David G. Gardner MD
Francis S. Greenspan MD
Acute or chronic failure of an endocrine gland can occasionally result in catastrophic illness and even death. Thus, it is important to recognize and appropriately manage these endocrine emergencies. In this chapter we shall discuss crises involving the thyroid, anterior pituitary or adrenal glands; diabetes mellitus, and abnormalities in calcium, sodium, and water balance.
Myxedema coma is the end stage of untreated or inadequately treated hypothyroidism. The clinical picture is often that of an elderly obese female who has become increasingly withdrawn, lethargic, sleepy, and confused and then slips into a comatose state. The history from the patient may be inadequate, but the family may report that the patient had thyroid surgery or radioiodine in the past or that she has previously been receiving thyroid hormone therapy. Coma may be precipitated by an illness such a cerebrovascular accident, myocardial infarction, or an infection such as a urinary tract infection or pneumonia. Other precipitating factors include gastrointestinal hemorrhage, acute trauma, excessive hydration, or administration of a sedative, narcotic, or potent diuretic drug. However, myxedema coma is most frequently associated with discontinuation of thyroid hormone therapy by the patient.
The physical findings are not very specific. The patient may be semicomatose or comatose with dry, coarse skin, hoarse voice, thin head and eyebrow hair, possibly a scar on the neck, and slow reflex relaxation time. There is marked hypothermia, with body temperature sometimes falling to as low as 24 °C (75 °F). It is important to look for complicating factors such as pneumonia, urinary tract infection, ileus, anemia, hypoglycemia, or seizures. Often there are pericardial, pleural, or peritoneal effusions. The key laboratory tests are a low free thyroxine (FT4) and elevated TSH. Note that in an emergency situation, serum TSH can be done in 1 hour. If the FT4 is low and the TSH is low-normal, consider central or pituitary hypothyroidism. Pituitary insufficiency can be confirmed with a low serum cortisol, impaired response to the cosyntropin stimulation test, and low FSH and LH. It is essential to check blood gasses, electrolytes, creatinine and an electrocardiogram, in evaluating pulmonary, renal, cardiac and central nervous system status. It may be necessary to differentiate myxedema coma from the “euthyroid sick”syndrome associated with coma due to other causes. These patients may present with a low T3, normal or low TSH, but the free T4 (by dialysis) is normal.
Myxedema coma is a complex problem involving a number or organ systems. The pathogenesis is presented in Figure 24-1. The decrease in serum T4 results in a lowering of intracellular T3. This can directly affect central nervous system function with altered mental status. The decrease in intracellular T3 causes decreased thermogenesis, resulting in hypothermia, which in turn causes decreased central nervous system sensitivity to hypercapnia and hypoxia. The resulting respiratory insufficiency induces cerebral anoxia and coma. At the same time the decreased intracellular T3 results in decreased
cardiac inotropism and chronotropism, decreased sensitivity to adrenergic stimuli, decreased cardiac output, and generalized vasoconstriction. This results in a low-output state which, if untreated, culminates in hypovolemia, decreased blood pressure, and eventually shock and death. Finally, there is a change in fluid balance with increased water retention due to impaired renal perfusion as well as increased vascular permeability. These changes result in effusions and hyponatremia which in turn contribute to the coma.
Figure 24-1. Pathogenesis of myxedema coma. (See text for details.)
Management of myxedema coma involves much more than simply replacing T4 (Table 24-1). The patient is severely ill and usually is admitted to the ICU for intubation and ventilatory support. Oral medications are poorly absorbed (due to ileus), and all medications should be given intravenously. A loading dose of 300–400 ľg of T4 intravenously is given initially to saturate T4 binding sites in plasma binding proteins. The patient is then maintained on 50 ľg of T4 intravenously daily. In addition, small doses of T3 (eg, 10 ľg intravenously every 8 hours) may be given over the first 48 hours, but this is usually not necessary. Water restriction is necessary to correct the hyponatremia, and intravenous glucose will counteract the tendency to hypoglycemia. It is essential to treat precipitating disease, eg, pneumonia or urinary tract infection. The routine use of hydrocortisone is controversial, but it is necessary in patients with hypopituitarism or multiple endocrine gland failure. If the initial serum cortisol is more than
30 ľg/dL, steroid support is probably unnecessary. However, if serum cortisol is less than 30 ľg/dL, cortisol should be given intravenously in a dosage of 50–100 mg every 6 hours for the first 48 hours and the dose then tapered over the next week while the pituitary-adrenal axis undergoes formal testing.
Table 24-1. Management of myxedema coma.
Prior to the recognition of the need for intravenous T4 and for respiratory support, the mortality from myxedema coma was about 80%. Currently, the mortality is about 20% and is mostly due to the underlying or precipitating illness.
Thyroid storm, or thyrotoxic crisis, is an acute life-threatening exacerbation of thyrotoxicosis. It may occur in a patient with a history of Graves' disease who has discontinued antithyroid medication or in a patient with previously undiagnosed hyperthyroidism. The clinical picture is that of an acute onset of hyperpyrexia (with temperature over 40 °C [104 °F]), sweating, marked tachycardia often with atrial fibrillation, nausea, vomiting, diarrhea, agitation, tremulousness, and delirium. Occasionally, the presentation will be “apathetic” without the restlessness and agitation but with symptoms of weakness, confusion, cardiovascular dysfunction, gastrointestinal upset, and hyperpyrexia. Some of the factors that may precipitate thyroid storm are listed in Table 24-2.
The diagnosis is largely based in the clinical findings. Serum T4, free T4, T3, and free T3 are all elevated, and TSH is suppressed. These findings are not different from what is seen in other patients with hyperthyroidism, but the difference is in the setting. It is thought that the pathogenesis of thyroid storm is an exacerbation of thyrotoxicosis due to decreased binding of T4 (associated with saturation of binding sites on thyroxine-binding proteins) with an increase in free T3 and T4, as well as an exaggerated response to a surge of catecholamines that results from the stress of the precipitating event. The cause of death is usually cardiac arrhythmia and failure.
Table 24-2. Thyroid storm—precipitating factors.
The management of thyroid storm is summarized in Table 24-3. Initially it is important to block further synthesis and secretion of thyroid hormone, first with antithyroid drugs and then with iodide. One may give propylthiouracil, 150 mg every 6 hours orally or per rectum, or methimazole, 20 mg every 8 hours orally or per rectum. A few hours after initiation of antithyroid drug therapy, iodides may be started. Traditionally, saturated solution of potassium iodide, 5 drops twice daily, has been used, but currently iopanoic acid in a dose of 0.5 g twice daily orally or intravenously or iohexol 0.6 g (2 mL of Omnipaque 300) intravenously twice daily is the treatment of choice. These drugs will not only inhibit thyroid hormone synthesis but also block the conversion of T4 to T3, lowering the thyroid hormone level in the blood. Additional specific therapy includes β-adrenergic blockade with propranolol, 40–80 mg orally every 6 hours or 0.5–1 mg intravenously every 3 hours, monitoring its effect on cardiac rate. In patients with asthma or heart failure, propranolol
may be contraindicated, but calcium channel blockade with diltiazem may be very helpful. The half-life of glucocorticoids is markedly reduced in severe thyrotoxicosis, so that adrenal support may be very useful. For this purpose, dexamethasone is given in a dosage of 2 mg every 6 hours for 48 hours, followed by tapering of the dose. Finally, cholestyramine or colestipol will bind T4 in the gut during its enterohepatic circulation and may help to bring the circulating level of T4 down more quickly. Supportive therapy includes adequate fluids, oxygen, digoxin for atrial fibrillation or heart failure, parenteral water-soluble vitamins, and a cooling blanket and acetaminophen for hyperpyrexia. Aspirin should be avoided since it will displace T4 from TBG, resulting in an increase in FT4. Phenobarbital may be a useful sedative since it stimulates T4 metabolism via the hepatic microsomal enzyme system. Plasmapheresis or dialysis to remove FT4 has been reported to be useful in nonresponders, but this is rarely necessary.
Table 24-3. Management of thyroid storm.
Therapy for thyroid storm has improved markedly, so that the mortality has dropped from 100% in the 1920s to about 20–30% in recent series. However, since storm is often associated with other underlying medical problems, it still represents a serious medical complication.
THYROTOXIC PERIODIC PARALYSIS
Thyrotoxic periodic paralysis is a rare but frightening thyroid emergency. The usually clinical presentation is of an Asian male with symptoms of untreated hyperthyroidism who awakens at night or in the morning with flaccid paralysis of the lower limbs. Further history reveals that he exercised vigorously or had a large high-carbohydrate meal before retiring. There is no family history of periodic paralysis, but there may be a family history of autoimmune thyroid disease. The paralysis usually involves the lower portion of the body but may involve the arms also. Facial or respiratory muscles are rarely involved. The acute episode may be complicated by extensive paralysis and arrhythmias due to the hypokalemia. The illness has also been reported to occur in Native Americans and patients of Mexican or South American descent.
The diagnosis is based on the absence of a family history of periodic paralysis, the characteristic presentation, the presence of hyperthyroidism due either to Graves' disease or toxic nodular goiter, and usually a low serum potassium level.
The pathogenesis is summarized in Figure 24-2. Thyrotoxicosis, increased β-adrenergic activity, and an assumed genetic predisposition result in increased Na+-K+ ATPase activity with increased intracellular transport of K+. A high-carbohydrate meal with increased insulin secretion, glycogen deposition, vigorous exercise, a high salt intake, and the normal nocturnal potassium flux then drive serum potassium levels even lower, resulting in flaccid neuromuscular paralysis. Note that there is no loss of total body potassium, merely a shift from extracellular to intracellular space.
The management of this problem is presented in Table 24-4. Supplemental potassium should be given orally in a dose of 2 g potassium chloride every 2 hours while monitoring serum K+. Propranolol in doses of 60 mg every 6 hours will block the β-adrenergic stimulation of Na+-K+ ATPase. Antithyroid drug therapy should be started immediately even though it will take time to bring the patient into a euthyroid state. It is particularly important to avoid intravenous potassium, which may
raise total body potassium to toxic levels; intravenous glucose, which will stimulate more insulin secretion and hypokalemia; and β-adrenergic agonists such as isoproterenol, which will promote movement of K+ into the intracellular compartment and exacerbate the problem. With appropriate treatment, the recovery is rapid, and once the thyrotoxicosis is controlled the paralysis will not recur.
Figure 24-2. Pathogenesis of thyrotoxic periodic paralysis. (See text for details.)
Table 24-4. Management of thyrotoxic periodic paralysis.
AMIODARONE INDUCED THYROTOXICOSIS
Amiodarone is a benzofuran derivative that is widely used in the treatment of cardiac arrhythmias. It contains two atoms of iodine per molecule, which represents 37.5% iodine by weight. The compound is stored in adipose tissue and has a half-life in the body of 2–3 months, with gradual and continuous release of iodide. The usual daily maintenance dose of amiodarone of 200–400 mg/d will release 6,000–12,000 ľg of iodine daily, which when compared to the normal daily requirement of about 150 ľg of iodide represents an enormous iodide load.
