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Three major classes of hormones—androgens, glucocorticoids, and mineralocorticoids—are secreted by the adrenal cortex.[163] [164] For each class, an excess or a deficiency of hormone produces a characteristic clinical syndrome. The widespread use of steroids can also make the adrenal cortex unable to respond normally to the demands placed on it by surgical trauma and subsequent healing.[165] [166] [167] [168] [169] [170] [171] [172] [173] [174] The increase in unindicated (scanning) computed tomographic (CT) abdominal imaging procedures has meant that many adrenal masses have unfortunately been discovered only incidentally.[175] [176] [177] [178] Several points relative to adrenal cortical management deserve attention:
Controlled comparisons of perioperative management for patients who have disorders of adrenal function are lacking, although we use steroids more and more commonly, with the results of some controlled trials available for specific uses.[163] [179] However, a review of the possible pathophysiologic changes in the adrenal cortex and techniques for their management should enable us to improve the perioperative care of patients with adrenal abnormalities.
Androstenedione and dehydroepiandrosterone, weak androgens arising from the adrenal cortex,[180] constitute major sources of androgen in women (and have gained
The principal glucocorticoid, cortisol, is an essential regulator of carbohydrate, protein, lipid, and nucleic acid metabolism. Cortisol is believed to exert its biologic effects through a sequence of steps initiated by binding of hormone to stereospecific intracellular cytoplasmic receptors. This bound complex stimulates nuclear transcription of specific mRNAs. These mRNAs are then translated to give rise to proteins that mediate the ultimate effects of hormones.
Most cortisol is bound to corticosterone-binding globulin (CBG, transcortin). It is the relatively small amounts of unbound cortisol that enter cells to induce actions or to be metabolized. Conditions that induce changes in the amount of CBG include liver disease and nephrotic syndrome, both of which result in decreased circulating levels of CBG, and estrogen administration and pregnancy, which result in increased CBG production. Total serum cortisol levels may become elevated or depressed under conditions that alter the amount of bound cortisol, and yet the unbound, active form of cortisol is present in normal amounts. The most accurate measure of cortisol activity is the level of urinary cortisol—that is, the amount of unbound, active cortisol filtered by the kidney.
The serum half-life of cortisol is 80 to 110 minutes.[171] However, because cortisol acts through intracellular receptors, pharmacokinetic data based on serum levels are not good indicators of cortisol activity. After a single dose of glucocorticoid, serum glucose is elevated for 12 to 24 hours; improvement in pulmonary function in patients with bronchial asthma can still be measured 24 hours after glucocorticoid administration.[171] Treatment schedules for glucocorticoid replacement are therefore based not on the measured serum half-life but on the well-documented prolonged end-organ effect of these steroids. Hospitalized patients requiring chronic glucocorticoid replacement therapy are usually treated twice daily, with a slightly higher dose given in the morning than in the evening to simulate the normal diurnal variation in cortisol levels.[163] For patients who require parenteral "steroid coverage" during and after surgery (see later paragraphs), administration of glucocorticoid every 12 hours is appropriate.[169] [170] The relative potencies of glucocorticoids are listed in Table 27-8 . Cortisol is inactivated primarily in the liver and is excreted as 17-hydroxycorticosteroid. Cortisol is also filtered and excreted unchanged into urine.
The synthetic glucocorticoids vary in their binding specificity in a dose-related manner. When given in supraphysiologic doses (more than 30 mg/day), cortisol and cortisone bind to mineralocorticoid receptor sites and cause salt and water retention and loss of potassium and hydrogen ions.[171] When these steroids are administered in maintenance doses of 30 mg/day or less, patients require a specific mineralocorticoid for electrolyte and volume homeostasis. [171] Many other steroids do not bind to mineralocorticoid receptors, even at high doses, and have no mineralocorticoid effect[171] (see Table 27-8 ).
