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Medicamentos sedativo-analgésicos em adultos

gravemente enfermos: propriedades, regimes
posológicos e efeitos adversos
autores: Karen J Tietze, PharmD, Barry Fuchs, MD
editores de seção: Polly E Parsons, MD, Michael F O'Connor, MD, FCCM
editor adjunto: Geraldine Finlay, MD

Todos os tópicos são atualizados à medida que novas evidências são disponibilizadas e nosso processo de revisão
por pares é concluído.

Revisão da literatura atualizada até: setembro de 2023.

Última atualização deste tópico: 02 de novembro de 2022.

INTRODUÇÃO

Angústia devido à dor, medo / ansiedade, dispneia ou delírio é comum entre pacientes
gravemente enfermos, especialmente aqueles que estão intubados ou têm dificuldade de
comunicação com seus cuidadores [1 ] . A angústia pode manifestar-se clinicamente como
agitação que está frequentemente associada à assincronia do ventilador e anormalidades
nos sinais vitais. Independentemente disso, o sofrimento precisa ser tratado para
confortar o paciente, melhorar a agitação que pode interferir nos cuidados de suporte e
atenuar o aumento do tônus simpático, que pode ter efeitos fisiológicos adversos [2 ] .

Medicamentos sedativos-analgésicos comuns usados para tratar sofrimento em adultos

gravemente enfermos são revisados aqui. A identificação da causa do sofrimento e o uso
dessas informações para selecionar o agente sedativo-analgésico ideal são discutidos
separadamente. (Consulte "Medicamentos sedativos-analgésicos em adultos gravemente
enfermos: seleção, início, manutenção e retirada" .)

O manejo da dor e do bloqueio neuromuscular em pacientes críticos também são

descritos separadamente. (Ver “Controle da dor no paciente adulto gravemente enfermo”
e “Agentes bloqueadores neuromusculares em pacientes gravemente enfermos: uso,
seleção de agentes, administração e efeitos adversos” .)

ANALGÉSICOS

A dor pode ser controlada na unidade de terapia intensiva (UTI) com analgésicos opioides
e analgésicos não opioides. A escolha do agente deve ser direcionada à etiologia da dor,
mas os opióides são, em geral, frequentemente administrados para o tratamento da dor
em pacientes sob ventilação mecânica.

Opioid analgesics — Morphine sulfate, fentanyl, and hydromorphone are the intravenous
opioids that are most commonly used to manage distress due to pain in critically ill
patients. Oral opioids such as oxycodone, methadone, and morphine are also given to
patients where oral or enteral administration is preferred. Remifentanil is also an option;
advantages include its rapid onset of action and prompt clearance that are independent of
hepatic and renal function, although there is debate as to whether its use is associated
with a higher risk of tolerance [3-5].

All of the opioids lack amnestic properties, induce tolerance, and have similar analgesic
and sedative properties when administered in equipotent doses [6]. Specific agents differ
in their onset, duration of action, histamine-related side effects, and risk of accumulation
in organ failure. The pharmacologic properties of the opioids and principles for selection
of intermittent, preprocedural, continuous, and patient-controlled dosing are described in
detail elsewhere. (See "Pain control in the critically ill adult patient", section on 'Opioid
analgesics'.)

The Society of Critical Care Medicine 2018 guidelines place emphasis on the
administration of intravenous opioids for non-neuropathic pain and analgesia-first
sedation for the management of agitation in mechanically ventilated ICU patients [7]. The
comparative advantages and disadvantages and typical dose regimens, as well as the
roles of analgesics, sedatives, anxiolytics, and antipsychotics in critically ill patients, are
described in the table ( table 1). Limited information is available regarding drug dosing
in patients with obesity who are critically ill [8]. Dosing for patients with obesity is
described separately. (See "Intensive care unit management of patients with obesity".)

Numerous drugs used commonly in the ICU have the potential to interact with opioids.
Central nervous system (CNS) and respiratory depressants (eg, benzodiazepines) enhance
the CNS and respiratory depressant effect of opioids, while CNS stimulants (eg,
methylphenidate) decrease the CNS depressant effect of opioids. Other drug interactions
are related to the metabolism of opioids via CYP3A4. As examples, the azole antifungals
(eg, fluconazole, itraconazole, posaconazole, ketoconazole, voriconazole) and the
macrolides and related antibiotics (eg, clarithromycin, erythromycin, telithromycin) may
prolong fentanyl activity by inhibiting CYP3A4. The rifamycins (eg, rifampin, rifabutin) may
decrease the serum concentration and effects of opioids.

The ultrashort-acting opioids alfentanil and sufentanil are generally not used in critically ill
patients, because they do not offer advantages and may be more costly. The long-acting
opioid agonist-antagonist analgesics are also not used very often, because they are long-
acting and may not produce sufficient analgesia due to ceiling effects. This class of agents
includes buprenorphine, butorphanol, dezocine, nalbuphine, and pentazocine.

Nonopioid analgesics — Acetaminophen (enteral or intravenous), nonsteroidal

antiinflammatory agents, and intravenous ketamine can be used as alternatives or
additives to opioids for the management of nonneuropathic pain in the ICU ( table 1).
Additionally, they can be used as opioid-sparing agents to reduce or eliminate the need
for opioids in adult ICU patients [7]. Enteral gabapentin, pregabalin, and/or
carbamazepine, in addition to intravenous opioids, can be used to treat neuropathic pain
in adult ICU patients. (See "Pain control in the critically ill adult patient", section on
'Nonopioid analgesics'.)

PROPOFOL

Propofol is an intravenous anesthetic that is commonly used for sedation of the agitated
adult intensive care unit (ICU) patient. It is particularly useful when rapid sedation and
rapid awakening is desirable (eg, patients who require frequent neurologic examinations)
because it has a short duration of effect. In one large, randomized, open label trial,
compared with intermittent bolus lorazepam (median dose 11.5 mg/day), propofol
infusions with daily interruption (mean dose 24.4±16.3 mcg/kg/min) resulted in
significantly lower number of mechanical ventilation days but did require higher
morphine doses per ventilator day [9]. A multicenter ICU database analysis of over 3000
patients reported that, when compared with midazolam or lorazepam, propofol infusions
were associated with a lower mortality (risk ratio 0.76 and 0.78, respectively), earlier
discharge, and discontinuation from mechanical ventilation [10]. Data from comparative
trials with current sedation guidelines are needed to confirm these results.
Mechanism — Activation of the central gamma-aminobutyric acid receptors (GABA[A]
receptors) with modulation of hypothalamic sleep pathways appear to be the mechanism
by which propofol exerts its effect [11-14].

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
intravenous administration. Although labeled contraindications include hypersensitivity to
eggs, egg products, soy, or soy products, reviews suggest a need for further evaluation of
this issue [15,16]. Propofol has amnesic, anxiolytic, anticonvulsant, and muscle relaxant
(including bronchodilation) effects. It has no direct analgesic effects.

● 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. 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 [17]. These data, however, may overestimate the magnitude
of the sedative prolongation. Another study found that, when compared with
patients receiving short-term sedation with propofol (<24 hours), the mean recovery
time to extubation in those that received propofol for extended periods categorized
as medium (1 to 7 days, n = 16) and long term (>7 days; n = 10) was delayed by only
10 and 30 minutes, respectively [18].

The elimination of propofol is not impaired by hepatic or renal dysfunction. Propofol has a
large volume of distribution and is highly protein bound.

Dose regimens — A typical dose regimen for propofol is listed in the table ( table 1) [7].
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.

The US Food and Drug Administration emergency use authorization to temporarily permit
use of a product containing propofol 2% (propofol 20 mg/mL) emulsion during the
coronavirus disease 2019 (COVID-19) pandemic was revoked (July 2022), and the product
is no longer approved for use.
Administration — Propofol is administered by continuous infusion in the ICU and not by
intermittent infusion, because it is associated with dose- and rate-dependent hypotension.
This was best illustrated by an observational study of 25,981 patients receiving propofol
anesthesia: 4079 patients (15.7 percent) developed hypotension, defined as a systolic
blood pressure <90 mmHg [19]. Among those who became hypotensive, 77 percent of the
hypotensive episodes occurred within 10 minutes of induction via a bolus infusion.

