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Jun.14.2020

Sedatives for ICU Sedation

Summary

  • Sedatives are used in critically ill patients to reduce discomfort, increase tolerance of mechanical ventilation, prevent agitation-related harm, and reduce metabolic demands during cardiovascular and respiratory instability.
  • Long-term sedation may have serious adverse effects including prolonged mechanical ventilation, delirium, impaired cognitive function, prolonged hospitalization, increased costs, and mortality.
  • In general, nonbenzodiazepine sedatives are preferred; however, the choice of sedative should be driven by the specific indication, sedation goal, and clinical pharmacology of the drug (e.g., onset and duration, adverse effects).

Pharmacology/Mechanism of Action

Benzodiazepines act through gamma-aminobutyric acid type A (GABAA) receptors in the brain to produce anxiolytic, amnestic, sedative, hypnotic, and anticonvulsant effects. Propofol binds to multiple receptors in the central nervous system including GABAA, glycine, nicotinic, and M1 muscarinic receptors to produce anxiolytic, amnestic, sedative, hypnotic, antiemetic, and anticonvulsant effects. Dexmedetomidine is a selective alpha2-receptor agonist with sedative, analgesic/opioid-sparing, and sympatholytic properties.[57161][65633]

Therapeutic Use

  • Sedatives are used in critically ill patients to reduce discomfort, increase tolerance of mechanical ventilation, prevent agitation-related harm, and reduce metabolic demands during cardiovascular and respiratory instability.[65297] [65629]
  • Nonbenzodiazepine sedatives are recommended over benzodiazepines in non-cardiac surgery, mechanically ventilated patients.[57161] [65297]
  • Propofol is recommended over benzodiazepines for mechanically ventilated patients after cardiac surgery.[65297]
  • Dexmedetomidine is recommended over benzodiazepines when sedation is required during delirium unless the delirium is related to alcohol or benzodiazepine withdrawal.[57161]
  • Dexmedetomidine has a relatively short half-life, limited effects on respiratory drive, and opioid-sparing effects, making it an attractive option in various clinical scenarios; it does not have amnestic properties and is associated with dose-related hypotension and bradycardia.[57161] [65632]
  • Benzodiazepines are important for ICU sedation, especially when treating anxiety, seizures, and alcohol or benzodiazepine withdrawal, or when deep sedation, amnesia, or when more than 1 sedative is required.[57161]
  • Midazolam has a quicker onset of action compared to lorazepam; however, unlike lorazepam, it is metabolized to an active metabolite, so offset may be less predictable or prolonged in critically ill patients, especially those with renal impairment.[57161] [65633] [65635]
  • Lorazepam is more potent than midazolam but its use is limited by the fact that it is dissolved in propylene glycol, which can accumulate and produce metabolic acidosis and renal dysfunction.[57161] [65635]
  • At light sedation levels, propofol's amnestic effects are less than that of benzodiazepines. With short term use, propofol has a rapid onset and offset of action where emergence is related to redistribution and not metabolic clearance, which is advantageous in patients with renal or hepatic impairment; however, long-term use leads to peripheral saturation and emergence becomes more dependent on metabolic clearance.[57161] [65635]

Clinical Pharmacology of Sedatives [57161]

Drug

Onset*

Elimination Half-Life

Active Metabolites

Dexmedetomidine

5 to 10 minutes

2 to 3 hours

None

Lorazepam

15 to 20 minutes

8 to 15 hours

None

Midazolam

2 to 5 minutes

3 to 11 hours

Yes

Propofol

1 to 2 minutes

Short-term use:

3 to 12 hours

Long-term use:

50 hours

None

*After IV loading dose

Comparative Efficacy

  • Overall, benzodiazepines are associated with less time at light sedation, longer duration of mechanical ventilation, and higher incidence of delirium when compared to dexmedetomidine or propofol. While bradycardia is common with dexmedetomidine use, bradycardia necessitating treatment was not significantly different than comparators during clinical trials.[65626] [65627] [65629] [65630]
  • Use of propofol infusions with daily sedative interruption resulted in fewer ventilator days compared with intermittent lorazepam boluses in medical ICU patients requiring more than 48 hours of mechanical ventilation (n = 132); however, there was no difference in ventilator-free survival, length of stay (ICU or hospital), or mortality.[65626]
  • Sedation with dexmedetomidine resulted in 4 more days alive without delirium or coma and more time within the target sedation range as compared with lorazepam infusion in mechanically ventilated medical and surgical ICU patients (n = 106); however, there was no difference in mortality, ventilator-free days, and ICU length of stay.[65627]
  • Despite similar times within the target sedation range, dexmedetomidine-treated patients developed delirium about 20% less than and were extubated almost 2 days earlier than midazolam-treated patients in a double-blind, randomized trial in medical and surgical ICU patients (n = 375).[65630]
  • Dexmedetomidine was associated with fewer ventilator days compared to midazolam, decreased time to extubation compared to both propofol and midazolam, reduced incidence of delirium as compared to propofol, and improved patient interaction compared to both midazolam and propofol in 2 trials comparing dexmedetomidine and midazolam (n = 500) and dexmedetomidine and propofol (n = 498) in mechanically ventilated patients requiring light to moderate sedation for more than 24 hours; however, there was no difference in time within target sedation range, length of stay (ICU or hospital), or mortality.[65629]
  • Dexmedetomidine as the sole or primary sedative did not improve 90-day mortality and was associated with more adverse effects (e.g., bradycardia, hypotension, asystole) compared to usual care with propofol, midazolam, or other sedatives in an open-label trial of mechanically ventilated patients (n = 3,904).[65628]

Adverse Reactions/Toxicities

Hypotension and bradycardia

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

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]

Injection site pain

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]

Excipient toxicity

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]

Hypertriglyceridemia

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]

Drug Interactions

Central nervous system depressants

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]

Valproate

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]

Vasodilators

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

CYP3A4 inhibitors

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]

Safety Issues

Cardiovascular instability

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]

Respiratory insufficiency

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]

Abrupt discontinuation

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

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

Arousability

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]

Increased intracranial pressure

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]

Egg and soy hypersensitivity

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]

Disorders of lipid metabolism

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]

Zinc deficiency

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]

Glaucoma

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]

Hepatic impairment

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]

Renal impairment

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]

[29112]Precedex (dexmedetomidine) injection package insert. Lake Forest, IL: Hospira; 2020 Feb.

[31036]Diprivan (propofol injection, emulsion) package insert. Lake Zurich, IL: Fresenius Kabi USA, LLC; 2019 Dec.

[41537]Ativan (lorazepam) injection package insert. Berkeley Heights, NJ: Hikma Pharmaceuticals; 2021 Feb.

[44859]Midazolam injection package insert. Lake Forest, IL: Hospira, Inc.; 2020 Jan.

[52904]Lorazepam oral concentrate package insert. Amityville, NY: Hi-Tech Pharmacal Co., Inc. 2020 Sept.

[52949]American Academy of Pediatrics Committee on Drugs. "Inactive" ingredients in pharmaceutical products: update (subject review). Pediatrics 1997;99:268-278.

[55035]Cannon ML, Glazier SS, Bauman LA. Metabolic acidosis, rhabdomyolysis, and cardiovascular collapse after prolonged propofol infusion. J Neurosurg 2001;95:1053-1056.

[55036]Timpe EM, Eichner SF, Phelps SJ. Propofol-related infusion syndrome in critically ill pediatric patients: coincidence, association, or causation? J Pediatr Pharmacol Ther 2006;11:17-42.

[55042]Devlin JW, Lau AK, Tanios MA. Propofol-associated hypertriglyceridemia and pancreatitis in the intensive care unit: an analysis of frequency and risk factors. Pharmacotherapy 2005;25:1348-1352.

[55062]Tobias JD. Sedation and analgesia in paediatric intensive care units: a guide to drug selection and use. Paediatr Drugs 1999;1:109-126.

[55076]Pate MF, Steelman R. Questions unanswered: propofol use in the pediatric intensive care unit. AACN 2007;18:248-252.

[57161]Barr J, Fraser GL, Puntillo K, et al. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med 2013;41:263-306.

[65297]Devlin JW, Skrobik Y, Gelinas C, 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;46:e825-e873.

[65468]Propofol 1% injection package insert. Princeton, NJ: Dr. Reddy's Laboratories, Inc.; 2017 Sep.

[65626]Carson SS, Kress JP, Rodger JE, et al. A randomized trial of intermittent lorazepam versus propofol with daily interruption in mechanically ventilated patients. Crit Care Med 2006;34:1326-1332.

[65627]Pandharipande PP, Pun BT, Herr DL, et al. Effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechanically ventilated patients: the MENDS randomized controlled trial. JAMA 2007;298;2644-2653.

[65628]Shehabi Y, Howe BD, Bellomo YM, et al. Early sedation with dexmedetomidine in critically ill patients. N Engl J Med 2019;380:2506-2517.

[65629]Jakob SM, Ruokonen E, Grounds RM, et al. Dexmedetomidine vs midazolam or propofol for sedation during prolonged mechanical ventilation: two randomized controlled trials. JAMA 2012;307:1151-1160.

[65630]Riker RR, Shehabi Y, Bokesch PM, et al. Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial. JAMA 2009;301:489-499.

[65632]Engelman DT, Ali WB, Williams JB, et al. Guidelines for perioperative care in cardiac surgery: enhanced recovery after surgery society recommendations. JAMA Surg 2019;154:755-766.

[65633]Reade MC, Finfer S. Sedation and delirium in the intensive care unit. N Engl J Med 2014;370:444-454.

[65635]Hughes CG, Stuart M, Pandharipande PP. Sedation in the intensive care unit. Clin Pharmacol 2012;4:53-63.