Endocrine Disorders

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Chapter 36 Endocrine Disorders

Critical illness leads to widespread changes in the endocrine system; the extent of the changes depends on the severity and duration of the physiologic insult. These changes are similar in nature irrespective of whether the insult involves surgery, sepsis, trauma, or a major cardiovascular event. In this chapter the endocrine disorders that are commonly encountered in postoperative cardiac surgery patients are described and an approach to their management is provided. The stress response to surgery and cardiopulmonary bypass is discussed in Chapter 2.

HYPERGLYCEMIA

Hospitalized patients with hyperglycemia can be classified as follows ¹:

1. Those having previously diagnosed diabetes mellitus.

2. Those having previously unrecognized diabetes mellitus, as evidenced by fasting blood glucose levels greater than 126 mg/dl (7 mmol/l) or random blood glucose levels greater than 200 mg/dl (11.1 mmol/l) that persist after hospital discharge.

3. Those having hospital-related hyperglycemia, as evidenced by fasting blood glucose levels greater than 126 mg/dl or random blood glucose levels greater than 200 mg/dl that revert to normal after hospital discharge.

Hyperglycemia in nondiabetic patients is a risk factor for adverse outcomes. The stress of critical illness or major surgery increases circulating levels of the counterregulatory hormones glucagon, epinephrine, cortisol, and growth hormone. The net effect is hyperglycemia due to increased hepatic glucose production and decreased peripheral glucose uptake. A number of therapies commonly used in the intensive care unit (ICU) can also precipitate hyperglycemia. These include corticosteroids, β₂-adrenoreceptor agonists (epinephrine, isoproterenol, and albuterol), excessive calories in parenteral or enteral nutrition, and dextrose-containing intravenous fluids.

Adverse Effects of Hyperglycemia and Rationale for Treatment

The adverse effects of hyperglycemia are shown in Table 36-1. Treatment with insulin reverses these effects and improves outcome in both diabetic and nondiabetic patients. In a study of diabetic patients with acute myocardial infarction, intensive control of hyperglycemia for at least 3 months, with a target blood glucose level of lower than 180 mg/dl (10 mmol/l), reduced mortality rates for at least 3 years.² In studies of diabetic patients undergoing cardiac surgery, glucose control with a target of lower than 150 mg/dl (8.3 mmol/l) during the first 2 postoperative days reduced the rates of sternal wound infection and overall mortality.^3,⁴ Intensive insulin therapy with a target glucose level of lower than 110 mg/dl (6.1 mmol/l) in surgical intensive care patients—of whom approximately 60% had undergone cardiac surgery—led to a marked reduction in mortality rates, principally among patients staying in an ICU for more than 5 days.⁵ In this study, progressively worse outcomes were seen at higher glucose levels. In a medical ICU setting, the same authors reported a reduction in morbidity with tight glucose control and a benefit in mortality rates in patients whose ICU stay was longer than 3 days.⁶ This later study also reported a much higher rate of hypoglycemia than was seen in the surgical ICU study. In both trials, nutritional targets were met early, with a high proportion of patients receiving parenteral nutrition. This complicates the applicability of these results to centers with less aggressive feeding practices.

Table 36-1 Adverse Effects of Hyperglycemia

Rights were not granted to include this table in electronic media. Please refer to the printed book.

From Clement S, Braithwaite SS, Magee MF, et al: Management of diabetes and hyperglycemia in hospitals. Diabetes Care 27:553-591, 2004. TNF-α, tumor necrosis factor α; NFκB, nuclear factor kappa B.