Secretion of glucocorticoids is regulated by pituitary adrenocorticotropic hormone (ACTH). ACTH is synthesized from a precursor molecule (pro-opiomelanocortin) that is metabolized to form an endorphin (β-lipotropin) and ACTH. Episodic secretion of ACTH has a diurnal rhythm that is normally greatest during the early morning hours in men, later in women, and is regulated at least in part by light-dark cycles. Its secretion is stimulated by release of corticotropin-releasing factor (CRF) from the hypothalamus. (An abnormality in the diurnal rhythm of corticoid secretion has been implicated as a cause of so-called jet lag.) Cortisol and other glucocorticoids exert negative feedback at both the pituitary and hypothalamic levels to inhibit the secretion of ACTH and CRF. If one destroys the CRF- or ACTH-producing cells, the adrenal takes more than 30 days to atrophy to the point where acute administration of exogenous ACTH will cause almost no adrenal responsiveness.
Aldosterone, the major mineralocorticoid secreted in humans, comes
from the zona glomerulosa of the adrenal cortex and causes reabsorption of sodium
and secretion of potassium and hydrogen ions, thereby contributing to electrolyte
and volume homeostasis.[181]
This action is most
prominent in the distal renal tubule but also occurs in the salivary and sweat glands.
The major regulator of aldosterone secretion is the renin-angiotensin system. Juxtaglomerular
cells in the cuff of the renal arterioles are sensitive to decreased renal perfusion
pressure or volume
| Steroids | Relative Glucocorticoid Potency | Equivalent Glucocorticoid Dose (mg) |
|---|---|---|
| Short Acting |
|
|
| Cortisol (hydrocortisone) | 1.0 | 20.0 |
| Cortisone | 0.8 | 25.0 |
| Prednisone | 4.0 | 5.0 |
| Prednisolone | 4.0 | 5.0 |
| Methylprednisolone | 5.0 | 4.0 |
| Intermediate Acting |
|
|
| Triamcinolone | 5.0 | 4.0 |
| Long Acting |
|
|
| Betamethasone | 25.0 | 0.60 |
| Dexamethasone | 30.0 | 0.75 |
| Data from Axelrod L: Glucocorticoid therapy. Medicine (Baltimore) 55:39, 1976. | ||
Glucocorticoid excess (Cushing's syndrome) resulting from either endogenous oversecretion or chronic treatment with higher than physiologic-dose glucocorticoids produces a moon-faced plethoric individual with a centripetal distribution of fat (truncal obesity and skinny extremities), thin skin, easy bruising, and striae. Muscle wasting is common, but the heart and diaphragm are usually spared. A test for this syndrome is to ask the patient to get up from a chair without using the hands. An inability to do so indicates proximal muscle weakness consistent with Cushing's syndrome. These patients often have osteopenia as a result of decreased formation of bone matrix and impaired absorption of calcium. Fluid retention and hypertension (because of increases in renin substrate and vascular reactivity caused by glucocorticoid) are common. Such patients may also have hyperglycemia and even diabetes mellitus from inhibition of peripheral use of glucose, as well as anti-insulin action and concomitant stimulation of gluconeogenesis ( Table 27-9 ).
The most common cause of Cushing's syndrome is the administration
of glucocorticoids for such conditions as arthritis, asthma, and allergies.[163]
In these conditions, the adrenal glands atrophy and cannot respond to stressful
| Cushing's Syndrome | Hypoadrenalism |
|---|---|
| Central obesity | Weight loss |
| Proximal muscle weakness | Weakness, fatigue, lethargy |
| Osteopenia at a young age and back pain | Muscle and joint pain |
| Hypertension | Postural hypotension and dizziness |
| Headache | Headache |
| Psychiatric disorders | Anorexia, nausea, abdominal pain, constipation, diarrhea |
| Purple stria |
|
| Spontaneous ecchymoses |
|
| Plethoric facies |
|
| Hyperpigmentation | Hyperpigmentation |
| Hirsutism |
|
| Acne |
|
| Hypokalemic alkalosis | Hyperkalemia, hyponatremia |
| Glucose intolerance | Occasional hypoglycemia |
| Kidney stones | Hypercalcemia |
| Polyuria | Prerenal azotemia |
| Menstrual disorders |
|
| Increased leukocyte count |
|
Special preoperative and preprocedure considerations for patients with Cushing's syndrome include regulating diabetes and hypertension and ensuring that intravascular fluid volume and electrolyte concentrations are normal. Ectopic ACTH production may cause marked hypokalemic alkalosis.[163] Treatment with the aldosterone antagonist spironolactone will stop the potassium loss and help mobilize excess fluid. Because of the high incidence of severe osteopenia and the risk of fractures, meticulous attention must be paid to positioning of the patient.[163] In addition, glucocorticoids are lympholytic and immunosuppressive and thus increase the patient's susceptibility to infection.[183] The tensile strength of healing wounds decreases in the presence of glucocorticoids, an effect that is at least partially reversed by the topical administration of vitamin A.[184]
Specific considerations pertain to the surgical approach for each cause of Cushing's syndrome. For example, nearly three fourths of cases of spontaneous Cushing's disease result from a pituitary adenoma that secretes ACTH. Our perioperative treatment of patients who have Cushing's disease and a pituitary microadenoma differs from that of patients who have a pituitary adenoma associated with amenorrhea and galactorrhea. A patient with Cushing's disease is inclined to bleed more easily and (on the basis of anecdotal evidence) tends to have higher central venous pressure (CVP). Thus, during transsphenoidal tumor resection in such patients, we routinely monitor CVP and maintain it in the low end of the normal range. In other cases of transsphenoidal resection of microadenoma, such monitoring is needed only infrequently.