The structure of amiodarone resembles that of T3, and it is thought that part of the cardiac depressant effect of amiodarone may be due to binding to and blocking the T3 receptor in cardiac muscle. However, the effect of amiodarone on the thyroid gland is different and is due in part to a direct effect of iodine on the thyroid cell—to inhibit or stimulate hormone synthesis—and a cytotoxic effect of amiodarone on the follicular cell—inducing destruction of the cell and release of stored hormone. Thus, the drug may induce hypothyroidism, which is easily managed by thyroxine replacement, or hyperthyroidism, which, because of the underlying heart disease, is much more difficult to manage and represents a true thyroid emergency. Two mechanisms have been suggested to explain the development of hyperthyroidism: (1) The high iodine level in a multinodular gland, or in the gland of a patient with latent Graves' disease, or even in a previously normal gland, can induce hyperthyroidism if the gland fails to develop the Wolff-Chaikoff block. This is the jodbasedow effect (see Chapter 7). (2) The toxic effect of amiodarone itself may cause acute and chronic thyroiditis with release of T4 and T3 into the circulation and severe thyrotoxicosis.
The patient with amiodarone-induced thyrotoxicosis may have been on the drug for months or years. The underlying heart disease gradually worsens with increasingly frequent episodes of arrhythmia and heart failure. At the same time there may be weight loss, heat intolerance, increased nervousness, and marked muscle weakness. On physical examination, one may find nontender nodular or diffuse thyroid enlargement, tachycardia with or without atrial fibrillation, tremor, hyperreflexia, and, occasionally, lid lag and stare. Laboratory findings are unique because amiodarone inhibits the conversion of T4 to T3. Thus, even in the euthyroid patient taking amiodarone, total T4 may be elevated while FT4and TSH will be normal. In the hyperthyroid patient, the FT4 will be markedly elevated and TSH will be less than 0.03 mU/L. Radioiodine uptake in the iodide-loaded patient will be low. It has been difficult to distinguish thyrotoxicosis due to follicular cell hyperfunction from that due to follicular cell destruction. Thyroid ultrasound with color Doppler studies may show increased circulation with hyperfunction and decreased blood flow with thyroiditis. Also, the cytokine IL-6 is low in patients with hyperfunction, whereas it is markedly elevated in patients with thyroiditis.
Management of amiodarone-induced hyperthyroidism is difficult (Table 24-5). Ideally, amiodarone should be discontinued, but often it cannot be stopped because of the underlying heart disease, and even if it is discontinued the iodine load will persist for several months. Further synthesis of T4 should be blocked with methimazole
in a dosage of 40–60 mg/d. Beta-adrenergic blockade should be instituted with propranolol or a similar drug if cardiac status will permit it. Potassium perchlorate in a dosage of 250 mg every 6 hours will block further iodine uptake and lower intrathyroidal iodide content. Aplastic anemia has occurred in patients on high-dose or long-term potassium perchlorate therapy, so that use of this medication has usually been limited to 1 month. Cholestyramine or colestipol in a dosage of 20–30 g/d will bind T4 and T3 in the gut and bring blood levels down more quickly. If there is reason to suspect thyroiditis (elevated serum IL-6, or decreased blood flow on ultrasound), corticosteroid therapy will often yield dramatic results. Prednisone is given in a dosage of 40 mg/d for 1 month, gradually tapering the dose over the following 2 months. If medical therapy is unable to control the disease, thyroidectomy effects a permanent cure and may be used as a last resort.
Table 24-5. Management of amiodarone-induced hyperthyroidism.
ACUTE ADRENAL INSUFFICIENCY
Acute adrenal insufficiency usually occurs as an acute illness in a patient with chronic adrenal insufficiency. The chronic adrenal insufficiency may be primary, due to destruction of the adrenal glands associated with autoimmune adrenalitis or, rarely, tuberculosis or metastatic malignancy. Chronic adrenal insufficiency may also be secondary to pituitary or hypothalamic disease. However, acute adrenal insufficiency may occur with bilateral adrenal hemorrhage in a previously healthy individual during the course of septicemia with diffuse intravascular coagulopathy or in a patient receiving anticoagulant therapy. In the patient with known adrenal insufficiency, an acute crisis may be precipitated by inadvertent omission of medication or by the concurrent development of a precipitating illness such as severe infection, acute myocardial infarction, cerebrovascular hemorrhage or infarction, surgery without adrenal support, or severe acute trauma. Acute adrenal insufficiency may also be precipitated by the sudden withdrawal of steroid therapy in a patient previously on long-term steroid therapy with associated adrenal atrophy (ie, secondary adrenal insufficiency). Finally, administration of drugs impairing adrenal hormone synthesis such as ketoconazole or mitotane—or drugs increasing steroid metabolism such as phenytoin or rifampin—may precipitate an adrenal crisis.
The patient presents with an acute onset of nausea, vomiting, hyperpyrexia, abdominal pain, dehydration, hypotension and shock. A clue to the diagnosis of primary adrenal insufficiency is the presence of pigmentation in unexposed areas of the skin, particularly in the creases of the palms and in the buccal mucosa. The differential diagnosis includes consideration of other causes of cardiovascular collapse, sepsis and intra-abdominal abscess. Failure of the hypotension to respond to pressors is suggestive of adrenal insufficiency and is an indication for a trial of glucocorticoid therapy.
Primary adrenal insufficiency is characterized by hyponatremia and hyperkalemia. However, in situations of adrenal crisis, the hyponatremia may be obscured by dehydration. Random serum cortisol determinations are not helpful unless the levels are very low (< 5 ľg/dL [138 nmol/L]) during a period of great stress. The key diagnostic test is failure of serum cortisol to rise above 20 ľg/dL (552 nmol/L) 30 minutes after intravenous injection of 0.25 mg synthetic ACTH (cosyntropin) (see Chapter 9 for details). Basal serum ACTH will be elevated (> 52 pg/mL [> 11 pmol/L]) in patients with primary adrenal insufficiency but not in patients with secondary adrenal insufficiency due to pituitary or hypothalamic disease. CT scan or sonogram of the abdomen will reveal adrenal enlargement in patients with adrenal hemorrhage, active tuberculosis, or metastatic malignancy.
The management of adrenal crisis is outlined in Table 24-6. Hydrocortisone should be administered in a dosage of 100 mg intravenously followed by 50 mg every 4 hours thereafter. Fluids and Na+ should be replaced with several liters of 5% glucose in normal saline. After the first 24 hours, the dose of intravenous hydrocortisone can be slowly reduced, but intravenous doses should be given at least every 6 hours because of the short half-life (1 hour) of hydrocortisone in the circulation. When the patient can tolerate oral feedings,
hydrocortisone can be given orally, but the first oral dose should overlap the last intravenous dose. Alternatively, hydrocortisone can be administered as a continuous infusion at the rate of 10 mg/h for the first 24 hours, followed by a gradual decrease in the dose. Mineralocorticoid is not necessary during the acute replacement period since enough salt and glucocorticoid are being administered to accommodate the mineralocorticoid deficiency. However, in patients with chronic primary adrenal insufficiency, mineralocorticoid supplementation is necessary when shifting to an oral maintenance program (see Chapter 9). After steroid therapy has been instituted, it is extremely important to evaluate and treat the illness that may have precipitated the acute crisis—infection, myocardial infarction, etc.
Table 24-6. Management of adrenal crisis.
Prevention of acute adrenal insufficiency in patients with chronic adrenal insufficiency exposed to stress (eg, severe infection) can be achieved using intravenous hydrocortisone in dosages as outlined above or by administration of dexamethasone sodium phosphate, 4 mg intramuscularly every 24 hours for two doses. Dexa methasone would replace glucocorticoids but not mineralocorticoid and would not be adequate in the presence of severe dehydration and hyponatremia.
Pituitary apoplexy is a rare but frightening syndrome of violent headache, visual and cranial nerve disturbances, and mental confusion, resulting from hemorrhage or infarction of the pituitary gland.
Pituitary apoplexy usually occurs as a sudden crisis in a patient with a known or previously unrecognized pituitary tumor. However, it may occur in a normal gland during or after parturition or associated with head trauma or anticoagulation therapy. The patient presents with severe headache and visual disturbances, often a bitemporal hemianopia due to compression of the optic chiasm. There may be oculomotor defects, either bilateral or unilateral. Often there are meningeal symptoms with stiff neck and mental confusion, so that the differential diagnosis includes subarachnoid hemorrhage, meningitis, or brain tumor. Finally there may be symptoms of acute secondary adrenal insufficiency with nausea, vomiting, hypotension, and collapse.
The neurologic problem is best approached with a CT scan of the head, including the anterior pituitary gland. Pituitary enlargement and signs of hemorrhage are diagnostic. Hormonal studies are of academic interest only since therapy would include glucocorticoid support regardless of the acute findings. After appropriate acute therapy, evaluation of anterior and posterior pituitary function may be indicated because of the possibility of permanent pituitary destruction.
Management involves both hormonal and neurosurgical therapy. High-dose dexamethasone, 4 mg twice daily, will provide both glucocorticoid support and relief of cerebral edema. Transsphenoidal pituitary decompression will provide dramatic relief and often preserves some normal pituitary function. After the acute episode has subsided, the patient must be evaluated for the possibility of multiple pituitary deficiencies (see Chapter 5).
Diabetic ketoacidosis occurs in a setting of absolute or relative insulin deficiency. Specific clinical settings should generate a high index of suspicion for the disorder. Interruptions of normal insulin delivery due to purposeful reduction in insulin dosage or interference with the delivery system (eg, kinking in pump tubing) are frequent precipitating events, as are reduced insulin sensitivity in the setting of systemic infection, myocardial infarction, burns, trauma, or pregnancy. In a significant percentage of patients, diabetic ketoacidosis is the presenting feature of diabetes. In these instances, clinical suspicion and accurate interpretation of the initial laboratory studies will usually lead to the correct diagnosis.
Diabetic ketoacidosis is characterized metabolically by two prominent features: hyperglycemia and ketoacidosis (see Chapter 17). Patients with diabetic ketoacidosis present with evidence of volume contraction (eg, dry mucous membranes, thirst, orthostatic hypotension) and labored breathing (Kussmaul respiration) related to the underlying acidosis. The breath often has a fruity odor, reflecting the presence of acetone. Patients may have abdominal pain mimicking an acute abdomen, nausea, and vomiting. The latter symptoms may be related to elevated prostaglandins that accrue in the presence of insulin deficiency. Presentation may be dominated by symptoms of the precipitating illness (eg, urinary tract infection, pneumonia, or myocardial infarction).
Plasma glucose levels are elevated, usually to over 250 mg/dL. This reflects impairment in glucose utilization (see above), increased gluconeogenesis and glycogenolysis,
and reduced renal clearance of glucose in the setting of decreased glomerular filtration rate (GFR). Osmotic diuresis related to glucose filtration results in reduction in intravascular volume and depletion of total body water, sodium, potassium, phosphate, and magnesium. In general, the relative depletion of water is roughly twice that of the solutes it contains. Hypertonicity in the extracellular fluid compartment, while typically not as severe as that seen in hyperosmotic nonketotic coma (see below), can be significant. Calculated plasma osmolalities greater than 340 mosm/kg are associated with coma. Plasma osmolality—rather than acidemia—correlates most closely with mortality in diabetic ketoacidosis (Figure 24-3).
