Endocrine emergencies are frequently encountered in the intensive care unit (ICU). This chapter will focus on several of the more common disorders, including diabetic hyperglycemia, thyroid storm, myxedema coma, and adrenal insufficiency. Understanding the pathophysiology of these different disease states will enable the intensivist to make a rapid diagnosis, initiate proper therapy, and avoid major pitfalls.
Diabetic Ketoacidosis
Diabetic ketoacidosis (DKA) is a life-threatening hyperglycemic condition that accounts for over 140,000 annual hospital admissions. With improved therapy, the age-adjusted mortality rate has fallen dramatically and is currently less than 5%. Although DKA is considered a pathognomonic complication of insulin-dependent diabetes (type 1), 5% to 30% of people with type 2 diabetes may have this condition. The defining features of DKA include metabolic acidosis (arterial pH <7.35 with bicarbonate <16 mEq/L), hyperglycemia (>250 mg/dL), and ketonemia. The severity of DKA can be graded as mild, moderate, or severe according to the degree of metabolic acidosis and the presence of an altered mental status ( Table 72-1 ).
| Criteria | DKA | HHS | ||
|---|---|---|---|---|
| Mild | Moderate | Severe | ||
| Plasma glucose (mg/dL) | >250 | >250 | >250 | >600 |
| Arterial pH | 7.25-7.30 | 7.00-7.24 | <7.00 | >7.30 |
| Serum bicarbonate (mEq/L) | 15-18 | 10 to <15 | <10 | >18 |
| Urine ketones ∗ | Positive | Positive | Positive | Small |
| Serum ketones ∗ | Positive | Positive | Positive | Small |
| Effective serum osmolality † | Variable | Variable | Variable | >320 |
| Anion gap ‡ | >10 | >12 | >12 | Variable |
| Alteration in mental state | Alert | Alert/drowsy | Stupor/coma | Stupor/coma |
∗ Nitroprusside reaction method.
† Effective serum osmolality = 2[measured Na + ] + glucose/18.
Pathophysiology
DKA is a dysregulated catabolic state that occurs in the setting of insulin deficiency coupled with high levels of counter-regulatory hormones such as glucagon, cortisol, catecholamines, and growth hormone. This hormonal imbalance inhibits carbohydrate metabolism with a preferential shift toward fat metabolism. Impaired glucose uptake, increased gluconeogenesis, and enhanced lipolysis all contribute to a marked increase in serum glucose. To compensate for the increase in osmolarity, water is shifted from the intracellular to the extracellular compartment. Because the kidney cannot effectively reabsorb glucose in the presence of marked hyperglycemia, an osmotic diuresis ensues. Hypovolemia and profound electrolyte depletion soon follow.
DKA is defined by the development of acidosis. As the liver oxidizes free fatty acids, ketones (acetone, beta-hydroxybutyrate, and acetoacetate) are generated. These ketones are relatively strong acids and deplete the body’s buffering capacity.
Clinical Presentation
The symptoms of DKA are directly related to hyperglycemia and acidosis. Hyperglycemia leads to polyuria, polydipsia, and dehydration. The generation of ketoacids results in nausea, vomiting, and abdominal pain. The metabolic acidosis also triggers compensatory hyperventilation with acetone excretion leading to a classic fruity odor on the patient’s breath. Although an increased white blood cell count is common even in the absence of an infection, a fever is rare and should prompt an aggressive search for a concomitant infection. Likewise, an altered mental status is not typical and warrants further investigation.
Therapy
In 2009, the American Diabetes Association published an updated consensus statement regarding the management of DKA in terms of fluids, electrolytes, and insulin therapy.
Fluid and Electrolyte Replacement
Volume replacement is the initial therapy, and isotonic saline (0.9% NaCl) should be infused rapidly (1 to 2 L/h), even if the serum sodium is elevated. After intravascular volume repletion, fluids can be changed to 0.45% NaCl if the serum sodium is 140 mEq/L or greater.
Almost all patients with DKA will have an overall potassium deficit, primarily reflecting urinary losses; however, serum potassium is often initially elevated because potassium is shifted out of cells in response to the insulin deficiency and hyperosmolality. With insulin therapy, potassium is returned to the intracellular space. Profound hypokalemia can result and may lead to life-threatening cardiac arrhythmias and respiratory muscle weakness. Potassium replacement should be initiated when the serum potassium concentration falls below 5.0 to 5.2 mEq/L. If there urine output is adequate (>50 mL/h), potassium should be included in each liter of intravenous (IV) fluid (20 to 30 mEq) with the goal of maintaining the potassium in the range of 4.0 to 5.0 mEq/L.
