Corticosteroids General Statement

AHFS Class: Adrenals (68:04)

VA Class: HS051
ATC Class: H02AB10

Introduction

Corticosteroids are hormones secreted by the adrenal cortex or synthetic analogs of these hormones. They exhibit glucocorticoid and/or mineralocorticoid activity and affect almost all body systems, but are used principally for their potent anti-inflammatory and immunosuppressant effects and for replacement.

Uses

In physiologic dosages, corticosteroids are used to replace deficient endogenous hormones. In pharmacologic dosages, the drugs have both therapeutic and diagnostic applications based on their ability to suppress secretion of normal adrenal hormones. Glucocorticoids are also used in pharmacologic dosages for their anti-inflammatory and immunosuppressant properties and their effects on blood and lymphatic systems in the palliative treatment of various diseases.

When glucocorticoids are used for their anti-inflammatory and immunosuppressant properties, synthetic glucocorticoids that have minimal mineralocorticoid activity are preferred to cortisone or hydrocortisone. Glucocorticoid therapy is not curative and is rarely indicated as the primary method of treatment, but rather as supportive therapy to be used adjunctively with other indicated therapies. If prolonged oral administration of glucocorticoids is required, alternate-day therapy should be used whenever possible to minimize adverse reactions, and continual attempts should be made to reduce the dosage or, preferably, to withdraw glucocorticoid therapy completely. (See General Dosage in Dosage and Administration: Dosage.)

Adrenocortical Insufficiency

Corticosteroids are administered in physiologic dosages to replace deficient endogenous hormones in patients with adrenocortical insufficiency. Because production of both mineralocorticoids and glucocorticoids is deficient in these patients, hydrocortisone or cortisone (in conjunction with liberal salt intake) is usually the corticosteroid of choice for replacement therapy. Concomitant administration of a more potent mineralocorticoid (fludrocortisone) may be required in some patients, particularly in infants.⁷³¹ If synthetic glucocorticoids are used instead of hydrocortisone or cortisone, a mineralocorticoid must also be given. In suspected or known adrenal insufficiency, parenteral therapy may be used preoperatively or during serious trauma, illness, or shock unresponsive to conventional therapy.⁷³¹ In shock caused by acute adrenocortical insufficiency, IV administration of hydrocortisone (or a synthetic glucocorticoid) in conjunction with other therapy for shock is essential.

Adrenogenital Syndrome

In salt-losing forms of congenital adrenogenital syndrome, cortisone or hydrocortisone is administered in conjunction with liberal salt intake. Because of the risk of growth retardation with excessive dosage (see Cautions: Pediatric Precautions), the minimum dosage of the corticosteroid required to suppress adrenocortical hyperfunction should be used. If sodium loss and hypotension are not adequately controlled by cortisone or hydrocortisone, an additional mineralocorticoid drug should be given. Mineralocorticoid replacement can usually be discontinued in children 5–7 years of age, but a glucocorticoid must be continued throughout life. Patients with the hypertensive form of congenital adrenogenital syndrome (who secrete excessive amounts of desoxycorticosterone) should be treated with a “short-acting” glucocorticoid with minimal mineralocorticoid activity (e.g., prednisone). Longer acting glucocorticoids (e.g., dexamethasone) should not be used in such patients because there is a tendency toward overdosage and growth may be retarded.

Hypercalcemia

Glucocorticoids promote a reduction in serum calcium concentrations and are effective as hypocalcemic agents in patients with steroid-sensitive malignancies (e.g., multiple myeloma, lymphoma) and in patients with hypercalcemia due to sarcoidosis or vitamin D intoxication.^{770 771} Glucocorticoids are not effective in hypercalcemia caused by hyperparathyroidism.

Thyroiditis

The anti-inflammatory action of glucocorticoids dramatically relieves symptoms such as fever and acute thyroid pain and swelling in granulomatous (subacute, nonsuppurative) thyroiditis. The drugs are indicated in moderate to high dosages for palliative therapy in severely ill patients unresponsive to salicylates and thyroid hormones. Glucocorticoids may also be effective in reducing orbital edema in endocrine exophthalmos (thyroid ophthalmopathy). Changes in thyroid status may necessitate adjustment of glucocorticoid dosage.

Rheumatic Disorders and Collagen Diseases

In rheumatic disorders and collagen diseases, glucocorticoids relieve inflammation and suppress symptoms, but do not affect progression of the disease. The drugs are rarely indicated except for palliative, short-term treatment of acute exacerbations and systemic complications in patients refractory to more conservative therapy. Dosage in life-threatening situations is often high and is reduced rapidly after the crisis is past. Maintenance therapy with glucocorticoids is rarely indicated in rheumatoid arthritis, acute gouty arthritis, or systemic lupus erythematosus, but may be used as part of a total treatment program in selected patients when more conservative therapies have proven ineffective. Glucocorticoid withdrawal is extremely difficult in patients with these conditions, as relapses or rebounds usually occur upon discontinuance of the drugs.

In the symptomatic treatment of rheumatoid arthritis that involves only a few persistently inflamed joints or in the treatment of inflammation of tendons or bursae, local injections of slightly soluble glucocorticoids may be beneficial. Patients usually experience dramatic relief initially. Although inflammation tends to recur and sometimes it is more intense after cessation of therapy, the drugs can prevent invalidism by facilitating movement of joints that might otherwise become immobile.

Systemically administered glucocorticoids control acute manifestations of rheumatic carditis more rapidly than salicylates and may be life-saving in certain conditions, but glucocorticoids, like salicylates, cannot prevent valvular damage and are no better than salicylates for long-term treatment. Salicylates used concomitantly with glucocorticoids may decrease inflammatory rebound when the steroids are withdrawn. (See Drug Interactions: Nonsteroidal Anti-Inflammatory Agents.) Cytotoxic therapy is the treatment of choice in Wegener’s granulomatosis, but glucocorticoids may be used adjunctively for severe systemic complications.

Glucocorticoids remain the primary treatment to control symptoms and prevent severe, often life-threatening complications in patients with dermatomyositis and polymyositis, polyarteritis nodosa, relapsing polychondritis, polymyalgia rheumatica and giant-cell (temporal) arteritis, or mixed connective tissue disease syndrome. High dosage may be required for acute situations; after a response has been obtained, glucocorticoids must often be continued for long periods at low dosage. Polymyositis associated with malignancy and childhood dermatomyositis may not respond well to glucocorticoids.

Systemic glucocorticoids are rarely indicated in psoriatic arthritis, diffuse scleroderma (progressive systemic sclerosis), acute and subacute bursitis, and osteoarthritis. Risks outweigh benefits received, and more conservative therapy should be used. In osteoarthritis, intra-articular injections of glucocorticoids may be beneficial but should be limited in number as joint damage may occur.

Dermatologic Diseases

In dermatologic diseases such as pemphigus and pemphigoid, exfoliative dermatitis, bullous dermatitis herpetiformis, severe erythema multiforme (Stevens-Johnson syndrome), uncontrollable eczema, cutaneous sarcoidosis, mycosis fungoides, and lichen planus, systemic glucocorticoids should generally be reserved for acute exacerbations unresponsive to conservative therapy. In all these dermatologic diseases, high dosage of glucocorticoids may be required. Early initiation of systemic glucocorticoid therapy may be life-saving in pemphigus vulgaris and pemphigoid, and high or massive doses may be required. Dosage should be reduced gradually to the lowest effective level, but discontinuance may not be possible; alternate-day therapy may often be used beneficially.

Although chronic skin disorders are seldom an indication for systemic glucocorticoids, intralesional or sublesional injections may occasionally be indicated for localized chronic disorders (including keloids, psoriatic plaques, alopecia areata, discoid lupus erythematosus, and granuloma annulare) unresponsive to topical therapy. Systemic glucocorticoids are rarely indicated for psoriasis or alopecia (areata, totalis, or universalis). When systemic corticosteroids are used in the treatment of psoriasis, exacerbation of the disease may occur when the drugs are withdrawn or dosage is decreased. Although glucocorticoids may stimulate hair growth in patients with alopecia, hair loss returns when the drugs are discontinued.

