Other Endocrine Drugs

Structure–Activity Relationships

All corticosteroids are constructed on the same primary molecular framework, designated as the steroid nucleus (see Fig. 40-1). Changes in molecular structure may result in altered biologic responses due to changes in absorption, protein binding, rate of metabolism, and intrinsic effectiveness of the drug at receptors. Modifications of structure, such as introduction of a double bond in prednisolone and prednisone, have resulted in synthetic corticosteroids with more potent glucocorticoid effects than the two closely related natural hormones, cortisol and cortisone, respectively (Table 40-1). At the same time, mineralocorticoid effects and the rate of hepatic metabolism of these synthetic drugs are less than those of the natural hormones. Despite increased antiinflammatory effects, it has not been possible to separate this response from alterations in carbohydrate and protein metabolism. This suggests that the multiple manifestations of drug-induced glucocorticoid effects are mediated by the same receptor.

Mechanism of Action

Glucocorticoids attach to cytoplasmic receptors to enhance or suppress changes in the transcription of DNA and thus the synthesis of proteins. Glucocorticoids also inhibit the secretion of cytokines via posttranslational effects.¹ Two distinct types of corticosteroid receptors have been identified (mineralocorticoid and glucocorticoid). Mineralocorticoid receptors are present in distal renal tubules, colon, salivary glands, and the hippocampus. In contrast, glucocorticoids receptors are more widely distributed and do not bind aldosterone, making these receptors glucocorticoid-selective. Local mechanisms that result in release of steroids from their carrier proteins serve to facilitate steroid entry into cells. Target cells also contain an enzyme, 11-β hydroxysteroid dehydrogenase that controls the interconversion of cortisol (active) and cortisone (inert). The concentration of glucocorticoids receptors may fluctuate and thus influence responsiveness to glucocorticoids.

Maintenance of Homeostasis

Permissive and protective effects of glucocorticoids are critical for the maintenance of homeostasis during severe stress. The permissive and protective actions of glucocorticoids are complementary and permit the individual to affect an appropriate stress response and to maintain homeostasis.

Permissive Actions

Permissive actions of glucocorticoids occur at low physiologic steroid concentrations and serve to prepare the individual for responding to stress. These permissive actions of glucocorticoids maintain basal activity of the HPA by providing negative feedback and by setting the threshold for a response to stress.

Protective Actions

The protective mode of glucocorticoids occurs when high plasma concentrations of steroids exert antiinflammatory and immunosuppressive effects. This protective response prevents the host-defense mechanisms that are activated during stress from overshooting and damaging the organism. Other important protective actions of glucocorticoids include redirection of metabolism to meet energy needs during stress.

Pharmacokinetics

Synthetic cortisol and its derivatives are effective orally (see Table 40-1). Antacids, but not food, interfere with the oral absorption of corticosteroids. Water-soluble cortisol succinate can be administered intravenously (IV) to achieve prompt increases in plasma concentrations. More prolonged effects are possible with intramuscular (IM) injection. Cortisone acetate may be given orally or intramuscularly but cannot be administered IV. The acetate preparation is a slow-release preparation lasting 8 to 12 hours. After release, cortisone is converted to cortisol in the liver. Corticosteroids are also promptly absorbed after topical application or aerosol administration.

Cortisol is highly bound (90% or more) in the plasma to corticosteroid-binding globulin. Cortisol also binds albumin and erythrocytes.² Nevertheless, cortisol and related compounds readily cross the placenta. Small amounts of cortisol appear unchanged in the urine, but at least 70% is conjugated in the liver to inactive or poorly active metabolites. These water-soluble conjugated metabolites appear in the urine and bile. The elimination half-time of cortisol is 1.5 to 3.0 hours but its biologic effects persist for several hours. The half-lives of synthetic glucocorticoids range from 1 hour (prednisolone) to more than 4 hours (dexamethasone) and clearance may be prolonged in older individuals.³ Individuals who clear glucocorticoids slowly may be subject to an increased incidence of side effects.⁴

Cortisol is released from the adrenal glands in an episodic manner and the frequency of pulses follows a circadian rhythm that is linked to the sleep-wake cycle. Maximal plasma concentrations of cortisol occur just before awakening and the lowest levels occur 8 to 10 hours later. Stress-induced changes in the plasma concentrations of cortisol are superimposed on the background baseline release of cortisol. Synthesis of cortisol is governed by adrenocorticotrophic hormone (ACTH) that is controlled by the hypothalamic hormones, corticotropin-releasing hormone and arginine vasopressin.

