VA Class:HS051

ATC Class:H02AB10

AHFS Class:

• Adrenals 68:04

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.

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 under 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 magnetic resonance imaging [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).731,742,763,764 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

Corticosteroids are used as adjunctive treatment of asthma.774 The Global Initiative for Asthma (GINA) guidelines provide evidence-based recommendations for the management of asthma in adults, adolescents, and children ≥6 years of age.774 The guideline states that all patients with asthma should be evaluated for symptom control, risk of future exacerbations, treatment issues (e.g., inhaler technique and adherence), and comorbidities.774 A stepwise approach to treatment is recommended where specific drugs are added or adjusted up or down through a series of steps (1 through 5) to achieve symptom control while keeping the patient on the lowest effective treatment.774 Drugs used in the management of asthma include inhaled corticosteroids (ICS)-formoterol, long-acting beta agonists (LABA), short-acting β₂-adrenergic agonists (SABA), long-acting muscarinic agonists (LAMA), leukotriene receptor antagonists, theophylline, oral corticosteroids, and biologic agents.774

Chronic Obstructive Pulmonary Disease

Oral and inhaled corticosteroids have been used in the management of chronic obstructive pulmonary disease (COPD).564 The Global Initiative for Chronic Obstructive Lung Disease (GOLD) guideline states that oral glucocorticoids play a role in the acute management of COPD exacerbations, but have no role in the chronic daily treatment of COPD because of the lack of benefit and high rate of systemic complications.564

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

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 younger 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 jirovecii Pneumonia

The use of systemic glucocorticoids as an adjunct to anti-infective therapy for the treatment of moderate to severe pneumonia caused by Pneumocystis jirovecii † (formerly Pneumocystis carinii ) in patients with human immunodeficiency virus (HIV) infection, including acquired immunodeficiency syndrome (AIDS), can decrease the likelihood of deterioration of oxygenation, respiratory failure, and/or death in those with moderate to severe pneumonia.430,431,432,433,434,435,1017 Based on the results of controlled, randomized studies,430,431,432,433,434,435 experts recommend that adults and adolescents older than 13 years of age with documented or suspected 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 35 mm Hg or greater on room air.430,1017 It is not known whether patients with mild pneumocystis pneumonia (arterial oxygen pressure exceeding 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

It is recommended that adjunctive glucocorticoid therapy be initiated as early as possible, preferably within the first 24-72 hours after initiation of specific anti-infective therapy.430,431,432,433,434,435,456,1017 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 however, most clinicians would initiate such therapy in those with moderate to severe pneumocystis pneumonia even if it has been more than 72 hours after initiation of anti-infective therapy.1017 Glucocorticoid therapy can be started in patients with presumed AIDS-associated pneumocystis pneumonia if these patients meet the recommended oxygenation criteria.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

When glucocorticoid therapy is used as an adjunct to anti-infective therapy in HIV-infected patients with moderate to severe pneumocystis pneumonia, experts recommend specific regimens of prednisone or, if parenteral therapy is required, methylprednisolone.430,1017 (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

Coronavirus Disease 2019 (COVID-19)

Corticosteroid therapy (e.g., dexamethasone, hydrocortisone, methylprednisolone, prednisone) has been used as adjunctive therapy in the treatment of serious complications from coronavirus disease 2019 (COVID-19)†.1004,1005,1006,1007,1008,1009,1010,1011,1012,1013,1014 Patients with severe COVID-19 may develop a systemic inflammatory response that can result in lung injury and multisystem organ dysfunction.1005 The potent anti-inflammatory effects of corticosteroids may prevent or mitigate these deleterious effects.1005

The National Institutes of Health (NIH) COVID-19 Treatment Guidelines Panel issued guidelines for the treatment of COVID-19, including recommendations for use of corticosteroids in patients with COVID-19.1005 For the treatment of COVID-19 in nonhospitalized adults and hospitalized adults who do not require supplemental oxygen, the NIH guidelines panel recommends against the use of dexamethasone or other corticosteroids.1005 However, the NIH panel recommends use of dexamethasone (6 mg daily orally or IV for up to 10 days or until hospital discharge, whichever comes first) in hospitalized adults with COVID-19 who require supplemental oxygen or are receiving mechanical ventilation or extracorporeal membrane oxygenation (ECMO).1005 The NIH panel states that it is not known at this time whether other corticosteroids will have a similar benefit as dexamethasone.1005 However, if dexamethasone is not available, the panel recommends using alternative corticosteroids (e.g., hydrocortisone, methylprednisolone, prednisone).1005

Data regarding potential adverse effects of dexamethasone in patients with COVID-19, efficacy in combination with other treatments (e.g., remdesivir, tocilizumab, baricitinib), and efficacy in other patient populations (e.g., pediatric patients, pregnant women) are insufficient to date.1005 Although efficacy of concomitant use of dexamethasone and remdesivir has not been rigorously studied, the NIH panel states there is a theoretical rationale for using dexamethasone plus remdesivir in some patients with severe COVID-19 and clinically important drug interactions are not expected.1005 Specifically, the NIH guideline panel recommends concomitant use of dexamethasone and remdesivir in hospitalized patients requiring increasing amounts of supplemental oxygen or use of dexamethasone alone when combined therapy with remdesivir cannot be used or is unavailable in such patients.1005 Similarly, the NIH panel recommends the use of dexamethasone alone or in combination with remdesivir in hospitalized patients requiring high-flow oxygen or noninvasive ventilation.1005 For such patients who were recently hospitalized with rapidly increasing oxygen needs and systemic inflammation, the panel also recommends the addition of baricitinib or tocilizumab to either monotherapy with dexamethasone or combination therapy with dexamethasone and remdesivir.1005 For hospitalized COVID-19 patients requiring invasive mechanical ventilation or ECMO, the NIH panel recommends therapy with dexamethasone alone, although dexamethasone in combination with remdesivir may be considered in patients who were recently intubated.1005 For those receiving invasive mechanical ventilation or ECMO who are within 24 hours of ICU admission with rapid respiratory decompensation, the NIH panel recommends dexamethasone in combination with tocilizumab.1005 Clinicians should consult the most recent NIH COVID-19 treatment guidelines for additional information on use of corticosteroids in patients with COVID-19.1005

The World Health Organization (WHO) Guideline Development Group also issued guidelines for the use of systemic corticosteroids in patients with COVID-19.1006 For the treatment of patients with nonsevere COVID-19, the WHO Guideline Development Group suggests not using systemic corticosteroids, regardless of hospitalization status;1006 however, if the clinical condition of such patients worsens (e.g., increased respiratory rate, signs of respiratory distress, or hypoxemia), systemic corticosteroids are recommended for treatment.1006 The WHO Guideline Development Group strongly recommends the use of systemic corticosteroids (e.g., dexamethasone 6 mg orally or IV once daily or hydrocortisone 50 mg IV every 8 hours for 7-10 days) over no systemic corticosteroid therapy for the treatment of patients with severe and/or critical COVID-19, regardless of hospitalization status.1006 This treatment recommendation includes critically ill patients with COVID-19 who could not be hospitalized or receive oxygen supplementation because of resource limitations.1006 The WHO Guideline Development Group also recommends the concomitant use of systemic corticosteroids with an interleukin (IL-6) inhibitor (e.g., sarilumab, tocilizumab) for patients with severe or critical COVID-19.1006 These experts recommend against discontinuing systemic corticosteroids in patients with nonsevere COVID-19 who are receiving systemic corticosteroids for chronic conditions (e.g., COPD, autoimmune diseases).1006 Clinicians should consult the most recent WHO COVID-19 treatment guidelines for additional information.1006

In one randomized, controlled, open-label study (NCT04381936; RECOVERY), the effect of potential treatments (including low-dose dexamethasone) on all-cause mortality in hospitalized patients with COVID-19 was evaluated.1004 Patients were randomized to receive dexamethasone (6 mg once daily orally or IV for up to 10 days) plus standard care or standard care alone.1004 Preliminary data analysis indicated that overall 28-day mortality was reduced in patients who received dexamethasone compared with those who received standard care alone, and the greatest benefit was observed in patients receiving invasive mechanical ventilation or those receiving supplemental oxygen without mechanical ventilation.1004 However, no survival benefit was observed with dexamethasone and there was a possibility of harm in patients who did not require respiratory support at study enrollment.1004 (See Uses: Coronavirus Disease 2019 [COVID-19] in Dexamethasone 68:04.)

In another randomized, controlled, open-label, multicenter study (NCT04327401; CoDEX), the effect of dexamethasone on the number of ventilator-free days was evaluated in patients with COVID-19-associated moderate or severe acute respiratory distress syndrome (ARDS) who were receiving mechanical ventilation.1007 Patients were randomized to receive dexamethasone (20 mg IV once daily for 5 days followed by 10 mg IV once daily for another 5 days or until ICU discharge) plus standard care or standard care alone.1007 Preliminary data analysis indicated that use of dexamethasone plus standard care was associated with a higher mean number of ventilator-free days (6.6 days) compared with those receiving standard care alone (4 days).1007 This trial was terminated early after results of the RECOVERY trial became available and, therefore, was likely underpowered to determine secondary outcomes such as mortality.1007 (See Uses: Coronavirus Disease 2019 [COVID-19] in Dexamethasone 68:04.)

In one randomized, double-blind sequential trial (NCT02517489; CAPE COVID), the effect of low-dose hydrocortisone on treatment failure was evaluated in critically ill patients with COVID-19-related acute respiratory failure compared with placebo.1008 In the hydrocortisone treatment group, 76 patients received a continuous IV infusion of hydrocortisone at an initial dosage of 200 mg daily for 7 days followed by 100 mg daily for 4 days, and then 50 mg daily for 3 days (total of 14 days; some patients received a shorter regimen); 73 patients received placebo.1008 The primary study end point was treatment failure (defined as death or persistent dependency on mechanical ventilation or high-flow oxygen therapy) on day 21.1008 Treatment failure on day 21 occurred in 42.1% of patients receiving hydrocortisone compared with 50.7% of patients receiving placebo.1008 No substantial difference was observed between the treatment groups; however, the study was discontinued early after results of the RECOVERY trial became available and, therefore, was likely underpowered to determine a statistically and clinically important difference in the primary outcome.1008

In another randomized, open-label, multicenter study (NCT02735707; REMAP-CAP), an embedded multifactorial adaptive platform was used to evaluate patients receiving multiple interventions within multiple domains.1009 In the COVID-19 corticosteroid domain, adults with suspected or confirmed COVID-19 following ICU admission for respiratory or cardiovascular organ support were randomized to receive a fixed 7-day regimen of IV hydrocortisone (50 or 100 mg every 6 hours), a shock-dependent regimen of IV hydrocortisone (50 mg every 6 hours when shock was clinically evident), or no hydrocortisone or other corticosteroid.1009 The primary study end point was organ support-free days (defined as days alive and free of ICU-based respiratory or cardiovascular support) within 21 days.1009 The 7-day fixed regimen and the shock-dependent regimen of hydrocortisone were associated with a 93 and 80% probability of benefit in terms of organ support-free days compared with no hydrocortisone.1009 However, the trial was discontinued early after results of the RECOVERY trial were available and no treatment strategy met the prespecified criteria for statistical superiority, precluding definitive conclusions.1009 In addition, serious adverse effects were reported in 2.6% of patients in the study (4 patients receiving the fixed-dosage regimen and 5 patients receiving the shock-dependent regimen compared with 1 patient receiving no hydrocortisone).1009

In one randomized, parallel, double-blind, placebo-controlled, phase 2b trial (NCT04343729; Metcovid), the effect of a short course of IV methylprednisolone was evaluated compared with placebo in hospitalized adults with suspected COVID-19 from a single center in Brazil.1005,1010 Patients were enrolled prior to laboratory confirmation of COVID-19 to avoid treatment delays and the presence of COVID-19 was later confirmed based on RT-PCR testing in 81.3% of these patients.1010 At time of enrollment, 34% of patients in each treatment group required invasive mechanical ventilation.1010 Supplemental oxygen was required in 51% of patients receiving methylprednisolone and in 45% of those receiving placebo.1010 In the methylprednisolone treatment group, 194 patients received IV methylprednisolone at a dosage of 0.5 mg/kg twice daily for 5 days; 199 patients received placebo.1010 A modified intent-to-treat analysis was conducted; the primary study end point was 28-day mortality.1010 Overall, the 28-day mortality rate was 37.1 or 38.2% in patients who received methylprednisolone or placebo, respectively, showing no substantial difference in overall mortality between the treatment groups.1010 However, a subgroup analysis found a lower mortality rate in patients older than 60 years of age who received methylprednisolone compared with placebo (46.6 vs 61.9%, respectively).1010 Patients older than 60 years of age reportedly had a higher degree of systemic inflammatory disease as manifested by increased median concentrations of C-reactive protein (CRP) compared with patients 60 years of age or younger.1010 In those 60 years of age or younger, there was a higher incidence of fatal outcomes in the methylprednisolone group.1010 The authors concluded that caution is needed when using systemic corticosteroids in patients with less severe COVID-19 since a trend toward more harm was noted in the younger age group.1010

In another multicenter, observational, longitudinal study (NCT04323592), the association between use of prolonged, low-dose methylprednisolone treatment and ICU admission, intubation, or all-cause death within 28 days (composite primary end point) was evaluated in patients with severe COVID-19 pneumonia admitted to 14 respiratory high-dependency units in Italy.1011 A total of 173 patients were enrolled in the study with 83 patients receiving methylprednisolone plus standard care and 90 patients receiving standard care alone.1011 In the methylprednisolone treatment group, patients received a loading dose of IV methylprednisolone 80 mg at study entry followed by IV infusion of the drug at a dosage of 80 mg daily at a rate of 10 mL/hr for at least 8 days until achievement of either a PaO2/FiO2 (P/F ratio) greater than 350 mm Hg or CRP concentrations less than 20 mg/L.1011 Subsequently, twice-daily administration of either oral methylprednisolone 16 mg or IV methylprednisolone 20 mg was given until achievement of a P/F ratio greater than 400 mm Hg or CRP concentrations reached less than 20% of the normal range.1011 The composite primary end point was reached by 22.9 or 44.4% of patients in the group receiving methylprednisolone or standard care alone, respectively.1011 Therefore, use of methylprednisolone was associated with a reduction in the risk of ICU admission, invasive mechanical ventilation, or death within 28 days (adjusted hazard ratio: 0.41).1011 Specifically, 18.1 or 30% of patients required ICU admission and 16.9 or 28.9% of patients required invasive mechanical ventilation in those receiving methylprednisolone or standard care alone, respectively.1011 In addition, use of methylprednisolone was associated with a 28-day lower risk of all-cause mortality than use of standard care alone (7.2 vs 23.3%, respectively) with an adjusted hazard ratio of 0.29.1011 Overall, there was no difference in adverse effects between treatment groups with the exception of increased reports of hyperglycemia and mild agitation in the methylprednisolone-treated patients; no adverse effects resulted in drug discontinuation.1011 The authors concluded that early, low-dose, prolonged therapy with methylprednisolone resulted in decreased ICU burden, reduced need for invasive mechanical ventilation, and lower mortality along with improvement in systemic inflammation and oxygenation markers in hospitalized patients with severe COVID-19 pneumonia at high risk of progression to acute respiratory failure.1011

In one multicenter quasi-experimental study with single pretest and posttest (NCT04374071), the efficacy of early, short-term therapy with systemic methylprednisolone was evaluated in hospitalized adults with confirmed moderate to severe COVID-19 from a multicenter health system in Michigan.1014 A total of 213 patients were enrolled with 132 patients receiving early therapy with IV methylprednisolone at dosages of 0.5-1 mg/kg daily in 2 divided doses for 3 days plus standard care and 81 patients receiving early therapy with standard care alone.1014 The primary end point was a composite based on the need for ICU transfer, progression to respiratory failure requiring mechanical ventilation, or in-hospital all-cause mortality.1014 The primary composite end point occurred at a substantially lower rate in the group receiving early corticosteroid therapy (34.9%) compared with the group receiving early therapy with standard care alone (54.3%).1014 The early corticosteroid group had a median time to initiation of methylprednisolone of 2 days compared with 5 days for the standard care group.1014 The median hospital length of stay was substantially reduced from 8 to 5 days in patients receiving early corticosteroid therapy compared with those receiving early therapy with standard care alone.1014 ARDS occurred in 26.6% of patients receiving early corticosteroid therapy compared with 38.3% of those in the standard care group.1014 The authors concluded that early, short-term therapy with methylprednisolone in patients with moderate to severe COVID-19 may prevent disease progression and improve clinical outcomes.1014

In a prospective meta-analysis of studies using systemic corticosteroids (i.e., dexamethasone, hydrocortisone, or methylprednisolone) from the WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group, data were pooled from 7 randomized clinical trials in 12 countries that evaluated the efficacy of corticosteroids in 1703 critically ill patients with COVID-19.1013 The primary outcome was all-cause mortality up to 30 days after randomization to treatment.1013 Administration of systemic corticosteroids was associated with lower all-cause mortality at 28 days compared with usual care or placebo (222 deaths among 678 patients who received corticosteroids and 425 deaths among 1025 patients who received usual care or placebo).1013 The effect of corticosteroids on reduced mortality was observed in critically ill patients who were and were not receiving mechanical ventilation at randomization and also in patients from the RECOVERY trial who required supplemental oxygen with or without noninvasive ventilation, but who were not receiving invasive mechanical ventilation at the time of randomization.1013 The odds ratios for the association between corticosteroids and mortality were similar for dexamethasone and hydrocortisone.1013 The optimal dosage and duration of corticosteroid treatment could not be determined from this analysis; however, there was no evidence suggesting that a higher dosage of corticosteroids was associated with greater benefit than a lower dosage.1013 The authors also concluded that there was no suggestion of an increased risk of serious adverse effects associated with corticosteroid use.1013

In a retrospective, case-control study, the efficacy of early, low-dose, short-term therapy with systemic methylprednisolone or prednisone was evaluated in hospitalized adults with nonsevere COVID-19 pneumonia from a single center in China.1012 A total of 475 patients were enrolled with 55 of these patients receiving early, low-dose corticosteroids.1012 Methylprednisolone 20 or 40 mg IV daily was administered to 50 of these patients for 3-5 days, and oral prednisone 20 mg daily (equivalent dosage to methylprednisolone) was administered to 5 such patients for 3 days.1012 Systemic corticosteroid therapy was initiated within a median of 2 days following hospital admission.1012 A total of 420 patients received standard therapy (no corticosteroids); using propensity score matching, 55 of these patients were selected as matched controls.1012 The primary outcome was the rate of patients who developed severe disease and mortality.1012 In the corticosteroid treatment group, 12.7% of patients developed severe disease compared with 1.8% of patients in the control group.1012 There was one death in the group receiving methylprednisolone and none in the control group.1012 Regarding secondary outcomes, duration of fever, virus clearance time, and length of hospital stay were all substantially longer in patients receiving corticosteroids compared with no corticosteroid therapy.1012 Because of the finding that early, low-dose, short-term systemic corticosteroid therapy was associated with worse clinical outcomes in hospitalized adult patients with nonsevere COVID-19 pneumonia, the authors concluded that the study results do not support the use of corticosteroids in this population.1012 However, it is difficult to interpret these results because of potential confounding factors inherent in the nonrandomized study design.1005 It is unclear if the results of this study apply to corticosteroids other than methylprednisolone or prednisone.1005

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 Advanced Pulmonary and Extrapulmonary Tuberculosis under Uses: Respiratory Diseases) 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.529,531,534,535,542,543,755

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 is 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 younger 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 phosphate (6 mg every 12 hours for 2 days) or IM betamethasone sodium phosphate in fixed combination with betamethasone acetate (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 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.529,537,540 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.529,537,540 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 (exceeding 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

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

Glucocorticoids (e.g., dexamethasone, prednisone) also have been used as a component of various combination chemotherapeutic regimens in the treatment of multiple myeloma.778 Dexamethasone has been used in combination chemotherapeutic regimens in various doses (20-40 mg) and schedules.778 Although high-dose dexamethasone has been associated with increased adverse effects (e.g., hyperglycemia, psychiatric effects, insomnia, hyperactivity, infectious complications), high-dose dexamethasone is an effective component of combination chemotherapeutic regimens for the treatment of multiple myeloma.778

Cancer Chemotherapy-induced Nausea and Vomiting

Corticosteroids (e.g., dexamethasone, methylprednisolone) have been used for the prevention of nausea and vomiting associated with emetogenic cancer chemotherapy† including that associated with cisplatin.769 Most clinical experience to date has been with dexamethasone.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 not exceeding 14 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

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 hydrochloride (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 study464,465 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 While 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 serious adverse neurologic effects have been reported following epidural glucocorticoid injection both with and without fluoroscopic guidance.1000,1001,1002,1003 (See Cautions: Nervous System Effects.) 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 hexacetonide) 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 of 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)477,728,730,731 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.477,716,735 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,477,692,698,705 seizures,697,716 bladder or bowel dysfunction,477,716 paraparesis or paralysis,477,716 brain damage),692,705 ocular effects,697,700,715,717,718 embolic vascular complications,733 and death692,697,705 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†724,726 are minimally effective or ineffective in the treatment of low back pain, although some clinicians report that facet joint injections may be useful in some patients with facet arthropathy.597 Inclusion of a glucocorticoid in trigger point injections also does not appear to be beneficial.648,695 Sacroiliac joint injections performed using fluoroscopic guidance may provide temporary pain relief in some patients when the principal source of spinal pain is the sacroiliac joint.597,695,734

Although oral glucocorticoids have been used by some clinicians in the treatment of low back pain†, they do not appear to be effective and evidence supporting such use is lacking.597,645,649,695,696,697

Bacterial Meningitis

Glucocorticosteroids have been used as adjunctive therapy in patients with bacterial meningitis†; however, results of many studies evaluating this use have been inconclusive or conflicting.419 Most trials were conducted with dexamethasone.419 In a Cochrane review which included 25 randomized controlled studies of corticosteroid use in acute bacterial meningitis, corticosteroids were found to reduce hearing loss and neurological sequelae, but did not improve overall mortality.419 Subgroup analysis showed that the benefits were limited to high-income countries; there was no beneficial effect of corticosteroid therapy in low-income countries.419 In most of the studies, the corticosteroid used was dexamethasone; hydrocortisone or prednisone were used in a few studies.419

Multiple Sclerosis

Glucocorticoids currently are considered the drugs of choice for the management of acute relapses of multiple sclerosis.574 The anti-inflammatory and immunomodulating effects of the drugs can accelerate neurologic recovery by restoring the blood-brain barrier, reducing edema, and possibly improving axonal conduction.574

For moderate to severe relapses, methylprednisolone has been administered IV in a dosage of 1 g daily for 3-5 days, followed by 60 mg of oral prednisone daily, tapering the dosage over 12 days.574 Alternative regimens have included 1 g or 15 mg/kg of IV methylprednisolone tapered over 15 days to 1 mg/kg and followed by oral prednisone or prednisolone in gradually decreasing dosages over several weeks to months.