Allergic Conditions

Systemic glucocorticoids are used for control of severe or incapacitating allergic conditions that do not respond to adequate trials of conventional therapy in patients with bronchial asthma, seasonal or perennial allergic rhinitis, atopic dermatitis, urticaria associated with transfusion, or acute noninfectious laryngeal edema (although epinephrine is the drug of choice). Systemic glucocorticoids also may be used in acute manifestations of angioedema, serum sickness, contact dermatitis, drug hypersensitivity, and allergic symptoms of trichinosis. In acute conditions, the drugs may be used for short periods in high dosage with other therapy such as antihistamines and sympathomimetics.

In the symptomatic treatment of chronic allergic conditions, systemic glucocorticoids generally should be reserved for acute conditions and severe exacerbations. Prolonged treatment of chronic allergic conditions should be reserved for patients with disabling conditions unresponsive to more conservative therapy and for whom the risks of long-term glucocorticoid therapy are justified.

Ocular Disorders

Optic Neuritis

Systemic glucocorticoids have been used for the treatment of acute optic neuritis†.^{574 575 576 577 580} Interest in the use of IV methylprednisolone in the management of acute relapses of multiple sclerosis has been heightened as a result of the Optic Neuritis Treatment Trial.^{574 576 581} In this trial in which short-term glucocorticoid therapy (IV methylprednisolone 1 g daily for 3 days followed by oral prednisone 1 mg/kg daily for 11 days versus oral prednisone alone at this dosage for 14 days) was compared with placebo for the treatment of initial episodes of acute optic neuritis, the rate of vision recovery was faster with the methylprednisolone regimen, with the greatest benefit being observed in patients with visual acuity of 20/50 or worse at entry; however, there were no substantial differences in visual outcomes between the groups at 6 months.^{574 575} Use of oral prednisone alone did not improve the rate of vision recovery compared with placebo and was associated with an increased risk of new episodes of optic neuritis in either eye.^{575 576}

At 2-year follow-up, patients who had received the methylprednisolone regimen had a lower rate of progression to clinically definite multiple sclerosis than those who received placebo.⁵⁷⁶ This beneficial effect was most evident in patients at the highest risk for multiple sclerosis (i.e., those with multicentric brain lesions on MRI at study entry).⁵⁷⁶ However, after 3 years, differences between the treatment groups were no longer significant, suggesting that IV methylprednisolone delayed but did not arrest the development of multiple sclerosis after optic neuritis.^{574 577} At 5-year follow-up, most patients who had received the methylprednisolone regimen retained good to excellent vision, even if there had been single or multiple recurrences of optic neuritis during the 5-year period.⁵⁸⁰ The cumulative probability of having a new episode of optic neuritis over the 5-year follow-up period was 19% for affected eyes, 17% for fellow eyes, and 30% for either eye.⁵⁸⁰

Patients who developed clinically diagnosed multiple sclerosis over the follow-up period were more likely to have recurrences of optic neuritis in the affected or fellow eye and also were more likely to have slight worsening of vision between the 6-month and 5-year follow-up examinations than patients without clinically diagnosed multiple sclerosis.⁵⁸⁰

Other Ocular Disorders

Systemic glucocorticoids may be used to suppress a variety of allergic and nonpyogenic ocular inflammations and to reduce scarring in ocular injuries. Glucocorticoids have been used for the treatment of severe acute and chronic allergic and inflammatory processes involving the eye that are intractable to adequate trials of conventional treatment (e.g., allergic conjunctivitis, keratitis, allergic corneal marginal ulcers, herpes zoster ophthalmicus, iritis and iridocyclitis, chorioretinitis, diffuse posterior uveitis and choroiditis, anterior segment inflammation, temporal arteritis, sympathetic ophthalmia).^{731 742 762 763 764} Moderate dosage is used initially and is quickly discontinued after the acute condition is controlled. Some disorders may relapse upon discontinuance of therapy and low-dose maintenance therapy may be required. Glucocorticoids are of no value in the treatment of degenerative ocular diseases such as cataracts.

Topically applied glucocorticoids appear to be as effective as systemic steroids for the treatment of most anterior ocular inflammations. Systemic glucocorticoid therapy may be required, however, in stubborn cases of anterior segment eye disease and is necessary when deeper ocular structures are involved.

Respiratory Diseases

Asthma

In the stepped-care approach to antiasthmatic drug therapy, maintenance therapy with low doses of an inhaled glucocorticoid (200–600 mcg of budesonide or equivalent daily in adults or 200–400 mcg of budesonide or equivalent daily in children 12 years of age or younger)⁵⁵⁴ is the preferred treatment for adults and children with mild persistent asthma ^{554 556} (i.e., patients with daytime symptoms of asthma more than twice weekly but less than once daily, and nocturnal symptoms of asthma more than twice per month).⁵⁵⁴ Alternatives to low-dose inhaled glucocorticoids as long-term control therapy for mild persistent symptoms include mast-cell stabilizers (e.g., cromolyn, nedocromil), extended-release theophylline, or leukotriene modifiers (e.g., montelukast, zafirlukast, zileuton), but these therapies are less effective^{554 556} and not preferred as initial therapy according to some experts.⁵⁵⁴ Some experts state that initiation of long-term control therapy (e.g., inhaled glucocorticoids) should be strongly considered for infants and young children who in the past year have experienced more than 3 episodes of wheezing that lasted more than 1 day and affected sleep, and who also have identifiable risk factors for the development of asthma, including parental history of asthma, clinician-diagnosed atopic dermatitis, or 2 of the following conditions: clinician-diagnosed allergic rhinitis, peripheral blood eosinophilia exceeding 4%, or wheezing unrelated to colds.⁵⁵⁴ These recommendations are in addition to those advising initiation of long-term control therapy (e.g., low-dose inhaled glucocorticoids) in infants and young children who require symptomatic treatment for asthma more than twice weekly or treatment for severe exacerbations less than 6 weeks apart.⁵⁵⁴ In children 5 years of age or younger with mild persistent asthma, cromolyn or leukotriene modifiers may be considered as alternatives to inhaled glucocorticoids.⁶⁸⁶

When daily asthmatic symptoms (moderate persistent asthma) develop, a long-acting inhaled β₂-agonist (e.g., formoterol, salmeterol) added to low- to medium-dose inhaled glucocorticoids is the preferred therapy in adults and children older than 5 years of age; ⁵⁵⁴ alternatively, maintenance dosage of the inhaled glucocorticoid can be increased (e.g., doubled) within the medium-dosage range (600–1200 or 400–800 mcg of budesonide or equivalent daily in adults or children 12 or younger, respectively).^{554 556} Combination therapy with a long-acting inhaled β₂-agonist is preferable to increasing the dosage of inhaled glucocorticoids in most of these patients.^{554 556} There is, however, a clear relationship between the dosage of inhaled glucocorticoids and prevention of severe acute exacerbations of asthma.⁵⁵⁶ Some patients with moderate persistent asthma who have recurrent severe exacerbations requiring oral glucocorticoids, emergency department visits, or hospitalizations may benefit from increased dosages of an inhaled glucocorticoid within the medium-dose range (up to 1200 mcg of budesonide or equivalent daily in adults or up to 800 mcg of budesonide or equivalent daily in children 12 years of age or younger) in addition to therapy with a long-acting inhaled β₂-agonist or, alternatively, a leukotriene modifier, or extended-release theophylline.⁵⁵⁴ In children 5 years of age or younger with moderate persistent asthma, addition of a long-acting inhaled β₂-agonist to low-dose inhaled glucocorticoid therapy or increasing the dosage of the inhaled glucocorticoid within the medium-dosage range are equally preferred options.⁵⁵⁴ Alternative therapy in such children who are intolerant of long-acting inhaled β₂-agonists or who have a marked preference for oral therapy includes addition of extended-release theophylline or a leukotriene modifier to low-dose inhaled glucocorticoids, if alternative therapy demonstrates superior effectiveness during a therapeutic trial.⁵⁵⁴ Maintenance therapy with an inhaled glucocorticoid at high dosages, an inhaled long-acting β₂-agonist, and, if needed, oral glucocorticoids is the preferred treatment for adults and children with severe persistent asthma (i.e., patients with continuous daytime and frequent nocturnal symptoms of asthma).⁵⁵⁴ Other add-on therapy recommended by some clinicians includes extended-release theophylline, a leukotriene modifier, omalizumab, and/or a long-acting oral β₂-agonist bronchodilator.⁵⁵⁶ Some glucocorticoids are recommended for IM use for control of severe or incapacitating allergic bronchial asthma in patients whose disease is intractable to adequate trials of conventional oral corticosteroid treatment, those who are vomiting, or those who are noncompliant with oral corticosteroid therapy.^{417 477 554 731} Patients with severe persistent asthma generally should be managed in consultation with an asthma specialist.⁵⁵⁴