Synthetic Corticosteroids

Synthetic corticosteroids administered for their glucocorticoid effects include prednisolone, prednisone, methylprednisolone, betamethasone, dexamethasone, and triamcinolone (see Table 40-1, Fig. 40-2). Fludrocortisone is a synthetic halogenated derivative of cortisol that is administered for its mineralocorticoid effect (see Table 40-1 and Fig. 40-2). Naturally occurring corticosteroids, such as cortisol and cortisone, are also available as synthetic drugs (see Table 40-1 and Fig. 40-1).

Prednisolone

Prednisolone is an analogue of cortisol that is available as an oral or parenteral preparation. The antiinflammatory effect of 5 mg of prednisolone is equivalent to that of 20 mg of cortisol. This drug and prednisone are suitable for sole replacement therapy in adrenocortical insufficiency because of the presence of glucocorticoid and mineralocorticoid effects.

Prednisone

Prednisone is an analogue of cortisone that is available as an oral or parenteral preparation. It is rapidly converted to prednisolone after its absorption from the gastrointestinal tract. Its antiinflammatory effect and clinical uses are similar to those of prednisolone.

Methylprednisolone

Methylprednisolone is the methyl derivative of prednisolone. The antiinflammatory effect of 4 mg of methylprednisolone is equivalent to that of 20 mg of cortisol. The acetate preparation administered intraarticularly has a prolonged effect. Methylprednisolone succinate is highly soluble in water and is used IV to produce an intense glucocorticoid effect.

Betamethasone

Betamethasone is a fluorinated derivative of prednisolone. The antiinflammatory effect of 0.75 mg is equivalent to that of 20 mg of cortisol. Betamethasone lacks the mineralocorticoid properties of cortisol and thus is not acceptable for sole replacement therapy in adrenocortical insufficiency. Oral or parenteral administration is acceptable.

Dexamethasone

Dexamethasone is a fluorinated derivative of prednisolone and an isomer of betamethasone. The antiinflammatory effect of 0.75 mg is equivalent to that of 20 mg of cortisol. Oral and parenteral preparations are available. The acetate preparation is used as a long-acting repository suspension. Dexamethasone sodium phosphate is water soluble, rendering it appropriate for parenteral use. This corticosteroid is commonly chosen to treat certain types of cerebral edema.

Triamcinolone

Triamcinolone is a fluorinated derivative of prednisolone. The antiinflammatory effect of 4 mg is equivalent to that of 20 mg of cortisol. Triamcinolone has less mineralocorticoid effect than does prednisolone. Oral and parenteral preparations are available. The hexacetonide preparation injected intraarticularly may provide therapeutic effects for 3 months or longer. This drug is often used for epidural injections in the treatment of lumbar disc disease.

During the first days of treatment with triamcinolone, mild diuresis with sodium loss may occur. Conversely, edema may occur in patients with decreased glomerular filtration rates. Triamcinolone does not increase urinary potassium loss except when administered in large doses.

An unusual adverse side effect of triamcinolone is an increased incidence of skeletal muscle weakness. Likewise, anorexia rather than appetite stimulation, and sedation rather than euphoria may accompany administration of triamcinolone.

Clinical Uses

The only universally accepted clinical use of corticosteroids and their synthetic derivatives is as replacement therapy for deficiency states. With this exception, the use of corticosteroids in disease states is empirical and not curative, although antiinflammatory responses exert an intense palliative effect. The safety of corticosteroids is such that it is acceptable to administer a single large dose in a life-threatening situation on the presumption that unrecognized adrenal or pituitary insufficiency may be present.

Prednisolone or prednisone is recommended when an antiinflammatory effect is desired. The low mineralocorticoid potency of these drugs limits sodium and water retention when large doses are administered to produce the desired glucocorticoid effect. It must be recognized, however, that the antiinflammatory effect of corticosteroids is palliative because the underlying cause of the response remains. Nevertheless, suppression of the inflammatory response may be lifesaving in some situations. Conversely, masking of the symptoms of inflammation may delay diagnosis of life-threatening illness, such as peritonitis due to perforation of a peptic ulcer.

