Version May 2024
INTRODUCTION — Distress due to pain, fear, anxiety, dyspnea, or delirium is common among critically ill patients, especially those who are intubated or are having difficulty communicating with their caregivers. Distress may manifest clinically as agitation that is often associated with ventilator asynchrony and increased sympathetic tone, which may have untoward clinical effects.
The mechanism of action, efficacy, properties, dosing, and adverse effects of common sedative-analgesic medications used to treat distress in critically ill adults are reviewed in this topic. Selecting the optimal sedative-analgesic strategy and management of pain and neuromuscular blockade in critically ill patients are discussed separately. (See "Sedative-analgesia in ventilated adults: Management strategies, agent selection, monitoring, and withdrawal" and "Pain control in the critically ill adult patient" and "Neuromuscular blocking agents in critically ill patients: Use, agent selection, administration, and adverse effects".)
CHOOSING AGENT — No sedative-analgesic agent is sufficiently superior to warrant its use in all clinical situations. As a result, selection of an agent must be individualized according to pharmacokinetic variables (eg, potential interactions with other drugs) and nonpharmacokinetic variables (eg, renal and liver failure, presence of bradycardia or hypotension), the etiology of the distress, and the desired depth of sedation. The selection of sedative agents in the critically ill patient is discussed in detail separately. (See "Sedative-analgesia in ventilated adults: Management strategies, agent selection, monitoring, and withdrawal", section on 'Selection of agent(s)'.)
ANALGESICS — Pain is a common reason for agitation in critically ill patients. Pain is managed with opioid and nonopioid analgesic agents.
Opioid analgesics — The most common opioids used to manage distress due to pain in critically ill patients are fentanyl, hydromorphone, and morphine sulphate. They can be administered as intermittent dosing or continuous infusions. Oral opioids such as oxycodone, methadone, and morphine are also given to patients when oral or enteral administration is preferred. Remifentanil is also an option. Choice of opioid analgesic and their individual properties are discussed in detail separately (table 1). (See "Pain control in the critically ill adult patient", section on 'Opioid analgesics'.)
Nonopioid analgesics — Acetaminophen (enteral or intravenous [IV]), nonsteroidal anti-inflammatory agents, IV ketamine, and IV dexmedetomidine can be used as alternatives or additives to opioids for the management of nonneuropathic pain in the intensive care unit (ICU) (table 1). Additionally, they can be used as opioid-sparing agents to reduce or eliminate the need for opioids in critically ill adult patients [1]. Enteral gabapentin, pregabalin, and/or carbamazepine, in addition to IV opioids, can be used to treat neuropathic pain in adult ICU patients. Use of nonopioid analgesics is discussed separately. (See "Pain control in the critically ill adult patient", section on 'Nonopioid analgesics'.)
PROPOFOL — Propofol is an intravenous (IV) anesthetic that is commonly used for sedation of the agitated adult intensive care unit (ICU) patient.
Mechanism — Activation of the central gamma-aminobutyric acid (GABA) type A receptors with modulation of hypothalamic sleep pathways appears to be the mechanism by which propofol exerts its effect [2-5]. Propofol has amnesic, anxiolytic, anticonvulsant, and muscle relaxant (including bronchodilation) effects. It has no direct analgesic effects.
Properties — Propofol is a highly lipophilic phenol derivative that is insoluble in water. Therefore, it is formulated as an emulsion of soybean oil, egg lecithin, and glycerol for IV administration. Although hypersensitivity reactions are rare, labeled contraindications include hypersensitivity to eggs, egg products, soy, or soy products [6,7].
The elimination of propofol is not impaired by hepatic or renal dysfunction. Propofol has a large volume of distribution and is highly protein bound. Its rapid onset and short duration make it a useful agent in the ICU.
●Onset of action – Propofol has an onset of action of less than one minute because its high lipophilicity facilitates passage through the blood-brain barrier.
●Duration of effect – Propofol's duration of effect is 3 to 10 minutes during short-term use (<48 hours). The short duration reflects the rapid metabolism of propofol by the liver and elsewhere to minimally active metabolites, which are renally excreted.
Less is known about propofol's duration of effect following long-term administration (eg, a few days). One study reported an elimination half-life of 31 hours after prolonged administration, suggesting that propofol's high lipophilicity leads to its accumulation in fatty tissues and prolonged sedation [8]. Another study reported a longer time to extubation in patients who received propofol for extended periods compared with patients receiving short-term sedation with propofol (<24 hours); extubation was delayed by 10 minutes in patients on propofol for one to seven days and by 30 minutes for patients on propofol for greater than seven days [9,10].
Dosing and administration — A typical dose regimen for propofol is listed in the table (table 1) [1]. A loading dose is not typically administered when a propofol infusion is started in the ICU for sedation unless a bolus dose is required for emergency care (eg, intubation, transport, procedures).
Propofol is administered by continuous infusion in the ICU and not by intermittent bolus because it is associated with dose- and rate-dependent hypotension.
