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Critical Care Medicine
Clinical Practice Guidelines for the Management
of Pain, Agitation, and Delirium in Adult Patients
in the Intensive Care Unit
Juliana Barr, MD, FCCM1; Gilles L. Fraser, PharmD, FCCM2; Kathleen Puntillo, RN, PhD, FAAN, FCCM3; E. Wesley Ely, MD, MPH, FACP, FCCM4; Céline Gélinas, RN, PhD5; Joseph F. Dasta, MSc, FCCM, FCCP6; Judy E. Davidson, DNP, RN7; John W. Devlin, PharmD, FCCM, FCCP8; John P. Kress, MD9; Aaron M. Joffe, DO10; Douglas B. Coursin, MD11; Daniel L. Herr, MD, MS, FCCM12; Avery Tung, MD13; Bryce R. H. Robinson, MD, FACS14; Dorrie K. Fontaine, PhD, RN, FAAN15; Michael A. Ramsay, MD16; Richard R. Riker, MD, FCCM17; Curtis N. Sessler, MD, FCCP, FCCM18; Brenda Pun, MSN, RN, ACNP19; Yoanna Skrobik, MD, FRCP20; Roman Jaeschke, MD21
1 VA Palo Alto Health Care System, Palo Alto, CA, and Stanford University
developing specific statements and recommendations on that topic. Final
School of Medicine, Stanford, CA.
decisions regarding strength of evidence and strength of recommenda-
2 Tufts University School of Medicine, Maine Medical Center, Portland, ME.
tions for all questions were voted on anonymously by all Task Force mem-
Department of Physiological Nursing, University of California, San
bers. Voting distributions for all statements and recommendations can be
Francisco, CA.
found on line at e refer readers to
4 VA-GRECC (Geriatric Research Education Clinical Center) for the VA
Tennessee Valley Healthcare System, Vanderbilt University Medical
the Methods Section of these Guidelines for more details.
Center, Nashville, TN.
Supporting Organizations: American College of Critical Care Medicine
5 Ingram School of Nursing, McGill University and Centre for Nursing Research/
(ACCM) in conjunction with Society of Critical Care Medicine (SCCM)
Lady Davis Institute, Jewish General Hospital, Montreal, QC, Canada.
and American Society of Health-System Pharmacists (ASHP).
6 The Ohio State University, College of Pharmacy, Columbus, OH, and
The University of Texas, College of Pharmacy, Austin, TX.
Mr. Dasta has consultancies with Hospira, Axel Rx, Cadence Pharmaceuti-
7 Scripps Clinical Center, Scripps Health, La Jolla, CA.
cals, and Pacira Pharmaceuticals and has received honoraria/speaking fees
8 Department of Pharmacy Practice, Northeastern University Special
from the France Foundation (speakers bureau CME program) sponsored
and Scientific Staff, Division of Pulmonary, Critical Care, and Sleep
by Hospira. Dr. Devlin has received honoraria/speaking fees, consultancies,
Medicine, Tufts University of Medicine, Boston, MA.
and grants from Hospira. Dr. Ely has received honoraria/speaking fees from
9 Department of Medicine, Section of Pulmonary and Critical Care,
GSK and Hospira; and has received grants from Hospira, Pfizer, and As-
University of Chicago, Chicago, IL.
pect. Dr. Herr has received honoraria/speaking fees from Hospira. Dr. Kress
Department of Anesthesiology and Pain Medicine, University of has received honorar ia/speaking fees from Hospira; and has received a
Washington/Harborview Medical Center, Seattle, WA.
grant from Hospira (unrestricted research). Ms. Pun has received honoraria/
11 Departments of Anesthesiology and Internal Medicine, University of
Wisconsin School of Medicine and Public Health, Madison, WI.
speaking fees from Hospira. Dr. Ramsay has received honoraria/speaking
Shock Trauma Center, Division of Trauma Critical Care Medicine,
fees from Hospira and Masimo; and has received a grant from Masimo. Dr.
University of Maryland, Baltimore, MD.
Riker has consultancies with Masimo; and has received honoraria/speak-
13 Department of Anesthesia and Critical Care, University of Chicago,
ing fees from Orion. Dr. Sessler has received honoraria/speaking fees from
Chicago, IL.
Hospira and consulting fees from Massimo. The remaining authors have not
14 Department of Surgery, Division of Trauma and Critical Care, University
disclosed any potential conflicts of interest.
of Cincinnati, Cincinnati, OH.
These guidelines have been reviewed and endorsed by the American Col-
15 University of Virginia, School of Nursing, Charlottesville, VA.
16 Baylor University Medical Center, Dallas, TX.
lege of Chest Physicians and the American Association for Respiratory
17 Tufts University School of Medicine, Maine Medical Center, Portland, ME.
Care; are supported by the American Association for Respiratory Care;
18 Department of Internal Medicine, Virginia Commonwealth University
and have been reviewed by the New Zealand Intensive Care Society.
Heath System, Richmond, VA.
For information regarding this article, E-mail: [email protected]
19 Department of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt
University Medical Center, Nashville, TN.
The American College of Critical Care Medicine (ACCM), which honors individu-
20 Université de Montréal, Montréal, Canada.
als for their achievements and contributions to multidisciplinary critical care medi-
21 Departments of Medicine and Clinical Epidemiology and Biostatistics, St.
cine, is the consultative body of the Society of Critical Care Medicine (SCCM)
Joseph's Hospital and McMaster University, Hamilton, Ontario, Canada.
that possesses recognized expertise in the practice of critical care. The College
Supplemental digital content is available for this article. Direct URL cita-
has developed administrative guidelines and clinical practice parameters for the
tions appear in the printed text and are provided in the HTML and PDF ver-
critical care practitioner. New guidelines and practice parameters are continually
sions of this on the journal's Web site ().
developed, and current ones are systematically reviewed and revised.
To minimize the perception of bias in these Guidelines, individual Task
Copyright 2013 by the Society of Critical Care Medicine
Force members with a significant conflict of interest on a particular topic
were recused from grading the literature, writing evidence summaries, and
Critical Care Medicine
www.ccmjournal.org
Objective: To revise the "Clinical Practice Guidelines for the Sus-
was completed in December 2010. Relevant studies published
tained Use of Sedatives and Analgesics in the Critically Ill Adult"
after this date and prior to publication of these guidelines were
published in Critical Care Medicine in 2002.
referenced in the text. The quality of evidence for each statement
Methods: The American College of Critical Care Medicine and recommendation was ranked as high (A), moderate (B), or assembled a 20-person, multidisciplinary, multi-institutional task
low/very low (C). The strength of recommendations was ranked
force with expertise in guideline development, pain, agitation and
as strong (1) or weak (2), and either in favor of (+) or against (–)
sedation, delirium management, and associated outcomes in adult
an intervention. A strong recommendation (either for or against)
critically ill patients. The task force, divided into four subcommittees,
indicated that the intervention's desirable effects either clearly
collaborated over 6 yr in person, via teleconferences, and via outweighed its undesirable effects (risks, burdens, and costs) electronic communication. Subcommittees were responsible or it did not. For all strong recommendations, the phrase "We for developing relevant clinical questions, using the Grading of
recommend …" is used throughout. A weak recommendation,
Recommendations Assessment, Development and Evaluation either for or against an intervention, indicated that the trade-method (, evaluate,
off between desirable and undesirable effects was less clear.
and summarize the literature, and to develop clinical statements
For all weak recommendations, the phrase "We suggest …" is
(descriptive) and recommendations (actionable). With the help
used throughout. In the absence of sufficient evidence, or when
of a professional librarian and Refworks® database software, group consensus could not be achieved, no recommendation (0) they developed a Web-based electronic database of over was made. Consensus based on expert opinion was not used 19,000 references extracted from eight clinical search engines,
as a substitute for a lack of evidence. A consistent method for
related to pain and analgesia, agitation and sedation, delirium,
addressing potential conflict of interest was followed if task force
and related clinical outcomes in adult ICU patients. The group
members were coauthors of related research. The development of
also used psychometric analyses to evaluate and compare pain,
this guideline was independent of any industry funding.
agitation/sedation, and delirium assessment tools. All task force
Conclusion: These guidelines provide a roadmap for developing
members were allowed to review the literature supporting each
integrated, evidence-based, and patient-centered protocols for
statement and recommendation and provided feedback to the preventing and treating pain, agitation, and delirium in critically subcommittees. Group consensus was achieved for all statements
il patients. (Crit Care Med 2013; 41:263–306)
and recommendations using the nominal group technique and the
Key Words: agitation; analgesia; critical care medicine; delirium;
modified Delphi method, with anonymous voting by all task force
evidence-based medicine; GRADE; guidelines; intensive care;
members using E-Survey (). All voting outcomes; pain; protocols; sedation
STATEMENTS AND RECOMMENDATIONS
iv. We suggest that vital signs may be used as a cue to
begin further assessment of pain in these patients,
1. Pain and Analgesia
however (+2C).
a. Incidence of pain
c. Treatment of pain
i. Adult medical, surgical, and trauma ICU patients i. We recommend that preemptive analgesia and/or
routinely experience pain, both at rest and with rou-
nonpharmacologic interventions (e.g., relaxation)
tine ICU care (B).
be administered to alleviate pain in adult ICU
ii. Pain in adult cardiac surgery patients is common and
poorly treated; women experience more pain than
patients prior to chest tube removal (+1C).
men after cardiac surgery (B).
ii. We suggest that for other types of invasive and
iii. Procedural pain is common in adult ICU patients (B).
potentially painful procedures in adult ICU patients,
b. Pain assessment
preemptive analgesic therapy and/or nonpharmaco-
i. We recommend that pain be routinely monitored in
logic interventions may also be administered to alle-
all adult ICU patients (+1B).
