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Intravenous* sedative and analgesic dosing regimens for managing pain, agitation, and delirium in the intensive care unit

Intravenous* sedative and analgesic dosing regimens for managing pain, agitation, and delirium in the intensive care unit
Drug Loading dose Maintenance dose range Onset (minutes) Duration of intermittent dose (minutes) Characteristics and role
Opioid analgesics
Fentanyl

1 to 2 mcg/kgΔ

(25 to 100 mcg)

0.35 to 0.5 mcg/kg every 0.5 to 1 hour intermittent (25 to 50 mcg)

and/or

0.7 to 10 mcg/kg/hour infusion[1]

For most patients, 1 to 3 mcg/kg/hour infusion (50 to 300 mcg/hour) with as-needed intermittent bolus doses is sufficient
<1 to 2 30 to 60

Advantages: Potent analgesic-sedative with immediate onset and less hypotension than other opioid analgesic choices due to relative lack of histamine release. Metabolized hepatically by CYP3A4 to inactive metabolites.

Disadvantages: Highly lipophilic parent drug accumulates in adipose and other tissue with repeated or prolonged administration. Chest wall rigidity may occur with higher dosing§.

Role: A good choice for analgesia for most critically ill patients.
Hydromorphone 0.5 to 2 mgΔ

0.2 to 0.6 mg every 1 to 2 hours intermittent

and/or

0.5 to 3 mg/hour infusion
5 to 10 240 to 300

Advantages: IV administration requires small volumes relative to other opioids. Non-CYP metabolism (glucuronidation) may be an advantage for patients receiving drugs that significantly alter CYP3A4 metabolism and thereby interact with fentanyl.

Disadvantages: Potentially neurotoxic (excitatory) metabolite(s) may accumulate in hepatic and/or renal dysfunction§.

Role: Analgesic option alternative to fentanyl or morphine. Dose adjustment and gradual titration needed for patients with renal and/or hepatic impairment.
Morphine sulfate 2 to 10 mgΔ

2 to 4 mg every 1 to 2 hours intermittent

and/or

2 to 30 mg/hour infusion
5 to 10 240 to 300

Advantage: Non-CYP metabolism (glucuronidation) may be an advantage for selected patients receiving drugs that significantly alter CYP3A4 metabolism and thereby interact with fentanyl.

Disadvantages: Can accumulate in hepatic or renal dysfunction and prolong effects. Histamine release and vagally mediated venodilation, hypotension, and bradycardia can be significant§.

Role: Analgesic alternative to fentanyl or hydromorphone where preload reduction and myocardial depressive effects are desirable or tolerable. Dose adjustment and gradual titration needed for patients with renal and/or hepatic impairment. Avoid in patients with advanced or decompensated liver disease with renal impairment due to risk of accumulation of neurotoxic metabolite. Infusions are not generally used for sedation or analgesia in the ICU but are more commonly used for palliative purposes.
Remifentanil

Optional:
1.5 mcg/kg[1]

Most ICU patients can be managed without bolus doses; if required, a bolus of 0.5 mcg/kg is usually sufficient; larger boluses are associated with significant reductions in HR and MAP

0.5 to 15 mcg/kg/hour infusion

Use ideal body weight to determine dose for obese patients
1 to 3 5 to 10 (after cessation of infusion)

Advantages: Ultra-short-acting. Cleared by nonspecific plasma esterases to inactive metabolites. Does not accumulate in renal or hepatic impairment. Prompt reversal of analgesia and sedation upon discontinuation.

Disadvantages: Anticipate pain and discomfort upon abrupt cessation. Glycine excipient may accumulate in renal impairment§.

Role: An alternative to fentanyl for patients requiring frequent neurologic assessments or those with multiorgan failure.
Nonopioid analgesics (adjunctive or opioid sparing)
Acetaminophen
(paracetamol)
None

Oral, rectal: 325 to 1000 mg every 4 to 6 hours

IV: 650 mg IV every 4 hours to 1000 mg IV every 6 hours, or 15 mg/kg IV every 6 hours for patients weighing <50 kg

Maximum ≤4 g/day

Oral: 30 to 60

Rectal: Variable

IV: 5 to 10
240 to 360

Advantages: Lacks dependence and tolerance of opioids. Lacks antiplatelet effect and gastrointestinal toxicity of NSAIDs.