Interest in the use of IV methylprednisolone in the management of acute relapses of multiple sclerosis heightened as a result of the Optic Neuritis Treatment Trial in which the rate of recovery in vision was faster in those receiving the drug574,575 and the risk of development of clinically definite multiple sclerosis was reduced during the first 2 years of follow-up.574,576,581 (See Uses: Ocular Disorders.) The beneficial effect of the methylprednisolone regimen on disease progression was transient since results at 3- and 5-year follow-up indicate that there were not clinically important differences among treatment groups in the rate of development of clinically definite multiple sclerosis or the degree of neurologic disability among those who developed the disease during the 5-year follow-up period.580,581 Additional study is needed and under way to determine whether pulsed doses of glucocorticoids given every other month can slow progression of the disease in patients with moderate disability and secondary progressive multiple sclerosis.574

Myasthenia Gravis

Glucocorticoids (e.g., prednisone) are used in the management of myasthenia gravis, usually in patients who have had an inadequate response to anticholinesterase therapy.627,628 Glucocorticoids also have been administered parenterally in the treatment of myasthenic crisis.629

Organ Transplants

In massive dosage, glucocorticoids may be used concomitantly with other immunosuppressive drugs to prevent rejection of transplanted organs. Because the incidence of secondary infections is high in patients receiving these drugs, such therapy should be administered by physicians experienced in its use.

Nephrotic Syndrome

Glucocorticoids can induce diuresis and remission of proteinuria in children and adults with nephrotic syndrome secondary to primary renal disease, especially when there is minimal renal histologic change. Lupus nephritis may also respond to glucocorticoids. High dosage may be required for prolonged periods, and alternate-day therapy should be used to decrease adverse effects. Nephrotic syndrome secondary to diabetes mellitus, renal amyloidosis, glomerulonephritis, or other diseases is generally refractory to glucocorticoids.

Diagnostic Uses

Dexamethasone inhibits pituitary adrenocorticotropic hormone (ACTH) release and decreases output of endogenous corticosteroids when given in an amount which does not itself appreciably affect concentrations of urinary 17-hydroxycorticosteroids. This effect is utilized in the dexamethasone suppression test for the diagnosis of Cushing's syndrome and the differential diagnosis of adrenocortical tumors. (See Dexamethasone 68:04.)

The dexamethasone suppression test (DST) has been used for the detection, diagnosis, and management of mental depression; however, considerable controversy currently exists regarding the clinical utility of the test.398,424,425 The sensitivity of the DST in patients with major depression is relatively modest (about 40-50%),424 and a positive test result (nonsuppression) does not appear to reliably predict response to antidepressant therapy398,424,425 and a negative test result (suppression) is not an indication for withholding antidepressant therapy.424 Therefore, the American Psychiatric Association, American College of Physicians, and other experts currently state that, pending further studies and evaluation, the DST should not be used routinely for the diagnosis and management of depression,398,424,425 although judicious use of the DST may be a useful adjunct in clinical decision making in selected situations424 and as a research tool.424,425

Duchenne Muscular Dystrophy

The current standard of care for patients with Duchenne muscular dystrophy includes the use of corticosteroids (e.g., prednisone, deflazacort) for improving muscle function and strength.775,776 The American Academy of Neurology recommends the use of prednisone or deflazacort to improve muscle strength, pulmonary function, and possibly also slow the development of scoliosis and need for surgery in patients with Duchenne muscular dystrophy.775 Results of direct comparative studies suggest that prednisone and deflazacort are similarly effective in improving motor function, but differ in their adverse effect profiles (e.g., prednisone may be associated with more weight gain while deflazacort may be associated with a greater risk of cataracts).775

Cardiovascular Disorders

Shock

Use of corticosteroids in the treatment of septic shock has been controversial.399,400,401,409,410,411,412,413,414,415,416,418 Although some controlled studies have shown beneficial effects of high-dose regimens on morbidity and mortality in septic shock,402 many studies have not.401,409,410,416,417,418,426 Results of one prospective, controlled study suggest that glucocorticoids do not improve overall survival in patients with severe, late septic shock but may be beneficial early in the course of septic shock and in certain subgroups of patients.403 However, 2 subsequent, prospective, controlled studies failed to show a benefit of high-dose glucocorticoid therapy that was initiated early (i.e., within 2.8 hours of diagnosis) in patients with presumed sepsis or septic shock.409,410,414,415,416,417,426 In addition, there was some evidence that such therapy may be associated with an increased risk of mortality in certain patients (i.e., those with serum creatinine concentrations exceeding 2 mg/dL at diagnosis and those who developed secondary infection).409,414,416,417,426 More recent meta-analyses found that systemic corticosteroid use accelerated the resolution of shock and increased vasopressor-free days; however, corticosteroids increased neuromuscular weakness without a clear effect on short- or long-term mortality.416 The Surviving Sepsis Campaign guidelines suggest the use of IV corticosteroids for adults with septic shock and an ongoing requirement for vasopressor therapy; this recommendation is based on a moderate quality of evidence.416 The optimal dose, timing of initiation, and duration of corticosteroids remain uncertain.416 The typical corticosteroid used in adults with septic shock is IV hydrocortisone at a dose of 200 mg daily given as 50 mg IV every 6 hours or as a continuous infusion.416 The guidelines suggest that this is commenced at a dose of norepinephrine or epinephrine ≥0.25 mcg/kg/min at least 4 hours after initiation.416

Pericarditis

Systemic corticosteroids (e.g. prednisone) have been used in the treatment of pericarditis†, but is generally considered a second- or third-line treatment.582 Corticosteroid use (mostly with high dosages) in this setting has been associated with recurrence and a prolonged disease course.582 In a nonrandomized observational study, use of higher doses of corticosteroids (i.e., prednisone 1 mg/kg/day) for recurrent pericarditis was associated with increased risk of adverse effects, recurrence, and hospitalizations compared with low-dose corticosteroid therapy (i.e., prednisone 0.2 to 0.5 mg/kg).779

Chronic Fatigue Syndrome

Because of evidence that chronic fatigue syndrome† is associated with subnormal cortisol secretion secondary to impaired activation of the hypothalamic-pituitary-adrenal (HPA) axis,567,568,569 glucocorticoid supplementation has been studied in patients with this condition.567,568 In a study in patients 18-55 years of age who met the US Centers for Disease Control and Prevention (CDC) case criteria for chronic fatigue syndrome, low-dose oral glucocorticoid therapy (approximately 13 mg/m² [20-30 mg] of hydrocortisone every morning and 3 mg/m² [5 mg] every afternoon for about 12 weeks) produced some symptomatic improvement as determined by a global self-rating wellness scale; however, there was no evidence of improvement in several other self-rating scales, including mood, depression, and activity scales.567 Because the modest symptomatic improvement with glucocorticoid therapy was associated with clinically important adrenal suppression, such therapy is not practical nor advisable for the chronic management of chronic fatigue syndrome.567,568

Other Uses

In miscellaneous inflammatory reactions, such as those resulting from dental procedures, short-term glucocorticoid therapy can decrease edema and may alleviate pain associated with such inflammations.

Local injection of glucocorticoids (e.g., methylprednisolone, betamethasone) into the tissue near the carpal tunnel has been used in a limited number of patients to relieve symptoms (e.g., pain, edema, sensory deficit) of carpal tunnel syndrome.600,601,602 In clinical studies, short-term response was noted in most patients, but the improvement in symptoms waned during the following 11-24 months.600,601,602 Limited evidence suggests that injection technique may influence the duration of effect.600

Glucocorticoids (e.g., betamethasone, dexamethasone, methylprednisolone) have been used by local injection for the management of cystic tumors of an aponeurosis or tendon (ganglia).477,731,752

For EENT and topical uses of the corticosteroids, see 52:08.08 and 84:06.08.

Administration

Glucocorticoids, in appropriate forms, may be administered orally, by oral inhalation, and by IV, IM, subcutaneous, intra-articular, intrabursal, intradermal, intrasynovial, intralesional, or soft tissue injection. Long-acting injectable suspension formulations of some glucocorticoids (e.g., betamethasone, methylprednisolone, triamcinolone) have been administered by epidural injection, although the safety of epidural injections using preserved glucocorticoid formulations is controversial and epidural administration of these formulations is not recommended by the manufacturers. (See Uses: Low Back Pain and see Cautions: Nervous System Effects.) The manufacturer of Depo-Medrol^® (sterile methylprednisolone acetate suspension) states that this formulation of methylprednisolone acetate contains benzyl alcohol, which is potentially toxic when administered locally to neural tissue, and that this formulation should not be administered intrathecally because of reports of severe adverse events with such use. (See Cautions: Nervous System Effects.) Whenever possible, topical corticosteroid therapy (see 52:08.08 and 84:06.08) is preferable to systemic therapy.

Because injections of slightly soluble glucocorticoids may produce atrophy at the site of injection, IM injections of these products should be made deeply into gluteal muscle; repeated IM injections at the same site should be avoided, and these products should not be administered subcutaneously. Knee, ankle, wrist, elbow, shoulder, phalangeal, and hip joints are suitable sites for intra-articular injections of glucocorticoids; spinal joints and joints without synovial spaces are not suitable for intra-articular injection. For intra-articular injections, a 20- to 24-gauge needle should be used; needle placement should be verified by aspirating a few drops of synovial fluid prior to drug administration with a second syringe.477,731 Joints should be injected where the synovial cavity is most superficial and free from large vessels and nerves. Joint fluid should be examined to exclude sepsis, and injection into an infected site should be avoided; if joint sepsis is evident, appropriate antibacterial therapy should be instituted. Symptoms of septic arthritis include local swelling, further restriction of joint motion, fever, or malaise.477,731,773 Glucocorticoids should not be injected into unstable joints and patients should be cautioned not to overuse joints in which the inflammatory process is still active despite symptomatic improvement.

For management of tenosynovitis and tendinitis, glucocorticoids should be injected into affected tendon sheaths rather than into tendons.477,731

For disorders of the foot (bursitis, tenosynovitis, acute gouty arthritis), a tuberculin syringe with a 25-gauge, ¾-inch needle should be used for intra-articular or soft-tissue administration.731

For dermatologic conditions, a tuberculin syringe with a 25-gauge, ½-inch needle should be used for intralesional administration.731

In treatment of intercostal neuritis or neuralgia, local injections of glucocorticoids should be made cautiously to avoid penetration of the pleura, which may be indicated by appearance of sudden sharp pain during the injection.

Dosage

General Dosage

In the management of acute disorders, glucocorticoid dosage should be sufficient to ensure that symptoms are controlled quickly, and treatment should be discontinued as soon as possible. Acute disorders respond most rapidly to divided daily doses. In life-threatening situations where adrenal insufficiency may be the precipitating cause, glucocorticoids can be administered in any dosage required without serious complications, even before a definite diagnosis has been made.

Dosage ranges for glucocorticoids are extremely wide, and patient responses are quite variable. The amount of drug each patient receives should be individualized according to the diagnosis, severity, prognosis and probable duration of the disease, and patient response and tolerance. Occasionally, patients may respond better to one glucocorticoid than another but this is unpredictable.

Types of dosages generally used in various disease states are: physiologic or replacement (amount of glucocorticoid normally secreted by the adrenal cortex each day—approximately 20 mg of hydrocortisone), pharmacologic (any dosage greater than a physiologic dosage) which includes maintenance or low (dosage slightly in excess of physiologic amounts—e.g., 5-15 mg of prednisone daily), moderate (approximately 0.5 mg of prednisone/kg daily), high (approximately 1-3 mg of prednisone/kg daily), and massive (approximately 15-30 mg of prednisolone/kg daily). The approximate equivalent oral glucocorticoid dosages established by various laboratory assays are as follows:

“Equivalent dosages” are general approximations and may not apply to all diseases or routes of administration (especially oral inhalation, IM or intrasynovial injections). In addition, duration of HPA-axis suppression and degree of mineralocorticoid activities must be considered separately. (See Pharmacology.)

Estimated equivalent daily dosages of inhaled glucocorticoids for the treatment of asthma for adults and adolescents 12 years of age or older are as follows:772

Estimated equivalent daily dosages of inhaled glucocorticoids for the treatment of asthma for infants and children are as follows (Table 3):772

Long-term glucocorticoid therapy should not be initiated without due consideration of its risks. Other less dangerous drugs should be used if possible. If glucocorticoids are clearly necessary, the drugs should be administered in the smallest dosage possible and should generally be used only as adjuncts to other treatments. Patients should be continually monitored for signs that indicate dosage adjustment is necessary, such as remission or exacerbations of the disease and stress (surgery, infection, trauma). Periodic attempts should be made to decrease dosage or, preferably, to withdraw the drugs completely. Prescription refills should always be limited so that periodic evaluations can be made of the patient's condition.

Coronavirus Disease 2019 (COVID-19)

When used for adjunctive treatment in adults with coronavirus disease 2019 (COVID-19)†, dexamethasone has been used IV or orally in a dosage of 6 mg daily for up to 10 days or until hospital discharge, whichever comes first.1004,1005 If dexamethasone is not available, use of other systemic corticosteroids is recommended.1005 It is not known at this time whether other corticosteroids (e.g., hydrocortisone, methylprednisolone, prednisone) will have a similar benefit as dexamethasone.1005 For equivalent daily dosages of these alternative corticosteroids to dexamethasone, see Table 4.1005

When used for adjunctive treatment in pediatric patients with COVID-19†, the NIH COVID-19 Treatment Guidelines Panel recommends dexamethasone 0.15 mg/kg (maximum dosage 6 mg) given IV or orally for up to 10 days.1005 If dexamethasone is not available, equivalent dosages of alternative corticosteroids may be considered.1005

Clinicians should consult the most recent NIH COVID-19 treatment guidelines for additional information on use of corticosteroids in patients with COVID-19.1005

Alternate-Day Therapy

Alternate-day therapy is the dosage regimen of choice for long-term oral glucocorticoid treatment of most conditions. In alternate-day therapy, a single dose is administered every other morning. The drug is administered in the morning to simulate the natural circadian rhythm of corticosteroid secretion which is high in the morning and low in the evening. This regimen provides relief of symptoms while minimizing adrenal suppression, protein catabolism, and other adverse effects. However, some patients, especially those with rheumatoid arthritis or ulcerative colitis, require daily glucocorticoid therapy because symptoms of the underlying disease cannot be controlled by alternate-day therapy. Only “short-acting” steroids (e.g., prednisone, prednisolone, methylprednisolone) that suppress the HPA axis for less than 1.5 days after a single oral dose should be used for alternate-day therapy.

Several methods of transferring patients from initial divided-dose oral therapy to alternate-day therapy have been described. Twice the total daily dose that has been found to be effective may be administered as a single dose every other morning; this dose may then be gradually decreased to maintenance levels. Alternatively, the daily dose may be decreased to maintenance levels prior to initiation of alternate-day therapy; then twice the daily dose is given every other day. A third method is to establish a maintenance dose that is administered every morning as a single dose; alternate-day therapy is then introduced by gradual increases of this dose on alternate mornings with corresponding decreases in the dose administered on intervening mornings until twice the daily dose is being taken on alternate mornings.

Because an intact HPA axis is necessary for alternate-day therapy to be effective, it may be difficult to transfer a patient who has been maintained on divided-dose therapy for prolonged periods to alternate-day therapy, but continual attempts should be made to do so. Symptomatic treatment with other drugs on the “off day” or a trial of more than double the daily dose every other day may be helpful. When alternate-day therapy is not possible, the entire daily dose of glucocorticoid can usually be administered as a single morning dose; however, some patients will require divided daily doses of glucocorticoids.

Discontinuance of Therapy

Although high-dose glucocorticoid therapy used for only brief periods in emergency situations may be reduced and discontinued quite rapidly, withdrawal following long-term therapy with pharmacologic dosages of systemic glucocorticoids should be very gradual until recovery of HPA-axis function occurs. (See Cautions: Adrenocortical Insufficiency.) These precautions also apply when a patient is transferred from a systemic glucocorticoid to oral or nasal inhalation therapy with beclomethasone dipropionate, budesonide, fluticasone propionate, or flunisolide.

For certain acute allergic conditions (e.g., contact dermatitis such as poison ivy), glucocorticoids may be administered short term (e.g., for 6 days), giving an initially high dose (e.g., 30 mg of prednisone in divided doses) on the first day of therapy, and then withdrawing therapy by tapering the dose over several days (e.g., by 5 mg of prednisone daily). (See Dosage and Administration: Dosage, in Methylprednisolone 68:04 and also Prednisone 68:04.)

Many methods of slow withdrawal or “tapering” have been described. In one suggested regimen, glucocorticoid dosage is decreased by the equivalent of 2.5-5 mg of prednisone every 3-7 days until the physiologic dose (e.g., 5 mg of prednisone or prednisolone, 0.75 mg of dexamethasone, or 20 mg of hydrocortisone) is reached. Other recommendations state that decrements usually should not exceed 2.5 mg of prednisone (or its equivalent) every 1-2 weeks except in patients on alternate-day therapy in whom it may be possible to decrease dosage in decrements of 5 mg of prednisone (or its equivalent) at 1- to 2-week intervals. If the disease flares up during withdrawal, dosage may need to be increased and followed by a more gradual withdrawal. In addition, increased dosage will be required during periods of stress. When a physiologic dosage has been reached, it has been suggested that single 20-mg oral morning doses of hydrocortisone be substituted for whatever glucocorticoid the patient has been receiving. After 2-4 weeks, the dosage of hydrocortisone may be decreased by 2.5 mg every week until a single morning dosage of 10 mg daily is reached.

The time required for complete HPA function recovery following discontinuance of glucocorticoid therapy is variable. Tests of adrenal function may be used to measure recovery of adrenocortical function. Normal morning plasma cortisol concentrations (exceeding 10 mcg/dL) indicate that basal pituitary-adrenal function is adequate and that maintenance therapy can be discontinued. However, this does not assure that adrenal function has recovered sufficiently to adequately increase cortisol production in response to stress and, therefore, supplemental glucocorticoids may still be required during stress. Complete recovery of HPA function generally can be assumed and supplementary therapy during stress can usually be discontinued when response to a corticotropin or cosyntropin test is normal.

Short-term administration of glucocorticoids, even in massive dosages, is unlikely to produce harmful effects. When the drugs are used for longer than brief periods, however, they can produce a variety of devastating effects, including adrenocortical atrophy and generalized protein depletion.

Adrenocortical Insufficiency

When given in supraphysiologic doses for prolonged periods, glucocorticoids may cause decreased secretion of endogenous corticosteroids by suppressing pituitary release of corticotropin (secondary adrenocortical insufficiency). The degree and duration of adrenocortical insufficiency produced by the drugs is highly variable among patients and depends on the dose, frequency and time of administration, and duration of glucocorticoid therapy. This effect may be minimized by use of alternate-day therapy. (See Alternate-Day Therapy under Dosage and Administration: Dosage.)

