Corticosteroids were first used in clinical practice in 1949 for the treatment of rheumatoid arthritis. Indications since then have spanned multiple specialties and organ systems, including dermatology, rheumatology, immunology and oncology. This review covers practical uses of steroids as well as current and frequently overlooked clinical applications that may be helpful to family physicians.
Actions and Side Effects
If physicians understand the composition and physiologic effects of corticosteroid agents, appropriate drug selection can be made and inappropriate or problematic uses can be avoided. Corticosteroid agents mimic the endogenous steroid hormones produced in the adrenal cortex—mineralocorticoid (aldosterone) and glucocorticoid (cortisol). Mineralocorticoids are primarily regulated by the renin-angiotensin system and possess salt-retaining properties. Glucocorticoids are primarily regulated by corticotropin (ACTH) and can have anti-inflammatory effects, as well as several metabolic and immunogenic effects, on the body.1
While several corticosteroid agents possess properties of both hormones, fludrocortisone is most commonly used for its mineralocorticoid activity and hydrocortisone, cortisone, prednisone and prednisolone are used for their glucocorticoid effects. Table 1 summarizes the relative potencies of the hormonal effects in addition to providing equivalent doses.1
|Corticosteroid||Activity||Relative potency||Equivalent dose (mg)|
Therapeutic effects of steroids can often parallel undesirable side effects, especially when high doses and long-term therapy are required. By anticipating the potential side effects and implementing preventive measures where possible (Table 2),1–4 patients can obtain maximum benefits with minimum adverse effects.
|Fluid/electolyte disturbances||Sodium retention||Use with caution in CHF or hypertensive patients.|
|Edema||Decreased salt intake|
|Increased potassium excretion||Potassium supplements may be necessary.|
|Increased calcium excretion||Use with caution in patients at increased risk of developing osteoporosis; calcium supplements may be necessary, especially in postmenopausal women.|
|Gastrointestinal||Gastric irritation||Take with meals to prevent gastric upset.|
|Nausea/vomiting, weight loss/weight gain, abdominal distention, peptic ulcer, ulcerative esophagitis, pancreatitis||The risk of these effects increases with increased dosages and prolonged use; use of antiulcer agents is suggested only in patients requiring long-term steroid therapy at high dosages; use with caution or avoid in patients with GI diseases in which perforation or hemorrhage are potential risks.|
|Endocrine||Hypercortisolism (Cushingoid state), secondary adrenal insufficiency||Associated with long-term use even at lower dosages|
|Menstrual difficulties, including amenorrhea and postmenopausal bleeding|
|Precipitation of diabetes mellitus|
|Glucose intolerance, hyperglycemia||In patients with diabetes, increased dosages of insulin or oral hypoglycemic agent and changes in diet should be expected.|
|Cardiovascular||Hypertension||Use with extreme caution in patients with recent myocardial infarction because of an apparent association with left ventricular free-wall rupture.|
|Thromboembolism||Use with caution in patients with thromboembolic disorders because of reports of (rare) increased blood coagulability.|
|Ocular||Posterior subcapsular cataracts||Prolonged use may result in increased intraocular pressure or damaged ocular nerve.|
Use in patients with ocular herpes simplex may cause corneal perforation.
