An algorithm for corticosteroid withdrawal

An algorithm for corticosteroid withdrawal – Clinical Pharmacology, part 193

David S. Kountz

An Algorithm for Corticosteroid Withdrawal The indications for therapy with pharmacologic doses of corticosteroids are extensive. The dangers of steroid therapy are also well known.(1-3) The plasma half-life, biologic half-life and relative potency of the most commonly used corticosteroids are given.

During a course of corticosteroid therapy, the reduction from pharmacologic dose to physiologic dose is largely dependent on the activity of the underlying disease. In many instances, too rapid a reduction leads to a flare of the disease symptoms. Ultimately, however, corticosteroids must be tapered to prevent unacceptable toxicity. The higher the dose and the longer the duration of therapy, the more difficult the process of tapering becomes.

Studies have shown that it takes only five days of therapy with prednisone (50 mg per day) or another equivalent corticosteroid to significantly depress the adrenal response to adrenocorticotropic hormone (ACTH). After a month or more of steroid therapy, the hypothalamic-pituitary-adrenal axis may be severely depressed for as long as a year. Depression of this axis leaves the patient extremely vulnerable to stress from infection, minor surgery or emotional upset. Steroid supplementation is mandatory if a patient exhibits signs of stress or must undergo a surgical procedure following steroid withdrawal.(4,5)

In order to limit the toxic effects of corticosteroids, the physician must reduce the corticosteroid dose gradually, with the rate of withdrawal determined by the requirements of the individual patient. Steroid withdrawal should be done on an ambulatory basis over a long period of time, and it requires the cooperation of both the patient and the family.

Regimens That Lessen Toxicity

When possible, pharmacologic doses of corticosteroids should be administered in a manner that is least likely to produce unwanted side effects or suppress the hypothalamic-pituitary-adrenal axis.

PULSE THERAPY Although few well-controlled studies of steroid pulse therapy have been performed, many investigators feel that this therapy is effective in arresting life-threatening disease processes, with minimal toxicity. The best-known indication for steroid pulse therapy is acute organ rejection. Because of the short duration of megadose therapy with “pulse” regimens (usually less than ten days), the withdrawal symptoms discussed in this article do not usually occur.(6)

TOPICAL THERAPY

The use of topical and local corticosteroid therapy eliminates many of the adverse effects of steroids and tends to minimize suppression of the hypothalamic-pituitary-adrenal axis. Examples are topical use in skin and eye disorders, inhalation therapy in asthma and intra-articular injection in arthritis.(2,7)

Even with topical and local therapy, corticosteroids may suppress the hypothalamic-pituitary-adrenal axis if the dose is high enough.(8) Furthermore, it is sometimes necessary to combine oral administration with local administration to achieve a therapeutic goal.(9)

ALTERNATE-DAY THERAPY

Alternate-day corticosteroid therapy attempts to mimic the normal diurnal cortisol cycle. It is less likely to produce the catabolic actions of steroids when prolonged high-dose therapy is required.

An intermediate-acting corticosteroid, such as prednisone or prednisolone, should be used in alternate-day therapy. The total daily dose is given in the morning between 8 and 9 a.m. After the first week (or sooner if possible), the dose is taken every other day. When possible (usually after another three weeks), the corticosteroid is discontinued.(10)

It is not yet clear that alternate-day therapy is as effective as daily therapy in all the diseases for which steroids are used. When applicable, however, alternate-day therapy may have significant advantages.

Algorithm for Corticosteroid Withdrawal

The first requirement for an ambulatory program of corticosteroid withdrawal is that it should be convenient and safe for the patient. Second, it should provide, as much as possible, for the adjustment of steroid dosage and rate of withdrawal to prevent relapse of the disease and to allow the hypothalamic-pituitary-adrenal axis to recover its physiologic function. After limited courses of steroids, an elaborate withdrawal scheme is usually not needed. When steroid therapy has been prolonged, the withdrawal regimen is important and a reliable laboratory test is needed to establish the degree of hypothalmic-pituitary-adrenal axis recovery.(11)

Before starting the steroid withdrawal program, the patient and the family must be given careful instructions for handling emergencies. The patient should wear a medical identification bracelet specifying steroid dependency. The need for additional steroid therapy during periods of stress and illness should be noted on the bracelet. The patient should be given a prepackaged syringe containing 4 mg of dexamethasone, with instructions on how to administer the medication intramuscularly if pills cannot be taken because of vomiting or diarrhea. The patient’s family should be instructed to administer the dexamethasone intramuscularly if the patient is found unconscious.(12)

STAGE I

The steroid withdrawal program should be started by reducing the dose gradually each week, as disease activity allows, until a dosage equivalent to 20 mg of hydrocortisone per day is reached. As the corticosteroid is tapered, the patient may experience some mild withdrawal symptoms, including fatigue, anorexia, nausea and orthostatic dizziness. It is during this tapering period that the patient is most vulnerable to acute stress. If a minor illness occurs or a minor surgical procedure is to be performed, the steroid dosage should be increased to the equivalent of 100 mg of hydrocortisone per day in divided doses. If the patient is under more intense stress, the dosage needs to be increased to the equivalent of 400 to 500 mg of hydrocortisone per day in order to mimic the normal adrenal response. After the stress has resolved, the steroid is again tapered and then stabilized at a dosage equivalent to 20 mg of hydrocortisone per day. The patient should remain on this physiologic replacement dosage for four weeks after the resolution of acute stress. The patient is then instructed to hold off taking the morning dose of steroid and to have an 8 a.m. fasting plasma cortisol measurement.