The manufacturer recommends that the bottles and tubing be discarded every twelve
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

intravenous catheter (often in the antecubital fossa) to reduce burning, stinging, and pain
that can occur with peripheral administration.

During administration, routine biochemical monitoring (triglycerides, serum lactate,

creatinine kinase, myoglobin) may allow early identification of the propofol infusion
syndrome (PRIS) [20]. Propofol should be discontinued as soon as any abnormality is
identified. (See 'Propofol-related infusion syndrome' below.)

Adverse effects — Hypotension is a common consequence of propofol infusion,

estimated to occur in approximately 25 percent of ICU patients who receive propofol for
sedation [21]. Other potential adverse effects of propofol which are uncommon include
bradycardia, arrhythmias, neuroexcitatory effects (seizure-like activity, myoclonus,
choreoathetoid movements, meningismus), infections from contaminated vials or tubing,
respiratory acidosis, pancreatitis, hypertriglyceridemia, anaphylaxis, and green or white
discoloration of urine [17,22-25].

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, continuous infusion of propofol for greater than 24 hours
does not appear to increase overall mortality, according to a meta-analysis of 14
randomized trials (1184 patients) [26].

Propofol-related infusion syndrome — PRIS is a rare complication of propofol infusion.

It is generally associated with high doses (>4 mg/kg/hour or >67 mcg/kg/min) and
prolonged use (>48 hours) [27-30], though it has been reported with high-dose short-term
infusions [31,32]. Additional proposed risk factors include a young age, critical illness, high
fat and low carbohydrate intake, inborn errors of mitochondrial fatty acid oxidation, and
concomitant catecholamine infusion or steroid therapy [32]. Characteristics of PRIS
include acute refractory bradycardia, severe metabolic acidosis, cardiovascular collapse,
rhabdomyolysis, hyperlipidemia, renal failure, and hepatomegaly [28,33].

The incidence of PRIS is unknown, but it is probably less than 1 percent [34]. Mortality is
variable but high (33 to 66 percent) [28,35,36]. Treatment involves discontinuation of the
propofol infusion and supportive care [32].

Drug interactions — Central nervous system (CNS) and respiratory depressants (eg,
opioid narcotics, sedatives) 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. Coadministration of propofol with alfentanil increases the risk of opisthotonus
and/or grand mal seizures.

DEXMEDETOMIDINE

Dexmedetomidine is a highly selective, centrally acting alpha-2-agonist with anxiolytic,

sedative, and some analgesic effects. According to the approved product information from
the US Food and Drug Administration, dexmedetomidine is indicated for initial sedation of
mechanically ventilated patients for up to 24 hours. The rationale for the 24-hour limit is
that longer use may increase the risk of withdrawal effects (eg, hypertension), although
these effects have not been consistently found in studies [37,38].

Efficacy — Dexmedetomidine may reduce the duration of mechanical ventilation and

intensive care unit (ICU) stay when compared with traditional sedatives in the ICU,
although the effect may depend upon the comparative agent [39-48]. As examples:

● A 2022 meta-analysis of 77 randomized trials reported that dexmedetomidine

reduced the duration of mechanical ventilation (mean difference [MD] -1.8 h, 95% CI
-2.89 to -0.71; low certainty) and ICU length of stay (MD -0.32 days, 95% CI -0.42 to
-0.22; low certainty) but increased the risk of bradycardia by 6 percent and
hypotension by 4 percent [48].

● When compared with midazolam, two studies suggest that dexmedetomidine

 decreased the duration of mechanical ventilation (SEDCOM: 3.7 versus 5.6 days;
MIDEX: 5.1 versus 6.8 days, respectively) but had no effect of length of ICU stay [40-
42].

● While small observational studies have shown mixed effects of dexmedetomidine in

duration of mechanical ventilation [43,46,49], one large randomized study of a mixed
population of critically ill patients showed no effect of dexmedetomidine (PRODEX)
on the duration of mechanical ventilation when compared with propofol [40].
Similarly, another multicenter, double-blind trial of adults with sepsis (MENDS 2) also
reported no difference in the number of ventilator-free days at 28 days in patients
who received dexmedetomidine compared with propofol when a target goal of light
sedation was set [50].

● Another trial of a mixed population of 71 ICU patients, in whom agitated delirium

was prohibiting extubation, reported that compared with the addition of a placebo,
the addition of dexmedetomidine to standard sedation (mostly propofol) resulted in
an increase in ventilator-free hours at seven days (145 versus 128 hours) as well as
reduced time to extubation (22 versus 44 hours) [51].

● A meta-analysis of four studies of a mixed population of older adults (≥60 years of

age) reported that compared with propofol, dexmedetomidine did not reduce
duration of mechanical ventilation (risk ratio [RR] 0.7, 95% CI 0.52-0.95) [52]. Duration
of mechanical ventilation was short (<24 hours) in three of the four studies [52].

● The comparative sedative activity of dexmedetomidine versus clonidine, another

systemic central alpha-2-adrenoceptor agonist, in mechanically ventilated critically ill
adults is being evaluated in an ongoing randomized clinical trial [53].

Similarly, data reporting the effects of dexmedetomidine on delirium are mixed [39-
41,48,50,51,54-59] but overall favor a reduction in delirium, prompting a guideline
committee to issue a weak recommendation to favor dexmedetomidine as a sedative
when reducing delirium was desirable by clinicians and outweighed by the undesirable
effects of hypotension and bradycardia [60]:

● A 2022 meta-analysis of 77 randomized trials reported that compared with other

medications, dexmedetomidine reduced the rate (or incidence) of delirium (RR 0.67,
95% CI 0.55-0.81; moderate certainty) but increased the risk of bradycardia by 6
percent and hypotension by 4 percent [48].
 ● In contrast, a multicenter, double-blind trial of adults with sepsis (MENDS 2) reported
no difference in the number days alive without delirium or coma in patients who
received dexmedetomidine compared with propofol when a target goal of light
sedation was set [50].

Use of dexmedetomidine in critically ill patients does not appear to confer a mortality
benefit.

● Best illustrating this was an open-label trial (SPICE III) that randomly assigned 4000
patients who were mechanically ventilated for less than 12 hours to either
dexmedetomidine (as the sole sedative) or to usual care [61]. The target sedation
was a Richmond Agitation and Sedation Scale (RASS) of -2 to +1 (lightly sedated to
restless). Mortality at 90 days was not impacted by dexmedetomidine (29 percent in
each group), and, in fact, patients receiving dexmedetomidine required
supplemental sedative (eg, propofol, midazolam) to achieve the target level of
sedation. In addition, bradycardia and hypotension were more common in patients
receiving dexmedetomidine. This study had several limitations including a lack of
blinding and a high percentage of patients who needed a deeper level of sedation
(approximately 40 percent). In addition, there was no significant reduction in either
ventilator- or delirium-free days in the dexmedetomidine group.

● Although dexmedetomidine has been associated with a small decrease in

postoperative mortality in patients undergoing cardiac surgery, a meta-analysis of
seven trials (that did not include SPICE III) reported no survival advantage associated
with its use [39,55].

● In another randomized trial of 201 mechanically ventilated patients with sepsis,

compared with standard sedation (with fentanyl, propofol, and/or midazolam),
dexmedetomidine did not result in any mortality benefit or increase in ventilator-free
days despite a higher rate of well-controlled sedation [49]. However, the study was
powered to detect a 20 percent difference in mortality and, consequently, may have
been unable to detect smaller differences in mortality.

● Another multicenter, double-blind trial of adults with sepsis (MENDS 2)also reported
no difference in mortality at 90 days in patients who received dexmedetomidine
compared with propofol when a target goal of light sedation was set [50].

Dexmedetomidine may decrease the need for alternative sedatives especially in patients
withdrawing from alcohol, the details of which are discussed separately [62,63]. (See
"Management of moderate and severe alcohol withdrawal syndromes", section on
'Alternative and contraindicated agents'.)