When symptoms are not controlled with maintenance therapy plus supplemental, as needed therapy with a short-acting inhaled β₂-agonist bronchodilator (e.g., if there is a need to increase the dose or frequency of administration of the short-acting sympathomimetic agent), prompt reevaluation is required to adjust dosage of the maintenance regimen or institute an alternative maintenance regimen.^{554 556} In patients with acute exacerbations of asthma, initial home treatment consists of use of an inhaled short-acting β₂-agonist (2–4 inhalations every 20 minutes for the first hour).⁵⁵⁴ Some clinicians recommend adding oral glucocorticoids (0.5–1 mg/kg prednisolone or equivalent during a 24-hour period) to speed resolution of all but the mildest exacerbations of asthma in patients whose response to a short-acting inhaled β₂-agonist is not prompt or sustained (e.g., peak expiratory flow [PEF] greater than 80% of predicted or personal best) after 1 hour or in those who have a history of severe exacerbations.^{554 556} Oral glucocorticoids such as prednisone, prednisolone, or methylprednisolone are preferred because of their minimal mineralocorticoid effect, their relatively short half-life, and their limited effects on striated muscle.⁵⁵⁶ Effects of glucocorticoids may not be evident for several hours, so the drugs should not be the only treatment in an emergency.^{556 637} If there is further deterioration or if clinical improvement is not apparent within 2–6 hours following initiation of oral glucocorticoid therapy, immediate medical attention should be sought.⁵⁵⁶ Patients at a high risk of asthma-related death, those with severe exacerbations (e.g., PEF remains less than 60% of predicted or personal best following use of a short-acting inhaled β₂-agonist), and those whose response to bronchodilator therapy is not prompt or not sustained for at least 3 hours also should not delay in seeking urgent medical attention.⁵⁵⁶

Initial hospital management of an acute exacerbation of asthma includes administration of oxygen and inhaled short-acting β₂-agonist therapy via metered-dose inhaler aerosol or nebulization.⁵⁵⁶ If response to initial treatment of the asthma exacerbation is not immediate, if patients used oral glucocorticoids as self-medication prior to hospitalization, or if the episode is severe, systemic glucocorticoids should be added to the regimen.^{554 556 761} Other intensive measures for treating an acute exacerbation of asthma include addition of an orally inhaled anticholinergic agent.^{554 556} Some experts recommend the addition of a subcutaneous, IM, or IV β₂-agonist, subcutaneous epinephrine, IV aminophylline,⁵⁵⁶ or IV magnesium for severe exacerbations.⁵⁵⁶ However, it has not been established that parenteral therapy with β₂-agonists or epinephrine offers any advantage over orally inhaled β₂-agonists in hospitalized patients with severe asthma exacerbations.^{554 686 687}

Many clinicians recommend making repeated attempts to reduce use of systemic glucocorticoids and maintain control with high-dose inhaled glucocorticoids (dosages exceeding 1200 or 800 mcg of budesonide or equivalent daily in adults or children 12 years of age or younger, respectively)⁵⁵⁴ in patients with severe persistent asthma once control of asthma is achieved.^{554 556} High dosages of inhaled glucocorticoids are preferable to oral glucocorticoids because inhaled glucocorticoids have fewer systemic effects.^{554 556}

For more information on the stepped-care approach to drug therapy in asthma, see Asthma under Uses: Bronchospasm, in Albuterol 12:12.08.12.

Chronic Obstructive Pulmonary Disease

The effects of oral and inhaled glucocorticoids in patients with stable chronic obstructive pulmonary disease†(COPD) are much less dramatic than in those with asthma, and the role of glucocorticoids in the management of stable COPD is limited to very specific indications.^{624 737} Because inhaled glucocorticoids do not affect the decline in lung function or reliably improve quality of life in patients with COPD, use of inhaled glucocorticoids is not considered first-line therapy for the treatment of COPD.^{624 737} However, in patients with severe to very severe COPD (e.g., forced expiratory volume in 1 second [FEV₁] less than 50% of predicted, history of exacerbations), the addition of an inhaled glucocorticoid to one or more long-acting bronchodilators may reduce the frequency of exacerbations and improve health status.^{737 738 739} Use of an inhaled glucocorticoid/long-acting bronchodilator combination should be reserved for patients with are symptomatic (repeated exacerbations) despite optimal or maximal dosages of long-acting bronchodilators.^{737 739} Beneficial effects of inhaled glucocorticoids in such patients have been seen with dosages equivalent to 800 mcg of budesonide daily.⁷³⁷ Short-acting bronchodilators may be used as needed for relief of acute symptoms that occur despite regular use of an inhaled glucocorticoid and long-acting bronchodilators.^{737 739} If symptoms are not adequately controlled with inhaled glucocorticoids and a long-acting bronchodilator, or if limiting adverse effects occur, oral extended-release theophylline may be added or substituted.^{736 738 739} Long-term treatment with oral glucocorticoids should be avoided in patients with COPD.^{737 739}

Management of acute exacerbations of COPD at home is based initially on the same drugs used for management of the stable patient.^{736 738 739} A short-acting β₂-adrenergic agonist is the preferred bronchodilator for treatment of acute exacerbations of COPD.⁷³⁹ For more severe exacerbations of COPD (e.g., FEV₁ less than 50% of predicted), a short (e.g., 10–14 days) course of oral glucocorticoids (e.g., equivalent to 30–40 mg of prednisone daily) can be added to bronchodilator therapy.^{564 565 624 626 736 738 739} Some clinicians consider inhaled glucocorticoids as an alternative to oral glucocorticoids for management of acute exacerbations of COPD.^{738 739} Oral glucocorticoids are especially helpful within the first 72 hours of an acute exacerbation and should be initiated early at the first signs of an exacerbation.⁷³⁶ If symptoms of COPD continue to deteriorate several hours after administration of oral glucocorticoids (e.g., sudden development of resting dyspnea, cyanosis, peripheral edema, changes in mental status, inability to eat or sleep because of symptoms), hospital assessment or admission should be considered.^{736 739} If patients cannot tolerate oral glucocorticoids, IV glucocorticoids should be used.⁷³⁶

For additional information on the stepped-care approach to COPD, see Chronic Obstructive Pulmonary Disease under Uses: Bronchospasm, in Albuterol 12:12.08.12 and in Ipratropium 12:08.08.

Sarcoidosis

In the management of sarcoidosis, systemic glucocorticoids are indicated for ocular, CNS, glandular, myocardial, or severe pulmonary involvement or for hypercalcemia or severe skin lesions unresponsive to intralesional or sublesional injections of glucocorticoids. Long-term therapy may be required.

Advanced Pulmonary and Extrapulmonary Tuberculosis

Systemic glucocorticoids have been used as adjunctive therapy in some patients with severe pulmonary or extrapulmonary tuberculosis in an attempt to suppress manifestations related to the host’s inflammatory response to the Mycobacterium tuberculosis bacillus and ameliorate complications of the disease.^{585 586 587 588 589 590 591 592 593 594 595 596} While evidence from studies of M. tuberculosis infection in both animals and humans indicates that glucocorticoids can have deleterious effects (e.g., increased virulence of the organism) in the absence of adequate antituberculosis therapy, such effects generally appear to be prevented by coadministration of effective antimycobacterial agents (e.g., streptomycin, isoniazid).^{585 591 597} Data from randomized, controlled trials are limited and principally consist of studies conducted before the use of current 4-drug, short-course antituberculosis regimens; however, an analysis of available evidence suggests that adjunctive glucocorticoid therapy may enhance short-term resolution of disease manifestations (e.g., clinical and radiographic abnormalities) in patients with advanced pulmonary tuberculosis and also may reduce mortality associated with certain forms of extrapulmonary disease (e.g., meningitis, pericarditis).^{585 586 587 591 592 595 596 597 684} Additional randomized, controlled studies in patients receiving current short-course antituberculosis regimens are needed to fully elucidate the potential benefits and risks of adjunctive glucocorticoid therapy in pulmonary or extrapulmonary tuberculosis.^{585 586} Dosage of adjunctive corticosteroids may need to be adjusted upward in patients receiving rifampin-containing antituberculosis regimens as a result of rifampin-induced increases in corticosteroid metabolism.^{591 594 595 596} (See Drugs Affecting Hepatic Microsomal Enzymes: Other Drugs under Drug Interactions in Rifampin 8:16.04.)