viate pain (+2C).
ii. The Behavioral Pain Scale (BPS) and the Critical-Care
iii. We recommend that intravenous (IV) opioids be
Pain Observation Tool (CPOT) are the most valid and
considered as the first-line drug class of choice to
reliable behavioral pain scales for monitoring pain in
treat non-neuropathic pain in critically ill patients
medical, postoperative, or trauma (except for brain injury)
adult ICU patients who are unable to self-report and in
iv. All available IV opioids, when titrated to similar pain
whom motor function is intact and behaviors are observ-
intensity endpoints, are equally effective (C).
able. Using these scales in other ICU patient populations
v. We suggest that nonopioid analgesics be considered
and translating them into foreign languages other than
to decrease the amount of opioids administered (or
French or English require further validation testing (B).
to eliminate the need for IV opioids altogether) and
iii. We do not suggest that vital signs (or observational
to decrease opioid-related side effects (+2C).
pain scales that include vital signs) be used alone for
vi. We recommend that either enterally administered
pain assessment in adult ICU patients (–2C).
gabapentin or carbamazepine, in addition to IV
www.ccmjournal.org
January 2013 • Volume 41 • Number 1
opioids, be considered for treatment of neuropathic
adjunct to subjective sedation assessments in adult
ICU patients who are receiving neuromuscular
vii. We recommend that thoracic epidural anesthesia/
blocking agents, as subjective sedation assessments
analgesia be considered for postoperative analgesia
may be unobtainable in these patients (+2B).
in patients undergoing abdominal aortic aneurysm
iv. We recommend that EEG monitoring be used to
surgery (+1B).
monitor nonconvulsive seizure activity in adult
viii. We provide no recommendation for using a lumbar
ICU patients with either known or suspected sei-
epidural over parenteral opioids for postoperative anal-
zures, or to titrate electrosuppressive medication
gesia in patients undergoing abdominal aortic aneu-
to achieve burst suppression in adult ICU patients
rysm surgery, due to a lack of benefit of epidural over
with elevated intracranial pressure (+1A).
parenteral opioids in this patient population (0,A).
c. Choice of sedative
ix. We provide no recommendation for the use of
i. We suggest that sedation strategies using nonben-
thoracic epidural analgesia in patients undergoing
zodiazepine sedatives (either propofol or dexme-
either intrathoracic or nonvascular abdominal sur-
detomidine) may be preferred over sedation with
gical procedures, due to insufficient and conflicting
benzodiazepines (either midazolam or lorazepam)
evidence for this mode of analgesic delivery in these
to improve clinical outcomes in mechanically venti-
patients (0,B).
lated adult ICU patients (+2B).
x. We suggest that thoracic epidural analgesia be con-
sidered for patients with traumatic rib fractures a. Outcomes associated with delirium(+2B).
i. Delirium is associated with increased mortality in
We provide no recommendation for neuraxial/
adult ICU patients (A).
regional analgesia over systemic analgesia in medi-
ii. Delirium is associated with prolonged ICU and
cal ICU patients, due to lack of evidence in this
hospital LOS in adult ICU patients (A).
patient population (0, No Evidence).
iii. Delirium is associated with the development of
2. Agitation and Sedation
post-ICU cognitive impairment in adult ICU
a. Depth of sedation vs. clinical outcomes
patients (B).
i. Maintaining light levels of sedation in adult ICU
b. Detecting and monitoring delirium
patients is associated with improved clinical out-
i. We recommend routine monitoring of delirium in
comes (e.g., shorter duration of mechanical venti-
adult ICU patients (+1B).
lation and a shorter ICU length of stay [LOS]) (B).
The Confusion Assessment Method for the ICU
ii. Maintaining light levels of sedation increases the
(CAM-ICU) and the Intensive Care Delirium Screen-
physiologic stress response, but is not associated with
ing Checklist (ICDSC) are the most valid and reliable
an increased incidence of myocardial ischemia (B).
delirium monitoring tools in adult ICU patients (A).
iii. The association between depth of sedation and psy-
Routine monitoring of delirium in adult ICU
chological stress in these patients remains unclear (C).
patients is feasible in clinical practice (B).
We recommend that sedative medications be c. Delirium risk factorstitrated to maintain a light rather than a deep level
i. Four baseline risk factors are positively and signifi-
of sedation in adult ICU patients, unless clinically
cantly associated with the development of delirium
in the ICU: preexisting dementia, history of hyper-
b. Monitoring depth of sedation and brain function
tension and/or alcoholism, and a high severity of
i. The Richmond Agitation-Sedation Scale (RASS)
illness at admission (B).
and Sedation-Agitation Scale (SAS) are the most
ii. Coma is an independent risk factor for the develop-
valid and reliable sedation assessment tools for
ment of delirium in ICU patients (B).
measuring quality and depth of sedation in adult
iii. Conflicting data surround the relationship between
ICU patients (B).
opioid use and the development of delirium in
ii. We do not recommend that objective measures of
adult ICU patients (B).
brain function (e.g., auditory evoked potentials
iv. Benzodiazepine use may be a risk factor for the
[AEPs], Bispectral Index [BIS], Narcotrend Index
development of delirium in adult ICU patients (B).
[NI], Patient State Index [PSI], or state entropy
v. There are insufficient data to determine the rela-
[SE]) be used as the primary method to monitor
tionship between propofol use and the develop-
depth of sedation in noncomatose, nonparalyzed
ment of delirium in adult ICU patients (C).
critically ill adult patients, as these monitors are
vi. In mechanically ventilated adult ICU patients at
inadequate substitutes for subjective sedation scor-
risk of developing delirium, dexmedetomidine
ing systems (–1B).
infusions administered for sedation may be associ-
iii. We suggest that objective measures of brain func-
ated with a lower prevalence of delirium compared
tion (e.g., AEPs, BIS, NI, PSI, or SE) be used as an
to benzodiazepine infusions (B).
Critical Care Medicine
www.ccmjournal.org
d. Delirium prevention
in mechanically ventilated adult ICU patients, as
i. We recommend performing early mobilization of
insufficient evidence exists for the efficacy of these
adult ICU patients whenever feasible to reduce the
interventions (0, No Evidence).
incidence and duration of delirium (+1B).
e. We recommend using an interdisciplinary ICU team
ii. We provide no recommendation for using a phar-
approach that includes provider education, pre-
macologic delirium prevention protocol in adult
printed and/or computerized protocols and order
ICU patients, as no compelling data demonstrate
forms, and quality ICU rounds checklists to facili-
that this reduces the incidence or duration of delir-
tate the use of pain, agitation, and delirium manage-
ium in these patients (0,C).
ment guidelines or protocols in adult ICUs (+1B).
iii. We provide no recommendation for using a com-
bined nonpharmacologic and pharmacologic delir-ium prevention protocol in adult ICU patients, as this has not been shown to reduce the incidence of
Since these guidelines were last published, we have made
significant advances in our understanding of how to pro-
delirium in these patients (0,C).
vide physical and psychological comfort for patients ad-
iv. We do not suggest that either haloperidol or atypi-
mitted to the ICU (1). The development of valid and reliable
cal antipsychotics be administered to prevent delir-
bedside assessment tools to measure pain, sedation, agitation,
ium in adult ICU patients (–2C).
and delirium in ICU patients has allowed clinicians to man-
v. We provide no recommendation for the use of dex-
age patients better and to evaluate outcomes associated with
medetomidine to prevent delirium in adult ICU both nonpharmacologic and pharmacologic interventions (2, patients, as there is no compelling evidence regard-
3). Our expanded knowledge of the clinical pharmacology of
ing its effectiveness in these patients (0,C).
medications commonly administered to treat pain, agitation,
e. Delirium treatment
and delirium (PAD) in ICU patients has increased our ap-
i. There is no published evidence that treatment with
preciation for both the short- and long-term consequences of
haloperidol reduces the duration of delirium in prolonged exposure to these agents (4–6). We have learned that adult ICU patients (No Evidence).
the methods of administering and titrating these medications
ii. Atypical antipsychotics may reduce the duration of
can affect patient outcomes as much as drug choice (7–16). For
delirium in adult ICU patients (C).
most ICU patients, a safe and effective strategy that ensures
iii. We do not recommend administering rivastigmine
patient comfort while maintaining a light level of sedation is
to reduce the duration of delirium in ICU patients
associated with improved clinical outcomes (9–13, 16–20).
Ensuring that critically ill patients are free from pain, agi-
iv. We do not suggest using antipsychotics in patients at
tation, anxiety, and delirium at times may conflict with other
significant risk for torsades de pointes (i.e., patients
clinical management goals, such as maintaining cardiopul-
with baseline prolongation of QTc interval, patients
monary stability while preserving adequate end-organ perfu-
receiving concomitant medications known to pro-
sion and function (21, 22). Management goals may be further
long the QTc interval, or patients with a history of
complicated by the growing number of "evidence-based" bun-
this arrhythmia) (–2C).
dles and clinical algorithms, some of which have been widely
v. We suggest that in adult ICU patients with delirium
adopted by regulatory agencies and payers (23–30). Finally,
unrelated to alcohol or benzodiazepine withdrawal,
tremendous worldwide variability in cultural, philosophical,
continuous IV infusions of dexmedetomidine rather
and practice norms, and in the availability of manpower and
than benzodiazepine infusions be administered for
resources, makes widespread implementation of evidence-
sedation to reduce the duration of delirium in these
based practices challenging (31–36).
patients (+2B).