Dexmedetomidine may be more cost-effective than other sedatives. As an example,

sedation with dexmedetomidine lowered ICU costs compared with standard care; cost
savings were achieved primarily by reducing the duration of total ICU stay without
prolonging post-ICU hospitalization [45].

Transitioning from dexmedetomidine to oral clonidine may be a safe and cost-effective

way to continue sedation with a centrally acting alpha-2-agonist in patients who are
hemodynamically stable and have a functional gastrointestinal tract [64]. In a single-
center prospective observational pilot study, 15 of 20 patients were successfully
transitioned from dexmedetomidine to clonidine [64]. Dexmedetomidine and clonidine
doses were titrated during the transition period; maintenance clonidine doses ranged
from 0.2 to 0.5 mg every six hours and were adjusted to achieve target sedation levels
[64].

Dose regimen — An initial loading dose is typically not performed but can be
administered if necessary [65]. 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 usual dexmedetomidine maintenance dose is 0.2 to 1.5 mcg/kg/hour, with dose
increases no more frequently than every 30 minutes [41,54]. Doses >1.5 mcg/kg/hour do
not appear to add to dexmedetomidine's clinical efficacy [66]. The variability in patient
response to dexmedetomidine may be due to as yet unidentified patient characteristics,
pharmacokinetics, and genetic polymorphisms [67].

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.

The advantages, disadvantages, role, and dose regimen of dexmedetomidine are

described in the table ( table 1).

Adverse effects — Potential adverse events during sedation with dexmedetomidine

include hypotension [40], hypertension, nausea, bradycardia [40], and atrial fibrillation.
While bradycardia and hypotension can be seen with loading doses and during
maintenance, hypertension can also been seen, especially during loading [68-72]. In
addition, hypotension may be most commonly seen during rapid dose escalation.
Refractory cardiogenic shock has also been reported [73]. Abrupt cessation should be
avoided since prolonged dosing can lead to withdrawal. Thus, after cessation of
dexmedetomidine, patients should be monitored for withdrawal. Case reports of fever or
hyperthermia have also been reported [74-76].

Drug interactions — Although dexmedetomidine is metabolized by glucuronidation and

cytochrome P450, clinically important cytochrome P450-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.

BENZODIAZEPINES

Midazolam and lorazepam are the benzodiazepines that are 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 diazepam is
used less often to sedate patients in the ICU. It can be administered by intermittent
infusion 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 [77]. 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.

Properties — The benzodiazepines are equally efficacious if they are administered in

equipotent doses, but they 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
[78].

● 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 2 to 5 minutes following intravenous 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 – The duration of effect soon after initiating intermittent infusions
differs from the duration of effect following repeated dosing. Initially, lipophilic
benzodiazepines have a short duration of effect because there is rapid redistribution
from the central nervous system to peripheral tissue sites. With repeated dosing,
however, all benzodiazepines accumulate in adipose tissue. This increases the
duration of effect because there is more drug that needs to be mobilized for
elimination, particularly if a large cumulative dose was administered. Patients with
obesity may store more drug than lean patients and are at greater risk for prolonged
benzodiazepine effects. A drug's 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.

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) [79]. The active metabolite is most likely to
accumulate in patients who have poor hepatic or renal function or who are receiving
medications that inhibit CYP3A4 metabolism (eg, fluconazole, macrolide antibiotics,
amiodarone, metronidazole).

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 [80]. 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 [81].

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) 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.

Selection — The comparative advantages and disadvantages, as well as the roles of

midazolam, lorazepam, and diazepam in critically ill patients, are described in the table
( table 1).

Dose regimens — 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".)

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 as a
consequence of sedation with benzodiazepines. Pharmacokinetically, this is more likely
among patients who are sedated with benzodiazepines for longer than 48 hours or on
continuous infusions [82].

Benzodiazepines, particularly infusions, can increase the risk for delirium in critically ill
patients [54,83-87]. In an observation study of 198 mechanically ventilated patients
receiving pharmacologic sedation, lorazepam was identified as an independent risk factor
for delirium [83]. 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
[84,86]. Three studies indicated that, compared with dexmedetomidine, the
administration of midazolam resulted in a higher prevalence of delirium (SEDCOM: 77
versus 54 percent; MIDEX: visual assessment scale score difference of 19.7 in favor of
dexmedetomidine; and MENDS trial: seven versus three days without delirium or coma)
without any change in length of ICU stay [40,41] or mortality [40]. In a small, single-center
unblinded study of sequential midazolam-dexmedetomidine versus sequential
midazolam-propofol or midazolam alone, sequential midazolam-dexmedetomidine had a
significantly lower incidence of delirium than midazolam alone (19.5 versus 43.5 percent;
odds ratio 0.31, 95% CI 0.15-0.63) [88].

Patients may rarely have a paradoxical reaction to benzodiazepines. This is characterized

by agitation, restlessness, and hostility [89]. 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 [90,91].

Intravenous diazepam may increase the risk of venous thrombosis and phlebitis at the
injection site [92]. The latter can cause injection site pain.

Propylene glycol toxicity — Propylene glycol is the carrier (solvent) that is used to
administer intravenous lorazepam or diazepam. Infusion of either drug may be
complicated by propylene glycol toxicity [93-96].

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 [93-96]. It can occur with normal doses and renal
function, but it is usually associated with doses above the recommended range of 0.1
mg/kg/hour and/or renal impairment [95,97,98]. An osmolar gap >10 mmol/L suggests
that the serum propylene glycol concentration is high enough to cause toxicity [99].
Treatment consists of discontinuing the offending agent and, if severe, dialysis [96].

Propylene glycol is not the solvent for intravenous midazolam. Therefore, patients who
receive intravenous midazolam are not at risk for propylene glycol toxicity.

Drug interactions — Numerous drugs used commonly in the ICU may interact with
benzodiazepines. Some increase the benzodiazepine effect, while others decrease the
effect.

Central nervous system (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 cytochrome
P450 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, telithromycin) 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 cytochrome P450-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 cytochrome P450 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 cytochrome P450,
because it undergoes extensive glucuronidation in the liver to an inactive 3-O-
phenolic metabolite.

KETAMINE

Ketamine is rarely used and is not approved for use in the adult intensive care unit (ICU)
population. Unlabeled uses include procedural sedation/analgesia, treatment of extreme
agitation, and as an adjunct to opioid analgesia [7].

Ketamine is an intravenous anesthetic agent with analgesic and bronchodilator properties

in subanesthetic doses. Ketamine 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 [100].

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 several cytochrome 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 use of ketamine is limited by its psychoactive effects (vivid hallucinations, confusion,
and delirium). Hallucinations or delirium may also occur during recovery from ketamine.
Ketamine is contraindicated in patients with known hypersensitivity to it and in patients at
risk from potentially significant elevations in blood pressure. Other significant adverse
reactions include excessive salivation and respiratory and cardiac depression.

Small randomized studies of patients with burns suggest that during painful procedures
oral ketamine provides better analgesia than dexmedetomidine or the combination of
midazolam, acetaminophen, and codeine (eg, dressing changes) [101,102]. Another review
suggested a reduction in opioid consumption postoperatively [103]. Data from well-
designed randomized controlled trials are needed to determine a clear role of ketamine in
procedural sedation/analgesia and ICU analgesia. (See "Pain control in the critically ill
adult patient", section on 'Ketamine' and "Management of burn wound pain and itching",
section on 'Nonopioid analgesics'.)

ANTIPSYCHOTICS

Antipsychotics can be used in the intensive care unit (ICU) for the treatment of delirium.
Haloperidol can be administered intravenously, has a mild sedative effect, and has
relatively low cardiorespiratory depressive effects. Despite its widespread use for the
treatment of delirium in the ICU, there is no published evidence supporting a reduction in
the duration of mechanical ventilation or duration of delirium by haloperidol and
guidelines make no recommendation favoring its use over other antipsychotics for the
management of delirium in adult ICU patients [7].