The manufacturer recommends that the bottles and tubing be discarded every 12 hours and that line integrity be maintained to minimize the risk of bacterial contamination.
When administered peripherally, propofol is generally given through a large-bore IV catheter (often in the antecubital fossa) to reduce burning, stinging, and pain that can occur with peripheral administration.
During administration, we perform routine biochemical monitoring with a daily basic metabolic panel, triglycerides (eg, once daily for the first three days); if propofol-related infusion syndrome (PRIS) is suspected, we also measure serum lactate, creatinine kinase, and myoglobin. [11]. This approach may allow for the early identification of worrisome side effects (See 'Adverse effects' below.)
Propofol should be discontinued as soon as any significant abnormality is identified (eg, clinical suspicion for PRIS, high serum triglyceride concentration >300 mg/dL). The upper limit of tolerance for hypertriglyceridemia is unknown. Data suggest that levels up to 300 mg/dL, sometimes 400 mg/dL is reasonable [12-14]. (See 'Propofol-related infusion syndrome' below.)
Adverse effects
General — Hypotension is a common consequence of propofol infusion, estimated to occur in approximately 25 percent of ICU patients who receive propofol for sedation [15]. Hypotension is frequent following bolus administration but can even occur with low-dose infusions. In an observational study of almost 26,000 patients receiving propofol anesthesia, 16 percent developed hypotension and over three-quarters of the hypotensive episodes occurred within 10 minutes of induction via a bolus infusion [16].
Other potential adverse effects of propofol that are uncommon include bradycardia, arrhythmias, neuroexcitatory effects (seizure-like activity, myoclonus, choreoathetoid movements, meningismus), infections from contaminated vials or tubing, respiratory depression, pancreatitis, hypertriglyceridemia, anaphylaxis, and green or white discoloration of urine [8,17-20].
Unusual and potentially serious complications are associated with continuous infusion of propofol for longer than 24 to 48 hours. These include progressive hypertriglyceridemia, pancreatitis, increased carbon dioxide production, and an excessive caloric load (the emulsion contains approximately 1.1 kcal/mL, most of which is derived from lipids). Despite these complications, a meta-analysis of 14 randomized trials reported that in critically ill patients, prolonged propofol infusions (>24 hours) do not increase overall mortality compared with other sedatives (eg, benzodiazepines) [21].
Propofol-related infusion syndrome — PRIS is a rare complication of propofol infusion (<1 percent) with an unclear pathogenesis [22,23].
●Clinical features – PRIS is characterized by one or more of the following that is otherwise unexplained [22,24,25]:
•Acute refractory bradycardia, less commonly ventricular tachycardia or fibrillation, asystole, widened QRS complex
•Severe metabolic acidosis
•Cardiovascular collapse
•Rhabdomyolysis
•Hyperlipidemia
•Hyperkalemia
•Acute kidney injury
•Hepatomegaly
•Transaminitis
•Fever
●Risk factors – Risk factors for PRIS include high doses (>4 mg/kg/hour or >67 mcg/kg/min) and prolonged use (>48 hours) [22,24,26,27], although it has also been reported with high-dose short-term infusions [28,29]. Additional proposed risk factors include young age, critical illness, high fat and low carbohydrate intake, inborn errors of mitochondrial fatty acid oxidation, and concomitant catecholamine infusion or glucocorticoid therapy [29].
●Diagnosis – PRIS is a diagnosis of exclusion. Once PRIS is suspected, propofol should be stopped while investigations are ongoing.
●Treatment – Treatment involves immediate discontinuation of the propofol infusion and supportive care [29]. Successful use of extracorporeal membrane oxygenation has been described [30,31] as has hemofiltration to remove propofol rapidly from the body [32].
●Prognosis – Mortality is variable but high (33 to 66 percent) [22,24,33,34]. Predictors of death vary among studies and are unclear [22].
●Prevention – Prevention involves monitoring during administration (eg, clinically and daily basic metabolic panel) (see 'Dosing and administration' above) and avoidance of high doses for prolonged periods [11]. We do not actively avoid concomitant glucocorticoid or vasopressor administration, but in patients with known or suspected mitochondrial dysfunction, we may consider using an alternate sedative since mitochondrial uncoupling has been implicated as a possible mechanism underlying PRIS [35,36].
It is not known if a history of PRIS places patients at greater risk of PRIS upon re-exposure to the drug, but it is reasonable to avoid its use in such cases.
Drug interactions — Central nervous system (CNS) and respiratory depressants (eg, opioid narcotics, benzodiazepines) enhance the CNS and respiratory depressant effect of propofol. Propofol undergoes hepatic conjugation to inactive metabolites; thus, metabolically related drug interactions of major clinical importance have not been identified.
DEXMEDETOMIDINE — Dexmedetomidine is commonly used for sedation of mechanically ventilated patients.
Mechanism — Dexmedetomidine is a highly selective, centrally acting alpha-2-agonist with anxiolytic, sedative, and some analgesic effects. While dexmedetomidine is a weak analgesic by itself, it potentiates the analgesic effects of opiates and endogenous enkephalins [37,38].