Although there is no consensus on a threshold glucose level at which to start insulin in patients in an ICU, tighter glucose control is warranted with increasing severity of illness and anticipated length of ICU stay. Particular care should be taken with tight glucose control regimes to avoid hypoglycemia, especially in patients with variable or unreliable nutritional intakes. However, with appropriate education of staff and frequent bedside monitoring of blood glucose, tight control of blood glucose can be achieved. Except in the setting of myocardial ischemia and reperfusion (see subsequent material), it appears that the benefits arise from better control of hyperglycemia rather than from insulin per se.^7,⁸

Treatment of Hyperglycemia

Metabolic Support in Myocardial Ischemia using High-Dose Glucose-Insulin-Potassium Infusions

Myocardial Substrate Metabolism

As part of the stress response to surgery or myocardial ischemia, insulin activity is reduced and circulating levels of catecholamines, growth hormone, glucagon, and cortisol are increased (see Chapter 2). This results in increased myocardial utilization of free fatty acids and reduced utilization of glucose—despite hyperglycemia. In the absence of oxygen, the myocardium ceases to oxidize lactate and may become a net lactate producer (as the result of anaerobic glycolysis).^14,¹⁵ These changes are potentially harmful to the ischemic myocardium. Increased reliance on free fatty acid metabolism leads to increased oxygen requirements, which may exacerbate ischemia. Ischemia-induced inhibition of β-oxidation leads to the accumulation of the toxic intermediates of fatty acid metabolism such as acyl CoA, which is associated with intracellular calcium overload and membrane instability. During postischemic reperfusion, myocardial fatty acid oxidation is poorly coupled with contractile function so that increased oxygen consumption is not associated with increased myocardial work. The net result is an increase in myocardial oxygen requirements, reduced contractility, and arrhythmias.

Insulin, given in doses sufficient to suppress circulating free fatty acid levels and optimize myocardial glucose uptake (≥ 0.1 units/kg/hr),¹⁶ protects ischemic myocardium and reduces reperfusion injury. Reduced mitochondrial fatty acid uptake and increased glucose uptake (with increased adenosine triphosphate [ATP] production resulting from glycolysis) improve membrane function and thereby reduce the risk for arrhythmias. Increased glucose oxidation and anaplerosis (replenishment of citric acid cycle substrates) reduce myocardial oxygen consumption and improve coupling between substrate oxidation and contractile function.

Glucose-Insulin-Potassium Infusions in Cardiac Surgery

High-dose infusions of glucose-insulin-potassium (GIK) have been reported to improve outcomes in patients with unstable angina undergoing urgent coronary artery bypass graft (CABG) surgery ¹⁷ and in patients with refractory left ventricular failure following CABG surgery.¹⁸ The maximum benefit from perioperative high-dose GIK infusion is likely to be obtained if the infusion is commenced prior to the induction of anesthesia, continued for at least 12 hours postoperatively (to cover the period of reperfusion), and combined with tight glycemic control.^19,²⁰

Whether high-dose GIK improves outcome in patients with acute myocardial infarction, in addition to the benefit received from reperfusion therapy, is uncertain. Early small trials reported a benefit,^21,²² but a more recent large, randomized trial in patients with ST-elevation myocardial infarction reported no benefit.²³

One method of administering high-dose GIK is shown in Table 36-2. The principal risks in this technique are hypoglycemia and hyperkalemia, the latter after discontinuation of the infusions and in the presence of renal dysfunction. It is essential that the insulin and potassium supplements be stopped first, then the patient slowly weaned from the dextrose infusion (see Table 36-2).

Table 36-2 Protocol for High-Dose Glucose-Insulin-Potassium Infusion

Initiation of Infusion

Infusion 1

50 units soluble insulin in 50 ml 0.9% saline at a fixed infusion rate of 0.1 units/kg/hr

Infusion 2

500 ml 50% dextrose with 25 mmol KCl, 25 mmol KH2PO4, 20 mmol MgSO4

Infusion is commenced at 0.5 ml/kg/hr and adjusted to maintain the blood glucose at 100 to 150 mg/dl (5.6 to 8.3 mmol/l)

Cessation of Infusions

Infusion 1

Stop insulin infusion

Infusion 2

Replace infusion of 50% dextrose + electrolytes with plain 50% dextrose

Run at same rate as previous infusion

Commence 5% dextrose at 1 ml/kg/hr

Measure blood glucose every 1/2 hr and potassium hourly

If blood glucose >250 mg/dl (13.9 mmol/l) reduce 50% dextrose by a half

If blood glucose 200 to 250 mg/dl (11.1 to 13.9 mmol/l) reduce 50% dextrose by a quarter