Atypical antipsychotics (quetiapine, olanzapine, risperidone, ziprasidone) have also been

used in adult ICU patients to treat delirium. While there is some evidence that the oral
atypical antipsychotics improve delirium in critically ill patients [104,105], there is a paucity
of studies that examine outcome or compare the efficacy and safety of oral atypical
antipsychotics to haloperidol and to one another. The few studies that exist suggest that
the efficacy and safety of oral atypical antipsychotics may be similar to that of haloperidol
[104,106,107]. In a retrospective review of 156 adult patients admitted to an ICU and
treated with an atypical antipsychotic for management of delirium, 31 percent developed
QTc prolongation; 24 percent had a QTc greater than 500 msec [108]. (See 'Adverse effects'
above.)

Although haloperidol and atypical antipsychotics can be used, further studies are
necessary to validate the role of haloperidol or oral atypical antipsychotics, such as
quetiapine, as effective therapies to reduce the duration of mechanical ventilation in adult
ICU patients.

Among ventilated patients, haloperidol does not appear to prevent or decrease the
duration of delirium or mortality [109-113].

● One randomized trial of 1789 critically ill patients at risk of delirium (defined as an
anticipated intensive care unit stay of at least two days) reported that compared with
placebo, 2 mg of haloperidol administered intravenously three times a day had no
impact on the incidence of delirium, survival, duration of mechanical ventilation, or
length of stay [111]. Although outcomes may have been affected by factors including
the high prevalence of nonpharmacologic interventions that were integrated into
daily ICU care and heterogeneity of background treatment across multiple sites, the
consistent lack of impact of haloperidol on any of the 16 outcomes studied suggests
that the lack of benefit is real. This study justifies not using haloperidol
prophylactically in the ICU for the prevention of delirium.

● In another randomized trial of 566 ICU patients with hyperactive or hypoactive

delirium, compared with placebo, there was no difference in the number of days
alive without delirium or coma when patients were treated with haloperidol or the
atypical antipsychotic, ziprasidone [112]. There was also no difference in 30- or 90-
day mortality, duration of mechanical ventilation, or time to ICU or hospital
discharge.

● In a randomized trial of 1000 mechanically ventilated patients, treatment of delirium

with haloperidol did not alter the number of days alive outside the hospital at 90
days compared with placebo [113]. The overall adverse event rate was low and was
no different between the groups. However, this trial did not collect data on other
sedatives used, and the number of patients with hypoactive delirium (as opposed to
hyperactive delirium) may have been under enrolled. Nonetheless, these findings are
in keeping with other studies and suggest no mortality benefit when haloperidol is
 used to treat delirium in critically ill patients [112].

Mechanism — Haloperidol and the other neuroleptics antagonize dopamine and other
neurotransmitters. However, their precise mechanism of action remains unknown.

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 infusion.

● Duration of effect – Haloperidol's duration of effect varies and depends upon the
cumulative dose. Generally speaking, 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 CYP3A4, CYP2D6, and glucuronidation; the hydroxymetabolite (reduced
haloperidol) is active [114]. The pyridinium metabolite, a structural analogue of a known
neurotoxin, may be neurotoxic [115].

Dose regimens — The administration of haloperidol intravenously is common, but it has

not been approved by the US Food and Drug Administration (FDA). The reason that it has
not been approved is that intravenous administration may have a greater risk of serious
adverse events than oral or intramuscular administration, most notably torsades de
pointes and sudden cardiac death [116].

Numerous dosing regimens have been used for the treatment of delirium in adult ICU
patients, none of which have been validated. Continuous infusions ( table 1) are rarely
indicated, but studies suggest that they are probably safe and effective [117-119]. Most
commonly used regimens are:

● 2.5 to 5 mg intravenous bolus doses administered every six hours, as needed

( table 1) [120].

● An initial dose determined by the severity of the agitation. Examples include a 0.5 to
2 mg intravenous bolus dose for mild agitation, a 2 to 5 mg intravenous bolus dose
for moderate agitation, and a 10 to 20 mg intravenous bolus dose for severe
agitation. Following the initial dose, some clinicians give repeat doses as frequently
as every 15 to 30 minutes in patients with severe agitation until the desired level of
sedation is achieved.
 ● A continuous haloperidol infusion beginning at a dose of 10 mg/h and then
increasing 5 mg/hr every thirty minutes as needed until calm is achieved [117-119].

Once calm is restored, a maintenance dose is desirable unless it appears that the delirium
may quickly resolve. A reasonable approach to maintenance dosing is to administer 25
percent of the total loading dose every six hours ( table 1).

The safe maximum daily dose of haloperidol is not known. There are case reports of doses
as high as 945 mg/day [117,121]. Doses greater than 200 mg/day have been safely
administered for up to 15 consecutive days [117,122].

Adverse effects — Haloperidol-associated polymorphic ventricular tachycardia (including

torsades de pointes) is an uncommon but severe adverse reaction [123,124]. It is primarily
associated with intermittent high dose intravenous administration and prolonged QTc
interval. When intermittent haloperidol infusions are used, the QT interval should be
monitored every shift (ie, every 8 to 12 hours) and haloperidol should not be given if the
corrected QT 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 intravenous
haloperidol than among those receiving oral haloperidol [125]. (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 or typical 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) [126]. These findings were supported by two subsequent studies [127,128].
The FDA has since issued a black box warning for the atypical antipsychotics. Prescribing
information for all antipsychotics now includes the black box warning. Antipsychotics
(typical and atypical) should be used with caution in all older adults with dementia,
including the critically ill.

Drug interactions — Haloperidol interacts with numerous drugs that are common 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 cytochrome P450-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 (eg, amiodarone, dronedarone, ranolazine, methadone, high-dose
ondansetron, domperidone, erythromycin, fluoroquinolone antibiotics, tricyclic
antidepressants, posaconazole, voriconazole) should be avoided. Additional agents are
listed in the table ( table 2). Metoclopramide may increase haloperidol toxicity and
should also not be given concurrently.

BARBITURATES

Thiopental (Pentothal) and methohexital (Brevital) are barbiturates that are occasionally
used to sedate critically ill patients. Barbiturates produce sedation by binding to the
gamma aminobutyric acid (GABA)-receptor complex via a different receptor from
benzodiazepines. They commonly cause hypotension and may produce profound
cardiovascular and respiratory depression. As a result, the use of barbiturates should be
limited to patients not tolerating or responding to other agents. Other undesirable
characteristics of barbiturates include prolonged elimination half-lives, induction of the
cytochrome p-450 enzyme system, and accumulation of drugs in renal and hepatic
dysfunction. Thiopental is no longer manufactured in the United States or Canada.
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. 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) [129]. HFIP in the blood is conjugated by
glucuronic acid and then secreted by the kidney.

Potential advantages of sevoflurane as a sedating agent for critically ill ICU patients
include the short duration of action and rapid elimination [130]. Potential disadvantages
include fluoride accumulation with prolonged use (especially in patients with impaired
renal function) and malignant hyperthermia [130]. Additionally, sevoflurane undergoes
degradation on contact with alkaline carbon dioxide absorbents used to remove carbon
dioxide from the circuit, to a potentially nephrotoxic product (trifluoromethyl vinyl ether;
Compound A) [129]. Administration of volatile anesthetic agents in the ICU is not a
standard practice; investments in technology and clinician education will be required
before sevoflurane can be used as a routine sedative in critically ill patients. (See
"Malignant hyperthermia: Diagnosis and management of acute crisis" and "Susceptibility
to malignant hyperthermia: Evaluation and management".)

A trial randomly assigned 60 mechanically ventilated ICU patients to sedation with

sevoflurane, propofol, or midazolam [131]. All of the patients received remifentanil for
analgesia, most were relatively young trauma patients, and 47 completed the trial. The
median duration of sedation in the sevoflurane group was 50 hours (range 39 to 71
hours). Wake-up time and time to extubation were significantly shorter in the sevoflurane
group compared with the propofol or midazolam groups. The study had too few events to
conclusively detect differences in ICU length of stay or mortality.

