia, hypomagnesemia, and hypocalcemia are all common findings in AKA.

Glucose

Glucose levels range from hypoglycemia to moderately elevated (up to 250 mg/dL) in the absence of diabetes. DKA can present with lower serum glucose in diabetics who took exogenous insulin just prior to arrival. This may mimic AKA with ketoacidosis and low blood glucose.

ETOH Levels

ETOH levels may or may not be elevated at the time of presentation because of the inability to maintain oral intake. Watch for signs of withdrawal which can greatly complicate the situation.

Treatment

Thiamine

Thiamine 100 mg IV/IM/PO (often along with folic acid 1 mg and a multivitamin) should be given to all patients suspected of chronic ETOH use because of poor nutrition and the risk of Wernicke's encephalopathy.

Glucose

After thiamine administration, give 5% dextrose in 0.9% normal saline at 1 L/h for the first 1–2 hours and then 5% dextrose in 0.45% normal saline at ∼250 mL/h.

Potassium

Total body potassium is usually low due to poor nutrition and losses due to vomiting. Acidosis, however, will shift potassium out of the cells causing initial serum values to be normal to high. Once urine output is established, 10–20 mEq/L of potassium chloride may be given intravenously. Once vomiting is controlled, replacement can be done orally with up to 40 mEq every 2 hours. Assume a 100-mEq deficit for every 1 mEq/L below the normal value. Check potassium every 2 hours during early course of treatment.

Insulin

Insulin is generally not required in the treatment of AKA. It may be required in the treatment of diabetics with combinations of AKA and DKA, or it may be used to treat severe hyperkalemia above 6.0 mEq/L with ECG changes.

Magnesium

Consider giving 1–2 g of IV magnesium sulfate empirically with the first liter of fluid since magnesium deficiency is very common in alcoholic patients. This will make myocardium less susceptible to dysrhythmias and help restore calcium homeostasis. In addition, replacement of magnesium may be necessary to treat hypokalemia.

Bicarbonate

Since acidosis generally responds well to volume and glucose administration, bicarbonate is rarely indicated. Its use may be justified as therapy of severe hyperkalemia or severe acidosis below pH of 6.9 (which is rarely caused by AKA alone).

Phosphate

Phosphate replacement is rarely necessary unless levels are below 1 mg/dL. The oral route is preferred because of safety concerns of rapid IV phosphate infusion.

Treatment of Underlying Causes

Since AKA has very nonspecific symptoms and signs, do not assume that all symptoms are caused by the syndrome alone. Pancreatitis, GI bleed, infection, or other ingestions may complicate the presentation.

Disposition

Metabolic disorders tend to correct relatively quickly with proper treatment. Many patients with AKA, however, are extremely unreliable and are unlikely to comply with outpatient treatment. Admission is often advisable, and should be considered in patients who remain symptomatic despite hydration. Prior to discharge, the patient should tolerate PO intake, have stable vital signs, and have no underlying illness as a contributor to the AKA. Remember that ETOH withdrawal is also a common and dangerous coinciding problem that will complicate treatment and recovery.

Thyroid Disorders

Thyroid Storm

Essentials of Diagnosis

• 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

General Considerations

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.

Causes

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.

Clinical Findings

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.

Symptoms and Signs

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.

Electrocardiographic Findings

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.

Treatment

Emergency Measures

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.

Hormone Release Blockers

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.

Hormone Action Blockers

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

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.

Disposition

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.

Myxedema Coma

Essentials of Diagnosis

• 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])

General Considerations

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%.

Clinical Findings

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.

History

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.

Symptoms and Signs

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.

Laboratory Findings

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.

Imaging

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.

Electrocardiographic Findings

The ECG may show bradycardia, low voltage of the QRS complex in all leads, flattening or inversion of the T waves, and conduction abnormalities.

Treatment

General and Supportive Measures

Stabilization

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.

Fluid Replacement

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.

Other Therapies

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.

Specific Therapy

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.

Disposition

Hospitalization in an intensive care unit is indicated for all patients with myxedema coma.

Adrenal Insufficiency and Crisis (Addisonian Crisis)

Essentials of Diagnosis

• 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

General Considerations

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.

Classification

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.

Clinical Findings

Symptoms and Signs

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.

Laboratory Findings

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.

Imaging

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.

Electrocardiographic Findings

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.

Diagnosis

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.

Treatment

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.

Specific Therapy

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.

Disposition

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.

Pheochromocytoma (Catecholamine Crisis)

Essentials of Diagnosis

• 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

General Considerations

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.

Clinical Findings

Symptoms and Signs

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.

Treatment

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).

Specific Therapy

Phentolamine

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.

Nitroprusside

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

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

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-Blockers

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

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.

Disposition

Hospitalization in an intensive care unit is indicated in all patients with pheochromocytoma.

Pituitary Apoplexy

Essentials of Diagnosis

• 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

General Considerations

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.

Clinical Findings

Symptoms and Signs

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.

Laboratory Findings

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.

Imaging

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.

Treatment

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.

Disposition

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.

Inappropriate Secretion of Antidiuretic Hormone

Essentials of Diagnosis

• 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

General Considerations

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.

Causes

Numerous diseases and drugs can cause SIADH. See Table 43–1.

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.

Clinical Findings

Symptoms and Signs

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.

Laboratory Findings

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.

Treatment

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.

Specific Therapy

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.

Disposition

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.

Diabetes Insipidus

Essentials of Diagnosis

• 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

General Considerations

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.

Causes

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.

Clinical Findings

Symptoms and Signs

ADH Deficiency/Resistance

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.

Laboratory Findings

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.

Imaging

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.

Treatment

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.

Specific Therapy

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.

Disposition

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.