Properties — Dexmedetomidine is the dextro-enantiomer of medetomidine, a racemic mixture of the stereoisomers levomedetomidine and dexmedetomidine; dexmedetomidine is the main active isomer. Intravenous (IV) dexmedetomidine is available as a water soluble hydrochloride salt.
Dexmedetomidine undergoes extensive first pass metabolism resulting in low oral bioavailability. Absorbed across buccal and intranasal mucosae, intranasal dexmedetomidine is used off-label for pediatric procedural distress [39]. Dexmedetomidine is highly protein-bound to albumin and alpha1-glycoprotein, has a distribution half-life of approximately six minutes, and a variable volume of distribution of approximately 109 to 223 L in critically ill patients receiving long-term infusion [40].
Dexmedetomidine undergoes extensive hepatic biotransformation by multiple cytochrome P450 (CYP) enzymes with <1 percent excreted unchanged. With a high hepatic extraction ratio of 0.7, dexmedetomidine clearance may be decreased in patients with significantly reduced cardiac output [41]. Other patient-specific factors such as hypoalbuminemia, end-organ damage, and hemodynamic variability contribute to the high interindividual variability in dexmedetomidine distribution volumes and clearance [40].
●Onset of action – Dexmedetomidine has an onset of action of approximately 15 to 20 minutes with continuous IV infusion.
●Duration of effect – Dexmedetomidine has an elimination half-life of 2.1 to 3 hours in normal volunteers and 2.2 to 3.7 hours in critically ill patients [40]. In intensive care unit patients receiving prolonged infusions (>24 hours) the elimination half-life is even longer and more variable (mean 3.7 hours, range 2.4 to 6.9 hours) [42].
Dosing and administration — Dexmedetomidine is administered as an infusion as outlined in the table (table 1).
An initial loading dose is typically not performed but can be administered, if necessary [43]. The initial loading dose may cause transient hypotension or hypertension, depending upon whether vasodilation from activation of central alpha 2a receptors or vasoconstriction from activation of peripheral alpha 2b receptors predominates.
The sedative response is variable and may be due to unidentified patient characteristics, pharmacokinetics, and genetic polymorphisms [44].
There are no specific guidelines for modifying the dose for older adults or patients who have renal or hepatic impairment. It is prudent to start at the low end of the dose range and titrate slowly based upon the patient's response.
Abrupt cessation from dexmedetomidine should be avoided in patients receiving prolonged infusions as this can lead to withdrawal symptoms (eg, agitation, delirium, tachycardia, elevated systolic blood pressure). Management of withdrawal is discussed separately. (See "Sedative-analgesia in ventilated adults: Management strategies, agent selection, monitoring, and withdrawal", section on 'Discontinuation'.)
Adverse effects — Potential adverse events during sedation with dexmedetomidine include hypotension [45], hypertension, nausea, bradycardia [45], and atrial fibrillation. While bradycardia and hypotension can be seen with loading doses and during maintenance, hypertension can also been seen, especially during loading [46-51]. In addition, hypotension is most common during rapid dose escalation.
Rare cases of refractory cardiogenic shock [52] and fever or hyperthermia have also been reported [53-55].
Drug interactions — Although dexmedetomidine is metabolized by glucuronidation and CYP, clinically important CYP-mediated drug interactions have not been identified. Drugs that lower systemic blood pressure may enhance dexmedetomidine's hypotensive effect while drugs that increase systemic blood pressure may enhance dexmedetomidine's hypertensive effect. Similarly, agents that slow the heart rate may also enhance the bradycardia-inducing effects of dexmedetomidine and may need dose-adjustment during the infusion.
BENZODIAZEPINES — Midazolam and lorazepam are the benzodiazepines best suited for sedation in the intensive care unit (ICU) because they can be administered by either intermittent or continuous infusion and have a relatively short duration of effect. Intravenous (IV) diazepam is used less often to sedate patients in the ICU. It can be administered by intermittent, but not continuous infusion.
Mechanism — Benzodiazepines bind to specific receptors in the gamma-aminobutyric acid (GABA) receptor complex, which enhances the binding of this inhibitory neurotransmitter [56]. Anxiolysis is achieved at low doses. Higher doses are associated with sedation, muscle relaxation, anterograde amnesia, anticonvulsant effects, and both respiratory and cardiovascular depression. Coadministration with an opioid analgesic may potentiate respiratory and cardiovascular depression.
Benzodiazepines are effective anxiolytics but increase the risk of delirium (see 'Adverse effects' below), may prolong mechanical ventilation, and result in excess sedation for prolonged periods due to metabolite storage in adipose tissue. Their efficacy compared with propofol and dexmedetomidine are discussed separately. (See "Sedative-analgesia in ventilated adults: Management strategies, agent selection, monitoring, and withdrawal", section on 'Dexmedetomidine' and "Sedative-analgesia in ventilated adults: Management strategies, agent selection, monitoring, and withdrawal", section on 'Propofol'.)