BACLOFEN

Baclofen is a gamma-aminobutyric acid type B receptor agonist that at high levels can
reduce consciousness. Its role as a sedative in the intensive care unit (ICU) is unclear, but
previous data suggest that baclofen may mitigate alcohol craving in patients with alcohol
use disorder [132,133]. One randomized trial used high-dose oral baclofen (50 to 150 mg
per day) for the management of agitation in 314 mechanically ventilated patients who had
unhealthy alcohol use (defined as consumption of more than 14 units per week for males
and more than 7 units per week for females and males >65 years) [134]. Baclofen resulted
in a reduction in the proportion of patients who experienced at least one agitation-related
event (19.7 versus 29.7 percent; eg, self-extubation, removal of venous catheters) but did
not impact the 28-day ICU mortality when compared with placebo. In addition, baclofen
was associated with a longer duration of mechanical ventilation and ICU length of stay.
The most common adverse effect was delayed awakening; others included stroke, seizure,
and bradycardia. Several flaws in study design including the lack of standardized baclofen
dosing, inaccurate assessment of alcohol consumption, and lack of parenteral formulation
limit interpretation and generalization of this study. Further studies are needed before
baclofen can be recommended for use in individuals with agitation from unhealthy
alcohol use.

CHOICE OF AGENT

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
patient characteristics and the clinical situation. The etiology of the distress, expected
duration of therapy, potential interactions with other drugs, desired depth of sedation,
and pharmacokinetic-modifying factors are important considerations whenever selecting
an agent. The selection of sedative analgesics in the critically ill patient is discussed
separately. (See "Sedative-analgesic medications in critically ill adults: Selection, initiation,
maintenance, and withdrawal", section on 'Selection of an agent'.)

COMBINATION THERAPY

Many clinicians believe that combination therapy using different types of sedatives is best.
The rationale is that agitation is often multifactorial and each potential cause deserves a
targeted therapy. This notion was supported by a trial that randomly assigned 30
mechanically ventilated patients to receive midazolam alone or midazolam plus fentanyl
[135]. Midazolam plus fentanyl maintained sedation level goals better, decreased the dose
of the primary agent, added analgesia, and did not appreciably increase the likelihood of
prolonged sedation. There were no differences in hemodynamic or respiratory adverse
effects. Two patients treated with the combination regimen developed ileus, compared
with none with midazolam alone. (See "Sedative-analgesic medications in critically ill
adults: Selection, initiation, maintenance, and withdrawal".)

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, anxiety, dyspnea, or delirium is common among

critically ill patients. Distress may cause ventilator asynchrony and increase
sympathetic tone, which may have untoward clinical effects. (See 'Introduction'
above.)

● Classes of agents – Classes of sedative-analgesic medications used to treat distress

include opioids, propofol, dexmedetomidine, benzodiazepines, neuroleptics, and,
rarely, barbiturates. Pilot studies of the propofol prodrug fospropofol, the volatile
anesthetic sevoflurane, and baclofen have been reported. (See 'Benzodiazepines'
above and 'Analgesics' above and 'Antipsychotics' above and 'Propofol' above and
'Dexmedetomidine' above and 'Barbiturates' above and 'Sevoflurane' 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 patient characteristics and the clinical situation.
The etiology of the distress, expected duration of therapy, potential interactions with
other drugs, desired depth of sedation, and pharmacokinetic-modifying factors are
important considerations whenever selecting an agent. (See "Sedative-analgesic
medications in critically ill adults: Selection, initiation, maintenance, and withdrawal",
section on 'Selection of an agent'.)

● Adverse effects – Dose-dependent respiratory and cardiovascular depression are

common among sedative-analgesic agents. Most classes of sedative analgesics also
have unique adverse effects. Examples include propylene glycol toxicity (eg, from
lorazepam or diazepam) and the propofol infusion syndrome. (See 'Propylene glycol
toxicity' above and 'Propofol-related infusion syndrome' above.)
 Use of UpToDate is subject to the Terms of Use.

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Topic 1616 Version 73.0
GRAPHICS

Intravenous* sedative and analgesic dosing regimens for managing

pain, agitation, and delirium in the intensive care unit

Duration of
Maintenance Onset intermittent Charac
Drug Loading dose
dose range (minutes) dose
(minutes)

Opioid analgesics

Fentanyl 1 to 2 mcg/kg ¶ 0.35 to 0.5 <1 to 2 30 to 60 Δ Advanta

mcg/kg every Potent a
(25 to 100 mcg)
0.5 to 1 hour sedative
intermittent (25 immedia
to 50 mcg) and less
hypoten
and/or
other op
0.7 to 10 analges
mcg/kg/hour due to r
infusion [1] lack of h
For most release.
patients, 1 to 3 Metabo
mcg/kg/hour hepatica
infusion (50 to CYP3A4
300 mcg/hour) metabo
with as-needed Disadva
intermittent Highly li
bolus doses is parent d
sufficient accumu
adipose
tissue w
repeate
prolong
adminis
Chest w
may occ
higher d

Role:
choice f
analges
most cri
 patients

Hydromorphone 0.5 to 2 mg ¶ 0.2 to 0.6 mg 5 to 10 240 to 300 Advanta

every 1 to 2 adminis
hours requires
intermittent volumes
to other
and/or
Non-CYP
0.5 to 3 metabo
mg/hour (glucuro
infusion may be
advanta
patients
drugs th
significa
CYP3A4
metabo
thereby
with fen

Disadva
Potentia
neuroto
(excitato
metabo
accumu
hepatic
renal
dysfunc

Role:
option a
to fenta
morphin
adjustm
gradual
needed
patients
renal an
hepatic
impairm

Morphine sulfate 2 to 10 mg ¶ 2 to 4 mg every 5 to 10 240 to 300 Advanta

1 to 2 hours CYP met
intermittent (glucuro
may be
and/or
advanta
2 to 30 mg/hour selected
infusion receivin
that sign
alter CY
metabo
thereby
with fen

Disadva
Can accu
hepatic
dysfunc
prolong
Histamin
and vag
mediate
venodila
hypoten
bradyca
be signi

Role:
alternat
fentanyl
hydrom
where p
reductio
myocard
depress
are desi
tolerabl
adjustm
gradual
needed
patients
renal an
hepatic
impairm
in patien
advance
decomp
liver dis
renal im
due to r
accumu
neuroto
 metabo
Infusion
generall
sedation
analges
ICU but
common
for pallia
purpose

Remifentanil Optional: 0.5 to 15 1 to 3 5 to 10 (after Advanta

1.5 mcg/kg [1] mcg/kg/hour cessation of Ultra-sh
infusion infusion) Cleared
Most ICU
nonspec
patients can be
plasma
managed
to inacti
without bolus
metabo
doses; if
not accu
required, a bolus
renal or
of 0.5 mcg/kg is
impairm
usually sufficient;
Prompt
larger boluses
analges
are associated
sedation
with significant
disconti
reductions in HR
and MAP Disadva
Anticipa
and disc
upon ab
cessatio
excipien
accumu
renal
impairm

Role:
alternat
fentanyl
patients
frequen
neurolo
assessm
those w
multiorg
failure.

Nonopioid analgesics (adjunctive or opioid sparing)

Acetaminophen None Oral, rectal: 325 Oral: 30 to 240 to 360 Advanta
(paracetamol) to 1000 mg 60 Lacks de
every 4 to 6 and tole
Rectal:
hours opioids.
Variable
antiplate
IV: 650 mg IV
IV: 5 to 10 and
every 4 hours to
gastroin
1000 mg IV
toxicity
every 6 hours,
or 15 mg/kg IV Disadva
every 6 hours Lacks sig
for patients anti-infla
weighing <50 effect. IV
kg prepara
requires
Maximum ≤4
adminis
g/day
over 15
Can cau
hepatot
chronic
overdos
or use a
daily do
adults a
patients
hepatot
heavy al
or maln
Interact
warfarin
prolong
CYP-ind
drugs (e
risk of h
inflamm

Role:
for treat
mild to m
acute pa
febrile c
Adjuncti
analges
may red
requirem
When h
 dysfunc
significa
conside
or reduc
(eg, ≤2
total).

