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Analgosedation: A Paradigm Shift in Intensive Care Unit Sedation Practice

Article  in  Annals of Pharmacotherapy · April 2012

DOI: 10.1345/aph.1Q525 · Source: PubMed

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Critical Care
Analgosedation: A Paradigm Shift in Intensive Care Unit Sedation
Practice
Sandeep Devabhakthuni, Michael J Armahizer, Joseph F Dasta, and Sandra L Kane-Gill
roviding effective analgesia and se-
P dation is a generally accepted goal
for critically ill mechanically ventilated
patients because of the increased dis-
comfort associated with intubation, inva-
sive bedside procedures for management
or monitoring, surgery, and intensive
care unit (ICU) environment. To manage
patient discomfort, the use of a continu-
ous sedative-hypnotic approach with
benzodiazepines and propofol is com-
monly used to optimize comfort care.1,2
In fact, these agents are used for sedation
in more than 80% of critically ill pa-
tients.3 Benzodiazepines and propofol
are associated with significant adverse
effects and risks that may prolong me-
chanical ventilation and ICU length of
stay.4,5 There is a trend toward using
lighter sedation with techniques like dai-
ly sedation interruption, which has been
shown to reduce escalation of medica-
tion doses resulting in a shorter duration
of mechanical ventilation and ICU stay.6
Despite efforts to optimize sedation
and comfort, a recent study showed that
77% of cardiac surgery ICU patients still
experience pain.7 Another study deter-
mined that more than 50% of 21 me-
chanically ventilated patients who re-
gained orientation within 72 hours of
ICU discharge recalled experiencing
Author information provided at end of text.
530 n The Annals of Pharmacotherapy
OBJECTIVE: To critically evaluate the use of analgosedation in the management of
agitation in critically ill mechanically ventilated patients.
DATA SOURCES: Literature was accessed through MEDLINE (1948-November
2011) and Cochrane Library (2011, issue 1) using the terms analgosedation, analgo-
sedation, or analgesia-based sedation alone or in combination with intensive care
unit or critically ill. Reference lists of related publications were also reviewed.
STUDY SELECTION AND DATA EXTRACTION: All articles published in English were
evaluated. Randomized controlled trials examining critically ill mechanically
ventilated patients older than 18 years were included.
DATA SYNTHESIS: Limitations of current sedation practices include serious
adverse drug events, prolonged mechanical ventilation time, and intensive care unit
(ICU) length of stay. Studies have demonstrated that analgosedation, a strategy that
manages patient pain and discomfort first, before providing sedative therapy, results
in improved patient outcomes compared to standard sedative-hypnotic regimens.
Nine randomized controlled trials comparing remifentanil-based analgosedation to
other commonly used agents (fentanyl, midazolam, morphine, and propofol) for ICU
sedation and 1 trial comparing morphine to daily sedation interruption with propofol
or midazolam were reviewed. Remifentanil is an ideal agent for analgosedation due
to its easy titratability and organ-independent metabolism. When compared to
sedative-hypnotic regimens, remifentanil-based regimens were associated with
shorter duration of mechanical ventilation, more rapid weaning from the ventilator,
and shorter ICU length of stay. Compared to fentanyl-based regimens, remifentanil
had similar efficacy with the exception of increased pain requirements upon
remifentanil discontinuation. Analgosedation was well tolerated, with no significant
differences in hemodynamic stability compared to sedative-hypnotic regimens.
CONCLUSIONS: Analgosedation is an efficacious and well-tolerated approach to
management of ICU sedation with improved patient outcomes compared to
sedative-hypnotic approaches. Additional well-designed trials are warranted to
clarify the role of analgosedation in the management of ICU sedation, including
trials with nonopioid analgesics.
KEY WORDS: analgosedation, remifentanil.
Ann Pharmacother 2012;46:530-40.
Published Online, 10 Apr 2012, theannals.com, DOI 10.1345/aph.1Q525
n 2012 April, Volume 46 theannals.com
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moderate to extreme pain, anxiety, fear, and inability to
sleep during their ICU stay. These patients’ care was man-
aged with either a sedation protocol or a combination of a
sedation protocol and daily sedative/analgesic interrup-
tion.8 In addition, severe pain at rest has been shown to be
an independent risk factor for developing postoperative
delirium following hip surgery.9
Recent publications promote the use of analgosedation
as compared to a sedative-hypnotic approach, where the
primary goal is to address pain and discomfort first, and
then add a hypnotic agent or agents if necessary.10-12 Also
known as analgesia-based sedation or analgesia-first seda-
tion, analgosedation has been demonstrated to be as effec-
tive as the sedative-hypnotic approach with reduced dose
requirements of hypnotic medications.13,14 To meet the
goals of analgesia and sedation in the ICU, clinicians may
need to consider a paradigm shift in ICU sedation practice
regarding protocol and medication use. The objectives of
this review article are to discuss the limitations of current
sedation practices, examine the clinical evidence for anal-
gosedation, and suggest the role of analgosedation in the
management of ICU patients with agitation as part of opti-
mizing comfort care.
Rationale for Analgosedation
LIMITATIONS OF CURRENT SEDATION PRACTICES
Traditional patient-targeted sedation protocols, which
provide a structured comfort care approach to assessment
of pain and distress combined with a medication algorithm,
have focused on hypnotic drugs such as benzodiazepines
and propofol, with opioids used as needed to control
pain.2,14,15 Sedation protocols,16,17 scales,17,18 and daily inter-
ruption of sedatives6,19 have been demonstrated to mini-
mize the accumulation of sedative effects, reduce the
length of mechanical ventilation, and minimize ICU length
of stay and mortality. Unfortunately, a recent systematic re-
view revealed that the use of sedation protocols and daily
interruption does not occur routinely in ICUs.20 In fact,
64% of 12,994 critical care clinicians in the US used pa-
tient-targeted sedation protocols and only 40% used daily
sedation interruption, whereas in Canada, only 29% of 223
intensivists used a sedation protocol and 40% used daily
interruption.20,21 This heterogeneity in sedation practices
may explain the variable outcomes observed in duration of
mechanical ventilation (10-70% reduction) and ICU length
of stay (11-64% reduction).22
Many patients experience inappropriate levels of seda-
tion (either undersedation or oversedation), with a tenden-
cy for oversedation in 40-60% of patients.23,24 The conse-
quences of undersedation include severe anxiety and agita-
tion, hypoxemia, unplanned extubations, increased stress
response, and myocardial ischemia, which can prolong
theannals.com
ICU stay and increase costs.25 Oversedation in critically ill
patients can depress the respiratory drive, cause cognitive
impairment, increase the risk of health care–associated in-
fections and drug accumulation, and result in longer time
on ventilatory support, which can prolong ICU duration of
stay and increase costs.25-27
An analysis of nurse-rated patients’ behavior and seda-
tion adequacy using objective measures (assessment of
motor activity and arousal) demonstrated that 32% of 274
mechanically ventilated patients were judged to be mini-
mally arousable or unarousable. Nurses also used subjec-
tive judgment of global sedation adequacy (adequate,
oversedation, or undersedation) based on clinical informa-
tion. They investigated possible causes for discomfort such
as hypoxia, tube obstruction, and pain and evaluated for
delirium by examining mental status. In contrast to objec-
tive measurements, with the use of subjective measures,
nurses rated these patients as oversedated less than 3% of
the time.28 Drug accumulation is a principal source of
oversedation and is often the result of altered pharmacoki-
netics in critically ill patients experiencing multiorgan dys-
function.4,5,29-33
LIMITATIONS OF COMMONLY USED HYPNOTIC AGENTS
Currently, in the US, the benzodiazepines, specifically
midazolam and lorazepam, and propofol are the most com-
monly used agents in ICU sedation.3 Diazepam’s use has
recently been documented in trauma ICU patients.34 With
the recent increased use of these medications, the risk fac-
tors for drug accumulation and their dangerous adverse
event profiles are of concern. The adverse events associat-
ed with sedatives used for ICU sedation are provided in
Table 1.35-46 For midazolam and lorazepam, the concern for
associated deliriogenic effects has been supported recently
with randomized controlled trials.38,47 Benzodiazepines are
γ-aminobutyric acid (GABA) agonists, which can predis-
pose patients to develop delirium.11 Also, there is recent ev-
idence demonstrating delirium as a strong independent pre-
dictor of death, prolonged mechanical ventilation, and
longer ICU length of stay, supporting the need to be more
aggressive in preventing delirium.48
Another hypnotic agent that is commonly used for ICU
sedation is propofol, which is also a GABA agonist. Propofol
has gained popularity because of its quick onset of action and
rapid elimination upon discontinuation, allowing for easy
titration and frequent neurologic examination. Propofol is as-
sociated with adverse events such as hypotension, hyper-
triglyceridemia, pancreatitis, respiratory depression, and the
propofol infusion syndrome.49 Propofol infusion syndrome is
the least predictable and most serious of these adverse effects,
and early recognition is essential but challenging.
The major alternative to the commonly used GABA-ago-
nists for ICU sedation is the α-2 agonist dexmedetomidine.
The Annals of Pharmacotherapy n 2012 April, Volume 46 n 531
S Devabhakthuni et al.