Advanced Pulmonary Tuberculosis. Adjunctive systemic glucocorticoid therapy has been used to treat severe systemic and respiratory manifestations in patients with advanced pulmonary tuberculosis.^{585 595} Although benefit to the patient is unclear, radiographically evident abnormalities (other than cavities) usually resolve more rapidly with glucocorticoid therapy.^{585 595} No improvement in long-term outcomes (chronic respiratory disease or death) has been observed.⁵⁸⁵ In patients receiving adequate antituberculosis therapy (2 or more effective agents), glucocorticoid use does not appear to delay the time to conversion of sputum culture to negative or affect long-term cure rates.⁵⁸⁵

Tuberculous Meningitis. Use of systemic adjunctive glucocorticoids (e.g., dexamethasone, prednisone) in patients with moderate to severe tuberculous meningitis appears to reduce sequelae (e.g., intellectual impairment) and/or improve survival.^{585 586 587 591 592 597} In a randomized, controlled study in young children (mean age less than 36 months) with tuberculous meningitis, therapy with prednisone (2–4 mg/kg daily) reduced mortality in patients with stage III disease from 17% to 4% but did not reduce the incidence of permanent motor deficits (hemiparesis and quadriparesis).⁵⁹² Results from a prospective, randomized, placebo-controlled study in adults and adolescents older than 14 years of age with tuberculous meningitis (with or without HIV infection) also showed reduced mortality (relative risk of death of 0.69; 95% confidence interval of 0.52–0.92) in patients receiving dexamethasone (IV therapy tapered over 2–4 weeks, depending on disease severity, followed by oral therapy tapered over 4 weeks), but dexamethasone therapy was not associated with a substantial reduction in the proportion of severely disabled patients among survivors or in the proportion of patients who had either died or were severely disabled after 9 months.⁶⁸⁴ A faster resolution of abnormal CSF parameters (e.g., elevated intracranial pressure, basal exudate, CNS tuberculomas)^{585 592 597} occurs with glucocorticoids use, which may aid in patient management.^{585 592} Available data suggest that response is most favorable in patients with disease of intermediate severity (as opposed to early or late disease) and that continuation of glucocorticoid therapy for at least 4 weeks may be associated with better outcomes than with shorter regimens.⁵⁸⁵

Tuberculous Pericarditis. Limited data suggest that adjunctive systemic glucocorticoid therapy is effective in the management of acute tuberculous pericarditis, rapidly reducing the size of pericardial effusions and the need for drainage procedures and decreasing mortality (probably through control of hemodynamically threatening effusion).^{585 586 595 596} However, glucocorticoid therapy does not appear to alter the incidence of progression to constrictive disease when used for treatment of either the acute or intermediate stage of pericarditis.⁵⁸⁵

Tuberculous Pleurisy. While most studies of adjunctive systemic glucocorticoid therapy in patients with tuberculous pleurisy have not been randomized or controlled, limited evidence suggests that such therapy hastens the resolution of pain, dyspnea, and fever associated with this form of the disease.^{585 586 591 595 596} However, glucocorticoids appear to have little efficacy in preventing fibrotic changes and resultant constrictive lung disease,^{593 594} and some clinicians advise against their routine use.^{589 593 594 596 597}

Other Tuberculosis Complications. Limited data suggest that intrathoracic adenopathy associated with primary tuberculosis may resolve more rapidly with the use of adjunctive systemic glucocorticoids.⁵⁸⁵ While a few studies have reported a reduced frequency of complications (e.g., recurrent abdominal pain, intestinal obstruction) with adjunctive glucocorticoid therapy in patients with peritoneal tuberculosis,^{585 588} data from randomized trials are lacking, and rapid improvement in symptoms occurred in these patients with antituberculosis therapy alone.⁵⁸⁵ Although it has been suggested that atelectasis associated with endobronchial tuberculosis may benefit from glucocorticoid therapy,⁵⁹⁵ results of a randomized, controlled trial in a limited number of patients with this form of the disease suggested no important benefit of glucocorticoid therapy over antituberculosis therapy alone with regard to healing rates and changes in pulmonary function.⁵⁹⁰ Inadequate data are available regarding the safety and efficacy of adjunctive glucocorticoid therapy in patients with tuberculous lymphadenitis, miliary or laryngeal tuberculosis, or HIV-associated tuberculosis.^{585 597}

Lipid Pneumonitis

In lipid pneumonitis, glucocorticoids appear to promote the breakdown or dissolution of pulmonary lesions and eliminate lipids in the sputum. Although high doses of glucocorticoids are commonly used in hydrocarbon pneumonitis to prevent pulmonary edema and fibrosis, there is no evidence that they prevent any complications or improve the recovery rate.

Pneumocystis carinii Pneumonia

The use of systemic glucocorticoids as adjunctive therapy for Pneumocystis carinii pneumonia in patients with acquired immunodeficiency syndrome† (AIDS) can decrease the likelihood of deterioration of oxygenation, respiratory failure, and/or death in those with moderate to severe pneumonia.^{430 431 432 433 434 435} Based on the results of controlled, randomized studies,^{430 431 432 433 434 435} the National Institutes of Health-University of California (NIH-UC) Expert Panel currently recommends that adults and adolescents older than 13 years of age with documented or suspected human immunodeficiency virus (HIV) infection and documented or suspected pneumocystis pneumonia be given systemic glucocorticoid therapy in addition to anti-infective treatment if they have moderate to severe pulmonary dysfunction, defined as an arterial oxygen pressure of less than 70 mm Hg or an arterial-alveolar gradient of more than 35 mm Hg on room air.^{430 435} It is not known whether patients with mild pneumocystis pneumonia (arterial oxygen pressure greater than 70 mm Hg or arterial-alveolar gradient less than 35 mm Hg on room air) might have clinically important benefit with adjunctive glucocorticoid therapy, and such benefit may be difficult to demonstrate in clinical studies because of the generally good clinical outcome of this group.^{430 433 434 435 456}

Current data suggest that glucocorticoids prevent the early deterioration in oxygenation associated with antipneumocystis therapy, and it is recommended that adjunctive glucocorticoid therapy be initiated as early as possible in patients with pneumocystis pneumonia.^{430 431 432 433 434 435 456} Benefit in controlled studies has not been demonstrated with initiation of glucocorticoid therapy more than 72 hours after initiation of specific antipneumocystis therapy.^{432 435 456} Therefore, glucocorticoid therapy can be started in patients with presumed AIDS-associated pneumocystis pneumonia if these patients meet the oxygenation criteria recommended by the Expert Panel.^{430 434} The diagnosis of HIV infection and pneumocystis pneumonia should be confirmed promptly to minimize the likelihood of masking and/or exacerbating other treatable diseases (e.g., tuberculosis) and to avoid adverse effects of unnecessary drugs.^{430 433 456} Pending the availability of specific efficacy or safety data, it may be reasonable to consider adjunctive systemic glucocorticoid therapy for pneumocystis pneumonia in immunosuppressed patients without HIV infection or in pregnant women with HIV infection according to the same criteria as for nonpregnant adults with HIV infection.⁴³⁰