Ketorolac Optional: Age <65 years IV: ~30 360 to 480 Advanta
30 mg once and weight ≥50 Lacks de
kg: 15 to 30 mg and tole
every 6 hours; opioids.
maximum 120 anti-infla
mg/day for up
Disadva
to 5 days
Can cau
Age ≥65 years worsen
or weight <50 insuffici
kg: 15 mg every Dose-re
6 hours; of gastr
maximum 60 Reversib
mg/day for up platelet
to 5 days function
alter
cardiopr
effect of

Role:
analges
may red
requirem

Avoid in
impairm
gastroin
bleeding
dysfunc
ischemic
disease,
failure, r
cardiac
hypovol
state, as
cirrhosis
Contrain
treatme
periope
 in coron
bypass g
surgery.
should b
hydrate

Ibuprofen None Oral: 400 mg Oral: 30 240 to 360 Advanta

orally every 4 Lacks de
IV: ~30
hours and tole
(maximum 2.4 opioids.
g/day chronic) anti-infla

IV: 400 to 800 Disadva

mg IV every 6 Can cau
hours worsen
(maximum 3.2 insuffici
g/day acute) Dose-re
of gastr
Reversib
platelet
function
alter
cardiopr
effect of

Role:
treatme
modera
pain and
conditio
Adjuncti
analges
may red
requirem

Avoid in
impairm
gastroin
bleeding
dysfunc
ischemic
disease,
failure, r
cardiac
hypovol
state, as
cirrhosis
 Contrain
treatme
periope
in coron
bypass g
surgery.
should b
hydrate

Gabapentin None Oral: Initially Variable – Advanta

100 mg 3 times Effective
per day treatme
neuropa
Oral:
Low risk
Maintenance
interacti
900 to 3600 mg
per day in 3 Disadva
divided doses Require
adminis
schedul
and indi
titration
to week
bioavail
variable
60%) an
inversel
proport
dose. Ad
effects i
sedation
dizzines
ataxia, w
be inten
renal im
requirin
adjustm
Should n
abruptly
due to r
disconti
symptom

Role:
adjunct
analges
treatme
 neuropa
postope
pain or
dysesth
patients
be treat
enteral
medicat
adjustm
needed
impairm

Pregabalin None Oral: Initially 75 Variable – Advanta

mg once or (hours to Effective
twice per day days) treatme
neuropa
Oral:
Oral bio
Maintenance
(>90%) i
150 to 300 mg
reliable
twice per day
gabapen
may pro
more ra
of analg
a shorte
of time n
titrate to
Low risk
interacti

Disadva
Require
adminis
schedul
and titra
days to
Adverse
include
blurred
mouth,
and atax
may be
in renal
impairm
requirin
adjustm
 Should n
abruptly
due to r
disconti
symptom

Role:
adjunct
analges
treatme
neuropa
postope
pain or
dysesth
patients
be treat
enteral
medicat
adjustm
needed
impairm

Anesthetic-sedative

Propofol Bolus doses are 5 to 50 <1 to 2 3 to 10 Δ Advanta

usually not given mcg/kg/minute Potent s
in the ICU hypnotic
Titrate every 5
associat
to 10 minutes in
immedia
increments of 5
and rap
to 10
awaken
mcg/kg/minute
disconti
Some patients when
require up to 70 adminis
mcg/kg/minute, short-te
which can Metabo
increase risk of reported
propofol unaltere
infusion hepatic
syndrome (refer impairm
to UpToDate subject
topics on significa
sedative- interacti
analgesic Infusion
medications in titratabl
critically ill desired
patients:
properties, dose sedation
regimens, and minimiz
adverse effects) oversed
Propofo
effective
decreas
intracra
pressure
cerebral
metabo
controls
intractab
seizures
reduce s
in the re
phase o
hypothe
followin
resuscit
cardiac

Disadva
Adverse
include
hypoten
bradyca
respirat
depress
decreas
myocard
contract
elevated
triglycer
periphe
injection
and rare
propofo
syndrom
to UpTo
topics o
sedative
medicat
critically
patients
properti
 regimen
adverse
Specific
presenta
may inc
potentia
allergen
soy, pea
others).
product
informa
analges

Role:
choice in
conjunc
appropr
analges
short-te
sedation
patients
rapid aw
is advan
Also a g
choice t
elevated
intracra
pressure
short-te
sedation
general
care pop
that is li
ready so
ventilato
weaning

Ketamine 0.25 to 0.5 mg/kg 0.05 to 0.4 ≤1 10 to 15 (single Advanta

bolus IV mg/kg/hour dose) potent
dissocia
Bolus doses may
sedative
be given prior to
anesthe
sedation with an
marked
infusion of
that ma
ketamine or as a
cardiac
single bolus (eg,
and MAP
patients with
burns prior to inhibitio
dress changes or respirat
for procedural Does no
sedation) protecti
reflexes
Bolus dosing
reduce a
may be repeated
opioid to
if necessary
during the Disadva
procedure Sympath
(maximum dose stimulat
2 mg/kg in a 30 increase
minute period) myocard
oxygen
elevated
intracra
pressure
systemic
pressure
intolera
dependi
clinical s
Rarely,
cardiore
depress
associat
rapid
adminis
higher d
Adverse
may inc
hallucin
delirium
withdraw
clonic
moveme
dissocia
experien
unpleas
hypersa
nausea,
vomiting
Complex
metabo
includes
 2C9, 2B6
non-CYP
transfor
and an a
metabo
(norketa
which m
accumu
renal an
hepatic
impairm
due to d
interacti

Role:
choice f
postsurg
manage
severe a
or as an
adjuncti
analges
patients
severe r
pain in c
settings
increase
myocard
oxygen
and sym
tone are

Central alpha2 agonist

Dexmedetomidine Optional: 0.2 to 1.5 5 to 10 60 to 120 Advanta

1 mcg/kg over 10 mcg/kg/hour (optional Effective
minutes if loading sympath
Initiate at 0.2
hemodynamically dose) (central
mcg/kg/hour
stable agonist)
and titrate 15 (without
modera
Usually not given every 30 loading
anxiolys
minutes dose)
analges
Charact
depth o
may per
critically
mechan
ventilate
patients
interacti
easily aw
yet com
Can be u
non-me
ventilate
patients
continue
needed
extubati
Reduces
in the re
phase o
hypothe
followin
resuscit
cardiac
May be
to cause
than oth
sedative

Disadva
Potentia
significa
hypoten
bradyca
hyperte
do not r
quickly u
abrupt
disconti
Metabo
hepatica
glucuron
and CYP
reductio
recomm
with ren
hepatic
impairm
adminis
 loading
be assoc
cardiova
instabili
tachycar
bradyca
heart bl
not indu
deep se
needed
neurom
blockad

Role:
choice f
and long
sedation
critically
patients
relevant
conditio
be usefu
sedation
patients
high risk
develop
delirium
this has
well esta

Benzodiazepines

Midazolam 0.01 to 0.05 0.02 to 0.1 2 to 5 30 Δ Advanta

¶
mg/kg mg/kg/hour potent a
infusion and anx
(0.5 to 4 mg; this
agent w
non-weight (2 to 8 mg/hour;
immedia
based dosing this non-weight
of action
may be based dosing
short du
preferred) may be
effect w
preferred) with
adminis
intermittent
short te
bolus dose(s) if
hours). I
needed. While
only IV
the patient is on
benzodi
a continuous
that is n
infusion,
periodic re- delivere
bolus may be propylen
needed to
Disadva
maintain the
Hepatica
sedation goal.
metabo
This approach
CYP3A4
may help
metabo
prevent
may acc
unnecessary
and cau
dose creep of
prolong
the infusion.
sedation
delivere
term. Ha
be prolo
critically
patients
hepatic
impairm
of deliriu
it intera
drugs u
ICU (eg,
antiretro
azole an
that alte
metabo
that exc
sedation
occur w
concom
of midaz
drugs
metabo
CYP3A4.