Dexmedetomidine has been demonstrated to have opioid-
sparing properties and is associated with reduction in ventila-
tor time and incidence of delirium compared to benzodi-
azepine infusions.47,50 Caution should be used in patients who
are hemodynamically unstable because of the drug’s potential
for causing bradycardia and hypotension.50 Dexmedetomi-
dine has generally not been shown to be deliriogenic and in
fact may prevent delirium,47,50,51 although one study reported
increased use of haloperidol in trauma patients treated with
high doses of dexmedetomidine, as compared to propofol.52
Analgosedation is an approach to ICU sedation that may
ameliorate these significant patient safety concerns associ-
ated with commonly used sedative agents and puts a focus
on the unmet need of providing adequate pain relief. To
support this change in practice, promising studies have
demonstrated that analgosedation may reduce sedation re-
quirements and shorten ventilator time.
OPIOID USE FOR ANALGOSEDATION
Like the sedatives, many of the opioids, such as fentanyl
and morphine, often have altered pharmacokinetics in criti-
cally ill patients, with different volumes of distribution and
elimination half-lives.30,31 This could partly explain why
the use of opioids as part of sedative-hypnotic approach
regimens was kept to a minimum to protect against redis-
tribution and accumulation.53 Also, there are data showing
that morphine possesses deleriogenic effects54,55 and
remifentanil has immunosuppressant effects.56 Although
not proven, these may be class effects that should be con-
sidered for all opioid analgesics.
In contrast to other opioids, remifentanil possesses a
unique pharmacokinetic profile with minimal drug accu-
mulation and rapid offset of effects.57,58 Remifentanil is a
potent, selective µ-opioid receptor agonist that is metabo-
lized by blood and tissue esterases independent of organ
function.59-61 Because of these properties, this easily titrat-
able drug can be used as the main agent to provide patient
comfort with the hypnotic agents being used secondarily
at lower doses. As a result of these advantages, remifen-
tanil has been used in most randomized controlled trials
investigating analgosedation. Other agents, including fen-
tanyl and morphine, have also been studied for analgose-
dation.

Table 1. Adverse Events Associated with Common Analgesic and Sedative Agents for ICU Sedation
Sedative Significant Adverse Effects Recommended Interventions
35 35
Dexmedetomidine Bradycardia, asystole, Avoid loading dose (1 µg/kg)
hypotension,36 and Monitor vital signs closely
hypertension35 Caution in hemodynamically unstable patients
Provide support for hemodynamic and cardiac dysfunction with fluids, vasopressors, and
anticholinergics
Lorazepam Propylene glycol toxicity Avoid high dosages ≥10-12 mg/h for long duration
(metabolic Dose-reduction protocol
acidosis)5,37 Monitor serum osmolar gap serially (risk higher if >10-12)
Consider alternative therapy if high serum osmolar gap
Delirium38 Routine monitoring of delirium
Midazolam Prolonged sedative effect4 Minimize duration of sedation
Dose-reduction protocol (eg, daily interruption)
Consider alternative in patients with renal impairment
Delirium38 Routine monitoring of delirium
Hypotension39 Monitor vital signs
Provide support for hemodynamic compromise with fluids and vasopressors
Opioids Respiratory depression30,31 Monitor respiratory status
(fentanyl, Dose-reduction protocol
morphine,
Hypotension (highest incidence Monitor vital signs
remifentanil)
with morphine)30,31 Provide support for hemodynamic compromise with fluids and vasopressors
Gastric dysmotility30,31 Provide stool softeners to prevent constipation
Chest wall rigidity30,31 Consider naloxone administration if suspected
Propofol PRIS (renal dysfunction, Avoid high dosages >80 µg/kg/min
rhabdomyopathy, dysrhythmias, Monitor creatine kinase, arterial blood gases, liver and renal function, and electrocardiogram
hypotension, or metabolic Discontinue drug and support cardiac dysfunction with fluids and vasopressors
acidosis)40,41
Hypertriglyceridemia,42 Monitor triglycerides, amylase, and lipase
pancreatitis42,43 Consider alternative if triglyceride concentration >500 mg/dL
Hypotension44,45 Monitor vital signs
Respiratory depression46 Monitor respiratory function (eg, ventilator settings, breathing) and arterial blood gases