The goal of these clinical practice guidelines is to recommend
4. Strategies for Managing Pain, Agitation, and Delirium to
best practices for managing PAD to improve clinical outcomes in
Improve ICU Outcomes
adult ICU patients. We performed a rigorous, objective, transpar-
a. We recommend either daily sedation interruption
ent, and unbiased assessment of the relevant published evidence.
or a light target level of sedation be routinely used in
We balanced this evidence against the values and preferences of
mechanically ventilated adult ICU patients (+1B).
ICU patients, family members, caregivers, and payer and regula-
b. We suggest that analgesia-first sedation be used in
tory groups, and important ICU clinical outcomes, to develop
mechanically ventilated adult ICU patients (+2B).
relevant statements and recommendations that can be applied at
c. We recommend promoting sleep in adult ICU the bedside.
patients by optimizing patients' environments,
The scope of these guidelines includes short- and long-term
using strategies to control light and noise, cluster-
management of PAD in both intubated and nonintubated
ing patient care activities, and decreasing stimuli at
adult medical, surgical, and trauma ICU patients. These guide-
night to protect patients' sleep cycles (+1C).
lines only briefly address the topic of analgesia and sedation for
d. We provide no recommendation for using specific
procedures, which is described in more detail in the American
modes of mechanical ventilation to promote sleep
Society of Anesthesiologists guidelines on conscious sedation
www.ccmjournal.org
January 2013 • Volume 41 • Number 1
(37). The American College of Critical Care Medicine (ACCM)
Controlled Trials, CINAHL, Scopus, ISI Web of Science, and
is currently developing separate guidelines on analgesia and
the International Pharmaceutical Abstracts. Search parameters
sedation for pediatric ICU patients.
included published (or in press) English-only manuscripts on
This version of the guidelines places a greater emphasis on
adult humans (> 18 yr), from December 1999 (the search limit
the psychometric aspects of PAD monitoring tools. It includes
for the 2002 guidelines) through December 2010. Studies with
both pharmacologic and nonpharmacologic approaches to less than 30 patients, editorials, narrative reviews, case reports, manage PAD in ICU patients. There is also greater emphasis
animal or in vitro studies, and letters to the editor were excluded.
placed on preventing, diagnosing, and treating delirium, reflect-
Biweekly automated searches were continued beyond this date,
ing our growing understanding of this disease process in criti-
and relevant articles were incorporated into the guidelines
cally ill patients. These guidelines are meant to help clinicians
through July 2012, but studies published after December 2010
take a more integrated approach to manage PAD in critically ill
were not included in the evidence review and voting process. The
patients. Clinicians should adapt these guidelines to the context
2002 guideline references were also included in the database, and
of individual patient care needs and the available resources of
targeted searches of the literature published before December
their local health care system. They are not meant to be pro-
1999 were performed as needed. Over 19,000 references were
scriptive or applied in absolute terms.
ultimately included in the Refworks database.
The statements and recommendations in this 2012 ver-
sion of the guidelines were developed using the Grading of
Recommendations, Assessment, Development and Evaluation
The ACCM's 20-member multidisciplinary task force, with ex-
(GRADE) methodology, a structured system for rating quality
pertise in PAD management, was charged with revising the 2002
of evidence and grading strength of recommendation in clini-
"Clinical Practice Guidelines for the Sustained Use of Sedatives
cal practice () (38–40).
and Analgesics in the Critically Ill Adult" (1). Subcommittees
Subcommittees worked with members of the GRADE Working
were assigned one of the four subtopic areas: pain and analge-
Group (R.J., D.C., H.S., G.G.) to phrase all clinical questions
sia, agitation and sedation, delirium, and related ICU outcomes.
in either "descriptive" or "actionable" terms. They structured
Each subcommittee developed relevant clinical questions and
actionable questions in the Population, Intervention, Compar-
related outcomes, identified, reviewed, and evaluated the lit-
ison, Outcomes format and classified clinical outcomes related
erature, crafted statements and recommendations, and drafted
to each intervention as critical, important, or unimportant
their section of the article.
to clinical decision making. Only important and critical out-
To facilitate the literature review, subcommittees developed a
comes were included in the evidence review, and only critical
comprehensive list of related key words. A professional librarian
outcomes were included in developing recommendations.
(C.K., University of Cincinnati) expanded and organized this
Subcommittee members searched the database for relevant
key word list; developed corresponding medical subject heading
articles and uploaded corresponding PDFs to facilitate group
(MeSH) terms (Supplemental Digital Content 1,
review. Two subcommittee members independently com-
); searched relevant clinical databases; and
pleted a GRADE evidence profile summarizing the findings of
created an electronic, Web-based, password-protected database
each study and evaluated the quality of evidence. The quality
using Refworks software (Bethesda, MD). Eight databases of evidence was judged to be high (level A), moderate (level were included in all searches: PubMed, MEDLINE, Cochrane
B), or low/very low (level C), based on both study design and
Database of Systematic Reviews, Cochrane Central Register of
specific study characteristics, which could result in a reviewer
TABLE 1. Factors That Affect the Quality of Evidencea
Quality of
Type of Evidence
Further research is unlikely to change our confidence in the
estimate of effect.
RCT with significant limitations
Further research is likely to have an important impact on our
(downgraded)b, or high-quality
confidence in the estimate of effect and may change the
OS (upgraded)c
Further research is very likely to have an important impact
on our confidence in the estimate of effect and is likely to
change the estimate.
RCT = randomized controlled trial; OS = observational study.
aAdapted from Guyatt et al (40).
bRCTs with significant limitations: 1) study design limitations (planning, implementation bias); 2) inconsistency of results; 3) indirectness of evidence; 4) imprecision
of results; 5) high likelihood of reporting bias.
cHigh-quality OS: 1) large magnitude of treatment effect; 2) evidence of a dose-response relationship; 3) plausible biases would decrease the magnitude of an
apparent treatment effect.
Critical Care Medicine
www.ccmjournal.org
TABLE 2. Factors That Affect the Strength of Recommendationsa
Effect on Strength of Recommendation
Quality of evidence
Lower quality of evidence reduces the likelihood of a strong recommendation, and
Uncertainty about the balance between
Higher degree of uncertainty about the balance between risks and benefits reduces
desirable and undesirable effects
the likelihood of a strong recommendation, and vice versa
Uncertainty or variability in values and
Wide variability in values and preferences across groups reduces the likelihood of a
strong recommendation, and vice versa
Uncertainty about whether the intervention
A higher the overall cost of treatment reduces the likelihood of a strong
represents a wise use of resources
recommendation, and vice versa
aAdapted from Guyatt et al (40).
either downgrading or upgrading the quality of the evidence
survey tool (E-Survey, Scottsdale,
(Table 1). If multiple studies related to a particular outcome
AZ). Consensus on the strength of evidence for each question
demonstrated disparate results, and no published systematic
required a majority (> 50%) vote. Consensus on the strength
reviews on the topic existed, a meta-analysis of the relevant lit-
of recommendations was defined as follows: a recommendation
erature was performed by a member of the GRADE Working
in favor of an intervention (or the comparator) required at least
Group (R.J.).
50% of all task force members voting in favor, with less than 20%
Subcommittees collectively reviewed the evidence profiles for
voting against; failure to meet these voting thresholds resulted in
each question, and using a nominal group technique, determined
no recommendation being made. For a recommendation to be
the overall quality of evidence (for both descriptive and action-
graded as strong rather than weak, at least 70% of those voting had
able questions), the strength of recommendation (for actionable
to vote for a strong recommendation, otherwise it received a weak
questions only), and drafted evidence summaries for review by
recommendation. This method for reaching consensus has been
other task force members. The strength of recommendations proposed by the GRADE Working Group and was adopted by the was defined as either strong (1) or weak (2), and either for (+) or
2008 Sepsis Guidelines Panel to ensure fairness, transparency, and
against (–) an intervention, based on both the quality of evidence
anonymity in the creation of guideline recommendations (46,
and the risks and benefits across all critical outcomes (Table 2)
47). Polling results and comments were then summarized and
(41, 42). A no recommendation (0) could also be made due to
distributed to all PAD guideline task force members for review.
either a lack of evidence or a lack of consensus among subcom-
When one round of voting failed to produce group consensus,
mittee members. Consensus statements based on expert opinion
additional discussion and a second and/or third round of voting
alone were not used when evidence could not support a recom-
occurred. Polling for all questions was completed by December
mendation. A strong recommendation either in favor of (+1) or
2010. Distribution of the final voting tallies along with comments
against (–1) an intervention implied that the majority of task
by task force members for each statement and recommendation is
force members believed that the benefits of the intervention sig-
summarized in Supplemental Digital Conte
nificantly outweighed the risks (or vice versa) and that the major-
ity of patients and providers would pursue this course of action
Task force members completed required, annual, conflict of
(or not), given the choice. A weak recommendation either in favor
interest statements. Those with significant potential conflicts
of (+2) or against (–2) an intervention implied that the benefits
of interest (e.g., manuscript coauthorship) recused themselves
of the intervention likely outweighed the risks (or vice versa), but
from reviewing and grading evidence and from developing a
that task force members were not confident about these trade-
subcommittee's evidence statements and recommendations for
offs, either because of a low quality of evidence or because the
related questions. All task force members voted anonymously
trade-offs between risks and benefits were closely balanced. On
on the final strength of evidence and strength of recommen-
the basis of this information, most people might pursue this
dations for all questions. No industry funding or support was
course of action (or not), but a significant number of patients
used to develop any aspect of these guidelines.
and providers would choose an alternative course of action (40, 43, 44). Throughout these guidelines, for all strong recommenda-
tions, the phrase "We recommend …" was used, and for all weak
These guidelines include statements and recommendations
recommendations, "We suggest …" was used.
