Case Objectives

• List the common adverse effects of corticosteroids.
• State the most common errors made in prescribing corticosteroids.
• Describe how to mitigate drug-related harm of corticosteroids, including strategies to minimize drug exposure and to administer appropriate prophylaxis.
• Recognize the frequency of medication adverse events during care transitions and the role that medication discrepancies have in these events.
• Outline the published interventions to reduce medication discrepancies and adverse events.

The Case

A 73-year-old woman with a history of nonsmall cell lung cancer with metastases to the brain was admitted to the hospital with a few weeks of cough and generalized weakness. After a complete evaluation, she was found to have multiple medical issues including Pneumocystis jiroveci pneumonia (PJP pneumonia), invasive pulmonary aspergillus, diffuse myopathy (muscle weakness), and gastrointestinal bleeding from peptic ulcer disease.

During medication reconciliation, it was discovered that 2 months prior to this illness, the patient had been prescribed dexamethasone (4 mg every 6 hours, equivalent to ~100 mg of prednisone per day, a very high dose of steroids) to reduce the brain swelling associated with the cancer. The intention had been to taper off the steroids a few weeks later, after she received radiotherapy for her brain metastases. However, the corticosteroids were never tapered, and she had continued to take high-dose steroids for more than 2 months.

The hospitalist, oncologist, and endocrinologist all believed that all of her acute issues were a result of the steroids. She was treated with antibiotics, the steroids were tapered, and she had no further gastrointestinal bleeding. However, because of the multiple complications, she required hospitalization for more than a week and was discharged to a skilled nursing facility for ongoing physical therapy. She remained at the nursing facility for more than 2 months before returning home.

A formal case review identified several issues that led to the errors and adverse events. Multiple providers were involved in her care (oncologist, radiation oncologist, primary care provider), and no one took ownership over the dexamethasone prescription. The patient lived far away from the hospital where she was receiving care. The patient and family spoke predominantly Tagalog, and there may have been miscommunication related to the language discordance.

The hospitalist caring for the patient wondered about the frequency of errors and adverse events related to corticosteroids and what individuals and institutions could do to prevent these errors.

The Commentary

Commentary by David J. Lucier, MD, MBA, MPH, and Jeffrey L. Greenwald, MD

This patient was prescribed corticosteroids to reduce brain swelling associated with cancer. The use of corticosteroid therapy in the primary treatment of malignancies (e.g., lymphoma [1] and multiple myeloma [2]) and in the management of cancer treatment-related anorexia (3,4), nausea (5), pain (6), and mass effect from tumor-associated edema of the brain (7) and spinal cord (8) are both common and well established. Nonetheless, such treatments come at a significant risk of adverse effects. Even short-term therapy with corticosteroids can induce fluid retention, hyperglycemia, agitated and psychotic behavior, hypertension, and electrolyte abnormalities. Longer exposure can result in Cushingoid appearance, osteoporosis, cataracts, vascular fragility, avascular necrosis, gastrointestinal bleeding, muscle weakness, and immunosuppression.(9) Higher doses and longer duration, as seen in this case, increase the prevalence and severity of adverse effects.(10)

Prevention of these untoward effects is an incomplete science. The cornerstone of adverse effect prevention is minimizing exposure—both in dose and duration—when clinically possible and appropriate. Specific prophylactic approaches to reduce immunosuppression-related adverse effects include treatments with antibiotics to reduce Pneumocystis jiroveci pneumonia (PJP) and immunization to prevent herpes zoster, pneumococcal pneumonia, and influenza.(10) The specific duration of corticosteroid exposure that warrants prophylaxis is not expressly answered in the literature in all cases. For example, for PJP prophylaxis, limited studies have suggested patients given at least 20 mg of prednisone or its equivalent for a month should receive antibiotic prophylaxis.(11) Even less specific guidance is available for the other indications listed, with the general proviso that patients with anticipated needs for courses of corticosteroids during their treatment should be considered for herpes zoster, pneumococcal pneumonia, and influenza vaccination before initiating the steroid treatment.

Prevention of osteoporosis (including prophylactic bisphosphonate or teriparatide therapy along with vitamin D measurement and supplementation and calcium supplementation) has been recommended, especially in higher-risk patients and when the duration of treatment is 3 months or longer.(12) Gastrointestinal bleeding prophylaxis has also been proposed. However, debate remains about the intrinsic risk from corticosteroids alone, as opposed to the risk associated with its use in combination with nonsteroidal anti-inflammatory drugs (NSAIDs) or aspirin. Most providers would prescribe a proton pump inhibitor if a patient is receiving a corticosteroid with an NSAID, or consider doing so if a patient is going to be on high doses of corticosteroids even without an NSAID for a prolonged period.(13)

In the case presented, the patient experienced multiple medication adverse events, which were due at least in part to an unnecessary and unintentionally protracted corticosteroid course. There is limited data regarding the frequency of such events with corticosteroids, with literature suggesting that they are rare, representing 2% or less of the medication adverse events identified in large national databases.(14,15) Like many adverse events, multiple systems-related factors contributed in this case, including having multiple care providers (and thus transitions of care [16]) and a language barrier.(17) We also wonder if there were issues with the completeness and clarity of the documentation about the medication plan, the availability of the documentation to subsequent providers, what patient education was provided (and how effective it was), and the health literacy of the patient. Importantly, these risk factors are not unique to corticosteroids.