Deficiency States

Acute adrenal insufficiency requires electrolyte and fluid replacement as well as supplemental corticosteroids. Cortisol is administered at a rate of 100 mg IV every 8 hours after an initial injection of 100 mg. Management of chronic adrenal insufficiency in adults is with the daily oral administration of cortisone, 25.0 to 37.5 mg. A typical regimen is 25.0 mg in the morning and 12.5 mg in the late afternoon. This schedule mimics the normal diurnal cycle of adrenal secretion. An orally effective mineralocorticoid such as fludrocortisone, 0.1 to 0.3 mg daily, is required by most patients.

Allergic Therapy

Topical corticosteroids are capable of potent antiinflammatory effects and are the mainstay of allergic therapy. These medications interfere with the inflammatory response, induce cutaneous vasoconstriction, and have antimitotic activity.⁵ Corticosteroids work by inhibiting the production of inflammatory cytokines and chemokines, thus decreasing inflammation, cellular edema, and cellular recruitment to sites of disease. Oral administration of steroids is effective but the risk of unacceptable side effects with chronic treatment limits use by this route. Side effects, although possible with topical administration of corticosteroids, are usually not significant. Unlike antihistamines that provide pharmacologic effects within 1 to 2 hours, topical corticosteroids may require 3 to 5 days of treatment to produce a therapeutic effect.

Manifestations of allergic diseases that are of limited duration, such as hay fever, contact dermatitis, drug reactions, angioneurotic edema, and anaphylaxis, can be suppressed by adequate doses of corticosteroids. Life-threatening allergic reactions, however, must be treated with epinephrine, because the onset of the antiinflammatory effect produced by corticosteroids is delayed. Indeed, any beneficial effect of corticosteroids in the management of severe allergic reactions is probably related to suppression of the antiinflammatory response rather than to inhibition of production of immunoglobulins.

Asthma

Asthma is an inflammatory disease of the lungs and inhaled glucocorticoids (beclomethasone, budesonide, fluticasone, ciclesonide, and triamcinolone) are often recommended as first-line therapy for controlling the symptoms of asthma, improving quality of life and lung function, and in preventing exacerbations.⁶ Inhaled glucocorticoids are highly lipophilic and rapidly enter airway cells, where they have direct inhibitory effects on many of the cells involved in airway inflammation. One possible antiinflammatory mechanism is the modulation of the release of cytokines from inflammatory cells. It is estimated that 80% to 90% of the dose inhaled from the metered-dose inhaler is deposited in the oropharynx and swallowed. Inhaled glucocorticoids have oropharyngeal side effects that include dysphonia and candidiasis. Dysphonia occurs in approximately one-third of treated patients and may reflect myopathy of the laryngeal muscles that is reversible when treatment is stopped. Inhaled glucocorticoids, in doses of 1,500 µg per day or less in adults and 400 µg per day or less in children, have little, if any, effect on pituitary adrenal function.

Parenteral corticosteroids are important in the emergent preoperative preparation of patients with active reactive airway disease and in the treatment of intraoperative bronchospasm. Doses equivalent to 1 to 2 mg/kg of cortisol (or the equivalent dose of prednisolone) are commonly recommended. Preoperative corticosteroid administration 1 to 2 hours before induction of anesthesia is important because the beneficial effects of corticosteroids may not be fully manifest for several hours. Corticosteroids also enhance and prolong the responses to β-adrenergic agonists. Some enhancement of β-agonist effect may be present within 1 hour, but 4 to 6 hours are required for an antiinflammatory effect. In noncompliant or newly diagnosed patients with bronchial hyperactivity, preoperative treatment with combined corticosteroids (40 mg orally for 5 days) and salbutamol (0.2 mg puffs for 5 days) but not salbutamol alone minimizes intubation-evoked bronchoconstriction.⁷

Antiemetic Effect

Dexamethasone prevents postoperative nausea and vomiting only when administered near the beginning of surgery, probably by reducing surgery-induced inflammation due to inhibition of prostaglandin synthesis.⁸ In addition, dexamethasone may exert antiemetic effects by increasing the release of endorphins resulting in mood elevation and appetite stimulation. Prophylactic administration of dexamethasone 4 mg, ondansetron 4 mg, or droperidol 1.25 mg produced similar decreases (about 26%) in the incidence of postoperative nausea and vomiting.⁹ Because antiemetic interventions are similarly effective and act independently, it is recommended that the safest and least expensive antiemetic should be selected for prophylaxis. Prophylaxis is rarely warranted in low-risk patients, moderate-risk patients may benefit from a single intervention, and multiple interventions should be reserved for high-risk patients.⁹ Rescue treatments are ineffective when the same drug has already been administered for prophylaxis. A suggested treatment strategy is to administer dexamethasone in conjunction with total intravenous anesthesia as first-line and second-line methods of prophylaxis against postoperative nausea and vomiting and to reserve serotonin antagonists as a rescue treatment.⁹ Administration of higher doses (8 to 10 mg) of dexamethasone has a similar clinical effect to lower doses (4 to 5 mg).¹⁰ Dexamethasone is also effective in suppressing chemotherapy-induced nausea and vomiting. The elimination half-time of dexamethasone is about 3 hours, but antiemetic effects, unlike other classes of antiemetics, often persist as long as 24 hours.

