Sedatives for ICU Sedation

Dexmedetomidine is associated with dose-related hypotension and bradycardia. Transient hypertension may also occur due to stimulation of alpha₂-receptors on arterial and venous smooth muscle. Propofol causes hypotension and bradycardia due to systemic vasodilation and negative inotropy; it has no vagolytic activity. Hemodynamic instability is more likely with bolus dosing; for this reason, loading doses of dexmedetomidine are often bypassed in critical care patients.[29112] [55062] [57161] [65633] [65635] If hypotension or bradycardia occur and require intervention, decrease or stop the infusion, increase the rate of intravenous fluids, elevate lower extremities, or use vasopressor as indicated.[29112] [31036] Consider an anticholinergic (e.g., glycopyrrolate, atropine) to modify vagal tone.[29112]

Propofol-related infusion syndrome (PRIS), a constellation of metabolic derangements and organ system failures characterized by severe metabolic acidosis, hyperkalemia, lipemia, rhabdomyolysis, hepatomegaly, renal failure, ECG changes (coved ST-segment elevations or Brugada-type changes), and/or heart failure has been associated with propofol use for intensive care sedation.[31036] PRIS is more common in pediatric patients, serious neurological injury, sepsis, prolonged infusion or high doses of propofol, and high doses of concomitant vasoconstrictors, inotropes, or corticosteroids.[31036] [55035] Monitor serum pH, lactate, creatinine kinase, triglycerides, myoglobin, and electrocardiograms if prolonged or high dose infusions are used.[55076] [65635] If PRIS is suspected, immediately discontinue propofol and do not rechallenge the patient.[55036]

Transient pain with injection is a well-known adverse reaction of propofol; pain can be minimized by using the larger veins of the forearm or antecubital fossa for peripheral administration and/or pretreating the patient with intravenous lidocaine.[31036] Injection site reactions have also been reported with parenteral benzodiazepine use.[41537][44859]

Injectable lorazepam contains propylene glycol and polyethylene glycol as solvents; lorazepam and some midazolam and propofol formulations contain benzyl alcohol as a preservative.[41537] [44859] [65468] Propylene glycol toxicity may manifest as metabolic acidosis, hyperosmolality, hypotension, acute kidney injury, and seizures. Polyethylene glycol toxicity may manifest as acute tubular necrosis. Both are more likely to occur with prolonged infusion, high doses, or renal dysfunction.[41537] [57161] Excessive amounts of benzyl alcohol in neonates have been associated with hypotension, metabolic acidosis, kernicterus, and a "gasping syndrome" characterized by central nervous system depression, metabolic acidosis, and gasping respirations. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known. Consider the daily metabolic load of benzyl alcohol from combined sources. Premature neonates and low-birth-weight neonates may be more likely to develop toxicity.[41537] [44859] [52904] [52949]

Propofol is formulated in an oil-in-water emulsion; prolonged use can cause hypertriglyceridemia and acute pancreatitis.[31036][57161][65633] Total caloric intake should account for propofol lipid content (1.1 kcal/mL). Monitor triglycerides in patients at risk for hyperlipidemia and in those receiving more than 48 hours of continuous propofol therapy with doses exceeding 50 mcg/kg/minute. Adjust the dose or consider alternative sedation if hypertriglyceridemia is detected.[31036][55042]

Coadministration of sedatives with other central nervous system depressants (e.g., anesthetics, hypnotics, opioids) may cause profound sedation, hypotension, and/or respiratory depression.[29112] [31036] [41537] [57161]

Concomitant use of valproate and lorazepam or propofol may result in increased plasma sedative concentrations; if used together, reduce the sedative dose and monitor the patient closely for signs of increased sedation or cardiorespiratory depression.[31036][41537]

Use dexmedetomidine and vasodilators or negative chronotropic agents together with caution; monitor patients closely for additive bradycardia or hypotension.[29112]

