What is the appropriate dose of Midazolam (Benzodiazepine) for palliative therapy in end-of-life care?

From the Guidelines

For palliative therapy at the end of life, midazolam should be started with a 2 mg intravenous bolus dose, followed by an infusion of 1 mg/h, which can be adjusted based on symptoms, size, age, and organ dysfunction, as recommended by the most recent guidelines 1. When considering the management of symptoms at the end of life, it's crucial to prioritize the patient's comfort and quality of life.

• The initial bolus dose of midazolam can be repeated every 5 minutes as required, and if a patient receives two bolus doses in an hour, it is reasonable to double the infusion rate 1.
• For patients who are already receiving an infusion of midazolam and become symptomatic, a bolus dose equal to or double the hourly infusion dose can be administered 1.
• Alternatively, for intermittent dosing, midazolam 2.5-5 mg subcutaneously every 2-4 hours as required can be considered, with the option to switch to a subcutaneous infusion via a syringe driver if needed frequently 1.
• It's essential to regularly assess symptom control and adjust the dose accordingly, taking into account the patient's individual needs and response to treatment.
• Additionally, midazolam should be administered alongside appropriate analgesics if pain is present, as it has no analgesic properties, and family support and clear communication about goals of care remain crucial components of end-of-life care.

From the FDA Drug Label

Onset is within 15 minutes, peaking at 30 to 60 minutes. Maintenance Dose: Additional doses to maintain the desired level of sedation may be given in increments of 25% of the dose used to first reach the sedative endpoint, but again only by slow titration, especially in the elderly and chronically ill or debilitated patient Patients Age 60 or Older, and Debilitated or Chronically Ill Patients: Because the danger of hypoventilation, airway obstruction, or apnea is greater in elderly patients and those with chronic disease states or decreased pulmonary reserve, and because the peak effect may take longer in these patients, increments should be smaller and the rate of injection slower.

The midazolam dose for palliative therapy at the end of life is not explicitly stated in the provided drug label. However, for sedation/anxiolysis/amnesia, the label recommends:

• Healthy Adults Below the Age of 60: 1-2.5 mg over at least 2 minutes, with additional increments as needed.
• Patients Age 60 or Older, and Debilitated or Chronically Ill Patients: 1-1.5 mg over at least 2 minutes, with additional increments as needed. It is essential to titrate slowly and monitor the patient's response to determine the optimal dose. The label also emphasizes the importance of caution when administering midazolam to elderly or debilitated patients due to the increased risk of hypoventilation, airway obstruction, or apnea 2.

From the Research

Midazolam in Palliative Care

• Midazolam is a commonly used benzodiazepine in palliative care, considered one of the four essential drugs needed for the promotion of quality care in dying patients 3.
• It is used for symptom control, such as treatment of dyspnea or anxiety, and for palliative sedation if symptoms are not controlled 4.
• Midazolam has a faster onset and shorter duration of action than other benzodiazepines, lending itself to greater flexibility in dosing 3.

Administration and Dosing

• Midazolam can be administered intranasally, which offers an important alternative administration route, with benefits including ease of administration, tolerability, and avoidance of needle use 5.
• The dosing of midazolam varies, with physicians in the UK using a higher starting dose for anxiety, dyspnoea, and pain treatment compared to Norway and Denmark 6.
• There is a lack of consensus on how midazolam should be used in palliative care, with differences in dosing and administration between countries 6.

Safety and Adverse Effects

• The undesired effects of midazolam can be life-threatening, and palliative care patients constitute a high-risk group prone to side effects of drugs due to polytherapy and multi-organ failure 7.
• The pharmacokinetics of midazolam depends on hepatic and renal functions, fat tissue mass, route and duration of administration, as well as potential drug-drug interactions 7.