ICU patients may require HIGH sedative doses

As a critical care pharmacist, you will care for more patients who need higher-than-average doses of continuous sedative infusions while mechanically ventilated. Continue to use your ICU liberation bundles, also known as ABCDEF or A2F bundles. These decrease sedative use by treating pain first and titrating to light sedation goals. But expect to need higher sedative doses to achieve light sedation in some patients, especially those with COVID-19. And patients with severe respiratory distress may need deeper sedation in order to breathe in sync with the mechanical ventilator. There aren’t hard-and-fast rules when treating these patients due to limited data. Consider these strategies...

Continue to generally use propofol first. Monitor for hypotension and symptoms of the rare but fatal propofol-related infusion syndrome (PRIS), unexplained metabolic acidosis, rhabdomyolysis, bradycardia, etc. There’s no consensus on a max propofol dose, but PRIS risk goes up with higher doses and longer durations. Think about allowing short-term use above your standard such as up to 80 mcg/kg/min for a few days. With higher doses, check triglycerides more frequently, such as a few times/week. Propofol is often stopped for triglycerides over 500 mg/dL. But consider a higher threshold, since pancreatitis is rare under 1,000 mg/dL. If giving high propofol doses for multiple days, think about adding other sedatives using lower doses of each medication may limit side effects. Also be prepared with alternatives when propofol is not an option due to issues such as shortages.

Consider dexmedetomidine for light sedation. Monitor for bradycardia and hypotension. Be aware, it doesn’t provide deep-enough sedation to use with a paralytic. If deep sedation is needed, add or switch to a midazolam drip (0.02 to 0.1 mg/kg/hour infusion). But limit use when able, since benzos (benzodiazepines) are linked to delirium risk. Think of a ketamine drip (0.05 to 0.4 mg/kg/hour) as an add-on option, especially with hypotensive patients, since it can raise blood pressure. It also has analgesic effects. Watch for increased heart rate and secretions and avoid in decompensated heart failure.

NPS-adv

Drug	IV Dosing (Adult)	Comments
Benzodiazepines
Midazolam	Initial dose:3,10 0.5 to 2.5 mg (or 0.05 mg/kg) given slowly over two minutes or more. Can repeat after about two minutes, and titrate slowly in small increments. Usual max total dose is 5 mg. Maintenance dose: 0.02 to 0.1 mg/kg/hour infusion.	Often combined with an opioid for synergy. Consider using lower fentanyl and midazolam doses (e.g., reduce by 25% to 50%) when using them together, and titrating to effect (sedation and respiratory depression effects may be synergistic). Rapid infusion or high doses can cause respiratory depression. Slightly slower onset, but longer duration compared to remimazolam. Reversal agent: flumazenil (0.2 mg IV over 15 seconds, may repeat in about one minute if needed). Max of 1 mg over five minutes. Monitor patients closely as resedation is possible if flumazenil wears off before midazolam. Lower doses may be needed in patients with kidney or liver impairment.
Opioids
Fentanyl	Initial dose: 25 mcg slowly over one to three minutes. Can repeat about every three to five minutes, as needed. Maintenance dose: 25 to 50 mcg or 0.35 to 0.5 mcg/kg every 30 to 60 minutes as needed.	Often combined with a benzodiazepine for synergy. Consider using lower fentanyl and benzodiazepine doses (e.g., reduce by 25% to 50%) when using them together, and titrating to effect (sedation and respiratory depression effects may be synergistic). Chest wall rigidity rarely occur, may be more likely with higher doses and rapid administration. Minimal histamine release compared to other opioids. Reversal agent: naloxone (0.4 mg IV initially, then 0.1 to 0.2 mg every two to three minutes as needed). Monitor patients closely as resedation is possible if naloxone wears off before fentanyl.
Other Procedural Sedation Options
Propofol (Diprivan, generics)	Initial dose: 0.5 to 1 mg/kg followed by 0.5 mg/kg every one to three minutes as needed. Maintenance dose: 5 to 50 mcg/kg/minute. Titrate every 5 to 10 minutes in increments of 5 to 10 mcg/kg/minute. Some patients require up to 70 mcg/kg/minute, which can increase risk of propofol infusion syndrome.	Carries a risk of hypotension and respiratory depression. More common with high doses and rapid increases in infusion rates. Some recommend normal saline bolus doses to counteract hypotension associated with propofol. Propofol may cause more dips in respiratory rate and oxygen saturation compared to remimazolam. However, these dips were NOT severe and did NOT impact time to discharge. No dosing adjustments needed for kidney or liver impairment. Similar onset and recovery time to remimazolam. Lower doses may be needed in elderly patients, due to decreased volume of distribution and clearance. No reversal agent available. Contraindicated in patients who have soybean or egg allergies or sensitivities. Patients may experience pain on injection.
Ketamine	Initial: 1 to 3 mg/kg. Can repeat 0.5 to 1 mg/kg doses every 5 to 10 minutes as needed. Maintenance dose: 0.05 to 0.4 mg/kg/hour.	Combines anesthesia and analgesia in one medication. Use associated with risk of hypertension or increased heart rate. Can cause recovery agitation (emergence phenomena), transient laryngospasm, and emesis. Can premedicate with midazolam to reduce emergence phenomena. Avoid in patients with a history of psychotic behavior. No reversal agent available.
Etomidate	Initial: 0.1 to 0.2 mg/kg over 30 to 60 seconds followed by 0.05 mg/kg every 3 to 5 minutes as needed.	Hypnotic only; has no analgesic properties. Minimal cardiac effects. Patients may experience: myoclonic jerks (can be mistaken for seizure activity) pain on injection. No reversal agent available.
Dexmedetomidine (Precedex)	Initial: 1 mcg/kg over 10 minutes followed by a maintenance infusion (0.2 to 1 mcg/kg/hr).	Does NOT cause respiratory depression, but commonly leads to dose-related hypotension and bradycardia. Not as routinely used as other options (e.g., propofol, midazolam with fentanyl) and some even question its use as sole sedative. No reversal agent available. Lower doses may be needed in patients with liver impairment.

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References

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4. Hemphill S, McMenamin L, Bellamy MC, Hopkins PM. Propofol infusion syndrome: a structured literature review and analysis of published case reports. Br J Anaesth. 2019 Apr;122(4):448-459.
5. Devlin JW, Skrobik Y, Gélinas C, Needham DM, et al. Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU. Crit Care Med. 2018 Sep;46(9):e825-e873.

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