ICU = intensive care unit; PRIS = propofol infusion syndrome.

532 n The Annals of Pharmacotherapy n 2012 April, Volume 46 theannals.com


Literature Selection and Assessment
Two reviewers (MJA, SD) searched the MEDLINE
databases (1948-November 2011) and the Cochrane con-
trolled trials register (2011, issue 1) independently. The re-
viewers included the following key words in their search:
analgosedation, analgo-sedation, or analgesia-based seda-
tion alone or in combination with intensive care unit or
critically ill. The search was limited to clinical trials, edito-
rial reviews, or randomized trials. Furthermore, the refer-
ence lists of the literature obtained were reviewed for rele-
vant trials.
Only randomized controlled trials published in English
comparing an analgesic (fentanyl, morphine, or remifen-
tanil) with a hypnotic (propofol or midazolam) or another
analgesic were included for review. To focus on ICU seda-
tion, the population included consisted of mechanically
ventilated patients older than 18 years. Two independent
reviewers examined all identified trials to ensure they ful-
filled the inclusion criteria and there was 100% agreement
between them.
Analgosedation Clinical Trials
Twelve clinical trials were identified, and 10 trials were
included in this review.13,62-70 The other 2 trials were ex-
cluded because they were not published in English. Nine
trials were conducted at multiple sites in Europe13,63-70 and
1 trial was performed in Thailand.62 Five trials compared
remifentanil primarily with another opioid (fentanyl or
morphine)62-66 and 4 trials compared remifentanil with a
hypnotic agent (midazolam or propofol).13,67-69 The tenth
trial compared the use of morphine (ie, no sedation) to dai-
ly interruption of sedation with propofol or midazolam.70
The details of the medications used in the trials reviewed
here are summarized in Tables 2 and 3. All studies exclud-
ed patients requiring neuromuscular blockade or epidural
anesthesia. Four trials were double-blind62-65 and 3 of these
had adequate allocation concealment.63,65,70 Allocation con-
cealment is the procedure for protecting the randomization
process so that the treatment to be allocated is not known
before the patient is entered into the study. The mean dura-
tion of sedation was variable among the studies, with 4 be-
ing longer than 48 hours.
In several studies, remifentanil was compared to fen-
tanyl and morphine. Compared to morphine, patients re-
ceiving remifentanil were more likely to require fewer
hypnotics and experience longer time in optimal sedation,
shorter mechanical ventilation time, and shorter ICU
length of stay.62,63,66 Remifentanil had similar efficacy com-
pared to fentanyl, except for an increased use of supple-
mental analgesics in the remifentanil group because of a
greater incidence of pain during drug deescalation with
remifentanil.64 In this trial, approximately 90% of patients
theannals.com The Annals of Pharmacotherapy
Analgosedation: Shift in ICU Sedation Practice
in both groups achieved optimal sedation, and less than
40% of patients required propofol.
In the trials comparing remifentanil to propofol or mida-
zolam, the approach of using remifentanil continuous infu-
sion titrated to a target sedation goal before using hyp-
notics as rescue therapy consistently led to optimal patient
comfort outcomes.13,67-68,69 None of the remifentanil studies
used daily sedation interruption. Patients treated with anal-
gosedation were more likely to be weaned from ventilation
more quickly, spend less time on ventilator support, and
have a shorter ICU length of stay compared to those who
received sedative-hypnotic therapy.13,67,68 In another trial,
compared to propofol or midazolam, patients receiving
analgosedation demonstrated no significant difference in
mechanical ventilation time or ICU length of stay but
showed a shorter weaning time from the ventilator. Pa-
tients were more likely to be extubated and discharged
from the ICU during the first 3 days.69
A modified analgosedation study compared a protocol
the authors called “no sedation” (morphine only) to daily
interruption of sedation (propofol for the first 48 hours then
midazolam and morphine provided as needed).70 Findings
from this study showed that morphine-only patients had
more ventilator-free days and shorter length of stay in the
ICU and hospital compared to those who received daily in-
terruption of sedation. Also, patients in the daily sedative
interruption group had a higher incidence of mortality;
however, this difference was not statistically significant.
The incidence of delirium was higher in the morphine-only
group, with increased requirements for haloperidol.
In all studies, remifentanil was well tolerated with no
significant differences in hemodynamic stability (eg,
bradycardia or hypotension) when compared to other opi-
oids and sedatives. The most common adverse events
(≥5% of patients) reported for remifentanil in the random-
ized controlled trials included hypotension, shivering,
vomiting, delirium, and tachycardia. When compared to an
alternative opioid or sedative, the incidence of these events
was not statistically significant.
LIMITATIONS OF ANALGOSEDATION STUDIES
The studies included in this review have several limita-
tions. Seven studies received funding from the manufactur-
er of remifentanil.13,62-64,67-69 None of the studies collected
information on concomitant medications and there were no
restrictions placed on prescribers.13,62-70 Not all of the stud-
ies collected data regarding tolerance to or withdrawal
from the study medications.13,62,64,66,68-70 Only 4 of the trials
were double-blind63-66 and only 3 provided adequate allo-
cation concealment schemes.62,65,70 Without these data, the
external validity of the trials must be questioned, as their
applicability may be limited in clinical practice. Sedation
and pain rating scales were not standardized across the
n 2012 April, Volume 46 n 533
S Devabhakthuni et al.

