The Case

A 64-year-old woman came to the emergency department complaining of cough and shortness of breath, along with an itchy throat and a runny nose. She had a past medical history of end-stage renal disease (on hemodialysis 3 times/week), hypertension, type 2 diabetes, and a left below-knee amputation. Her serum creatinine was 9.48 mg/dL. She was transferred to the hemodialysis unit where she underwent hemodialysis and was then admitted to the medical floor.

That night, the patient was given her home medications at the prescribed doses: zolpidem 10 mg at 22:03 and hydroxyzine 25 mg by mouth at 00:48. At 03:00, the nurse noted that the patient was agitated, crying out, "I will not cooperate until I get some rest." At 11:20, the nurse noted acute changes in mental and neurological status, including severe drowsiness, unresponsiveness to painful deep stimuli, and unequal pupil size. A "Code Stroke" was called. Laboratory results were suggestive of respiratory and metabolic acidosis. The patient was transferred to the medical intensive care unit for close observation and hemodialysis. All CNS depressants were discontinued. A CT scan showed no evidence of a new stroke. Two days later, the patient was alert, awake, fully oriented, and hemodynamically stable.

Case review revealed that prior to admission, the patient's nephrologist had added a prescription for hydroxyzine 25 mg by mouth at bedtime as needed, because the patient had been complaining of itchiness and continuously picked at her skin. The zolpidem dose had also been increased from 5 mg to 10 mg at bedtime as needed. Then, at the time of admission, she received additional doses of both medications. Although duplicate therapy alerts for zolpidem and hydroxyzine appeared on the order entry screen, it was a "soft stop" without management recommendations, and the ordering physician bypassed the alerts.

The Commentary

by Christine M. Gillis, PharmD; Jeremy R. Degrado, PharmD; and Kevin E. Anger, PharmD

This case highlights the risks associated with sleep aid utilization in hospitalized adults. Poor sleep among inpatients has multiple causes, including underlying illness(es), diagnostic and therapeutic procedures, medication effects, and environmental factors.(1,2) Surveys reveal that as many as half of hospitalized general medicine patients complain of sleep disruptions.(3) As a result, patients are frequently prescribed pharmacological sleep aids during hospitalizations. In fact, approximately 34% of patients who do not have a documented sleep disorder prior to hospitalization and were not previously prescribed a pharmacologic sleep aid are discharged from the hospital on a sleeping medication.(4)

Despite emerging evidence that sleep aid utilization is associated with adverse effects and detrimental outcomes, such medications are still commonly prescribed during hospital stays and on discharge.(4) A wide variety of medication classes are used as sleep aids, including first generation antihistamines (e.g., diphenhydramine), benzodiazepines (e.g., lorazepam), antidepressants (e.g., amitriptyline), typical antipsychotics (e.g., haloperidol), atypical antipsychotics (e.g., quetiapine), melatonin, and melatonin agonists (e.g., ramelteon). Common adverse effects of sleep aids include residual daytime sedation leading to increased risk for falls, altered mental status (delirium), and respiratory depression.(5) In one study (6), zolpidem tartrate was found to be an independent risk factor for falls in hospitalized patients. Patients may also experience anticholinergic adverse effects, such as urinary retention and xerostomia, from some sleep aid medications including diphenhydramine.

Patients with certain comorbid conditions may be at an increased risk for adverse effects from medications used to promote sleep. As patients age, the pharmacokinetics of many medications change due to slower metabolism and decreased clearance, which can lead to drug accumulation and a prolonged and increased effect. Since many medications are excreted by the kidneys, patients with renal dysfunction are at even higher risk for this. In this case, hydroxyzine, a medication where both the parent drug and active metabolite are renally excreted, was used in an older patient on hemodialysis (7), further escalating the risk for prolonged accumulation and adverse effects. Clinical judgment is needed to weigh the potential risks and benefits of utilizing such agents and to tailor therapy based on patient-specific characteristics such as age, organ dysfunction, and drug interactions. Other comorbid conditions, such as dementia, may also cloud a patient's clinical picture and make it difficult to determine if medications used as sleep aids are contributing to adverse effects.