Role:
choice f
term an
and trea
acute ag
Dose ad
and gra
titration
needed
patients
 renal an
hepatic
impairm

Lorazepam 0.02 to 0.04 0.02 to 0.06 15 to 20 360 to 480 Δ Advanta

¶
mg/kg mg/kg every 2 Sedative
to 6 hours amnesti
(1 to 2 mg; this
intermittent (1 anxiolys
non-weight
to 4 mg) anticonv
based dosing
properti
may be and/or
Hepatica
preferred)
0.01 to 0.1 metabo
If rapid effect is mg/kg/hour glucuron
needed, actual infusion (0.5 to inactive
body weight is 10 mg/hour) metabo
sometimes used Relative
Non-weight
based dosing of drug
may be interacti
preferred safety in
modera
and ren
impairm

Disadva
Relative
onset. R
oversed
when tit
to delay
respons
accumu
periphe
Risk of d
IV
incompa
and risk
precipita
Propylen
solvent
accumu
prolong
high dos
causing
acidosis
organ d
(refer to
 topics o
sedative
medicat
critically
patients
properti
regimen
adverse
Long ha
significa
accumu
older ad
patients
significa
or hepa
impairm

Role:
choice f
sedation
anxiolys
most pa
includin
who ma
long-ter
ongoing
Althoug
intermit
dosing m
preferre
continuo
infusion
initiated
patients
frequen
repeate
dosing.

Diazepam 0.05 to 0.2 0.03 to 0.1 2 to 5 20 to 60 Δ Advanta

mg/kg ¶ mg/kg every 0.5 Rapid on
to 6 hours potent s
(5 to 10 mg)
intermittent (1 and mu
to 7 mg) relaxant

Continuous Disadva
infusion is not Hepatica
recommended metabo
CYP2C19
to active
metabo
may acc
and cau
prolong
sedation
delivere
term. Ha
be prolo
critically
patients
hepatic
renal im
Risk of d
Also, it i
with dru
the ICU
CYP met
Injection
contains
propylen
solvent
cannot b
delivere
continuo
infusion
site pain
of phleb
usefulne
injection

Role:
used for
of critica
patients
useful fo
ill patien
of alcoh
withdraw
seizures
drug ov
poisonin
Antipsychotics

Haloperidol § 0.03 to 0.15 0.03 to 0.15 IV: 5 to 20 30 to 360 Δ Advanta

¶
mg/kg mg/kg every 30 Modera
minutes to 6 sedating
Variable dosing
hours dopamin
ranging from 1 to
antagon
2 mg IV every six Various
control o
hours intermittent
symptom
regimens have
delirium
been used.
psychos
Continuous
Minimal
infusions are
cardiore
are (eg, 0.5 to 2
effects i
mg/hour)
euvolem
hemody
stable p

Disadva
Complex
metabo
includes
and 2D6
transfor
Some ex
conside
metabo
active or
potentia
neuroto
life beco
prolong
repeate
adminis
Adverse
include
depende
prolong
hypoten
Interact
some co
ICU dru
interfere
metabo
and/or b
an addit
 prolong
QTc.
Extrapyr
symptom
neurole
maligna
syndrom
in critica

Role:
treatme
agitation
delirium
critically
patients

Olanzapine ¥ Optional: Oral: Initially 5 IM: 15 to 45 IM: ≥120 Advanta

5 to 10 mg IM to 10 mg once Availabi
daily; increase short-ac
May repeat every
every 24 hours formula
two to four hours
as needed by 5- risk of
if needed
mg increments extrapyr
(maximum total
up to 20 symptom
30 mg)
mg/day prolong
haloper

Disadva
Adverse
include
orthosta
hypoten
hypergly
somnole
prolong
antichol
effects.
Undergo
extensiv
metabo
includin
(ie,
glucuron
and CYP
transfor
Half-life
prolong
 ≥50 hou
increase
accumu
patients
older, fe
nonsmo
and/or i
setting o
or renal
impairm

Role:
alternat
on to as
IV halop
treatme
acute ag
and/or d
the ICU.
lowest s
dose an
more gr
patients
renal an
hepatic
impairm
and/or o
factors t
predispo
slowed
metabo
to
"Disadva
above).

Quetiapine ¥ None Oral: Initially 50 Oral: 60 Oral: 6 to 12 Advanta

mg every 12 (initial hours risk of
hours; increase effect); ≥24 extrapyr
every 24 hours hours (full symptom
as needed up to effect) possibly
400 mg/day of QT
prolong
haloper

Disadva
Require
 route of
adminis
and sch
dosing d
slow ons
action a
relativel
titration
Adverse
may inc
sedation
orthosta
hypoten
risk of Q
prolong
remains
Hepatica
metabo
CYP3A4
and inac
metabo

Role:
choice a
to as-ne
haloper
treatme
agitation
delirium
advance
impairm
initiate w
reduced
titrate in
increme

Ziprasidone ‡ Optional: Oral: 20 to 40 IM: 30 IM: ≥90 Advanta

10 mg IM mg orally every Availabi
12 hours short-ac
May repeat every
formula
two hours if
risk of
needed
extrapyr
(maximum 40 mg
symptom
total)
haloper
or
Disadva
20 mg IM Orthost
hypoten
May repeat once
hypergly
after 4 hours if
QT prolo
needed
undergo
(maximum 40 mg
extensiv
total)
metabo
hepatic
and CYP
transfor
to active
inactive
metabo
formula
contains
cyclodex
potentia
nephrot
which ca
accumu
renal im
an IV for
is not av
Oral for
needs to
in a fed
(≥500 ca
reliable
absorpt

Role:
alternat
on to as
IV halop
treatme
acute ag
the ICU
reductio
needed
advance
impairm
Specific
recomm
are not
Avoid pr
 use of IM
prepara
patients
renal im
due to r
accumu
cyclodex
additive

Dosing information in this table is for critically ill adults who are nonobese and includes
indications, dosing, duration of use, and routes of administration not listed in the US Food &
Drug Administration approved product labeling. In some cases, non-weight-based initial
dosing is preferred, and is shown in parentheses after weight-based dosing. For additional
information for patients who are obese, refer to UpToDate topic reviews on ICU management
of the obese critically ill patient.

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).

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

Δ 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 on emergency management of the acutely agitated or violent patient and
pharmacotherapy for acute schizophrenia. Importantly, haloperidol is not FDA-approved for
intravenous administration.

¥ 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]

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.

Graphic 79667 Version 45.0

Some reported causes and potentiators of the long QT syndrome

Congenital

Jervell and Lange-Nielsen syndrome (including "channelopathies")

Romano-Ward syndrome
Idiopathic

Acquired
Metabolic disorders Other factors Androgen deprivation therapy
Hypokalemia Myocardial GnRH agonist/antagonist therapy
Hypomagnesemia ischemia or Bilateral surgical orchiectomy
Hypocalcemia infarction,
Diuretic therapy via electrolyte disorders
especially with
Starvation particularly hypokalemia and
prominent T-wave
Anorexia nervosa hypomagnesemia
inversions
Liquid protein diets Herbs
Intracranial
Hypothyroidism Cinchona (contains quinine), iboga
disease
Bradyarrhythmias HIV infection (ibogaine), licorice extract in overuse
Sinus node via electrolyte disturbances
Hypothermia
dysfunction Toxic exposure:
AV block: Second or Organophosphate
third degree insecticides

Medications*

High risk

Adagrasib Cisaparide Lenvatinib Selpercatinib

Ajmaline ¶ (restricted Levoketoconazole Sertindole ¶
Amiodarone Δ availability) Methadone Sotalol
Arsenic trioxide Delamanid ¶ Mobocertinib Terfenadine ◊
Δ
Astemizole ◊ Disopyramide Papavirine Vandetanib
Bedaquline Dofetilide (intracoronary) Vernakalant ¶
Bepridil ◊ Dronedarone Procainamide Ziprasidone
Chlorpromazine Haloperidol (IV) Quinidine
Ibutilide Quinine
Ivosidenib