As in patients with primary adrenocortical insufficiency maintained on corticosteroids, patients who develop secondary adrenocortical insufficiency require higher corticosteroid dosage when they are subjected to stress (e.g., infection, surgery, trauma). In addition, acute adrenal insufficiency (even death) may occur if the drugs are withdrawn abruptly or if patients are transferred from systemic glucocorticoid therapy to oral inhalation therapy. Therefore, the drugs should be withdrawn very gradually following long-term therapy with pharmacologic dosages. (See Discontinuance of Therapy under Dosage and Administration: Dosage.) Adrenal suppression may persist up to 12 months in patients who receive large dosages for prolonged periods. Until recovery occurs, patients may show signs and symptoms of adrenal insufficiency when they are subjected to stress and replacement therapy may be required. Since mineralocorticoid secretion may be impaired, sodium chloride and/or a mineralocorticoid should also be administered.

Musculoskeletal Effects

Muscle wasting, muscle pain or weakness, delayed wound healing, and atrophy of the protein matrix of the bone resulting in osteoporosis, vertebral compression fractures, aseptic necrosis of femoral or humeral heads, or pathologic fractures of long bones are manifestations of protein catabolism which may occur during prolonged therapy with glucocorticoids. These adverse effects may be especially serious in geriatric or debilitated patients. Before initiating glucocorticoid therapy in postmenopausal women, the fact that they are especially prone to osteoporosis should be considered. Glucocorticoids should be withdrawn if osteoporosis develops, unless their use is life-saving. A high-protein diet may help to prevent adverse effects associated with protein catabolism.

An acute myopathy has been observed with the use of high doses of glucocorticoids, particularly in patients with disorders of neuromuscular transmission (e.g., myasthenia gravis) or in patients receiving concomitant therapy with neuromuscular blocking agents (e.g., pancuronium).417,599 This acute myopathy is generalized, may involve ocular and respiratory muscles, and may result in quadriparesis.417,599 Myopathy may be accompanied by elevated serum creatine kinase [CK, creatine phosphokinase, CPK] concentrations.417 Resolution or clinical improvement of the myopathy may occur weeks to years after discontinuance of glucocorticoid therapy.417,599

Tendon rupture, particularly of the Achilles tendon, has occurred in patients receiving glucocorticoids.417,477,485,486,599,603,760

Osteoporosis

Osteoporosis and related fractures are some of the most serious adverse effects of long-term glucocorticoid therapy.572 622,767,768 More than 10% of patients are diagnosed with a fracture and 30-40% have radiographic evidence of vertebral fractures during long-term glucocorticoid use.622 Glucocorticoid-induced bone loss and osteoporosis result from increased osteoclast-mediated bone resorption and decreased osteoblast-mediated bone formation.572 Contributing mechanisms include: 1) effects on calcium homeostasis (e.g., decreased intestinal absorption of calcium and phosphate, increased urinary calcium excretion possibly secondary to a direct effect on tubular reabsorption, resultant secondary hyperparathyroidism leading to increased bone resorption if persistent), 2) effects on sex hormones (e.g., decreased sex hormone production both indirectly by reducing endogenous pituitary hormone concentrations and adrenal androgen production and directly through effects on gonadal hormone release, decreased pituitary secretion of luteinizing hormone with resultant decreased ovarian estrogen and testicular androgen production), 3) inhibition of bone formation (e.g., inhibition of osteoblast proliferation and attachment to matrix, inhibition of the synthesis of type I collagen and noncollagenous proteins by osteoblasts, and dose-related decreases in circulating osteocalcin, possibly mediated by effects on oncogene expression, prostaglandin E production, and the production of insulin-like growth factors and transforming growth factor), and 4) other effects (e.g., effects on the normal forces of muscle contraction on bone resulting from glucocorticoid-induced myopathy and muscle weakness, contribution of the underlying inflammatory condition being treated).572,622 Bone loss is most rapid during the first 3-6 months following initiation of glucocorticoid therapy and continues at a slower, steadier rate with prolonged use.622

Patients with such bone loss are predisposed to fractures (particularly vertebral fractures because of greater effects of glucocorticoids on trabecular than cortical bone).622 The risk of fractures is both dose and duration dependent, with higher daily or cumulative doses of glucocorticoids and longer durations of use associated with greater risk.622 A high glucocorticoid dosage generally is considered a daily dosage equivalent to more than 7.5 mg of prednisone.622 However, some studies have reported an increased risk of fracture with daily dosages as low as 2.5-7.5 mg of prednisolone or equivalent, while others have found no appreciable decline in bone density with prednisone dosages averaging 8 mg daily or dosages of less than 5 mg daily.777 Alternate-day regimens have not been shown to be associated with less risk of bone loss than daily regimens.572 Bone loss has even been associated with oral inhalation of glucocorticoids.572,766 However, risk of osteoporosis is uncertain in patients receiving recommended doses of inhaled glucocorticoids.556

Glucocorticoid-induced bone loss can be both prevented and treated; however, many patients receiving long-term glucocorticoid therapy do not receive appropriate therapies to prevent bone loss or are treated only after a fracture has occurred.622 The American College of Rheumatology (ACR) recommends that preventive therapy be considered for patients in whom the benefits of such therapy outweigh the potential harms.622 ACR recommendations are based on a risk-stratification approach in which an individual's risk level for developing a fracture (low, moderate, or high) is determined based on predisposing factors including the individual's preexisting or anticipated glucocorticoid dosage.622 An initial clinical fracture risk assessment is recommended as soon as possible, but at least within 6 months of initiating long-term glucocorticoid therapy and reassessments are recommended every 12 months during continued treatment.622 ACR states that the available data on fracture risk and risk reduction are more limited in children and adults younger than 40 years of a nevertheless such patients also should be assessed for their fracture risk and managed accordingly.622

To minimize the risk of glucocorticoid-induced bone loss, the smallest possible effective dosage and duration should be used.572 Topical and inhaled preparations should be used whenever possible.572 Lifestyle modifications to reduce the risk of osteoporosis (e.g., cigarette smoking cessation, limitation of alcohol consumption, participation in a weight-bearing exercise for 30-60 minutes daily) should be encouraged in all patients.572,622 In addition, patients should receive adequate calcium and vitamin D supplementation to preserve bone mass and limit the extent of glucocorticoid-induced bone loss.572,622 Patients who are considered to be at moderate-to-high risk of fracture generally should receive additional pharmacologic therapy.572,622 Bisphosphonates generally are preferred and have been shown to reduce the incidence of radiographic vertebral fractures in patients with glucocorticoid-induced osteoporosis.622,623

The ACR guideline for the prevention and treatment of glucocorticoid-induced osteoporosis recommends calcium and vitamin D supplementation in addition to lifestyle modification in any patient receiving long-term (at least 3 months) glucocorticoid therapy at a daily dosage equivalent to at least 2.5 mg of prednisone.622 No further preventive measure is generally recommended in patients who are considered to be at low risk of fracture; however, such patients should be monitored closely during continued glucocorticoid therapy, with fracture risk assessments and bone mineral density (BMD) measurements performed at regular intervals.622 ACR recommends an additional pharmacologic agent in patients who are considered to be at moderate-to-high risk of fracture.622 Oral bisphosphonates generally are preferred in most situations because of their demonstrated benefits in reducing fracture risk as well as their safety and low cost; other suggested options include IV bisphosphonates, teriparatide, denosumab, and raloxifene (for postmenopausal women if no other therapy is appropriate).622 Because of some uncertainty regarding the relative benefits versus harms of these interventions, ACR states that most of their recommendations are conditional and that treatment decisions should be individualized based on patient preferences, values, and comorbidities.622

Increased Susceptibility to Infection

Glucocorticoids, especially in large doses, increase susceptibility to and mask symptoms of infection.417,485,486,599 Infections with any pathogen, including viral, bacterial, fungal, protozoan, or helminthic infections in any organ system, may be associated with glucocorticoids alone or in combination with other immunosuppressive agents.417,477,485,486,599,603 These infections may be mild, but they can be severe or fatal, and localized infections may disseminate.417,477,485,486,599,603

Patients who become immunosuppressed while receiving glucocorticoids have increased susceptibility to infections compared with healthy individuals.486,487,488,489,490,491,492,493,494,603,614,615 Some infections such as varicella (chickenpox) and measles can have a more serious or even fatal outcome in such patients, particularly in children.486,487,488,489,490,491,492,493,494,603,614,615,731

Immunosuppression is most likely to occur in patients receiving high-dose (e.g., equivalent to at least 1 mg/kg of prednisone daily), systemic glucocorticoid therapy for any period of time,486,487,488,489,490,491,492,493,494 particularly in conjunction with glucocorticoid-sparing drugs (e.g., troleandomycin) and/or concomitant immunosuppressant agents;489,493 however, patients receiving moderate dosages of systemic glucocorticoids for short periods or low dosages for prolonged periods also may be at risk.487,488,489

FDA states that the possibility of orally inhaled glucocorticoid therapy causing sufficient immunosuppression to place a patient at risk of infection also should be considered.487,488,489 However, the risk of such therapy, including any possible contribution of local pulmonary immunosuppressant effects of inhaled drug to the development of serious pulmonary infections (e.g., varicella pneumonia), remains to be more fully elucidated.489

Glucocorticoid-dependent children should undergo anti-varicella-zoster virus antibody testing.489 Vaccination should be considered for those who have absent or inadequate antibody concentrations.489 In addition, such children and any adult who are not likely to have been exposed to varicella or measles should avoid exposure to these infections while receiving glucocorticoids.486,487,488,489,603 If exposure to varicella or measles occurs in such individuals, administration of varicella zoster immune globulin (VZIG) or immune globulin, respectively, may be indicated.486,487,488,489,603 If varicella develops, treatment with an antiviral agent (e.g., acyclovir) may be considered,486,487,488,489,603 although fatal outcome (e.g., in those developing hemorrhagic varicella) may not always be avoided even if such therapy is initiated aggressively.489,493

The immunosuppressive effects of glucocorticoids may result in activation of latent infection or exacerbation of intercurrent infections, including those caused by Candida , Mycobacterium , Toxoplasma , Strongyloides , Pneumocystis , Cryptococcus , Nocardia , or Ameba .599,768 Glucocorticoids should be used with great care in patients with known or suspected Strongyloides (threadworm) infection.417,477,485,486,599 In such patients, glucocorticoid-induced immunosuppression may lead to Strongyloides hyperinfection and dissemination with widespread larval migration, often accompanied by severe enterocolitis and potentially fatal gram-negative septicemia.417,485,486,599,603

The National Institutes of Health (NIH) COVID-19 Treatment Guidelines panel states that prolonged use of systemic corticosteroids in patients with COVID-19† may increase the risk of reactivation of latent infections (e.g., hepatitis B virus [HBV], herpesvirus, strongyloidiasis, tuberculosis).1005,1015,1016 The risk of reactivation of latent infections following a 10-day course of dexamethasone (6 mg once daily) is not well established.1005 When initiating dexamethasone in patients with COVID-19, appropriate screening and treatment to reduce the risk of Strongyloides hyperinfection in those at high risk of strongyloidiasis (e.g., patients from tropical, subtropical, or warm, temperate regions or those engaged in agricultural activities) and reduce the risk of fulminant reactivation of HBV should be considered.1005,1015,1016

Some experts advise that the need to continue at least physiologic replacement dosages of glucocorticoids in glucocorticoid-dependent patients developing serious infection should be considered since discontinuance of the drugs before or after the development of varicella may have contributed to fatal outcome in some reported cases.489 Additional insight is needed regarding the dosages, routes, and types of glucocorticoids as well as immunologic characteristics likely to place patients at substantial risk of immunosuppression and serious infection.489

The most common adverse effect of oral inhalation therapy with glucocorticoids is Candida albicans or Aspergillus niger infections of the mouth, pharynx, and occasionally the larynx. Oral candidiasis also is one of the most frequent adverse effects of therapy with long-term oral glucocorticoids.768 The occurrence of these fungal infections appears to be dose dependent; they also occur more frequently in women than in men. Some clinicians recommend that patients rinse their mouths with water and swallow after each oral inhalation dose to prevent Candida infection. Usually, Candida or Aspergillus infections are of little clinical importance, but occasionally they may require antifungal therapy or discontinuance of the oral inhalation.

The principal risk of epidural injection therapy for low back pain and radiculopathy is rare epidural abscess.648,649 Infectious complications (including bacterial meningitis) have been reported following epidural injection.645,648,692,697,698,699,700,705 Fungal and bacterial infections (including meningitis) have been reported in patients who received epidural or intra-articular therapy with contaminated glucocorticoid injections prepared by compounding pharmacies.597,723,733

Fluid and Electrolyte Disturbances

Sodium retention with resultant edema, potassium loss, hypokalemic alkalosis, and hypertension may occur in patients receiving glucocorticoids. Congestive heart failure may occur in susceptible patients. These mineralocorticoid effects are less frequent with synthetic glucocorticoids (except fludrocortisone) than with hydrocortisone or cortisone, but may occur, especially when synthetic glucocorticoids are given in high dosage for prolonged periods. Dietary salt restriction is advisable and potassium supplementation may be necessary in patients receiving glucocorticoids for anti-inflammatory or immunosuppressant effects.477,731 When glucocorticoids with substantial mineralocorticoid activity are administered, patients should be instructed to notify their physicians if edema develops. All glucocorticoids increase calcium excretion and may cause hypocalcemia.

Ocular Effects

Prolonged use of glucocorticoids may result in posterior subcapsular and nuclear cataracts (particularly in children), exophthalmos, or increased intraocular pressure which may result in glaucoma or may occasionally damage the optic nerve.553,767,768 However, data from several studies indicate that the risk of subcapsular and nuclear cataracts associated with inhaled glucocorticoid use is negligible in young asthmatic patients, but the risk of such cataracts may be elevated in older patients.556,766 Data from a case-control study indicate that the risk of ocular hypertension or open-angle glaucoma was increased in patients receiving high dosages of orally inhaled glucocorticoids (at least 1600 mcg of beclomethasone dipropionate, budesonide, or triamcinolone acetonide) daily for at least 3 months.551 Patients receiving lower dosages of orally inhaled or intranasal glucocorticoids were not at increased risk for these adverse ocular effects.551 Results from a population-based study indicate that use of orally inhaled corticosteroids is associated with development of posterior subcapsular and nuclear cataracts.553 Establishment of secondary fungal and viral infections of the eye may also be enhanced in patients receiving glucocorticoids. Blindness has occurred rarely following intralesional injection of glucocorticoids around the face and head. Ocular effects (e.g., transient blindness, amblyopia, acute retinal necrosis syndrome, intraocular hemorrhage, cortical blindness) also have occurred following epidural injection.697,700,715,717,1001,1002,1003 Eye irritation and eyelid edema have been reported in patients receiving glucocorticoids in clinical trials.763

Endocrine Effects

When glucocorticoids are administered over a prolonged period, they may produce various endocrine disorders including hypercorticism (cushingoid state) and amenorrhea or other menstrual difficulties. Corticosteroids may decrease glucose tolerance, produce hyperglycemia, and aggravate or precipitate diabetes mellitus especially in patients predisposed to diabetes mellitus. If steroid therapy is required in patients with diabetes mellitus, changes in insulin or oral antidiabetic agent dosage or diet may be necessary. Corticosteroids have also been reported to increase or decrease motility and number of sperm in some men.

GI Effects

Adverse GI effects of corticosteroids include nausea, vomiting, anorexia which may result in weight loss, increased appetite which may result in weight gain, diarrhea or constipation, abdominal distention, pancreatitis, gastric irritation, and ulcerative esophagitis. Indigestion is one of the most frequently occurring adverse effects in patients receiving long-term therapy with oral corticosteroids.768 Blood in the stool has been reported in patients receiving prednisolone orally disintegrating tablets in clinical trials.763 Corticosteroids have been implicated in the development, reactivation, perforation, hemorrhage, and delayed healing of peptic ulcers. Although concomitant administration of antacids or other antiulcer agents (e.g., cimetidine) has been suggested to prevent peptic ulcer formation in patients receiving high dosages of corticosteroids, routine concomitant use of these agents does not appear to be warranted since corticosteroid-induced ulcers occur infrequently (in 2% or less of patients receiving corticosteroids) and the efficacy of antiulcer therapy in preventing these ulcers has not been established. However, selective use of preventive antiulcer therapy may be considered in patients receiving corticosteroids who are at increased risk of peptic ulcer formation (e.g., those receiving other ulcerogenic drugs). Gastric irritation may be reduced if oral corticosteroids are taken immediately before, during, or immediately after meals, or with food or milk.

Nervous System Effects

Adverse neurologic effects of glucocorticoids have included headache, vertigo, insomnia, restlessness and increased motor activity, ischemic neuropathy, electroencephalogram (EEG) abnormalities, and seizures. Glucocorticoids may precipitate mental disturbances ranging from euphoria, mood swings, depression and anxiety, and personality changes to frank psychoses. Emotional instability or psychotic tendencies may be aggravated by the drugs. Increased intracranial pressure with papilledema (i.e., pseudotumor cerebri) has been reported, generally in association with withdrawal of glucocorticoid therapy.

Aseptic meningitis,645,648,697,698,699,700,705 arachnoiditis, exacerbation of pain,645,698 spinal cord trauma,692,697 subdural injection,692 intracranial air injection,692 increased intracranial pressure,692 nerve injury,692,698,705 seizures,477,697,716 bladder or bowel dysfunction,477,716 paraparesis or paralysis,477,716 sensory disturbances, and brain damage692,705 have been reported following epidural injection648 and/or intrathecal administration. It is unclear whether reports of neurologic effects associated with epidural glucocorticoid administration involved improper needle placement or were related to administration of the drug and/or preservatives.597

Serious, potentially permanent, adverse neurologic events (e.g., spinal cord infarction, paraplegia, quadriplegia, cortical blindness, stroke, seizures, nerve injury, brain edema), including death, have been reported rarely following epidural glucocorticoid injection both with and without fluoroscopic guidance.1000,1001,1002,1003 In addition to potential direct needle trauma to the spinal cord, such adverse events also may be the result of inadvertent intra-arterial injection of the particulate glucocorticoid suspension with subsequent embolization.1002,1003 Many of the events occurred within minutes to 48 hours after epidural injection of the glucocorticoid.1001 In some cases, diagnoses of adverse neurologic events were confirmed by magnetic resonance imagining or computed tomography.1001 Patients should be advised to immediately seek emergency medical attention for unusual symptoms (e.g., loss of or changes in vision, tingling in extremities, sudden weakness or numbness affecting the face or occurring unilaterally or bilaterally in the arms or legs, dizziness, severe headache, seizures) occurring after epidural glucocorticoid injection.1001

Dermatologic Effects

Various adverse dermatologic effects are associated with systemic glucocorticoid administration and include impaired wound healing, skin atrophy and thinning, acne, increased sweating, hirsutism, facial erythema, striae, petechiae, ecchymoses, and easy bruising. Long-term therapy with high dosages of inhaled corticosteroids is associated with skin thinning and easy bruising, particularly among women.556,766 Dermatologic manifestations of hypersensitivity to the corticosteroids include hives and/or allergic dermatitis, urticaria, and angioedema. Burning or tingling of the perineal area may occur after IV injection of the drugs. Parenteral corticosteroid therapy has also produced hypopigmentation or hyperpigmentation, scarring, induration, delayed pain or soreness, subcutaneous and cutaneous atrophy, and sterile abscesses. Kaposi's sarcoma has been reported to occur in patients receiving glucocorticoid therapy; discontinuance of such therapy may result in remission of the disease.417,477,485,599,603,773

Dermal and/or subdermal changes forming depressions in the skin at the injection site have been reported with use of methylprednisolone acetate injectable suspension (Depo-Medrol^®).773 Caution should be used to minimize the incidence of dermal and subdermal atrophy.773

Other Adverse Effects

A steroid withdrawal syndrome seemingly unrelated to adrenocortical insufficiency and consisting of anorexia, nausea and vomiting, lethargy, headache, fever, joint pain, desquamation, easy bruising, myalgia, weight loss, and/or hypotension has been reported following abrupt withdrawal of glucocorticoids. Symptoms often occurred while plasma glucocorticoid concentrations were still high but were falling rapidly; apparently the abrupt change in glucocorticoid concentration rather than a low concentration per se was responsible for the phenomenon. Bradycardia has occurred during or after IV administration of large doses of methylprednisolone sodium succinate but did not appear to be related to the rate or duration of infusion.