Benzodiazepines are generally first-line agents for treating alcohol withdrawal. Further details on this indication are also provided separately. (See "Management of moderate and severe alcohol withdrawal syndromes", section on 'Treatment of psychomotor agitation'.)
Properties — The benzodiazepines differ in potency, rapidity of action, and duration of effect.
●Potency – A benzodiazepine's potency is determined by its binding affinity for the GABA receptor. Lorazepam has the highest binding affinity and the greatest potency. Midazolam and diazepam have progressively lower binding affinities and potencies [57].
●Rapidity of action – A benzodiazepine's rapidity of action is related to how quickly it crosses the blood-brain barrier. Midazolam and diazepam readily cross the blood-brain barrier because they are the highly lipophilic. Midazolam has an onset of action of two to five minutes following IV infusion, and diazepam has a nearly immediate onset of action. Lorazepam is less lipophilic and, therefore, has a slower onset of action of 5 to 20 minutes.
●Duration of effect – Initially, lipophilic benzodiazepines have a short duration of effect because there is rapid redistribution from the central nervous system (CNS) to peripheral tissue sites. With repeated dosing, however, all benzodiazepines accumulate in adipose tissue, which increases the duration of effect. Patients with obesity may store more drug than patients who are lean and are at greater risk for prolonged benzodiazepine effects. The duration of effect is also influenced by the presence of active metabolites, patient factors (ie, age, body weight, hepatic function, renal function), drug interactions, and mechanism of metabolism.
•Lorazepam has a moderate duration of effect (six to eight hours) when it is administered short-term (<48 hours) by intermittent infusion. This duration of effect reflects lorazepam's low hepatic clearance, small volume of distribution, and absence of active metabolites [58]. Lorazepam is a good choice for longer-term sedation because it has a low risk of drug interactions and its metabolism does not form active metabolites [59].
•Midazolam has a short duration of effect (two to four hours) when it is given short-term (<48 hours) by intermittent infusion to a patient with intact hepatic function because it has rapid hepatic clearance and there is rapid redistribution to peripheral tissue sites. Midazolam may cause prolonged sedation if it is administered over a longer duration because it has a large volume of distribution, binds to peripheral tissues, and has an active metabolite (alpha-hydroxymidazolam) [60]. The active metabolite is most likely to accumulate in patients who have poor hepatic or renal function or who are receiving medications that inhibit cytochrome P450 (CYP) 3A4 metabolism (eg, fluconazole, macrolide antibiotics, amiodarone, metronidazole).
•Diazepam has a short duration of effect (30 to 60 minutes) when it is administered short-term (<48 hours) by intermittent infusion. This duration of effect reflects diazepam's rapid redistribution to peripheral tissue sites and hepatic clearance. Diazepam may cause prolonged sedation with repeated dosing because it has a large volume of distribution and it has two active metabolites (desmethyldiazepam and methyloxazepam). These active metabolites are most likely to accumulate in older adults, patients who have obesity, or patients with renal or hepatic dysfunction.
●Tolerance – The need for an increased dose to achieve the same effect with continued administration (ie, tolerance) occurs with all benzodiazepines. It may reflect changes in the volume of distribution or in the density, binding affinity, and/or occupancy of the benzodiazepine receptor.
Dosing and administration — For sedation in the ICU, most benzodiazepines are administered intravenously. Typical dose regimens for midazolam, lorazepam, and diazepam are listed in the table (table 1). Dosing for patients with obesity is described separately. (See "Intensive care unit management of patients with obesity".)
A loading dose is not commonly administered unless needed during more emergent situations. The typical infusion dosing varies depending upon the benzodiazepine used.
Patients with suspected tolerance, defined as needing increasing doses over time with episodic agitation episodes (ie, tachyphylaxis), may need to be gradually weaned off the benzodiazepine. Patients who remain sedated on stable doses may do well with abrupt discontinuation of the benzodiazepine ("auto-wean"). Oral agents may facilitate weaning from IV administration. Suggested approaches to weaning are described separately. (See "Sedative-analgesia in ventilated adults: Management strategies, agent selection, monitoring, and withdrawal", section on 'Discontinuation'.)
Adverse effects
General — Respiratory and cardiovascular depression are well-known dose-dependent complications of benzodiazepines.
Excess sedation due to the accumulation of drug in adipose tissue can also occur with benzodiazepine-related sedation. Pharmacokinetically, this is more likely among patients who are sedated with benzodiazepines for prolonged periods (eg, >48 hours) or on continuous infusions [61].
Benzodiazepines increase the risk for delirium in critically ill patients [62-68]. Three studies indicated that the administration of midazolam resulted in a higher prevalence of delirium compared with dexmedetomidine (MIDEX: visual assessment scale score difference of 19.7; SEDCOM: 77 versus 54 percent; and MENDS: seven versus three days without delirium or coma) [45,62,69]. Delirium appears to be more common among those who receive deep sedation (even if the deep sedation is for a short duration), are older, or have dementia [64,66].