Table 2. Study Design Description of Analgosedation Randomized Trials

Mean Duration of
Reference Population Exclusion Criteria Interventions Treatment

Chinachoti 152 Mechanically Neurologic disease, weight >120 kg, age Remifentanil 9-60 µg/kg/h with midazolam Remifentanil and
(2002)62 ventilated pts.; <18 years, allergy to study drugs, drug 0.03-0.2 mg/kg/h as rescue treatment morphine: 14-16
normal or or alcohol abuse, neuromuscular (n = 74) hours
mildly impaired blockade or epidural anesthesia Morphine 0.045-0.3 mg/kg/h with
renal function midazolam 0.03-0.2 mg/kg/h as rescue
treatment (n = 78)
Dahaba 40 Mechanically Modified ICU admission SAPS II >52, Remifentanil 9-12 µg/kg/h with midazolam Remifentanil: 14 hours
(2004)63 ventilated pts. creatinine clearance <50 mL/min, 0.03 mg/kg/h as rescue therapy (n = 20) Morphine: 18 hours
after orthopedic neurologic disease, estimated 20% Morphine 0.04-0.06 mg/kg/h with
or general deviation from ideal body weight midazolam 0.03 mg/kg/h as rescue
surgery therapy (n = 20)
Muellejans 152 Mechanically Neuromuscular blockade or epidural Remifentanil 9-12 µg/kg/h, then propofol Remifentanil: 16 hours
(2004)64 ventilated pts. anesthesia, neurologic disorder, moderate 0.5-4 mg/kg/h as rescue therapy (n = 77) Fentanyl: 16 hours
for 12-72 hours or severe renal impairment (creatinine Fentanyl 1-2 µg/kg/h with propofol 0.5-4
after clearance <50 mL/min), modified ICU mg/kg/h as rescue therapy (n = 75)
randomization entry SAPS II >52, alcohol or drug abuse
Rauf 20 Elective off- Severely impaired cardiac or pulmonary Remifentanil 6 µg/kg/h titrated with Remifentanil: 11 hours
(2005)65 pump cardiac function, diabetes mellitus, renal failure, concurrent propofol 100-200 mg/h and Normal saline: 9 hours
surgical drug dependence, uncontrolled morphine 1-2 mg/h (n = 10)
mechanically hypertension, age >75 years Normal saline (same volume as
ventilated pts. remifentanil) with concurrent propofol
up to 12 hours 100-200 mg/h and morphine 1-2 mg/h
(n = 10)
Carrer 100 Mechanically Uncooperative pts., change in surgical Morphine 0.01-0.08 mg/kg/h with diazepam Morphine only: 18 hours
(2007)66 ventilated plan to palliative care, age <18 years 0.1 mg/kg as rescue therapy (n = 50) Morphine + remifentanil:
postsurgical Morphine 0.01 mg/kg/h + remifentanil 17 hours
pts. 0.6-6.6 µg/kg/h and titrated with
diazepam 0.1 mg/kg as rescue therapy
(n = 50)
Karabinis 161 Mechanically Neuromuscular blockade by infusion, Remifentanil 9-60 µg/kg/h, additional Remifentanil: 47 hours
(2004)13 ventilated barbiturate, epidural anesthesia, sedation provided if needed with propofol Fentanyl: 35 hours
pts. with expected tracheostomy within 5 days of 0.5-4 mg/kg/h (first 3 days) or midazolam Morphine: 41 hours
acute, severe study drug, severe associated traumatic 0.03-0.3 mg/kg/h (days 3-5) (n = 84)
neurologic injury, status epilepticus, alcohol or drug Propofol (first 3 days) or midazolam (days
injury for abuse, pregnancy 3-5) and fentanyl 0.1-7.9 µg/kg/h (n = 37)
1-5 days or morphine 0-6.8 mg/kg/h (n = 40)
Breen 105 Mechanically Neurologic disease; epidural anesthesia Remifentanil 6-45 µg/kg/h with midazolam Remifentanil: 147 hours
(2005)67 ventilated pts. or neuromuscular blockade by infusion; 2 mg boluses (n = 57)
for 3-10 days sensitivity to study drugs, alcohol, or Midazolam and morphine or fentanyl Fentanyl: 126 hours
drug abuse; pregnancy (n = 48) Morphine: 121 hours
Muellejans 80 Mechanically Neurologic disease, weight >120 kg, Remifentanil 6-60 µg/kg/h, then propofol Remifentanil: 18.5 hours
(2006)68 ventilated pts. neuromuscular blockade, epidural 0.5-4 mg/kg/h (n = 39)
after cardiac anesthesia, allergy to study drugs, opioid Midazolam 0.03-0.2 mg/kg bolus, then Fentanyl: 18.5 hours
surgery for 12- abuse, pregnancy, need for analgesia 0.02-0.4 mg/kg/h and fentanyl 1-2 µg/kg
72 hours and sedation >72 hours boluses, then 1-7 µg/kg/h (n = 33)
Rozendaal 205 Mechanically Resuscitation within 24 hours, Remifentanil infusion up to 12 µg/kg/h, Remifentanil: 3.9 days
(2009)69 ventilated pts. neurotrauma, neuromuscular blockade then propofol 0.5-4 mg/kg/h added Conventional therapy:
up to 10 days or epidural anesthesia, drug or alcohol (n = 96) 5.1 days
abuse, pregnancy, age <18 years, Propofol 0.5-4 mg/kg/h, midazolam 0.01-
allergy to study drug 0.2 mg/kg/h, or lorazepam 0.01-0.1
mg/kg/h with morphine 1-10 mg/h or
fentanyl 25-100 µg/h (n = 109)
Strom 140 Mechanically Increased intracranial pressure, age <18 Morphine, intermittent intravenous 2.5 or Not reported
(2010)70 ventilated years, need for sedation (eg, status 5 mg boluses as needed (n = 55)
medical and epilepticus), pregnancy, no cerebral Propofol 0.7 mg/kg/h and morphine,
surgical pts. contact, ability to wean from ventilator intermittent intravenous 2.5 or 5 mg
with expected boluses as needed (n = 58)
intubation
>24 hours

ICU = intensive care unit; SAPS = Simplified Acute Physiology Score.