Coadministration of midazolam, a CYP3A4 substrate, with CYP3A4 inhibitors (e.g., erythromycin, ketoconazole, verapamil, itraconazole, saquinavir) may result in prolonged sedation due to decreased benzodiazepine clearance.[44859]

Patients with compromised myocardial function, intravascular volume depletion, or abnormally low vascular tone (e.g., sepsis) may be more susceptible to hypotension.[29112] [31036] [57161] Use dexmedetomidine with caution in patients with advanced heart block or severe ventricular dysfunction.[29112] Correct hypovolemia prior to initiation and ensure adequate hydration throughout sedation.[31036]

Although use of sedatives in mechanically ventilated patients with pulmonary insufficiency is necessary, it should be noted that pulmonary instability is more likely to occur in patients with baseline respiratory disease; continuous respiratory monitoring is required in intubated and non-intubated patients receiving sedatives.[57161] Hypoventilation, airway obstruction, and apnea are more likely to occur in patients with decreased pulmonary reserve.[44859] Lorazepam is contraindicated in patients with severe respiratory insufficiency or sleep apnea who are not mechanically ventilated.[41537]

Avoid abrupt discontinuation of prolonged or high-dose sedation; gradually decrease dosing to minimize agitation, anxiety, resistance to mechanical ventilation, or withdrawal symptoms. Maintain a light level of sedation for daily sedation awakening and neurologic evaluation. Repeated or continuous benzodiazepine doses over a prolonged period may result in physical dependence.[29112][31036][41537]

Tolerance to benzodiazepines develops with long-term administration.[57161] Use of dexmedetomidine beyond 24 hours has been associated with tolerance and tachyphylaxis.[29112]

Dexmedetomidine does not provide deep sedation, and patients may be arousable and alert when stimulated; this should not be considered a lack of efficacy in the absence of other clinical signs and symptoms. Dexmedetomidine does not produce amnesia and is not appropriate in clinical situations where amnesia is required (e.g., during neuromuscular blockade).[29112] [57161] [65297]

Use propofol with caution in patients with increased intracranial pressure or impaired cerebral circulation; significant decreases in mean arterial pressure and subsequent decreases in cerebral perfusion pressure (CPP) may occur. To avoid significant hypotension and decreases in CPP, utilize small boluses and slow titration.[31036]

Propofol is dissolved in a lipid emulsion containing egg lecithin and soybean oil, which can precipitate allergic reactions in patients with egg or soy allergies. Some generic formulations contain sulfite preservatives, which may also cause allergic reactions.[31036] [57161]

Propofol is formulated in an oil-in-water emulsion; use with caution in patients with disorders of lipid metabolism such as primary hyperlipoproteinemia, diabetic hyperlipemia, and pancreatitis.[31036]

Certain formulations of propofol contain ethylenediaminetetraacetic acid (EDTA), which is a strong chelator of trace metals including zinc. Consider zinc supplementation during prolonged therapy for patients predisposed to zinc deficiency, including those with burns, diarrhea, or sepsis. Do not infuse propofol for more than 5 days without providing a drug holiday to safely replace estimated or measured urine zinc losses.[31036]

Benzodiazepines can increase intraocular pressure in patients with glaucoma and are contraindicated in patients with acute narrow-angle glaucoma. Lorazepam and midazolam may be used in patients with open-angle glaucoma receiving appropriate therapy.[41537][44859]

Consider dexmedetomidine dosage reduction in patients with hepatic impairment; dexmedetomidine clearance decreases with increasing severity of hepatic impairment.[29112] [57161] Benzodiazepines are hepatically metabolized and can accumulate in patients with hepatic impairment.[41537] [44859] [57161]

Benzodiazepines may have a prolonged duration of effect in patients with renal impairment due to prolonged half-life and reduced clearance. Risk of lorazepam-associated propylene glycol or polyethylene glycol toxicity increases with renal dysfunction.[41537][44859][57161]