Ten percent to 15% of patients with Cushing's syndrome exhibit adrenal overproduction of glucocorticoids from an adrenal adenoma or carcinoma.[163] If either unilateral or bilateral adrenal resection is planned, we normally begin administering glucocorticoids at the start of resectioning of the tumor. Despite the absence of definitive studies, we normally give 100 mg of hydrocortisone hemisuccinate or hydrocortisone phosphate every 24 hours intravenously. We reduce this amount over a period of 3 to 6 days until a maintenance dose is reached. Beginning on day 3, the surgeons that we have worked with most also give a mineralocorticoid, 9α-fluorocortisol (0.05 to 0.1 mg/day). In certain patients, both steroids may require several adjustments. This therapy continues if the patient has undergone bilateral resection. For a patient who has undergone unilateral adrenal resection, therapy is individualized according to the status of the remaining adrenal gland. The incidence of pneumothorax in open adrenal resection approaches 20%; the diagnosis of pneumothorax
Bilateral adrenalectomy in patients with Cushing's syndrome is associated with a high incidence of post-operative complications and a perioperative mortality rate of 5% to 10%; it often results in permanent mineralocorticoid and glucocorticoid deficiency. Ten percent of patients with Cushing's syndrome who undergo adrenalectomy have an undiagnosed pituitary tumor. After reduction of high levels of cortisol by adrenalectomy, the pituitary tumor enlarges. These pituitary tumors are potentially invasive and may produce large amounts of ACTH and melanocyte-stimulating hormone, thereby increasing pigmentation.
Adrenal tumors are at least 85% incidentalomas—that is, discovered incidentally during screening (and largely unindicated) CT scans. Nonfunctioning adrenal adenomas are found in up to 10% of patients on autopsy.[178] Functioning adenomas are generally treated surgically; often, the contralateral gland resumes functioning after several months. Frequently, however, the effects of carcinomas are not cured by surgery. In such cases, administration of inhibitors of steroid synthesis, such as metyrapone or mitotane (o,p'-DDD[2,2-bis92-chlorophenyl-4-chlorophenyl)-1,1-dichloroethane]), may ameliorate some symptoms but may not improve survival. These drugs and the aldosterone antagonist spironolactone may aid in reducing symptoms in the case of ectopic ACTH secretion if the primary tumor proves unresectable. Patients given these adrenal suppressants are also prescribed chronic glucocorticoid replacement therapy (i.e., the goal of therapy is complete adrenal suppression). These patients should be considered to have suppressed adrenal function, and glucocorticoid replacement should be increased perioperatively.
Excess mineralocorticoid activity (common with glucocorticoid excess because most glucocorticoids have some mineralocorticoid properties) leads to potassium depletion, sodium retention, muscle weakness, hypertension, tetany, polyuria, inability to concentrate urine, and hypokalemic alkalosis.[185] These symptoms constitute primary hyperaldosteronism, or Conn's syndrome (a cause of low-renin hypertension because renin secretion is inhibited by the effects of the high levels of aldosterone).