Postoperative Analgesia

Glucocorticoids peripherally inhibit phospholipase enzyme that is necessary for the inflammatory chain reaction along both the cyclooxygenase and lipoxygenase pathways.¹¹ As a result, glucocorticoids may be effective in decreasing postoperative pain but with a different side effect profile than nonsteroidal antiinflammatory drugs. For example, administration of betamethasone 12 mg intramuscularly 30 minutes before induction of anesthesia for outpatient foot or hemorrhoid surgery, resulted in reductions in postoperative pain and the incidence of postoperative nausea and vomiting.¹² A meta-analysis of perioperative intravenous dexamethasone suggests that dexamethasone at doses more than 0.1 mg/kg decreases acute postoperative pain and reduces opioid use, especially when administered preoperatively.¹³

Cerebral Edema

Corticosteroids in large doses are of value in the reduction or prevention of vasogenic cerebral edema and the resulting increases in intracranial pressure that may accompany intracranial tumors and metastatic lesions and bacterial meningitis.¹⁴ Dexamethasone, with minimal mineralocorticoid activity, is frequently selected to decrease cerebral edema and associated increases in intracranial pressure. Conversely, the administration of glucocorticoids to patients with severe head injury, cerebral infarction, and intracranial hemorrhage is not useful and can be associated with worse outcomes.^15,16

Aspiration Pneumonitis

The use of corticosteroids in the treatment of aspiration pneumonitis is controversial. There is evidence in animals that corticosteroids administered immediately after the inhalation of acidic gastric fluid may be effective in decreasing pulmonary damage.¹⁷ Conversely, other data show no beneficial effect or suggest that the use of corticosteroids may enhance the likelihood of gram-negative pneumonia.^18,19 Despite the absence of confirming evidence that corticosteroids are beneficial, it is not uncommon for the treatment of aspiration pneumonitis to include the empiric use of pharmacologic doses of these drugs.

Lumbar Disc Disease

An alternative to surgical treatment of lumbar disc disease is the epidural placement of corticosteroids.²⁰ Corticosteroids may decrease inflammation and edema of the nerve root that has resulted from compression. A common regimen is epidural injection of 25 to 50 mg of triamcinolone, or 40 to 80 mg of methylprednisolone, in a solution containing lidocaine at or near the interspace corresponding to the distribution of pain. In animals, the epidural injection of triamcinolone, 2 mg/kg, interferes with the ability of the adrenal cortex to release cortisol in response to hypoglycemia for 4 weeks. Injection of triamcinolone, 80 mg, into the lumbar epidural space of patients with lumbar disc disease results in acute suppression of plasma concentrations of ACTH and cortisol between 15 minutes (midazolam sedation) and 45 minutes (midazolam not administered) of corticosteroid injection.²¹ Median suppression of the HPA axis was less than 1 month and all patients had recovered by 3 months. Exogenous corticosteroid coverage during this potentially vulnerable period should be considered in patients undergoing major stress, especially if the adrenocortical response to ACTH is subnormal. Although epidural injections of methylprednisolone may result in short-term improvement of symptoms (pain, sensory loss) due to sciatic nerve compression from a herniated nucleus pulposus, this treatment offers no significant functional benefit nor does it decrease the need for surgery.²²

Immunosuppression

In organ transplantation, high doses of corticosteroids are often administered at the time of surgery to produce immunosuppression and decrease the risk of rejection of the newly transplanted organ. Smaller maintenance doses of corticosteroids are continued indefinitely, and the dosage is increased if rejection of the transplanted organ is threatened.