Likewise, phosphate levels in DKA are often deceptively elevated on presentation despite total body phosphate depletion. Although phosphate replacement has not been associated with improved clinical outcomes, supplementation is prudent when the serum phosphate concentration is less than 1.0 mg/dL to avoid cardiopulmonary muscle weakness.
Despite significant acidosis (pH >7.0), supplemental bicarbonate is rarely needed and may contribute to worsening intracellular acidosis and may increase the risk of hypokalemia and cerebral edema. Bicarbonate supplementation should only be considered when the arterial pH is less than 6.9 and should be terminated once a pH greater than 7.0 is achieved.
Insulin Therapy
Insulin therapy should only be initiated after adequate volume replacement and once the serum potassium is 3.3 mEq/L or greater. Once these goals have been achieved, a continuous infusion of regular insulin is recommended. Although a bolus of insulin has been traditionally used, a randomized trial has recently demonstrated this “priming” bolus is unnecessary, and effective glycemic control can be achieved by starting the insulin drip at 0.14 U/kg/h. Glucose levels should decrease by 50 to 70 mg/dL/h. The insulin infusion rate should be doubled until there is a steady rate of decline in the serum glucose concentration. Glucose should be hourly monitored by finger stick and confirmed by frequent serum glucose measurements. It is important to note, however, that the serum glucose will normalize before ketoacid production stops.
Insulin therapy should be continued along with supplemental glucose until the anion gap normalizes. An abrupt discontinuation of insulin can lead to a recurrence of hyperglycemia and ketoacidosis. Conversely, to prevent hypoglycemia, it is recommended that glucose be added to IV fluids and the insulin infusion adjusted once the serum glucose falls to 250 mg/dL or less. Normalization of glucose levels and reversal of the metabolic acidosis and anion gap should prompt a switch to subcutaneous (SQ) insulin, although the IV and SQ should overlap for several hours.
Precipitating Factors
In most cases, a precipitating cause of DKA can be identified. Although noncompliance or inadequate insulin therapy (i.e., insulin pump failure) can initiate a hyperglycemic crisis, DKA is frequently associated with infection. Myocardial ischemia, stroke, or other acute medical illness can also precipitate a diabetic crisis and should be carefully investigated. Finally, DKA has been associated with the use of glucocorticoids, thiazides, pentamidine, second-generation antipsychotics, and sympathomimetic agents including cocaine.
Complications
Major complications are rare and frequently attributable to underlying medical conditions; however, several DKA-specific complications warrant mention. Cerebral edema is an uncommon complication that primarily develops in children. Clinical symptoms include headache and behavioral and mental status changes that may rapidly progress to seizures, coma, and death. If neurologic findings progress beyond lethargy and behavioral changes, then the mortality rate is over 70%, with only 7% to 14% of patients recovering without permanent disability. Treatment is primarily supportive. Mannitol, hypertonic saline, and dexamethasone have been used, but their role has not been subjected to study. This devastating complication can be minimized by gradually correcting the sodium, water, and glucose abnormalities. Pulmonary edema can occur on occasion as the result of overzealous fluid replacement, poor cardiac function, or reduced osmotic pressure.
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Estimated water and sodium deficits should be gradually corrected with normal saline. For the risk of cerebral edema to be minimized, plasma osmolality should not be reduced too rapidly.
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IV insulin therapy is recommended for severe or complicated DKA.
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Dextrose should be added to the IV fluids once serum glucose levels reach 200 mg/dL. Serum glucose levels should be maintained at 200 mg/dL or greater until ketogenesis resolves.
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The resolution of DKA can either be assessed by directly measuring beta-hydoxybutyrate or by measuring the serum anion gap.
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Potassium should be given when the serum potassium concentration is 5.3 mEq/L or less. Correction of potassium levels should be started before starting insulin therapy if the serum concentration is 3.3 mEq/L or less.
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Sodium bicarbonate therapy is not indicated in patients with an arterial pH greater than 7.00.
