Sedation Agents

A variety of pharmacological agents are used for sedation in mechanically ventilated ICU patients. Choosing an appropriate sedative involves balancing factors like onset/duration of action, organ function, and risk profiles. This chapter reviews common drug classes used for ICU sedation including analgesics, propofol, dexmedetomidine, and benzodiazepines.

Analgesics

Providing adequate analgesia is a priority in critically ill patients. Unrelieved pain increases sympathetic tone, physiological stress, and risks of complications. Opioids form the foundation of analgesic therapy in ventilated patients.

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Opioids

Mechanism & Dosing

Opioids like fentanyl, hydromorphone, and morphine produce effects through mu receptor agonism in the central and peripheral nervous systems. This leads to analgesia, sedation, euphoria, respiratory depression, constipation, and other effects.

Dosing is highly patient-specific. Intermittent IV bolus dosing is preferred to match analgesic needs. Starting doses are 25-100 mcg IV push for fentanyl, 0.5-2 mg IV push for hydromorphone, and 2-10 mg IV push for morphine. Continuous infusions may be required in some patients but should be minimized.

Fentanyl 25-250 mcg/hr, hydromorphone 0.5-10 mg/hr, and morphine 2-20 mg/hr are typical infusion ranges. However, there is large interpatient variability in opioid requirements for analgesia. Regular reassessment of pain and sedation is crucial to avoid oversedation while ensuring comfort.

Key Considerations

• Potent analgesia at low doses
• Risks of respiratory depression and hypotension, especially with bolus dosing
• Increased hyperalgesia, tolerance, and delirium risk with prolonged infusions
• Withdrawal symptoms may occur on abrupt discontinuation
• Preferred agents for managing pain in critically ill patients

Literature Review

• Analgesia-first approach – A focus on pain control using opioids before adding sedatives can reduce sedative needs. Observational studies find most agitated ICU patients calm with analgesia alone.
• Role in pain/agitation – Multiple RCTs show opioids effectively reduce pain and agitation in ICU patients. They should be first-line for pain and second-line for agitation after non-pharmacological de-escalation.

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Non-Opioid Analgesics

Agents like acetaminophen, gabapentinoids, ketamine, and NSAIDs may supplement opioid analgesia. However, none replace opioids as the primary analgesic in most ventilated ICU patients.

Acetaminophen has analgesic and antipyretic effects without anti-inflammatory activity. Usual dosing is 650-1000 mg enterally/IV every 6 hours, up to 4 grams daily. Acetaminophen reduces opioid consumption but does not treat pain in the absence of opioids.

Gabapentin and pregabalin bind to calcium channels, exerting analgesic, anxiolytic, and sedative effects. Gabapentin 300-900 mg daily in divided doses and pregabalin 75-450 mg daily in two divided doses are typical. Dose reduction is required with renal impairment.

Ketamine is an IV anaesthetic and NMDA receptor antagonist. At low infusion doses (0.1-2 mg/kg/hr), it provides analgesia without dissociation. Ketamine offers opioid-sparing effects18 but may increase airway secretions.

NSAIDs like ketorolac are avoided in critically ill patients with renal dysfunction or bleeding risks. However, NSAIDs may supplement opioid analgesia in lower risk patients. Typical dosing of IV ketorolac is 15-30 mg every 6 hours.

Propofol

Mechanism & Dosing

Propofol enhances GABA receptor activity, promoting sedation, amnesia, and hypnosis. It has a rapid onset and short duration of action. Loading doses of 0.5-1 mg/kg IV push provide quick sedation, followed by infusions of 5-75 mcg/kg/min or higher based on response. Frequent assessment is key to avoid excessive sedation.

Key Considerations

• Very short wake-up time facilitates neurologic evaluation
• Dose-dependent hypotension, especially with loading doses
• Uncommon propofol infusion syndrome may cause organ failure
• Lipid emulsion promotes microbial growth with prolonged use
• Preferred agent for brief, deep procedural sedation

Literature Review

• PRODEX Trial – Among mechanically ventilated ICU patients, continuous propofol infusion led to less delirium compared to midazolam (45% vs. 76%).
• Similar to dexmedetomidine – The MENDS trial found no significant difference between dexmedetomidine and propofol in time at target sedation or duration of mechanical ventilation.

Dexmedetomidine

Mechanism & Dosing

Dexmedetomidine is a selective alpha-2 receptor agonist with anxiolytic and sedative properties without respiratory depression. A 1 mcg/kg IV loading dose infused over 10 minutes prevents blood pressure drop. Maintenance doses of 0.2-1.5 mcg/kg/hr are titrated to a light level of sedation. Bradycardia and hypotension may occur.

Key Considerations

• Avoids respiratory depression
• Less delirium compared to benzodiazepines
• Delayed extubation versus propofol in some studies
• Can maintain light sedation for cooperative patients

Literature Review

• MIDEX Trial – Among mechanically ventilated patients, dexmedetomidine infusion led to less delirium compared to midazolam (54% vs. 76%).
• Comparable to propofol – The MENDS trial found dexmedetomidine had similar duration of mechanical ventilation versus propofol.

Benzodiazepines

Mechanism & Dosing

Benzodiazepines like midazolam and lorazepam enhance GABA activity, producing sedation, anxiolysis, amnesia, and muscle relaxation. Midazolam usual dose is 1-5 mg q1-4hrs IV prn or 0.5-5 mg/hr continuous infusion. Lorazepam is dosed 1-4 mg IV q2-6hrs prn or 1-10 mg/hr infusion. Respiratory depression is a risk.

Key Considerations

• Long-acting agents (lorazepam) risk drug accumulation
• High delirium risk, especially with prolonged use
• First-line agents for alcohol withdrawal
• Should be avoided in most mechanically ventilated patients

Literature Review

• Increased delirium risk – Multiple RCTs show increased delirium with benzodiazepine infusions compared to dexmedetomidine or propofol.
• Prolonged ventilation – Benzodiazepine use is associated with delayed extubation compared to propofol or dexmedetomidine.