Arthritis

The criterion for initiating corticosteroid therapy in patients with rheumatoid arthritis is rapid control of symptomatic flares and progressive disability despite maximal medical therapy. Corticosteroids are administered in the smallest dose possible that provides significant but not complete symptomatic relief. The usual initial dose is prednisolone, 10 mg or its equivalent, in divided doses. Intraarticular injection of corticosteroids is recommended for treatment of episodic manifestations of acute joint inflammation associated with osteoarthritis. However, painless destruction of the joint is a risk of this treatment.

Collagen Diseases

Manifestations of collagen diseases, such as polymyositis, polyarteritis nodosa, and Wegener granulomatosis, but not scleroderma, are decreased and longevity is improved by corticosteroid therapy. Fulminating systemic lupus erythematosus is a life-threatening illness that is aggressively treated initially with large doses of prednisone, 1 mg/kg, or its equivalent. Large doses of corticosteroids are effective for inducing a remission of sarcoidosis. In temporal arteritis, corticosteroid therapy is necessary to prevent blindness, which occurs in about 20% of untreated patients. Some forms of nephrotic syndrome respond favorably to corticosteroids. Rheumatic carditis may be suppressed by large doses of corticosteroids.

Ocular Inflammation

Corticosteroids are used to suppress ocular inflammation (uveitis and iritis) and thus preserve sight. Instillation of corticosteroids into the conjunctival sac results in therapeutic concentrations in the aqueous humor. Topical and intraocular corticosteroid therapy often increases intraocular pressure and is associated with cataractogenesis. For this reason, it is recommended that intraocular pressure be monitored when topical corticosteroids are used for more than 2 weeks. Corticosteroids are not recommended in herpes simplex infections (dendritic keratitis) of the eye. Topical corticosteroids should not be used for treatment of ocular abrasions because delayed healing and infections may occur.

Cutaneous Disorders

Topical administration of corticosteroids is frequently effective in the treatment of skin diseases. Effectiveness is increased by application of the corticosteroid as an ointment under an occlusive dressing. Systemic absorption is also occasionally enhanced to the degree that suppression of the HPA axis occurs or manifestations of Cushing syndrome appear. Corticosteroids may also be administered systemically for treatment of severe episodes of acute skin disorders and exacerbations of chronic disorders.

Postintubation Laryngeal Edema

Treatment of postintubation laryngeal edema may include administration of corticosteroids, such as dexamethasone, 0.1 to 0.2 mg/kg IV. Nevertheless, the efficacy of corticosteroids for treatment of this condition has not been confirmed. Dexamethasone, 0.6 mg/kg orally is an effective treatment for children with mild croup.²³

Ulcerative Colitis

Corticosteroid therapy is indicated in selected patients with chronic ulcerative colitis. A disadvantage of this therapy is that signs and symptoms of intestinal perforation and peritonitis may be masked.

Myasthenia Gravis

Corticosteroids are usually reserved for patients with myasthenia gravis who are unresponsive to medical or surgical therapy. These drugs seem to be most effective after thymectomy. The mechanism of beneficial effects produced by corticosteroids is not known but may reflect drug-induced suppression of the production of an immunoglobulin that normally binds to the neuromuscular junction.

Respiratory Distress Syndrome

Administration of corticosteroids at least 24 hours before delivery decreases the incidence and severity of respiratory distress syndrome in neonates born between 24 and 36 weeks’ gestation. Dexamethasone administered for prolonged periods (42 days) improves pulmonary and neurodevelopmental outcome of low-birth-weight infants at risk for bronchopulmonary dysplasia.²⁴ Glucocorticoid administration in the setting of acute respiratory distress syndrome is controversial and the effect may vary according to timing. Early administration (≤72 hours) of methylprednisolone in one small study has been associated with improved outcomes.²⁵ Later administration (>14 days) of glucocorticoids is associated with increased mortality, ventilator-free days, oxygenation, and compliance.²⁶

Leukemia

The antilymphocytic effects of glucocorticoids are used to advantage in combination chemotherapy of acute lymphocytic leukemia and lymphomas, including Hodgkin disease and multiple myeloma. For example, prednisone and vincristine produce remissions in about 90% of children with lymphoblastic leukemia.