534 n The Annals of Pharmacotherapy n 2012 April, Volume 46 theannals.com


studies, making it difficult to correlate the multitude of
scales that are commonly used in clinical practice with the
aggregate results of the included studies.13,62-70 Also, the
studies differed in their analysis of efficacy outcomes.
While some focused on the time in optimal sedation as
their primary outcome measure, other studies focused on
time on mechanical ventilation. These variations in out-
come measures and assessment scales make it difficult to
compare findings from each study.
Perhaps most importantly, daily sedation interruptions
were not used in the selected studies,13,62-68,69 with the ex-
ception of one trial.70 Daily sedation interruptions have
been shown to be important in clinical practice and have
been advocated as requirements in many ICUs. Addition-
ally, an intention-to-treat analysis was not performed in
some of the included studies13,64,68 and many patients in the
conventional treatment groups often experienced switching
of analgesic and sedative regimens.13,67,68-70 While this may
occur in clinical practice, it can confound the results. Hav-
ing a variety of comparators and relatively short duration
of therapy (<48 hours) in some of the studies limits the ex-
ternal generalizability of the results since these designs
may not reflect routine ICU sedation practice in many ICU
settings. Finally, some studies used small sample sizes,
which may have hindered their ability to find any statisti-
cally significant differences between the study groups.66-69
A randomized controlled trial powered adequately to over-
come the limitations discussed here would be beneficial in
confirming the current data.
In the study that compared a protocol of no sedation to
daily interruption of sedation (control group), there were
additional limitations.70 First, because morphine has a
sedative effect, both groups likely received some sedation;
however, morphine doses were comparable between the
groups. Second, the generalizability of the results is limited
by the nurse-to-patient ratio of 1:1, which is not feasible in
many ICUs. Finally, the first interruption of sedation in the
control group occurred within 24 hours of randomization.
This may have increased the number of patients who were
extubated within 48 hours and excluded from statistical
analysis, which may have led to an overestimation of the
results observed with the no-sedation group.
Discussion
ADVANTAGES OF ANALGOSEDATION
Despite these limitations, many advantages of analgose-
dation were noted in the studies. In general, patients treated
with analgosedation experienced a reduction in hypnotic
use.13,62,64,66-67,70 This reduction contributed to a lower risk of
prolonged sedative effects and may translate into a lower risk
of adverse events in clinical practice because of the decreased
number and dosage of hypnotic agents. Analgosedation was
theannals.com
Analgosedation: Shift in ICU Sedation Practice
shown to decrease mechanical ventilation time13,63,67-70 and
shorten the ICU length of stay.63,67-70
The favorable pharmacokinetics of remifentanil also
provide for a rapid onset and offset of action and organ
function–independent metabolism. No evidence of accumu-
lation of remifentanil was noted in patients who were receiv-
ing longer term continuous infusions.63 In fact, the safety pro-
file of remifentanil seems to equal or exceed that of agents
typically employed in sedative-hypnotic approach schemes.63
Despite the significantly higher cost of remifentanil com-
pared to that of other sedatives and analgesics, dexmedetomi-
dine excluded, analgosedation appears to be cost-neutral and
in fact may lead to overall ICU cost savings.71 Fentanyl also
may be effective for analgosedation since it has demonstrated
similar outcomes when compared to remifentanil, except for
decreased need for supplemental analgesics during drug de-
escalation. Further studies with fentanyl are needed to deter-
mine its application in analgosedation.
DISADVANTAGES OF ANALGOSEDATION
Despite the apparent advantages of analgosedation, dis-
advantages of this treatment scheme must be discussed. Al-
though more commonly associated with benzodiazepines,
delirium has also been found to be associated with morphine
administration, although the true cause-effect relationship has
not been fully elucidated.54,55 The delirium noted in mor-
phine-treated patients may be related to the patient’s pain
rather than the drug. Also, the use of analgosedation in criti-
cally ill patients has resulted in a high incidence of recall for
unpleasant events before regaining consciousness (17% of
289 patients), and some patients have experienced night-
mares (9.3%) and hallucinations (6.6%).72 Additionally, opi-
oids have been shown to be associated with immunosuppres-
sion, an adverse effect that could be devastating in a critically
ill patient.56 Patients can also experience a strong withdrawal
effect following the discontinuation of opioids, although
these effects have also been found with benzodiazepines. Fi-
nally, reports of increased analgesic requirements and hyper-
algesia following the cessation of remifentanil infusions have
been published.73 Clinicians must be aware of this effect and
should consider transitioning treatment to longer-acting anal-
gesics before discontinuation of the remifentanil infusion, as
this could have a deleterious effect on successful weaning
from ventilator support.
CLINICAL RECOMMENDATIONS
In light of the findings of this review, a shift in current se-
dation practices to analgosedation should be considered in the
care of mechanically ventilated critically ill patients. Other
recommendations for the care of these patients also merit dis-
cussion. Clinicians must be cognizant to avoid oversedation
of critically ill patients, which can be accomplished through
The Annals of Pharmacotherapy n 2012 April, Volume 46 n 535
 Table 3. Analgosedation Randomized Controlled Trial Outcome Measures and Major Results

536
Primary Outcome

n
Reference Assessment Measures Measure Outcomes Comments

Chinachoti Pain: 6-point pain intensity scale (score ≥3 = clinically Percentage of hours of Percentage of optimal sedation similar (82.7% with remifentanil, Double-blind
(2002)62 significant pain optimal sedation during 84.3% with morphine) Allocation concealment unclear
Sedation: SAS and Vancouver Interaction and study period and Midazolam not required in 75% of pts. Treatment discontinued in 9.5% of pts.
Calmness Scale (secondary measure) treatment phase Morphine group required twice the amount of midazolam vs
S Devabhakthuni et al.