Disadvantages: Lacks significant anti-inflammatory effect. IV preparation requires administration over 15 minutes. Can cause hepatotoxicity in chronic or acute overdose. Avoid or use a lower daily dose in older adults and patients at risk for hepatotoxicity (eg, heavy alcohol use or malnourished). Interacts with warfarin (may prolong INR) and CYP-inducing drugs (elevated risk of hepatic inflammation).

Role: First choice for treatment of mild to moderate acute pain and febrile conditions. Adjunctive analgesic that may reduce opioid requirements. When hepatic dysfunction is significant, consider avoiding or reducing dose (eg, ≤2 g/day total).
Ketorolac Optional:
30 mg once

Age <65 years and weight ≥50 kg: 15 to 30 mg every 6 hours; maximum 120 mg/day for up to 5 days

Age ≥65 years or weight <50 kg: 15 mg every 6 hours; maximum 60 mg/day for up to 5 days
IV: ~30 360 to 480

Advantages: Lacks dependence and tolerance of opioids. Effective anti-inflammatory.

Disadvantages: Can cause or worsen renal insufficiency. Dose-related risk of gastropathy. Reversibly inhibits platelet functioning. May alter cardioprotective effect of aspirin.

Role: Adjunctive analgesic that may reduce opioid requirements.

Avoid in renal impairment, gastrointestinal bleeding, platelet dysfunction, ischemic heart disease, heart failure, reduced cardiac output, hypovolemic state, asthma, or cirrhosis. Contraindicated in treatment of perioperative pain in coronary artery bypass graft surgery. Patients should be well hydrated.
Ibuprofen None

Oral: 400 mg orally every 4 hours (maximum 2.4 g/day chronic)

IV: 400 to 800 mg IV every 6 hours (maximum 3.2 g/day acute)

Oral: 30

IV: ~30
240 to 360

Advantages: Lacks dependence and tolerance of opioids. Effective anti-inflammatory.

Disadvantages: Can cause or worsen renal insufficiency. Dose-related risk of gastropathy. Reversibly inhibits platelet functioning. Can alter cardioprotective effect of aspirin.

Role: Short-term treatment of moderate acute pain and febrile conditions. Adjunctive analgesic that may reduce opioid requirements.

Avoid in renal impairment, gastrointestinal bleeding, platelet dysfunction, ischemic heart disease, heart failure, reduced cardiac output, hypovolemic state, asthma, or cirrhosis. Contraindicated in treatment of perioperative pain in coronary artery bypass graft surgery. Patients should be well hydrated.
Gabapentin None

Oral: Initially 100 mg 3 times per day

Oral: Maintenance 900 to 3600 mg per day in 3 divided doses
Variable --

Advantages: Effective for treatment of neuropathic pain. Low risk of drug interactions.

Disadvantages: Requires enteral administration, scheduled dosing, and individualized titration over days to weeks. Oral bioavailability is variable (27 to 60%) and inversely proportional to dose. Adverse effects include sedation, dizziness, and ataxia, which may be intensified in renal impairment, requiring dose adjustment. Should not be abruptly stopped, due to risk of discontinuation symptoms.

Role: Useful adjunct to other analgesics for treatment of neuropathic and postoperative pain or dysesthesias in patients who can be treated with enteral medication. Dose adjustment needed for renal impairment.
Pregabalin None

Oral: Initially 75 mg once or twice per day

Oral: Maintenance 150 to 300 mg twice per day
Variable (hours to days) --

Advantages: Effective for treatment of neuropathic pain. Oral bioavailability (>90%) is more reliable than gabapentin and may provide for more rapid onset of analgesia with a shorter amount of time needed to titrate to full dose. Low risk of drug interactions.

Disadvantages: Requires enteral administration, scheduled dosing, and titration over days to weeks. Adverse effects include sedation, blurred vision, dry mouth, dizziness, and ataxia, which may be intensified in renal impairment, requiring dose adjustment. Should not be abruptly stopped, due to risk of discontinuation symptoms.