Arterial blood pH is low and, in the absence of coexistent respiratory disease, is partially compensated by a reduction in PCO2. The acidosis is metabolic in origin and accompanied by an anion gap which is calculated by subtracting the combined concentrations of chloride and bicarbonate from serum sodium concentration. Anion gaps greater than 12 mEq/L are considered abnormal. Keto acids account for most of the unmeasured anions that generate the abnormal gap, though under conditions of extreme volume contraction and hypoperfusion lactate accumulation may also contribute. Levels of serum and urinary ketones (measured using the nitroprusside reagent) are typically high in diabetic ketoacidosis. It should be recalled, however, that this reagent reacts strongly only with acetoacetate, less strongly with acetone (which is not a keto acid and does not contribute to the anion gap), and not at all with β-hydroxybutyrate. Thus, paradoxically, the most extreme levels of ketoacidosis may be accompanied by relatively modest levels of ketones measured by this method. As a corollary of this, resolution of severe diabetic ketoacidosis may be linked to transient increases in measurable ketone levels as β-hydroxybutyrate is converted to the more readily detectable acetoacetate.
Serum sodium levels may be high, normal, or low, but in all instances total body sodium is depressed. Estimates
of depletion range from 7 mEq to 10 mEq/kg body weight. As blood glucose levels rise in diabetic ketoacidosis, they create an osmotic gradient that draws water, as well as intracellular solutes, into the extracellular space. This results in moderate hyponatremia, which can be corrected to account for the dilutional effect of the transmembrane flux of water by adding 1.6 mEq/L to the sodium concentration for every 100 mg/dL increment in plasma glucose above a basal concentration of 100 mg/dL (see below). The decrease in serum sodium partially offsets the increase in tonicity that accompanies the elevation in serum glucose. This results in a net increase in plasma osmolality of 2 mosm/kg H2O per 100 mg/dL elevation in serum glucose.
Figure 24-3. A: Relationship between state of consciousness and blood pH in patients with diabetic ketoacidosis. B: Relationship between state of consciousness and plasma osmolality in diabetic ketoacidosis. Note that the state of consciousness correlates with plasma osmolality rather than blood pH. (Reproduced, with permission, from Fulop M et al: Ketotic hyperosmolar coma. Lancet 1973;2:635.)
Total body potassium levels are also severely depleted in diabetic ketoacidosis to an average of 5–7 mEq/kg body weight. This results from a number of factors, including exchange of intracellular potassium for extracellular hydrogen ion, impaired movement of K+ into cells in the insulinopenic state, and increased urinary potassium excretion secondary to the osmotic diuresis and, in those instances where intravascular volume contraction is present, secondary hyperaldosteronism. Serum potassium levels may be high, normal, or low depending on the severity and duration of diabetic ketoacidosis, the status of extracellular fluid volume, and the adequacy of renal perfusion and excretory function. A low serum potassium at presentation generally indicates severe potassium deficiency and, in the presence of adequate renal function, is an indication for early and aggressive repletion (see below). Potassium depletion can result in muscle weakness and cardiac arrhythmias, including ventricular fibrillation.
The H+ excess in diabetic ketoacidosis titrates endogenous buffer systems including serum bicarbonate, resulting in reduction in concentrations of the latter. Chloride levels may also be low, reflecting the osmotic diuresis alluded to above. Ketone bodies have been estimated to account for one-third to one-half of the osmotic diuresis seen in diabetic ketoacidosis. Electrolyte depletion is further aggravated by the obligate cation (eg, sodium) excretion required to maintain electrical neutrality. In patients who have maintained adequate hydration during the development of diabetic ketoacidosis or in those who are aggressively resuscitated with normal saline, chloride levels may be elevated and the anion gap narrowed. This reflects the enhanced clearance of the keto anions in the kidney, converting the system from an anion gap acidosis to a hyperchloremic, nongap acidosis (ie, the hydrogen ion excess persists despite clearance of the anion). Since the excreted keto anions represent a lost source for bicarbonate regeneration, correction of the hyperchloremic acidosis may proceed slowly.
Total body magnesium and phosphate levels are also depleted by the osmotic diuresis in diabetic ketoacidosis. Phosphate depletion is amplified by diffusion of the anion from the intracellular to the extracellular compartment in the absence of insulin. Phosphate depletion can result in muscle weakness, rhabdomyolysis, hemolytic anemia, respiratory distress, and altered tissue oxygenation (due to reduction in 2,3-diphosphoglycerate levels in the red blood cell).
Treatment of diabetic ketoacidosis is focused on two major objectives. The first is restoration of normal tonicity, intravascular volume, and solute homeostasis. The second is correction of the insulinopenic state with suppression of counterregulatory hormone secretion, glucose production, and ketogenesis and improved utilization of glucose in target tissues. The flow outline in Table 24-7 provides a general approach to the management of this disorder.
Because depletion of intracellular and extracellular fluids may be severe in diabetic ketoacidosis (typically in the range of 5–10 L), early and aggressive resuscitation with fluids is mandatory. This is usually initiated with administration of 1–2 L of isotonic normal saline (0.9% NaCl) over the first hour of therapy. As intravascular volume is restored, renal perfusion will increase, with a consequent increase in renal clearance of glucose and a fall in plasma glucose levels. If volume contraction is severe, a second liter of normal saline can be administered. If not, half-normal saline (0.45% NaCl) can be initiated at a rate of 250–500 mL/h depending on intravascular volume status. Since water is typically lost in excess of solute in diabetic ketoacidosis, half-normal saline will address both volume depletion and the hypertonicity. It has been suggested that approximately half of the total fluid deficit should be corrected within the first 5 hours of therapy. Half-normal saline can be continued until intravascular volume has been restored or plasma glucose levels fall to 250 mg/dL, at which point D5W should be started. The latter maneuver reduces the likelihood of insulin-induced hypoglycemia and avoids the theoretical complication of cerebral edema due to osmotically induced fluid shifts from plasma into the central nervous system. This complication is, in fact, seen rarely in adults and uncommonly in children with diabetic ketoacidosis.
Once fluid resuscitation has been initiated, insulin should be administered. Only short-acting (ie, regular)
insulins should be used. While a number of different insulin regimens have demonstrated efficacy in the treatment of diabetic ketoacidosis, a commonly used regimen includes a loading dose (10–20 units) of regular insulin intravenously followed by a continuous infusion at a rate of 0.1 unit/kg/h. This regimen provides plasma insulin levels in a physiologic range (100–150 mU/mL) with minimal risk of hypoglycemia or hypokalemia. It restores plasma glucose levels at rates equivalent to those obtained with regimens using higher insulin doses. Plasma glucose levels should fall at a rate of 50–100 mg/dL/h. Failure to achieve this end point over a 2-hour period should lead to doubling of the infusion rate with reevaluation an hour later. When plasma glucose concentrations reach 250 mg/dL, D5W is begun to prevent hypoglycemia (see above). The insulin infusion is continued to suppress ketogenesis and allow restoration of normal acid-base balance.
Table 24-7. Management of diabetic ketoacidosis.
As noted above, total body potassium stores are depleted in diabetic ketoacidosis and plasma K+ levels fall with treatment. Repletion of K+is almost always indicated in management of diabetic ketoacidosis (one notable exception being diabetic ketoacidosis that occurs in the setting of chronic renal insufficiency); however, the timing of repletion varies as a function of the plasma K+ level. If the initial K+ level is less than 4 mEq/L, K+ depletion is severe and repletion should begin with the first administration of parenteral fluids if renal function is adequate. Twenty milliequivalents of potassium chloride can be added to the first liter of normal saline if the serum K+ is in the 3.5–4 mEq/L range; 40 mEq should be added for K+ levels less than 3.5 mEq/L. Particular attention should be devoted to these latter patients, since K+levels may plummet to very low levels with initiation of insulin therapy. The general goal of therapy should be to keep the K+ in a near-normal range. This may require several hundred milliequivalents of potassium chloride administered over several days.
The administration of bicarbonate in the setting of diabetic ketoacidosis has been controversial. Acidosis, in addition to increasing ventilatory work (Kussmaul's respiration), may also suppress cardiac contractile function. Therefore, restoration of normal pH would seem to make sense in the setting of diabetic ketoacidosis. However, there is considerable risk associated with the use of sodium bicarbonate in this setting, including paradoxical acidification of the central nervous system due to the selective diffusion of CO2 versus HCO3- across the blood-brain barrier and an increase in intracellular acidosis, which may worsen rather than ameliorate cardiac function. Volume overload related to the high tonicity (44.6–50 mEq/50 mL) of the bicarbonate solution, hypokalemia resulting from overly rapid correction of the acidosis, hypernatremia, and rebound alkalosis are also potential complications of bicarbonate therapy. In general, pH of 7.0 or greater is not life-threatening to the average patient with diabetic ketoacidosis and will resolve with appropriate volume expansion and insulin therapy. For pH < 7.0, many clinicians would argue for a limited administration of sodium bicarbonate. If bicarbonate is used, careful patient monitoring looking for alterations in mental status or cardiac decompensation is indicated. The goal of therapy should be to maintain pH > 7.0, not to return pH to normal.
Similarly, phosphate administration, once considered a key component in the management of diabetic ketoacidosis, has come under closer scrutiny. Phosphate depletion definitely occurs in diabetic ketoacidosis for the reasons outlined above, and in the past repletion of phosphate (much of it as potassium phosphate salts) has
been advocated to forestall the development of muscle weakness and hemolysis and to promote tissue oxygenation through generation of 2,3-diphosphoglycerate in erythrocytes. However, the administration of phosphate salts has been associated with the development of hypocalcemia and deposition of calcium phosphate precipitates in soft tissues, including the vasculature. Thus, in general, parenteral phosphate repletion is not routinely provided for diabetic ketoacidosis patients unless plasma phosphate falls to very low levels (< 1 mmol/L). In this case, 2 mL of a mixture of KH2PO4 and K2HPO4 solution, containing 3 mmol of elemental phosphorus and 4 mEq of potassium, may be added to 1 L of fluids and introduced over 6–8 hours. In no instance should all K+ repletion be in the form of potassium phosphate salts. In general, renewal of food ingestion and insulin therapy will complete restoration of total body phosphate stores and return plasma phosphate levels to normal over a period of several days.
Finally, it is necessary to actively seek out and treat the precipitants of diabetic ketoacidosis when they are identified. This includes appropriate cultures of urine and blood (and cerebrospinal fluid, if indicated) and empiric antibiotic therapy directed against the most likely pathogenic organisms (pending the results of the cultures). The presence of fever is typically a good marker for infection or other inflammatory process since it is not a feature of diabetic ketoacidosis per se. Elevated white blood cell counts, on the other hand, are frequently seen with diabetic ketoacidosis alone. Other precipitants should also be looked for. Myocardial infarction, which is often clinically “silent” in diabetic patients, is an uncommon but life-threatening precipitant of diabetic ketoacidosis in patients with established diabetes.
Aggressive resuscitation with isotonic or hypotonic fluids is a theoretical but uncommon cause of fluid overload during management of diabetic ketoacidosis. Careful attention to the cardiovascular examination, chest x-ray, and urine output should aid in preventing this complication.
Hypoglycemia is relatively rare in the current era given the low doses of insulin used in management and appropriate initiation of glucose-containing fluids as plasma glucose levels fall below 250 mg/dL.