Pending further accumulation of data, the NIH-UC Expert Panel recommends specific regimens of prednisone or, if parenteral therapy is required, methylprednisolone.^{430 433 435} (See Dosage and Administration, in Prednisone 68:04 and Methylprednisolone 68:04.) Higher dosages for patients whose condition is not improving on glucocorticoids, or newly initiated glucocorticoid therapy for those patients in whom standard treatment alone is failing, may or may not be beneficial; available evidence is inadequate to provide specific recommendations.^{430 433 435} Data also are needed to elucidate further the safety of adjunctive systemic glucocorticoid therapy in adolescents older than 13 years of age and adults with pneumocystis pneumonia^{430 435} and to establish the safety and efficacy of such therapy in pediatric AIDS patients with pneumocystis pneumonia.⁴³⁰ The regimen recommended by the Expert Panel was associated with a possible increased risk of reactivation of localized herpetic lesions and oral thrush lesions but no increase in the incidence of other opportunistic infections or malignancies (i.e., Kaposi’s sarcoma).^{430 433 456}

Other Respiratory Diseases

Systemic glucocorticoids may be used for symptomatic relief of acute manifestations of respiratory diseases including symptomatic idiopathic eosinophilic pneumonias (e.g., Löffler’s syndrome) not manageable by other means, idiopathic pulmonary fibrosis, allergic bronchopulmonary aspergillosis, idiopathic bronchiolitis obliterans with organizing pneumonia, aspiration pneumonitis, hypersensitivity pneumonitis, and berylliosis. Glucocorticoids also are used in fulminating or disseminated tuberculosis (see also Advanced Pulmonary and Extrapulmonary Tuberculosis, in Uses) in conjunction with appropriate antituberculosis therapy. High dosage may be required for several days. Glucocorticoids are not indicated for uncomplicated chronic respiratory diseases.

Complications of Prematurity

Antenatal Use in Preterm Labor

Short-course IM therapy with glucocorticoids (e.g., dexamethasone, betamethasone) is used in selected women with preterm labor to hasten fetal maturation (e.g., lungs, cerebral blood vessels), including women with preterm premature rupture of membranes, preeclampsia, or third-trimester hemorrhage.^{529 530 532 539 541 755} Antenatal administration of glucocorticoids generally appears to reduce the incidence and/or severity of neonatal respiratory distress syndrome (RDS) as indicated by a reduction in requirements for neonatal ventilatory support or surfactant therapy, and the beneficial effects are additive with those of surfactant.^{529 531 534 535 535 542 543 755}

Antenatal glucocorticoid therapy also can improve neonatal circulatory stability and reduce the incidence or severity of intraventricular hemorrhage.^{529 531 532 533 539 540 541 755} The incidence of necrotizing enterocolitis also is reduced by the use of antenatal glucocorticoids.⁷⁵⁵ The combined effects on multiple organ maturation during glucocorticoid therapy reduces the incidence of neonatal mortality, and the beneficial effects extend to a broad range of gestational ages (i.e., 24–34 weeks) and are not limited by gender or race.^{529 530 531 532 535 540 755}

Data are conflicting concerning the effects of antenatal glucocorticoids on the incidence of bronchopulmonary dysplasia, and patent ductus arteriosus in neonates,^{529 531 534 535} and the efficacy and safety of antenatal therapy with the drugs before 24 weeks or after 34 weeks of gestation have not been established.^{529 531} Short-term adverse effects of antenatal glucocorticoid administration include transient neonatal and maternal adrenal suppression and increased risk of infection.^{530 531 534} No long-term sequelae were noted in children up to 12 years of age who had been exposed to short-term antenatal glucocorticoids.^{529 531}

Antenatal use of glucocorticoids to reduce infant morbidity and mortality in women with preterm premature rupture of membranes is somewhat controversial, since the magnitude of neonatal benefit on RDS appears to be less and the risk of neonatal infection greater than those in women with intact membranes.^{529 531} However, even in the presence of preterm premature rupture of membranes, the incidence of neonatal mortality and intraventricular hemorrhage is reduced with antenatal glucocorticoid therapy.⁵²⁹ In addition, the magnitude of increased risk of neonatal infection associated with such therapy appears to be small.^{529 531} Therefore, because of the benefit on mortality and hemorrhage in fetuses of less than 30–32 weeks’ gestation and the apparently small risk, antenatal maternal glucocorticoid therapy is considered appropriate in the absence of clinically important chorioamnionitis.⁵²⁹

Antenatal therapy with IM dexamethasone (6 mg every 12 hours for 2 days) or IM betamethasone (12 mg once daily for 2 days) has been studied most extensively, and some experts state that these drugs generally have been preferred for use in preterm labor because of similarities in potency and efficacy and their ability to readily cross the placenta, as well as the relative absence of mineralocorticoid activity and relatively weak immunosuppressive effects.^{529 530 621} These glucocorticoids also have been preferred because of their longer duration of action compared with hydrocortisone or methylprednisone.^{529 530 531}

Beneficial effects of IM glucocorticoids on fetal maturation are greatest more than 24 hours after initiating therapy and extend up to at least 7 days;^{529 531 536} however, clinically important improvement in neonatal outcomes also has been observed in women receiving an incomplete course of glucocorticoid therapy (i.e., less than 24 hours), and antenatal administration of even a partial course of glucocorticoids should be attempted unless immediate delivery is anticipated.^{529 532 534 538 541} Some experts recommend a single course of treatment for all pregnant women between 24–34 weeks’ gestation who are at risk of preterm delivery within 7 days and state that repeat courses of antenatal glucocorticoids should not be used routinely because data evaluating the risks and benefits of such therapy are insufficient.⁶²¹ A recent clinical study evaluated the overall effect on neonatal morbidity of repeated weekly courses of antenatal glucocorticoid therapy compared with a single course of treatment in pregnant women at risk of preterm delivery.⁶²⁰ The incidence of neonatal morbidity (defined as the presence of severe RDS, bronchopulmonary dysplasia, severe intraventricular hemorrhage [IVH], periventricular leukomalacia, necrotizing enterocolitis, proven sepsis, or death between randomization and nursery discharge) observed with weekly treatment courses (22.5%) was similar to that observed with single courses of therapy (28%).⁶²⁰ Other clinical studies are in progress to determine if a specific number of exposures to antenatal corticosteroids or an increased interval between treatment courses will improve neonatal outcomes in women at risk of preterm delivery.⁶²⁰

Maternal use of tocolytic agents in conjunction with glucocorticoids may delay delivery in patients with preterm labor long enough for the fetus to derive benefit from glucocorticoid-induced accelerated fetal maturation.^{529 536 537 540} Combined use of the drugs has been shown to reduce the risk of neonatal RDS, and women between 24–34 weeks’ gestation at risk of preterm delivery are candidates for antenatal glucocorticoid therapy regardless of fetal race, gender, or availability of surfactant.^{529 536 537 540} Because β-adrenergic tocolytic monotherapy may be associated with an increased risk of intraventricular hemorrhage, the addition of antenatal glucocorticoid therapy could have a secondary benefit of reducing this risk.^{529 540}

Antenatal glucocorticoid therapy appears to have an additive effect with postnatal prophylactic lung surfactant therapy in reducing the incidence of RDS and neonatal mortality.^{529 534 535 543} In addition, antenatal glucocorticoids can reduce the incidence and/or severity of intraventricular hemorrhage, which surfactant therapy alone does not appear to benefit.^{529 532 533 542} However, data are limited concerning the prophylactic use of combination therapy for respiratory distress syndrome in women less than 28 weeks’ gestation.^{533 534 543}

Postnatal Use for Bronchopulmonary Dysplasia

Although some evidence indicates that postnatal IV glucocorticoids (e.g., dexamethasone) may be useful in preventing or treating bronchopulmonary dysplasia in preterm neonates with very low birth weight (i.e., less than 1.5 kg) who require mechanical ventilation, other evidence suggests that such therapy may be associated with an increased risk of serious adverse effects.^{688 689} Glucocorticoid therapy may provide short-term pulmonary benefits (e.g., reduced incidence of bronchopulmonary dysplasia, facilitation of weaning from mechanical ventilation) but does not reduce overall mortality and may be associated with both short-term adverse effects (e.g., hyperglycemia, hypertension, GI bleeding or intestinal perforation, hypertrophic obstructive cardiomyopathy, poor weight gain, poor growth of head circumference) and long-term sequelae.⁶⁸⁸ Long-term follow-up of preterm infants receiving IV glucocorticoids within 12 hours after birth indicates that postnatal glucocorticoid therapy is associated with an increased incidence of neurodevelopmental delay, cerebral palsy, impaired cognitive function, and stunted growth at or before school age.^{688 689} Therefore, the American Academy of Pediatrics (AAP) currently states that routine use of systemic glucocorticoids for prevention or treatment of bronchopulmonary dysplasia in very low birth weight infants is not recommended.⁶⁸⁸

Hematologic Disorders

Glucocorticoids are used in the management of acquired (autoimmune) hemolytic anemia, idiopathic thrombocytopenic purpura (ITP), secondary thrombocytopenia, erythroblastopenia, congenital (erythroid) hypoplastic anemia (Diamond-Blackfan syndrome), and pure red cell aplasia.