Hyperosmolar Hyperglycemic State
Although various terms have been used in the past, the syndrome of hyperglycemia-induced volume depletion without acidosis is now referred to as a “hyperglycemic hyperosmolar state” (HHS) to capture the range of clinical variability involved. Although most patients with HHS have type 2 diabetes, 20% of patients will have no previous history of diabetes. In contrast to DKA, HHS occurs infrequently but carries a much higher mortality rate. Importantly, patients usually do not die because of the severe hypertonicity associated with HHS, but rather as the result of the comorbidities that precipitated or developed during the treatment of HHS.
The hallmark features of HHS are hyperglycemia (glucose >600 mg/dL), hyperosmolality (>320 mOsm/kg), and volume depletion with an average total body water deficit of 9 L. Unlike DKA, HHS is not associated with a significant acidosis. Mild ketonemia, however, does not preclude the diagnosis ( Table 72-1 ).
Pathophysiology
The pathogenesis of HHS is similar to DKA. Traditionally, in HHS, serum insulin levels were thought to be sufficient to prevent the severe ketogenesis, but not high enough to prevent hyperglycemia. This theory, though, is not supported by measurements of serum insulin. More likely, the lack of ketogenesis in HHS is related to lower levels of counter-regulatory hormones (e.g., glucagon, catecholamines).
As with DKA, insulin deficiency coupled with an altered counter-regulatory hormone profile leads to increased gluconeogenesis and impaired glucose use. Large amounts of glucose saturate the urine and impair the concentrating capacity of the kidney. If adequate fluid intake is preserved and renal perfusion is maintained, then major hyperglycemia will not develop. If renal function deteriorates because of underlying kidney disease or intravascular volume depletion, though, plasma glucose levels will increase, and hyperosmolality will develop. Profound hyperglycemia (glucose >600 mg/dL) and hyperosmolality (>320 mOsm/kg) lead to an exuberant osmotic diuresis and severe dehydration.
Clinical Presentation
Although HHS typically occurs in the elderly, it may occur at any age. Symptoms are primarily related to hyperglycemia (e.g., polydipsia, polyuria, fatigue, and visual disturbances) and profound dehydration (e.g., weakness, anorexia, weight loss, dizziness, confusion, and lethargy). The most common clinical presentation is altered mental status and neurologic symptoms. Central nervous symptoms typically occur when the osmolality reaches 230 to 330 mOsm/kg and range from headache to seizures to coma.
Therapy
Although there are some important differences, the treatment of DKA and HHS are very similar.
Fluid and Electrolyte Replacement
Fluid and electrolyte deficits are often more profound than those seen with DKA, but they may not be appreciated on the initial chemistry values. Volume resuscitation is the mainstay of therapy and can lower serum glucose by as much as 50%. This is primarily due to improved renal perfusion and subsequent excretion of glucose. After the initial resuscitation, corrected serum sodium should be calculated with the following equation:
Replacement of one half of the fluid deficit within the initial 12 hours followed by the remainder over the next 12 to 24 hours is recommended. More gradual administration may be needed in patients younger than 20 years to avoid cerebral edema.
The free water deficit can be estimated with the following formula:
where
TBW (total body water) = body weight (kg) × 0.6 for males (or 0.5 for females).
Although the initial potassium levels may be normal or elevated, patients with HHS have a significant potassium deficit. Replacement should be initiated when serum values are between 3.3 and 5.3 mEq/L if urine output is sufficient. Phosphate and magnesium replacement are only needed when levels are extremely low.
Insulin Therapy
Adequate intravascular volume resuscitation should precede instituting insulin therapy to prevent vascular collapse. As with DKA, a potassium level of 3.3 mEq/L or less should be treated before initiating insulin therapy. The rate of decrease of glucose tends to be more precipitous in HHS than in DKA because these patients tend to be more volume depleted. The serum glucose should be maintained between 250 and 300 mg/dL until the plasma osmolality is 315 mOsm/kg or less and the patient is mentally alert. The use of a SQ insulin protocol to initially treat HHS has not been investigated.
Precipitating Factors
The two most common precipitating factors in the development of HSS are inadequate insulin therapy and infection. Because infection precipitates 60% of HHS cases, cultures should be taken and antibiotics should be instituted early. Myocardial infarction or stroke also may provoke the release of counter-regulatory hormones and promote gluconeogenesis. Medications that affect carbohydrate metabolism (e.g., glucocorticoids, thiazide diuretics, phenytoin, beta blockers) may also play a contributing role, and an association with alcohol and cocaine use has been observed.