The withdrawal program can be carried out even more successfully using alternate-day therapy. Therefore, if the patient is not on alternate-day therapy before steroid withdrawal, it would be wise to switch to this regimen before the withdrawal program is started.

The tissue effects of the intermediate-acting corticosteroids (prednisone, prednisolone, methylprednisolone, triamcinolone) cease after 36 hours, giving the hypothalamic-pituitary-adrenal axis 12 hours to recover before repeat exposure to exogenous steroid. This makes the shorter-acting agents particularly advantageous in steroid withdrawal. In the pediatric and adolescent populations, where growth suppression is a feared complication of daily steroid use, alternate-day regimens lessen the inhibition of sulfate incorporation into cartilage and lessen the inhibition of somatomedin A generation.(7)

It is advisable to administer exogenous corticosteroids in the early morning (between 6 and 8 a.m.) in order to synchronize with the natural cortisol cycle. The objective is to expose the tissues to the maximum dose at the “normal” time. This corresponds to the circadian rhythm governing the secretion of endogenous cortisol. Cortisol secretion peaks around 6 a.m., influenced by the secretion of ACTH in the early morning hours (about 2 a.m.). Cortisol levels then fall consistently, reaching a nadir in the late afternoon and evening.(13)

STAGE II

If the fasting plasma cortisol level is less than 10 micro g per dL (280 nmol per L), the patient’s adrenal glands are still suppressed. In an otherwise well patient with a fasting plasma cortisol level of less than 10 micro g per dL, the physician can begin to reduce the hydrocortisone dose by 2.5 mg per day until a dosage of 10 mg per day is reached. Once a fasting plasma cortisol level of greater than 10 micro g per dL is sustained, hydrocortisone maintenance therapy may be terminated.

STAGE III

The final tapering process involves holding the morning dose of corticosteroid and evaluating adrenal responsiveness. In the presence of a marginal 8 a.m. fasting plasma cortisol level, it may be necessary to perform a test to evaluate adrenal gland responsiveness. A true test of the hypothalamic-pituitary-adrenal axis is the response of the adrenal gland to cosyntropin (Cortrosyn), a synthetic analog of ACTH. A dose of cosyntropin, 0.25 mg, is administered intramuscularly or by rapid intravenous infusion. (Cosyntropin also may be given as a slow intravenous infusion over four to eight hours for more specific testing, but this test should be performed by an endocrinologist.) A plasma cortisol level is obtained 30 to 60 minutes after the cosyntropin is administered. If the plasma cortisol level increment is less than 6 micro g per dL (170 nmol per L) or the maximum level of cortisol in the bloodstream is less than 20 micro g per dL (550 nmol per L), the patient still requires steroid supplementation for stress. After four weeks, the cosyntropin challenge is repeated.

When the plasma cortisol level increment is 6 micro g per dL or higher and the cortisol level in the bloodstream is 20 micro g per dL or higher, supplementation during times of stress is no longer necessary and the patient may be considered to have competent adrenal responsiveness.

Final Comment

The withdrawal of exogenous corticosteroids is often a vexing problem. The keys to success include improving patient awareness of the signs and symptoms of steroid withdrawal, close follow-up, and monitoring of the 8 a.m. fasting plasma cortisol level. During the steroid withdrawal period, it is extremely important that the patient wear a medical identification bracelet indicating steroid dependency.

TABLE 1

Some Indications for Systemic Corticosteroid Therapy Acute rheumatic fever Cerebral edema Dermatomyositis Hypercalcemia Hypersensitivity and allergic reactions Idiopathic nephrotic syndrome Immune-mediated cytopenias Mixed connective tissue disease Organ transplantation (antirejection) Polymyalgia rheumatica Polymyositis Severe asthma Systemic lupus erythematosus Temporal arteritis Ulcerative colitis

TABLE 2

Complications of Systemic Corticosteroid Therapy Cardiovascular and renal Hypertension Sodium and water retention Hypokalemic alkalosis Central nervous system Psychiatric disorders Pseudocerebral tumor Endocrine Growth retardation Secondary amenorrhea Suppression of hypothalamic-pituitary-adrenal

axis Gastrointestinal Peptic ulceration Gastric hemorrhage Intestinal perforation Pancreatitis Inhibition of fibroplasia Impaired wound healing Subcutaneous tissue atrophy Metabolic Secondary diabetes mellitus Hyperosmolar nonketotic coma Hyperlipidemia Centripetal obesity Musculoskeletal Myopathy Osteoporosis Aseptic necrosis of bone Ophthalmologic Glaucoma Posterior subcapsular cataracts Suppression of immune response Recurrence of tuberculosis, chickenpox Increased susceptibility to bacterial, fungal, viral

and parasitic infections

TABLE 3

Plasma Half-Life, Biologic Half-Life and Relative Potency of Commonly Used Corticosteroids

Plasma half-life Biological half-life Equivalent

Corticosteroid (minutes) (hours) dose (mg)

Cortisone 30 8-12 25

Cortisol (hydrocortisone) 80-118 8-12 20

Prednisone 60 18-36 5

Prednisolone 115-212 18-36 5

Methylprednisolone 78-188 18-36 4

Triamcinolone 200+ 18-36 4

Dexamethasone 110-210 36-54 0.75

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