Cerebral edema due to rapid correction of plasma hypertonicity has usually been reported with plasma glucose levels below 250 mg/dL. Clinically significant cerebral edema is relatively uncommon in adult patients. Milder forms of cerebral edema have been noted in many patients being treated for diabetic ketoacidosis but have not been strongly correlated with changes in extracellular tonicity. At present, in a symptomatic adult patient, it would appear prudent to treat hypertonicity exceeding 340 mosm/kg aggressively with hypotonic fluids to avoid complications related to plasma hyperviscosity. Further correction from that point to normal plasma osmolality (about 285 mosm/kg) can probably be accomplished in slower fashion over several days. Cerebral edema occurs in 1–2% of children with diabetic ketoacidosis, frequently with devastating results. Approximately one-third of children with clinically significant cerebral edema will die during the acute illness, and another third will sustain permanent neurologic impairment. Cerebral edema in children may be associated with high initial rates of fluid resuscitation (> 4 L/m2/d) and rapid falls in plasma sodium (or corrected sodium) concentration, though it can occur in clinical settings without an apparent cause. In the absence of definitive trial data to guide therapy, lower rates of fluid administration (< 2.5 L/m2/d) with volume resuscitation spread over a longer time interval would seem appropriate if the clinical situation permits. When signs of cerebral edema appear—deterioration in level of consciousness, focal neurologic signs, hypotension or bradycardia, sudden decline in urine output after an initial period of apparent recovery following treatment for diabetic ketoacidosis—fluid administration should be reduced and mannitol (0.2–1 g/kg intravenously over 30 minutes) should be administered with repetition at hourly intervals based on response. CT or MRI scan of the brain can be done once therapy has been initiated to confirm the diagnosis. Consideration can also be given to mechanical hyperventilation to reduce PCO2 and in that way decrease intracranial pressure.
Patients with diabetic ketoacidosis are also prone to develop acute respiratory distress syndrome (ARDS), presumably reflecting the sequelae of a damaged pulmonary endothelium and elevated capillary hydrostatic pressures following fluid resuscitation. Patients who present with rales at the time of initial diagnosis may be at higher risk for the development of this complication. Patients may also be at increased risk for development of pancreatitis as well as systemic infection, including fungal infections (eg, mucormycosis).
Abdominal pain and gastric stasis seen in diabetic ketoacidosis may put a semistuporous patient at risk for aspiration. Patients who are felt to be at risk with regard to airway protection should have a nasogastric tube in place for evacuation of stomach contents.
Finally, patients with diabetic ketoacidosis are at risk for recurrence of the disorder if insulin is withdrawn prematurely. The current infusion protocols, because they raise plasma insulin only to physiologic levels, have
a very short half-life for control of blood glucose and ketogenesis. Premature cessation of insulin therapy before depot insulin (eg, NPH) can exert its effect may allow the patient to regress into ketoacidosis. To preclude this possibility, subcutaneous regular and intermediate-acting insulin should be provided on the morning when feeding is to be resumed. The insulin drip should be continued for 1 hour following this injection to provide coverage until the depot insulin effect comes on board.
NONKETOTIC HYPEROSMOLAR COMA
Hyperosmolar nonketotic coma, like diabetic ketoacidosis, is a consequence of uncontrolled diabetes mellitus; however, there are a number of features of this disorder which clearly distinguish it from diabetic ketoacidosis. First, plasma glucose levels in ketoacidosis are usually in the 250–400 mg/dL rather than the 700–1000 mg/dL range that can be seen with hyperosmolar nonketotic coma. Second, ketosis is rare in hyperosmolar nonketotic coma. Circulating insulin levels are probably adequate to control ketogenesis in the latter, though they are incapable of establishing euglycemia. Third, hyperosmolar nonketotic coma tends to occur more commonly in the elderly population, often those receiving chronic care who have difficulty reporting symptoms or maintaining adequate hydration. Like diabetic ketoacidosis, hyperosmolar nonketotic coma may present as the first manifestation of diabetes mellitus. Mortality remains high in hyperosmolar nonketotic coma (perhaps as high as 20% versus 1–2% in diabetic ketoacidosis); in both cases, mortality increases with age.
Precipitants of hyperosmolar nonketotic coma include many of the same complicating illnesses that lead to diabetic ketoacidosis. Infections (pneumonias are said to be the most common precipitating infection in 40–60% of cases, with urinary tract infections representing 5–16% of the total), myocardial infarction, cerebrovascular accident, pancreatitis, burns, heat stroke, and endocrine dysfunction (eg, Cushing's syndrome, acromegaly) are frequently associated with hyperosmolar nonketotic coma. Administration of hyperosmolar fluids (eg, tube feedings, total parenteral nutrition, peritoneal dialysis) can precipitate hyperosmolar nonketotic coma, as can medications that impair insulin secretion or action (eg, β-adrenergic blocking agents, phenytoin, corticosteroids, or diazoxide). Diuretics—particularly thiazides—can reduce intravascular volume, reduce glomerular filtration rate (the dominant mechanism for glucose clearance), and activate counterregulatory hormones (eg, catecholamines), all of which promote development of the hyperosmolar state. Finally, limited access to free water intake, particularly in patients who are dependent on others for water consumption, is a major determinant in the progression of the hyperosmolar state.
These factors interact in a highly variable fashion to promote the hyperosmolar state associated with hyperosmolar nonketotic coma. In a typical scenario, poorly controlled diabetes—or undiagnosed diabetes presenting for the first time—is aggravated by coincident infection (or other precipitant). This results in significant hyperglycemia as the balance of counterregulatory hormones versus insulin shifts in favor of the former. Hyperglycemia promotes increased insulin resistance and further elevations in blood glucose levels. This leads to an osmotic diuresis in the kidney as plasma glucose levels exceed the threshold for tubular reabsorption. This threshold typically increases with age, leading to even higher plasma glucose levels in the elderly. The osmotic diuresis results in a progressive loss of water and, to a lesser degree, solutes (eg, Na+, Cl-, K+) in the urine. As with diabetic ketoacidosis, the water loss is “buffered” initially by an osmotically driven movement of water out of the cells into the extracellular compartment. As the diuresis continues, however, contraction of intravascular volume ensues and glomerular filtration falls, shutting off the body's primary mechanism for controlling plasma glucose levels in this setting. Glucose levels increase dramatically, often to extraordinarily high levels (normal renal excretory function generally limits elevations in plasma glucose to 500–600 mg/dL). Nausea and vomiting, related to the infection, uremia or hyperosmolality per se, may further aggravate intravascular volume contraction. Factor into this an elderly patient with age-dependent suppression of the thirst mechanism and difficulty communicating a sense of thirst to caregivers and the stage is set for severe dehydration and the hyperosmolar state of hyperosmolar nonketotic coma.
The diagnosis is usually based on strong clinical suspicion and laboratory assessments of plasma glucose levels and serum osmolality. The typical patient may be a known type 2 diabetic (often taking an oral hypoglycemic agent) who has shown a subtle but steady deterioration over several days immediately preceding admission. The patient demonstrates significant dehydration, somnolen ce, stupor, or coma. The course may be marked by a precipitating illness, as described above. Tachycardia and low-grade fever may be present, but blood pressure and respiratory rate are normal. Urine output typically is reduced to low levels as the hyperosmolar state progresses.
The clinical presentation is usually dominated by the central nervous system findings. Patients with hyperosmolar nonketotic coma are lethargic and weak, with an altered sensorium. True coma is less common and usually does not appear until plasma osmolality is significantly elevated (see below). Hallucinations are occasionally present, and seizures may be occur in 25% of patients with hyperosmolar nonketotic coma. Focal findings suggesting cortical ischemia may also be seen. A minority of these reflect true cerebrovascular accidents related to thromboembolic complications (see below). Most represent low-flow states in areas of baseline cerebrovascular ischemia and recover with correction of the metabolic abnormality.
Plasma glucose levels are typically high (occasionally > 1000 mg/dL). Measured plasma osmolality is often > 350 mosm/kg. These measurements usually include the contribution of urea, which may accumulate to significant levels in the setting of volume contraction and prerenal azotemia; however, urea does not contribute to the osmotic force that drives fluid movement across cellular membranes since it is freely permeable in these membranes and distributes itself in equivalent concentrations in the intracellular and extracellular compartments. A more accurate measure of the effective osmolality is obtained from the following formula:
where Na+ and glucose are the concentrations of sodium ion and glucose, respectively. Normal effective osmolalities are in the range of 275–295 mosm/kg. Hyperosmolar nonketotic coma is diagnosed with an effective osmolality > 320 mosm/kg, while coma itself is seen with osmolalities > 340 mosm/kg. Coma at effective osmolalities ≤ 340 mosm/kg suggest some other cause (eg, meningitis, cerebrovascular accident, or other metabolic abnormality).
Anion gap acidosis is usually not a major component of hyperosmolar nonketotic coma since ketogenesis is suppressed (see above). If gap acidosis is present, it may suggest lactate accumulation due to tissue hypoperfusion, low-output state or metformin toxicity, or coexistent renal failure or toxic ingestion. Measurement of serum lactate levels, standard renal function tests, or a screen for toxic substances in blood (if a suggestive history is obtained) should help to discriminate among these possibilities.
Therapy is in some ways similar to that for diabetic ketoacidosis except that there is less concern about correction of the acidosis, which is mild or nonexistent with most conventional cases of hyperosmolar nonketotic coma, and greater emphasis is placed on restoration of intravascular volume and serum osmolality.
Resuscitation of intravascular volume is initiated with parenteral fluids. One to two liters of normal saline are administered over the first hour. If the patient is profoundly hyperosmolar (> 330 mosm/L), half-normal saline (0.45% NaCl) should be substituted for normal saline. Volume status is reassessed based on blood pressure, urine output, central venous pressure, or pulmonary capillary wedge pressure, if available. If volume contractions persist, normal saline (or half-normal saline if hypertonicity persists) can be continued at a rate of 1 L/h. Once blood pressure and urine output have been restored, hypotonic fluids (eg, half-normal saline) can be substituted for isotonic saline at a rate of 250–500 mL/h depending on the need for continued volume resuscitation. The total free water deficit can be approximated using the following formula:
where plasma osmolality is in milliosmoles per kilogram, body weight in kilograms, and water deficit in liters. Fluid rates should be adjusted to correct half of the free water deficit in the first 12 hours and the remainder over the ensuing 24–36 hours. As with diabetic ketoacidosis, glucose-containing fluids (eg, D5W) should be started when plasma glucose levels fall to 250 mg/dL.
Insulin therapy is of secondary importance in the management of hyperosmolar nonketotic coma. It is imperative that insulin therapy not be initiated until volume resuscitation is well under way (eg, following 1–2 L of crystalloid). Insulin will promote movement of glucose, electrolytes, and water into the intravascular compartment. In the absence of adequate volume resuscitation, this can lead to hypotension and cardiovascular collapse. Therapy should be initiated with a loading dose of 10–20 units intravenously followed by a drip delivering 0.1 units/kg/h. Conversion back to the outpatient regimen once the acute event has resolved can be accomplished using a strategy similar to that outlined above for diabetic ketoacidosis.
Electrolytes (ie, Na+, K+, Cl-, PO43-, and Mg2+) are significantly depleted in hyperosmolar nonketotic coma due to the osmotic diuresis. These should be repleted as needed (beginning with the first liter of fluids if necessary). Once again, parenteral phosphate should be administered with care, keeping serum phosphate above 1 mg/dL until feeding can reestablish phosphate balance.