Stop 50% dextrose when infusion rate <5 ml/hr

Continue to check blood glucose and serum potassium hourly for at least 6 hr

Continue 5% dextrose (1 ml/kg/hr) for at least 6 hr

DIABETES MELLITUS

About 30% of patients undergoing CABG surgery in the United States have diabetes.²⁴ Diabetic patients undergoing cardiac surgery are more likely to have preexisting hypertension, renal insufficiency, previous myocardial infarction, congestive heart failure, or triple-vessel or left main coronary artery disease. Furthermore, they have higher hospital mortality rates and higher rates of postoperative complications than nondiabetic patients.²⁵ Diabetic patients also have a severalfold higher risk for mortality following acute myocardial infarction as well as an increased incidence of congestive heart failure, reinfarction, and recurrent ischemia.^2,^11,²⁶ Although the rate of death due to coronary heart disease has declined in the overall population over the past few decades, this decline has been less marked among diabetics.²⁷ Furthermore, the incidences of insulin resistance and type 2 diabetes are increasing in North America.

Type 1 diabetes results from immunologic destruction of pancreatic β cells at a young age. Patients with type 1 diabetes are insulin deficient and require treatment with insulin to avoid ketoacidosis. Type 2 diabetes results from a combination of insulin resistance (due to obesity, physical inactivity, and genetic susceptibility) and an age-related decline in insulin secretion. Insulin resistance is often present for many years before type 2 diabetes becomes apparent. Increased insulin secretion compensates for insulin resistance at first, but as insulin secretion declines, hyperglycemia occurs, initially after meals or during periods of stress and later when fasting. Hyperglycemia can usually be controlled by diet initially but subsequently it is common for patients to require treatment with oral hypoglycemic drugs and eventually with insulin. Insulin resistance is associated with dyslipidemia, hypertension, and a prothrombotic tendency, each of which is an independent risk factor for coronary heart disease.¹¹ Of patients with diabetes mellitus, 90% have type 2.

Diabetic Hyperglycemic Emergencies

The emergencies of diabetic ketoacidosis and a nonketotic hyperosmolar state can occur with both type 1 and type 2 diabetes.^28,²⁹ The underlying mechanism in both disorders is reduced circulating insulin with concurrent elevation of counterregulatory hormones, principally glucagon. Diabetic ketoacidosis occurs more commonly with type 1 diabetes and manifests as hyperglycemia and metabolic acidosis. Metabolic acidosis is caused by ketoacid formation resulting from fatty acid metabolism. Patients with type 2 diabetes are more likely to develop nonketotic hyperosmolar state, in which there is sufficient circulating insulin to prevent ketogenesis but insufficient to prevent hyperglycemia. Metabolic acidosis may develop in a nonketotic hyperosmolar state as the result of a combination of lactic acidosis (due to hypoperfusion), a low level of ketoacidosis (due to starvation), and inorganic acidosis (due to renal failure). Profound hyperosmolarity can lead to coma. Both conditions result in glycosuria, osmotic diuresis, and water and electrolyte depletion (Table 36-3). Dehydration tends to be more severe in the nonketotic hyperosmolar state. Common precipitants of both conditions include sepsis, acute coronary syndromes, glucocorticoids, sympathomimetics, and inadequate insulin therapy.

Table 36-3 Laboratory Features and Water and Electrolyte Deficits for Diabetic Ketoacidosis and Nonketotic Hyperosmolar State

	DKA	NKHS
Blood glucose (mg/dl)	>250	>600
Serum osmolality (mOsm/l)	variable	>350
Arterial PH	<7.3	>7.3
Serum bicarbonate (mmol/l)	<15	>15
Ketones	moderate	small
Anion gap (mmol/l)	>12	variable
Total Deficits
Water (l)	6	9
Sodium (mmol)	500-700	350-900
Potassium (mmol)	200-350	300-400
Phosphate (mmol)	50-100	20-100
Magnesium (mEq)	50-150	50-150
Calcium (mEq)	50-150	50-150

DKA, diabetic ketoacidosis; L, liter; NKHS, nonketotic hyperosmolar state.