Rarely, patients may have a paradoxical reaction to benzodiazepines. This is characterized by agitation, restlessness, and hostility [70]. Increasing the dose may worsen the agitation. The most appropriate management is to discontinue the benzodiazepine and sedate the patient with an alternative sedative. Flumazenil has been reported to reverse the paradoxical reaction [71,72].
IV diazepam may increase the risk of venous thrombosis and phlebitis at the injection site [73]. The latter can cause injection site pain.
Propylene glycol toxicity — Propylene glycol is the carrier (solvent) that is used to administer IV lorazepam or diazepam. Infusion of either drug may be complicated by propylene glycol toxicity [74-77]. However, since diazepam infusions are rarely administered, it is classically seen with high-dose lorazepam infusions. Propylene glycol is not the solvent for IV midazolam. Therefore, patients who receive IV midazolam are not at risk for propylene glycol toxicity.
Propylene glycol toxicity is characterized by hyperosmolarity and an anion gap metabolic acidosis, which is often accompanied by acute kidney injury and can progress to multisystem organ failure, if severe [74-77]. While it can occur with normal doses in patients with normal renal function, it is usually associated with doses above the recommended range of 0.1 mg/kg/hour and/or renal impairment [76,78,79]. An osmolar gap >10 mmol/L suggests that the serum propylene glycol concentration is high enough to cause toxicity [80]. Treatment consists of discontinuing the offending agent and, if severe, initiating dialysis [77,81].
Drug interactions — Numerous drugs used commonly in the ICU may interact with benzodiazepines. Some increase the benzodiazepine effect while others decrease the effect.
CNS and respiratory depressants (eg, opioids) enhance the CNS and respiratory depressant effect of benzodiazepines. Conversely, CNS stimulants (eg, methylphenidate) decrease the CNS depressant effect of benzodiazepines. Many other drug interactions are related to the metabolism of benzodiazepines via the CYP system:
●Midazolam is susceptible to interactions with drugs that either inhibit or induce CYP3A4 since CYP3A4 hydroxylates midazolam to two active metabolites, 1-hydroxy-midazolam and 3-hydroxy-midazolam. As examples, the azole antifungals (eg, fluconazole, itraconazole, ketoconazole, voriconazole) and the macrolides and related antibiotics (eg, clarithromycin, erythromycin) may prolong midazolam activity by inhibiting CYP3A4. Conversely, carbamazepine may decrease midazolam activity by inducing CYP3A4. Rifamycins (eg, rifampin, rifabutin) may decrease midazolam activity by increasing CYP-mediated oxidative metabolism. Hydantoins (eg, phenytoin, fosphenytoin) may increase midazolam clearance and midazolam inhibits hydantoin clearance; the latter leads to increased serum concentrations of the hydantoins.
●Diazepam is susceptible to interactions with many of the same drugs that inhibit or induce CYP because it is hydroxylated by CYP3A4 to temazepam and N-demethylated by CYP3A4 and CYP2C19 to desmethyldiazepam. Temazepam and desmethyldiazepam are active metabolites that are subsequently metabolized to another active metabolite, oxazepam.
●Lorazepam does not interact with drugs that inhibit or induce CYP because it undergoes extensive glucuronidation in the liver to an inactive 3-O-phenolic metabolite.
ANTIPSYCHOTICS — Antipsychotics (typical and atypical) are dopamine antagonists but have an unclear mechanism of action. They can be used intermittently as supplements to other agents in the intensive care unit (ICU) for the treatment of delirium. Haloperidol, a typical antipsychotic, was frequently used in the past but use has declined since data are not supportive of routine use for delirium prevention. Data also suggest a similar limited role for atypical antipsychotics. (See "Sedative-analgesia in ventilated adults: Management strategies, agent selection, monitoring, and withdrawal", section on 'Delirium'.)
Mechanism — Haloperidol and the other neuroleptics antagonize dopamine and other neurotransmitters. However, their precise mechanism of action remains unknown. Haloperidol lactate can be administered intravenously, has a mild sedative effect, and has relatively low cardiorespiratory depressive effects. It is primarily used as a supplement to sedation when delirium is thought to be the main driver of agitation.
Atypical antipsychotics (quetiapine, olanzapine, risperidone, ziprasidone) are oral agents that may also be used for similar indications (eg, nocturnal delirium, interfering with sleep).
Properties — Haloperidol causes dose-dependent sedation. It tends to be less sedating and has less anticholinergic activity than other neuroleptics.
●Rapidity of onset – Haloperidol has an onset of action 5 to 20 minutes after intravenous (IV) infusion.
●Duration of effect – Haloperidol's duration of effect varies and depends upon the cumulative dose. In general, redosing may be needed 4 to 12 hours after symptoms have been controlled with the initial doses.
Haloperidol is highly protein bound, has a large volume of distribution, and is metabolized hepatically by cytochrome P450 (CYP) 3A4, CYP2D6, and glucuronidation; the hydroxymetabolite (reduced haloperidol) is active [82]. The pyridinium metabolite may be neurotoxic [83].