|May enhance secondary fungal or viral infections of the eye|
|Musculoskeletal||Muscle pain or weakness, muscle wasting, pathologic long bone or vertebral compression fractures, atrophy of protein matrix of bone, aseptic necrosis of femoral or humeral heads||Use with caution in patients prone to development of osteoporosis; risk versus benefit should be reassessed if osteoporosis develops; elderly, debilitated or poorly nourished patients may be more prone to these effects. Supplementation with calcium, 1,500 mg per day, and vitamin D, 800 IU per day, is recommended.4 Alendronate (Fosamax) therapy should also be considered.|
|Neuropsychiatric||Headache, vertigo, seizures, increased motor activity, insomnia, mood changes, psychosis||Use with caution in patients with convulsive or psychiatric disorders. Use may aggravate preexisting psychiatric conditions. Steroid-induced psychosis is dose-related, occurs within 15 to 30 days of therapy and is treatable if steroid therapy must be continued. Pseudotumor cerebri reported during withdrawal.|
|Dermatologic||Acne, impaired wound healing, hirsutism, skin atrophy/increased fragility, ecchymoses||Ecchymoses due to easy bruisability should be restricted to exposed, potentially traumatized extremities, when associated with steroid use.|
|Other||Increased susceptibility to infections, masked symptoms of infections||Contraindicated in patients with systemic fungal infections (except to control drug reactions associated with amphotericin B [Fungizone] therapy). Do not use live virus vaccinations during therapy. Reactions to skin tests may be suppressed.|
The dosage range for steroids is wide, and patient response is variable. A low or maintenance dosage is approximately 0.1 to 0.25 mg per kg per day of prednisone, a moderate dosage is approximately 0.5 mg per kg per day of prednisone, a high dosage is 1 to 3 mg per kg per day of prednisone, and a massive dosage is approximately 15 to 30 mg per kg per day of prednisone.2
Short-term, low-dose steroid therapy rarely results in any of the adverse effects listed in Table 2.1–4 However, as the dosage or duration of therapy increases, so does the risk of undesirable effects. In long-term therapy, alternate-day administration should be considered. Some disease states, however, such as temporal arteritis and systemic lupus erythematosus, may not be adequately controlled with alternate-day therapy. Doubling the dosage and administering the drug every other day in the morning more closely mimics the endogenous corticosteroid circadian rhythm. This form of administration enables the patient to experience the therapeutic effects while side effects are minimized.3 This therapeutic alternative is only possible with the intermediate-acting corticosteroid agents (Table 1).1 Whenever possible, the goal of steroid therapy should be to maintain the lowest dosage that results in adequate clinical response and to discontinue therapy by tapering the drug when a patient's disease state allows (Table 3).1–3,5
|Purpose of gradual withdrawal||To allow recovery of normal pituitary-adrenal responsiveness to secretion of endogenous corticosteroid without exacerbating the underlying disease state. In most patients, endogenous corticosteroid secretions are equivalent to 5 to 7.5 mg of prednisone.|
|Recommended tapering schedules||Tapering the dosage over 2 months or more may be necessary for patients on prolonged treatment (more than 1 year).|
|Depending on dosage, duration of therapy and risk of systemic disease, decrease dosage by the equivalent of 2.5 to 5 mg prednisone every 3 to 7 days until a dosage of 5 mg of prednisone is reached. Then perform a challenge to determine the extent of HPA axis recovery.|
|Depending on the results and patient's symptoms, therapy may be discontinued or a slower taper considered.5|
|Symptoms of adrenal insufficiency due to rapid withdrawal||Headache, dizziness, fainting, fatigue, lethargy, myalgia, joint pain, dyspnea, orthostatic hypotension, nausea, vomiting, anorexia, weight loss, fever, hypoglycemia, desquamation of skin.|
|If symptoms do not subside when steroid dosage is adjusted, other causes must be considered.|
In certain severe illnesses or during acute flare ups, daily dosing may be re-initiated.
Viral croup is a common childhood disease. In fact, it is the most common form of upper airway obstruction in children six months to six years of age.6 Management has always been supportive, using humidification, oxygen and racemic epinephrine.7 The anti-inflammatory effects of corticosteroids were theorized to be useful in the treatment of croup. Corticosteroids have been studied in the management of croup for the past 30 years, but their use in this condition is controversial.8 Most of the recognized use has previously been in hospitalized patients with acute laryngotracheo-bronchitis. The use of steroids in children with croup is associated with significant clinical improvement at about 12 hours post-treatment and results in less endotracheal intubation.9
Most current research focuses on outpatient use of corticosteroids in the treatment of moderate and severe croup. Some authors have found that routine use of steroids reduces the need for hospitalization.10 The use of nebulized budenoside, an inhaled corticosteroid, has been shown in multiple randomized double-blind trials to result in clinical improvement in children with mild to moderate croup who present to the emergency room or are admitted to the hospital.11,12
Although budenoside is well tolerated with minimal side effects because of limited systemic availability, it is not yet available for use in the United States except in a nasal form. A single intramuscular injection of 0.6 mg per kg of dexamethasone has also proved to be helpful in the treatment of viral croup of moderate severity. Therefore, intramuscular corticosteroid treatment should be considered in patients with moderate croup before discharge from the emergency department when outpatient therapy is entertained.13
Pneumocystis carinii Pneumonia
Pneumocystis carinii pneumonia (PCP) is a leading cause of morbidity and mortality in patients infected with human immunodeficiency virus (HIV). This clinically significant complication of HIV infection occurs in 60 to 80 percent of patients with acquired immunodeficiency syndrome not receiving prophylaxis14 and causes death in approximately 25 percent of its victims.15 Once antibiotic therapy for PCP is initiated, a further deterioration in lung function often occurs, resulting from an increase in inflammation possibly resulting from the lysis of P. carinii organisms. Since the late 1980s, adjunctive treatment with corticosteroids has been documented in case reports and research studies with favorable clinical results, and it is currently endorsed by the National Institutes of Health as a standard therapy.16
Documented benefits of corticosteroid therapy in patients with PCP include reduced morbidity and mortality, decreased need for mechanical ventilation assistance and a reduced long-term decline in pulmonary function or exercise tolerance.16 In addition, studies suggest that steroids may decrease the severity of toxic side effects, such as fever and rash associated with the use of trimethoprim-sulfamethoxazole (Bactrim, Septra), the primary anti-pneumocystis treatment.15,17 This benefit may enable the patient to complete the required course of antibiotic therapy.