Goal: SAS score of 4 without clinically significant pain remifentanil group

Dahaba Pain: 6-point pain intensity scale (score ≥3 =clinically Mean percentage hours Mean percentage hours of optimal sedation significantly longer Double-blind
(2004)63 significant pain) of optimal sedation with remifentanil vs morphine (78% vs 68%, p = 0.0427) Adequate allocation concealment
Sedation: SAS Remifentanil group had shorter duration of mechanical No pt. discontinuation after
Goal: SAS score of 4 without clinically significant pain ventilation (14 vs 18 hours, p = 0.0433), extubation time randomization
(17 vs 73 minutes, p = 0.0149), and ICU length of stay (21 Rapid offset of remifentanil offset by
vs 42 hours, p = 0.0136) piritramide, a synthetic opioid
More pts. in remifentanil group did not need midazolam analgesic, and nonopioid analgesic use

The Annals of Pharmacotherapy

Muellejans Pain: 6-point pain intensity scale (score ≥3 = clinically Between-pt. variability Similar efficacy for time of optimal sedation (88.3% with Double-blind
(2004)64 significant pain) about mean percentage remifentanil vs 89.3% with fentanyl) Allocation concealment unclear

n
Sedation: SAS of hours of optimal 40% of pts. with fentanyl required propofol vs 35% with No pt. discontinuation after randomization
Goal: SAS score of 4 without clinically significant pain sedation during remifentanil (p = NS) Lower dose of fentanyl used so more pts.
maintenance phase Greater incidence of pain with remifentanil discontinuation vs requiring propofol was observed
fentanyl (p = NS)
Rauf Pain: VAS Morphine requirement in Morphine requirement 1 hour after stopping sedation significantly Double-blind
(2005)65 Sedation: agitation (0 = calm, comfortable with no first hour after stopping higher in remifentanil group (8.15 vs 3.29 mg, p < 0.01) Adequate allocation concealment
intervention; 1 = agitated and distressed but settles sedation No significant differences in either pain or sedation scores No pt. discontinuation after randomization
and responds to verbal command; 2 = agitated and between groups Agitation score not validated
needs analgesics, mild sedation, or both; 3 = agitated 2 pts. in remifentanil group vs 6 pts. in other group required drug
and requires heavy sedation) to stabilize arterial blood pressure and heart rate

2012 April, Volume 46

Goal: VAS score ≤5 and agitation score <2
Carrer Pain: NRS Proportion of pts. Diazepam was requested by 60% with morphine-only and 28% Nonblinded
(2007)66 Sedation: Ramsey sedation scale achieving optimal level with morphine + remifentanil Allocation concealment unclear
Goal: Ramsey score of 2-3 and NRS score <3 of sedation without Ramsay score values higher in combination group vs morphine- No pt. discontinuation after randomization
rescue therapy only group Higher sedation score with opioid
Time on ventilator, ICU length of stay, and mortality similar combination
between groups
Karabinis Pain: 6-point pain intensity scale (score ≥3 = clinically Overall between-pt. Remifentanil had smaller between-pt. variability and time for Nonblinded
(2004)13 significant pain) variability near mean neurologic assessment Allocation concealment unclear
Sedation: SAS time to neurologic Shorter extubation time with remifentanil vs morphine (1 vs 1.93 No pt. discontinuation after
Goal: SAS score of 1-3 without clinically significant pain assessment hours, p = 0.001) but not fentanyl (1 vs 0.68 hours, p = 0.474) randomization
Both groups had optimal sedation >95% of period Propofol used >3 days in
No difference in ICU stay some pts.
Comparable hemodynamic stability between regimens
Breen Pain: 6-point pain intensity scale (score ≥3 = clinically Time from start of study Remifentanil group had significant reduction in time on ventilator Nonblinded
(2005)67 significant pain) drug to extubation by >2 days (53.5 hours, p = 0.033) Allocation concealment unclear
Sedation: SAS Nonsignificant trend toward shorter ICU length of stay by 1 day No pt. discontinuation after
Goal: SAS score of 3-4 without clinically significant pain in remifentanil group randomization
Median time of optimal sedation similar in both groups No daily interruption
No accumulation or development of tolerance to remifentanil

theannals.com
 Analgosedation: Shift in ICU Sedation Practice

the use of protocols and daily sedation interruptions. Recent

All pts. received propofol and remifentanil

sedatives (eg. lorazepam, midazolam)

Morphine use based on subjective pain

Remifentanil group had higher severity
surveys of current practices indicated that there is substantial

28 pts. in remifentanil group received

Propofol changed to midazolam after

16.6% of pts. did not complete study
Nonvalidated sedation scale used
opportunity for improvement in the use of protocols and se-
10% of randomized pts. excluded

Adequate allocation concealment

Standard nurse:patient ratio 1:1

postextubation analgesics and
Allocation concealment unclear
Allocation concealment unclear

dation interruption.20,21 When possible, analgesic effective-

27 randomized pts. excluded

ness and requirements should be monitored through patient
self-report. In the case of patients who are unable to commu-
prerandomization

nicate, a validated assessment tool for pain (eg, visual analog

of illness score

pain scale or behavioral pain scale) should be used. Sedation

Nonblinded

Nonblinded

Nonblinded

48 hours
interruptions should be targeted at achieving the lightest level
of sedation possible to prevent excessive drug accumulation.
Examples of validated assessment tools for sedation include
Sedation-Agitation Scale or Richmond Agitation Sedation
p < 0.05) and shorter ICU length of stay (46 vs 62 hours, p < 0.05)

days with remifentanil vs 5.1 days with conventional treatment)

Shorter time to extubation in remifentanil group (21 vs 24 hours,

stay in ICU (13.1 vs 22.8 days, p = 0.0316) and hospital (34 vs

Remifentanil-based regimen reduced weaning time by 18.9 hours

Pts. in morphine-only group had significantly more days without

No differences noted in occurrence of accidental extubations or

ventilation (13.8 vs 9.6 days, p = 0.019) and shorter length of Scale).
Nonsignificant difference in median duration of ventilation (3.9
Mean percentage time of adequate sedation similar between

Median ICU length of stay not significantly different between

Patient discomfort should be treated with analgesics

such as remifentanil or fentanyl, with morphine being re-
served as a second-line agent due to the risk of drug accu-
69% of pts. in remifentanil group required propofol
Overall ICU costs per pt. similar between groups

mulation, its comparatively longer duration of action, and

Propofol added to remifentanil in 54% of pts.