Primary hyperaldosteronism is present in 0.5% to 1% of hypertensive patients who have no other known cause of hypertension.[185] Primary hyperaldosteronism most often results from unilateral adenoma, although 25% to 40% of patients have been found to have bilateral adrenal hyperplasia. Intravascular fluid volume, electrolyte concentrations, and renal function should be restored to within normal limits preoperatively by administering the aldosterone antagonist spironolactone. The effects of spironolactone are slow in onset and increase for 1 to 2 weeks.[185] A patient who has a serum potassium level of 2.9 mEq/L may have a total-body potassium deficit of as little as 40 mEq or as much as 400 mEq. Frequently, at least 24 hours is required to restore potassium equilibrium.[186] [187] [188] A normal serum potassium level does not necessarily imply correction of a total-body deficit of potassium. In addition, patients with Conn's syndrome have a high incidence of hypertension and ischemic heart disease; hemodynamic monitoring should be appropriate for the degree of cardiovascular impairment.[189] A retrospective anecdotal study indicated that the intraoperative hemodynamic status was more stable when BP and electrolytes were controlled preoperatively with spironolactone than when other antihypertensive drugs were used.[164] However, the efficacy of optimizing the perioperative status of patients who have disorders of glucocorticoid or mineralocorticoid secretion has not been clearly established. We have assumed that gradual restoration of a normal condition is good medicine and that it would decrease perioperative morbidity and mortality.
Withdrawal of steroids or suppression of synthesis by steroid therapy is the leading cause of underproduction of corticosteroids.[163] Management of this type of glucocorticoid deficiency is discussed in the later section "Patients Taking Steroids for Other Reasons." Other causes of adrenocortical insufficiency include defects in ACTH secretion and destruction of the adrenal gland by autoimmune disease, tuberculosis, hemorrhage, or cancer; some forms of congenital adrenal hyperplasia (see previous discussion); and administration of cytotoxic drugs.
Primary adrenal insufficiency (Addison's disease) is associated with local destruction of all zones of the adrenal cortex and results in both glucocorticoid and mineralocorticoid deficiency if the insufficiency is bilateral; common symptoms and signs are listed in Table 27-9 . Autoimmune disease is the most common cause of primary (nonexogenous) bilateral ACTH deficiency in the United States, whereas tuberculosis is the most common cause worldwide. Tuberculosis is associated with decreased adrenal function but large adrenal glands, as is also common in sarcoidosis, histoplasmosis, amyloidosis, metastatic malignancy, and adrenal hemorrhage. Destruction or partial destruction by trauma and by human immunodeficiency virus (HIV) and other infections such as cytomegalovirus, mycobacteria, and fungi is being recognized more frequently.
An increasingly common cause of adrenal insufficiency associated with large adrenal glands is heparin-induced thrombocytopenia, which might be considered in every patient who has received heparin and has hypotension.
Autoimmune destruction of the adrenals may be associated with other autoimmune disorders, such as some forms of type 1 diabetes and Hashimoto's thyroiditis. Enzymatic defects in cortisol synthesis also cause glucocorticoid insufficiency, compensatory elevations in ACTH, and congenital adrenal hyperplasia.[180] Because adrenal insufficiency usually develops slowly, such patients are subject to marked pigmentation (from excess ACTH trying to stimulate an unproductive adrenal gland) and cardiopenia (apparently secondary to chronic hypotension).[163]
Secondary adrenal insufficiency occurs when ACTH secretion is deficient, often because of a pituitary or hypothalamic tumor. Treatment of pituitary tumors by surgery or radiation may result in hypopituitarism and subsequent adrenal failure.[163]
If unstressed, glucocorticoid-deficient patients usually have no perioperative problems. However, acute adrenal crisis (addisonian crisis) can occur when even a minor stress is present (e.g., upper respiratory infection).[163] [167] [190] Preparation of such a patient for anesthesia and surgery should include treatment of hypovolemia, hyperkalemia, and hyponatremia.[173] Because these patients cannot respond to stressful situations, it was traditionally recommended that they be given a stress dose of glucocorticoids (about 200 mg hydrocortisone/70 kg body weight/day) perioperatively. However, Symreng and colleagues[169] gave 25 mg of hydrocortisone phosphate intravenously to adults at the start of the operative procedure, followed by 100 mg intravenously over the next 24 hours. Because using the minimum drug dose that would produce an appropriate effect is desirable, this latter regimen seems attractive. Such a regimen has proved to be as successful as a regimen using maximum doses (about 300 mg hydrocortisone per 70 kg body weight per day—see the later section "Patients Taking Steroids for Other Reasons"). Thus, we now recommend giving 100 mg of hydrocortisone phosphate intravenously every 24 hours.[169] [170]
Hypoaldosteronism, a less common condition,[191] can be congenital or can occur after unilateral adrenalectomy or prolonged administration of heparin. In addition, it can also be a consequence of long-standing diabetes and renal failure. Nonsteroidal inhibitors of prostaglandin synthesis may also inhibit renin release and exacerbate this condition in patients who have renal insufficiency. [191] Plasma renin activity is below normal and fails to increase appropriately in response to sodium restriction or diuretic drugs. Most symptoms are caused by hyperkalemic acidosis rather than hypovolemia; in fact, some patients are hypertensive. These patients can have severe hyperkalemia, hyponatremia, and myocardial conduction defects.[191] These defects can be treated successfully by administering mineralocorticoids (9α-fluorocortisol, 0.05 to 0.1 mg/day) preoperatively.[191] Doses must be carefully titrated and monitored to avoid an increase in hypertension.