Data from Kitabachi AE, Umpierrez GE, Murphy MB, et al: Hyperglycemic crises in diabetes. Diabetes Care 27(suppl 1): S94-S102, 2004; Lebovitz HE: Diabetic ketoacidosis. Lancet 345:767-772, 1995.

Management of Diabetic Ketoacidosis and Nonketotic Hyperosmolar States

Fluids, insulin, and electrolytes are used to treat ketoacidosis and hyperosmolar states.^28,²⁹

Fluid Therapy

Severe hypovolemia should be treated by administering a rapid infusion of 1 to 2 liters of 0.9% saline. In the absence of marked hypovolemia 1 liter of 0.9% saline may be infused over the first hour followed by 500 ml/hr over the next 8 hours. Hartmann solution (see Table 32-3) may be used in place of 0.9% saline if there is profound acidosis. If, after the first hour, the corrected sodium (see Chapter 32) is greater than 150 mmol/l, 0.45% saline should be used in place of 0.9% saline.

When the blood glucose level has decreased to less than 250 mg/dl (13.9 mmol/l), an infusion of 5% or 10% dextrose should be commenced at a rate of 150-250 ml/hr. 0.45% saline should be continued at 250 ml/hr if there is ongoing evidence of extracellular fluid depletion or polyuria.

Insulin

Intravenous insulin should be commenced at 0.1 units/kg/hr, and the dose adjusted to achieve a fall in the blood glucose level of about 50 to 75 mg/dl (3-4 mmol/l) per hour until it reaches 250 mg/dl (13.9 mmol/l). Blood glucose should then be maintained at this level with an infusion of 5% or 10% dextrose for the first 24 hours. Insulin should be continued (at about 0.05 units/kg/hr) until ketosis is reversed.

Electrolyte and Bicarbonate Therapy

Potassium, at 20 to 40 mmol/l of infusion fluid, should be administered once hyperkalemia has been excluded and urine output has been established. Insulin therapy should be temporarily withheld if the patient is initially hypokalemic. As a rule, phosphate and magnesium replacement are also warranted. Sodium bicarbonate should be avoided unless the pH is less than 6.9.

Monitoring Progress

Blood glucose levels should be checked hourly and electrolytes every 2 to 4 hours. Resolution of ketoacidosis is evidenced by a fall in plasma ketone (β-hydroxybutyrate) concentration, a rise in pH, and a narrowing of the anion gap.

ADRENOCORTICAL DISORDERS

Normal Adrenal Glucocorticoid Function

The adrenal cortex secretes the glucocorticoid cortisol in response to corticotropin from the anterior pituitary, which is released in response to corticotropin-releasing hormone from the hypothalamus. Corticotropin and corticotropin-releasing hormone are both subject to negative feedback control by cortisol. Cortisol secretion normally follows a pulsatile and diurnal pattern, with peak secretion in the morning and a nadir in the late evening. Only 5% of circulating cortisol is in the free-form; the remainder is bound to corticosteroid-binding globulin and albumin.

Although cortisol has some mineralocorticoid (aldosterone-like) effects, its predominant action is on intermediary metabolism. Cortisol raises blood glucose directly by promoting gluconeogenesis and glycogenolysis and indirectly by suppressing insulin. Protein catabolism and lipolysis are increased. The cardiovascular effects of cortisol include maintaining vascular tone, endothelial integrity, and cardiac contractility. Cortisol also potentiates the vasoconstrictor and inotropic effects of catecholamines. Cortisol modulates the balance of pro- and antiinflammatory mediators by means of a net antiinflammatory and immunosuppressive effect.³⁰

Adrenocortical Stress Response

Any stressful stimulus, such as pain, cold, fever, hypovolemia, surgery, trauma, or inflammation, results in a sustained increase in corticotropin and cortisol secretion, with loss of diurnal variation. The magnitude and duration of this response is proportional to the severity of the stimulus. Following major surgery, peak plasma cortisol levels are approximately 30 μg/dl (828 nmol/l); return to basal levels (approximately 14 μg/dl [386 nmol/l]) occurs over the subsequent 72 hours.³¹ With severe illness or injury, the plasma cortisol may be closer to 50 μg/dl (1380 nmol/l), and can be as high as 200 μg/dl (5520 nmol/l), and remain elevated for many days.³² In addition, corticosteroid-binding globulin levels decrease, and cortisol is cleaved from corticosteroid-binding globulin by neutrophil elastase, which results in increased free cortisol levels.