Although there is no evidence that glucocorticoids affect the course or duration of hematologic disorders, high or even massive dosage of the drugs is often used to decrease bleeding tendencies and normalize blood counts. When treatment is indicated in adults or children with moderate to severe idiopathic thrombocytopenic purpura (ITP), glucocorticoids, immune globulin IV (IGIV), or splenectomy are considered first-line therapies depending on the extent of bleeding involved.^{578 579} Other methods of treatment, such as splenectomy, should be considered if glucocorticoids must be continued for prolonged periods (more than several months), especially in patients with idiopathic or secondary thrombocytopenia, acquired (autoimmune) hemolytic anemia, erythroblastopenia (RBC anemia), or congenital (erythroid) hypoplastic anemia. Cytotoxic drugs produce better results in erythroblastopenia, but glucocorticoids may enhance response.

Glucocorticoids may not affect or prevent renal complications in Henoch-Schoenlein purpura. Glucocorticoids have been widely used in aplastic anemia in children, but there is no evidence to prove their effectiveness.

GI Diseases

In ulcerative colitis, regional enteritis, and celiac disease, moderate to high dosage glucocorticoids may be useful as short-term palliative therapy for acute exacerbations and systemic complications of these chronic conditions. Glucocorticoids should not be used if there is a probability of impending perforation, abscess, or other pyogenic infection. Systemic and topical (rectal enema) glucocorticoids may be useful in acute ulcerative colitis. Sulfasalazine is the drug of choice for chronic ulcerative colitis, and a gluten-free diet is the primary method of therapy for celiac disease.

Glucocorticoids are rarely indicated for maintenance therapy in chronic GI diseases (ulcerative colitis, celiac disease) as they do not prevent relapses and may produce severe adverse reactions with long-term administration. Gastric hemorrhage and malignant hypertension are especially frequent. Occasionally, however, low dosages of glucocorticoids, in conjunction with other supportive therapy, may be useful for patients unresponsive to the usual therapy indicated for chronic conditions.

Crohn's Disease

Conventional systemic glucocorticoids (e.g., prednisone, prednisolone, methylprednisolone) have been used for the management of mildly to moderately active and moderately to severely active Crohn's disease†,^{635 652 653 654 655 656 658 659 660 661 662 663 664 665 666 668} while budesonide (a more recently approved glucocorticoid) is used orally as delayed-release capsules for the management of mildly-to-moderately active Crohn's disease involving the ileum and/or ascending colon.⁶⁷⁸ Conventional glucocorticoids are at least as effective as sulfasalazine, mesalamine, budesonide, or azathioprine in patients with Crohn's disease;^{635 654 656 657} however, many clinicians and experts state that conventional glucocorticoids should not be used for the management of mildly to moderately active disease, because of their high incidence of adverse effects and, therefore, their use should be reserved for patients with moderately to severely active disease.^{662 664}

Although no appropriate dose-ranging studies have been performed to evaluate conventional glucocorticoid dosing or dosage schedules for Crohn's disease,⁶⁵² comparable clinical effects have been reported in placebo-controlled and active comparator clinical trials in which 50–70% of patients received glucocorticoid dosages equivalent to prednisone (40 mg daily; tapered after clinical response).^{635 652 654 655 656 657} In these patients, resolution of certain symptoms and resumption of weight gain usually occurred after 1–4 weeks of therapy, while clinical remission was achieved over 8–12 weeks.⁶⁵² Parenteral glucocorticoids (dosages equivalent to prednisone 40–60 mg, given as divided doses or as a continuous infusion) are recommended for patients with severe fulminant Crohn's disease†; ⁶⁵⁸ individuals with inflammatory abdominal mass should receive broad-spectrum anti-infective agents in conjunction with glucocorticoids.^{652 658} Once patients respond to parenteral therapy, they should gradually be switched to an equivalent regimen of an oral glucocorticoid.⁶⁵² About 50% of patients with active Crohn's disease, who are receiving systemic glucocorticoids, become glucocorticoid-dependent or glucocorticoid-resistant;^{652 666 667 670 671 673} such patients should receive drugs with steroid-sparing effects (e.g., azathioprine, mercaptopurine) or, alternatively, infliximab.^{652 661} Glucocorticoids should not be used for maintenance therapy of Crohn's disease, because both conventional glucocorticoids and budesonide usually do not prevent relapses and the drugs (especially conventional glucocorticoids) may produce severe adverse reactions with long-term administration.^{652 653 654 655 659 660 663 669 672}

Systemic conventional glucocorticoids (e.g., prednisone 1–2 mg/kg daily up to 60 mg daily) have been used in pediatric patients with mild esophageal or gastroduodenal Crohn’s disease†.⁶⁷⁶ In addition, glucocorticoids (e.g., prednisone or methylprednisolone 1–2 mg/kg daily up to 60 mg daily) are recommended for the management of moderately to severely active Crohn’s disease, in children.⁶⁷⁶ Results of a 12-week comparator-drug (prednisone versus budesonide) controlled study in pediatric patients 8–18 years of age (weighing more than 20 kg) with mildly to moderately active Crohn’s disease (Pediatric Crohn’s Disease Activity Index [PCDI] score of 12.5–40) indicate that remission rates in children receiving prednisone (40 mg daily for 2 weeks and then tapered until discontinuance) were similar (50% for prednisone versus 47% for budesonide) to those receiving budesonide (9 mg daily for 8 weeks, tapered until discontinuance).⁶⁷⁵ Incidence of adverse effects was substantially lower (about 32% for budesonide versus 71% for prednisone) and less severe in pediatric patients receiving budesonide than in those receiving prednisone.⁶⁷⁵

(For further information about the management of Crohn's disease, see Uses: Crohn's Disease, in Mesalamine 56:36.)

Trichinosis

Glucocorticoids are used in the treatment of trichinosis with neurologic or myocardial involvement.

Neoplastic Diseases

Glucocorticoids in high dosage are used alone or as a component of various chemotherapeutic regimens in the palliative treatment of neoplastic diseases of the lymphatic system (e.g., leukemias and lymphomas in adults and acute leukemias in children). Massive dosage of glucocorticoids has occasionally been used in the treatment of neoplastic diseases but rarely offers any additional benefit and greatly increases adverse effects. Beneficial results are enhanced, however, when glucocorticoids are used as part of a total treatment regimen in combination with cytotoxic and immunosuppressive drugs; such a regimen should be administered only by an experienced oncologist.

In adults, acute lymphocytic (lymphoblastic) leukemia, chronic lymphocytic leukemia, and Hodgkin’s disease respond well to combination regimens that include a glucocorticoid (usually prednisone or prednisolone). Acute myeloblastic leukemia, lymphosarcoma, and the blast crisis of chronic myelocytic leukemia may fail to respond or may relapse upon discontinuance of therapy.

In moderate dosage, glucocorticoids induce tumor remission in approximately 15% of patients with breast cancer. Because glucocorticoids used alone are not as effective as other agents (e.g., cytotoxic agents, hormones, antiestrogens) in the treatment of breast cancer, their use should be reserved for patients unresponsive to other therapy.