Many experimental studies and other reports (mostly anecdotal) concerning the adrenal responses of normal patients to the perioperative period, as well as the responses of patients taking steroids for other diseases, indicate the following:
In a well-controlled study of glucocorticoid replacement in primates, the investigators clearly defined the life-threatening events that can be associated with inadequate perioperative corticosteroid replacement.[170] This study further defined the physiologic and hemodynamic consequences of inadequate cortisol replacement; an alternative dose regimen is suggested that has stood the test of a decade and has altered management methods to possibly improve patient safety. In this study, adrenalectomized primates and sham-operated controls were maintained on physiologic doses of steroids for 4 months. The animals were then randomly allocated to groups that received subphysiologic (one tenth the normal cortisol production), physiologic, or supraphysiologic (10 times the normal cortisol production) doses of cortisol for 4 days preceding abdominal surgery (cholecystectomy). Hemodynamic variables were measured by means of arterial and pulmonary artery catheters. The animals were maintained on their randomized dosage schedules during and after surgery. The group given subphysiologic doses of steroid perioperatively had a significant increase in postoperative mortality. Death rates for the physiologic and supraphysiologic replacement groups were the same and did not differ from the rate for sham-operated controls. Death in the subphysiologic replacement group was related to severe hypotension associated with a significant decrease in systemic vascular resistance and a reduced left ventricular stroke work index. Filling pressures of the heart were unchanged when compared with those in control animals. There was no evidence of hypovolemia or severe CHF. Despite the low systemic vascular resistance, the animals did not become tachycardic. All these responses are compatible with the previously documented interaction of glucocorticoids and catecholamines and thus suggest that glucocorticoids mediate catecholamine-induced increases in cardiac contractility and maintenance of vascular tone.
The investigators used a sensitive measure of wound healing involving hydroxyproline accumulation. All treatment groups, including the group given supraphysiologic doses of glucocorticoids, had the same capacity for wound healing. Furthermore, perioperative administration of supraphysiologic doses of corticosteroids produced no adverse metabolic consequences.
This well-conducted study confirms several long-standing intuitive impressions concerning patients who have inadequate adrenal function as a result of either underlying disease or administration of exogenous steroids. Inadequate replacement of corticosteroids perioperatively can lead to addisonian crisis and death. Administration of supraphysiologic doses of steroids for a short time perioperatively caused no discernible complications. However, at least theoretical negative consequences can occur when large doses of steroids are given (see later). It is clear that inadequate corticosteroid coverage can cause death. What is not
Which patients definitely need supplementation? If in doubt, how can a patient's need for glucocorticoid supplementation be determined? Because the risk is low, we normally provide supplementation for any patient who has received steroids within a year.[165] [166] [169] [170] [171] [172] [173] [174] [180] [181] [182] [184] Data indicate that topical application of steroids (even without the use of occlusive dressings) can suppress normal adrenal responses for as long as 9 months to 1 year[165] [171] ( Table 27-10 ).