The increased secretion and action of cortisol is an essential component of the adaptation to illness or stress, and a defective response leads to adverse outcomes. However, the definition of a defective response, or relative adrenal insufficiency, is unclear.

Clinical Features of Relative Adrenal Insufficiency

Relative adrenal insufficiency most commonly manifests as vasopressor-dependent hypotension,^30,³³ difficulty in weaning from ventilatory support,³⁴ or persistent inflammation. The hemodynamic state may mimic both septic shock, with high cardiac output and vasodilation, and hypovolemic shock, with depressed cardiac contractility, decreased preload, and vasoconstriction. Most of the clinical manifestations of chronic adrenal insufficiency are nonspecific. However, the presence of hypoglycemia or eosinophilia, which is uncommon in the ICU, should raise suspicion of adrenal insufficiency. Hyponatremia and hyperkalemia may be present, but they are more commonly due to other causes or masked by intravenous fluid therapy (see Chapter 32).³⁵ Adrenal insufficiency may predispose to increased blood loss in patients undergoing CABG surgery.³⁶

Causes of Relative Adrenal Insufficiency

Circulating cytokines cause relative adrenal insufficiency in 30% to 60% of patients with severe sepsis or septic shock or after major surgery.^33,³⁷ Destructive processes directly affecting the adrenal glands include adrenal or retroperitoneal hemorrhage, metastatic malignancy, or systemic infection (HIV, tuberculosis, cytomegalovirus, or fungal infection). The anesthetic agent etomidate and the antifungal ketoconazole inhibit enzymes involved in cortisol synthesis. Phenytoin and rifampicin enhance hepatic metabolism of cortisol.

Diagnostic Tests for Relative Adrenal Insufficiency

An ideal test of adrenal function would identify patients who would benefit from treatment with corticosteroids in terms of earlier recovery of organ function and improved survival rates.³⁷ Unfortunately, no such test exists. Current tests (Table 36-4) are based on the measurement of total plasma cortisol, which may not be reflective of free cortisol and does not take into account tissue resistance. In critically ill patients, the adrenal axis should be maximally stimulated, thus negating the rationale for corticotropin-stimulation tests in patients in the ICU. However, the combination of baseline and stimulated plasma cortisol levels may have more prognostic significance.³⁵

Table 36-4 Diagnostic Tests for Relative Adrenal Insufficiency

Test	Result	Comments
Random plasma total cortisol	Value less than 25 μg/dl (<690 nmol/l)37	Arbitrary threshold value that should be correlated with severity of stress Poor at distinguishing which patients would benefit from glucocorticoid therapy

High-dose (250 μg intravenous) corticotropin stimulation test Rise in plasma total cortisol less than 9 μg/dl (250 nmol/l)³³

Criteria for adrenal insufficiency based on response in unstressed subjects

Relatively insensitive (misses increased tissue resistance and secondary insufficiency)

May identify patients who would benefit from glucocorticoid therapy

Low-dose (1 μg intravenous) corticotropin stimulation test Rise in plasma total cortisol less than 9 μg/dl (250 nmol/l)^36,⁴⁷

May be more sensitive than high-dose corticotropin test, but limited data in critically ill patients

Preoperative test may predict postoperative cortisol response to CABG surgery

Plasma-free cortisol Value less than 2 μg/dl (55 nmol/l)⁴⁸ Tests physiologically active portion of circulating cortisol, but assay not commercially available

CABG, coronary artery bypass graft

Treatment of Relative Adrenal Insufficiency

Older studies of short-term, high-dose glucocorticoid therapy showed no reduction in mortality rates in patients with severe sepsis or septic shock. More recent studies have shown that a longer course (>7 days) of lower, “stress” doses of glucocorticoids reduce vasopresssor requirements, shorten the duration of ventilation, and may improve survival rates in patients with laboratory evidence of adrenal insufficiency.^31,^33,^34,^38,³⁹ Stress dose glucocorticoid therapy is not associated with an increased risk for infection.