potential association with delirium and immunosuppres-

sion. Clinicians should consider using hypnotic agents
ICU = intensive care unit; NRS = numeric rating scale; NS = not significant; SAS = Sedation Agitation Scale; VAS = visual analog scale.

such as propofol or dexmedetomidine in patients requiring

ventilator-associated pneumonia

rescue therapy after the initiation of analgosedation. Fur-

thermore, benzodiazepine use should be kept to a mini-
mum. This recommendation may invoke a concern for
58 days, p = 0.0039)

costs; however, cost considerations should include total

cost of care and not simply drug acquisition costs.74
(p = 0.0001)

More research should be focused on the use of adjunc-

groups

groups

tive opioid-sparing agents, such as parenteral acetaminophen

and nonsteroidal antiinflammatory drugs in critically ill me-
chanically ventilated patients, as their current role in this pa-
to eligible ICU discharge
Time from arrival on ICU

tient population is evolving. One study in postoperative ICU

Number of days without
mechanical ventilation

patients reported lower opioid dosage and shorter time to ex-

Median duration of

tubation in patients randomized to receive intravenous acet-

aminophen and meperidine versus meperidine alone.75 The
mechanical
ventilation

newer intravenous formulations of these medications can be

considered in patients who may respond adequately to this
form of pain control, although the use of previously approved
oral formulations should also be considered for this indica-
Sedation: Ramsey scale with daily sedative interruption
Pain: 6-point pain intensity scale (score ≥3 = clinically
grimaces without stimuli; 2 = pt. calm and moves on

tion, if appropriate. These studies should have a pharma-

Sedation: 3-point sedation scale (1 = pt. moves or

Goal: Ramsey score of 3-4 (control group only)

coeconomic component to assess cost-effectiveness differ-

stimuli; 3 = patient does not react to stimuli)

ences between therapies, which could be considered as “anal-

goeconomics.” Future investigations on the economic
Goal: Sedation score of 2 (adequate)

evaluation of analgesics for acute pain management are war-

ranted.
Patients should be diligently monitored for signs and
Goal: SAS score of 3-4

symptoms of delirium. Although not commonly reported,

delirium has been associated with the use of opioid anal-
significant pain)

gesics and should be considered as a source. At this time,

Sedation: SAS
Pain: No scale

Pain: No scale

the association between the use of analgosedation and risk

of delirium remains unclear; further investigation is war-
ranted. In the meantime, clinicians must always be vigilant
for this dangerous adverse effect and be prepared to ade-
Rozendaal
Muellejans
(2006)68

(2009)69

(2010)70

quately treat patients.