A few patients have experienced hoarseness, dry mouth, and sore throat during oral inhalation therapy with glucocorticoids; these adverse effects have also occurred in patients receiving only the aerosol vehicle and may be minimized by rinsing the mouth and swallowing after using the aerosol. Pharyngolaryngeal pain has been reported in patients receiving glucocorticoids in clinical trials.763 Dysphonia also has been reported following epidural glucocorticoid injection.718

Injections of slightly soluble glucocorticoids may produce atrophy at the site of injection. (See Dosage and Administration: Administration.) Intra-articularly administered corticosteroids have caused postinjection flare and Charcot-like arthropathy. Epidural lipomatosis692 has been reported with repeated epidural glucocorticoid injections but appears to resolve following discontinuance of such therapy.650 Cerebral or pulmonary embolism,692 hematoma formation,692,705 pneumothorax,692 intravascular injection,692 and vascular injury692 also have been reported following epidural injection therapy.

Minor transient complications of epidural glucocorticoid therapy include headache, nausea, facial flushing, fever, and inadvertent spinal tap.648,649,698 Headache appears to occur commonly with epidural injection of glucocorticoids presumably secondary to pressure changes in the epidural space or accidental puncture of the dura.645,648,698,699,705

Intranasal administration of these drugs has been associated with allergic reactions and rhinitis. Temporary or permanent visual impairment, including blindness, has been reported with glucocorticoid administration by intranasal, ophthalmic, and other routes of administration. Increased intraocular pressure, infection, residue or slough at the injection site, and ocular and periocular inflammation, including allergic reactions, have been reported with ophthalmic administration of glucocorticoids.

Hypercholesterolemia, atherosclerosis, thrombosis, thromboembolism, fat embolism, and thrombophlebitis have also been associated with corticosteroid therapy, particularly with cortisone. Hypertrophic cardiomyopathy has been reported in premature infants receiving glucocorticoids (e.g., prednisolone). Thrombocytopenia has been observed in a few patients following prolonged, high-dose glucocorticoid therapy. Palpitation, tachycardia, swelling of mouth and tongue, frequency and urgency of urination, and enuresis have been reported rarely. Anaphylactic reactions also have been reported rarely with parenteral glucocorticoid therapy. Glucocorticoids may decrease serum concentrations of ascorbic acid (vitamin C) and vitamin A; symptoms of vitamin A or C deficiency may occur rarely.

Transient, mild, asymptomatic elevations in ALT (SGPT), AST (SGOT), and alkaline phosphatase concentrations have been reported in patients receiving glucocorticoids; these effects are not associated with any clinical syndrome and generally resolve upon discontinuance of glucocorticoid therapy.

Precautions and Contraindications

Prior to initiation of long-term glucocorticoid therapy, baseline ECGs, blood pressures, chest and spinal radiographs, glucose tolerance tests, and evaluations of HPA-axis function should be performed on all patients. Upper GI radiographs should be performed in patients predisposed to GI disorders, including those with known or suspected peptic ulcer disease. During long-term therapy, periodic height, weight, chest and spinal radiographs, hematopoietic, electrolyte, glucose tolerance, and ocular and blood pressure evaluations should be performed.551,599,605

Patients receiving glucocorticoids should be instructed to notify their physicians of any infections, signs of infections (e.g., fever, sore throat, pain during urination, muscle aches), or injuries that develop during therapy or within 12 months after therapy is discontinued, so that adjustments in dosage can be made or glucocorticoid therapy reintroduced if necessary. In addition, when surgery is required, patients should be advised to inform the attending physician, dentist, or anesthesiologist that they are receiving or have recently (within 12 months) received glucocorticoids. Patients should carry identification cards listing the diseases for which they are being treated, the glucocorticoid they are receiving and its dosage, and the name and telephone number of their physician. Patients being transferred from systemic corticosteroid to oral inhalation therapy should carry special identification (e.g., card, bracelet) indicating the need for supplementary systemic corticosteroids during periods of stress.614,615,617,618 Patients receiving orally inhaled glucocorticoid therapy who are currently being withdrawn or who have been withdrawn from systemic corticosteroids should be advised to immediately resume full therapeutic dosages of systemic corticosteroids and to contact their clinician for further instructions during stressful periods (e.g., severe infection, severe asthmatic attack).614,615,617,618

Because anaphylactoid reactions have occurred in patients receiving glucocorticoids parenterally, precautionary measures should be taken prior to parenteral administration of the drugs, particularly in patients with history of a drug allergy. Some patients who appear to be hypersensitive to parenteral glucocorticoids may actually be hypersensitive to the paraben preservatives present in some injectable formulations.

Because an apparent association has been suggested between use of corticosteroids and left ventricular free-wall rupture after a recent myocardial infarction, corticosteroids should be used with extreme caution in these patients.

Some commercially available oral preparations of prednisolone, and triamcinolone contain the dye tartrazine (FD&C yellow No. 5), which may cause allergic reactions including bronchial asthma in susceptible individuals. Although the incidence of tartrazine sensitivity is low, it frequently occurs in patients who are sensitive to aspirin.

Some commercially available formulations of dexamethasone, hydrocortisone, and prednisolone contain sulfites that may cause allergic-type reactions, including anaphylaxis and life-threatening or less severe asthmatic episodes, in certain susceptible individuals. The overall prevalence of sulfite sensitivity in the general population is unknown but probably low; such sensitivity appears to occur more frequently in asthmatic than in nonasthmatic individuals.

Glucocorticoids should be used with caution in patients with hypothyroidism or cirrhosis, because such patients often show exaggerated response to the drugs. Glucocorticoids should be used with caution in psychotic patients or patients with hypertension or congestive heart failure.

Corticosteroids should be used with caution in patients with active or latent peptic ulcer,599,605,744,745 diverticulitis, nonspecific ulcerative colitis (if there is a probability of impending perforation, abscess, or other pyogenic infection), and in those with recent intestinal anastomoses.731 Manifestations of peritoneal irritation following GI perforation may be minimal or absent in patients receiving glucocorticoids.

Glucocorticoids should be used cautiously in patients with myasthenia gravis, particularly in those receiving anticholinesterase therapy.599,605,743,744 If possible, anticholinesterase agents should be withdrawn at least 24 hours prior to initiating glucocorticoid therapy.599,742,743 Because cortisone has been reported rarely to increase blood coagulability and to precipitate intravascular thrombosis, thromboembolism, and thrombophlebitis, corticosteroids should be used with caution in patients with thromboembolic disorders. Glucocorticoids should be used with caution in patients with seizure disorders, renal insufficiency, osteoporosis, or herpes simplex infections of the eye; some manufacturers state that glucocorticoids should not be used in patients with active ocular herpes simplex infections. Corneal perforation may occur in patients with ocular herpes simplex infections who are receiving glucocorticoids.731 Glucocorticoids are not recommended for use in the treatment of optic neuritis as such use may increase the risk of new episodes.477,773

Because glucocorticoids increase susceptibility to and mask symptoms of infection, the drugs should not be used, except in life-threatening situations, in patients with viral infections or bacterial infections not controlled by anti-infectives. Manufacturers state that glucocorticoid oral inhalation therapy should be used with caution, if at all, in patients with untreated systemic fungal, bacterial, viral, or parasitic infections.614,615,617,618 Patients whose susceptibility to infection is high, such as those receiving glucocorticoids as immunosuppressive therapy, are especially likely to develop secondary infections. Patients receiving glucocorticoids who are potentially immunosuppressed should be warned of the risk of exposure to certain infections (e.g., chickenpox, measles) and of the importance of obtaining medical advice if such exposure occurs.486,487,488,489 Since glucocorticoid therapy can reactivate tuberculosis, treatment of latent tuberculosis infection should be included in the regimen of patients with a history of active tuberculosis undergoing prolonged glucocorticoid therapy. If glucocorticoids are indicated in patients with latent tuberculosis or tuberculin reactivity, close observation is necessary.599,605,731,742,743,744,745 Use of glucocorticoids in patients with active tuberculosis should be restricted to those with fulminating or disseminated tuberculosis in which glucocorticoids are used in conjunction with appropriate antimycobacterial chemotherapy.599,605,731,742,743,744,745 Manufacturers state that glucocorticoid oral inhalation therapy should be used with caution, if at all, in patients with clinical or asymptomatic Mycobacterium tuberculosis infections of the respiratory tract.614,615,617,618 Since glucocorticoids can reactivate latent amebiasis, any patient who has been in the tropics or who has unexplained diarrhea should be evaluated for amebiasis to exclude these patients prior to initiating therapy. In the treatment of acute or disseminated tuberculosis, glucocorticoids should only be used as part of a total antituberculosis regimen. Corticosteroids should not be used in patients with cerebral malaria.477,773 The manufacturers of methylprednisolone warn that the efficacy of glucocorticoids in the treatment of sepsis syndrome and septic shock has not been established, and that at least one study suggested that such use in certain patients (e.g., those with serum creatinine concentrations exceeding 2 mg/dL at diagnosis and those who develop secondary infections) may be associated with an increased risk of mortality.

Some clinicians state that glucocorticoid oral inhalation therapy probably should be avoided when the risk of activating bronchopulmonary mycoses appears high, as in patients with bronchiectasis or inadequate immunologic responses. Although manufacturers state that glucocorticoids are contraindicated in patients with systemic fungal infections, most authorities believe that glucocorticoid therapy may be initiated in patients with known infections (including those from fungi) if effective specific chemotherapy is administered concomitantly. The manufacturers of methylprednisolone acetate state that although the drug is contraindicated in patients with systemic fungal infections, it may be used as an intra-articular injection for localized joint conditions.773 In patients with acute infection, methylprednisolone acetate should not be administered intra-articularly, bursally, or into a tendon for local effects.477,773

FDA states that the efficacy and safety of epidural administration of glucocorticoids have not been established, and glucocorticoids are not FDA-labeled for such use.1000,1001 Prior to initiating such therapy, healthcare providers should discuss with patients the potential benefits and risks of epidural glucocorticoid injections and alternative treatments.1000,1001 Epidural administration of glucocorticoids is contraindicated in patients with local or systemic infection;647,691,698,699 individuals with bleeding disorders or receiving concurrent anticoagulant therapy (e.g., warfarin, heparin, antiplatelet agents);647,691,692,698,699 patients with known hypersensitivity to local anesthetic agents, contrast agents, or glucocorticoids;647 and patients who experienced complications with prior glucocorticoid injections.647 Epidural glucocorticoid therapy should be used with caution in patients with congestive heart failure or diabetes mellitus.647,692,706 Fluoroscopy (recommended for ensuring proper needle placement) is contraindicated in pregnant women.647,698

IM administration of corticosteroids is contraindicated in patients with idiopathic thrombocytopenic purpura.773

Pediatric Precautions

The effects of glucocorticoids on the pathophysiology and course of diseases are considered to be similar in adults and children. Evidence of safety and efficacy for prednisolone in pediatric patients has been provided through studies using the drug in pediatric patients for the treatment of nephrotic syndrome (in patients older than 2 years of age) and aggressive leukemias and lymphomas (in patients older than 1 month of age). However, some of the conclusions of these studies, and evidence of safety and efficacy for other pediatric indications (e.g., severe asthma and wheezing), are based on controlled trials in adults.

The adverse effects of prednisolone in pediatric patients are similar to those in adults. As in adults, periodic evaluations of height, weight, ocular pressure, and blood pressure should be performed in children receiving glucocorticoids. Children, like adults, also should undergo clinical evaluation for the presence of infection, psychosocial disturbances, thromboembolism, peptic ulcers, cataracts, and osteoporosis.

Long-term administration of pharmacologic dosages of glucocorticoids to children should be avoided if possible, since the drugs may retard bone growth when administered by any route. If prolonged therapy is necessary, the growth and development of infants and children should be closely monitored, and the potential effects on growth should be weighed against clinical benefits and the availability of alternative therapy. Most children receiving recommended dosages of inhaled glucocorticoids achieved their predicted adult heights but at a later than normal age, and the potential but small risk of delayed growth is well balanced by the improved health outcomes associated with inhaled glucocorticoid therapy for mild or moderate persistent asthma in such children.554,556,772 Therapy with low-to-medium dose inhaled glucocorticoids is associated with a short-term (first year of treatment) decrease in growth rates (approximately 1 cm),772 but such effects appear to be temporary and do not predict final adult height.556,766 Effects on growth are not likely with inhaled glucocorticoid dosages of up to 200 mcg daily, and HPA-axis suppression is unlikely at dosages of less than 200 mcg daily of budesonide [or its equivalent] daily dosage.556 Results of controlled longitudinal studies and several cross-sectional studies in children with asthma receiving long-term inhaled glucocorticoid (2-5 years) therapy indicate that bone mineral density was not affected by use of inhaled glucocorticoids.556,766 High dosages of inhaled glucocorticoids for prolonged periods of time (e.g., exceeding 1 year), particularly in combination with frequent courses of systemic glucocorticoid therapy may be associated with adverse growth effects and/or reduced bone mineral density.772 Retardation of bone growth has been observed at low systemic doses of glucocorticoids and in the absence of hypothalamic-pituitary-adrenal (HPA) axis suppression (e.g., as determined by tests of HPA axis function such as cosyntropin stimulation and basal plasma cortisol concentrations). Growth velocity may therefore be a more sensitive indicator of systemic glucocorticoid exposure than some commonly used tests of HPA axis function. In order to minimize the potential effects of glucocorticoids on growth, dosage in children should be titrated to the lowest effective level. Alternate-day therapy minimizes growth suppression and should be instituted if growth suppression occurs.

Glucocorticoid-induced osteoporosis and associated fractures are common in children and adolescents receiving long-term systemic therapy with the drugs since bone turnover is high and the rates of bone formation required to maintain adequate mineralization of the rapidly growing skeleton also are high in this age group.572 In addition, glucocorticoids by inhibiting bone formation may prevent achievement of peak bone mass during adolescence.572 The underlying pediatric condition for which glucocorticoids are prescribed also may be associated independently with an increased risk of osteoporosis.572 Methods for monitoring bone mineralization (e.g., dual-energy x-ray absorptiometry [DXA]) in children and adolescents are similar to those in adults.572 However, the roles of various preventive or corrective therapies for glucocorticoid-induced bone loss in children currently are not well defined.572 At this time, the most prudent approach to minimizing the negative effects of glucocorticoids on BMD in children and adolescents is by ensuring that the patients consistently ingest adequate calcium and vitamin D, either through diet or supplementation.572

High dosages of glucocorticoids in children may cause acute pancreatitis leading to pancreatic destruction. Children have developed increases in intracranial pressure (pseudotumor cerebri), causing papilledema, oculomotor or abducens nerve paralysis, visual loss, and headache. Pseudotumor cerebri has occurred most frequently following reduction of dosage or a change in the steroid administered.

Some commercially available injections of dexamethasone, hydrocortisone, methylprednisolone, and triamcinolone contain benzyl alcohol as a preservative. Although a causal relationship has not been established, administration of injections preserved with benzyl alcohol has been associated with toxicity in neonates. Toxicity appears to have resulted from administration of large amounts (i.e., 100-400 mg/kg daily) of benzyl alcohol in these neonates. Although manufacturers of some benzyl alcohol-containing injectable glucocorticoids state that these drugs are contraindicated in premature infants and use of drugs preserved with benzyl alcohol should be avoided in neonates whenever possible, the American Academy of Pediatrics states that the presence of small amounts of the preservative in a commercially available injection should not proscribe its use when the medication is indicated in neonates and comparable benzyl alcohol-free preparations are not available.

The safety and efficacy of dexamethasone or other corticosteroids for COVID-19† treatment have not been fully evaluated in pediatric patients.1005 Therefore, caution should be used when extrapolating recommendations for adults with COVID-19 to patients younger than 18 years of age.1005 The NIH COVID-19 Treatment Guidelines Panel recommends use of dexamethasone (see Coronavirus Disease 2019 [COVID-19] under Dosage and Administration: Dosage) for hospitalized pediatric patients with COVID-19 who are receiving high-flow oxygen, noninvasive ventilation, invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO);1005 dexamethasone is not routinely recommended for pediatric patients who require only low levels of oxygen support (i.e., nasal cannula only).1005 If dexamethasone is not available, the NIH panel states that alternative corticosteroids such as hydrocortisone, methylprednisolone, or prednisone may be considered.1005 Use of corticosteroids for treatment of severe COVID-19 in pediatric patients who are profoundly immunocompromised has not been evaluated to date and may be harmful; therefore, the NIH panel states that such use should be considered only on a case-by-case basis.1005 IV corticosteroids have been used as first-line therapy in pediatric patients with multisystem inflammatory syndrome in children (MIS-C); however, the NIH panel recommends consultation with a multidisciplinary team when considering and managing immunomodulating therapy for children with this condition.1005 The optimal choice and combination of immunomodulating therapies for children with MIS-C have not been definitely established.1005 Clinicians should consult the most recent NIH COVID-19 treatment guidelines for additional information on the use of corticosteroids in pediatric patients with COVID-19.1005

Pregnancy and Lactation

Pregnancy

Glucocorticoids may cause fetal damage when administered to pregnant women. One retrospective study of 260 women who received pharmacologic dosages of glucocorticoids during pregnancy revealed 2 instances of cleft palate, 8 stillbirths, 1 spontaneous abortion, and 15 premature births. Another study reported 2 cases of cleft palate in 86 births. Occurrence of cleft palate in these studies is higher than in the general population but could have resulted from the underlying diseases as well as from the steroids. Other fetal abnormalities that have been reported following glucocorticoid administration in pregnant women include hydrocephalus and gastroschisis. Women should be instructed to inform their physicians if they become or wish to become pregnant while receiving glucocorticoids. If glucocorticoids must be used during pregnancy or if the patient becomes pregnant while taking one of these drugs, the potential risks should be carefully considered.

In a retrospective study of 260 women, administration of glucocorticoids throughout pregnancy has been reported to precipitate adrenal crisis in one neonate, but in other studies there was no evidence of this. Infants born to women who receive glucocorticoids during pregnancy should be carefully monitored for symptoms of adrenal insufficiency and appropriate therapy begun immediately if such symptoms appear.

Lactation

Corticosteroids may be distributed into milk and could suppress growth, interfere with endogenous glucocorticoid production, or cause other adverse effects in nursing infants. Since adequate reproductive studies have not been performed in humans with glucocorticoids, these drugs should be administered to nursing mothers only if the benefits of therapy are judged to outweigh the potential risks to the infant.

Drugs Affecting Hepatic Microsomal Enzymes

Metabolism of certain glucocorticoids is mediated by the cytochrome P-450 (CYP) isoenzyme 3A4, and the possibility exists that drugs that induce, inhibit, or compete for this isoenzyme may alter metabolism and clearance of glucocorticoids. Conversely, some glucocorticoids (e.g. betamethasone) inhibit the action of CYP3A4,758 and some glucocorticoids (e.g., dexamethasone) induce CYP3A4.747 These glucocorticoids may alter the metabolism of drugs metabolized by CYP3A4.747,758

Cyclosporine

Concomitant administration of prednisolone and cyclosporine may result in decreased plasma clearance of prednisolone, and plasma concentrations of cyclosporine may be increased during concomitant therapy with methylprednisolone. In addition, seizures reportedly have occurred in adult and pediatric patients receiving high-dose glucocorticoid therapy concurrently with cyclosporine. The mechanism of this interaction may involve competitive inhibition of hepatic microsomal enzymes. The potential drug interaction between cyclosporine and prednisolone or methylprednisolone and the possibility of exacerbated toxicity, as well as the need for appropriate dosage adjustment, should be considered when these drugs are administered concomitantly.

Other Drugs

Drugs that induce cytochrome P-450 (CYP) isoenzyme 3A4 (e. g., barbiturates, phenytoin, rifampin, ephedrine, carbamazepine) may enhance metabolism of, and reduce, glucocorticoid concentrations.773 Dosage of glucocorticoids given in combination with such cytochrome P-450 inducers may need to be increased to achieve the desired response. Conversely, concomitant administration of certain glucocorticoids with drugs that inhibit CYP3A4 (e.g., macrolide antibiotics, ketoconazole) may decrease glucocorticoid clearance; dosage of glucocorticoids given in combination with cytochrome P-450 inhibitors may need to be decreased to avoid potential adverse effects.

Antidiabetic Therapy

Because glucocorticoids may increase blood glucose concentrations, patients with diabetes mellitus receiving concurrent insulin and/or oral hypoglycemic agents may require adjustments in the dosage of such therapy.599

Estrogens

Estrogens may potentiate effects of hydrocortisone, possibly by increasing the concentration of transcortin and thus decreasing the amount of hydrocortisone available to be metabolized. Effects of other glucocorticoids that bind to transcortin could be similarly potentiated and dosage adjustments may be required if estrogens are added to or withdrawn from a stable dosage regimen.

Nonsteroidal Anti-inflammatory Agents

Concomitant administration of ulcerogenic drugs such as indomethacin during corticosteroid therapy may increase the risk of GI ulceration. Aspirin should be used cautiously in conjunction with glucocorticoids in patients with hypoprothrombinemia. Although concomitant therapy with salicylates and corticosteroids does not appear to increase the incidence or severity of GI ulceration, the possibility of this effect should be considered.