As a practical approach, a trial of intravenous hydrocortisone (100-mg bolus followed by infusion of 10 mg/hr or 50 mg every 6 hr) is warranted in patients with vasopressor-dependent vasodilatory shock. A significant reduction in vasopressor requirements within 24 hours probably justifies continuing therapy until the shock has resolved. If there is no beneficial response, hydrocortisone should be discontinued to avoid the deleterious side effects of glucocorticoids, which include hyperglycemia, gastrointestinal bleeding, neuromuscular weakness, and psychosis.

Specific mineralocorticoid replacement by fludrocortisone is not necessary if more than 50 mg daily of hydrocortisone is given. Even with dexamethasone (which has minimal mineralocorticoid activity), administration of 0.9% saline eliminates the need for separate mineralocorticoid therapy. Various glucocorticoids are compared in Table 36-5.

Table 36-5 Characteristics of Corticosteroids

Acute Adrenal Crisis

Acute, complete loss of adrenal function is rare and is usually caused by hemorrhage or infarction of the adrenal glands, most often in patients already severely ill with thromboembolic disease, coagulopathy, or shock. Patients present with acute circulatory failure, sometimes accompanied by abdominal or flank pain. Biochemical derangement is uncommon.³⁵ The diagnosis is confirmed by a random plasma cortisol level of less than 3 μg/dl (80 nmol/l) and no response to a corticotropin stimulation test. Treatment involves intravenous hydrocortisone (100-mg bolus followed by a 10 mg/hr infusion or 100 mg every 6 hr) and fluid resuscitation with 0.9% saline. Intravenous glucose may be required to prevent hypoglycemia. If testing is delayed, intravenous dexamethasone (4 mg every 12 hr), which does not interfere with the cortisol assay, can be used initially in place of hydrocortisone.

Hemorrhage or infarction of the pituitary gland (pituitary apoplexy) causes the same clinical picture but is distinguished by a positive cortisol response to corticotropin stimulation. Adrenal crisis may also occur in patients with chronic adrenal insufficiency who are given insufficient glucocorticoids during stress.

Management of Patients With Preexisting Adrenal Insufficiency

Patients on long-term glucocorticoid therapy who develop critical illness or undergo major surgery are unable to mount a maximal adrenal stress response. This includes patients with chronic adrenal insufficiency (e.g., Addison disease or hypopituitarism) and those receiving corticosteroids for autoimmune or inflammatory diseases. Such patients should receive intravenous hydrocortisone (10 mg/hr as a continuous infusion or 50 to 100 mg intravenously every 6 hr) during periods of surgery or critical illness. This dosage can be reduced to the previous maintenance dose over 2 to 3 days once the stressful stimulus or critical illness has resolved.

In patients recently treated with corticosteroids, the time to recovery of the adrenal axis after discontinuation of therapy is highly variable. Recovery from prolonged exposure to high doses of corticosteroids may take as long as a year. As a guide, any patient who has taken at least 20 mg per day of prednisone or the equivalent for more than 5 days is at risk for adrenal insufficiency and should receive a course of hydrocortisone to cover the period of stress.

THYROID DISORDERS

Normal Thyroid Function

The thyroid gland synthesizes and secretes thyroxine (T4) and triiodothyronine (T3) under stimulation of thyrotropin from the anterior pituitary gland, which in turn is stimulated by thyrotropin-releasing hormone from the hypothalamus. Some T4 subsequently undergoes conversion to T3 in the peripheral tissues. Thyroid hormone (principally T3) regulates thyrotropin secretion by direct negative feedback and by antagonizing the action of thyrotropin-releasing hormone on thyrotropin secretion. Circulating T4 and T3 are almost entirely bound to plasma proteins, principally thyroxine-binding globulin; only about 0.03% of T4 and 0.3% of T3 are in the free state and available to tissues. The relatively weaker binding of T3 to the plasma proteins results in a more rapid onset and offset of action than occurs with T4. The metabolic effects of thyroid hormone are mediated through T3.