- THROMBOEMBOLIC EVENTS
Coagulopathies related to increased platelet aggregation, hyperviscosity of circulating blood, or disseminated intravascular coagulation can develop in hyperosmolar nonketotic coma. The most appropriate therapy is resuscitation of intracellular volume and treatment of systemic infections. Focal neurologic findings that fail to improve with fluid resuscitation should be further investigated with appropriate consultation and imaging studies, if indicated. Some investigators have recommended low-dose heparin anticoagulation in patients with hyperosmolar nonketotic coma to guard against thromboembolic sequelae. If such therapy is initiated, patients should be closely monitored for development of gastrointestinal bleeding.
- CEREBRAL EDEMA
This is a serious—though fortunately uncommon—complication of fluid resuscitation in hyperosmolar nonketotic coma (and diabetic ketoacidosis; see above). It occurs more commonly in children than in adults and frequently follows an overly aggressive management strategy involving administration of large amounts of parenteral fluids. The pathogenesis is not completely defined but probably relates to the increase in cortical capillary hydrostatic pressure and the osmotic gradient engendered by the aggressive use of hypotonic fluids in this setting. Cerebral edema rarely appears with serum glucose levels above 250 mg/dL. Appropriate introductions of glucose-containing fluids into the management strategy when plasma glucose approaches this level is an effective way to guard against this complication.
Clinically, brain edema develops after an initial period of improvement. It is often heralded by the development of headache, altered mental status, and seizure activity. If untreated, this can progress to herniation, with respiratory arrest and death. Recognition of the syndrome and appropriate treatment with mannitol, dexamethasone, and furosemide can be life-saving in this setting.
Severe hypercalcemia, defined arbitrarily as a total Ca2+ > 14 mg/dL, usually occurs in the setting of a known hypercalcemic illness but may represent the initial manifestation of such an illness. Patients present initially with polyuria and polydipsia and, with a more protracted course, develop evidence of intravascular volume contraction with decreased urine output. Alterations in the sensorium dominate the clinical picture and range from behavioral changes and drowsiness to stupor and coma. Bradyarrhythmias and heart block are major cardiac sequelae of hypercalcemia. Hypercalcemia also potentiates digoxin activity, increasing the risk of cardiac glycoside toxicity. Gastrointestinal complaints are prominent. Anorexia, nausea, and vomiting, which further aggravates the volume contraction, are frequently present. Abdominal pain may be of sufficient intensity to mimic an acute abdomen.
Most chronic hypercalcemia is caused by primary hyperparathyroidism and is usually detected as a result of routine laboratory screening. Cancer-related hypercalcemia, most of which is caused by parathyroid hormone-related protein (PTHrP), is a less frequent but important cause of chronic hypercalcemia. In acute hypercalcemic crises, malignancy emerges as the major cause of the elevations in serum calcium. Other causes of hypercalcemia (eg, vitamin D intoxication, thiazides, or Addison's disease) are either too uncommon or cause such small increments in serum calcium that they rarely need to be considered in the differential diagnosis.
Hypercalcemia due to any cause creates a state of nephrogenic diabetes insipidus by uncoupling vasopressin from its receptor-effector system in the kidney (Table 24-8). This results in a water diuresis that eventually promotes intravascular volume contraction and reduced glomerular filtration rate, effectively suppressing the only route of egress for calcium mobilized from bone or transported across the gut lumen. Thus, volume contraction is in large part responsible for the very high levels of serum calcium found in hypercalcemic crisis. By inference, resuscitation of intravascular volume (see below) represents an excellent initial intervention to improve renal perfusion and tubular clearance of Ca2+.
Table 24-8. Pathogenesis of hypercalcemic crisis.
Hypercalcemic crisis should be considered in any patient with disseminated malignancy, particularly epidermoid carcinomas of the head, neck, and lung. This is especially true when there is a change in the patient's mental status or general clinical condition that cannot be explained by tumor progression, infection, or other metabolic abnormality (eg, uremia). It should also be considered in patients with known primary hyperparathyroidism, particularly in a clinical setting characterized by vomiting, diarrhea, or dehydration (eg, due to thiazide therapy).
The diagnosis is confirmed by measurement of a total or ionized serum calcium level. The latter may be preferable in the presence of low serum albumin, the predominant Ca2+-binding protein in blood, since hypoalbuminemia may mask an elevation in the free fraction if only total calcium levels are assessed. A convenient measure for adjusting total calcium measurements for the presence of hypoalbuminemia is to increase the total calcium by 0.8 mg/dL for each 1 g/dL decrease in serum albumin, based on a normal albumin level of 4 g/dL. The adjusted calcium does not always correlate with the measured ionized calcium, however, and should not be relied upon for more than a rough estimate of the free calcium fraction, particularly if ionized calcium measurements are available.
On the initial presentation with hypercalcemia, plasma samples should be sent for measurement of PTH (preferably using one of the newer immunoradiometric assays that measure only the bioactive, intact hormone), PTHrP, and, if the clinical setting is suggestive, 25-hydroxycholecalciferol or 1,25-dihydroxycholecalciferol levels. Primary hyperparathyroidism is a common disease, and even in a patient with known malignancy it should be excluded as a potentially curable cause of the hypercalcemia.
Intravenous fluids represent the first avenue of approach for management of severe hypercalcemia (Table 24-9). Normalization of intravascular volume will improve GFR and increase renal excretion of calcium. Sodium and calcium handling are closely linked in the distal nephron. Fluid resuscitation with normal saline (0.9% NaCl) both restores GFR and promotes natriuresis and calciuresis by flooding transporter mechanisms responsible for sodium and calcium handling in the distal nephron. Five hundred to 1000 milliliters of normal saline is given over the first hour, with rates of 250–500 mL/h thereafter depending on the state of volume contraction. The latter can be assessed based on clinical examination, urine output, and assessment of renal function. Several liters of fluid are frequently required before intravascular volume is restored. Continued infusions should be matched with urine outputs to avoid fluid overload. Loop diuretics (eg, furosemide) may be used to accomplish this in patients with an underlying predilection toward fluid retention (eg, congestive heart failure). Saline and loop diuretics can increase urinary calcium excretion by as much as 800 mg/d. This is typically accompanied by a moderate but significant reduction in serum calcium levels (1–3 mg/dL). Careful attention should be devoted to detection of signs of fluid overload. Potassium and magnesium depletion related to the diuresis should be corrected. If loop diuretics are used, it is important that the volume of normal saline administered should at least match urine output. Diuretic-induced volume contraction may lead to reduced GFR and worsening hypercalcemia.
Table 24-9. Therapy for hypercalcemic crisis.
At this point, more definitive and specific therapy should be introduced. Severe hypercalcemia is almost always a result of increased mobilization of calcium from bone. Therefore, most effective therapies for hypercalcemia have been directed against the osteoclasts of bone. Bisphosphonates represent the mainstay of therapy. Pamidronate administered at a dose of 60–90 mg in 250 mL of saline over 24 hours is effective in reducing serum calcium levels, often into the normal range. The effect can take 2–4 days to peak and the duration of the response is variable, lasting from 1 week to several months. Retreatment for recurrent hypercalcemia is usually successful. Side effects of therapy include inflammation at the infusion site, low-grade fever, and transient depression of serum calcium, phosphate, and magnesium. Bisphosphonates derive additional attractiveness from their efficacy in controlling
pain and fracture in osteolytic metastases from breast cancer. The mechanism here is not completely understood but may relate to suppression of tumor-induced osteoclastic activity in the neighborhood of the metastases. Etidronate, a first-generation bisphosphonate, has been used parenterally to manage hypercalcemia of malignancy. In general, it is less effective than pamidronate, and it has largely been supplanted by the newer-generation aminobisphosphonates.
Calcitonin has a long history of use in the management of hypercalcemia. It has a direct effect on the osteoclast to suppress bone resorption. It is given either subcutaneously or intramuscularly at a dose of 2–4 units/kg body weight every 6–12 hours after administration of a test dose to exclude hypersensitivity to the drug. In general, the response to calcitonin, which should be noted after 6–12 hours, is modest in magnitude (decrease in serum calcium levels of 1–2 mg/dL) and declines with increasing duration of therapy (tachyphylaxis). Coadministration of glucocorticoids with calcitonin may limit this latter effect and extend the duration of the hypocalcemic effect. Calcitonin is useful largely as adjunctive therapy in controlling hypercalcemia in the acute setting until the effects of more powerful but slower-acting agents (eg, bisphosphonates) become available.
Plicamycin is a tumoricidal antibiotic with pronounced hypocalcemic properties at nontumoricidal doses. It presumably targets the osteoclast and its bone resorptive activity. It is administered as an infusion at a dosage of 15–25 ľg/kg body weight over 4–24 hours. Calcium levels fall, often into the normal range, within 24–48 hours in a majority of patients treated. Plicamycin has significant renal and hepatic toxicity, and it induces platelet abnormalities that may result in clinically significant hemorrhage. Toxicity tends to increase with repeated administration, limiting chronic use of the drug. Given the ready availability of less toxic treatment modalities, plicamycin has largely been reduced to second-line status in the management of severe hypercalcemia.
Gallium nitrate has shown efficacy in the management of tumoral hypercalcemia in clinical trials. Like the bisphosphonates and plicamycin, the target of gallium therapy appears to be the osteoclast of bone. Patients are infused with gallium nitrate at a dosage of 200 mg/m2 over a 5-day period. As with bisphosphonates and plicamycin, normocalcemia is achieved in the majority of patients (about 75% in some studies). In head-to-head comparisons, it appears to be more effective than either etidronate or calcitonin. Its major limitations are the duration of the infusion (often requiring hospitalization) and the potential for significant nephrotoxicity, particularly if it is used in the setting of other nephrotoxic agents.
Other nonselective treatment modalities which are available for management of hypercalcemic crisis include steroids, phosphate, and dialysis. Aside from their potentiation of calcitonin's effects, as described above, steroids are usually effective only in the management of hypercalcemia due to lymphoproliferative disease (eg, multiple myeloma) or vitamin D toxicity (eg, due to ingestion of vitamin D or disseminated granulomatous disease). They are best suited for chronic management of hypercalcemia associated with these disorders. Parenteral phosphate effectively reduces serum calcium levels, though often at the expense of deposition of calcium phosphate salts in parenchymal tissues. Given the availability of the agents described above, it is rarely needed for the management of hypercalcemic crisis. Peritoneal or hemodialysis against a low-calcium bath is also very effective in reducing serum calcium levels and is the treatment of choice for severe hypercalcemia in renal failure patients incapable of tolerating or responding to saline diuresis. In clinically tenuous patients not in renal failure undergoing maximal saline diuresis, persistent hypercalcemia may be an indication for hemodialysis as a tool to bridge the interval until more definitive therapy (eg, bisphosphonates or plicamycin) can achieve its maximal effect.
Finally, some effort should be devoted to addressing the primary cause of the hypercalcemia. In some instances (eg, disseminated malignancy) therapeutic options may be limited and ineffective in controlling serum calcium levels. In other instances (eg, primary hyperparathyroidism), a definitive surgical approach can be curative and limit downstream morbidity. Thus, careful investigation of the source of the hypercalcemia is warranted. Such investigation—even in patients with an obvious potential source of hypercalcemia (eg, malignancy)—may identify correctable problems and, at the very least, assist in the development of long-term management strategies once the acute crisis has resolved.
Hypocalcemia may be seen in a number of disorders affecting the synthesis or action of parathyroid hormone or vitamin D or following sequestration of calcium into a functionally inaccessible compartment (see Chapter 8). Many of these represent chronic illnesses where hypocalcemic symptoms develop insidiously or where the complication of hypocalcemia is anticipated early and appropriate treatment initiated prior to acute decompensation. However, in selected situations, acute hypocalcemia may dominate the clinical presentation. Appropriate recognition of the high-risk clinical setting
should lead to earlier diagnosis and therapeutic intervention with reduced morbidity and mortality.