Serum salicylate concentrations may decrease when corticosteroids are administered concomitantly. Likewise, when corticosteroids are discontinued in patients receiving salicylates, serum salicylate concentration may increase; salicylate intoxication has been precipitated rarely. Several mechanisms may be involved in this interaction. In one study in healthy individuals and in patients with polyarthritis who received both drugs concomitantly, corticosteroids increased the renal clearance of salicylate, possibly by increasing glomerular filtration rate. Corticosteroids may also induce the metabolism of salicylate. Salicylates and corticosteroids should be used concurrently with caution. Patients receiving both drugs should be observed closely for adverse effects of either drug. It may be necessary to increase salicylate dosage when corticosteroids are administered concurrently or decrease salicylate dosage when corticosteroids are discontinued in patients receiving salicylates.

In one study in patients with rheumatoid arthritis, concomitant administration of indomethacin and prednisolone resulted in increased plasma concentrations of free prednisolone; total plasma prednisolone concentrations were unchanged. It was suggested that indomethacin may have a steroid-sparing effect.

Potassium-depleting Drugs

Potassium-depleting diuretics (e.g., thiazides, furosemide, ethacrynic acid) and other drugs that deplete potassium, such as amphotericin B, may enhance the potassium-wasting effect of glucocorticoids. Serum potassium should be closely monitored in patients receiving glucocorticoids and potassium-depleting drugs.

Vaccines and Toxoids

Because corticosteroids inhibit antibody response, the drugs may cause a diminished response to toxoids and live or inactivated vaccines. In addition, corticosteroids may potentiate replication of some organisms contained in live, attenuated vaccines and supraphysiologic dosages of the drugs can aggravate neurologic reactions to some vaccines. Routine administration of vaccines or toxoids should generally be deferred until corticosteroid therapy is discontinued. Administration of live virus or live, attenuated vaccines, including smallpox vaccine, is contraindicated in patients receiving immunosuppressive dosages of glucocorticoids.599,742,743,750 In addition, if inactivated vaccines are administered to such patients, expected serum antibody response may not be obtained.599,742,743 The Advisory Committee on Immunization Practices (ACIP) states that administration of live virus vaccines usually is not contraindicated in patients receiving corticosteroid therapy as short-term (less than 2 weeks) treatment, in low to moderate dosages, as long-term alternate-day treatment with short-acting preparations, in maintenance physiologic dosages (replacement therapy), or if corticosteroids are administered topically, ophthalmically, intra-articularly, bursally, or into a tendon.750 If immunization is necessary in a patient receiving corticosteroid therapy, serologic testing may be needed to ensure adequate antibody response and additional doses of the vaccine or toxoid may be necessary. Immunization procedures may be undertaken in patients receiving nonimmunosuppressive doses of glucocorticoids or in patients receiving glucocorticoids as replacement therapy (e.g., Addison's disease). For specific information on administration of vaccines or toxoids in patients receiving corticosteroids, see the individual monographs in 80:00.

Oral Anticoagulants

The effect of glucocorticoids on oral anticoagulant therapy is variable, and the efficacy of oral anticoagulants has been reported to be enhanced or diminished with concomitant glucocorticoid administration. Patients receiving glucocorticoids and oral anticoagulants concomitantly should be monitored (e.g., using coagulation indices) in order to maintain desired anticoagulant effect.

Laboratory Test Interferences

Glucocorticoids may decrease iodine 131 uptake and protein-bound iodine concentrations, making it difficult to monitor the therapeutic response of patients receiving the drugs for thyroiditis. Glucocorticoids may produce false-negative results in the nitroblue tetrazolium test for systemic bacterial infection. Glucocorticoids may suppress reactions to skin tests. Phenytoin interferes with dexamethasone suppression tests.

Pharmacology

Pharmacology of the corticosteroids is complex and the drugs affect almost all body systems. Maximum pharmacologic activity lags behind peak blood concentrations, suggesting that most effects of the drugs result from modification of enzyme activity rather than from direct actions by the drugs.

Aldosterone is a naturally occurring mineralocorticoid, and it affects electrolyte and fluid balance by acting on the distal renal tubule to promote sodium reabsorption and potassium and hydrogen excretion. Although glomerular filtration rate is also increased which promotes sodium excretion, the net effect is almost always sodium retention with resultant edema and hypertension. The naturally occurring glucocorticoids, hydrocortisone (cortisol) and cortisone, have some mineralocorticoid activity in addition to their glucocorticoid activity. Synthetic glucocorticoids also exhibit some degree of mineralocorticoid activity, especially with prolonged, high-dose therapy. Fludrocortisone has extremely potent mineralocorticoid properties and is only used for this purpose; prednisone and prednisolone have approximately half the mineralocorticoid activity of hydrocortisone and cortisone; and betamethasone, dexamethasone, meprednisone (no longer commercially available in the US), methylprednisolone, and triamcinolone have relatively little mineralocorticoid activity.

In physiologic doses (see General Dosage under Dosage and Administration: Dosage), corticosteroids are administered to replace deficient endogenous hormones. In larger (pharmacologic) doses, glucocorticoids decrease inflammation by stabilizing leukocyte lysosomal membranes, preventing release of destructive acid hydrolases from leukocytes; inhibiting macrophage accumulation in inflamed areas; reducing leukocyte adhesion to capillary endothelium; reducing capillary wall permeability and edema formation; decreasing complement components; antagonizing histamine activity and release of kinin from substrates; reducing fibroblast proliferation, collagen deposition, and subsequent scar tissue formation; and possibly by other mechanisms as yet unknown. The drugs suppress the immune response by reducing activity and volume of the lymphatic system, producing lymphocytopenia, decreasing immunoglobulin and complement concentrations, decreasing passage of immune complexes through basement membranes, and possibly by depressing reactivity of tissue to antigen-antibody interactions. Glucocorticoids stimulate erythroid cells of bone marrow, prolong survival time of erythrocytes and platelets, and produce neutrophilia and eosinopenia. Glucocorticoids promote gluconeogenesis, redistribution of fat from peripheral to central areas of the body, and protein catabolism, which results in negative nitrogen balance. They reduce intestinal absorption and increase renal excretion of calcium.

In pharmacologic doses, systemically administered glucocorticoids suppress release of corticotropin (adrenocorticotropic hormone, ACTH) from the pituitary; thus the adrenal cortex ceases secretion of endogenous corticosteroids (secondary adrenocortical insufficiency). The degree and duration of hypothalamic-pituitary-adrenal (HPA) axis suppression produced by the drugs is highly variable among patients and depends on the dose, frequency and time of administration, and duration of glucocorticoid therapy. If suppressive doses of glucocorticoids are administered for prolonged periods, the adrenal cortex atrophies and patients develop cushingoid (hypercorticism) features and respond to stress like patients with primary adrenocortical insufficiency (Addison's disease, hypocorticism). (See Cautions: Adrenocortical Insufficiency.)

The duration of anti-inflammatory activity of glucocorticoids approximately equals the duration of HPA-axis suppression. In one study, the duration of HPA-axis suppression after a single oral dose of glucocorticoids was as follows:

Following IM administration of a single dose of 40-80 mg of triamcinolone acetonide, 50 mg of triamcinolone diacetate, 9 mg of betamethasone sodium phosphate and betamethasone acetate suspension, or 40-80 mg of methylprednisolone, the duration of HPA suppression is 2-4 weeks, 1 week, 1 week, and 4-8 days, respectively. Suppression of the HPA axis below the normal clinical range did not occur when beclomethasone dipropionate was administered by oral inhalation in dosages up to and including 640 mcg daily; however, a dose-dependent reduction of adrenal cortisol production was observed.651 Since inhaled beclomethasone dipropionate is absorbed into circulation and can be systemically active, HPA axis suppression could occur when recommended dosages are exceeded or in particularly sensitive individuals.651 With recommended dosages of triamcinolone acetonide administered by oral inhalation, suppression of the HPA axis has occurred within 6-12 weeks in some patients.636

In a comparative pharmacodynamic study in healthy geriatric individuals (65-89 years of age) and in younger adults (23-34 years of age), geriatric individuals receiving a single dose of IV prednisolone (0.8 mg/kg, no longer commercially available in the US) or oral prednisone (0.8 mg/kg) exhibited a higher area under the concentration-time curve (AUC) for cortisol than that observed in younger adults.599,742,746 Increased cortisol concentrations in geriatric patients may be the result of attenuated suppression of endogenous cortisol or decreased hepatic clearance of cortisol compared with younger adults.742,746

The mechanism of antiemetic action of corticosteroids remains to be established.

Pharmacokinetics

Absorption

Most glucocorticoids appear to be readily absorbed when administered orally as free alcohols, ketones, cypionates, or acetates. Following IM administration, absorption of the water-soluble sodium phosphate and sodium succinate salts is rapid; the rate of absorption of the lipid-soluble acetate and acetonide esters is much slower. Following intra-articular administration of betamethasone sodium phosphate and betamethasone acetate injectable suspension, systemic absorption of the soluble portion (betamethasone sodium phosphate) is rapid.731 When the most rapid onset of action is desired, a water-soluble glucocorticoid ester should be administered IV. Systemic absorption occurs slowly following intra-articular, intrabursal, intrasynovial, intradermal, or soft tissue injection of most glucocorticoids.

Following oral inhalation, glucocorticoids are absorbed from the GI and respiratory tracts. After oral inhalation of beclomethasone dipropionate given via metered-dose aerosol with a tetrafluoroethane (non-CFC) propellant, most of the dose (e.g., 51-60% is deposited in the respiratory tract; approximately 27-33% of a dose is deposited in the oropharynx.638,639 Systemic bioavailability of fluticasone propionate is about 30 or 13.5% following oral inhalation of the aerosol (via metered spray) or of the powder (via the Diskhaler^® device, no longer commercially available in the US), respectively.614,615 Systemic bioavailability of budesonide is about 39% in healthy individuals following oral inhalation of the powder (via the Turbuhaler^® device)632 and about 6% in asthmatic children (4-6 years of age) following administration of the micronized suspension for nebulization (via jet nebulizer).631 Following oral inhalation of 320 mcg of flunisolide, the oral bioavailability is less than 7%.617 Absolute (compared with IV administration) bioavailability of orally inhaled mometasone furoate as a powder averaged less than 1%.740 Bioavailability following oral administration of fluticasone propionate is negligible (less than 1%), principally because of incomplete absorption and presystemic metabolism of the drug.614,615 Systemic bioavailability of a single orally ingested dose of budesonide is higher in patients with Crohn's disease (21%) than in healthy individuals (about 9%);630 however, bioavailabilities approach those of healthy individuals following multiple dosing.630

Prednisolone sodium phosphate orally disintegrating tablets and solution are bioequivalent based on comparison of area under the plasma concentration-time curves (AUCs) and peak plasma concentrations of the 2 formulations.763

Results of a pharmacokinetic study in healthy geriatric adults and younger adults (23-34 years of age) receiving a single IV dose of prednisolone (0.8 mg/kg, no longer commercially available in the US) or oral dose of prednisone (0.8 mg/kg) indicate that the plasma prednisolone concentrations and AUCs of total and unbound prednisolone in geriatric adults are higher than that reported in younger adults.599,742,763 (See Pharmacokinetics: Elimination.)

Normal endogenous plasma concentrations of cortisol and cortisone are 4-30 mcg/dL and 1-2 mcg/dL, respectively.

Distribution

Animal studies indicate that most glucocorticoids are rapidly removed from the blood and distributed to muscles, liver, skin, intestines, and kidneys.

Glucocorticoids vary in the extent to which they are bound to plasma proteins. Cortisol (hydrocortisone) is extensively bound to corticosteroid-binding globulin (transcortin) and albumin, which are plasma proteins. With physiologic concentrations, cortisol is bound primarily to transcortin and only 5-10% of cortisol in plasma is unbound and is biologically active. Prednisolone (unlike other synthetic glucocorticoids such as betamethasone, dexamethasone, or triamcinolone) has a high affinity for transcortin and competes with cortisol for this binding protein. Results of a pharmacokinetic study in healthy geriatric adults and younger adults (23-34 years of age) receiving a single IV dose of prednisolone (0.8 mg/kg, no longer commercially available in the US) or oral dose of prednisone (0.8 mg/kg) indicate that the mean unbound fraction of prednisolone was higher, and the steady-state volume of distribution of unbound prednisolone was reduced in geriatric adults compared with younger adults.599,742 Because only unbound drug is pharmacologically active, patients with low serum albumin concentrations may be more susceptible to effects of glucocorticoids than patients with normal serum albumin concentrations.

Glucocorticoids cross the placenta and may be distributed into milk.

Elimination

Glucocorticoids having a ketone group at C-11 (e.g., cortisone, prednisone) must be reduced (primarily in the liver) to their corresponding 11-hydroxy analogs (hydrocortisone, prednisolone, and meprednisolone) in order to be pharmacologically active. Prednisone is rapidly converted to prednisolone, but much of cortisone is inactivated before it can be converted to hydrocortisone.

Pharmacologically active glucocorticoids are metabolized in most tissues, but primarily in the liver, to biologically inactive compounds. The metabolic clearance of hydrocortisone may be decreased in patients with hypothyroidism and increased in those with hyperthyroidism. Changes in thyroid status may necessitate adjustment of glucocorticoid dosage.599 The metabolic clearance of prednisolone is impaired in geriatric patients (as evidenced by a reduced fractional urinary clearance of 6β-hydroxyprednisolone) compared with younger adults.599,742 Inactive metabolites are excreted by the kidneys, primarily as glucuronides and sulfates, but also as unconjugated products. Small amounts of unmetabolized drugs are also excreted in urine. Negligible amounts of most of the drugs are excreted in bile; enterohepatic circulation does not occur.

Chemistry

Corticosteroids are hormones secreted by the adrenal cortex or synthetic analogs of these hormones. Traditionally, corticosteroids have been classified as mineralocorticoids or glucocorticoids based on their primary pharmacologic activity; however, separation of the drugs into these classes is not absolute. (See Pharmacology.) Of the corticosteroids that are used clinically, beclomethasone, betamethasone, budesonide, cortisone, dexamethasone, flunisolide, fluticasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, and triamcinolone are classified as glucocorticoids. Although fludrocortisone is also a glucocorticoid, it has very potent mineralocorticoid properties and is used for its mineralocorticoid effects.

398. Health and Public Policy Committee, American College of Physicians. The dexamethasone suppression test for the detection, diagnosis, and management of depression. Ann Intern Med . 1984; 100:307-8. [PubMed 6691676]

399. Sheagren JN. Septic shock and corticosteroids. N Engl J Med . 1981; 305:456-8. [PubMed 7254284]

400. Young LS. Pathogenesis of septic shock: approaches to management. Ann Intern Med . 1980; 93:728-31.

401. Weitzman S, Berger S. Clinical trial design in studies of corticosteroids for bacterial infections. Ann Intern Med . 1974; 81:36-42. [PubMed 4366291]

402. Schumer W. Steroids in the treatment of clinical septic shock. Ann Surg . 1976; 184:333-41. [PubMed 786190][PubMedCentral]

403. Sprung CL, Caralis PV, Marcial EH et al. The effects of high-dose corticosteroids in patients with septic shock: a prospective, controlled study. N Engl J Med . 1984; 311:1137-43. [PubMed 6384785]

404. Hoffman SL, Rustama D, Punjabi NH et al. High-dose dexamethasone in quinine-treated patients with cerebral malaria: a double-blind, placebo-controlled trial. J Infect Dis . 1988; 158:325-31. [PubMed 3042874]

405. Wyler DJ. Steroids are out in the treatment of cerebral malaria: what's next? J Infect Dis . 1988; 158:320-4. Editorial.

406. Krogstad DJ, Herwaldt BL, Schlesinger PH. Antimalarial agents: specific treatment regimens. Antimicrob Agents Chemother . 1988; 32:957-61. [PubMed 3056248][PubMedCentral]

407. World Health Organization Malaria Action Programe. Severe and complicated malaria. Trans R Soc Trop Med Hyg . 1986; 80(Suppl):1-50. [PubMed 3014688]

408. Cook GC. Prevention and treatment of malaria. Lancet . 1988; 1:32-7. [PubMed 2891898]

409. Bone RC, Fisher CJ, Clemmer TP et al and the Methylprednisolone Severe Sepsis Study Group. A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis. N Engl J Med . 1987; 317:653-8. [PubMed 3306374]

410. The Veterans Administration Systemic Sepsis Cooperative Study Group. Effect of high-dose glucocorticoid therapy on mortality in patients with clinical signs of systemic sepsis. N Engl J Med . 1987; 317:659-65. [PubMed 2888017]

411. Neugebauer E, Schirren J, Lorenz W. High-dose steroids and sepsis. N Engl J Med . 1988; 318:514. [PubMed 3340132]

412. Greisman SE, Johnston CA. High-dose steroids and sepsis. N Engl J Med . 1988; 318:514-5. [PubMed 3340132]

413. Hoffman SL. High-dose steroids and sepsis. N Engl J Med . 1988; 318:515.

414. Bone RC, Metz CA, Fisher CJ Jr et al and the Methylprednisolone Severe Sepsis Study Group. High-dose steroids and sepsis. N Engl J Med . 1988; 318:515-6.

415. The Veterans Administration Systemic Sepsis Cooperative Study Group. High-dose steroids and sepsis. N Engl J Med . 1988; 318:517.

416. Novitch M. Dear doctor letter regarding warning that was added to Solu-Medrol^® labeling concerning use in septic shock. Kalamazoo, MI: The Upjohn Company; 1986 Aug 21 (received 1988 Feb 24).

417. Pfizer. Solu-Medrol^® (methylprednisolone sodium succinate) sterile powder for injection prescribing information. New York, NY; 2009 May.

418. Kass EH. High-dose corticosteroids for septic shock. N Engl J Med . 1984; 311:1178-9. [PubMed 6482936]

419. Brouwer MC, McIntyre P, Prasad K, van de Beek D. Corticosteroids for acute bacterial meningitis. Cochrane Database Syst Rev. 2015 Sep 12;2015(9):CD004405. [PubMed 26362566][PubMedCentral]

424. The APA Task Force on Laboratory Tests in Psychiatry. The dexamethasone suppression test: an overview of its current status in psychiatry. Am J Psychiatry . 1987; 144:1253-62. [PubMed 3310667]

425. Hirschfeld RMA, Koslow SH, Kupfer DJ. The clinical utility of the dexamethasone suppression test in psychiatry: summary of a National Institute of Mental Health Workshop. JAMA . 1983; 250:2172-4. [PubMed 6620522]

426. Abbott Laboratories. A-methaPred^® (methylprednisolone sodium succinate) for injection prescribing information. In: Huff BB, ed. Physicians' desk reference. 43rd ed. Oradell, NJ: Medical Economics Company Inc; 1989:507-8.

427. Messer J, Reitman D, Sacks HS et al. Association of adrenocorticoid therapy and peptic ulcer disease. N Engl J Med . 1983; 309:21-4. [PubMed 6343871]

428. Spiro HM. Is the steroid ulcer a myth? N Engl J Med . 1983; 309:45-7. Editorial.

429. Conn HO, Blitzer BL. Nonassociation of adrenocorticoid therapy and peptic ulcer. N Engl J Med . 1976; 294:473-9. [PubMed 173997]

430. The National Institutes of Health-University of California Expert Panel for Corticosteroids as Adjunctive Therapy for Pneumocystis Pneumonia. Consensus statement on the use of corticosteroids as adjunctive therapy for pneumocystis pneumonia in the acquired immunodeficiency syndrome. N Engl J Med . 1990; 323:1500-4. [PubMed 2136587]

431. Montaner JSG, Lawson LM, Leavitt N et al. Corticosteroids prevent early deterioration in patients with moderately severe Pneumocystis carinii pneumonia and the acquired immunodeficiency syndrome (AIDS). Ann Intern Med . 1990; 113:14-20. [PubMed 2190515]

432. Clement M, Edison R, Turner J et al. Corticosteroids as adjunctive therapy in severe Pneumocystis carinii pneumonia: a prospective placebo-controlled trial. Am Rev Respir Dis . 1989; 139(Suppl):A250.

433. Bozzette SA, Sattler FR, Chiu J et al. A controlled trial of early adjunctive treatment with corticosteroids for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. N Engl J Med . 1990; 323:1451-7. [PubMed 2233917]

434. Gagnon S, Boota AM, Fischl MA et al. Corticosteroids as adjunctive therapy for severe Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome: a double-blind, placebo-controlled trial. N Engl J Med . 1990; 323:1444-50. [PubMed 2233916]

435. Kovacs JA, Masur H. Are corticosteroids beneficial as adjunctive therapy for Pneumocystis carinii pneumonia in AIDS? Ann Intern Med . 1990; 113:1-3. Editorial.