Other common factors that contribute to poor outcomes with sleep aid use include inappropriate administration time, use of multiple sleep aids, and frequent dose titrations. Based on anecdotal experience, delayed administration time (i.e., administration after 11 PM) may increase the risk of residual daytime sedation. Polypharmacy also may play a role in increasing adverse effects through drug interactions or additive effects. Clinicians should be aware that patients frequently utilize over-the-counter and prescription medications for sleep. Multiple providers may also prescribe different sleep aids for patients without knowing what else the patient is taking at home. In this case, it is unclear whether the nephrologist who prescribed the hydroxyzine knew that the patient was also taking zolpidem tartrate and that the dose had been recently increased.

What can be done to address this issue? One strategy is to emphasize the use of nonpharmacological interventions to improve sleep hygiene. Patients should be encouraged to utilize relaxation techniques, including massage, meditation, and drinking warm beverages at bedtime. Patients should also be encouraged to avoid taking frequent or prolonged daytime naps. Often, patients are unaware of the benefits or availability of nonpharmacological sleep aids during hospitalization and may believe they have no other options besides medication to relieve insomnia.(8)

Many hospitals have developed protocols aimed at improving the quality, quantity, and continuity of patients' sleep. These protocols have historically focused on addressing environmental factors such as loud noise, bright lights, and night staff disruptions.(9) Interventions to reduce noise include keeping the patient's doors closed, posting notices reminding staff to lower their voices, reducing the volume of monitors and alarms, changing beepers to vibrate mode, and limiting telephone conversations near patients. Lights can also be kept turned off or dimmed at night. In an effort to reduce night staff disruptions, routine medication administration times should be standardized. Diagnostic and therapeutic procedures as well as routine lab draws should be avoided during nighttime hours. By decreasing nighttime staff disruptions, one study demonstrated a decrease in sleep aid use among hospitalized patients.(10)

Other steps involve education of the clinical staff. Providing clinicians with education on appropriate use of sleep aids as well as on utilizing electronic health records to guide clinical decision-making can help. If a patient complains of difficulties with sleep, a thorough sleep history should be obtained before initiating a pharmacological agent. If the problem is due to an underlying disease state, such as obstructive sleep apnea or restless leg syndrome, addressing that condition should be the first step in improving sleep. Utilizing electronic provider order entry systems with insomnia orders sets to guide clinical decision-making may lead to decreased inappropriate drug combinations, dosing, and poor outcomes. Alerting physicians to duplicate sleep aid therapies and implementing hard stops in provider order entry systems can decrease the likelihood of poor outcomes.(11) Although there is only anecdotal evidence at the present time, setting standard administration times for sleep aids may help to avoid inappropriate administration time and decrease risk of residual daytime sedation.

Finally, because sleeping aids are so often added during a hospitalization, the appropriateness of ongoing prescriptions should also be evaluated before the patient leaves the hospital. There are so many factors that disrupt sleep during a hospital stay, many patients who may have needed help to sleep as inpatients may not have any such need at home. It would be best if these patients did not receive a prescription for a pharmacologic sleep aid at the time of discharge.

Take-Home Points

• Poor sleep is common among hospitalized patients and is caused by underlying illness(es), diagnostic and therapeutic procedures, and environmental factors.
• Older patients are at an increased risk for adverse effects and poor outcomes, such as residual daytime sedation, altered mental status, and respiratory depression, associated with sleep aids. This is commonly due to altered pharmacokinetics, comorbid conditions, and polypharmacy.
• Utilization of nonpharmacological interventions and development of hospital protocols aimed at decreasing the use of sleep aids should be implemented.
• Clinical decision-making can be improved through the use of insomnia order sets to prevent inappropriate sleep aid selection, dosing, and timing of administration.
• Patients who received new sleep aids in the hospital may not need them after discharge and so should not automatically be prescribed them for home use.

Christine M. Gillis, PharmD PGY-2 Transitional Care Pharmacy Resident Department of Pharmacy Services Brigham and Women's Hospital, Boston, MA

Jeremy R. Degrado, PharmD Critical Care Clinical Pharmacy Specialist Department of Pharmacy Services Brigham and Women's Hospital, Boston, MA

Kevin E. Anger, PharmD Critical Care Clinical Pharmacy Specialist Manager of Investigational Drug Services Department of Pharmacy Services Brigham and Women's Hospital, Boston, MA

References

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