Cardiovascular Effects of Hyperthyroidism

An excess of thyroid hormone causes vasodilation, increased cardiac output, and tachycardia.⁴⁰ Blood pressure may fall. Atrial fibrillation may occur, even with subclinical hyperthyroidism. Reduced blood pressure leads to sodium and water retention. Heart failure may develop as a result of tachycardia (or atrial fibrillation) or sodium and water retention or because of an impaired ability to respond to the increased metabolic rate that is associated with hyperthyroidism (high-output heart failure).

Diagnosis and Treatment of Hyperthyroidism

The changes in T3, T4, and thyrotropin that occur with primary (thyroid) and secondary (pituitary or hypothalamic) hyperthyroidism are shown in Table 36-6. Treatment should include a β blocker for control of tachycardia. Propranolol (40 to 120 mg/day in divided doses orally) is the β blocker of choice because of its rapid onset of action and ability to inhibit peripheral conversion of T4 to T3. Thyroid hormone production can be reduced by antithyroid drugs (e.g., carbimazole), radioactive iodine, or surgery. Treatment of hyperthyroidism usually results in spontaneous reversion of atrial fibrillation to sinus rhythm. Electrical or pharmacologic cardioversion may be successful only after the patient has been rendered euthyroid. With severe hyperthyroidism, intravenous hydrocortisone (50 to 100 mg every 6 hr) should also be given because it reduces the peripheral conversion of T4 to T3.

Table 36-6 Changes in Free Triiodothyronine (T3) and Free Thyroxine(T4) and Thyrotropin Levels With Thyroid Disease

Cardiovascular Effects of Hypothyroidism

The cardiovascular manifestations of hypothyroidism ⁴⁰ are bradycardia, reduced myocardial contractility, increased systemic resistance, and mild hypertension. Despite reduced contractility, heart failure is uncommon because the metabolic rate is reduced. There may be prolongation of the cardiac action potential, manifested as a prolonged QT interval, which predisposes to ventricular arrhythmias (see Chapter 21). With severe hypothyroidism, there may be nonpitting edema (myxedema), pericardial effusion, and elevated plasma concentrations of cholesterol and creatine kinase.

Diagnosis and Treatment of Hypothyroidism

The changes in T3, T4, and thyrotropin that occur with hypothyroidism are shown in Table 36-6. Treatment with thyroxine reverses all of the cardiovascular effects of hypothyroidism. Young patients who do not have other cardiac disease can be given full replacement doses (100 to 150 μg orally once daily) of thyroxine at the outset. Older patients and those with ischemic heart disease should initially be given 25 μg daily, with a gradual increase in dosage in increments of 25 μg every month, up to the full replacement dosage. In suspected secondary (pituitary or hypothalamic) hypothyroidism, intravenous hydrocortisone (100 mg every 6 hr) should be given prior to starting thyroxine because acute adrenal insufficiency may be precipitated by thyroxine-induced increased metabolic rate.

Amiodarone and Thyroid Function

Amiodarone ⁴⁰ inhibits the peripheral conversion of T4 to T3, leading to a 25% fall in T3 concentration and a slight rise in T4 and thyrotropin concentrations. Because of its high iodine content, amiodarone can also inhibit the synthesis and secretion of T3 and T4. Amiodarone causes hypothyroidism in 5% to 25% of patients who are treated chronically with the drug. Thyroid function tests should be measured every few months, and thyroxine therapy should be instituted if indicated amiodarone does not have to be discontinued.

Hyperthyroidism occurs in 2% to 10% of patients chronically treated with amiodarone; it is the result of either iodine excess or thyroiditis. The former responds to radioactive or antithyroid drug treatment. The latter is best treated by a course of prednisone (40 mg orally daily for several weeks). Unlike hypothyroidism, hyperthyroidism is an indication to stop amiodarone.