How can one determine when adrenal responsiveness has returned to normal? The morning plasma cortisol level does not reveal whether the adrenal cortex has recovered sufficiently to ensure that cortisol secretion will increase adequately to meet the demands of stress. Inducing hypoglycemia with insulin has been advocated as a sensitive test of pituitary-adrenal competence but is impractical and probably a more dangerous practice than simply administering glucocorticoids. If the plasma cortisol concentration is measured during acute stress, a value of more than 25 µg/dL assuredly (and a value > 15 µg/dL probably) indicates normal pituitary-adrenal responsiveness. In another test of pituitary-adrenal sufficiency, the baseline plasma cortisol level is determined. Then, 250 µg of synthetic ACTH (cosyntropin) is given, and plasma cortisol is measured 30 to 60 minutes later. [172] An increase in plasma cortisol of 6 to 20 µg/dL or more is normal.[193] A normal response indicates recovery of pituitary-adrenal axis function. A lesser response usually indicates pituitary-adrenal insufficiency, possibly requiring perioperative supplementation with steroids.
Typically, laboratory data defining pituitary-adrenal adequacy are not available before surgery. However, rather than delay surgery or test most patients, we assume that any patient who has taken steroids at any time during the preceding year has suppressed pituitary-adrenal function and will require perioperative supplementation.
| Recovery Time (mo) | Plasma 17-Hydroxycorticoid Values | Plasma ACTH Values | Adrenal Response to Exogenous ACTH | Response to Metyrapone |
|---|---|---|---|---|
| 1 | Low * | Low | Low | Low |
| 2–5 | Low | High † | Low | Low |
| 6–9 | Normal | Normal | Low | Low |
| >9 | Normal | Normal | Normal | Normal |
| ACTH, adrenocorticotropic hormone. | ||||
| Data from Graber AL, Ney RI, Nicholson WE, et al: Natural history of pituitary-adrenal recovery following long-term suppression with corticosteroids. J Clin Endocrinol Metab 25:11, 1965. | ||||
Under perioperative conditions, the adrenal glands secrete 116 to 185 mg of cortisol daily. Under maximum stress, they may secrete 200 to 500 mg/day. Good correlation exists between the severity and duration of the operation and the response of the adrenal gland. "Major surgery" would be represented by procedures such as colectomy and "minor surgery" by procedures such as herniorrhaphy. In one study of 20 patients during major surgery, the mean maximal concentration of cortisol in plasma was 47 µg/dL (range, 22 to 75 µg/dL). Values remained above 26 µg/dL for a maximum of 72 hours after surgery. During minor surgery, the mean maximal concentration of cortisol in plasma was 28 µg/dL (range, 10 to 44 µg/dL).
Although the precise amount required has not been established, we usually intravenously administer the maximum amount of glucocorticoid that the body manufactures in response to maximal stress (i.e., approximately 200 mg/day of hydrocortisone phosphate/70 kg body weight).[169] [170] [192] For minor surgical procedures, we usually give hydrocortisone phosphate intravenously, 100 mg/day/70 kg body weight. Unless infection or some other perioperative complication develops, we decrease this dose by approximately 25% per day until oral intake can be resumed. At this point, the usual maintenance dose of glucocorticoids can be administered.
Rare complications of perioperative steroid supplementation include aggravation of hypertension, fluid retention, inducement of stress ulcers, and psychiatric disturbances. Although data are not available to assess the incidence of the following risks, two common complications of short-term perioperative supplementation with glucocorticoids are described in the literature: abnormal wound healing and an increased rate of infections.[166] [169] [170] [171] [172] [173] [174] [181] [182] [183] [184] [185] This evidence is inconclusive, however, because it relates to acute glucocorticoid administration and not to chronic administration of glucocorticoids with increased doses at times of stress. Ehrlich and Hunt[184] found that moderate to large doses of steroids exert their morphologic effects best within 3 days of injury. They postulated that inhibition of the early inflammatory process by steroids after wounding was responsible for the delay in healing. Vitamin A was found to be somewhat protective against delayed healing, presumably because of its effect on
Information regarding the risk of infection from perioperative glucocorticoid supplementation is also unclear. Winstone and Brooke[194] reported 4 cases of septicemia in 18 surgical patients given perioperative glucocorticoid supplementation. No similar complications occurred in 17 others who were also taking glucocorticoids but who were not given perioperative supplementation. In other studies, no increased risk of serious infections was reported.[163] Data indicate that the risk of infection in a patient chronically taking steroids is real, but these data are inadequate to conclude that perioperative supplementation with steroids increases that risk.