Glucocorticoids (e.g., prednisone) also have been used alone or as a component of various combination chemotherapeutic regimens in the treatment of advanced, symptomatic (i.e., painful) hormone-refractory prostate cancer.^{544 545 546 547 549 550} Use of glucocorticoids and/or chemotherapeutic agents in the treatment of advanced, hormone-resistant prostate cancer is palliative, with patients having median survival durations of less than 1 year; no therapy has been shown to improve survival to date, and therefore the principal goal of therapy in such cancer currently is improvement in quality of life, particularly pain.^{545 546 547 548 549 550} Randomized studies have shown that the addition of an antineoplastic agent (e.g., mitoxantrone) to glucocorticoid therapy results in a greater proportion of patients achieving a palliative response (i.e., pain reduction) and a longer duration of such response compared with glucocorticoid treatment alone.^{544 545 546 547 549} Improvement in certain quality-of-life measures, including indicators related to pain, physical activity or function, constipation, and mood, also may favor combination therapy.^{546 547}

Cancer Chemotherapy-induced Nausea and Vomiting

Glucocorticoid (e.g., dexamethasone, methylprednisolone) regimens have been used extensively for the prevention of nausea and vomiting associated with emetogenic cancer chemotherapy†.^{495 496 497 498 514 526 527} including that associated with cisplatin.^{498 499 769} Most clinical experience to date has been with dexamethasone.^{495 496 497 498 499 500 501 502 504 505 506 507 508 509 511 526 769}

Clinical evaluations of dexamethasone in the prevention of chemotherapy-induced emesis have shown that the antiemetic effect of the glucocorticoid is greater than that of placebo^{495 497 769} or prochlorperazine.⁴⁹⁶ The addition of a glucocorticoid (e.g., dexamethasone) to therapy with a type 3 serotonin (5-HT₃) receptor antagonist (e.g., granisetron, ondansetron)^{505 506 507 508 509 510 511 512 526 527 528} , aprepitant,⁷⁶⁹ and/or a substituted benzamide (e.g., metoclopramide^{503 504 505 508 510} )⁵²⁶ appears to increase the antiemetic efficacy of either drug alone, and such combined therapy may be useful in preventing acute or delayed emesis in patients receiving emetogenic cancer chemotherapy.^{503 769}

To prevent chemotherapy-induced nausea and vomiting associated with chemotherapy regimens with a high emetic risk (i.e., incidence of emesis exceeds 90% if no antiemetics are administered), the American Society of Clinical Oncology (ASCO) currently recommends a 3-drug antiemetic regimen consisting of dexamethasone, aprepitant, and a 5-HT₃ receptor antagonist (e.g., dolasetron, granisetron, ondansetron, palonosetron, tropisetron [not commercially available in the US]).⁷⁶⁹ Antiemetic agents with a lower therapeutic index (i.e., less efficacious and generally associated with more frequent adverse effects), including cannabinoids (e.g., dronabinol, nabilone), metoclopramide, butyrophenones, and phenothiazines are not considered by ASCO to be appropriate first-line antiemetics for any group of patients receiving chemotherapy of high emetic risk; ASCO states that these drugs should be reserved for patients unable to tolerate or refractory to first-line agents.⁷⁶⁹

The antiemetic combination of dexamethasone, aprepitant, and a 5-HT₃ receptor antagonist also is preferred in patients receiving combination chemotherapy with an anthracycline and cyclophosphamide.⁷⁶⁹

For patients receiving other chemotherapy of moderate emetic risk (i.e., incidence of emesis without antiemetics exceeds 30% but does not exceed 90%), ASCO recommends a 2-drug antiemetic regimen consisting of dexamethasone and a 5-HT₃ receptor antagonist.⁷⁶⁹

For patients receiving chemotherapy regimens with a low emetic risk (i.e., incidence of emesis without antiemetics exceeds 10% but does not exceed 30%), ASCO recommends dexamethasone alone on the first day of chemotherapy.⁷⁶⁹

Antiemetics can be prescribed on an as-needed basis in patients receiving chemotherapy with a minimal antiemetic risk (incidence of emesis is less than 10% without antiemetics).⁷⁶⁹

For the prevention of delayed emesis in patients receiving cisplatin or other chemotherapy associated with a high emetic risk, these authorities currently recommend a 2-drug combination of dexamethasone and aprepitant.⁷⁶⁹

Although antihistamines (e.g., diphenhydramine) and benzodiazepines (e.g., alprazolam, lorazepam) may be useful as adjunctive antiemetic agents, they currently are not recommended as monotherapy as antiemetic agents.⁷⁶⁹ However, many clinicians find benzodiazepines useful in the management of anticipatory emesis.⁷⁶⁹

Liver Diseases

Glucocorticoids may be beneficial or harmful in patients with liver disease. Although evidence is conflicting, the drugs probably are of no value in patients with acute hepatitis and massive necrosis. In patients with subacute hepatic necrosis and chronic active hepatitis, administration of glucocorticoids in high dosage can decrease serum bilirubin, ascites, and mortality rate. Prolonged low-dosage maintenance therapy may be necessary. In nonalcoholic cirrhosis in women, glucocorticoids increase survival rate in the absence of ascites, but not when ascites is present. The drugs are ineffective in men with nonalcoholic cirrhosis. Glucocorticoids may decrease mortality rate in patients with alcoholic cirrhosis with hepatic encephalopathy, but they should not be used in less seriously ill patients. Acute viral hepatitis is usually benign and self-limited, and glucocorticoids are rarely indicated.

Cerebral Edema

Glucocorticoids administered parenterally, in high dosage, may be useful to decrease cerebral edema associated with brain tumors and neurosurgery. Some patients with cerebral edema associated with pseudotumor cerebri may also benefit from use of glucocorticoids, but the efficacy of the drugs is controversial and remains to be established. Edema resulting from brain abscesses is less responsive than that resulting from brain tumors.

The use of glucocorticoids in the management of cerebral edema is not a substitute for careful neurosurgical evaluation and definitive management such as neurosurgery or other specific therapy. Effects of glucocorticoids are not apparent for several hours and in acute situations the drugs should only be used adjunctively with other indicated therapy. Although any glucocorticoid may be effective, those having minimal mineralocorticoid activity are preferable. Glucocorticoids do not appear to be beneficial in cerebral edema associated with cerebral infarction.

Head Injury

Pooled analyses of small controlled studies of glucocorticoids in patients with head injury have failed to clearly establish the efficacy of glucocorticoid therapy in this patient population.⁶⁸⁵ Because of a lack of evidence of efficacy, some experts have recommended against the use of glucocorticoids for improving outcomes or reducing intracranial pressure in patients with head injury.^{679 680} More recent evidence from a large, international, randomized, placebo-controlled study (Corticosteroid Randomization after Significant Head Injury [CRASH]) indicates that use of glucocorticoids in patients with head injuries may be detrimental.^{681 682 683} Results from this study in more than 10,000 patients with head injury and a Glasgow coma score of 14 or less within 8 hours of injury indicate that glucocorticoid therapy (e.g., methylprednisolone 2 g administered by IV infusion over 1 hour, followed by methylprednisolone 0.4 g/hour by IV infusion for 48 hours) is associated with a substantial increase in risk of death (21.1% with methylprednisolone versus 17.9% with placebo) within 2 weeks after head injury; the relative risk of death from all causes within 2 weeks in patients receiving methylprednisolone compared with placebo in this study was 1.18 (95% confidence interval of 1.09–1.27).⁶⁸¹ The cause of the observed increase in mortality in patients receiving glucocorticoids is unclear because cause of death was not documented.⁶⁸¹ Recruitment of patients for this study was halted after results from interim analyses were reported.⁶⁸¹ Results regarding effects of glucocorticoid therapy on disability 6 months after head injury are pending.⁶⁸¹

Cerebral Malaria

Glucocorticoids are not effective and can have detrimental effects in the management of cerebral malaria caused by Plasmodium falciparum; the drugs are no longer recommended for this condition.

