ORAL MIDAZOLAM FOR DEMENTIA‐RELATED RESPONSE AGITATION

To the Editor: Patients with moderate to severe dementia commonly develop agitation and aggression in response to personal care. Response agitation is a distressing problem that can endanger the patient and caregivers and that often persists despite identification and correction of factors that trigger the agitation. Behavioral and environmental strategies to manage dementia-related response agitation are often ineffective, and medications commonly used to manage dementia-related response agitation are increasingly being found to have specific risks in patients with dementia. Although often effective for short-term management of severe agitation, use of antipsychotic medications in patients with dementia has been associated with risk of serious adverse effects, including stroke,1 pneumonia,2 and death.1 Among other risks, benzodiazepine use in patients with dementia often causes daytime oversedation owing to the half-life of even commonly used short-acting agents (lorazepam, 9–16 hours; oxazepam, 4–14 hours; temazepam, 8–20 hours).3 Regular use of antipsychotic medications or benzodiazepines such as lorazepam for the management of dementia-related response agitation is therefore often unsafe and impractical. The case of a patient suffering from severe dementia with refractory response aggression that remitted with the use of oral midazolam is presented. A 93-year-old woman with a history of dementia of the Alzheimer's type in the severe stages was admitted to a geriatric psychiatry ward for assessment and management of severe aggression and agitation during personal care. The patient presented with extended care needs; she was unable to walk or transfer independently, requiring total assistance for basic activities of daily living, and flexion contractures had developed in her arms and legs. She directed severe agitation and aggression toward nursing staff during toileting, bathing, and transfers but remained calm when unattended during the remainder of the day and slept well most nights. Rigorous nursing care planning and environmental and behavioral management strategies were ineffective. Identification and treatment of potential triggers such as pain failed to extinguish the agitation and aggression. Management of pain included injection of flexion contractures with Botox by a physiatrist and gabapentin titrated up to the maximum tolerated dose (600 mg twice a day) in addition to regular dosing of acetaminophen 1,000 mg every 6 hours. The patient had a disappointing response to pharmacotherapy specifically targeting response agitation. This included quetiapine up to 150 mg daily (ineffective and oversedating), citalopram up to 30 mg daily (ineffective), a low dose of zuclopenthixol (a 72-hour depot-typical antipsychotic; 5 mg intramuscularly) (caused severe extrapyramidal side-effects), pre-care lorazepam use at the minimum effective dose (caused 6–8 hours or more of daytime oversedation), and olanzapine (pre-care use was ineffective and oversedating). Midazolam oral solution was prepared at a concentration of 2 mg/mL. The dosage was started at 2 mg and titrated gradually (over the course of 2 weeks) up to 6 mg given 15 to 30 minutes before personal care or transfers. The patient's response agitation and aggression resolved with no consequent daytime oversedation, and all antipsychotics were discontinued. Midazolam3 is an ultra-brief-acting benzodiazepine with a half-life of 1.5 to 6 hours. It is commonly used for conscious sedation in emergency departments, in minor procedures such as endoscopy,4 and for uncooperative patients such as in pediatric dentistry.5 It has an oral bioavailability of 35% to 40% when given orally and greater than 90% when given parenterally. Parenteral routes are usually limited to emergency department and intensive care settings. Dosage reductions are required with parenteral administration. It undergoes hepatic metabolism and renal excretion. In this patient, the use of oral midazolam was associated with marked improvement in severe dementia-related response agitation. Based on this case study, preparation of a midazolam oral solution with a concentration of 2 to 3 mg/mL is recommended. Nursing staff should be requested to shake the solution to ensure proper constitution before administration. Starting at a dose of 1 to 2 mg given orally 15 to 30 minutes before personal care or transfers is suggested, titrating in increments of 1 to 2 mg as tolerated to induce the required level of sedation. It is anticipated that the usual effective dose would be in the range of 2 to 8 mg. Careful monitoring for respiratory depression is recommended, with a precaution to avoid administration of midazolam to patients with preexisting respiratory compromise, low baseline respiratory rate, or concurrent use of opioid-based medications. Midazolam-related oversedation can be reversed with the benzodiazepine inverse-agonist flumazenil. Conflict of Interest: The editor in chief has reviewed the conflict of interest checklist provided by the authors and has determined that the authors have no financial or any other kind of personal conflicts with this letter. Author Contributions: All the authors made substantial contributions to every aspect of this letter. Sponsor's Role: None.

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