Probably the most important cause of PTH-deficient hypocalcemia occurs in the postoperative setting following neck surgery for treatment of malignancy or resection of adenomatous or hyperplastic parathyroid glands. This may reflect accidental or purposeful (eg, radical neck dissection) removal of all functioning parathyroid tissue or inadvertent vascular compromise of tissue left in the neck. Residual normal parathyroid tissue can also be functionally atrophied in a patient undergoing surgery for hyperparathyroidism. It can take 1–2 days for PTH secretion and calcium levels to return to normal following resection of the adenoma. Magnesium deficiency can compromise both PTH secretion from the parathyroid gland and PTH action at target tissues in the periphery. Magnesium repletion in patients with low serum magnesium and calcium should be undertaken before launching an exhaustive workup of the hypocalcemia.
Hypocalcemia can be seen in chronic renal insufficiency. Hyperphosphatemia and reduced 1-hydroxylase activity result in deficient 1,25-dihydroxyvitamin D3 generation and consequent hypocalcemia. Aggressive management of the hyperphosphatemia (eg, with phosphate-binding antacids) and calcitriol are generally useful in promoting normal calcium balance.
Acute sequestration of calcium into bone or nonphysiologic compartments can lead to severe hypocalcemia. Hypocalcemia following removal of a parathyroid adenoma may reflect a hypoparathyroid or aparathyroid state, as discussed above. Alternatively, in patients with severe osteitis fibrosa cystica, the bones, in the absence of PTH-driven bone resorption, serve as a sink for extracellular calcium deposition as previously unmineralized osteoid becomes calcified. This results in the syndrome termed “hungry bones.” It is usually distinguished from PTH deficiency by measurements of the hormone (PTH is typically elevated in the hungry bones syndrome). A similar sequestration phenomenon is seen in osteoblastic metastases (eg, in breast or prostatic carcinoma). Typically, osteoclastic activity in these metastases is abrogated through some specific therapeutic intervention, leaving unmineralized matrix to calcify at the expense of extracellular calcium levels.
Sequestration may also occur in nonphysiologic settings such as the peritoneal cavity in acute pancreatitis, where deposition of calcium soaps leads to a subsequent reduction in serum calcium levels. A similar phenomenon occurs in damaged muscle following rhabdomyolysis. Deposition of calcium salts in damaged muscle beds leads to a reduction in serum calcium levels. Interestingly, serum calcium returns to normal or even elevated levels during the recovery phase, reflecting dissolution of the precipitates as the muscle undergoes repair.
Hypocalcemia occurs in the setting of acute systemic illness (eg, toxic shock syndrome), a finding that has been linked to elevated free fatty acids levels in this setting. It has also been associated with specific drugs, including antineoplastic agents such as doxorubicin and cytarabine and other agents such as ketoconazole, pentamidine, and foscarnet.
Symptomatic hypocalcemia presents with a predictable constellation of signs and symptoms. Most of these findings are related to the increased neuroexcitability that is seen with reductions of extracellular calcium levels (Table 24-10). Symptoms frequently begin as circumoral paresthesias or paresthesias of the fingers or toes. This is followed by increased muscle cramping and spasm (particularly carpopedal spasm) (see Figure 8-17) and diffuse hyperreflexia. The increased propensity for muscle spasm can provoke generalized tetany which if extended to the laryngeal muscles can lead to laryngospasm and respiratory arrest. Increased excitability in the central nervous system can result in seizures, particularly in patients with a history of seizure disorder.
Physical examination looking for evidence of neuromuscular hyperexcitability is often revealing (Table 24-11). Chvostek's sign is evoked by repetitive tapping of the area overlying the facial nerve approximately 2 cm anterior to the ear lobe below the zygomatic arch. A positive test is contraction of musculature innervated by the facial nerve. The extent of the contraction is roughly proportionate to the severity of the hypocalcemia. Trousseau's sign is triggered by inflating a blood pressure cuff on an upper extremity to a level that roughly equates with the systolic blood pressure for 3–5
minutes. Spasm of the hand musculature (see carpopedal spasm, above) due to transient ischemia of hyperexcitable nerves innervating the hand is regarded as a positive test.
Table 24-10. Symptoms and signs of acute hypocalcemia.
Hypocalcemia can also have significant effects on cardiovascular function, including decreased blood pressure, impaired cardiac contractility, and conduction disturbances. On the electrocardiogram, significant hypocalcemia can manifest as prolongation of the QT interval. Evidence of sequelae of chronic hypocalcemia may also identify individuals who are at risk for acute hypocalcemia. Subcapsular cataracts and basal ganglia calcification are features associated with long-standing hypocalcemia.
Measurement of total serum calcium, albumin, or ionized calcium, if available, leads quickly to the correct diagnosis. Measurement of plasma PTH, 25-hydroxy cholecalciferol, and 1,25-dihydroxycholecalciferol will assist in identifying deficiency of PTH secretion, adequacy of vitamin D stores, or impaired synthesis of bioactive vitamin D, respectively. Mg2+ levels should be obtained to exclude hypomagnesemia. If present, magnesium repletion should be initiated before additional diagnostic tests are undertaken.
Examination of the medication list looking for drugs with hypocalcemic properties (eg, bisphosphonates, calcitonin, asparaginase, cisplatin, foscarnet) should be performed.
Measurement of serum amylase and lipase should aid in identifying pancreatitis as a source of the hypocalcemia. Creatine kinase and aldolase levels will exclude the presence of rhabdomyolysis.
One area of potential confusion is the evaluation of patients in the immediate postparathyroidectomy period. Differentiating a hypoparathyroid or aparathyroid state from hungry bones syndrome can be difficult acutely. As pointed out above, measurement of plasma PTH levels (high in hungry bones syndrome and low in hypoparathyroidism) provides the most definitive separation of the two but typically takes several days and thus is usually not helpful in the acute setting. Measurement of serum phosphate (elevated in hypoparathyroidism and low-normal or low in hungry bones syndrome) or urinary phosphate (often low or absent in hypoparathyroidism) may be useful in identifying the source of hypocalcemia. Fortunately, the treatment of hypocalcemia in these two conditions is largely the same. Thus, establishment of a definitive diagnosis is important mainly for planning the subacute and long-term management of the patient's disease.
In a life-threatening situation (eg, cardiovascular collapse) or in the setting of frank generalized tetany, 10 mL of calcium gluconate (93 mg of elemental calcium) can be administered intravenously over a 5- to 10-minute period and repeated if necessary. Less acute but recurrent hypocalcemic episodes can be managed with continuous calcium infusions. Nine hundred and thirty milligrams (ten ampules) of calcium gluconate can be mixed in 500 mL of D5W. Infusion rates are established empirically. The initial infusion rate is typically 0.3 mg/kg/h but may be increased to as much as 2 mg/kg/h in patients with high demands for calcium (eg, hungry bones syndrome).
As the acute situation resolves, selected patients will become candidates for chronic replacement therapy. Those with minor hypocalcemia may be treated with calcium supplements alone. Administration of 1–3 g of elemental calcium (conventional calcium carbonate antacids contain about 40% elemental calcium) may suffice to restore calcium to the low-normal range and eliminate hypocalcemic symptoms. In those with more refractory hypocalcemia—a category that includes most patients with hypoparathyroidism—the addition of some form of vitamin D or a derivative will be required. If cholecalciferol (vitamin D3) is employed to manage patients with hypoparathyroidism, supraphysiologic doses (50,000 units/d or higher) may be required, reflecting the limited capacity for 1-hydroxylation of the vitamin D prohormone in the hypopara thyroid state. 1,25-Dihydroxycholecalciferol (calcitriol) works faster than vitamin D3 and circumvents the 1-hydroxylase blockade, but it is more expensive and the risk for acute hypercalcemia may be higher. It is given in a dose of 0.25–1 ľg daily.
In all cases the goal of therapy should be to alleviate hypocalcemic symptoms and restore serum calcium levels to the low-normal range. This can usually be accomplished with some combination of vitamin D and supplemental calcium. The latter allows the practitioner additional flexibility in controlling serum calcium levels without requiring frequent dose modification of the longer-acting vitamin D. Efforts to push calcium levels higher may come at the expense of significant hypercalciuria and increased risk for renal stone formation. Difficulty in maintaining calcium even in the low-normal range without unacceptable hypercalciuria may be managed by addition of a thiazide diuretic to the regimen. These agents reduce hypercalciuria and, secondarily, raise serum calcium levels. If thiazides are used, careful follow-up is required to guard against the possibility of iatrogenic hypercalcemia. Efforts should be made to restore calcium to the target range and maintain it at this level indefinitely. Chronic hypocalcemia is associated with development of subcapsular cataracts and basal ganglia calcification which, in some cases, leads to the development of a parkinsonism-like syndrome.
Hyponatremia is the most frequent electrolyte problem observed in hospitalized patients. It is often asymptomatic when mild to moderate in severity and subacute to chronic in its time course of development. However, significant hyponatremia (< 120 mEq/dL) of rapid onset is frequently symptomatic and can be life-threatening.
Hyponatremia typically occurs in one of three clinical settings, each of which is linked to a specific pathophysiologic paradigm (Table 24-11). Hypovolemic hyponatremia is associated with volume contraction. As intravascular volume is reduced by more than about 9%, there is a nonosmotic stimulation of ADH release as the body attempts to retain water to support intravascular volume. Hyponatremia of this type is seen with protracted vomiting, diarrhea, or excessive sweating, particularly when fluid loses are replenished with water or hypotonic fluids alone. Volume contraction and hyponatremia may also be seen with disorders of renal sodium handling (eg, diuretic use, mineralocorticoid deficiency, or other salt wasting syndromes). Urinary Na+ concentration is typically elevated (> 20 mEq/L) in these latter disorders, while in the former urinary Na+ concentration is low, reflecting aggressive resorption of Na+ in all tubular segments.
Table 24-11. Classification of hyponatremia.
Hypervolemic hyponatremia includes those edematous disorders typified by paradoxical retention of Na+ and water in the face of a total body excess of each. Specific causes of hyponatremia in this group include congestive heart failure, cirrhosis of the liver with ascites, and nephrotic syndrome. Hyponatremia in this setting presumably results from perceived hypoperfusion by baroreceptors in the arterial circulation. Neural impulses transmitting this information to the hypothalamus trigger an increase in ADH release and net water retention.
Normovolemic hyponatremia is probably the most heterogeneous category and the most difficult to define pathophysiologically. It includes the syndrome of inappropriate ADH (SIADH) secretion, hypothyroidism, glucocorticoid insufficiency (eg, secondary adrenal insufficiency), psychogenic polydipsia, postoperative hyponatremia, and hyponatremia seen following transurethral resection of the prostate (Table 24-11).