436. Schiff MJ, Farber BF, Kaplan MH. Steroids for Pneumocystis carinii pneumonia and respiratory failure in the acquired immunodeficiency syndrome: a reassessment. Arch Intern Med . 1990; 150:1819-21. [PubMed 2203321]

456. Reviewers' comments (personal observations); 1991 Mar.

457. Bracken MB, Shepard MJ, Collins WF et al. A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal-cord injury: results of the second National Acute Spinal Cord Injury Study. N Engl J Med . 1990; 322:1405-11. [PubMed 2278545]

458. National Institutes of Health. Clinical alert: new treatment for acute spinal cord injury. Bethesda, MD;1 990 Apr 13.

459. Ducker TB. Treatment of spinal-cord injury. N Engl J Med . 1990; 322:1459-61. [PubMed 2184359]

460. Anon. Steroids after spinal cord injury. Lancet . 1990; 336:279-80. [PubMed 1973973]

461. Taylor TKF, Ryan MD. Methylprednisolone in the management of acute spinal cord injuries. Med J Aust . 1990; 153:307-8. [PubMed 2392088]

462. Bracken MB. Methylprednisolone in the management of acute spinal cord injuries. Med J Aust . 1990; 153:368. [PubMed 2233469]

463. Bracken MB, Freeman DH Jr, Hellenbrand K. Incidence of acute traumatic hospitalized spinal cord injury in the United States, 1970-77. Am J Epidemiol . 1981; 113:615-22. [PubMed 7234849]

464. Bracken MB, Collins WF, Freeman DF et al. Efficacy of methylprednisolone in acute spinal cord injury. JAMA . 1984; 251:45-52. [PubMed 6361287]

465. Bracken MB, Shepard MJ, Hellenbrand KG et al. Methylprednisolone and neurological function 1 year after spinal cord injury: results of the National Acute Spinal Cord Injury Study. J Neurosurg . 1985; 63:704-13. [PubMed 3903070]

466. DeMaria EJ, Reichman W, Kenney PR et al. Septic complications of corticosteroid administration after central nervous system trauma. Ann Surg . 1985; 202:248-52. [PubMed 4015231][PubMedCentral]

467. Hall ED, Wolf DL, Braughler JM. Effects of a single large dose of methylprednisolone sodium succinate on experimental posttraumatic spinal cord ischemia: dose-response and time-action analysis. J Neurosurg . 1984; 61:124-30. [PubMed 6374068]

468. Yarkony GM, Roth EJ. A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal-cord injury. N Engl J Med . 1990; 323:1208.

469. Bracken MB, Shepard MJ, Collins WF et al. A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal-cord injury. N Engl J Med . 1990; 323:1209. [PubMed 2120586]

470. Young W, DeCrescito V, Flamm ES et al. Pharmacological therapy of acute spinal cord injury: studies of high-dose methylprednisolone and naloxone. Clin Neurosurg . 1988; 34:675-97. [PubMed 3378379]

471. Roos KL. Dexamethasone and nonsteroidal anti-inflammatory agents in the treatment of bacterial meningitis. Clin Ther . 1990; 12:290-6. [PubMed 2224944]

472. Committee on Infectious Diseases, American Academy of Pediatrics. Report of the Committee on Infectious Diseases. 22nd ed. Elk Grove Village, IL: American Academy of Pediatrics; 1991:373-8,566-70.

473. Odio CM, Faingezicht I, Paris M et al. The beneficial effects of early dexamethasone administration in infants and children with bacterial meningitis. N Engl J Med . 1991;324;:525-31. [PubMed 2027357][PubMedCentral]

474. Sandoz Pharmaceuticals Corporation. Sandimmune^® (cyclosporine) oral solution and I.V. prescribing information. East Hanover, NJ; 1988 Apr 1.

475. Ost L. Effects of cyclosporin on prednisolone metabolism. Lancet . 1984; 1:451. [PubMed 6142174]

476. Klintmalm G, Sawe J. High dose methylprednisolone increases plasma cyclosporin levels in renal transplant recipients. Lancet . 1984; 1:731. [PubMed 6143058]

477. Pfizer. Depo-Medrol^® (methylprednisolone acetate) injectable suspension (single-dose vials) prescribing information. New York, NY; 2009 Apr.

478. Cohen DJ, Loertscher R, Rubin MF et al. Cyclosporine: a new immunosuppressive agent for organ transplantation. Ann Intern Med . 1984; 101:667-82. [PubMed 6385799]

479. Durrant S, Chipping PM, Palmer S et al. Cyclosporin A, methylprednisolone, and convulsions. Lancet . 1982; 1:906.

480. Boogaerts MA, Zachee P, Verwilghen RL. Cyclosporin, methylprednisolone, and convulsions. Lancet . 1982; 2:1216-7. [PubMed 6128517]

481. Rubin AM, Kang M. Cerebral blindness and encephalopathy with cyclosporin A toxicity. Neurology . 1987; 37:1072-6. [PubMed 3587633]

482. Adams DH, Ponsford S, Gunson B et al. Neurological complications following liver transplantation. Lancet . 1987; 1:949-51. [PubMed 2882342]

483. Sandoz Pharmaceuticals. Sandimmune^® (cyclosporine) practical guide. East Hanover, NJ; 1985 Sep. SDI-103.

484. Upjohn Solu-Medrol^® (methylprednisolone sodium succinate) sterile powder and for injection prescribing information. In: Barnhart ER, publisher. Physicians' desk reference. 45th ed. Oradell, NJ: Medical Economics Company Inc; 1991(Suppl A):A73.

485. Pfizer. Medrol^® (methylprednisolone) tablets prescribing information. New York, NY; 2006 Nov.

486. Pharmacia & Upjohn. Deltasone^® (prednisone) tablets prescribing information. Kalamazoo, MI; 2002 Apr.

487. Anon. Revised label warns of severe viral problems with corticosteroids. FDA Med Bull . 1991 Dec; 21:3.

488. Peterson F (US Food and Drug Administration). Corticosteroid drugs and chickenpox. Rockville, MD; 1991 Dec 2. Press release no. P91-31 (from FDA electronic bulletin board).

489. Jones JF. FDA varicella warning. Pediatrics . 1992; 90:480-1.

490. Kasper WJ, Howe PM. Fatal varicella after a single course of corticosteroids. Pediatr Infect Dis . 1990; 9:729-32.

491. Close GC, Houston IB. Fatal hemorrhagic chickenpox in a child on long term steroids. Lancet . 1981; 2:480. [PubMed 6115244]

492. Gershon A, Brunell PA, Doyle E. Steroid therapy and varicella. J Pediatr . 1972; 81:1034. [PubMed 4117587]

493. Lantner R, Rockoff JB, DeMasi J et al. Fatal varicella in a corticosteroid-dependent asthmatic receiving troleandomycin. Allergy Proc . 1990; 11:83-7. [PubMed 2338242]

494. Silk HJ, Guay-Woodford L, Perez-Atayde AR et al. Fatal varicella in steroid-dependent asthma. J Allergy Clin Immunol . 1988; 81:47-51. [PubMed 3339190]

503. Tyson LB, Gralla RJ, Clark RA et al. Combination antiemetic trials with metoclopramide. Proc Am Soc Clin Oncol . 1983; 2:91.

504. Bruera ED, Roca E, Cedaro L et al. Improved control of chemotherapy-induced emesis by the addition of dexamethasone to metoclopramide in patients resistant to metoclopramide. Cancer Treat Rep . 1983; 67:381-3. [PubMed 6342770]

505. Italian Group for Antiemetic Research. Ondansetron + dexamethasone vs metoclopramide + dexamethasone + diphenhydramine in prevention of cisplatin-induced emesis. Lancet . 1992; 340:96-99. [PubMed 1352024]

506. Smith DB, Newlands ES, Rustin GJS et al. Comparison of ondansetron and ondansetron plus dexamethasone as antiemetic prophylaxis during cisplatin-containing chemotherapy. Lancet . 1991; 338:487-90. [PubMed 1714532]

507. Anon. Ondansetron vs dexamethasone for chemotherapy-induced emesis. Lancet . 1991; 338:478-9. [PubMed 1714531]

508. Ohmatsu H, Eguchi K, Shinkai T et al. A randomized cross-over study of high-dose metoclopramide plus dexamethasone versus granisetron plus dexamethasone in patients receiving chemotherapy with high-dose cisplatin. Jpn J Cancer Res . 1994; 85:1151-8. [PubMed 7829401]

509. Heron JF, Goedhals L, Jordaan JP et al. Oral granisetron alone and in combination with dexamethasone: a double-blind randomized comparison against high-dose metoclopramide plus dexamethasone in prevention of cisplatin-induced emesis. The Granisetron Study Group. Ann Oncol . 1994; 5:579-84. [PubMed 7993831]

510. Gralla RJ. Adverse effects of treatment: antiemetic therapy. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: principles and practice of oncology. 4th ed. Philadelphia: J.B. Lippincott Company; 1993:2338-48.

511. Ahn MJ, Lee JS, Lee KH et al. A randomized double-blind trial of ondansetron alone versus in combination with dexamethasone versus in combination with dexamethasone and lorazepam in the prevention of emesis due to cisplatin-based chemotherapy. Am J Clin Oncol . 1994; 17:150-6. [PubMed 8141107]

512. Cunningham D, Hill M, Dicato M et al. Optimal anti-emetic therapy for cisplatin induced emesis over repeat courses. Proc Ann Meet Am Soc Clin Oncol . 1994; 13:A1553.

513. McKeage MJ. Comparative adverse effect profile of platinum drugs. Drug Saf . 1995; 13:228-44. [PubMed 8573296]

514. Mason BA, Dambra J, Grossman B et al. Effective control of cisplatin-induced nausea using high-dose steroids and droperidol. Cancer Treat Rep . 1982; 66:243-5. [PubMed 7198937]

515. Jacobs AJ, Deppe G, Cohen CJ. A comparison of the antiemetic effects of droperidol and prochloroperazine in chemotherapy with cis -platinum. Gynecol Oncol . 1980; 10:55-7. [PubMed 7190532]

516. Wilson J, Weltz M, Solimando D et al. Continuous infusion droperidol: anti-emetic therapy for cis -platinum (DDP) toxicity. Proc Am Soc Clin Oncol . 1981; 22:421.

517. Neidhart JA, Gagen M, Young D et al. Specific antiemetics for specific cancer chemotherapeutic agents: haloperidol versus benzquinamide. Cancer . 1981; 47:1439-43. [PubMed 7013968]

518. Cubeddu LX, Hoffmann IS. Participation of serotonin on early and delayed emesis induced by initial and subsequent cycles of cisplatinum-based chemotherapy: effects of antiemetics. J Clin Pharmacol . 1993; 33:691-7. [PubMed 7691898]

519. Hesketh PJ, Gandara DR. Serotonin antagonists: a new class of antiemetic agents. J Natl Cancer Inst . 1991; 83:613-20. [PubMed 1850806]

520. du Bois A, Vach W, Thomssen C et al. Comparison of emetogenic potential between cisplatin and carboplatin in combination with akylating agents. Acta Oncol . 1994; 33:531-5. [PubMed 7917367]

521. Gebbia V, Cannata G, Testa A et al. Ondansetron versus granisetron in the prevention of chemotherapy-induced nausea and vomiting. Results of a prospective randomized trial. Cancer . 1994; 74:1945-52. [PubMed 8082100]

522. Kris MG, Pisters KM, Hinkley L. Delayed emesis following anticancer chemotherapy. Support Care Cancer . 1994; 2:297-300. [PubMed 8000726]

523. Malik IA, Khan WA, Qazilbash M et al. Clinical efficacy of lorazepam in prophylaxis of anticipatory, acute, and delayed nausea and vomiting induced by high doses of cisplatin. A prospective randomized trial. Am J Clin Oncol . 1995; 18:170-5. [PubMed 7900711]

524. Clerico M, Bertetto O, Cardinali C et al. Antiemetic activity of lorazepam in the prophylactic treatment of vomiting induced by cisplatin: a double-blind placebo controlled study with cross-over design. Ann Oncol . 1992; 3(Suppl 5):188.

525. De Mulder PHM, Seynaeve C, Vermorken JB et al. Ondansetron compared with high-dose metoclopramide in prophylaxis of acute and delayed cisplatin-induced nausea and vomiting: a multicenter, randomized, double-blind, crossover study. Ann Intern Med . 1990; 113:834-40. [PubMed 2146911]

526. Grunberg SM, Hesketh PJ. Control of chemotherapy-induced emesis. N Engl J Med . 1993; 329:1790-6. [PubMed 8232489]

527. Mitchelson F. Pharmacological agents affecting emesis: a review (part I). Drugs . 1992; 43: 295-315.

528. Aapro MS. 5-HT₃ receptor antagonists: an overview of their present status and future potential in cancer therapy-induced emesis. Drugs . 1991; 42:551-68. [PubMed 1723361]

529. National Institutes of Health Office of Medical Applications of Research. NIH consensus statement: effect of corticosteroids for fetal maturation on perinatal outcomes. 1994; 12:1-24.

530. Ballard PL, Ballard RA. Scientific basis and therapeutic regimens for use of antenatal glucocorticoids. Am J Obstet Gynecol . 1995; 173:254-62. [PubMed 7631700]

531. Crowley PA. Antenatal corticosteroid therapy: a meta-analysis of the randomized trials, 1972 to 1994. Am J Obstet Gynecol . 1995; 173:322-35. [PubMed 7631713]

532. Garland JS, Buck R, Leviton A. Effect of maternal glucocorticoid exposure on risk of severe intraventricular hemorrhage in surfactant-treated preterm infants. J Pediatr . 1995; 126:272-9. [PubMed 7844678]

533. Silver RK, Vyskocil C, Solomon SL et al. Randomized trial of antenatal dexamethasone in surfactant-treated infants delivered before 30 weeks' gestation. Obstet Gynecol . 1996; 87:683-91. [PubMed 8677067]

534. Andrews EB, Marcucci G, White A et al. Associations between use of antenatal corticosteroids and neonatal outcomes within the Exosurf Neonatal Treatment Investigational New Drug program. Am J Obstet Gynecol . 1995; 173:290-5. [PubMed 7631706]

535. Jobe AH, Mitchell BR, Gunkel JH. Beneficial effects of the combined use of prenatal corticosteroids and postnatal surfactant on preterm infants. Am J Obstet Gynecol . 1993; 168:508-13. [PubMed 8438919]

537. Papageorgiou AN, Doray JL, Ardila R et al. Reduction of mortality, morbidity, and respiratory distress syndrome in infants weighing less than 1,000 grams by treatment with betamethasone and ritodrine. Pediatrics . 1989; 83:493-7. [PubMed 2927987]

538. Wright LL, Horbar JD, Gunkel H et al. evidence from multicenter networks on the current use and effectiveness of antenatal corticosteroids in low birth weight infants. Am J Obstet Gynecol . 1995; 173:263-9. [PubMed 7631701]

539. Shankaran S, Bauer CR, Bain R et al. Prenatal and perinatal risk and protective factors for neonatal intracranial hemorrhage. Arch Pediatr Adolesc Med . 1996; 150:491-7. [PubMed 8620230]

540. Atkinson MW, Goldenberg RL, Gaudier FL et al. Maternal corticosteroid and tocolytic treatment and morbidity and mortality in very low birth weight infants. Am J Obstet Gynecol . 1995; 173:299-305. [PubMed 7631708]

541. Shankaran S, Bauer CR, Bain r et al. Relationship between antenatal steroid administration and grades III and IV intracranial hemorrhage in low birth weight infants. Am J Obstet Gynecol . 1995; 173:305-12. [PubMed 7631710]

542. Kari MA, Hallman M, Eronen M et al. Prenatal dexamethasone treatment in conjunction with rescue therapy of human surfactant: a randomized placebo-controlled multicenter study. Pediatrics . 1994; 93:730-6. [PubMed 8165070]

543. Farrell EE, Silver RK, Kimberlin LV et al. Impact of antenatal dexamethasone administration on respiratory distress syndrome in surfactant-treated infants. Am J Obstet Gynecol . 1989; 161:628-33. [PubMed 2675599]

544. Immunex Corporation. Novantrone^® (mitoxantrone) for injection concentrate prescribing information. Seattle, WA; 1996 Nov.

545. Immunex Corporation. Mitoxantrone for injection concentrate: clinical use in hormone-resistant prostate cancer. Seattle, WA: 1996.

546. Vogelzang NJ. One hundred thirteen men with hormone-refractory prostate cancer died today. J Clin Oncol . 1996; 14:1753-5. [PubMed 8656242]

547. Tannock IF, Osoba D, Stockler MR et al. Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points. J Clin Oncol . 1996; 14:1756-64. [PubMed 8656243]

548. Prostate Cancer Trialists' Collaborative Groups. Maximum androgen blockade in advanced prostate cancer: an overview of 22 randomized trials with 3283 deaths in 5710 patients. Lancet . 1995; 346:265-9. [PubMed 7630245]

549. Prostate cancer. From: PDQ Physician data query (database). Bethesda, MD: National Cancer Institute; 1996 Dec 20.

550. Tannock I, Gospodarowicz M, Meakin W et al. Treatment of metastatic prostatic cancer with low-dose prednisone: evaluation of pain and quality of life as pragmatic indices of response. J Clin Oncol . 1989; 7:590-7. [PubMed 2709088]

551. Garbe E, Lelorier J, Boivin JF et al. Inhaled and nasal glucocorticoids and the risks of ocular hypertension or open-angle glaucoma. JAMA . 1997; 277:722-7. [PubMed 9042844]

552. Seckl JR, Miller WL. How safe is long-term prenatal glucocorticoid treatment? JAMA . 1997; 277:1077-9.

553. Cumming RD, Mitchell P, Leeder SR. Use of inhaled corticosertoids and the risk of cataracts. N Engl J Med . 1997; 337:8-14. [PubMed 9203425]

554. National Asthma Education and Prevention Program. Expert panel report: guidelines for the diagnosis and management of asthma. Update on selected topics-2002. Bethesda, Md: National Heart, Lung, and Blood Institute, National Asthma Education and Prevention Program Coordinating Committee; 2003 Jun. Available from National Heart, Lung, and Blood Institute Information Center, NIH Publication No. 02-5074. Also available from website. Accessed 2006 Jan. 5. [Web]

555. National Asthma Education Program. Executive summary: guidelines for the diagnosis and management of asthma. NIH Publ. No.94-3042A. Washington, DC: US Government Printing Office; 1994 Jul.

556. National Institutes of Health, National Heart, Lung, and Blood Institute. Global initiative for asthma: global strategy for asthma management and prevention NHLBI/WHO Workshop Report. Bethesda, MD: National Institutes of Health. 2007 Dec 19. NIH/NHLBI Publication No. 02-3659. Available from website. Accessed Jul 27, 2008. [Web]

557. British Thoracic Society/Scottish Intercollegiate Guidelines Network. Guidelines on the management of asthma: a national clinical guideline. London, Eng; British Thoracic Society. 2008 May. Available from website. Accessed 2008 Oct 10. [Web]

558. Allen & Hanburys. Serevent^® (salmeterol xinafoate) inhalation aerosol prescribing information. Research Triangle Park, NC; 1994 Dec.

559. Allen & Hanburys. Serevent^® (salmeterol xinafoate) inhalation aerosol patient instructions. Research Triangle Park, NC; 1994 Feb.

560. Bone RC. Another word of caution regarding a new long-acting bronchodilator. JAMA . 1995; 273:967-8. [PubMed 7884959]

561. Reviewers' comments (personal observations) on salmeterol 12:12.08.12.

562. Anon. Warnings from the CSM. Int Pharm J . 1991; 5:247-8.

563. Key Pharmaceuticals. Proventil HFA^® (albuterol sulfate) inhalation aerosol for oral inhalation prescribing information. Kenilworth, NJ; 2000 Jan.

564. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease 2023 report. Accessed Feb 2, 2023. [Web]

565. Siafakas NM, Vermeire P, Pride NB et al. Optimal assessment and management of chronic obstructive pulmonary disease (COPD). Eur Respir J . 1995: 8; 1398-420.

566. Boehringer Ingelheim. Atrovent^® (ipratropium bromide) inhalation aerosol prescribing information. Ridgefield, CT; 1993 Jun.