Role: Useful adjunct to other analgesics for treatment of neuropathic and postoperative pain or dysesthesias in patients who can be treated with enteral medication. Dose adjustment needed for renal impairment.
Anesthetic-sedative
Propofol Bolus doses are usually not given in the ICU

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 (refer to UpToDate topics on sedative-analgesic medications in critically ill patients: properties, dose regimens, and adverse effects)
<1 to 2 3 to 10

Advantages: Potent sedative-hypnotic associated with an immediate onset and rapid awakening upon discontinuation when administered for short-term use. Metabolism is reportedly unaltered in hepatic or renal impairment and subject to few significant drug interactions. Infusion is readily titratable to desired depth of sedation, minimizing risk of oversedation. Propofol effectively decreases intracranial pressure, lowers cerebral metabolism, controls intractable seizures, and may reduce shivering in the rewarming phase of induced hypothermia following resuscitation from cardiac arrest.

Disadvantages: Adverse effects include hypotension, bradycardia, respiratory depression, decreased myocardial contractility, elevated triglycerides, peripheral injection site pain, and rarely propofol infusion syndrome (refer to UpToDate topics on sedative-analgesic medications in critically ill patients: properties, dose regimens, and adverse effects). Specific product presentations may include potential allergens (egg, soy, peanut, others). Consult product label information. No analgesic effects.

Role: A good choice in conjunction with appropriate analgesia for short-term sedation of patients in whom rapid awakening is advantageous. Also a good choice to decrease elevated intracranial pressure or for short-term sedation in a general critical care population that is likely to be ready soon for ventilator weaning trials.
Ketamine

0.25 to 0.5 mg/kg bolus IV

Bolus doses may be given prior to sedation with an infusion of ketamine or as a single bolus (eg, patients with burns prior to dress changes or for procedural sedation)

Bolus dosing may be repeated if necessary during the procedure (maximum dose 2 mg/kg in a 30 minute period)
0.05 to 0.4 mg/kg/hour ≤1 10 to 15 (single dose)

Advantages: A potent dissociative sedative-anesthetic with marked analgesia that maintains cardiac output and mean arterial pressure without inhibition of respiratory drive. Does not inhibit protective reflexes. May reduce acute opioid tolerance.

Disadvantages: Sympathetic stimulation (ie, increased heart rate and myocardial oxygen demand, elevated intracranial pressure and systemic blood pressure) may be intolerable depending upon clinical setting. Rarely, cardiorespiratory depression associated with rapid administration or higher doses. Adverse effects may include hallucinations, delirium upon withdrawal, tonic-clonic movements, dissociative experiences, unpleasant recall, hypersalivation, nausea, and vomiting. Complex metabolism includes CYP3A4, 2C9, 2B6, and non-CYP hepatic transformations and an active metabolite (norketamine), which may accumulate in renal and/or hepatic impairment or due to drug interactions.

Role: An alternate choice for postsurgical pain management, severe agitation, or as an adjunctive analgesic in patients with severe refractory pain in clinical settings where increased myocardial oxygen demand and sympathetic tone are tolerable.
Central alpha2 agonist
Dexmedetomidine

Optional:
1 mcg/kg over 10 minutes if hemodynamically stable

Usually not given

0.2 to 1.5 mcg/kg/hour

Initiate at 0.2 mcg/kg/hour and titrate every 30 minutes**

5 to 10 (optional loading dose)

15 (without loading dose)
60 to 120

Advantages: Effective sedative sympatholytic (central alpha2 agonist) with moderate anxiolysis and analgesia. Character and depth of sedation may permit critically ill, mechanically ventilated patients to be interactive or easily awakened, yet comfortable. Can be used in non-mechanically ventilated ICU patients and continued as needed following extubation. Reduces shivering in the rewarming phase of induced hypothermia following resuscitation from cardiac arrest. May be less likely to cause delirium than other sedative choices.