Acute Spinal Cord Injury

Some evidence indicates that therapy with large IV doses of glucocorticoids (i.e., methylprednisolone) can improve motor and sensory function in patients with acute spinal cord injury† when treatment is initiated promptly following injury.^{457 458 459 460} However, benefit in controlled studies in humans has been demonstrated to date only in patients receiving high-dose IV methylprednisolone within 8 hours after spinal cord injury,^{456 457 458 459 460} and whether improvement in neurologic function with such therapy will routinely lead to specific improvements in disability has not been established.^{456 457 460 461 462 468 469}

In a multicenter, comparative study, patients with acute spinal cord injuries† who received an initial 30-mg/kg dose of methylprednisolone (as the sodium succinate salt) by rapid IV injection (over 15 minutes) within 8 hours of injury, followed by infusion of the drug at 5.4 mg/kg per hour for an additional 23 hours, had substantial improvement in motor function and pinprick and touch sensation at 6 weeks and 6 months compared with those who received IV naloxone (5.4 mg/kg by rapid IV injection followed by 4 mg/kg per hour for an additional 23 hours) or placebo.^{457 458} The benefits of methylprednisolone therapy were observed in patients with complete as well as incomplete loss of motor and sensory function,^{457 458} and neurologic improvement observed at 6 weeks in methylprednisolone-treated patients was still evident at 6 months.^{456 458} Patients receiving naloxone or placebo and those in whom therapy with high-dose methylprednisolone was initiated later than 8 hours (but usually within 14 hours) after injury did not have substantial improvement in motor function or touch sensation.^{457 458} Mortality at 6 months was similar among treatment groups, and overall mortality was low (6%) compared with that of previous studies.^{457 458 463 465} Although the use of glucocorticoids in patients with spinal cord injuries has been associated with increased morbidity in some studies,^{464 465 466} clinically important differences in the incidence of wound infections, GI bleeding, and other complications among treatment groups in this study were not observed.^{457 458}

Limited evidence in animals suggests that the ameliorative effects of glucocorticoids in spinal cord injury† are related to dose and time of initiation of therapy; these effects appear to be characterized by a biphasic, bell-shaped response curve.^{456 457 467 470} In one study in animals with experimentally induced spinal cord injury, posttraumatic spinal cord ischemia was effectively minimized by a 30-mg/kg dose of methylprednisolone administered 30 minutes but not several hours after injury; at 30 minutes, a 15-mg/kg dose produced little benefit, while a dose of 60 mg/kg was ineffective or deleterious.^{457 467} Such studies suggest that the lack of appreciable benefit observed in an earlier controlled study^{464 465} of patients with acute spinal cord injury who were treated up to 48 hours after injury using a methylprednisolone dose of 100 mg or 1 g (approximately 15 mg/kg) daily for 10 days may have been related in part to delayed administration of the drug or administration of an insufficient dose.^{456 459 460} Additional studies are needed to determine the optimal timing, dosage, and duration of therapy with methylprednisolone or other glucocorticoids in patients with acute spinal cord injury and to elucidate further the potential benefits of glucocorticoid therapy on functional status in such patients.^{457 460}

Low Back Pain

Glucocorticoids (alone or combined with a local anesthetic and/or an opiate analgesic) have been used epidurally for symptomatic relief of low back pain†.^{640 641 642 643 644 645 646 647 648 649 690 691 692 693 695 698 700 701 702 703 705 711 719 720 721 722 725 726} Although this use remains controversial and convincing evidence of efficacy remains to be established,^{640 641 642 643 644 645 646 647 648 649 691 694 696 698 701 702 703 710 722} most experts state that this invasive form of therapy is an option for short-term relief of acute, subacute, or chronic radicular pain in patients with low back pain and radiculopathy associated with disk disease or herniation or spinal stenosis when more conservative therapies (e.g., rest, analgesics, physical therapy) fail and as a means of potentially avoiding surgery.^{647 648 649 690 691 692 693 695 698 702} The effect of epidural glucocorticoid injections on long-term outcomes of unremitting low back pain remains unclear.^{640 644 690 699} Epidural therapy for low back pain and radiculopathy involves injection of the drug(s) into the epidural space near the site where the nerve roots pass before entering the intervertebral foramen.^{648 649} Such therapy theoretically allows a concentrated amount of drug(s) to be deposited and retained locally, exposing nerves to the drug(s) for prolonged periods in an attempt to reduce inflammation, swelling, and pain.^{648 649 711} Epidural injections may be performed by caudal, interlaminar, or transforaminal approaches;^{692 698 725} the transforaminal approach requires the smallest injection volume and appears to be the most specific and possibly most effective route.^{647 691 692 698}

Because of the potential for complications related to improper needle placement or drug administration,^{692 698 699} many experts state that epidural injections should be performed by an experienced clinician using fluoroscopic guidance and contrast control to ensure that the needle is correctly positioned and that the injection is not performed intravascularly, intrathecally, or into tissues other than the epidural space.^{647 691 692 695 698 725} However, some clinicians suggest that fluoroscopic guidance may not be necessary in patients who have not undergone previous surgery and whose spinal anatomy is normal, and for whom there are no other factors making the procedure technically difficult (e.g., obesity).⁵⁹⁷ Long-acting injectable suspension formulations of methylprednisolone, triamcinolone, and betamethasone are the most commonly used preparations for epidural injections.^{645 691 692 699} Optimal technique, dosage, timing of initial injection, and injection frequency, as well as maximum number of epidural glucocorticoid injections, remain to be established.^{597 692 698 703 722}

Water-soluble glucocorticoid preparations typically have not been used for epidural injection because they are cleared rapidly from the spinal canal and have been associated with adverse neurologic effects (e.g., seizures, segmental hyperalgesia) when injected intrathecally in animals.⁶⁹⁹ Limited evidence suggests that large particles (e.g., exceeding 50 μm) in glucocorticoid suspension preparations potentially may cause embolic vascular occlusion during inadvertent intra-arterial injection; it appears that some particulate suspensions (e.g., methylprednisolone acetate, triamcinolone acetonide) may contain substantial amounts of these large particles, and some clinicians have suggested that a glucocorticoid solution preparation (e.g., dexamethasone sodium phosphate) or a suspension with an overall smaller size of particulate matter (e.g., fixed combination betamethasone sodium phosphate and betamethasone acetate) may be preferred for epidural injections.^{597 733} Long-acting injectable suspension preparations of glucocorticoids (e.g., Aristospan^®, Celestone^® Soluspan^®, Depo-Medrol^®, Kenalog^®) also contain preservatives and/or suspending agents (e.g., benzalkonium chloride, benzyl alcohol, myristyl-γ-picolinium chloride, polyethylene glycol)^{728 729 730 731} that have been associated with neurotoxic effects in animals or humans.^{645 697 699 704 707 708 709 713 714} While most reports of neurotoxicity with intraspinal glucocorticoid therapy in humans have involved intrathecal administration,^{645 699 704} the safety of epidural injections using preserved glucocorticoid formulations is controversial,^{645 704 709 713} and epidural administration of these formulations is not recommended by the manufacturers.^{716 729 735} Currently there are no studies supporting the use of any one formulation over any other in terms of safety.⁷³³

The principal risk of epidural injection therapy for low back pain and radiculopathy is rare epidural abscess.^{648 649} However, other serious adverse effects, including infectious complications (e.g., meningitis),^{645 648 692 697 698 699 700 705} neurologic effects (e.g., arachnoiditis, spinal cord trauma,⁶⁹² increased intracranial pressure,⁶⁹² nerve injury,^{692 698 705} seizures,^{697 716 729} bladder or bowel dysfunction,^{716 729} paraparesis or paralysis,^{716 729} brain damage^{692 705} ), ocular effects,^{697 700 715 717 718} embolic vascular complications,⁷³³ and death^{692 697 705} may occur following attempted epidural injection (see Cautions).⁶⁴⁸ Systemic glucocorticoid effects (e.g., hypothalamic-pituitary-adrenal [HPA] axis suppression, hypercorticism, Cushing's syndrome, osteoporosis, fluid retention, hyperglycemia) also may occur after epidural glucocorticoid administration.^{645 692 698 700 706}

Data from the American Society of Anesthesiologists (ASA) Closed Claims Project database, which includes closed anesthesia malpractice claims arising from chronic pain management, suggest that serious injuries (e.g., brain damage, death) can occur when glucocorticoids are combined with local anesthetics and/or opiate analgesics for epidural injection and that patient safety may be improved by excluding typical epidural doses (volumes in excess of intrathecal test doses) of local anesthetics and/or opiate analgesics from epidural glucocorticoid injections.⁷⁰⁵

Limited evidence suggests that therapeutic facet joint†^{597 640 641 648 649 692 693 695} and intradiscal glucocorticoid injections†⁷²⁴<