Moderate risk

Amisulpride ¶ (oral) § Droperidol Inotuzumab Propafenone

Azithromycin Encorafenib ozogamacin Propofol
Capecitabine Entrectinib Isoflurane Quetiapine
¶
 Carbetocin ¶ Erythromycin Levetiracetam Quizartinib
Certinib Escitalopram Levofloxacin Ribociclib
Chloroquine Etelcalcetide (systemic) Risperidone
Citalopram Fexinidazole Lofexidine Saquinavir
Clarithromycin Flecainide Meglumine Sevoflurane
Clofazimine Floxuridine antimoniate Sparfloxacin ¶
Clomipramine ¥ Fluconazole Midostaurin Sunitinib
Clozapine Fluorouracil Moxifloxacin Tegafur ¶
Crizotinib (systemic) Nilotinib Terbutaline
Dabrafenib Flupentixol ¶ Olanzapine Thioridazine
Dasatinib Gabobenate Ondansetron (IV > Toremifene
dimeglumine oral)
Deslurane Vemurafenib
Gemifloxacin ¶ Osimertinib
Domperidone ¶ Voriconazole
¥ Gilteritinib Oxytocin
Doxepin
Halofantrine Pazopanib
Doxifluridine ¶
Haloperidol (oral) Pentamidine
Imipramine ¥ Pilsicainide ◊
Pimozide
Piperaquine
Probucol ◊

Low risk ‡

Albuterol Fingolimod Mefloquine Radotinib

Alfuzosin Fluoxetine Mequitazine Ranolazine
Amisulpride (IV) §
Fluphenazine Methotrimeprazine (due to
Amitriptyline ¥ Formoterol Metoclopramide bradycardia)

Anagrelide Foscarnet (rare reports) Relugolix

Apomorphine Fostemsavir Metronidazole Rilpivirine

Arformoterol Gadofosveset (systemic) Romidepsin

Artemether- Gepirone Mifepristone Roxithromycin

lumefantrine Glasdegib Mirtazapine Salmeterol
Asenapine Goserelin Mizolastine Sertraline
Atomoxetine Granisetron Nelfinavir Siponimod
Benperidol Hydroxychloroquine Norfloxacin Solifenacin
Bilastine ¶ (rare reports) Nortriptyline ¥ Sorafenib
Bosutinib Hydroxyzine Ofloxacin Sulpiride
Bromperidol Iloperidone (systemic) Tacrolimus
Buprenorphine † Indacaterol Olodaterol (systemic)

Buserelin Itraconazole Osilodrostat Tamoxifen

Ciprofloxacin Ketoconazole Oxaliplatin Telavancin

ΔΔ
 (Systemic) (systemic) Ozanimod ΔΔ Teneligliptin
Cocaine (Topical) Lacidipine Pacritinib Tetrabenazine
Degarelix Lapatinib Paliperidone Trazodone
Desipramine ¥ Lefamulin Panobinostat Triclabendazole
Deutetrabenazine Leuprolide Pasireotide Triptorelin
Dexmedetomidine** Leuprolide- Pefloxacin Tropisetron ¶
Dolasetron norethindrone Periciazine ¶ Vardenafil
Donepezil Levalbuterol Pimavanserin Vilanterol
Efavirenz Levomethadone Pipamperone Vinflunine
Eliglustat Lithium Pitolisant Voclosporin
Eribulin Loperamide ¶¶ in Ponesimod Vorinostat
Ezogabine overdose Primaquine Zuclopenthixol
Lopinavir Promazine
Macimorelin

This is not a complete list of all corrected QT interval (QTc)-prolonging drugs and does not
include drugs with either a minor degree or isolated association(s) with QTc prolongation that
appear to be safe in most patients but may need to be avoided in patients with congenital
long QT syndrome depending upon clinical circumstances. A more complete list of such drugs
is available at the CredibleMeds website. For clinical use and precautions related to
medications and drug interactions, refer to the UpToDate topic review of acquired long QT
syndrome discussion of medications and the Lexicomp drug interactions tool.

AV: atrioventricular; IV: intravenous; QTc: rate-corrected QT interval on the electrocardiogram.

* Classifications provided by Lexicomp according to US Food & Drug Administration guidance:

Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythic Potential for Non-
Antiarrhythmic Drugs – Questions and Answers; Guidance for Industry US Food and Drug
Administration, June 2017 (revision 2) available at:
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidance
s/UCM073161.pdf as updated August 8, 2023 (https://www.fda.gov/media/170814/download)
with additional data from CredibleMeds QT drugs list [1,2] . The use of other classification
criteria may lead to some agents being classified differently by other sources.

¶ Not available in the United States.

Δ In contrast with other class III antiarrhythmic drugs, amiodarone is rarely associated with
torsades de pointes; refer to accompanying text within UpToDate topic reviews of acquired
long QT syndrome.

◊ Withdrawn from market in most countries due to adverse cardiovascular effects.

§ IV amisulpride antiemetic use is associated with less QTc prolongation than the higher doses
administered orally as an antipsychotic.
¥ Some other cyclic antidepressants (ie, amoxapine, maprotiline, protriptyline, trimipramine)
may also prolong the QT interval, but data are insufficient to identify level of risk with
confidence; refer to UpToDate content on cyclic antidepressant pharmacology, administration,
and side effects.

‡ The "low risk" category includes drugs with limited evidence of clinically significant QTc
prolongation or TdP risk; many of these drugs have label warnings regarding possible QTc
effects or recommendations to avoid use or increase ECG monitoring when combined with
other QTc prolonging drugs.

† Rarely associated with significant QTc prolongation at usual doses for treatment of opioid
use disorder, making buprenorphine a suitable alternative for patients with methadone-
associated QTc prolongation. Refer to UpToDate clinical topic reviews.

** A rotulagem da FDA dos Estados Unidos para a preparação sublingual de

dexmedetomidina alerta contra o uso em pacientes com risco elevado de prolongamento do
intervalo QTc. Tanto as formulações intravenosas (ou seja, sedativas) quanto as sublinguais de
dexmedetomidina apresentam baixo risco de prolongamento do intervalo QTc e não foram
implicadas na TdP.

¶¶ Em cima do balcão; disponível sem receita médica.

ΔΔ Não está associado a prolongamento significativo do intervalo QTc em pessoas saudáveis.

Consulte o tópico clínico do UpToDate para possíveis efeitos cardiovasculares (CV) adversos
em pacientes com doença cardiovascular.

Dados de:
1. Lexicomp Online. Copyright © 1978-2023 Lexicomp, Inc. Todos os direitos reservados.
2. Site da lista de medicamentos CredibleMeds QT, patrocinado pela Science Foundation da Universidade do
Arizona. Disponível em http://crediblemeds.org/ .

Gráfico 57431 Versão 148.0

Divulgações do Colaborador
Karen J Tietze, PharmD Não há relacionamento(s) financeiro(s) relevante(s) com empresas
inelegíveis para divulgar. Barry Fuchs, MD Não há relacionamento(s) financeiro(s) relevante(s) com
empresas inelegíveis para divulgar. Polly E Parsons, MD Emprego: Alliance for Academic Internal
Medicine [Presidente e CEO]. Todas as relações financeiras relevantes listadas foram mitigadas.
Michael F O'Connor, MD, Consultor/Conselho Consultivo da FCCM: Intensix/CLEW [Análise preditiva
em medicina]. Todas as relações financeiras relevantes listadas foram mitigadas. Geraldine Finlay,
MD Não há relacionamento(s) financeiro(s) relevante(s) com empresas inelegíveis para divulgar.

As divulgações dos colaboradores são revisadas quanto a conflitos de interesse pelo grupo editorial.
Quando encontrados, estes são abordados através de um processo de revisão multinível e através de
requisitos para referências a serem fornecidas para apoiar o conteúdo. O conteúdo referenciado
adequadamente é exigido de todos os autores e deve estar em conformidade com os padrões de
evidência do UpToDate.

Política de conflito de interesses