Disadvantages: Potentially significant hypotension and bradycardia or hypertension that do not resolve quickly upon abrupt discontinuation. Metabolized hepatically by glucuronidation and CYP2A6. Dose reduction recommended with renal and/or hepatic impairment. Rapid administration of loading dose may be associated with cardiovascular instability, tachycardia, bradycardia, or heart block. Does not induce the deep sedation needed for neuromuscular blockade.

Role: A good choice for short- and long-term sedation in critically ill patients without relevant cardiac conditions. May be useful for sedation of patients with or at high risk of developing delirium, although this has not been well established.
Benzodiazepines
Midazolam

0.01 to 0.05 mg/kgΔ

(0.5 to 4 mg)

0.02 to 0.1 mg/kg/hour infusion

(2 to 8 mg/hour) with intermittent bolus dose(s) if needed. While the patient is on a continuous infusion, periodic re-bolus may be needed to maintain the sedation goal. This approach may help prevent unnecessary dose creep of the infusion.
2 to 5 30

Advantages: A potent amnestic and anxiolytic agent with an immediate onset of action and a short duration of effect when administered short term (<48 hours). It is the only IV benzodiazepine that is not delivered in propylene glycol.

Disadvantages: Hepatically metabolized by CYP3A4 to active metabolites that may accumulate and cause prolonged sedation if delivered long term. Half-life may be prolonged in critically ill patients with hepatic or renal impairment. Risk of delirium. Also, it interacts with drugs used in the ICU (eg, some antiretrovirals, azole antifungals) that alter CYP metabolism such that excess sedation can occur with concomitant use of midazolam and drugs metabolized by CYP3A4.

Role: A good choice for short-term anxiolysis and treatment of acute agitation. Dose adjustment and gradual titration are needed for patients with renal and/or hepatic impairment.
Lorazepam

0.02 to 0.04 mg/kgΔ

(1 to 2 mg)

0.02 to 0.06 mg/kg every 2 to 6 hours intermittent (1 to 4 mg)

and/or

0.01 to 0.1 mg/kg/hour infusion (0.5 to 10 mg/hour)
15 to 20 360 to 480

Advantages: Sedative, amnestic, potent anxiolysis with anticonvulsant properties. Hepatically metabolized by glucuronidation to inactive metabolites. Relatively low risk of drug interactions and safety in mild to moderate hepatic and renal impairment.

Disadvantages: Relatively slow onset. Risk of oversedation when titrating due to delayed response and accumulation in peripheral tissues. Risk of delirium. IV incompatibilities and risk of line precipitate. Propylene glycol solvent may accumulate with prolonged use or high dosing causing metabolic acidosis and end-organ dysfunction (refer to UpToDate topics on sedative-analgesic medications in critically ill patients: properties, dose regimens, and adverse effects). Long half-life, with significant risk of accumulation in older adults or in patients with significant renal or hepatic impairment.

Role: A good choice for sedation and anxiolysis for most patients, including those who may require long-term ongoing sedation. Although intermittent bolus dosing may be preferred, a continuous infusion may be initiated for patients requiring frequently repeated higher dosing.
Diazepam

0.05 to 0.2 mg/kgΔ

(5 to 10 mg)

0.03 to 0.1 mg/kg every 0.5 to 6 hours intermittent (1 to 7 mg)

Continuous infusion is not recommended
2 to 5 20 to 60

Advantages: Rapid onset with potent sedative and muscle-relaxant effects.

Disadvantages: Hepatically metabolized by CYP2C19 and 3A4 to active metabolites that may accumulate and cause prolonged sedation if delivered long term. Half-life may be prolonged in critically ill patients with hepatic and/or renal impairment. Risk of delirium. Also, it interacts with drugs used in the ICU that alter CYP metabolism. Injection solution contains propylene glycol solvent and cannot be delivered as a continuous infusion. Injection site pain and risk of phlebitis limit usefulness of IV injections.