Sick Euthyroid Syndrome

Sick euthyroid syndrome ⁴⁰ is a condition characterized by low plasma levels of T3. Plasma levels of T4 and thyrotropin are usually normal but with severe forms of the syndrome are also reduced (see Table 36-6). Thus, the biochemical picture may resemble secondary hypothyroidism, that is, hypothyroidism due to pituitary failure, which is very rare. Sick euthyroid syndrome occurs in association with severe systemic illness, including acute myocardial infarction, heart failure, and cardiac surgery. It also develops within 24 hours of a fast. The main pathophysiologic mechanism of the syndrome is reduced peripheral conversion of T4 to T3. In addition, thyroid hormone binding globulin and albumin levels may be decreased, and the tissue uptake and intracellular effects of T3 and T4 may be reduced.

Following cardiac surgery, levels of free and total T3 typically decline by 50% to 75% for 1 to 4 days. Patients may have reduced myocardial contractility and increased peripheral vascular resistance similar to that seen with hypothyroidism, although clinically these findings may be difficult to distinguish from the underlying illness. Treatment of sick euthyroid syndrome with T4 or T3 does not improve outcome ⁴¹ and is not recommended.

Triiodothyronine and Cardiac Surgery

The rationale for using thyroid hormones following cardiac surgery ⁴² is primarily to improve cardiac performance rather than to correct hypothyroidism or sick euthyroid syndrome. Treatment with intravenous T3 during the intraoperative and postoperative periods increases cardiac output, reduces systemic vascular resistance, has an inotrope-sparing effect, and may reduce the incidence of atrial fibrillation.^43,⁴⁴ However, a reduction in postoperative morbidity and mortality rates has not been demonstrated.⁴³

OTHER HORMONES

Growth Hormone

In critically ill patients, growth hormone secretion becomes nonpulsatile and has variable circulating levels. Treatment with high-dose growth hormone is detrimental for patients in the ICU,⁴⁵ but physiologic doses may improve hemodynamics and functional status in patients with idiopathic dilated cardiomyopathy.⁴⁶ Currently, there is no role for the routine use of growth hormone in patients after cardiac surgery.

Vasopressin (Antidiuretic Hormone)

In normal subjects, the primary role of vasopressin is to maintain water homeostasis (see Chapters 1 and Chapter 32). However, in response to hypotension resulting from hemorrhage or sepsis, vasopressin secretion acts as a potent vasoconstrictor by potentiating the effects of circulating catecholamines, by inactivating vascular smooth muscle potassium-ATP channels, and by blunting the vasodilatory effects of nitric oxide. During severe vasodilatory shock, vasopressin stores rapidly become depleted. Low-dose vasopressin infusion (0.04 μg/min) can restore blood pressure in such patients despite catecholamine resistance (see Chapters 20 and Chapter 35). Its role in brain-dead organ donors is discussed in Chapter 38.

REFERENCES

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2 Malmberg K. Prospective randomised study of intensive insulin treatment on long term survival after acute myocardial infarction in patients with diabetes mellitus. DIGAMI (Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction) Study Group. BMJ. 1997;314:1512-1515.

3 Furnary AP, Gao G, Grunkemeier GL, et al. Continuous insulin infusion reduces mortality in patients with diabetes undergoing coronary artery bypass grafting. J Thorac Cardiovasc Surg. 2003;125:1007-1021.

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7 van den Berghe G, Wouters PJ, Bouillon R, et al. Outcome benefit of intensive insulin therapy in the critically ill: insulin dose versus glycemic control. Crit Care Med. 2003;31:359-366.

8 Finney SJ, Zekveld C, Elia A, et al. Glucose control and mortality in critically ill patients. JAMA. 2003;290:2041-2047.

9 UK Prospective Diabetes Study Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:854-865.

10 Lalau JD, Lacroix C, de Cagny B, et al. Metformin-associated lactic acidosis in diabetic patients with acute renal failure: a critical analysis of its pathogenesis and prognosis. Nephrol Dial Transplant. 1994;9(suppl 4):126-129.

11 Clement S, Braithwaite SS, Magee MF, et al. Management of diabetes and hyperglycemia in hospitals. Diabetes Care. 2004;27:553-591.