Production of androgens by the adrenal gland progressively decreases with age.[195] This decrease in androgen activity has no known implications for anesthesia. Plasma levels of cortisol are unaffected by increasing age. Levels of CBG are also unaffected by age, which suggests that a normal fraction of free cortisol (1% to 5%) is present in elderly patients. Several investigators have noted a progressively impaired ability of aged patients to metabolize and excrete glucocorticoids. In normal individuals, the quantity of 17-hydroxycorticosteroids excreted is reduced by half by the seventh decade. This decreased excretion undoubtedly reflects the reduced renal function that occurs with aging. When excretion of cortisol metabolites is expressed as a function of creatinine clearance, the age difference disappears. Further reductions in cortisol clearance may be due to impaired hepatic metabolism of circulating cortisol.
The rate of secretion of cortisol is 30% lower in the elderly. This reduced secretion is an appropriate compensatory mechanism for maintaining a normal level of cortisol in the face of decreased hepatic and renal clearance of cortisol. It is important to the anesthesiologist that the reduced cortisol production can be overcome during periods of stress and that the elderly display an entirely normal adrenal response to the administration of ACTH and to stresses such as hypoglycemia.
Both underproduction and overproduction of glucocorticoids are generally considered diseases of younger individuals. The highest incidence of Cushing's disease of either pituitary or adrenal origin occurs during the third decade of life. The most common cause of spontaneous Cushing's disease is benign pituitary adenoma. [182] However, in patients older than 60 years in whom Cushing's disease develops, the most likely cause is adrenal carcinoma or ectopic ACTH production from tumors usually located in the lung, pancreas, or thymus.
Even a single dose of etomidate for induction of anesthesia suppresses adrenal function.[196] The clinical significance of adrenal suppression by etomidate is unknown, but there is justifiable concern over the continued use of etomidate without steroid supplementation.
Etomidate is an imidazole sedative-hypnotic that induces rapid loss of consciousness with minimal cardiovascular depression, even in compromised patients. Etomidate has been administered in two clinical settings—as a bolus for induction of anesthesia and as a continuous infusion for prolonged sedation in the ICU setting. The pattern of adrenal suppression appears to be related to dose and time and is associated with narcotic coadministration; it differs with the duration of administration and the absence of narcotic coadministration.[196]
In rats and humans, etomidate inhibits two essential adrenocortical enzymes, 11β-hydroxylase and cholesterol side chain cleavage enzyme.[196] We believe that it is important to clarify the difference between the adrenal suppression caused by etomidate and the stated goal of several anesthesiologists to provide stress-free anesthesia. It appears that providing a level of anesthesia that prevents grimacing, sweating, extreme elevations in BP and heart rate, and an outpouring of the neurohumoral mediators of stress is evidence that we have adequately depressed CNS function and protected our patients from some of the unwanted side effects of surgery. This goal is different from etomidate's inhibition of peripheral adrenocortical enzymes that occurs as an unwanted side effect of the drug when it is administered in combination with narcotics.
Thus, it has been documented that adrenal reserve is compromised for at least 24 hours after a single induction dose of etomidate in most patients. [197] Should hypotension or electrolyte abnormalities associated with adrenal insufficiency (hyponatremia and hyperkalemia) occur in a patient who has recently received etomidate, we agree with previous suggestions[196] that corticosteroids should be administered in stress doses (e.g., cortisol, 100 mg/day) and be tapered as noted in the earlier section "Patients Taking Steroids for Other Reasons."
Adrenal tumors are found in as many as 10% of autopsies, and the increased use of imaging techniques brings many of these tumors to clinical attention before death. Previously, size was used as a discriminator: tumors larger than 6 cm were surgically removed because of the high probability of malignancy. Those smaller than 3 cm were monitored, and those 3 to 6 cm were investigated.
Recent data from three large series[175] [176] [177] [178] and success from laparoscopic removal[198] [199] have called for a re-evaluation. The three series found a significant number of adrenal carcinomas and pheochromocytomas (approximately 3% of each), an occasional aldosteronoma (approximately 1%), and a not insignificant number of metastases from as yet undiscovered primary tumors (approximately 10%). These data may indicate the need for a more aggressive
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