Role: Seldom used for sedation of critically ill patients. May be useful for critically ill patients at risk of alcohol withdrawal or seizures due to drug overdose or poisoning.
Antipsychotics
Haloperidol¥

0.03 to 0.15 mg/kgΔ

Variable doses; refer to UpToDate topics on sedative-analgesic medications in critically ill patients: properties, dose regimens, and adverse effects

0.03 to 0.15 mg/kg every 30 minutes to 6 hours

Various regimens; refer to UpToDate topics on sedative-analgesic medications in critically ill patients: properties, dose regimens, and adverse effects
5 to 20 minutes (IV) 30 to 360

Advantages: Moderately sedating dopamine2 antagonist for control of positive symptoms of delirium and ICU psychoses. Minimal cardiorespiratory effects in euvolemic, hemodynamically stable patients.

Disadvantages: Complex hepatic metabolism includes CYP3A4 and 2D6 transformations. Some experts consider certain metabolites to be active or potentially neurotoxic. Half-life becomes prolonged with repeated administration. Adverse effects include dose-dependent QT interval prolongation and hypotension. Interacts with some common ICU drugs by interference with metabolism and/or by having an additive effect, prolonging the QTc. Extrapyramidal symptoms and neuroleptic malignant syndrome are rare in critical care use.

Role: Potential treatment for agitation and/or delirium in critically ill patients.
Olanzapine

Optional:
5 to 10 mg IM

May repeat every two to four hours if needed (maximum total 30 mg)
Oral: Initially 5 to 10 mg once daily; increase every 24 hours as needed by 5-mg increments up to 20 mg/day IM: 15 to 45 IM: ≥120

Advantages: Availability of short-acting IM formulation; less risk of extrapyramidal symptoms and QT prolongation than haloperidol.

Disadvantages: Adverse effects include orthostatic hypotension, hyperglycemia, somnolence, QT interval prolongation, and anticholinergic effects. Undergoes extensive hepatic metabolism including non-CYP (ie, glucuronidation) and CYP1A2 transformations. Half-life may be prolonged (ie, ≥50 hours) with increased risk of accumulation in patients who are older, female, nonsmoking, and/or in the setting of hepatic or renal impairment.

Role: Potential alternative or add-on to as-needed IV haloperidol for treatment of acute agitation and/or delirium in the ICU. Use lowest starting dose and titrate more gradually in patients with renal and/or hepatic impairment and/or other factors that predispose for slowed metabolism (see "Disadvantages" above).
Quetiapine None Oral: Initially 50 mg every 12 hours; increase every 24 hours as needed up to 400 mg/day Oral: 60 (initial effect); ≥24 hours (full effect) Oral: 6 to 12 hours

Advantages: Less risk of extrapyramidal symptoms and possibly less risk of QT prolongation than haloperidol.

Disadvantages: Requires enteral route of administration and scheduled dosing due to slow onset of action and relatively gradual titration schedule. Adverse effects may include sedation or orthostatic hypotension, and risk of QT interval prolongation remains. Hepatically metabolized by CYP3A4 to active and inactive metabolites.

Role: A potential choice as adjunct to as-needed IV haloperidol for treatment of agitation and/or delirium. In advanced hepatic impairment, initiate with reduced dose and titrate in lower increments.
Ziprasidone

Optional:
10 mg IM

May repeat every two hours if needed (maximum 40 mg total)

or

20 mg IM

May repeat once after 4 hours if needed (maximum 40 mg total)
Oral: 20 to 40 mg orally every 12 hours IM: 30 IM: ≥90

Advantages: Availability of short-acting IM formulation; less risk of extrapyramidal symptoms than haloperidol.

Disadvantages: Orthostatic hypotension, hyperglycemia, QT prolongation; undergoes extensive hepatic metabolism by hepatic non-CYP and CYP3A4 transformations to active and inactive metabolites; IM formulation contains cyclodextrin (a potential nephrotoxin), which can accumulate in renal impairment; an IV formulation is not available. Oral formulation needs to be taken in a fed state (≥500 calories) for reliable absorption.

Role: A potential alternative or add-on to as-needed IV haloperidol for treatment of acute agitation in the ICU. Dose reduction is needed in advanced hepatic impairment. Specific recommendations are not available. Avoid prolonged use of IM preparation in patients with renal impairment due to risk of accumulation of cyclodextrin additive.