about using a variety of bedside behavioral assessment tools
Group consensus for all statements and recommendations was
used to 1) detect and evaluate pain, 2) assess depth of sedation
achieved using a modified Delphi method with an anonymous
and degree of agitation, and 3) detect delirium in critically ill
voting scheme (41, 45). Task force members reviewed the adult patients who are unable to communicate clearly. To date, subcommittees' GRADE Evidence Summaries, and statements and
a comparative assessment of the psychometric properties (i.e.,
recommendations, and voted and commented anonymously on
reliability and validity) and feasibility related to the use of these
each statement and recommendation using an on-line electronic
tools in ICU patients has not been published. Scale reliability
www.ccmjournal.org
January 2013 • Volume 41 • Number 1
refers to the overall accuracy of the use of a scale in replicat-
may be unable to self-report their pain (either verbally or with
ing pain, sedation, or delirium scores over time (i.e., test–retest
other signs) because of an altered level of consciousness, the
reliability) or between raters (i.e., inter-rater reliability) (48).
use of mechanical ventilation, or high doses of sedative agents
Validity refers to the conclusions that can be drawn from the
or neuromuscular blocking agents (57). Yet, the ability to reli-
results of a test or scale (e.g., does a delirium assessment tool
ably assess patient's pain is the foundation for effective pain
actually detect delirium?) (49). Content, criterion, and dis-
treatment. As the International Association for the Study of
criminant validation are specific strategies of validity testing. A
Pain also states, "the inability to communicate verbally does not
tool can be shown to be both reliable and valid when used for
negate the possibility that an individual is experiencing pain
a specific purpose with specified individuals in a given context
and is in need of appropriate pain-relieving treatment" (58).
(48, 49). Feasibility refers to the ease with which clinicians can
Therefore, clinicians must be able to reliably detect pain, using
apply a particular scale in the clinical setting (e.g., in the ICU).
assessment methods adapted to a patient's diminished com-
The task force evaluated and compared the psychometric
munication capabilities. In such situations, clinicians should
properties of behavioral pain scales (BPSs) used in adult ICU
consider patients' behavioral reactions as surrogate measures of
patients and compared their analyses to a previously published
pain, as long as their motor function is intact (59). Detection,
process (50). Similar scoring systems were not available to eval-
quantification, and management of pain in critically ill adults
uate and compare the psychometric properties of sedation and
are major priorities and have been the subject of research for
delirium scales, which have different validation strategies from
over 20 yr (60). Despite this fact, the incidence of significant
those used for pain scales. With input from three psychomet-
pain is still 50% or higher in both medical and surgical ICU
ric testing experts (D.S., C.J., C.W.), the task force developed
patients (61, 62).
similar scoring systems to assess and compare sedation and
In addition to experiencing pain at rest (61) and pain relat-
delirium scales (48).
ed to surgery, trauma, burns, or cancer, patients also experi-
The psychometric properties of pain, sedation, and delirium
ence procedural pain (63–70). This was highlighted in the first
scales were evaluated based on: 1) item selection and content vali-
practice guideline published on acute pain management 20 yr
dation, 2) reliability, 3) validity, 4) feasibility, and 5) relevance or
ago by the Agency for Health Care Policy and Research (71).
impact of implementation on patient outcomes. Psychometric
Pain related to procedures is ubiquitous, and inadequate treat-
raw scores ranged from 0 to 25 for pain scales, 0 to 18 for seda-
ment of procedural pain remains a significant problem for
tion scales, and 0 to 21 for delirium scales. Weighted scores were
many ICU patients (68).
established for each criterion to address variations in scores and to
The negative physiologic and psychological consequences of
facilitate the interpretation of results, resulting in a total weighted
unrelieved pain in ICU patients are significant and long-last-
score 0 to 20 for all three domains. The details of each of the three
ing. For many years, ICU patients have identified pain as their
psychometric scoring systems used are summarized in Supple-
greatest concern and a leading cause of insufficient sleep (72).
mental Digital Conte).
More recently, studies on ICU-discharged but still-hospitalized
Scales with weighted scores ranging from 15 to 20 had very good
patients showed that 82% (n = 75) (56) remembered pain or
psychometric properties, 12 to 14.9 had moderate psychometric
discomfort associated with the endotracheal tube and 77%
properties, 10 to 11.9 had some acceptable psychometric prop-
(n = 93) remembered experiencing moderate to severe pain
erties which required validation in additional studies, and 0 to
during their ICU stay (73). One week after discharge from the
9.9 had very few psychometric properties reported and/or unac-
ICU, 82% (n = 120) of cardiac surgery patients reported pain
ceptable results. Scales with moderate to very good psychometric
as the most common traumatic memory of their ICU stay; 6
properties (i.e., weighted score ≥ 12) were considered to be suf-
months later, 38% still recalled pain as their most traumatic
ficiently valid and reliable scales for use in adult ICU patients. The
ICU memory (74). Granja and colleagues (75) noted that 17%
quality of evidence for each individual scale was also evaluated
(n = 313) of patients remembered experiencing severe pain 6
using categories similar to those used in the GRADE system, with
months after an ICU stay and 18% were at high risk of devel-
modifications adapted for the psychometric analyses. All studies
oping posttraumatic stress disorder (PTSD). Schelling and col-
were reviewed, and all scales were scored independently by two
leagues (25) conducted a long-term follow-up (median, 4 yr)
questionnaire study of 80 patients who had been treated in the ICU for acute respiratory distress syndrome. In comparison
Pain and Analgesia
with normal controls, both medical and surgical patients who
Incidence of Pain in ICU Patients. The International Associa-
recalled pain and other traumatic situations while in the ICU
tion for the Study of Pain defines pain as an "unpleasant senso-
had a higher incidence of chronic pain (38%) and PTSD symp-
ry and emotional experience associated with actual or potential
toms (27%), and a lower health-related quality of life (21%).
tissue damage, or described in terms of such damage" (51). This
The stress response evoked by pain can have deleterious
definition highlights the subjective nature of pain and suggests
consequences for ICU patients. Increased circulating catechol-
that it can be present only when reported by the person experi-
amines can cause arteriolar vasoconstriction, impair tissue per-
encing it. Most critically ill patients will likely experience pain
fusion, and reduce tissue-oxygen partial pressure (76). Other
sometime during their ICU stay (52) and identify it as a great
responses triggered by pain include catabolic hypermetabolism
source of stress (53–56). However, many critically ill patients
resulting in hyperglycemia, lipolysis, and breakdown of muscle
Critical Care Medicine
www.ccmjournal.org
TABLE 3. Pharmacology of Opiate Analgesics (1, 128, 440, 472)
Dose (mg)
Elimination
IV Infusion
Side Effects and Other Information
200 min (6 hr infusion); 300
0.35–0.5 μg/kg IV
0.7–10 μg/kg/hr
Less hypotension than with morphine. Accumulation with
min (12 hr infusion)a
CYP3A4/5 substrate
hepatic impairment.
Therapeutic option in patients tolerant to morphine/fentanyl.
q1–2 hrb
Accumulation with hepatic/renal impairment.
6- and 3-glucuronide
Accumulation with hepatic/renal impairment. Histamine
q1–2 hrb
IV/PO: 10–40 mg
May be used to slow the development of tolerance where
CYP3A4/5, 2D6, 2B6,
there is an escalation of opioid dosing requirements.
Unpredictable pharmacokinetics; unpredictable
pharmacodynamics in opiate naïve patients. Monitor QTc.d
Hydrolysis by plasma
No accumulation in hepatic/renal failure. Use IBW if body
weight >130% IBW.
Maintenance dose:
0.5–15 μg/kg/hr IV
PO = oral; N/A = not applicable; IBW = ideal body weight.
aAfter 12 hrs, and in cases of end-organ dysfunction, the context-sensitive half-life increases unpredictably.
bMay increase dose to extend dosing interval; hydromorphone 0.5 mg IV every 3 hrs, or morphine 4–8 mg IV every 3–4 hrs.
cEquianalgesic dosing tables may underestimate the potency of methadone. The morphine- or hydromorphone-to-methadone conversion ratio increases (i.e., the
potency of methadone increases) as the dose of morphine or hydromorphone increases. The relative analgesic potency ratio of oral to parenteral methadone is
2:1, but the confidence intervals are wide.
dQTc is the Q-T interval (corrected) of the electrocardiographic tracing.
to provide protein substrate (77). Catabolic stimulation and
Although reviews of behavioral pain assessment tools have
hypoxemia also impair wound healing and increase the risk of
been published, an updated discussion is needed about their
wound infection. Pain suppresses natural killer cell activity (78,
development, validation, and applicability to ICU patients (50,
79), a critical function in the immune system, with a decrease in
84). A detailed, systematic review of the processes of item selec-
the number of cytotoxic T cells and a reduction in neutrophil
tion and psychometric properties of pain scales (i.e., validity and
phagocytic activity (80). Acute pain may be the greatest risk fac-
reliability) may encourage clinicians to adopt pain scales and to
tor for developing debilitating chronic, persistent, often neuro-
standardize their use in ICU patients. Recent studies have dem-
pathic pain (81). Unrelieved acute pain in adult ICU patients
onstrated that implementing behavioral pain scales improves
is ubiquitous and far from benign, with both short- and long-
both ICU pain management and clinical outcomes, including
term consequences. Adequately identifying and treating pain in
better use of analgesic and sedative agents and shorter durations
these patients require focused attention.
of mechanical ventilation and ICU stay (2, 3, 85).