Progression of other opportunistic infections associated with HIV infection as a result of the immunosuppressive effects of corticosteroids is a risk that must be considered. While some studies report only minor complications associated with steroid therapy, such as reactivation of localized herpetic lesions,18 others have reported an increased incidence of infection and cancer.15 Whether the development of these severe complications is due to effects of the steroids or to the increased longevity and survival rate of these severely immunocompromised patients is unknown.15
Based on the benefits and risks of adjunctive corticosteroid therapy, the current recommendations are not intended for all patients but only for those with confirmed or suspected HIV and PCP infection who are at high risk of respiratory failure and death. Patients at risk include those with an arterial oxygen pressure of less than 70 mm Hg or an arterial-alveolar gradient of more than 35 mm Hg.14,16,19
The recommended dosing regimen is oral prednisone, 40 mg twice daily for five days, then 40 mg once daily for five days, then 20 mg daily for the duration of the anti-pneumocystis therapy. Methylprednisolone, given at 75 percent of the oral prednisone dosage, can be substituted if parenteral therapy is necessary.14,16,19 This therapy should be initiated along with anti-pneumocystis treatment. A confirmatory diagnosis of PCP and HIV infection should be obtained, and other diseases, such as tuberculosis and cryptococcosis, should be ruled out before steroid therapy is begun.14 Corticosteroids may mask the symptoms of these diseases once the immunosuppressive effect of therapy occurs.
Further investigation is required to determine the appropriate use and benefits of steroid therapy when the patient has concomitant life-threatening infections and when the patient has already received more than three days of anti-pneumocystis therapy and has developed significant hypoxia.
Hyperthyroidism is a common disease affecting around 2 percent of women and 0.2 percent of men.20 Graves' disease is the most common cause of thyrotoxicosis, but other causes are toxic nodular goiter and toxic adenoma.21 Graves' disease is commonly treated with antithyroid drugs, radioactive iodine or thyroid surgery.22 Glucocorticoids may decrease the release of hormones and possibly protect against the adrenal insufficiency that may be associated with the hyperthyroid state. The amount of benefit and the effect on patient outcome in this circumstance is not yet known.23
Graves' eye disease is treated by first normalizing the thyroid function and then administering diuretics and systemic glucocorticoids.22 Some sources suggest that the treatment of Graves' disease with glucocorticoids may decrease the development of ophthalmopathy,24 while others do not recommend the use of corticosteroids in patients with mild to moderate ophthalmopathy before radioiodine treatment.21
Other causes of hyperthyroidism that may be treated with corticosteroids are subacute thyroiditis and thyroid storm. Hyperthyroid disease related to thyroiditis is usually mild and self-limited. Beta blockers may be used to treat symptoms. In subacute thyroiditis, non-steroidal anti-inflammatory drugs or corticosteroids can be used to relieve thyroid pain and tenderness.25
Thyroid storm is a life-threatening condition of the hyperthyroid state.26 It most commonly occurs in patients with Graves' disease but may also occur in those with multinodular goiter or toxic adenoma.27 It is treated by correcting the hyperthyroidism and treating the precipitating events.26 Correction of the hyperthyroid state involves using drugs such as propylthiouracil or methimazole (Tapazole), beta blockers or corticosteroids, which decrease the peripheral effects of thyroid hormone and the conversion of thyroxine (T4) to the more potent triiodothyronine (T3).22,26 Dexamethasone can be used for that purpose, at a dosage of 2 mg intravenously every six hours, and can eventually can be switched to an oral dosage of 2 mg every six hours.28
Corticosteroids are used as adjuvant analgesics for pain in cancer patients and patients with neuropathic pain such as herpes zoster–related neuropathy, spinal cord compression and pain following oral surgery.