Dosing and administration — The IV route is the most common route used to administer haloperidol in the ICU. However, IV use has not been approved by the US Food and Drug Administration (FDA) due to the greater risk of serious adverse events compared with oral or intramuscular administration, most notably torsades de pointes and sudden cardiac death [84].
Dosing regimens ranging from 1 to 2 mg IV every six hours to 0.5 to 2 mg/hour IV infusion have been used for the prevention of delirium in adult ICU patients, none of which have been validated (table 1) [85]. Continuous infusions are rarely indicated, but studies suggest that they are probably safe and effective [86-88]. Typical initial regimens range from 1.25 to 5 mg IV bolus repeated every 8 to 12 hours depending on age and cardiovascular risk factors; subsequent doses may be repeated or titrated to the desired response to a maximum dose of 20 to 40 mg in 24 hours [89-92]. In a survey of 250 pharmacists, the most frequently cited daily IV dose range was 5 to 10 mg, although 8 percent of respondents cited daily IV doses of ≥21 mg [93].
The safe maximum daily dose of haloperidol is not known. There are case reports of doses as high as 945 mg/day [86,94]. Doses greater than 200 mg/day have been safely administered for up to 15 consecutive days [86,95].
We use antipsychotics (typical and atypical) with caution in all older adults with dementia, including the critically ill, since they carry an increased risk of cardiovascular death. (See 'Adverse effects' below.)
Adverse effects — Haloperidol-associated polymorphic ventricular tachycardia (including torsades de pointes) is an uncommon but severe adverse reaction [96,97]. It is primarily associated with intermittent high-dose IV administration and a prolonged corrected QT (QTc) interval. A prolonged QTc interval has also been described in patients taking atypical antipsychotics [98]. When intermittent haloperidol infusions or atypical antipsychotics are used, the QTc interval on electrocardiogram (EKG) should be monitored daily for the first two to three days. This is also advisable when the dose of these drugs is increased or when other QTc-prolonging meds are coadministered. If the QTc interval does not prolong, ongoing telemonitoring is sufficient to detect a relative change and prompt quantitation by EKG. Haloperidol and other antipsychotics should not be given if the QTc interval exceeds 500 msec. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes".)
Other potential side effects of haloperidol include acute dystonic reactions, parkinsonism, tardive dyskinesia, akathisia, and neuroleptic malignant syndrome. For unclear reasons, extrapyramidal side effects are less common among patients receiving IV haloperidol than among those receiving oral haloperidol [99]. (See "Treatment of dystonia in children and adults".)
Older adults with dementia may have an increased risk of cardiovascular-related death (due to heart failure or sudden cardiac death) or infection-related death (due to pneumonia) when treated with atypical antipsychotics. This was illustrated by a meta-analysis of 15 randomized trials (5204 patients) that found that older patients with dementia who were treated with atypical antipsychotics had an increased risk of death compared with those who received placebo (3.5 versus 2.2 percent; odds ratio 1.54, 95% CI 1.06-2.23) [100]. These findings were supported by two subsequent studies [101,102]. The FDA has since issued a black box warning for the atypical antipsychotics.
Drug interactions — Haloperidol interacts with numerous drugs that are commonly used in the ICU. As an example, drugs with central nervous system (CNS) depressant effects (eg, opioids, sedatives) may enhance the CNS-depressant effect of haloperidol.
Other drug interactions are related to the metabolism of haloperidol via the CYP3A4 and CYP2D6 pathways. These include azole antifungals and carbamazepine:
●Systemic azole antifungals (eg, fluconazole, itraconazole, posaconazole, voriconazole), HIV and HCV protease inhibitors, and cyclosporine, inhibit CYP3A4, which prolongs haloperidol activity.
●Carbamazepine increases CYP3A4 metabolism, which decreases haloperidol activity. This effect is enhanced because haloperidol increases carbamazepine activity by inhibiting carbamazepine metabolism.
The rifamycins (eg, rifampin, rifabutin) also induce CYP-mediated oxidative metabolism and decrease haloperidol activity. Anticholinergics (eg, atropine, glycopyrrolate) increase haloperidol clearance via an unknown mechanism.
When haloperidol is used, other drugs that enhance the QTc-prolonging effect of haloperidol should be avoided (eg, amiodarone, dronedarone, ranolazine, methadone, high-dose ondansetron, domperidone, erythromycin, fluoroquinolone antibiotics, tricyclic antidepressants, posaconazole, voriconazole). Additional agents are listed in the table (table 2). Metoclopramide may increase haloperidol toxicity and should also not be given concurrently.
LESS COMMONLY USED AGENTS — Barbiturates and ketamine are used as last resort or adjunctive agents when first-line agents have failed.
Barbiturates — Very limited data support the use of phenobarbital to sedate mechanically ventilated adult intensive care unit (ICU) patients [103].
Phenobarbital binds to gamma-aminobutyric acid (GABA) 2 receptors, increasing the duration of GABA-gated chloride channel opening.