Pain Assessment in ICU Patients. Treating pain in criti-
Treatment of Pain. Opioids, such as fentanyl, hydro-
cally ill patients depends on a clinician's ability to perform a
morphone, methadone, morphine, and remifentanil, are
reproducible pain assessment and to monitor patients over
the primary medications for managing pain in critically ill
time to determine the adequacy of therapeutic interventions
patients (Table 3) (62). The optimal choice of opioid and
to treat pain. A patient's self-report of pain is considered the
the dosing regimen used for an individual patient depends
"gold standard," and clinicians should always attempt to have
on many factors, including the drug's pharmacokinetic and
a patient rate his or her own pain first. Chanques and col-
pharmacodynamic properties (52). The use of meperidine is
leagues (82) demonstrated that a 0–10 visually enlarged hori-
generally avoided in ICU patients because of its potential for
zontal numeric rating scale was the most valid and feasible of
neurologic toxicity (52).
five pain intensity rating scales tested in over 100 ICU patients.
Several other types of analgesics or pain-modulating medica-
Yet when critically ill patients are unable to self-report their
tions, such as local and regional anesthetics (e.g., bupivacaine),
pain, clinicians must use structured, valid, reliable, and feasible
nonsteroidal anti-inflammatory medications (e.g., ketorolac,
tools to assess patients' pain (83). It is essential that pain in
ibuprofen), IV acetaminophen, and anticonvulsants, can be
ICU patients be assessed routinely and repetitively in a manner
used as adjunctive pain medications to reduce opioid require-
that is efficient and reproducible. No objective pain monitor
ments (Table 4). However, their safety profile and effectiveness
exists, but valid and reliable bedside pain assessment tools that
as sole agents for pain management have not been adequately
concentrate primarily on patients' behaviors as indicators of
studied in critically ill patients. Pharmacologic treatment prin-
pain do exist.
ciples extrapolated from non-ICU studies may not be applicable
www.ccmjournal.org
January 2013 • Volume 41 • Number 1
TABLE 3. Pharmacology of Opiate Analgesics (1, 128, 440, 472)
TABLE 3 (Continued).
Dose (mg)
Elimination
IV Infusion
Side Effects and Other Information
200 min (6 hr infusion); 300
0.35–0.5 μg/kg IV
0.7–10 μg/kg/hr
Less hypotension than with morphine. Accumulation with
min (12 hr infusion)a
CYP3A4/5 substrate
hepatic impairment.
Therapeutic option in patients tolerant to morphine/fentanyl.
q1–2 hrb
Accumulation with hepatic/renal impairment.
6- and 3-glucuronide
Accumulation with hepatic/renal impairment. Histamine
q1–2 hrb
IV/PO: 10–40 mg
May be used to slow the development of tolerance where
CYP3A4/5, 2D6, 2B6,
there is an escalation of opioid dosing requirements.
Unpredictable pharmacokinetics; unpredictable
pharmacodynamics in opiate naïve patients. Monitor QTc.d
Hydrolysis by plasma
No accumulation in hepatic/renal failure. Use IBW if body
weight >130% IBW.
Maintenance dose:
0.5–15 μg/kg/hr IV
PO = oral; N/A = not applicable; IBW = ideal body weight.
aAfter 12 hrs, and in cases of end-organ dysfunction, the context-sensitive half-life increases unpredictably.
bMay increase dose to extend dosing interval; hydromorphone 0.5 mg IV every 3 hrs, or morphine 4–8 mg IV every 3–4 hrs.
cEquianalgesic dosing tables may underestimate the potency of methadone. The morphine- or hydromorphone-to-methadone conversion ratio increases (i.e., the
potency of methadone increases) as the dose of morphine or hydromorphone increases. The relative analgesic potency ratio of oral to parenteral methadone is
2:1, but the confidence intervals are wide.
dQTc is the Q-T interval (corrected) of the electrocardiographic tracing.
to critically ill patients (52). IV acetaminophen has been recent-
gesic interventions to prevent potential negative sequelae due
ly approved for use in the United States and has been shown to
to either inadequate or excessive analgesic therapy. Clinicians
be safe and effective when used in conjunction with opioids for
should perform routine and reproducible pain assessments
postoperative pain in surgical ICU patients following major or
in all critically ill patients, using either patient self-report or
cardiac surgery (80, 86–89). Neuropathic pain, poorly treated
systematically applied behavioral measures. Pain management
with opioids alone, can be treated with enterally administered
can be facilitated by identifying and treating pain early rather
gabapentin and carbamazepine in ICU patients with sufficient
than waiting until it becomes severe (52).
gastrointestinal absorption and motility (90, 91).
Pain and Analgesia: Questions, Statements, and
Methods of dosing analgesics are another treatment consider-
ation. The choice of intermittent vs. continuous IV strategies may
1. Incidence of Pain
depend on drug pharmacokinetics, frequency and severity of pain,
Question: Do adult ICU patients experience nonproce-
and/or the patient's mental status (92). Enteral administration of
dural pain in the ICU and, if so, what events or situations
opioids and other pain medications should be limited to patients
are related to pain? (descriptive)
with adequate gastrointestinal absorptive capacity and motility.
Answer: Adult medical, surgical, and trauma ICU patients
Regional or neuraxial (spinal or epidural) modalities may also be
routinely experience pain, both at rest and with routine
used for postoperative analgesia following selected surgical proce-
ICU care (B). Pain in adult cardiac surgery patients is
dures (93, 94).
common and poorly treated; women experience more
Complementary, nonpharmacologic interventions for pain
pain than men after cardiac surgery (B).
management, such as music therapy and relaxation techniques,
Rationale: Medical, surgical, and trauma ICU patients
may be opioid-sparing and analgesia-enhancing; they are low
experience significant pain, even at rest (61, 63, 73).
cost, easy to provide, and safe. Although a multimodal approach
Therefore, all adult patients in any ICU should be evalu-
to pain management in ICU patients has been recommended,
ated for pain. Pain at rest should be considered a major
few studies have been published on the effectiveness of non-
clinical diagnostic syndrome. In cardiac surgery patients,
pharmacologic interventions in these patients (52, 95).
pain related to the surgery, coughing, respiratory care
Pain occurs commonly in adult ICU patients, regard-
procedures, and mobilization remains prevalent and
less of their admitting diagnoses. Pain can preclude patients
poorly treated; women experience more pain than men
from participating in their ICU care (e.g., early mobilization,
after cardiac surgery (73, 96–98). Therefore, activity pain
weaning from mechanical ventilation). Thus, clinicians should
in cardiac surgery patients must be assessed and treated.
frequently reassess patients for pain and carefully titrate anal-
Pain management should be individualized according to
Critical Care Medicine
www.ccmjournal.org
TABLE 4. Pharmacology of Nonopiate Analgesics (1, 91, 132, 440)
Elimination Half-Life Metabolic Pathway
Side Effects and Other Information
Loading dose 0.1–0.5 mg/kg IV followed by 0.05–
Attenuates the development of acute tolerance to opioids. May cause
hallucinations and other psychological disturbances.
Acetaminophen (PO)
325–1000 mg every 4–6 hr; max dose ≤ 4 g/day)
May be contraindicated in patients with significant hepatic dysfunction.
Acetaminophen (PR)
Acetaminophen (IV)
650 mg IV every 4 hrs – 1000 mg IV every 6 hr; max
Ketorolaca (IM/IV)
30 mg IM/IV, then 15–30 mg IM/IV every 6 hr up to
Avoid nonsteroidal anti-inflammatory drugs in following conditions: renal
dysfunction; gastrointestinal bleeding; platelet abnormality; concomitant
max dose = 120 mg/day × 5 days
angiotensin converting enzyme inhibitor therapy, congestive heart
failure, cirrhosis, asthma. Contraindicated for the treatment of
perioperative pain in coronary artery bypass graft surgery.
400–800 mg IV every 6 hr infused over > 30 mins;
Avoid nonsteroidal anti-inflammatory drugs in following conditions: renal
max dose = 3.2 g/day
dysfunction; gastrointestinal bleeding; platelet abnormality; concomitant
angiotensin converting enzyme inhibitor therapy, congestive heart
failure, cirrhosis, asthma. Contraindicated for the treatment of
perioperative pain in coronary artery bypass graft surgery.
400 mg PO every 4 hrs;
max dose = 2.4 g/day
Starting dose = 100 mg PO three times daily;
Side effects: (common) sedation, confusion, dizziness, ataxia. Adjust
maintenance dose = 900–3600 mg/day in 3
dosing in renal failure pts. Abrupt discontinuation associated with drug
withdrawl syndrome, seizures.
Carbamazepine immediate
25–65 hrs initially, then
Starting dose = 50–100 mg PO bid; maintenance
Side effects: (common) nystagmus, dizziness, diplopia, lightheadedness,
dose = 100–200 mg every 4–6 hr; max dose =
lethargy; (rare) aplastic anemia, and agranulocytosis; Stevens–Johnson
syndrome or toxic epidermal necrolysis with HLA-B1502 gene. Multiple
drug interactions due to hepatic enzyme induction.
PO = orally; PR = rectally; max = maximum; IM = intramuscular; N/A = not applicable.
aFor patients > 65 yr or < 50 kg, 15 mg IV/IM every 6 hrs to a maximum dose of 60 mg/day for 5 days.
the patient's experience of pain, with special attention to
Rationale: Routine pain assessments in adult ICU
its occurrence in women (97).
patients are associated with improved clinical outcomes.
Question: What is the pain experienced by adult ICU
Pain assessment, especially if protocolized, has been sig-
patients undergoing procedures? (descriptive)
nificantly associated with a reduction in the use of anal-
Answer: Procedural pain is common in adult ICU patients (B).
gesic medications, ICU length of stay (LOS), and dura-
Rationale: Pain associated with nonsurgical procedures
tion of mechanical ventilation (3, 62). Pain assessment
such as chest tube removal or wound care is prevalent in
is essential for appropriate treatment, especially when
adult ICU patients (68, 99). Generally at a moderate level
part of a comprehensive pain management protocol.