Prednisone, at a dosage of 7.5 to 10 mg per day, may be useful in decreasing pain in some patients with advanced prostate cancer.29 Higher dosages of prednisone have improved quality of life, decreased analgesic consumption and improved appetite in patients with preterminal cancer.30 Dexamethasone was shown to be more effective than prednisone in patients with terminal cancer. Patients with nerve compression pain or pain resulting from increased intracranial pressure showed a better response when compared with patients with other pain syndromes.31 Higher intravenous dosages of methylprednisolone, such as 125 mg per day, can be used for palliative therapy in patients with terminal cancer.32
Perioperative use of corticosteroids has been advocated to reduce pain and decrease edema and trismus following oral surgical procedures. The most significant improvement occurs in the treatment of postoperative edema. Dosages of prednisone between 40 and 80 mg per day can be used. Maximal benefit has been achieved after third-molar extraction, although some benefit has been reported after other surgeries.33,34
Some evidence indicates that combining corticosteroids with acyclovir (Zovirax) will decrease the duration of zoster-associated pain. Systemic treatment with corticosteroids such as prednisone, at 40 mg per day for three weeks, decreases the proportion of patients affected by postherpetic neuralgia, especially pain occurring six to 12 weeks after onset.35 A more recent study shows that acyclovir plus prednisolone was associated with more rapid resumption of activity, better sleep patterns and less use of analgesics compared with use of each agent alone.36 Other studies, however, have found that both acyclovir and corticosteroids play a limited role in the prevention of postherpetic neuralgia.37
Alcoholic hepatitis is a chronic, progressive and often fatal disease. Treatment has generally been supportive.38 Corticosteroid use has been widely studied for the treatment of alcoholic hepatitis for the past three decades.39,40 More recent studies have shown that methylprednisolone therapy decreases short-term mortality in patients with severe alcoholic hepatitis and hepatic encephalopathy.41 Treatment with prednisone improves the short-term survival of patients with severe biopsyproven alcoholic hepatitis.42
Meta-analysis of studies from 1966 to 1989 supports the finding that patients with acute severe alcoholic hepatitis and hepatic encephalopathy, without gastrointestinal bleeding, benefit from a trial of corticosteroid therapy.43 However, a more recent meta-analysis found that the overall effect on decreasing mortality in the corticosteroid-treated group is not statistically significant, even in the patient group presenting with encephalopahy. Further clinical trials were recommended to clarify the role of steroids in the treatment of alcoholic hepatitis.44
Bacterial meningitis is a serious disease that may result in death or permanent neurologic complications such as seizures, paralysis or sensorineural hearing loss.45 Data from animal studies indicate that bacterial wall elements affect white blood cells and endothelial cells in the brain. These produce inflammatory components such as cytokines, which lead to meningeal inflammation and increased intracranial pressure.46,47 Hence, reducing meningeal inflammation is thought to reduce central nervous system complications.48,49
Studies show that potent corticosteroids, such as dexamethasone, combined with appropriate antibiotics reduce the risk of acquired sensorineural deafness and the incidence of other neurologic sequelae in meningitis caused by Haemophilus influenzae.50 Corticosteroids were found to be more effective when administered simultaneously with antibiotics or 15 to 20 minutes before starting them. The drug was administered in a dosage of 0.6 to 0.8 mg per kg per day in four divided doses for two to four days.48,51 Although some authorities suggest the use of corticosteroids in the treatment of pneumococcal meningitis,52 this use is not supported by many studies.50,53 Moreover, evidence is insufficient to recommend corticosteroid treatment in patients with meningococcal meningitis.50,54
Corticosteroids may also be used in the treatment of tuberculous meningitis. In one randomized, controlled study55 involving 47 patients in India, dexamethasone was found to be useful as an adjunct treatment in cases of tuberculous meningitis, especially in patients with severe disease. A more recent randomized trial56 using prednisone in children with tuberculous meningitis showed that prednisone in a dosage of 2 to 4 mg per kg per day for one month improved survival rate and intellectual outcome.