Strom

Based on the review of the literature, analgosedation has

a promising role in ICU sedation practices. We believe that

theannals.com The Annals of Pharmacotherapy n 2012 April, Volume 46 n 537

S Devabhakthuni et al.
analgosedation will become routine clinical practice in var-
ious ICU settings. The more difficult question is which
agent will be the best choice for analgosedation. Remifen-
tanil is ideal because of its suitable pharmacokinetic prop-
erties. However, fentanyl is also a reasonable choice for
analgosedation and has similar clinical outcomes when
compared to remifentanil. Since many clinicians are more
comfortable with fentanyl, this will likely be the pharma-
cologic option that will be used in the majority of patients
for the next several years. Remifentanil may have a more
important role in patients with neurologic conditions that
require closer monitoring. With more clinical experience,
remifentanil will likely become an accepted option for rou-
tine analgosedation.
Summary
Providing adequate analgesia and sedation to mechani-
cally ventilated critically ill patients is an important com-
ponent of optimal ICU treatment. The routine use of seda-
tive-hypnotic approach strategies must be questioned be-
cause of recent evidence demonstrating serious adverse
events due to drug accumulation and prolonged mechani-
cal ventilation time and ICU length of stay. Also, despite
the implementation of sedation protocols and daily inter-
ruption, the incidence of oversedation remains concerning,
requiring a closer examination by clinicians. Due to these
concerns, clinicians should consider a shift in current seda-
tion practices from sedative-hypnotic approach to anal-
gosedation. The limitations of the current analgosedation
literature, such as sample size, lack of blinding, duration of
the studies, and lack of consideration for studying a variety
of analgesics is acknowledged. However, the practice of
analgosedation has been shown to improve the outcomes
of patients treated in ICUs and should be considered by
clinicians when making decisions regarding the analgesia
and sedation of critically ill patients.
Sandeep Devabhakthuni PharmD BCPS, at time of writing, Crit-
ical Care Resident, University of Pittsburgh Medical Center, Pitts-
burgh, PA; now, Assistant Professor of Pharmacy Practice and Sci-
ence, School of Pharmacy, University of Maryland, Baltimore
Michael J Armahizer PharmD BCPS, at time of writing, Critical
Care Resident, University of Pittsburgh Medical Center; now, Critical
Care Pharmacy Specialist, Cardiothoracic Intensive Care Unit, Uni-
versity of Pittsburgh Medical Center
Joseph F Dasta MSc FCCM FCCP, Professor Emeritus, The Ohio
State University, Columbus; Adjunct Professor, The University of
Texas, Austin
Sandra L Kane-Gill PharmD MSc FCCM FCCP, Associate Pro-
fessor of Pharmacy and Therapeutics and Clinical Translational Sci-
ence Institute, Critical Care Specialist, Center for Pharmacoinfor-
matics and Outcomes Research, University of Pittsburgh
Correspondence: Dr. Devabhakthuni, sdevabha@rx.umaryland.
edu
Reprints/Online Access: www.theannals.com/cgi/reprint/aph.1Q525
Conflict of Interest: Dr. Dasta is a consultant to Hospira, Cadence
Pharmaceuticals, and Pacira Pharmaceuticals and member of the
speaker’s bureau of Cadence Pharmaceuticals.
538 n The Annals of Pharmacotherapy n 2012 April, Volume 46
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EXTRACTO
Sedación Mediante Analgésicos: Un Cambio en Paradigma en la
Sedación de Cuidado Intensivo
S Devabhakthuni, MJ Armahizer, JF Dasta, y SL Kane-Gill
Ann Pharmacother 2012;46:530- 40.
OBJETIVO: Evaluar de forma crítica el uso de la sedación mediante
analgésicos en el manejo de agitación en pacientes gravemente enfermos
con ventilación mecánica.
FUENTE DE LOS DATOS: Se llevó a cabo una recuperación de literatura
accedida por MEDLINE (1948–noviembre de 2011) y Cochrane Library
(2011, edición 1) utilizando los términos “analgosedación”, “analgo-
sedación”, o “analgesia basada en sedación” sola o en combinación con
“unidad de cuidado intensivo: o “gravemente enfermo”. Además, se
revisó la lista de referencias de publicaciones relacionadas.
SELECCIÓN DE ESTUDIOS Y EXTRACCIÓN DE LOS DATOS: Se evaluaron los
artículos en inglés identificados de las fuentes de datos. Se incluyeron
estudios aleatorios, controlados que examinaron pacientes gravemente
enfermos >18 años en ventilación mecánica.
SÍNTESIS DE LOS DATOS: Las limitaciones de las prácticas actuales de
sedación incluyen eventos adversos graves de medicamentos, tiempo de
ventilación mecánica prolongado y duración de la estadía en la unidad
de cuidado intensivo (UCI). Los estudios han demostrado que la sedación
mediante analgesia, una estrategia que maneja primero el dolor y la
incomodidad del paciente antes de proveer terapia de sedación, produce
resultados mejorados en el paciente en comparación con los regímenes
regulares de sedantes hipnóticos. Se revisaron nueve estudios aleatorios
y controlados que compararon la sedación con analgésicos usando
remifentanil con otros agentes de uso común (fentanil, midazolam, morfina
y propofol) en sedación en la UCI y un estudio que comparó morfina
con la sedación diaria interrumpida con propofol o midazolam.
Remifentanil es un agente ideal para la sedación con analgésicos por su
fácil ajuste de dosis y su metabolismo que no depende de órganos. Al
540 n The Annals of Pharmacotherapy n 2012 April, Volume 46
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compararse con regímenes de sedantes hipnóticos, los regímenes a base
de remifentanil estuvieron relacionados con una duración más corta de la
ventilación mecánica, un retiro más rápido del ventilador y una estadía
más corta en la UCI. En comparación con los regímenes basados en
fentanil, el remifentanil tuvo una eficacia similar, a excepción de un
incremento en los requerimientos del dolor en la descontinuación del
remifentanil. La sedación mediante analgésicos fue bien tolerada sin
diferencias significativas en la estabilidad hemodinámica en
comparación con los regímenes de sedantes hipnóticos.
CONCLUSIONES: La sedación mediante analgésicos es una estrategia eficaz
y bien tolerada en el manejo de la sedación en la UCI con mejores
resultados en el paciente en comparación con las estrategias de tratamiento
de sedantes hipnóticos. Se requieren más estudios bien diseñados para
aclarar el rol de la sedación mediante analgésicos en el manejo de la
sedación en la UCI, incluidos estudios con analgésicos no opioides.
Traducido por Rafaela Mena
RÉSUMÉ
La Sédation-Analgésie: Une Révolution Scientifique à l’Unité des
Soins Intensifs
S Devabhakthuni, MJ Armahizer, JF Dasta, et SL Kane-Gill
Ann Pharmacother 2012;46:530- 40.
OBJECTIF: Évaluer l’utilisation de la sédation-analgésie dans le traitement
de l’agitation chez les patients ventilés mécaniquement.
SOURCES D’INFORMATION: Une recherche de littérature a été effectuée
dans les banques de données MEDLINE (de 1948 au mois de novembre
2011) et Cochrane (2011) en utilisant les mots-clés suivants: sédation-
analgésie, sédation basée sur l’analgésie, soins intensifs, unité de
réanimation. Les bibliographies des articles identifiés ont aussi été
revues afin d’obtenir des références additionnelles.
SÉLECTION DE L’INFORMATION ET EXTRACTION DES DONNÉES: Tous les articles
et les abrégés publiés en langue anglaise ont été retenus et évalués pour cet
article. Les essais cliniques contrôlés, à répartition aléatoire, ayant été
effectués chez des patients ventilés mécaniquement, ont été inclus.
RÉSULTATS: Il existe plusieurs limites aux pratiques courantes de sédation.
Les études ont démontré que la sédation-analgésie, une stratégie qui gère
d’abord la douleur et l’inconfort du patient avant d’administrer un agent
sédatif, permet d’atteindre de meilleurs résultats cliniques comparativement
aux régimes standards d’agents sédatifs et hypnotiques. Neuf essais
contrôlés à répartition aléatoire ont comparé une sédation-analgésie à
base de rémifentanil à d’autres agents couramment utilisés (tels que le
fentanyl, le midazolam, la morphine et le propofol). Un essai ayant
comparé la morphine à une sédation quotidienne utilisant le propofol ou
le midazolam est aussi disponible. Le rémifentanil est un agent idéal
pour la sédation-analgésie puisqu’il possède une bonne titrabilité et un
métabolisme ne dépendant ni du foie ni du rein. Lorsque comparée à
différents régimes d’agents sédatifs-hypnotiques, l’utilisation du
rémifentanil a été associée à de plus courtes périodes de ventilation
mécanique, un sevrage plus rapide du ventilateur et une durée
d’hospitalisation plus courte à l’unité des soins intensifs. Le rémifentanil
possède une efficacité similaire au fentanyl bien que les besoins
analgésiques soient plus importants lors de sa cessation. La sédation-
analgésie avec le rémifentanil est bien tolérée et aucune différence
significative au niveau de la stabilité hémodynamique n’a été notée
comparativement aux régimes d’agents sédatifs-hypnotiques.
CONCLUSIONS: La sédation-analgésie avec le rémifentanil est une approche
efficace pour gérer la sédation à l’unité des soins intensifs. Elle procure
de meilleurs résultats cliniques par rapport aux régimes d’agents sédatifs-
hypnotiques et elle est bien tolérée. Des études additionnelles sont
toutefois nécessaires afin de comparer la sédation-analgésie obtenue
avec le rémifentanil à celle associée avec l’utilisation d’agents
analgésiques non-opioïdes.
Traduit par Sylvie Robert
theannals.com