(68), pain is influenced by preprocedural pain levels and
Although the quality of evidence is moderate, a strong
the administration of analgesics (100). Less than 25% of
recommendation for performing routine pain assess-
patients receive analgesics before the procedures (68). Pro-
ments in all ICU patients is appropriate, as the benefits
cedural pain varies with age (64, 66) and is greater in non-
strongly outweigh the risks.
Caucasians than in Caucasians (64, 66, 68). Differences in
Question: What are the most valid and reliable behav-
procedural pain between nonsurgical and surgical patients
ioral measures of pain in critically ill adult patients who
vary according to procedure (64, 66). Hemodynamic
are unable to self-report? (descriptive)
changes are not valid correlates of procedural pain (99).
Answer: The Behavioral Pain Scale (BPS) and the Critical-
Available information suggests that preemptive analgesia
Care Pain Observation Tool (CPOT) are the most valid
has benefits, but the risks of procedural pain and the lack
and reliable behavioral pain scales for monitoring pain in
of preemptive treatment are unclear.
medical, postoperative, or trauma (except for brain injury)
2. Pain Assessment
adult ICU patients who are unable to self-report, and in
Question: Should pain assessments be routinely per-
whom motor function is intact and behaviors are observ-
formed in adult ICU patients? (actionable)
able. Using these scales in other ICU patient populations
Answer: We recommend that pain be routinely moni-
and translating them into foreign languages other than
tored in all adult ICU patients (+1B).
French or English require further validation testing (B).
www.ccmjournal.org
January 2013 • Volume 41 • Number 1
TABLE 4. Pharmacology of Nonopiate Analgesics (1, 91, 132, 440)
TABLE 4 (Continued).
Elimination Half-Life Metabolic Pathway
Side Effects and Other Information
Loading dose 0.1–0.5 mg/kg IV followed by 0.05–
Attenuates the development of acute tolerance to opioids. May cause
hallucinations and other psychological disturbances.
Acetaminophen (PO)
325–1000 mg every 4–6 hr; max dose ≤ 4 g/day)
May be contraindicated in patients with significant hepatic dysfunction.
Acetaminophen (PR)
Acetaminophen (IV)
650 mg IV every 4 hrs – 1000 mg IV every 6 hr; max
Ketorolaca (IM/IV)
30 mg IM/IV, then 15–30 mg IM/IV every 6 hr up to
Avoid nonsteroidal anti-inflammatory drugs in following conditions: renal
dysfunction; gastrointestinal bleeding; platelet abnormality; concomitant
max dose = 120 mg/day × 5 days
angiotensin converting enzyme inhibitor therapy, congestive heart
failure, cirrhosis, asthma. Contraindicated for the treatment of
perioperative pain in coronary artery bypass graft surgery.
400–800 mg IV every 6 hr infused over > 30 mins;
Avoid nonsteroidal anti-inflammatory drugs in following conditions: renal
max dose = 3.2 g/day
dysfunction; gastrointestinal bleeding; platelet abnormality; concomitant
angiotensin converting enzyme inhibitor therapy, congestive heart
failure, cirrhosis, asthma. Contraindicated for the treatment of
perioperative pain in coronary artery bypass graft surgery.
400 mg PO every 4 hrs;
max dose = 2.4 g/day
Starting dose = 100 mg PO three times daily;
Side effects: (common) sedation, confusion, dizziness, ataxia. Adjust
maintenance dose = 900–3600 mg/day in 3
dosing in renal failure pts. Abrupt discontinuation associated with drug
withdrawl syndrome, seizures.
Carbamazepine immediate
25–65 hrs initially, then
Starting dose = 50–100 mg PO bid; maintenance
Side effects: (common) nystagmus, dizziness, diplopia, lightheadedness,
dose = 100–200 mg every 4–6 hr; max dose =
lethargy; (rare) aplastic anemia, and agranulocytosis; Stevens–Johnson
syndrome or toxic epidermal necrolysis with HLA-B1502 gene. Multiple
drug interactions due to hepatic enzyme induction.
PO = orally; PR = rectally; max = maximum; IM = intramuscular; N/A = not applicable.
aFor patients > 65 yr or < 50 kg, 15 mg IV/IM every 6 hrs to a maximum dose of 60 mg/day for 5 days.
Rationale: A total of six behavioral pain scales were ana-
and adapted for nonintubated ICU patients (113), but it
lyzed: BPS; BPS—Non-Intubated (BPS-NI); CPOT; Non-
has been tested in a group of only 30 patients so far, and
Verbal Pain Scale (NVPS), both initial and revised (NVPS-
replication studies are needed to support its psychomet-
I, NVPS-R); Pain Behavioral Assessment Tool (PBAT); and
ric properties. More studies are also necessary to examine
the Pain Assessment, Intervention, and Notation (PAIN)
the psychometric properties of the NVPS (114), NVPS-R
Algorithm. Table 5 summarizes their psychometric scores.
(115), PBAT (116), and PAIN (117).
Observational studies, although somewhat limited, pro-
Question: Should vital signs be used to assess pain in
vide consistent evidence that the BPS (3–12 total score)
adult ICU patients? (actionable)
and CPOT (0–8 total score) scales have good psychomet-
Answer: We do not suggest that vital signs (or observa-
ric properties in terms of: inter-rater reliability (101–109),
tional pain scales that include vital signs) be used alone
discriminant validity (101, 102, 104, 107, 109, 110), and
for pain assessment in adult ICU patients (–2C). We sug-
criterion validity (103–105, 109, 110), in medical, postop-
gest that vital signs may be used as a cue to begin further
erative, and trauma ICU patients. A CPOT score of greater
assessment of pain in these patients, however (+2C).
than 2 had a sensitivity of 86% and a specificity of 78%
Rationale: Observational studies with major limitations
for predicting significant pain in postoperative ICU adults
provide inconsistent evidence of the validity of vital signs
exposed to a nociceptive procedure (111, 112). Investiga-
for the purpose of pain assessment in medical, postop-
tors suggested a similar cutoff score for the BPS (> 5), on
erative, and trauma ICU patients. Even if there is a trend
the basis of descriptive statistics in nonverbal ICU adults
for vital signs to increase when critically ill patients are
during nociceptive procedures compared with patients at
exposed to painful procedures, these increases are not reli-
rest (62). The CPOT and BPS can be successfully imple-
able predictors of pain (66, 101, 105, 107, 110). Vital signs
mented in the ICU following short, standardized train-
have been reported to increase both during nociceptive
ing sessions (2, 85). Their regular use can lead to better
and nonnociceptive procedures (109) or to remain stable
pain management and improved clinical outcomes in ICU
during nociceptive exposure (99). Vital signs do not cor-
patients (2, 3, 85). The BPS-NI is derived from the BPS
relate with either patients' self-report of pain (105, 110)
Critical Care Medicine
www.ccmjournal.org
or behavioral pain scores (101, 107). But because vital
compared to IV opioid use alone (90, 91). A lack of direct
signs may change with pain, distress, or other factors,
comparisons between opioids and nonopioids hinders
they can be a cue to perform further pain assessments in
conclusions regarding the effect of nonopioid analgesics,
these patients (118).
particularly in ICU patients.
3. Treatment of Pain
Question: What mode of analgesic delivery (i.e., either
a. Question: Should procedure-related pain be treated pre-
neuraxial or parenteral) is recommended for pain relief
emptively in adult ICU patients? (actionable)
in critically ill adults who have undergone either thoracic
Answer: We recommend that preemptive analgesia and/
or abdominal surgery or who have traumatic rib frac-
or nonpharmacologic interventions (e.g., relaxation) be
tures (including both mechanically ventilated and non-
administered to alleviate pain in adult ICU patients prior
mechanically ventilated ICU patients)? (actionable)
to chest tube removal (+1C). We suggest that for other
Answer: We recommend that thoracic epidural anesthe-
types of invasive and potentially painful procedures in
sia/analgesia be considered for postoperative analgesia in
adult ICU patients, preemptive analgesic therapy and/or
patients undergoing abdominal aortic surgery (+1B). We
nonpharmacologic interventions may also be adminis-
provide no recommendation for using a lumbar epidural
tered to alleviate pain (+2C).
over parenteral opioids for postoperative analgesia in
Rationale: Our strong recommendation is that patients
patients undergoing abdominal aortic aneurysm surgery,
undergoing chest tube removal should be preemptively
due to a lack of benefit when these routes of administra-
treated for pain, both pharmacologically and non-
tion are compared in this patient population (0,A). We
pharmacologically. Significantly lower pain scores were
provide no recommendation for the use of thoracic epi-
reported by patients if they received IV morphine plus
dural analgesia in patients undergoing either intrathoracic
relaxation (119), topical valdecoxib (120), IV sufentanil,
or nonvascular abdominal surgical procedures, because
or fentanyl (121) prior to chest tube removal. Accord-
of insufficient and conflicting evidence for this mode of
ing to these studies, the desirable consequences outweigh
analgesic delivery in these patients (0,B). We suggest that
undesirable effects. One can reasonably assume that
thoracic epidural analgesia be considered for patients with
most ICU patients would want their pain preemptively
traumatic rib fractures (+2B). We provide no recommen-
treated with nonpharmacologic and/or pharmacologic
dation for neuraxial/regional analgesia over systemic anal-
interventions prior to other painful procedures as well.
gesia in medical ICU patients, due to lack of evidence in
Question: What types of medications should be adminis-
this patient population (0, No Evidence).