Acute hyponatremia, developing over the course of 24 hours or less, presents with headache, nausea, vomiting, and altered sensorium, which may progress to stupor and coma. These findings are thought to result from cerebral edema as the hypotonic extracellular compartment shifts water into the cerebral cortical cells. Such fluid shifts are opposed early through a reduction in intracellular electrolyte concentration and later by depletion of intracellular solutes (eg, amino acids). This acts to reduce the osmotic gradient and limit the net movement of fluid into brain. With chronicity, such solute shifts can reduce brain water content to near normal. Thus, the acuteness of the reduction in serum Na+ concentration—as well as the magnitude of the reduction—are important markers of potential morbidity in this disorder. Young menstruating women are particularly susceptible to the deleterious effects of cerebral edema in the postoperative setting. They are 25 times more likely than postmenopausal women or men to die or have permanent brain damage. This increased susceptibility may reflect the effects of estrogen and progesterone to promote solute accumulation in the cells of the central nervous system. Such accumulation would be predicted to increase the osmotic drive that leads to cerebral edema in these patients.
The first step in making the diagnosis is to exclude the presence of pseudohyponatremia. The latter results from high circulating concentrations of triglycerides or osmotically active solutes (eg, glucose or proteins) in circulating plasma. Hypertriglyceridemia artifactually lowers serum sodium by physically excluding it from the sizable nonaqueous phase of the sample being measured. This is usually readily detected in the laboratory (eg, by noting the presence of lactescent serum) and is corrected by centrifuging the sample prior to measuring Na+ concentration in the aqueous phase. Osmotically active solutes, like glucose, draw water from the intracellular to the extracellular compartment, where it may transiently lower existing electrolyte (eg, Na+) concentrations (see Diabetic Ketoacidosis, above).
Assuming that the presence of hyponatremia is confirmed, an attempt to examine the different diagnostic possibilities listed above should be initiated. Evidence of congestive heart failure, cirrhosis, or nephrotic syndrome is usually apparent on physical examination and confirmable with standard laboratory or imaging studies. Similarly, renal dysfunction should be excluded using conventional renal function tests. Thiazide diuretic use is a frequent cause of hyponatremia and should be investigated early in the evaluation. A careful history of water consumption should be obtained and measurements of water intake in a monitored setting made to exclude psychogenic polydipsia or dipsogenic diabetes insipidus. Hypothyroidism can be excluded with measurement of plasma TSH and free thyroxine levels and glucocorticoid deficiency through an ACTH stimulation test (see Chapters 7 and 9).
Nonosmotic, non-volume-driven ADH secretion is found in SIADH. This is typically a diagnosis of exclusion in non-volume-contracted individuals without evidence of edema, renal insufficiency, hypothyroidism, or adrenal insufficiency. Serum Na+ and osmolality are low in the face of a concentrated urine. Urine Na+ may be modestly elevated (> 20 mEq/L), reflecting activation of natriuretic pathways responding to the increase in total body fluid volume. If findings are equivocal, an abnormal water load test (inability to excrete at least 90% of a 20 mL/kg water load in 4 hours or failure to dilute urine osmolality to below 100 mosm/kg) can be used to confirm the diagnosis. SIADH is seen with a variety of disorders affecting the central nervous system (eg, encephalitis, multiple sclerosis, meningitis, psychosis), the pulmonary system (eg, tuberculosis, pneumonia, aspergillosis), or as a paraneoplastic process associated with a number of solid tumors (eg, small-cell carcinoma of the lung; carcinoma of the pancreas, bladder, or prostate). It may also be seen with certain types of drugs (eg, cyclophosphamide, vinca alkaloids, opioids, prostaglandin synthesis inhibitors, tricyclic antidepressants, carbamazepine, clofibrate, and serotonin reuptake inhibitors).
Some difficulty may be encountered in differentiating SIADH from a second hyponatremic syndrome called cerebral salt wasting. The latter is also associated with central nervous system disease, particularly subarachnoid hemorrhage. It is thought to be due to a centrally mediated renal wasting of sodium with consequent volume contraction, volume-dependent activation of ADH secretion, and hyponatremia. It has been suggested that atrial natriuretic peptide or brain natriuretic peptide may play a central role in mediating the natriuresis associated with this disorder. Comparison of the features of these two disorders (Table 24-12) suggests that clinical or biochemical evidence of volume contraction is the major way to differentiate cerebral salt wasting from the euvolemic hyponatremia of SIADH. This is an important distinction since therapy in the former (ie, cerebral salt wasting) involves intravascular volume repletion while in the latter (ie, SIADH) fluid restriction may represent first line therapy.
When the primary stimulus provoking water retention (eg, diuretic use) or consumption (eg, psychogenic polydipsia) can be identified, specific therapy represents the most rational approach for long-term management.
Table 24-12. Comparison of laboratory findings in syndrome of inappropriate antidiuretic hormone secretion (SIADH) with cerebral salt-wasting (CSW).
When the cause of hyponatremia is unclear or unaddressable (eg, SIADH), a more generic approach may be adopted. Patients with asymptomatic (eg, mild or chronic) hyponatremia can be managed with water restriction. Calculations of daily water intake should incorporate that included in nonliquid foods consumed by the patient. For patients who are symptomatic but unable to adhere to water restriction, treatment with demeclocycline (600–1200 mg/d in divided doses), an antibiotic that uncouples ADH from activation of its receptor, may be sufficient to control serum Na+ levels. Water restriction is not required with demeclocycline therapy and may even be deleterious. Such therapy should be carefully monitored to guard against precipitous dehydration and renal insufficiency. Alternatively, patients can be managed with regular administration of a loop diuretic (eg, furosemide), which leads to excretion of urine approximately half the toxicity of plasma (loop diuretics disrupt the osmotic gradient required for urine concentration). Loop diuretics should be used concomitantly with NaCl supplementation (2–3 g/d) to increase urinary solute excretion and in that way amplify urinary water loss.
Symptomatic acute hyponatremia is an indication for hypertonic saline (3% NaCl) administration. Estimates of excess total body water can be made using the following equation:
with plasma osmolality in milliosmoles per kilogram, excess water in liters, and body weight in kilograms.
The rise in serum sodium effected by 1 L of 3% saline infusate can be calculated by the following formula:
where ΔNa+ is the change in sodium concentration effected by administration of 1 L of infusate; infusate Na+ is the concentration of Na+ in the infusion (eg, 513 mmol/L for 3% NaCl); and total body water is body weight (kg) × 0.6 (children or nonelderly men), × 0.5 (nonelderly women and elderly men), or × 0.45 (elderly women). The (+1) in the denominator accounts for the volume of the infusate. Based on the calculated ΔNa+, one can adjust the infusion rate to provide the desired increase in serum Na+ over a fixed time interval.
Calculation of infusion rates can be made using the formula described by Adrogue and Madias: Infusion rates should be adjusted to raise serum Na+ levels by no more than 0.5 mEq/h (total <8–12 mEq/d) to diminish the risk of central demyelination (see below). If necessary, infusion rates can be adjusted to increase serum sodium by 1–2 mEq/h for short periods of time in symptomatic patients; however, the limitation to 8 mEq/d should be adhered to, if possible. Furosemide can be administered, if necessary, to avoid intravascular fluid overload; however, given the ability of this drug to promote excretion of a hypotonic urine, the clinician should be aware that the plasma osmolality may increase faster than predicted by the formula set forth above. Once serum Na+ reaches 130 mEq/L, hypertonic saline infusion should be terminated and fluid restriction or normal saline (0.9% NaCl) plus furosemide used for the final correction of serum osmolality.
It is important to mention that interventions directed at the cause of the hyponatremia (versus treatment of the hyponatremia itself) also require close monitoring. Rapid correction of hyponatremia through administration of glucocorticoids in adrenal insufficiency, for example, may be associated with central myelinolysis. Careful monitoring of serum Na+ levels in the posttreatment period is mandatory. If Na+appears to be rising too rapidly (> 1 mEq/h), administration of hypotonic fluids or a small dose of desmopressin acetate (0.25–1 ľg parenterally) may be indicated.
Central pontine myelinolysis was first described in alcoholics and malnourished patients. In the original descriptions it was characterized by demyelination confined to the pons, resulting in quadriplegia and, not infrequently, death. Subsequent observational studies linked it to the treatment of hyponatremia. The classic presentation is of a patient who is aggressively treated for hyponatremia with resolution of the presenting findings (ie, those of cerebral edema), only to develop symptoms of mutism, dysphasia, spastic quadriparesis, pseudobulbar palsy, delirium, and, in many cases, death. Surviving patients often have severe neurologic sequelae. More recent studies using CT and MRI indicate that myelinolysis is not confined to the pons but present in many extrapontine locations as well. Lesions are typically symmetrically distributed and clustered in areas where there is close juxtaposition of gray and white matter.
There has been considerable controversy about the prevalence of this particular syndrome and its relationship to the treatment of hyponatremia. However, both animal and human studies are strongly suggestive of a link between this syndrome and rapid, aggressive correction of hyponatremia. Given the imperfect state of our understanding of this disorder, it would seem prudent to approach the correction of chronic hyponatremia, where solute distribution and water content in the brain are undoubtedly altered, cautiously, with rates
of correction no greater that 0.5 mEq/h, as indicated above. The risk of solute redistribution in documented acute hyponatremia (ie, duration < 24 hours) is substantially reduced. Clinical signs of cerebral edema in this setting may be approached more aggressively, though repletion rates greater than 1 mEq/h with a maximal correction of 12 mEq over the first 24 hours should be avoided if possible.
Diabetes insipidus is a disorder due to absolute or relative deficiency in the circulating levels or bioactivity of vasopressin, the antidiuretic hormone (ADH).
ADH release is normally suppressed at plasma osmolalities below 285 mosm/kg, leading to generation of a maximally dilute urine (< 100 mosm/kg). Above 285 mosm/kg, ADH secretion increases linearly with plasma osmolality. At a plasma ADH level of 5 pg/mL, which corresponds to a plasma osmolality of about 295 mosm/kg, the urine is maximally concentrated. Despite the fact that plasma ADH levels continue to rise beyond this point, there is no further concentration of the urine. At 295 mosm/kg, the osmotic threshold for the thirst mechanism is activated. Thirst also rises linearly with increasing plasma osmolality. It provides the body's main defense against hypertonicity, much as suppression of ADH secretion guards against hypotonicity. Provided that the patient remains awake and able to drink and provided that the thirst mechanism remains intact, even complete deficiency of ADH secretion can be adequately compensated by increased water intake.
Defects in ADH secretion (central diabetes insipidus) may occur on a heritable basis, occasionally in association with diabetes mellitus, optic atrophy, and sensorineural deafness (DIDMOAD, or Wolfram's syndrome). It may also be seen as a component of a polyendocrine autoimmune syndrome (see Chapter 4). Secondary causes of central diabetes insipidus include head injury (often with stalk section), pituitary surgery, granulomatous disease (sarcoidosis, tuberculosis, histiocytosis X), infections, vascular aneurysms and thrombosis, and tumors (craniopharyngioma, dysgerminoma, meningioma, metastatic disease from breast, lung, or gastrointestinal tumors). These lesions typically involve large sections of the hypothalamus, sufficient to destroy or functionally impair both the supraoptic and paraventricular nuclei bilaterally.
Osmoreceptors for ADH release are believed to reside in the organum vasculosum of the lamina terminalis, while those controlling thirst are thought to lie in an independent but neighboring location. Thus, those patients with an isolated defect in ADH secretion (either in the osmoreceptors or the secretory nuclei) are protected from severe dehydration by activation of the thirst mechanism. In those with combined involvement of both ADH secretion and the osmoreceptors controlling thirst (hypodipsic or adipsic diabetes insipidus), the risk of volume contraction and severe dehydration is extreme (see below).