567. McKenzie R, O'Fallon A, Dale J et al. Low-dose hydrocortisone for the treatment of chronic fatigue syndrome: a randomized controlled trial. JAMA . 1998; 280:1061-6. [PubMed 9757853]

568. Streeten DHP. The nature of chronic fatigue. JAMA . 1998; 280:1094-5. [PubMed 9757860]

569. Demitrack MA, Dale JK, Straus SE et al. Evidence for impaired activation of the hypothalamic-pituitary-adrenal axis in patients with chronic fatigue syndrome. J Clin Endocrinol Metab . 1991; 73:1224-34. [PubMed 1659582]

572. American College of Rheumatology Task Force on Osteoporosis Guidelines. Recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis. Arthritis Rheum . 1996; 39:1791-801. [PubMed 8912500]

573. Adinoff AD, Hollister JR. Steroid-induced fractures and bone loss in patients with asthma. N Engl J Med . 1983; 309:265-8. [PubMed 6866051]

574. Rudick RA, Cohen JA, Weinstock-Guttman B et al. Management of multiple sclerosis. N Engl J Med . 1997; 337:1604-11. [PubMed 9371858]

575. Beck RW, Cleary PA, Anderson MM Jr et al. A randomized, controlled trial of corticosteroids in the treatment of acute optic neuritis. N Engl J Med . 1992; 326:581-8. [PubMed 1734247]

576. Beck RW, Cleary PA, Trobe JD et al. The effect of corticosteroids for acute optic neuritis on the subsequent development of multiple sclerosis. N Engl J Med . 1993; 329:1764-9. [PubMed 8232485]

577. Beck RW. The Optic Neuritis Treatment Trial: three-year follow-up results. Arch Ophthalmol . 1995; 113:136-7. [PubMed 7864737]

578. George JN, Woolf SH, Raskob GE et al. Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for the American Society of Hematology. Ann Intern Med . 1997; 126:319-26. [PubMed 9036806]

579. The American Society of Hematology ITP Practice Guideline Panel. Diagnosis and treatment of idiopathic thrombocytopenic purpura: recommendations of the American Society of Hematology. Ann Intern Med . 1997; 126:319-26. [PubMed 9036806]

580. Optic Neuritis Study Group. Visual function 5 years after optic neuritis: experience of the Optic Neuritis Treatment Trial. Arch Ophthalmol . 1997; 115:1545-52. [PubMed 9400788]

581. Optic Neuritis Study Group. The 5-year risk of MS after optic neuritis: experience of the Optic Neuritis Treatment Trial. Neurology . 1997; 49:1404-13. [PubMed 9371930]

582. Chiabrando JG, Bonaventura A, Vecchié A et al. Management of Acute and Recurrent Pericarditis: JACC State-of-the-Art Review. J Am Coll Cardiol. 2020 Jan 7;75(1):76-92. doi: 10.1016/j.jacc.2019.11.021. [PubMed 31918837]

583. Bukley BH, Roberts WC. Steroid therapy during acute myocardial infarction: a cause of delayed healing and of ventricular aneurysm. Am J Med . 1974; 56:244-250. [PubMed 4812079]

584. Kloner RA, Fishbein MC, Lew H et al. Mummification of the infarcted myocardium by high dose carticosteroids. Circulation . 1978; 57:56-63. [PubMed 618398]

585. Dooley DP, Carpenter JL, Rademacher S. Adjunctive corticosteroid therapy for tuberculosis: a critical reappraisal of the literature. Clin Infect Dis . 1997; 25:872-87. [PubMed 9356803]

586. Cisneros JR, Murray KM. Corticosteroids in tuberculosis. Ann Pharmacother . 1996; 30:1298-1303. [PubMed 8913413]

587. Zoorob RJ, Cender D. A different look at corticosteroids. Am Fam Physician . 1998; 58:443-50. [PubMed 9713398]

588. Alrajhi AA, Halim MA, Al-Hokail A et al. Corticosteroid treatment of peritoneal tuberculosis. Clin Infect Dis . 1998, 27:52-6.

589. Morehead RS. Tuberculosis of the pleura. South Med J . 1998; 91:630-6. [PubMed 9671833]

590. Park IW, Choi BW, Hue SH. Prospective study of corticosteroid as an adjunct in the treatment of endobronchial tuberculosis in adults. Respirology . 1997; 2:275-81. [PubMed 9525297]

591. Cline JC, Davis SM. Risks of infection or reactivation of tuberculosis associated with chronic corticosteroid therapy. Ann Pharmacother . 1997; 31:775-6. [PubMed 9184722]

592. Schoeman JF, Van Zyl LE, Laubscher JA et al. Effects of corticosteroids on intracranial pressure, computed tomographic findings, and clinical outcome in young children with tuberculous meningitis. Pediatrics . 1997; 99:226-31. [PubMed 9024451]

593. Wyser C, Walzl G, Smedema JP et al. Corticosteroids in the treatment of tuberculous pleurisy. A double- blind, placebo-controlled, randomized study. Chest . 1996; 110:333-8. [PubMed 8697829]

594. Galarza I, Canete C, Granados A et al. Randomised trial of corticosteroids in the treatment of tuberculous pleurisy. Thorax . 1995; 50:1305-7. [PubMed 8553306][PubMedCentral]

595. Senderovitz T, Viskum K. Corticosteroids and tuberculosis. Respir Med . 1994; 88:561-5. [PubMed 7991879]

596. Alzeer AH, FitzGerald JM. Corticosteroids and tuberculosis: risks and use as adjunct therapy. Tuber Lung Dis . 1993; 74:6-11. [PubMed 8495021]

597. Reviewers' comments (personal observations).

598. Michalets E. Update: clinically significant cytochrome P-450 drug interactions. Pharmacotherapy . 1998; 18:84-112. [PubMed 9469685]

599. Celltech Pharmaceuticals. Pediapred^® (prednisolone sodium phosphate) oral solution prescribing information. Rochester, NY; 2004 May.

600. Dammers JWHH, Veering MM, Vermeulen M. Injection with methylprednisolone proximal to the carpal tunnel: ramdomised double blind trial. BMJ . 1999; 319:884-6. [PubMed 10506042][PubMedCentral]

601. Girlanda P, Dattola R, Venuto C et al. Local steroid treatment in idiopathic carpal tunnel syndrome: short- and long-term efficacy. J Neurol . 1993; 240:187-90. [PubMed 8482993]

602. Weiss AP, Sachar AP, Gendreau M. Conservative management of carpal tunnel syndrome: a reexamination of steroid injeciton and splinting. J Hand Surg . 1994; 19:410-5.

603. Pharmacia & Upjohn. Cortef^® (hydrocortisone) tablets prescribing information. Kalamazoo, MI; 2002 Dec.

604. Lottenberg SA, Gionella-Neto D, Derendorf H et al. Effect of fat distribution on the pharmacokinetics of cortisol in obesity. Int J Clin Pharmacol Ther . 1998; 36:501-5. [PubMed 9760012]

605. Aero Pharmaceuticals. Prelone^® (prednisolone) syrup prescribing information. Pompano Beach, FL; 2003 Aug.

606. Merck & Co. Fosamax^® (alendronate sodium) tablets prescribing information. West Point, PA; 1999 Jun.

607. Troiano R, Cook SD, Dowling PC. Steroid therapy in multiple sclerosis: point of view. Arch Neurol . 1987; 44:803-7. [PubMed 2820358]

608. Giesser B. Multiple sclerosis: current concepts in management. Drugs . 1985; 29:88-95. [PubMed 2982564]

609. Carter JL, Rodriguez M. Immunosuppressive treatment of multiple sclerosis. Mayo Clin Proc . 1989; 64:664-9. [PubMed 2473360]

610. Ohno R, Hamaguchi K, Sowa K et al. High-dose intravenous corticosteroids in the treatment of multiple sclerosis. Jpn J Med . 1987; 26:212-6. [PubMed 3626160]

611. Centers for Disease Control and Prevention. Update: investigation of bioterrorism-related anthrax and interim guidelines for exposure management and antimicrobial therapy, October 2001. MMWR . 2001: 50:909-19.

614. GlaxoSmithKline. Flovent^® (fluticasone propionate) inhalation aerosol prescribing information. Research Triangle Park, NC; 1999 Apr

615. GlaxoSmithKline. Flovent^® Rotadisk^® (fluticasone propionate) inhalation powder prescribing information. Research Triangle Park, NC; 2001 Mar.

616. Jarvis B, Faulds D. Inhaled fluticasone propionate: a review of its therapeutic efficacy at dosages ≤ 500 mcg/day in adults and adolescents with mild to moderate asthma. Drugs . 1999; 57:769-803. [PubMed 10353302]

617. Acton Pharmaceuticals, Inc. Aerospan^® (flunisolide) inhalation aerosol prescribing information. Marlborough, MA; 2013 Aug.

618. GlaxoSmithKline. Beclovent^® (beclomethasone dipropionate) inhalation aerosol (dated 1997 Dec). In: Physician's desk reference. 55th ed. Montvale, NJ: Medical Economics Company, Inc; 2001:1354-6.

619. GlaxoSmithKline. Beconase^® (beclomethasone dipropionate) inhalation aerosol prescribing information. Research Triangle Park, NC; 2001 Aug.

620. Guinn DA, Atkinson MW, Sullivan L et al. Single vs weekly courses of antenatal corticosteroids for women at risk of preterm delivery; a randomized controlled trial. JAMA . 2001; 286:1581-7. [PubMed 11585480]

621. National Institutes of Health Office of Medical Applications of Research. NIH consensus statement: antenatal corticosteroids revisited: repeat courses. 2000; 17:1-10.

622. Buckley L, Guyatt G, Fink HA et al. 2017 American College of Rheumatology Guideline for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis. Arthritis Rheumatol . 2017; 69:1521-1537. [PubMed 28585373]

623. American College of Rheumatology Ad Hoc Committee on Glucocorticoid-induced Osteoporosis. Recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis: 2001 update. Arthritis Rheum . 2001; 44:1496-503. [PubMed 11465699]

624. National Heart, Lung, and Blood Institute/World Health Organization. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Bethesda, MD: National Heart, Lung, and Blood Institute, Global Initiative for Chronic Obstructive Lung Disease, World Health Organization; 2001. Available from website. Accessed Sep. 26, 2002. [Web]

625. Veterans' Health Administration, Department of Veterans' Affairs. VHA/DOD clinical practice guideline for the management of chronic obstructive pulmonary disease: complete summary. Washington, DC: Veterans' Health Administration; 1999 Aug.

626. Snow V, Lascher S, Mottur-Pilson C for the Joint Expert Panel of Chronic Obstructive Pulmonary Disease of the American College of Chest Physicians and the American College of Physicians-American Society of Internal Medicine. Evidence base for management of acute exacerbations of chronic obstructive pulmonary disease. Clinical Practice Guideline, pt.1. Chest . 2001; 119:1185-9. [PubMed 11296188]

627. Vincent A, Palace J, Hilton-Jones D. Myasthenia gravis. Lancet . 2001; 357:2122-8. [PubMed 11445126]

628. Massey JM. Treatment of acquired myasthenia gravis. Neurology . 1997; 48(suppl 5):S46-51.

629. Berrouschot J, Baumann I, Kalischewski P et al. Therapy of myasthenic crisis. Crit Care Med . 1997; 25:1228-35. [PubMed 9233752]

630. AstraZeneca. Entocort^® EC (budesonide capsules) prescribing information. Wilmington, DE; 2002 Jan.

631. AstraZeneca. Pulmicort Respules^® (budesonide inhalation suspension) prescribing information. Wilmington, DE; 2001 Aug.

632. AstraZeneca. Pulmicort Turbuhaler^® budesonide inhalation powder) prescribing information. Wilmington, DE; 2001 Dec.

633. McKeage K, Goa KL. Budesonide (Entocort^® EC capsules): a review of its therapeutic use in the management of active Crohn's disease in adults. Drugs. 2002; 62:2263-82.

634. Valentine JF. Treatment of Crohn's disease with budesonide: this rose still has thorns! Am J Gastroenterol. 2002; 97:785-6.

635. Rutgeerts P, Löfberg R, Malchow H et al. A comparison of budesonide with prednisolone for active Crohn's disease. N Engl J Med. 1994; 331:842-5.

636. Aventis Pharmaceuticals. Azmacort^® (triamcinolone acetonide) inhalation aerosol prescribing information. Bridgewater, PA; 2003 Mar.

637. McFadden ER. Asthma. In: Braunwald E, Fauci AS, Kasper DL et al, eds. Harrison's principles of internal medicine. 15th ed. New York: McGraw-Hill Company; 2001:1456-63.

638. Fireman P, Prenner BM, Vincken W et al. Long-term safety and efficacy of a chlorofluorocarbon-free beclomethasone dipropionate extrafine aerosol. Ann Allergy Asthma Immunol . 2001; 86: 557-65. [PubMed 11379808]

639. Tashkin DP. Extra-fine corticosteroid aerosols from hydrofluoroalkane-134a metered-dose inhalers. Potential advantages and disadvantages. Chest . 1999; 115: 316-8. [PubMed 10027423]

640. Nelemans PJ, de Bie RA, de Vet HCW et al. Injection therapy for subacute and chronic benign low back pain (Cochrane Review). Cochrane Library. 2003. From website. Accessed 2003 Nov 10. [Web]

641. Nelemans PJ, deBie RA, deVet HC et al. Injection therapy for subacute and chronic benign low back pain. Spine . 2001; 26:501-15. [PubMed 11242378]

642. Rozenberg S, Dubourg G, Khalifa P et al. Efficacy of epidural steroids in low back pain and sciatica: a critical appraisal by a French Task Force of randomized trials. Critical Analysis Group of the French Society for Rheumatology. Rev Rheum Engl Ed . 1999; 66:79-85.

643. Watts RW, Silagy CA. A meta-analysis on the efficacy of epidural corticosteroids in the treatment of sciatica. Anaesth Intensive Care . 1995; 23:564-9. [PubMed 8787255]

644. Koes BW, Scholten RJ, Mens JM et al. Efficacy of epidural steroid injections for low-back pain and sciatica: a systematic review of randomized clinical trials. 1995; 63:279-88.

645. Tonkovich-Quaranta LA, Winkler SR. Use of epidural corticosteroids in low back pain. Ann Pharmacother . 2000; 34:1165-72. [PubMed 11054986]

646. Hopayian K, Mugford M. Conflicting conclusions from two systematic reviews of epidural steroid injections for sciatica: which evidence should general practitioners heed? Br J Gen Pract . 1999; 49:57-61. Erratum in Br J Gen Pract . 1999; 49:314.

647. Institute for Clinical Systems Improvement. Adult low back pain. Bloomington, MN: ICSI; 2002 Sep.

648. Agency for Health Care Policy and Research. Acute low back problems in adults. Clinical Practice Guideline No. 14; AHCPR Publication No. 95-0642. Rockville, MD: AHCPR; 1994 Dec.

649. Veterans Health Administration Office of Quality and Performance, Department of Veterans Affairs. Management of person with low back pain/sciatica in primary care. Washingon, DC: VA: 1999 Nov. From web site. Accessed 2003 Aug 25. [Web]

650. McCullen GM, Spurling GR, Webster JS. Epidural lipomatosis complicating lumbar steroid injections. J Spinal Disord . 1999; 12:526-9. [PubMed 10598996]

651. 3M Pharmaceuticals. QVAR^® prescribing information. Northridge, CA; 2002 May.

652. Hanauer SB, Sandborn W, and the Practice Parameters Committee of the American College of Gastroenterology. Management of Crohn's disease in adults: Practice Guidelines. Am J Gastroenterol . 2001; 96:635-43. [PubMed 11280528]

653. Scribano M, Pantera C. Review article: medical treatment of moderate to severe Crohn's disease. Aliment Pharmacol Ther . 2003; 17(Suppl. 2):23-30. [PubMed 12786609]

654. Summers RW, Switz DM, Sessions JT Jr et al. Results of drug treatment. Gastroenterology . 1979; 77:847-69. [PubMed 38176]

655. Malchow H, Ewe K, Brandes JW et al. European cooperative Crohn's disease study (ECCDS): results of drug treatment. Gastroenterology . 1984; 86:249-66. [PubMed 6140202]

656. Campieri M, Ferguson A, Doe W et al, for the Global Budesonide Study Group. Oral budesonide is as effective as oral prednisolone in active Crohn's disease. Gut . 1997;41:209-14 [PubMed 9301500][PubMedCentral]

657. Bar-Meir S, Chowers Y, Lavy A et al et al. Budesonide versus prednisone in the treatment of active Crohn's disease. Gastroenterology . 1998; 115:835-40. [PubMed 9753485]

658. Felder JB, Adler DJ, Korelitz BI. The safety of corticosteroid therapy in Crohn's disease with an abdominal mass. Am J Gastroenterol . 1991; 86:1450-5. [PubMed 1656728]

659. Greenberg GR, Feagan BG, Martin F et al et al. Oral budesonide as maintenance treatment for Crohn's disease: a placebo-controlled, dose-ranging study. Gastroenterology . 1996; 110:45-51. [PubMed 8536887]

660. Steinhart AH, Ewe K, Griffiths AM et al. Corticosteroids for maintenance of remission in Crohn's disease. Cochrane Database Syst Rev . 2003;(4):CD000301. [PubMed 14583917]

661. Plevy SE. Corticosteroid-sparing treatments in patients with Crohn's disease. Am J Gastroenterol . 2002; 97:1607-17 [PubMed 12135008]

662. Sandborn WJ, Feagan BG. Review article: mild to moderate Crohn's disease defining the basis for a new treatment algorithm. Aliment Pharmacol Ther . 2003; 18:263-77. [PubMed 12895211]

663. Biancone L, Tosti V, Fina D et al. Review article: maintenance treatment of Crohn's disease. Aliment Pharmacol Ther . 2003; 17(Suppl. 2):31-37. [PubMed 12786610]

664. Hanauer SB, Preemt DH. The state of the art in the management of inflammatory bowel disease. Rev Gastroenterol Disord. 2003; 3:81-92. Selby WS. Current issues in Crohn's disease. Med J Aust . 2003; 178:532-3. [PubMed 12765496]

665. Podolsky DK. Inflammatory Bowel Disease. N Engl J Med . 2002; 347:417-29. [PubMed 12167685]

666. Munkholm P, Langholz E, Davidsen M et al. Frequency of glucocorticoid resistance and dependency in Crohn's disease. Gut . 1994 Mar; 35(3):360-2.

667. Franchimont DP, Louis E, Croes F et al. Clinical pattern of corticosteroid dependent Crohn's disease. Eur J Gastroenterol Hepatol . 1998; 10:821-5 [PubMed 9831401]

668. Belaiche J, Louis E. Corticosteroid treatment in active Crohn's disease. Acta Gastroenterol Belg . 1998; 61:153-7. [PubMed 9658598]

669. Lichtenstein GR. Approach to corticosteroid-dependent and corticosteroid-refractory Crohn's disease. Inflamm Bowel Dis . 2001; 7(Suppl 1):S23-9.

670. Rutgeerts PJ. Review article: the limitations of corticosteroid therapy in Crohn's disease. Aliment Pharmacol Ther . 2001; 15:1515-25. [PubMed 11563990]

671. Reinisch W, Gasche C, Wyatt J et al. Steroid dependency in Crohn's disease. Lancet . 1995 Apr 1; 345(8953):859

672. Feagan BG. Maintenance therapy for inflammatory bowel disease. Am J Gastroenterol . 2003 Dec; 98(12 Suppl): S6-S17.

673. Sandborn WJ. Evidence-based treatment algorithm for mild to moderate Crohn's disease. Am J Gastroenterol . 2003; 98(12 Suppl):S1-5. [PubMedCentral]

674. Lofberg R. Review article: medical treatment of mild to moderately active Crohn's disease. Aliment Pharmacol Ther . 2003; 17 (Suppl 2):18-22 [PubMed 12786608]

675. Levine A, Weizman Z, Broide E et al for the Israeli Pediatric Gastroenterology Association Budesonide Study Group A comparison of budesonide and prednisone for the treatment of active pediatric Crohn disease. J Pediatr Gastroenterol Nutr . 2003; 36:248-52.

676. Kirschner BS. Differences in the management of inflammatory bowel disease in children and adolescents compared to adults. Neth J Med . 1998;53 :S13-8. [PubMed 9883009]

677. Grand RJ, Ramakrishna J, Calenda KA. Therapeutic strategies for pediatric Crohn disease. Clin Invest Med . 1996;19:373-80. [PubMed 8889277]

678. AstraZeneca. Entocort^® EC (budesonide capsules) prescribing information. Wilmington, DE; 2002 Oct.

679. Brain Trauma Foundation, Inc, American Association of Neurological Surgeons. Part 1: guidelines for the management of severe traumatic brain injury. New York, NY: Brain Trauma Foundation, Inc.; 2000. From website. Accessed 2004 Nov 30. [Web]

680. Adelson PD, Bratton SL, Carney NA et al. Guidelines for the acute medical management of severe traumatic brain injury in infants, children, and adolescents. Chapter 16. The use of corticosteroids in the treatment of severe pediatric traumatic brain injury. Pediatr Crit Care Med. . 2003; 4 (3 Suppl):S60-4.

681. Roberts I, Yates D, Sandercock P et al. Effect of intravenous corticosteroids on death within 14 days in 10008 adults with clinically significant head injury (MRC CRASH trial): randomised placebo-controlled trial. Lancet . 2004; 364:1321-28. [PubMed 15474134]

682. Sauerland S, Maegele M. A CRASH landing in severe head injury. Comment on Lancet . 2004 Oct 9;364:1321-8. Lancet . 2004; 364:1291-2. [PubMed 15474118]

683. Ghajar J, Hesdorffer DC. Steroids CRASH out of head-injury treatment. Lancet Neurol . 2004; 3:708. [PubMed 15556802]

684. Thwaites GE, Nguyen DB, Nguyen HD, et al. Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults. N Engl J Med . 2004; 351:1741-51.