tered for pain relief in adult ICU patients? (actionable)
Rationale: High-quality evidence suggests that thoracic epi-
Answer: We recommend that IV opioids be considered as
dural anesthesia/analgesia in patients undergoing abdomi-
the first-line drug class of choice to treat non-neuropathic
nal aortic surgery when the epidural catheter is placed
pain in critically ill patients (+1C). All available IV opi-
preoperatively provides superior pain relief to parenteral
oids, when titrated to similar pain intensity endpoints, are
opioids alone; rare complications of thoracic epidurals in
equally effective (C). We recommend that either enterally
these patients include postoperative heart failure, infections,
administered gabapentin or carbamazepine, in addition
and respiratory failure (138, 139). High-quality evidence
to IV opioids, be considered for the treatment of neuro-
demonstrates no benefit with lumbar epidural compared
pathic pain (+1A). We suggest that nonopioid analgesics
with parenteral opioids in these patients (139–141). Several
be considered to decrease the amount of opioids adminis-
shortcomings in research design make it difficult to rec-
tered (or to eliminate the need for IV opioids altogether)
ommend the use of thoracic epidural analgesia in patients
and to decrease opioid-related side effects (+2C).
undergoing either intrathoracic or nonvascular abdominal
Rationale: For non-neuropathic pain, evidence supports
surgical procedures (142–149). Epidural analgesia adminis-
using an opiate-based regimen to decrease pain intensity
tered to patients with rib fractures improved pain control,
(87, 90, 91, 122–136). Apart from drug cost and resource
especially during coughing or deep breathing, lowered the
utilization, all opioids administered IV appear to exhibit
incidence of pneumonia, but increased the risk of hypo-
similar analgesic efficacy and are associated with similar
tension (150, 151). No evidence supports using neuraxial/
clinical outcomes (e.g., duration of mechanical ventila-
regional analgesia in medical ICU patients.
tion, LOS) when titrated to similar pain intensity end-points. For non-neuropathic pain, nonopioids such as
Agitation and Sedation
IV acetaminophen (87), oral, IV, or rectal cyclooxygen-
Indications for Sedation. Agitation and anxiety occur fre-
ase inhibitors (122, 123, 135), or IV ketamine (132, 137)
quently in critically ill patients and are associated with adverse
can be used in addition to opioids. Using nonopioids
clinical outcomes (152–156). Sedatives are commonly adminis-
may also decrease the overall quantity of opioids admin-
tered to ICU patients to treat agitation and its negative conse-
istered and the incidence and severity of opioid-related
quences (157). Prompt identification and treatment of possible
side effects. In patients with neuropathic pain, IV opi-
underlying causes of agitation, such as pain, delirium, hypox-
oid use plus oral gabapentin or carbamazepine provides
emia, hypoglycemia, hypotension, or withdrawal from alcohol
superior pain relief in mechanically ventilated patients
and other drugs, are important. Efforts to reduce anxiety and
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January 2013 • Volume 41 • Number 1
TABLE 5. Psychometric Scores for Pain Scales
Critical
Assessment
Care Pain
Nonverbal
Behavioral
Psychometric Criteria
Observation
Assessment Intervention
Item selection description
Content validation
Limitations presented
Internal consistency
Inter-rater reliability
Inter-rater reliability tested
with nonresearch team
Intra-rater reliability tested if
inter-rater reliability is low or
Total number of participants
Criterion validation: correlation
with "gold standard"
Criterion validation: sensitivity
Criterion validation: specificity
Discriminant validation
Directives of use
Relevance of scale in practice
Total score (range: 0–25)
Weighted scoreb (range: 0–20)
I = 9.2/Rev = 8.7
Quality of psychometric evi-
dence (based on weighted
BPS = Behavioral Pain Scale; I = initial; Rev = revised; N/A = not applicable; M = moderate; L = low; VL = very low.
aNonverbal pain scale has two versions: I and Rev.
bWeighted score range (0–20): Very good psychometric properties(Very good): 15–20; Good psychometric properties (M): 12–14.9; Some acceptable psycho-
metric properties, but remain to be replicated in other studies (L): 10–11.9; Very few psychometric properties reported, or unacceptable results (VL): < 10.
agitation, including maintenance of patient comfort, provision
tilation, ICU and hospital LOS, and decreased incidences of
of adequate analgesia, frequent reorientation, and optimization
delirium and long-term cognitive dysfunction (7–10, 12, 13, 18,
of the environment to maintain normal sleep patterns, should
19, 159–162).
be attempted before administering sedatives.
Clinical Pharmacology of Sedatives. Historically, benzodiaz-
Sedatives can be titrated to maintain either light (i.e., patient
epines (i.e., midazolam and lorazepam) and propofol have com-
is arousable and able to purposefully follow simple com-
monly been used to sedate ICU patients. The 2002 guidelines
mands) or deep sedation (i.e., patient is unresponsive to pain-ful stimuli). Multiple studies have demonstrated the negative
recommended midazolam only for short-term sedation, loraz-
consequences of prolonged, deep sedation, and the benefits of
epam for long-term sedation, and propofol for patients requiring
maintaining lighter sedation levels in adult ICU patients (10,
intermittent awakenings (1). Recent surveys assessing sedation
14, 15, 20, 158). The use of sedation scales, sedation protocols
practices demonstrate that midazolam and propofol remain the
designed to minimize sedative use, and the use of nonbenzodi-
dominant medications used for ICU sedation, with decreasing
azepine medications are associated with improved ICU patient
lorazepam use, and rare use of barbiturates, diazepam, and ket-
outcomes, including a shortened duration of mechanical ven-
amine in the ICU (62, 163–166). Dexmedetomidine, approved
Critical Care Medicine
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TABLE 6. Clinical Pharmacology of Sedative Medications (1)
Loading Elimination
Maintenance
Dose (IV)
Dosing (IV)
Respiratory depression,
Respiratory depression,
kg q2–6 hr prn or
hypotension; propylene
0.01–0.1 mg/kg/
glycol-related acidosis,
0.03–0.1 mg/kg Respiratory depression,
hypotension, phlebitise
5–50 μg/kg/min Pain on injectionf,
respiratory depression,
hypertriglyceridemia,
pancreatitis, allergic
reactions, propofol-
related infusion
sedation with propofol
is associated with
significantly longer
emergence times than
with light sedation
0.2–0.7 μg/kg/hrd Bradycardia, hypotension;
hypertension with
loading dose; loss of
aActive metabolites prolong sedation, especially in patients with renal failure.
bAdminister IV loading dose of propofol only in those patients in whom hypotension is unlikely to occur.
cAvoid IV loading doses of dexmedetomidine in hemodynamically unstable patients.
dDexmedetomidine maintenance infusion rate may be increased to 1.5 µg/kg/h as tolerated.
ePhlebitis occurs when diazepam is injected into peripheral veins.
fPain at the injection site occurs commonly when propofol is administered through peripheral veins.
in the United States shortly before completion of the 2002 guide-
vascular instability (172). Tolerance to benzodiazepines develops
lines, is now more commonly administered for ICU sedation with long-term administration.
(166–168). The clinical pharmacology of sedatives prescribed for
All benzodiazepines are metabolized by the liver. Benzodiaz-
ICU patients is summarized in Table 6.
epine clearance is reduced in patients with hepatic dysfunction
Benzodiazepines. Benzodiazepines activate γ-aminobutyric
and other disease states, in elderly patients, and when admin-
acid A (GABA ) neuronal receptors in the brain. They have anx-
istered with other medications that inhibit cytochrome P
iolytic, amnestic, sedating, hypnotic, and anticonvulsant effects,
enzyme systems and/or glucuronide conjugation in the liver
but no analgesic activity (169, 170). Their amnestic effects extend
(173–175). The elimination half-life and duration of clinical
beyond their sedative effects (171). Lorazepam is more potent than
effect of lorazepam are also increased in patients with renal fail-
midazolam, which is more potent than diazepam. Midazolam and
ure (176, 177). The active metabolites of midazolam and diaze-
diazepam are more lipid soluble than lorazepam, resulting in a
pam may accumulate with prolonged administration, especially
quicker onset of sedation and a larger volume of distribution than
in patients with renal dysfunction (178). Benzodiazepine clear-
for lorazepam. Elderly patients are significantly more sensitive to
ance decreases with age (175, 179, 180).
the sedative effects of benzodiazepines (171). Benzodiazepines can
Delayed emergence from sedation with benzodiazepines
cause respiratory depression and systemic hypotension, especially
can result from prolonged administration of benzodiazepines
when administered in conjunction with other cardiopulmonary
(due to saturation of peripheral tissues), advanced age, hepatic
depressants, particularly opioids (172). Benzodiazepine-induced
dysfunction, or renal insufficiency (171, 175, 181). Because of the
cardiopulmonary instability is more likely to occur in critically
greater potency and slower clearance of lorazepam, emergence
ill patients with baseline respiratory insufficiency and/or cardio-
from short-term sedation (1–2 days) with lorazepam may be
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January 2013 • Volume 41 • Number 1
longer than with midazolam. However, comparative studies on
requirements, and arrhythmias. Acute kidney injury, hyperka-
the prolonged use of these drugs in ICU patients suggest greater
lemia, rhabdomyolysis, and liver dysfunction have also occa-
variability and longer time to awakening with midazolam than
sionally been reported with PRIS (205, 206). Possible PRIS
with lorazepam (171, 175, 182–184). Diazepam has a prolonged
mechanisms include mitochondrial dysfunction, impaired
duration of action due to saturation of peripheral tissues and
fatty acid oxidation, diversion of carbohydrate metabolism to
active metabolites that can accumulate in patients with renal
fat substrates, and propofol metabolite accumulation (207).