Adequacy of the renal response to ADH requires adequate delivery of glomerular filtrate to distal tubular segments, adequacy of tubular function in the ascending limb of the loop of Henle (to establish and maintain the gradient of medullary tonicity and to generate free water for excretion), and a normal response to vasopressin (ie, intact signal transduction mechanism) in the collecting duct. Unresponsiveness to ADH is due to genetic lesions in the V2 receptor (X-linked recessive diabetes insipidus) or the functionally linked aquaporin-2 water channel (autosomal recessive diabetes insipidus). It may also be seen in an acquired form with hypokalemia or hypercalcemia in various forms of intrinsic renal disease (eg, medullary cystic disease) and following therapy with demeclocycline or lithium.
The presentation of diabetes insipidus in an alert, conscious patient is typically an abrupt onset of polyuria and polydipsia. Hypertonicity is avoided as long as the thirst mechanism remains intact and water intake is able to keep up with urinary losses. In a patient who is unconscious or otherwise incapable of communicating the need for fluids or in patients with coexistent adipsia, polyuria is transient and quickly followed by evidence of severe dehydration and hyperosmolality. Urine volumes in this setting may be normal or even reduced. The clinical findings in hypernatremia associated with diabetes insipidus are dominated by the effects of cellular dehydration and contraction of intravascular volume. In the brain, this can lead to increased traction on dural veins and venous sinuses. This may result in avulsion of vessels from their cranial attachments and intracranial hemorrhage. Other findings include irritability, lethargy, weakness, muscle twitching, hyperreflexia, seizures, and coma.
The diagnosis of polyuria is usually reserved for urine outputs greater than 2.5 L/d. A careful history should be taken to document oral fluid intake (particularly beer or other hypotonic fluids) or parenteral fluid administration (eg, in a postoperative setting). Neurologic or endocrine symptoms that might suggest either a hypothalamic or intrasellar mass, use of medications that could impair water reabsorption (eg, furosemide, demeclocycline, or lithium) or intercurrent conditions that might mimic diabetes insipidus (eg, osmotic diuresis
associated with diabetes mellitus or resolving obstructive uropathy) should also be investigated.
Initial evaluation should include measurement of serum sodium, plasma osmolality, and urine osmolality. Diabetes insipidus is typically associated with normal or elevated serum sodium and osmolality in the face of a submaximally concentrated urine. Plasma glucose measurement and standard renal function tests should help to exclude osmotic diuresis as contributing to the polyuria. Measurement of serum K+ and Ca2+ will assist in excluding polyuria resulting from hypokalemia and hypercalcemia, respectively.
In patients with equivocal initial tests, a water deprivation test may be performed as described in Chapter 5. Patients with diabetes insipidus become progressively more hypertonic with water deprivation but fail to increase urine osmolality. Administration of desmopressin promotes water retention and an increase in urine osmolality in patients with central but not nephrogenic diabetes insipidus. Plasma ADH levels may also be of assistance in defining the nature of the diabetes insipidus. In the presence of high plasma but low urine osmolality, increased plasma ADH levels are associated with nephrogenic diabetes insipidus while subnormal levels are found with central diabetes insipidus.
Coexistence of glucocorticoid deficiency may “mask” the presence of central diabetes insipidus. The development of polyuria with the initiation of glucocorticoid replacement should alert the clinician to the possible presence of diabetes insipidus.
In the 48 hours following pituitary surgery or head trauma, transient diabetes insipidus with polyuria is not uncommon. Over the ensuing 2–14 days, a period of antidiuresis and hyponatremia may dominate the clinical course. This in turn may be followed by persistent polyuria. The first phase is thought to result from transient dysfunction or stunning of the ADH-producing neurons of the hypothalamus; the second from leakage of ADH from damaged or dying neurons; the third by permanent loss of ADH secretory neurons. Not all patients progress through the entire series of events. It is important to recognize the existence of this syndrome and the natural progression of the disorder in evaluating the need for chronic therapeutic intervention.
In pregnancy, there is a resetting of the osmostats controlling both ADH and thirst, resulting in a state of “physiologic”hypoosmolality (about 10 mosm/kg below that seen in the nonpregnant state). In addition, elevations in placental vasopressinase may promote polyuria in patients with otherwise compensated partial central diabetes insipidus. The appropriate treatment for this disorder is desmopressin acetate, an ADH analog that is resistant to degradation by vasopressinase.
Virtually anything that increases the rate of tubular flow (eg, primary polydipsia or central diabetes insipidus) may create a state of functional nephrogenic diabetes insipidus. This is due to washout of the medullary tonicity that is responsible for generating the osmotic gradient which promotes movement of water from the tubular lumen into the medullary interstitium. Primary polydipsia (eg, psychogenic polydipsia or dipsogenic diabetes insipidus) presents with a dilute urine, but plasma osmolality and serum Na+ levels are typically low or low-normal and ADH levels are low. Moreover, owing to the elevation in tubular flow rates, the response to desmopressin may be limited in magnitude. This may make it difficult to differentiate primary polydipsia from partial forms of nephrogenic diabetes insipidus. Plasma ADH levels may be of assistance in making this distinction.
Acute diabetes insipidus is characterized by polyuria in the presence or absence of plasma hyperosmolality. As noted above, the presence of hyperosmolality is determined by the adequacy of the patient's thirst mechanism. When a hyperosmolar state with clinical evidence of severe dehydration is present, it is necessary to correct intravascular volume. This is accomplished by administering hypotonic fluids (eg, D5W), which will both restore intravascular volume and move plasma osmolality back toward normal. The rate at which the hyperosmolality is corrected is dictated in part by the severity of the clinical symptoms and by the chronicity of the disorder. Chronic hyperosmolality (> 24 hours) leads to the accumulation of idiogenic osmoles (eg, taurine and myoinositol) in the central nervous system that serve to offset the osmotically driven movement of water out of that compartment. Aggressive correction of the hyperosmolar state can lead to cerebral edema if the rate of hypotonic fluid administration greatly exceeds the rate at which the neurons in the central nervous system eliminate these idiogenic osmoles. Following expansion of intravascular volume with normal saline, correction of plasma osmolality at a rate of 0.5–1 mosm/h—not to exceed 15 mosm within the first 24-hour period—appears to be reasonably effective in reducing plasma tonicity without incurring an increased risk of cerebral edema. Typically, higher infusion rates are used early in the course when serum osmolalities are highest and reduced as osmolality decreases into the range of 330 mosm/kg. Correction of the total free water deficit should be spread over about 48 hours. Total water deficit is defined above in the section dealing with diabetic ketoacidosis. Calculation of hypotonic fluid infusion rates can be made using the formula for change in serum sodium set out in the preceding section, substituting 0 mmol/L for D5W, 77 mmol/L for 0.45% NaCl, or 154 mmol/L for 0.9% NaCl into the
equation, as needed, to calculate the net reduction in serum Na+. Again, based on the calculated ΔNa+, one can adjust the rate of delivery of the infusate to provide a specific increment in serum Na+ concentration over a defined time interval. If signs of cerebral edema (seeHyponatremia, above) appear, hypotonic fluids should be discontinued and appropriate administration of hypertonic fluids (eg, mannitol) initiated.
If the diagnosis of central diabetes insipidus has been established, the patient should receive parenteral desmopressin acetate. The initial dose, in the range of 1–2 ľg every 24 hours (administered intravenously or intramuscularly), should be given in the evening with the aim of controlling nocturia and maintaining daily urine output under 2 L. If polyuria returns well before the end of the 24-hour dosing interval, the single dose can be increased or split doses can be administered every 12 hours. Ideally, one would like to see some degree of “breakthrough” polyuria at the end of the dosing interval. This serves to guard against the development of iatrogenic hyponatremia. If this proves difficult to achieve, a dose can be skipped every 48–72 hours. Once the patient has been stabilized on a fixed dose of parenteral desmopressin, conversion to a formulation more suitable for the outpatient setting is indicated. Desmopressin acetate is available in liquid form for insufflation through a nasal cannula or as a fixed-dose (10 ľg) nasal spray. The former has the advantage of greater flexibility in adjusting the nasal dose while the latter offers greater convenience for some patients. Parenteral desmopressin is generally about ten times more potent than the nasally administered drug; however, intranasal doses should be titrated for each individual patient. Desmopressin is also available in an oral form. Effective doses can range widely (from 50 ľg to 1200 ľg/d in divided doses) and should be adjusted for the individual patient.
Treatment of nephrogenic diabetes insipidus is more complex since the problem is one of resistance to—rather than deficiency of—the endogenous hormone. If possible, one should attempt to address the underlying cause of ADH resistance. This can be accomplished by correcting electrolyte abnormalities (eg, hypokalemia or hypercalcemia) or discontinuing medications (eg, demeclocycline, lithium) that are likely to contribute to ADH insensitivity. Failing this, administration of a thiazide diuretic together with salt restriction will often reduce the polyuria. This is assumed to result from contraction of intravascular volume with increased proximal reabsorption of fluids and solutes and, consequently, limited availability of fluid in distal nephron segments for free water generation and excretion. Prostaglandins are endogenous antagonists of ADH activity in the collecting duct. Administration of cyclooxygenase inhibitors (eg, indomethacin, 100 mg/d in divided doses) may improve sensitivity to endogenous ADH and reduce polyuria. If the impairment in ADH responsiveness is mild, higher doses of desmopressin will occasionally prove effective in promoting water retention. Amiloride is the preferred treatment for lithium toxicity. It is thought to prevent the uptake of lithium in collecting duct cells. Lithium-induced diabetes insipidus may not abate following discontinuation of the drug.
Disorders of thirst in the setting of central diabetes insipidus deserve special mention with regard to therapy. Excessive thirst due to altered osmoreceptor function or behavioral conditioning (eg, before desmopressin treatment) may result in severe hyponatremia once desmopressin treatment is initiated. The patient should be cautioned about excessive consumption of water, and fluid must be restricted if necessary.
Adipsic diabetes insipidus is probably one of the most difficult therapeutic problems faced by endocrinologists. These patients have essentially lost all ability to regulate water metabolism on their own. This function must be taken over by the medical team providing their care. Desmopressin is administered in a fixed parenteral dose which is sufficient to reduce urine output to about 1.5–2 L/d with a fluid intake of about 2–2.5 L. The difference here is intended to cover the daily insensible losses (about 500–1000 mL) and may need to be adjusted empirically to maintain normal fluid homeostasis. After plasma osmolality and sodium are in the normal range, fluid intake is balanced against urine output. Any net change in urine output over an 8-hour period (this may be extended as the patient's fluid requirements become more predictable) is accommodated by modifying the fluid orders for the ensuing 8 hours. The patient should also be weighed daily. Any alteration in weight is usually reflective of net changes in water retention and can be corrected through modification of fluid intake. Plasma osmolality and serum sodium should be monitored once or twice weekly and appropriate changes in fluid administration made depending on the direction and magnitude of the shift in osmolality. With this system of redundant monitoring, urine volumes and plasma osmolality can be reasonably well controlled for protracted periods of time.
If left untreated, polyuria secondary to diabetes insipidus can lead to dilation of the collecting system, hydronephrosis, and renal dysfunction. This is the dominant reason for treating polyuria even in patients with an intact thirst mechanism who are capable of controlling plasma osmolality through water ingestion.
Overly rapid correction of the hyperosmolality can result in cerebral edema. The relative risk of this complication
should be minimized by careful attention to the rate at which the water deficit is corrected (see above).
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