Phenobarbital commonly causes hypotension and may produce profound cardiovascular and respiratory depression. Other undesirable characteristics of phenobarbital include prolonged elimination half-life, induction of the cytochrome P450 (CYP) enzyme system, and accumulation of drugs in renal and hepatic dysfunction.
Ketamine — Use of ketamine as an adjunctive analgo-sedative in mechanically ventilated patients has resurged since the start of coronavirus disease 2019 (COVID-19) pandemic when it was needed as a second or third-line agent for sedation in the ICU [104,105]. With sedative and analgesic properties, ketamine may reduce opioid requirements [106].
Ketamine is approved by the US Food and Drug Administration (FDA) as an anesthetic agent for diagnostic and surgical procedures. Off-label uses include procedural sedation/analgesia, treatment of extreme agitation, and treatment of mood disorders; it can also be used as an adjunct to opioid analgesia as well as to manage opioid tolerance, withdrawal, hyperalgesia, or neuropathic pain [107-110].
Ketamine is a parenteral anesthetic agent with analgesic and bronchodilator properties in subanesthetic doses. Ketamine, a phencyclidine derivative, noncompetitively blocks glutamate N-methyl-D-aspartate (NMDA) receptors within sensory nerve endings; other pharmacologic actions at subanesthetic doses have been identified, including opioid and muscarinic agonist activities and nicotinic receptor blockade [111].
Due to its lipid solubility, an intravenous bolus dose of ketamine is active within one minute with a duration of action of 10 to 15 minutes. Ketamine is metabolized in the liver through CYP systems to several metabolites, including the weakly active metabolite norketamine, that are cleared by the kidneys.
Ketamine produces a "dissociated anesthesia," wherein patients remain conscious with spontaneous breathing and intact brain stem reflexes. By stimulating the sympathetic nervous system, there is less cardiovascular depression; this preserves and sometimes increases blood pressure, making it an attractive agent for use in patients in shock or with frank hypotension. Ketamine also has mild bronchodilatory activity such that it has been anecdotally used for sedation in patients with status asthmaticus. The value of anesthetic agents in this population is provided separately. (See "Acute exacerbations of asthma in adults: Emergency department and inpatient management", section on 'Anesthetic agents'.)
Ketamine side effects include adverse psychoactive effects (eg, vivid hallucinations, confusion, and delirium), hemodynamic instability, excessive salivation, and respiratory and cardiac depression. Ketamine is contraindicated in patients with known hypersensitivity to it and in patients at risk from potentially significant elevations in blood pressure. Cholestatic liver injury has been reported following prolonged high-dose ketamine administration in critically ill patients with COVID-19 [112,113]. Ketamine plasma concentrations producing analgesia are typically lower than concentrations producing psychomimetic effects (eg, hallucinations, confusion, nightmares) [114,115].
FDA-approved anesthesia dosing and administration for ketamine are shown on the table (table 1). There are no standard recommendations regarding dosing for analgo-sedation in mechanically ventilated critically ill patients. Reported regimens include a 0.1 to 0.5 mg/kg bolus followed by an initiation of a 0.2 to 0.5 mg/kg/hour continuous infusion then titrated to pain and sedation goal with a typical maintenance infusion of 0.04 to 2.5 mg/kg/hour. Higher median hourly doses are reported for analgo-sedation in mechanically ventilated patients with COVID-19-related acute respiratory distress syndrome [104,105,116].
INVESTIGATIONAL AGENTS
Sevoflurane — Sevoflurane, a polyfluorinated methyl-isopropyl compound, is a volatile inhalational anesthetic that is being evaluated as a potential sedative agent for intensive care unit (ICU) patients. Further study and clinician education will be required before sevoflurane can be used as a routine sedative in critically ill patients.
Ninety-five to 98 percent of sevoflurane is eliminated through the lungs while the remaining 2 to 5 percent undergoes rapid hepatic metabolism to inorganic fluoride and hexafluoroisopropanol (HFIP) [117]. HFIP in the blood is conjugated by glucuronic acid and then secreted by the kidneys.
Potential advantages of sevoflurane as a sedating agent for critically ill ICU patients include the short duration of action and rapid elimination [118]. Potential disadvantages include fluoride accumulation with prolonged use (especially in patients with impaired renal function) and malignant hyperthermia [118]. Additionally, sevoflurane undergoes degradation on contact with alkaline carbon dioxide absorbents used to remove carbon dioxide from the circuit, becoming a potentially nephrotoxic product (trifluoromethyl vinyl ether; compound A) [117]. (See "Malignant hyperthermia: Diagnosis and management of acute crisis" and "Susceptibility to malignant hyperthermia: Evaluation and management".)
Baclofen — Baclofen is a gamma-aminobutyric acid (GABA) type B receptor agonist that at high levels can reduce consciousness. Preliminary evidence describes its use in critically ill patients, but further studies are needed before baclofen can be recommended for use in individuals with agitation. This evidence is discussed separately. (See "Sedative-analgesia in ventilated adults: Management strategies, agent selection, monitoring, and withdrawal", section on 'Investigational agents'.)