In our experience, corticosteroid prescribing errors commonly revolve around tapering, drug choice, and providing appropriate prophylaxis to mitigate known adverse effects. Tapering errors include failing to taper (as in the case above), which can result in excessive and significant adverse effects, or tapering too rapidly, resulting in flares of chronic disease or precipitation of adrenal crisis in those who are steroid-dependent. The choice of drug can be important when targeting certain tissues. For instance, dexamethasone has higher central nervous system (CNS) penetration than other glucocorticoids and is a better choice for CNS-related pathology. Likely the most common corticosteroid prescribing error is failure to prescribe appropriate prophylaxis for patients on extended duration corticosteroids, as mentioned above. The etiology of these errors is complex, and can span from individual provider-level factors (e.g., inexperience) to patient-related factors (e.g., nonadherence) to system-level factors (e.g., electronic medical record incompatibility resulting in an inaccurate medication history during transitions of care).

Literature from the past 20 years has consistently shown that medication adverse events often occur surrounding times of transition, such as on admission to the hospital and at discharge.(18,19) A frequent cause of medication adverse events is medication discrepancies, such as when two documented sources of medication history have an unexplained difference between them. Discrepancies are common during transitions of care, with estimates of 70% or higher on hospital admission or discharge.(20-22) Risk factors for clinically significant medication discrepancies include polypharmacy (5 or more medications), multiple comorbidities, and age older than 65.(23,24)

Interventions have tried to address medication adverse events by focusing on eliminating discrepancies during periods of medication reconciliation (i.e., transitions of care) by incorporating pharmacists or pharmacy technicians, improving information technology (IT) infrastructure, or launching educational initiatives. Pharmacy-led interventions tend to work best, often identifying a significant number of discrepancies and correcting them in real time. Such interventions generally involve a pharmacist or pharmacy technician obtaining the most accurate medication history possible on admission, often using two sources of medication data to do so. One retrospective review found that of 200 patients who had a pharmacy-related intervention performed (review or reconciliation), 365 discrepancies were found (1.8 per patient).(25) Another large systematic review found that comprehensive safety programs that incorporate multiple interventions reduced medication discrepancies and adverse drug events.(26) Improvements in IT infrastructure, such as adopting technology that allows for electronic health record interoperability and querying of other hospital patient records, is likely to help prevent medication adverse events due to medication discrepancies. In the case above, such technology might have allowed providers to easily investigate what dose and duration of corticosteroid was intended, as opposed to relying on paper records or patient self-reporting.

While this case supports the need for rigorous medication reconciliation at each care transition, it also highlights the limitations of what protection medication reconciliation alone can provide (26), particularly given the other contributing factors mentioned. A multifaceted approach is needed to address each of these factors and ensure that systems issues do not lead to further medication adverse events beyond expected potential adverse effects. The most effective care transitions interventions span the entire transitional period and include elements of medication reconciliation, discharge planning, patient (and family/caregiver) discharge education, health and general literacy awareness, timely follow-up for complex patients, and clear communication of discharge needs to next providers.(27) Although less well supported by robust data, an additional area to consider might also be strategies to engage patients in their own safety, including programs to facilitate patient-reported medication adverse events and discrepancies.(28)

In conclusion, although even appropriate corticosteroid dose and duration can result in adverse effects, it is critical to establish robust systems to minimize drug exposure and mitigate additional medication-related harm.

Take-Home Points

• Fluid retention, hyperglycemia, agitated and psychotic behavior, hypertension, and electrolyte abnormalities are typical short-term adverse effects of corticosteroids.
• Common adverse effects with longer-term corticosteroid exposure include Cushingoid appearance, osteoporosis, cataracts, vascular fragility, avascular necrosis, gastrointestinal bleeding, muscle weakness, and immunosuppression.
• Minimizing dose and duration of corticosteroids is the most effective way to limit adverse effects.
• The most common errors made in prescribing corticosteroids include issues with tapering, drug choice, and failing to provide appropriate prophylaxis to mitigate adverse effects.
• Medication adverse events are common during times of transition in patient care (e.g., admission, discharge).
• Preventing adverse drug events during transitions in care is challenging. The most effective interventions are multifaceted and span the entire transitional period, relying on the collaboration of clinical personnel (both inpatient and ambulatory), supportive infrastructure (including IT systems), and appropriate patient and family support and education.

David J. Lucier, MD, MBA, MPH Director of Quality Improvement and Patient Safety Hospital Medicine Unit Department of Medicine Massachusetts General Hospital Boston, MA

Jeffrey L. Greenwald, MD Core Educator Faculty Department of Medicine Massachusetts General Hospital Boston, MA

Faculty Disclosure: Drs. Lucier and Greenwald have declared that neither they, nor any immediate member of their families, have a financial arrangement or other relationship with the manufacturers of any commercial products discussed in this continuing medical education activity. In addition, the commentary does not include information regarding investigational or off-label use of pharmaceutical products or medical devices.

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