Dosing information in this table is for critically ill adults and includes indications, dosing, duration of use, and routes of administration not listed in the US Food & Drug Administration approved product labeling. Refer to UpToDate content on managing pain, agitation, and delirium in critically ill adults, the Lexicomp drug monographs[2], and most recent product labeling for additional information.

Data provided in "Characteristics and role" on drug metabolism and the presence of active metabolite(s) are included and may be useful for assessing the potential for drug interactions and risk of drug accumulation in renal and/or hepatic organ impairment.

CYP: cytochrome P-450 metabolism; IV: intravenous; ICU: intensive care unit; HR: heart rate; MAP: mean arterial pressure; NSAIDs: nonsteroidal anti-inflammatory drugs; INR: international normalized ratio; QT: QT interval on the electrocardiogram; QTc: corrected QT interval; IM: intramuscularly.

* All doses shown are for IV administration except where otherwise noted (eg, oral or rectal acetaminophen, IM olanzapine optional initial dose).

¶ In patients who are obese, standard, non-weight-based initial dosing is preferred. Standard adult doses, ie, scaled to ideal body weight, are shown in parentheses following weight-based doses. A separate calculator to determine ideal body weight is available in UpToDate. For additional information, refer to UpToDate topic reviews on ICU management of the complicated postoperative bariatric surgery patient.

Δ One or more loading doses may be needed. See onset of action data for minimum time between re-dosing. Loading dose should be reduced or omitted in patients who are older, hypovolemic, having increasing vasopressor requirements, or at-risk for hemodynamic compromise.

◊ Duration of action shown is for initial dosing. Duration becomes significantly prolonged after repeated dosing or with administration as a continuous infusion due to accumulation of drug in adipose tissue.

§ As with all opioids, tolerance may require dose escalation, and withdrawal syndrome may be precipitated upon abrupt discontinuation.

¥ Dosing of haloperidol in agitated schizophrenia differs from the recommendations listed in this table for agitated delirium in the ICU and is reviewed separately. Refer to UpToDate topic reviews of emergency management of the acutely agitated or violent patient and pharmacotherapy for acute schizophrenia.

‡ The precise role of second-generation antipsychotics in the treatment or prevention of agitated delirium in ICU is not established. Quetiapine and olanzapine recommendations and data are based on limited experience and small trial results.[1,2] Some experts start at one-quarter to one-half of doses shown and titrate gradually based upon response particularly in older adults and patients with organ dysfunction.

† Ziprasidone recommendations and data are based on limited experience and small trial results in treatment of undifferentiated agitation without symptoms of delirium in non-critically ill emergency department patients.[3,4] Small trial results failed to demonstrate a benefit for scheduled oral ziprasidone in prevention of delirium in a general ICU population.[5]

** Dosing of dexmedetomidine in obese patients is typically performed according to the ideal body weight.
References:
  1. Devlin JW, Roberts RJ, Fong JJ, et al. Efficacy and safety of quetiapine in critically ill patients with delirium: a prospective, multicenter, randomized, double-blind, placebo-controlled pilot study. Crit Care Med 2010; 38:419.
  2. Skrobik YK, Bergeron N, Dumont M, Gottfried SB. Olanzapine vs haloperidol: treating delirium in a critical care setting. Intensive Care Med 2004; 30:444.
  3. Martel M, Sterzinger A, Miner J, et al. Management of acute undifferentiated agitation in the emergency department: a randomized double-blind trial of droperidol, ziprasidone, and midazolam. Acad Emerg Med 2005; 12:1167.
  4. Mantovani C, Labate CM, Sponholz A Jr, et al. Are low doses of antipsychotics effective in the management of psychomotor agitation? A randomized, rated-blind trial of 4 intramuscular interventions. J Clin Psychopharmacol 2013; 33:306.
  5. Girard TD, Pandharipande PP, Carson SS, et al. Feasibility, efficacy, and safety of antipsychotics for intensive care unit delirium: the MIND randomized, placebo-controlled trial. Crit Care Med 2010; 38:428.

Adapted from:

  1. 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.
  2. Lexicomp Online. Copyright © 1978-2023 Lexicomp, Inc. All Rights Reserved.
  3. Devlin JW, Skrobik Y, Gélinas 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.
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