Ciprofol — Ciprofol is a phenol derivative of propofol with increased stereoselective effects adding to its anesthetic properties [119,120]. The therapeutic index of ciprofol is 1.5 times that of propofol and its potency is four- to fivefold higher. Early phase II trials suggest noninferior efficacy and safety profile when compared with propofol [121].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Nonprocedural sedation".)
SUMMARY AND RECOMMENDATIONS
●Rationale – Distress due to pain, fear, anxiety, dyspnea, or delirium is common among critically ill patients in the intensive care unit (ICU). Distress may cause ventilator asynchrony and increase sympathetic tone, which may have untoward clinical effects. (See 'Introduction' above.)
●Agent selection – No sedative-analgesic agent is sufficiently superior to other agents to warrant its use in all clinical situations. As a result, selection of an agent must be individualized according to pharmacokinetic variables (eg, potential interactions with other drugs) and nonpharmacokinetic variables (eg, renal and liver failure, presence of bradycardia or hypotension), the etiology of the distress, and the desired depth of sedation. Selecting an agent is discussed in detail separately. (See "Sedative-analgesia in ventilated adults: Management strategies, agent selection, monitoring, and withdrawal", section on 'Selection of agent(s)'.)
●Classes of agents – Several classes of agent are available and most often used in combination (table 1). The most common agents used for sedation are the following:
•Opioid analgesics – Fentanyl, hydromorphone, and morphine sulphate are the most commonly used intravenous (IV) opioids to manage distress due to pain in critically ill patients. Nonopioid agents can also be used (eg, acetaminophen, nonsteroidal anti-inflammatory agents). Choice of opioid analgesic and their individual properties are discussed separately. (See "Pain control in the critically ill adult patient", section on 'Opioid analgesics'.)
•Propofol – Propofol is an IV anesthetic that activates central gamma-aminobutyric acid (GABA) type A receptors. Propofol has a rapid onset and short duration of effect. Propofol has amnesic, anxiolytic, anticonvulsant, and muscle relaxant (including bronchodilation) effects. Hypotension is the most common adverse effect while hypertriglyceridemia, pancreatitis, and propofol-related infusion syndrome (PRIS) are more serious complications. (See 'Propofol' above.)
PRIS is a rare complication of propofol. PRIS should be suspected in patients on high doses or a prolonged infusion of propofol who develop unexplained arrythmia, instability, acidosis, electrolyte disturbance, transaminitis, or acute kidney injury. When PRIS is suspected, work up includes obtaining a serum lactate creatinine kinase, and myoglobin. Patients who have PRIS require prompt discontinuation of the propofol infusion since PRIS-related mortality is high (33 to 66 percent). (See 'Propofol-related infusion syndrome' above.)
•Dexmedetomidine – Dexmedetomidine is a highly selective, centrally acting alpha-2-agonist with anxiolytic, sedative, and some analgesic effects. Dexmedetomidine has an onset of action of approximately 15 to 20 minutes and an elimination half-life of two to three hours, longer in those who are critically ill and on continuous infusions. The main adverse effects are hypotension and bradycardia, although hypertension and atrial fibrillation may be seen less commonly. (See 'Dexmedetomidine' above.)
•Benzodiazepines – Benzodiazepines are GABA receptor agonists. Midazolam and lorazepam are the most common benzodiazepines that are administered by either intermittent or continuous infusion and have a relatively short duration of effect. They are effective anxiolytics but can also induce muscle relaxation and retrograde amnesia and have anticonvulsant effects. However, benzodiazepines, when administered for long periods as an infusion (eg, >48 hours), can have a prolonged sedative effect due to metabolite storage in adipose tissue and can increase the risk of delirium compared with other agents, such as propofol and dexmedetomidine. Respiratory and cardiovascular depression are well-known, common, dose-dependent complications of benzodiazepines. Propylene glycol toxicity is a rare complication of high-dose lorazepam infusions that requires immediate cessation of the drug. (See 'Benzodiazepines' above.)
•Antipsychotics – Antipsychotics (typical [haloperidol] and atypical [quetiapine, olanzapine, risperidone, ziprasidone]) are dopamine antagonists that can be used intermittently as supplements to other sedative agents in the ICU for the treatment of delirium. IV haloperidol is not approved by the US Food and Drug Administration for the treatment of delirium, thus, IV administration for this indication is off-label. A prolonged corrected QT interval with consequent precipitation of ventricular arrythmias is the most worrisome adverse effect of antipsychotics. (See 'Antipsychotics' above.)
•Others – Phenobarbital and ketamine are less commonly used. Phenobarbital is a GABA2 agonist that can cause profound cardiac and respiratory depression. Ketamine is an anesthetic agent that blocks glutamate N-methyl-D-aspartate (NMDA) receptors and has some analgo-sedative properties; adverse reactions include vivid hallucinations, confusion, and delirium as well as hemodynamic instability, excessive salivation, and respiratory and cardiac depression. (See 'Barbiturates' above and 'Ketamine' above.)
آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟
