Corticosteroids: Management of Iatrogenic Cushing's Syndrome

Mary Carter, 49, an African-American woman, was diagnosed with systemic lupus erythematosus (SLE, or lupus) 20 years ago. For the first 10 years, her symptoms were confined mainly to her joints. The pain and swelling were controlled with NSAIDs and Plaquenil® (hydroxychloroquine sulfate, Sanofi) and she was able to lead a fairly active lifestyle. She taught second grade, cared for her two children and husband and loved to garden on weekends.

About 10 years ago, however, her condition worsened rapidly. She developed lupus-related pericarditis. She was started on prednisone 60 mg alternate day therapy, but after a month with little change in her cardiac symptoms, the drug was prescribed daily in the a.m. During the year Mary was maintained on prednisone, she developed steroid-induced diabetes, had frequent mood swings, a weight gain of 25 pounds distributed primarily in her abdomen and significant muscle wasting in her lower extremities.

Besides the decline in her physical health from the lupus, the side effects from the steroids caused Mary to become dissatisfied with her body image. In fact, after she had to take a leave of absence from teaching, she withdrew from almost all social activities. "I look like an ostrich.. - I have skinny legs, a big belly and a puffy face," she would frequently lament to her family.

MAINSTAY OF LUPUS TREATMENT

Lupus is a chronic autoimmune disease that causes inflammation of various parts of the body, especially the skin, joints, blood and kidneys. The form of lupus that affects multiple organ systems is known as SLE - some experts now believe it may be several diseases characterized by frequent flare-ups and remissions that may take as long as 7-10 years to diagnose.

Although there are many SLE patients who benefit from select immunosuppressive and cytotoxic drugs, corticosteroids are the mainstay of treatment. While debilitating side effects and secondary problems are associated with corticosteroids, experience in treating patients has resulted in preventing some of them.

Corticosteroids were first used in clinical practice in 1949 for the treatment of rheumatoid arthritis.1 Since then the indications for their use have spanned multiple specialties and organ systems including dermatology, rheumatology, immunology and oncology. The number of clinical conditions for which corticosteroids are indicated is extensive (see Table 1).

Table 1: Indications for Steroid Use (Partial Listing)1
Collagen Diseases
systemic lupus erythematosus (SLE)
mixed connective tissue disease
scleroderma
 
Rheumatoid Disorders and Various Types of Arthritis
osteoarthritis
rheumatoid
gout
posttraumatic
 
Inflammatory Bowel Disease
ulcerative colitis
Crohn's disease
 
Inflammatory Dermatologic Disorders
dermatitis
psoriasis
 
Hematologic Disorders
idiopathic thrombocytopenia purpura
 
Oncology
Hodgkin's
leukemia
lymphoma
 
Respiratory Chronic Diseases
COPD
sarcoidosis
 
Organ Transplants
Prevent and treat rejections
 
Spinal Cord Injuries
immediate post trauma swelling
 
Allergic Conditions
Asthma
 
Inflammatory Ophthalmic Problems
Pain Management
Meningitis
Alcoholic Hepatitis

MIMIC ENDOGENOUS STEROIDS

More than 30 different steroids have been isolated from the adrenal cortex, but only two of these are of major importance to the endocrine functions of the body - the mineralocorticoids (aldosterone) and the glucocorticoids (cortisol). In addition to these, small amounts of sex hormones are secreted from the adrenal cortex. Normally these are unimportant but in certain abnormalities they can be secreted in extreme quantities and cause masculinizing effects.

To understand the many uses of corticosteroids, the underlying physiology governing their use, the bases of their adverse effects and the nursing implications to minimize or prevent these effects, it is important for nurses to have a working knowledge of the normal physiology of the adrenal cortical steroids.

Mineralocorticoids include aldosterone, corticosterone (also has glucocorticoid properties) and deoxycorticosterone, with the aldosterone accounting for more than 90 percent of mineralocortocoid activity. The basic actions of the mineralocorticoids are to increase renal tubular reabsorption of sodium and renal excretion of potassium. There are several factors regulating the secretion of aldosterone. Of these, potassium ion concentration and the renin-angiotensin system are by far the most potent.

Glucocorticoids include cortisol and corticosterone with cortisol accounting for about 95 percent of all glucocorticoid activity. By far, the primary effects of cortisol are those directly related to carbohydrate, protein and fat metabolism.

The release of glucocorticoids causes an increase in gluconeogenesis in the liver. Gluconeogenesis results from cortisol increasing enzymes that are required to convert amino acids into glucose in the liver cells. Glucocorticoids also encourage glycogen synthesis in the liver and stimulate the release of insulin.

Glucocorticoids affect protein metabolism by decreasing protein synthesis and increasing protein catabolism in all body cells except the liver. The extrahepatic catabolism of proteins mobilizes amino acids that serve as a source for gluconeogenesis in the liver. In Mary's case, this caused significant muscle wasting in her lower extremities. Glucocorticoids affect fat metabolism by promoting mobilization of fatty acids from adipose tissue.

Generally, these metabolic functions of the glucocorticoids are to help the body respond to stress and change. With increased demands, more cortisol is secreted and gluconeogenesis is initiated: the liver is stimulated to raise the blood sugar, the body's response to inflammation is modified and fluid balance is controlled. In fact, during extreme periods of stress, cortisol secretion can cause a six- to 10-fold increase in gluconeogenesis.

MECHANISM AS ANTI-INFLAMMATORY

Glucocorticoids dramatically decrease inflammation due to their profound effects on the concentration, distribution and function of WBCs. It is important to remember that the underlying disease remains (the symptoms are masked), but the inflammation decreases. These effects include:

 Dereased neutrophils and macrophages at the sites of inflammation;

 Reduced chemotaxis and impaired phagocytosis in macrophages;

 Decreased production of prostaglandins and leukotrienes;

 Decreased histamine release by basophils;

 Decreased fibroblast proliferation and increased collagen breakdown (slower healing).

ANTI-IMMUNE EFFECTS

The other primary use for glucocorticoids is for their anti-immune effects in allergic states such as asthma and the prevention and treatment of organ rejection. The anti-immune effects include decreased:

 antigen processing by macrophages;

 T-helper cell function;

 production of interleukin-2;

 antigen release from grafted tissue and decreased sensitization of antibody-forming cells (decreased transplant rejection);

 number of circulating lymphocytes with a greater depletion of T lymphocytes than B lymphocytes.

In summary, the most important therapeutic effects of glucocorticoids are the inhibition of the accumulation of neutrophils and monocytes at the site of inflammation and the suppression of their phagocytic, bactericidal and antigen-processing activity. However, it must always be kept in mind that, with the use of glucocorticoids, the immune system is compromised and the patient is susceptible to opportunistic infections and cancers.

Steroids are also classified by biologic half-life - short, intermediate and long-acting drugs. Those that are used for daily administration (chronic diseases) include the intermediate-acting drugs prednisone and prednisolone, which have a half-life of 12-36 hours. Long-acting steroids such as dexamethasone have a half-life of 36-54 hours; the short-acting steroids (cortisone and hydrocortisone) have a half-life of 8-12 hours (see Table 2).2

Table 2: Glucocorticoid Equivalencies, Potencies and Half-Life2
Glucocorticoid approximate equivalent dose (mg) relative anti- inflammatory potency relative mineralocorticoid activity biologic plasma (min.) half-life biologic (hours)
Short-Acting
cortisone 25 0.8 2 30 8-12
hydrocortisone 20 1 2 2 8-12
Intermediate-Acting
prednisone 5 4 1 60 18-36
prednisilone 5 4 1 115-212 18-36
methylprednisolone 4 5 0 78-188 18-36
Long-Acting
dexamethasone 0.75 20-30 0 110-210 36-54

NEGATIVE-FEEDBACK SYSTEM

Glucocorticoid secretion is regulated by hormonal interactions among the hypothalamus, pituitary gland and adrenal cortex. The hypothalamic-pituitary-adrenal (HPA) axis forms a complex system that regulates basal and stress-induced glucocorticoid release. One of the most important feedback circuits is a negative feedback system where plasma levels of one type of hormone influence the level of other types of hormone. Negative feedback systems are important in maintaining hormones within normal physiological ranges.

The hypothalamus produces corticotropin-releasing hormone (CRH). CRH is secreted in small pulses and transported to the anterior pituitary gland. The anterior pituitary responds to CRH by synthesizing adrenocorticotropic hormone (ACTH). ACTH is released in secretory bursts of varying amplitude throughout the day and night. ACTH acts on the adrenal cortex to cause secretion of cortisol and other steroids. Cortisol exerts a negative feedback effect on the synthesis and secretion of ACTH and CRH (see Figure).

Another physiological characteristic of the HPA axis is the presence of rhythms. Rhythms are a common feature of the production of many hormones that originate in brain structures. ACTH provides an excellent example of this rhythmic or cyclic hormone release. When ACTH or cortisol are measured on an hourly basis for 24 hours, the levels rise early in the day, decline later and rise again during the night to reach a peak by the next morning. This type of rhythm is referred to as a diurnal or circadian rhythm.

Ultradian rhythms are periodic or intermittent functions with frequencies higher than once every 24 hours. In fact, 4-8 adrenocortical bursts occur in a 24-hour period; bursts of CRH and ACTH follow. These bursts are clustered closer in the early morning hours than at other times, when they may be so widely spaced that the adrenal secretion is minimal. Consequently, the adrenal cortex secretes glucocorticoids only about 25 percent of the time in unstressed individuals.

Pathophysiology: Iatrogenic Cushing's Syndrome

In Mary's case, prednisone was administered for its anti-inflammatory effects. Despite its benefits, prednisone is associated with a variety of side effects such as suppression of the HPA axis and Cushing's syndrome. The adverse effects related to corticosteroid therapy are usually related to the dose administered and the duration of therapy. Suppression of the HPA axis can last up to 1 year after stopping treatment. The time required to achieve significant suppression depends on the dosage and varies among individuals, probably because of differences in rates of steroid metabolism.

Cushing's syndrome is hypercortisolism. It can be caused by the hyperfunction of the HPA axis (disease state or spontaneous) or iatrogenically (treatment-caused) by the prolonged use of glucocorticoid hormones such as hydrocortisone, prednisone, methylprednisolone or dexamethasone. Steroid therapy is the most common cause of Cushing's.

The changes that Mary experienced after she had been taking prednisone for several months are typical of patients with iatrogenic Cushing's. The clinical features of Cushing's syndrome include: mood swings, insomnia, loss of libido, hair thinning, moon face and ruddy complexion, supraclavicular fat pad, buffalo hump, hirsutism, thinning of extremities with muscle wasting and fat mobilization, truncal obesity with pendulous breasts and abdomen, broad purple striae, ecchymosis, thin, fragile skin, and impaired wound healing and immune response. Osteopenia may be present due to decreased formation of bone matrix, increased renal calcium loss and impaired absorption of calcium.

Mary also exhibited hyperglycemia, probably resulting from insulin resistance. Eventually Mary's physician was able to taper her prednisone to 20 mg alternate day therapy and many of her symptoms began to remit.

NEUROPSYCHIATRIC CHANGES

The neuropsychiatric manifestations of glucocorticoid excess can occur with spontaneous Cushing's as well as iatrogenic in those receiving pharmacological doses of steroids like Mary. They are characterized by emotional lability, euphoria, insomnia and episodes of transient depression. Usually these changes are reversed upon normalization of cortisol levels. However, if patients have been on steroids for extended periods of time, returning to normal patterns of behavior may take awhile.

Some patients have minimal behavioral or emotional changes while on steroids; for others this course of treatment can trigger a steroid-induced psychosis and require antipsychotic medications and acute psychiatric intervention.

After Mary had been on a reduced dose of prednisone, she suddenly became very confused, had memory lapses, became combative and had to be hospitalized on an acute-care psychiatric unit. After a number of diagnostic tests that included an MRI, the diagnosis of SLE cerebritis was made. Mary was placed on prednisone 100 mg and haldol 20 mg bid.

Although there is minimal inflammation of the blood vessels of the brains of SLE patients who are diagnosed with this complication of the disease, it is really a misnomer, according to researchers. The term used to describe the neurological disturbances that range from mild complaints of headaches to severe behavioral disturbances such as Mary's and frequently include seizures and strokes is neuropsychiatric-SLE (NP-SLE).3 Currently, the revised American Rheumatism Association criteria for NP-SLE (1982) only include coma and seizures.

Making the NP-SLE diagnosis is difficult because there is no definitive test. Further complicating this, many of the patients are on high doses of steroids that could be the cause of the behaviors. To add one more confounding variable to the puzzle, if the rheumatologist is convinced the patient's symptoms are due to NP-SLE, the treatment is high-dose steroids, anti-seizure medications and, perhaps, other immunosuppressive medications. Drs. Zvaifler and Bluestein, two SLE investigators, believe that the studies looking at NP-SLE are still in their infancy.3

EDUCATION KEY TO COMPLIANCE

How normal are the lives of patients who must remain on steroids for extended periods of time? Controlling the symptoms of their disease by taking these potent drugs is a trade-off. These individuals may have to cope with persistent fatigue, muscle wasting, abdominal and facial weight gain, depression, mood swings and all the other signs and symptoms mentioned earlier. Regular visits to clinicians and specialists for checkups and tests are routine. Then there is the constant vigil to prevent infections and complications.

Nurses play a critical role in educating patients about the importance of compliance and appropriate administration; how to decrease adverse reactions (see Table 3); how to avoid drug interactions (see Table 4),4 and how to avoid emergency situations. Also, patients receiving steroid therapy undergo a number of body image changes. When the nurse assesses these patients, she should attempt to find out what these changes mean to them.

 

Table 3: Systemic Adverse Effects of Corticosteroids; Related Treatment and Patient Education4
System Effects Rx/Patient Education
Cardiovascular possible hypertension, thrombophlebitis thromboembolism, congestive heart failure exacerbation, increased sodium retention, depletion of potassium, fluid andelectrolyte changes associated with steroids Use with extreme caution in patients with recent myocardial infarction because of association with left ventricular free-wall rupture. Use with caution with patients with thromboembolic disorders because of increased blood coagulability. Can cause hypertension. Teach patient relationship of steroids to blood pressure. Encourage foods low in sodium. Assess for edema. Monitor weights and changes in potassium, supplements may be necessary.
Gastrointestinal gastric irritation, nausea and vomiting, peptic ulcer, ulcerative colitis, esophagitis, pancreatitis Administer steroids with meals and antacids to prevent gastric distress. The risk of these effects increases with increased dosages and prolonged use. In these cases or if patient is npo, anti-ulcer meds may need to be prescribed.
Musculoskeletal muscle pain and weakness, eventual muscle wasting, increased risk of osteoporosis pathological fractures Encourage weight-bearing exercises. Consider risk vs. benefits of therapy in elderly patients or patients prone to osteoporosis; supplementation with calcium 1,500 mg daily and vitamin D 800 IU daily. Alendronate (Fosamax®) should be considered.
Endocrine steroid diabetes, cushingoid appearance, secondary sex characteristics of opposite sex, sexual dysfunction Monitor blood sugars; treat diabetes accordingly. Help patient cope with body image changes.
Neuropsychiatric headaches, seizures, insomnia, mood changes, steroid psychosis Use with caution in patients with seizure or psychiatric history. Anti-convulsants, analgesics or anti-psychotics may need to be prescribed. Steroid-induced psychosis is dose-related and usually occurs within 15-30 days after the initiation of therapy.
Dermatologic acne, impaired wound healing, hirsutism, skin atrophy, fragility of skin Evaluate skin frequently. Treat acne. Cover fragile skin with thin-film (second skin) dressings.

BASICS OF ADMINISTRATION

Generally, the guidelines for the use of steroids are to use the route of administration that is effective and will minimize adverse reactions. For example, as long as local routes can achieve the therapeutic objectives, they should be used, i.e., inhaled steroids for asthma; intra-articular injections for an acute joint problem; topical ointments for dermatological conditions. Systemic steroids should be reserved for when the symptoms can't be managed with the local routes. However, with regard to inhaled corticosteroids, recent studies have shown that even though adverse effects are not commonly associated with inhaled corticosteroids, the trend toward higher dosing has led to a greater awareness of possible dose-related systemic adverse effects.5

Table 4: Corticosteroid Drug Interactions2,3
Drug interactions can occur when corticosteroids are administered with:
  • salicylates
  • warfarin
  • rifampin
  • estrogen
  • digitalis
  • salicylates
  • phenobarbital
  • ketoconazole
  • oral contraceptives
  • phenytoin (dilantin)
  • potassium-depleting drugs, e.g., thiazides, amphotericin B
  • cyclosporine - although this combination is therapeutically beneficial for organ transplants, toxicity may be enhanced
  • Steroids prescribed for 1x/day should be administered in the morning since the adrenal output is greatest between 2 a.m. and 8 a.m. and then falls to its lowest point between 4 p.m. and midnight.

    Some patients can be maintained quite well on alternate day therapy (ADT) if they are prescribed an intermediate-acting steroid such as prednisone. ADT allows the adrenal gland to continue functioning, possibly with fewer adverse effects. However, on the day patients do not take their steroid, they may experience the symptoms of their underlying disease and should be made aware of this. Patients on ADT need to be evaluated closely to determine if this is efficacious or if they need daily therapy.

    Besides the potential for adverse reactions while patients are on steroids, they are immunocompromised and very susceptible to all infections. In fact, before the first dose of any steroid is administered, a complete history and physical, along with a complete battery of baseline blood tests, should be done. Recent immunizations, current infections, medications, allergies and health problems must be noted. Patients need to be taught that, because steroids inhibit the antibody response to vaccines or toxoids, they may be at risk for infection from attenuated vaccines. Before getting any vaccines, they need to check with their clinician. Finally, chronic steroid users may need their drug dose adjusted when they experience increased stress, e.g., surgery.

    TAPERING: A GRADUAL PROCESS

    The longer patients are on corticosteroid therapy, the longer it will take to taper them off the medication. For example, if a patient with Crohn's disease received therapy with prednisone - 15 mg daily for 6 months - it will take 6 months to taper the dose to zero.2 During the time the patient received the corticosteroids, his own adrenal glands were not secreting the hormones.

    Too rapid a withdrawal of the steroids results in adrenal insufficiency that causes fever, muscle and joint pain, nausea, anorexia, orthostatic hypotension, vertigo and hypoglycemia. If the drug is stopped too abruptly, the patient may go into Addisonian crisis that can be life threatening. He should be taught that during the tapering (which may be as long as 9 months after long-term steroid therapy) he may require more than the prescribed dose if he is under more stress than usual, is ill or having surgery.

    As nurses, we have all seen patients have remarkable responses to difficult symptoms of their chronic diseases after steroids were administered. However, we also have seen the many adverse effects that can result; many of these can be decreased with patient education and good nursing care.

    Kay Bensing, a senior staff nurse consultant at ADVANCE, taught endocrine nursing for many years. Robert Blumenstein is dean of graduate programs and chair of the natural sciences department, DeSales University, Center Valley, PA.


    Corticosteroids: Management of Iatrogenic Cushing's Syndrome

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