685. Alderson P, Roberts I. Corticosteroids for acute traumatic brain injury (Cochrane Review). In: The Cochrane Library. Issue 4, 2004. Chichester, UK: John Wiley & Sons.

686. National Asthma Education and Prevention Program. Expert panel report: guidelines for the diagnosis and management of asthma-update on selected topics 2002. Bethesda, MD: National Heart, Lung, and Blood Institute, National Asthma Education and Prevention Program Coordinating Committee; 2003 Jun. Available from National Heart, Lung, and Blood Institute Information Center, NIH Publication No. 02-5074. Also available from website. Accessed 2004 Sep. 15. [Web]

687. National Institutes of Health, National Heart, Lung, and Blood Institute. Global initiative for asthma: global strategy for asthma management and prevention NHLBI/WHO Workshop Report. Bethesda, MD: National Institutes of Health. 2003 Nov 21. NIH/NHLBI Publication No. 02-3659. Available from website. Accessed Sep 22, 2004. [Web]

688. American Academy of Pediatrics Committee on Fetus and Newborn and Canadian Paediatric Society Fetus and Newborn Committee. Postnatal corticosteroids to treat or prevent chronic lung disease in preterm infants. Pediatrics . 2002; 109:330-8. [PubMed 11826218]

689. Yeh TF, Lin YJ, Lin HC et al. Outcomes at school age after postnatal dexamethasone therapy for lung disease of prematurity. N Engl J Med . 2004; 350:1304-13. [PubMed 15044641]

690. American Academy of Orthopaedic Surgeons (AAOS). AAOS clinical guideline on low back pain/sciatica (acute) (phases I and II). Rosemont, IL: American Academy of Orthopaedic Surgeons (AAOS); 2002. From web site. Accessed 2004 Nov 19. [Web]

691. Institute for Clinical Systems Improvement. Technology assessment report. Fluoroscopically guided transforaminal epidural steroid injections for lumbar radicular pain. Bloomington, MN: ICSI; 2004 Aug.

692. Manchikanti L, Staats PS, Singh V et al. Evidence-based practice guidelines for interventional techniques in the management of chronic spinal pain. Pain Physician . 2003; 6:3-81.

693. Deyo RA, Weinstein JN. Low back pain. N Engl J Med . 2001; 344:363-70. [PubMed 11172169]

694. Hicks GS, Duddleston DN, Russell LD et al. Low back pain. Am J Med Sci . 2002; 324:207-11. [PubMed 12385493]

695. Malanga GA, Nadler SF. Nonoperative treatment of low back pain. Mayo Clin Proc . 1999; 74:1135-48. [PubMed 10560603]

696. Gemmell HA, Fielding AS. Low back pain review. AJPM . 2003; 13:106-17.

697. Nelson DA, Landau WM. Intraspinal steroids: history, efficacy, accidentality, and controversy with review of United States Food and Drug Administration reports. J Neurol Neurosurg Psychiatry . 2001; 70:433-43. [PubMed 11254764][PubMedCentral]

698. Weinstein SM, Herring SA. Lumbar epidural steroid injections. Spine J . 2003; 3 (Suppl 3):37S-44S.

699. Abram SE. Treatment of lumbosacral radiculopathy with epidural steroids. Anesthesiology . 1999; 91:1937-41. [PubMed 10598637]

700. Benzon HT. Epidural steroid injections for low back pain and lumbosacral radiculopathy. Pain . 1986; 24:277-95. [PubMed 3008063]

701. Banaszkiewicz PA, Kader D, Wardlaw D. The role of caudal epidural injections in the management of low back pain. Bull Hosp Jt Dis . 2003; 61:127-31. [PubMed 15156811]

702. Papagelopoulos PJ, Petrou HG, Triantafyllidis PG et al. Treatment of lumbosacral radicular pain with epidural steroid injections. Orthopedics . 2001; 24:145-9. [PubMed 11284597]

703. Valat JP, Giraudeau B, Rozenberg S et al. Epidural corticosteroid injections for sciatica: a randomised, double blind, controlled clinical trial. Ann Rheum Dis . 2003; 62:639-643. [PubMed 12810426][PubMedCentral]

704. Latham JM, Fraser RD, Moore RJ et al. The pathological effects of intrathecal betamethasone. Spine . 1997; 22:1558-62. [PubMed 9253088]

705. Fitzgibbon DR, Posner KL, Domino KB et al. Chronic pain management: American Society of Anesthesiologists Closed Claims Project. Anesthesiology . 2004; 100:98-105. [PubMed 14695730]

706. Ward A, Watson P, Wood C. Glucocorticoid epidural for sciatica: metabolic and endocrine sequelae. Rheumatology . 2002; 41:68-71. [PubMed 11792882]

707. Nelson DA. Intraspinal therapy using methylprednisolone acetate. Spine . 1993; 18:278-86. [PubMed 8441945]

708. Wilkinson HA. Intrathecal Depo-Medrol: a literature review. Clin J Pain . 1992; 8:49-56. [PubMed 1533555]

709. Nelson DA. Dangers from methylprednisolone acetate therapy by intraspinal injection. Arch Neurol . 1988; 45:804-6. [PubMed 3291836]

710. Edwards WT. Comment on “intrathecal Depo-Medrol”. Clin J Pain . 1992; 8:57-8.

711. Samanta A, Samanta J. Is epidural injection of steroids effective for low back pain. BMJ . 2004; 328:1509-10. [PubMed 15217844][PubMedCentral]

712. Food and Drug Administration (FDA). Drug shortage: statement on Celestone Soluspan availability. Rockville, MD: Food and Drug Administration; 2004 Aug 26. From FDA website. Accessed 2004 Nov 17. [Web]

713. Haynes G, Bailey MK, Davis S et al. Use of methylprednisolone in epidural analgesia. Arch Neurol . 1989; 46:1167-8. Letter. [PubMed 2818247]

714. Hetherington NJ, Dooley MJ. Potential for patient harm from intrathecal administration of preserved solutions. MJA . 2000; 173:141-43. [PubMed 10979380]

715. Young WF. Transient blindness after lumbar epidural steroid injection. Spine . 2002; 27:E476-7. [PubMed 12439000][PubMedCentral]

716. Pfizer, New York, NY: Personal communication.

717. Browning DJ. Acute retinal necrosis following epidural steroid injections. Am J Ophthalmol . 2003; 136:192-4. [PubMed 12834695]

718. Slipman CW, Chow DW, Lenrow DA et al. Dysphonia associated with epidural steroid injection: a case report. Arch Phys Med Rehabil . 2002; 83:1309-10. [PubMed 12235614]

719. Stanczak J, Blankenbaker DG, De Smet AA et al. Efficacy of epidural injections of Kenalog and Celestone in the treatment of lower back pain. AJR . 2003; 181:1255-8. [PubMed 14573415]

720. Karppinen J, Malmivaara A, Kurunlahti M. Periradicular infiltration for sciatica: a randomized controlled trial. Spine . 2001; 26:1059-67. [PubMed 11337625]

721. Manchikanti L, Singh V. Comment on: periradicular infiltration for sciatica. Spine . 2002; 27:215-16. (Letter). 216-7 (Author reply). [PubMed 11805671]

722. Patel N. RE: Karppinen J et al. Periradicular infiltration for sciatica: a randomized controlled trial. Spine . 2002; 27:1588 (Letter) 1589 (Author reply).

723. Centers for Disease Control and Prevention. Exophiala infection from contaminated injectable steroids prepared by a compounding pharmacy - United States, July-November 2002. MMWR Morb Mortal Wkly Rep . 2002; 51:1109-12. [PubMed 12530707]

724. Khot A, Bowditch M, Powell J et al. The use of intradiscal steroid therapy for lumbar spinal discogenic pain: a randomized controlled trial. Spine . 2004; 29:833-7. [PubMed 15082979]

725. Vad VB, Bhat AL, Lutz GE et al. Transforaminal epidural steroid injections in lumbosacral radiculopathy: a prospective randomized study. Spine . 2002; 27:11-5. [PubMed 11805628]

726. Butterman GR. The effect of spinal steroid injections for degenerative disc disease. Spine J . 2004; 4:495-505. [PubMed 15363419]

727. Abram SE, O' Connor TC. Complications associated with epidural steroid injections. Reg Anesth . 1996; 21:149-62.

728. Bristol-Myers Squibb Company. Kenalog^®-40 (triamcinolone acetonide) injectable suspension prescribing information. Princeton, NJ; 2001 Apr.

729. Pharmacia. Depo-Medrol^® (methlyprednisolone acetate) injectable suspension prescribing information. Kalamazoo, MI; 2003 Mar.

730. SAB-Pharma Inc. Aristospan^® (triamcinolone hexacetonide) injectable suspension prescribing information. Lake Forest, IL; 2003 Dec.

731. Schering Corporation. Celestone^® Soluspan^® (betamethasone sodium phosphate and betamethasone acetate) injectable suspension prescribing information. Kenilworth, NJ; 2005 Oct.

732. Fox ER, Mullin S. Drug shortages resource center: Injectable corticosteroid suspensions; 2004 Sep 17. From American Society of Health-System Pharmacists website. [Web]

733. Tiso RL, Cutler T, Catania JA et al. Adverse central nervous system sequelae after selective transforaminal block: the role of corticosteroids. Spine J . 2004; 4:468-74. [PubMed 15246308]

734. Hansen HC, Helm S. Sacroiliac joint pain and dysfunction. Pain Physician . 2003; 6:179-89. [PubMed 16883378]

735. SAB-Pharma, Lake Forest, IL: Personal communication.

740. Schering. Asmanex^® Twisthaler^® (mometasone furoate) inhalation powder prescribing information. Kenilworth, NJ; 2005 Jul.

741. National Institutes of Health, National Heart, Lung, and Blood Institute. Global Initiative for asthma: global strategy for asthma management and prevention NHLBI/WHO Workshop Report. Bethesda, MD: National Institutes of Health. 2005 Oct. Available from website. Accessed Nov., 23, 2005. [Web]

742. Biomarin. Orapred^® (prednisolone sodium phosphate) oral solution prescribing information. Novato, CA; 2005 Jan.

743. Ethex. Prednisolone sodium phosphate oral solution prescribing information. St. Louis, MO; 2004 Nov.

744. Ethex. Prednisolone syrup (5 mg/5 mL) prescribing information. St. Louis, MO; 2001 Sep.

745. Ethex. Prednisolone syrup (15 mg/5 mL) prescribing information. St. Louis, MO; 2001 Aug.

746. Stuck AE, Frey BM, Frey FJ. Kinetics of prednisolone and endogenous cortisol suppression in the elderly. Clin Pharmcol Ther . 1988; 43:354-62.

747. Roxane Laboratories. Dexamethasone tablets, dexamethasone oral solution, dexamethasone intensol^® oral solution concentrate prescribing information. Columbus, OH; 2005 Oct.

748. Astellas Pharma US. Aristocort^® (triamcinolone) tablets prescribing information. Deerfield, IL; 1999 Feb.

749. Roxane Laboratories. Prednisone tablets, oral solution, prednisone Intensol^® concentrated solution prescribing information. Columbus, OH; 2002 Feb.

750. Kroger AT, Duchin J, Vazquez M. General best practice guidelines for immunization: best practices guidance of the advisory committee on immunization practices (ACIP). From website. Accessed on October 6, 2017. [Web]

751. Antman EM, Anbe DT, Armstrong PW et al. ACC/AHA guidelines for the management of patients with ST-elevation acute myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines for the Management of Patients with Acute Myocardial Infarction). 2004. From website. [Web]

752. Sicor Pharmaceuticals. Dexamethasone sodium phosphate injection prescribing information. Irvine, CA; 2005 June.

753. Watson. Prednisolone tablets prescribing information. Morristown, NJ; 1998 Mar.

754. Teva Pharmaceuticals. Prednisolone oral solution prescribing information. Sellersville, PA; 2005 May.

755. American College of Obstetricians and Gynecologists (ACOG) Committee on Practice Bulletins. Management of preterm labor. Practice Bulletin No. 43. Washington, DC: American College of Obstetricians and Gynecologists; 2003 May.

756. Rasmussen BB, Larsen LS, Senderovitz. Pharmacokinetic interaction studies of atosiban with labetalol or betamethasone in healthy female volunteers. BJOG . 2005; 112:1492-9. [PubMed 16225568]

757. Ballabh P, Kumari J, Cooper TB. Pharmacokinetics of betamethasone in twin and singleton pregnancy. Clin Pharmacol Ther . 2002; 71:39-45. [PubMed 11823756]

758. Abel SM, Back DJ. Cortisol metabolism in vitro -III. Inhibition of microsomal 6β-hydroxylase and cytsolic 4-ene-reductase. J Steroid Biochem Molecu Biol . 1993; 46:827-32.

759. Genovese MC. Joint and soft-tissue injection: a useful adjuvant to systemic and local treatment. Postgrad Med . 1998; 103:125-34. [PubMed 9479311]

760. Nelson KH, Briner W, Cummins J et al. Corticosteroid injection therapy for overuse injuries. Am Fam Physician . 1995; 52:1811-6. [PubMed 7484691]

761. Hegenbarth MA, . Preparing for pediatric emergencies: drugs to consider. Pediatrics . 2008; 121:433-43. [PubMed 18245435]

763. Alliant Pharmaceuticals. Orapred ODT^® (prednisolone sodium phosphate) orally disintegrating tablets prescribing information. Alpharetta, GA; 2006 May.

764. USP DI: drug information for the health care provider. 26th ed. Greenwood Village, CO: Thomson Micromedex; 2006;1:1005-12.

766. Leone FT, Fish JE, Szefler SJ et al. Systematic review of the evidence regarding potential complications of inhaled corticosteroid use in asthma: Collaboration of American College of Chest Physicians, American Academy of Allergy, Asthma, and Immunology, and American College of Allergy, Asthma, and Immunology. Chest . 2003; 124:2329-40. [PubMed 14665517]

767. Bello CE, Garrett SD. Therapeutic issues in oral glucocorticoid use. Lippincotts Prim Care Pract . 1999; 3:333-41. [PubMed 10711134]

768. Walsh LJ, Wong CA, Oborne J et al. Adverse effects of oral corticosteroids in relation to dose in patients with lung disease. Thorax . 2001; 56:279-84. [PubMed 11254818][PubMedCentral]

769. Hesketh PJ, Kris MG, Basch E, et al. Antiemetics: ASCO Guideline Update. J Clin Oncol. 2020 Aug 20;38(24):2782-2797. doi: 10.1200/JCO.20.01296. Epub 2020 Jul 13. Erratum in: J Clin Oncol. 2020 Nov 10;38(32):3825. Erratum in: J Clin Oncol. 2021 Jan 1;39(1):96. PMID: 32658626.

770. Davidson TG. Conventional treatment of hypercalcemia of malignancy. Am J Health Syst Pharm . 2001; 58(suppl 3):S8-15. [PubMed 11757206]

771. Hypercalcemia. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute. 2005 Sep 21.

772. Chung KF, Wenzel SE, Brozek JL et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J. 2014; 43:343-73. [PubMed 24337046]

773. Pfizer. Depo-Medrol^® (methylprednisolone acetate) injectable suspension (multiple-dose vials) prescribing information. New York, NY; 2009 May.

774. Global Initiative for Asthma (GINA). GINA Report, Global Strategy for Asthma Management and Prevention. GINA. Updated 2022. Accessed Jan 23, 2023. [Web]

775. Gloss D, Moxley RT, Ashwal S et al. Practice guideline update summary: Corticosteroid treatment of Duchenne muscular dystrophy: Report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology . 2016; 86:465-72. [PubMed 26833937]

776. Matthews E, Brassington R, Kuntzer T et al. Corticosteroids for the treatment of Duchenne muscular dystrophy. Cochrane Database Syst Rev . 2016; :CD003725. [PubMed 27149418]

777. Grossman JM, Gordon R, Ranganath VK et al. American College of Rheumatology 2010 recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis. Arthritis Care Res (Hoboken) . 2010; 62:1515-26. [PubMed 20662044]

778. Munshi NC, Anderson KC. Chapter 112: Plasma cell neoplasms. In: DeVita VT Jr, Lawrence TS, Rosenberg SA, eds. Cancer: principles and practice of oncology. 10th ed. From Lippincott Discovery online access.

779. Imazio M, Brucato A, Cumetti D, et al. Corticosteroids for recurrent pericarditis: high versus low doses: a nonrandomized observation. Circulation. 2008 Aug 5;118(6):667-71. Epub 2008 Jul 21. [PubMed 18645054]

1000. Food and Drug Administration. Epidural corticosteroid injection: drug safety communication - risk of rare but serious neurologic problems. 2014 Apr 23. From FDA website. Accessed 2014 May 19. [Web]

1001. Food and Drug Administration. FDA drug safety communication: FDA requires label changes to warn of rare but serious neurologic problems after epidural corticosteroid injections for pain. 2014 Apr 23. From FDA website. Accessed 2014 May 19. [Web]

1002. Rathmell JP. Toward improving the safety of transforaminal injection. Anesth Analg . 2009; 109:8-10. [PubMed 19535690]

1003. Cohen SP, Bicket MC, Jamison D et al. Epidural steroids: a comprehensive, evidence-based review. Reg Anesth Pain Med . 2013 May-Jun; 38:175-200.

1004. RECOVERY Collaborative Group., Horby P, Lim WS et al. Dexamethasone in Hospitalized Patients with Covid-19. N Engl J Med . 2021; 384:693-704. [PubMed 32678530][PubMedCentral]

1005. National Institutes of Health. COVID-19 treatment guidelines. Updated 2021 Aug 4. From NIH website. Accessed 2021 Aug 12. Updates may be available at NIH website. [Web]

1006. World Health Organization. Therapeutics and COVID-19: living guideline. 2021 Jul 6. From WHO website. Accessed 2021 Jul 7. [Web]

1007. Tomazini BM, Maia IS, Cavalcanti AB et al. Effect of Dexamethasone on Days Alive and Ventilator-Free in Patients With Moderate or Severe Acute Respiratory Distress Syndrome and COVID-19: The CoDEX Randomized Clinical Trial. JAMA . 2020; 324:1307-16. [PubMed 32876695][PubMedCentral]

1008. Dequin PF, Heming N, Meziani F et al. Effect of Hydrocortisone on 21-Day Mortality or Respiratory Support Among Critically Ill Patients With COVID-19: A Randomized Clinical Trial. JAMA . 2020; 324:1298-1306. [PubMed 32876689][PubMedCentral]

1009. Writing Committee for the REMAP-CAP Investigators, Angus DC, Derde L et al. Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial. JAMA . 2020; 324:1317-29. [PubMed 32876697][PubMedCentral]

1010. Jeronimo CMP, Farias MEL, Val FFA et al. Methylprednisolone as Adjunctive Therapy for Patients Hospitalized With Coronavirus Disease 2019 (COVID-19; Metcovid): A Randomized, Double-Blind, Phase IIb, Placebo-Controlled Trial. Clin Infect Dis . 2021; 72:e373-e381. [PubMed 32785710][PubMedCentral]

1011. Salton F, Confalonieri P, Meduri GU et al. Prolonged Low-Dose Methylprednisolone in Patients With Severe COVID-19 Pneumonia. Open Forum Infect Dis . 2020; 7:ofaa421. [PubMed 33072814][PubMedCentral]

1012. Li Q, Li W, Jin Y et al. Efficacy Evaluation of Early, Low-Dose, Short-Term Corticosteroids in Adults Hospitalized with Non-Severe COVID-19 Pneumonia: A Retrospective Cohort Study. Infect Dis Ther . 2020; 9:823-36. [PubMed 32880102][PubMedCentral]

1013. WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group., Sterne JAC, Murthy S et al. Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis. JAMA . 2020; 324:1330-41. [PubMed 32876694][PubMedCentral]

1014. Fadel R, Morrison AR, Vahia A et al. Early short-course corticosteroids in hospitalized patients with COVID-19. Clin Infect Dis. 2020; 71:2114-20. PMID: 32427279. DOI: 10.1093/cid/ciaa601.

1015. Stauffer WM, Alpern JD, Walker PF. COVID-19 and Dexamethasone: A Potential Strategy to Avoid Steroid-Related Strongyloides Hyperinfection. JAMA . 2020; 324:623-4. [PubMed 32761166]

1016. Liu J, Wang T, Cai Q et al. Longitudinal changes of liver function and hepatitis B reactivation in COVID-19 patients with pre-existing chronic hepatitis B virus infection. Hepatol Res . 2020; 50:1211-21. [PubMed 32761993][PubMedCentral]

1017. Panel on Opportunistic Infections in Adults and Adolescents with HIV. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. Accessed 2021 Aug 9. Updates may be available at the NIH hivinfo website. [Web]