Cardiac Arrest

Cardiac arrest is associated with lower cortisol levels (relative adrenal insufficiency), vasoplegia, and myocardial dysfunction. Recent studies preliminarily suggest that the administration of glucocorticoids (along with vasopressin and epinephrine) during a cardiac arrest may improve survival and is associated with better neurologic outcomes.²⁷ Potential explanations include attenuation of the systemic inflammatory response syndrome and enhancement of myocardial and vascular function.²⁸

Side Effects

The side effects of chronic corticosteroid therapy include (a) suppression of the HPA axis, (b) electrolyte and metabolic changes, (c) osteoporosis, (d) peptic ulcer disease, (e) skeletal muscle myopathy, (f) central nervous system dysfunction, (g) peripheral blood changes, and (h) inhibition of normal growth. Increased susceptibility to bacterial or fungal infection accompanies treatment with corticosteroids. Corticosteroid administration is associated with greater clearance of salicylates and decreased effectiveness of anticoagulants. Systemic corticosteroids used for short periods of time (<7 days) even at high doses are unlikely to cause adverse side effects. Inhaled corticosteroids are unlikely to evoke adverse systemic effects.

Corticosteroid Supplementation in the Perioperative Period

Corticosteroid supplementation should be increased whenever the patient being treated for chronic hypoadrenocorticism undergoes a surgical procedure. This recommendation is based on the concern that these patients are susceptible to cardiovascular collapse because they cannot release additional endogenous cortisol in response to the stress of surgery. More controversial is the management of patients who may manifest suppression of the HPA axis because of current or previous administration of corticosteroids for treatment of a disease unrelated to pituitary or adrenal function. Recommendations that prescribe supraphysiologic doses have been advocated despite the absence of supporting scientific data.²⁹ In adrenalectomized primates undergoing general anesthesia and surgery, the animals receiving physiologic replacement doses of cortisol were indistinguishable from those receiving supraphysiologic doses (10 times the normal production rate) of cortisol.³⁰ Subphysiologically treated animals (one-tenth the normal production rate) were hemodynamically unstable during surgery and had a significantly higher mortality rate. Based on these animal data, it was concluded that there is no advantage in supraphysiologic glucocorticoid prophylaxis during surgical stress, and replacement doses of cortisol equivalent to the daily unstressed cortisol production rate are sufficient to allow homeostatic mechanisms to function during surgery.³⁰

Patients taking greater than 20 mg per day of prednisone or its equivalent for more than 3 weeks have a suppressed HPA axis. Patients taking less than 5 mg per day of prednisone or its equivalent can be considered not to have suppression of their HPA axis. However, patients taking 5 to 20 mg per day of prednisone or its equivalent for more than 3 weeks may or may not have suppression of the HPA axis.

A rational regimen for corticosteroid supplementation in the perioperative period is to avoid steroid supplementation in patients who do not have a suppressed HPA axis (patients taking any dose of glucocorticoids for less than 3 weeks or a daily dose of prednisone <5 mg).

Patients taking 5 to 20 mg per day of prednisone or its equivalent for more than 3 weeks may or may not have suppression of the HPA axis. These patients may benefit from further assessment of their HPA axis. Glucocorticoid supplementation considers preoperative doses and the stress of surgery.

For patients with a suppressed HPA axis (patients taking >20 mg prednisone per day for more than 3 weeks), glucocorticoid supplementation should consider the stress of surgery. For minor surgical stress (inguinal hernia repair), the daily cortisol secretion rate and static plasma cortisol measurements suggest that a glucocorticoid replacement dose of 25 mg of hydrocortisone or 5 mg of methylprednisolone is sufficient. If the postoperative course is uncomplicated, the patient can be returned the next day to the prior glucocorticoid maintenance dose. For moderate surgical stress (nonlaparoscopic cholecystectomy, colon resection, total hip replacement), cortisol production rates suggest the glucocorticoid requirement is about 50 to 75 mg daily of hydrocortisone for 1 to 2 days. For major surgical stress (pancreatoduodenectomy, esophagectomy, cardiopulmonary bypass), the glucocorticoid dose should be 100 to 150 mg of hydrocortisone daily for 2 to 3 days. Even with this coverage, vascular collapse has been described in a patient experiencing massive hemorrhage during surgery.³¹ This approach maintains the plasma concentration of cortisol above normal during major surgery in patients receiving chronic treatment with corticosteroids and manifesting a subnormal response to the preoperative infusion of ACTH (Fig. 40-3).³² In those instances in which events such as burns or sepsis could exaggerate the need for exogenous corticosteroid supplementation, the continuous infusion of cortisol, 100 mg every 12 hours, should be sufficient. Indeed, endogenous cortisol production during stress introduced by major surgery or extensive burns is not greater than 150 mg daily.^33,34 It is likely that patients undergoing minor operations will need minimal to no additional corticosteroid coverage during the perioperative period.