Complications
Although serious complications are frequently the result of underlying comorbidities, subclinical rhabdomyolysis is common in HHS and may contribute to acute renal failure. Cerebral edema has also been described but is thankfully rare.
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Normal saline should be administered slowly so that the estimated water and sodium deficits can be corrected over the first 24 hours. For the risk of cerebral edema to be minimized, plasma osmolality should not be reduced by more than 3 mosmol/kg/h.
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IV insulin therapy—a bolus followed by an infusion—is recommended.
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Dextrose should be added to the IV fluids once serum glucose levels reach 300 mg/dL. Serum glucose levels should be maintained between 250 and 300 mg/dL until the osmolality is 315 mOsm/kg or less and the patient is mentally alert.
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Supplemental potassium chloride should be given when the serum potassium concentration is 5.3 mEq/L or less. Potassium replacement should be given before starting insulin therapy if the serum concentration is less than 3.3 mEq/L.
Thyrotoxic Crisis
Thyrotoxic crisis, or thyroid storm, is an acute, potentially life-threatening state that occurs in patients with untreated or incompletely treated hypothyroidism. Although the incidence of hyperthyroidism ranges between 0.02% and 1.3%, only 1% to 2% of patients with thyrotoxicosis will develop thyroid storm. If untreated, the mortality from thyroid storm can be extremely high (90%). With early management, mortality is 10% to 20%.
Pathophysiology
Thyroid hormone secretion is tightly regulated by the hypothalamic-pituitary-thyroid axis. Thyrotropin-releasing hormone (TRH) is released from the hypothalamus and stimulates the synthesis and secretion of thyroid-stimulating hormone (TSH). In turn, TSH controls the synthesis and secretion of the thyroid hormones, thyroxine (T 4 ) and triiodothyronine (T 3 ). Over 99.5% of serum T 4 and T 3 are protein bound and metabolically inactive. The small percentage of free T 4 and T 3 influence metabolic function and modulate the release of TRH and TSH via negative feedback.
Interestingly, T 4 has limited activity and must be converted to the more active hormone T 3 by deiodinases. More than 80% of the available T 3 is synthesized in peripheral tissues such as the kidney and liver. T 3 directly binds to cytoplasmic thyroid hormone receptor complexes and migrates with additional regulatory elements to the nucleus to directly activate or inhibit expression of genes encoding proteins that modulate cellular metabolism, adrenergic responsiveness, and thermoregulation. Hyperthyroidism typically results from an overactive thyroid nodule or gland. Less commonly, excessive pituitary secretion of TSH or the overingestion of thyroid hormone can result in hyperthyroidism. The pathologic transition from hyperthyroidism to thyroid storm is not fully understood, but it usually occurs in the setting of surgery, sepsis, injury, or other acute medical illness. Although total thyroid hormone levels may not be significantly higher than those observed in uncomplicated thyrotoxicosis, higher levels of free thyroid hormone and lower levels of binding proteins have been demonstrated. Elevated catecholamines in acute illness or trauma may further stimulate the synthesis and release of thyroid hormone.
Clinical Presentation
Thyroid storm can occur in the setting of hyperthyroidism from any cause, but it most frequently occurs as a complication of Graves disease. Thyroid storm classically presents with fever (>38.5° C) and profound tachycardia. Other cardiac findings may include atrial fibrillation, congestive heart failure, hypotension, and shock. Gastrointestinal symptoms include nausea, vomiting, diarrhea, abdominal pain, and occasionally liver failure. Gastrointestinal fluid losses may be profound, and dehydration may contribute to multiorgan failure. Central nervous system symptoms are common and range from confusion to psychosis to coma.
Serum T 4 or T 3 values cannot be used to differentiate thyrotoxicosis from thyroid storm—the diagnosis must be made on clinical grounds. Burch and Wartofsky developed a clinical scoring system to standardize the diagnosis ( Table 72-2 ). A score of 45 or more is highly suggestive of thyroid storm, a score of 25 to 44 is concerning for impending thyroid storm, and a score less than 25 makes thyroid storm unlikely.
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