PRIS is usually associated with prolonged administration of
Parenteral formulations of lorazepam contain propylene high propofol doses (> 70 µg/kg/min), but it may also occur
glycol as a diluent, which can cause toxicity in ICU patients
with low-dose infusions (208, 209). The incidence of PRIS
(186–190). Propylene glycol toxicity manifests as metabolic aci-
with propofol infusions is approximately 1% (210). Mortality
dosis and acute kidney injury. Because these conditions occur
from PRIS is high (up to 33%) and may occur even after dis-
frequently in critically ill patients, their possible association
continuing the infusion (202). The variable presentation, lack
with lorazepam administration may be overlooked. Although
of diagnostic specificity, and infrequent occurrence of PRIS
initially thought to accumulate only in patients receiving very
make detection of this potentially life-threatening condition
high lorazepam doses via continuous infusion (i.e., 15–25 mg/
difficult. Early recognition and discontinuation of propofol in
hr), current evidence suggests that total daily IV doses as low as
patients with suspected PRIS are critically important. Manage-
1 mg/kg can cause propylene glycol toxicity (191). The serum
ment of patients with PRIS is otherwise supportive.
osmol gap has been used as a reliable screening and surveil-
Dexmedetomidine. Dexmedetomidine is a selective α -
lance tool; an osmol gap greater than 10–12 mOsm/L may help
receptor agonist with sedative, analgesic/opioid sparing, and
identify patients receiving lorazepam who have significant pro-
sympatholytic properties, but with no anticonvulsant properties
pylene glycol accumulation (187, 191).
(211, 212). Dexmedetomidine produces a pattern of sedation
Propofol. Propofol is an IV sedative that binds to multiple that differs considerably from other sedative agents. Patients
receptors in the central nervous system to interrupt neural trans-
sedated with dexmedetomidine are more easily arousable and
mission, including GABA , glycine, nicotinic, and M muscarinic
interactive, with minimal respiratory depression (213, 214).
receptors (192–194). Propofol has sedative, hypnotic, anxiolytic,
The onset of sedation occurs within 15 mins and peak sedation
amnestic, antiemetic, and anticonvulsant properties, but no anal-
occurs within 1 hr of starting an IV infusion of dexmedetomi-
gesic effects (195, 196). In ICU patients, propofol's amnestic effects
dine (167, 215). Sedation onset may be hastened by adminis-
at light sedation levels are less than that of benzodiazepines (197).
tering an initial IV loading dose of dexmedetomidine, but this
Propofol is highly lipid soluble and quickly crosses the blood-brain
is more likely to cause hemodynamic instability in critically
barrier, resulting in the rapid onset of sedation. Because of its high
ill patients (216). Dexmedetomidine is rapidly redistributed
lipid solubility, propofol also rapidly redistributes into peripheral
into peripheral tissues and is metabolized by the liver (217). In
tissues. This rapid redistribution, combined with high hepatic and
patients with normal liver function, the elimination half-life is
extrahepatic clearance, results in a rapid offset of effect following
approximately 3 hrs (215). Patients with severe hepatic dysfunc-
short-term propofol administration. Because of its short duration
tion have impaired dexmedetomidine clearance, can experience
of sedative effect, propofol may be useful in patients requiring fre-
prolonged emergence, and may require lower dexmedetomi-
quent awakenings for neurologic assessments and it may facilitate
dine doses (218). Although dexmedetomidine has only been
daily sedation interruption protocols (183, 198, 199). However,
approved in the United States for short-term sedation of ICU
long-term propofol administration can lead to the saturation of
patients (< 24 hrs) at a maximal dose of 0.7 µg/kg/hr (up to 1.0
peripheral tissues and prolonged emergence (198).
µg/kg/h for procedural sedation), several studies demonstrate
Propofol causes dose-dependent respiratory depression and
the safety and efficacy of dexmedetomidine infusions adminis-
hypotension due to systemic vasodilation. These effects may be
tered for greater than 24 hrs (up to 28 days) and at higher doses
more pronounced when propofol is administered with other
(up to 1.5 µg/kg/hr) (216, 219–222).
sedative and opioid medications. Cardiopulmonary instabil-
The most common side effects of dexmedetomidine are
ity with propofol administration is more likely to occur in
hypotension and bradycardia (223). IV loading doses can
patients with baseline respiratory insufficiency and/or cardio-
cause either hypotension or hypertension (215, 224). Because
vascular instability. Other side effects include hypertriglyceri-
dexmedetomidine does not significantly affect respiratory
demia, acute pancreatitis, and myoclonus (200–204). Propofol
drive, it is the only sedative approved in the United States for
is dissolved in a 10% lipid emulsion containing egg lecithin
administration in nonintubated ICU patients, and infusions
and soybean oil, which can precipitate allergic reactions in
can be continued as needed following extubation (225–227).
patients with either egg or soybean allergies. Some generic for-
However, dexmedetomidine can cause a loss of oropharyngeal
mulations of propofol contain sulfite preservatives, which may
muscle tone which can lead to airway obstruction in
also cause allergic reactions (196).
nonintubated patients, so continuous respiratory monitoring
Propofol administration is rarely associated with developing
for both hypoventilation and hypoxemia in these patients is
propofol infusion syndrome (PRIS). The signs and symptoms
indicated (225). Dexmedetomidine's opioid-sparing effect may
of PRIS vary but may include worsening metabolic acidosis,
reduce opioid requirements in critically ill patients (219, 220,
hypertriglyceridemia, hypotension with increasing vasopressor
224, 228). The mechanism of action for the analgesic properties
Critical Care Medicine
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TABLE 7. Psychometric Scores for Sedation Scales
Observer's Assessment
Sedation
Motor Activity Adaptation to the
Minnesota
Vancouver
Richmond
of Alertness/Sedation
Sedation
New Sheffield
Intensive
Assessment
Intensive Care
Sedation
Interaction and Agitation
Psychometric Criteria Scored
Care Score
Assessment Tool Calmness Scale
Item selection description
Content validation
Limitations presented
Interrater reliability
Interrater reliability tested with
Interrater reliability tested if interrater
reliability is low or inconsistent
Total number of participants
Criterion validation
Discriminant validation
Directives of use
Relevance of scale in practice
Total score (range: 0–18)
Weighted scorea (range: 0–20)
Quality of psychometric evidence
(based on weighted scores)
N/A = not applicable; VL = very low; L = low; M = moderate; VG = very good.
aWeighted score range (0–20): Very good psychometric properties (VG): 15–20; Good psychometric properties (M): 12–14.9; Some acceptable psychometric
properties, but remain to be replicated in other studies (L): 10–11.9; Very few psychometric properties reported, or unacceptable results (VL): < 10.
of dexmedetomidine remains controversial (229). Although α-2
including duration of mechanical ventilation, ICU LOS, mea-
receptors are located in the dorsal region of the spinal cord and in
sures of physiologic stress, and assessments of post-ICU psy-
supraspinal sites, dexmedetomidine's nonspinal analgesic effects
chological stress (10, 14, 15, 20, 158, 231–238). Five studies
have been documented (230). One recent study suggests that ICU
demonstrated that deeper sedation levels are associated with
patients receiving dexmedetomidine may have a lower prevalence
longer durations of mechanical ventilation and ICU LOS
of delirium than patients sedated with midazolam (220).
(10, 14, 15, 20, 158). Three studies demonstrated evidence of
Agitation and Sedation: Questions, Statements, and Rec-
increased physiologic stress in terms of elevated catecholamine
concentrations and/or increased oxygen consumption at lighter sedation levels (232, 235, 236), whereas one study did not (233).
1. Depth of Sedation and Clinical Outcomes
The clinical significance of this is unclear, because no clear rela-
Question: Should adult ICU patients be maintained at a
light level of sedation? (actionable)
tionship was observed between elevated markers of physiologic
Answer: Maintaining light levels of sedation in adult ICU
stress and clinical outcomes, such as myocardial ischemia, in
patients is associated with improved clinical outcomes (e.g.,
these patients (232–234).
shorter duration of mechanical ventilation and a shorter ICU
Four studies examined the relationship between depth of seda-
LOS) (B). Maintaining light levels of sedation increases the phys-
tion and post-ICU psychological stress (20, 231, 237, 238). One
iologic stress response, but is not associated with an increased
showed that a protocol of daily sedation interruption did not
incidence of myocardial ischemia (B). The association between
cause adverse psychological outcomes (231), whereas another
depth of sedation and psychological stress in these patients
found a low incidence of such events in patients who were
remains unclear (C). We recommend that sedative medications
lightly sedated (20). A third study showed that deeper sedation
be titrated to maintain a light rather than deep level of sedation
levels were associated with a lower incidence of recall, but that
in adult ICU patients, unless clinically contraindicated (+1B).
delusional memories did not correlate with lighter levels of
Rationale: Thirteen studies examined the direct relationship
sedation (238). However, in the fourth study, periods of wake-
between sedative depth and clinical outcomes in ICU patients,
fulness were associated with recall of stressful ICU memories
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January 2013 • Volume 41 • Number 1
TABLE 7. Psychometric Scores for Sedation Scales
TABLE 7 (Continued).
Observer's Assessment
Sedation
Motor Activity Adaptation to the
Minnesota
Vancouver
Richmond
of Alertness/Sedation
Sedation
New Sheffield
Intensive
Assessment
Intensive Care
Sedation
Interaction and Agitation
Psychometric Criteria Scored
Care Score
Assessment Tool Calmness Scale
Item selection description
Content validation
Limitations presented
Interrater reliability
Interrater reliability tested with
Interrater reliability tested if interrater
reliability is low or inconsistent
Total number of participants
Criterion validation
Discriminant validation
Directives of use
Relevance of scale in practice
Total score (range: 0–18)
Weighted scorea (range: 0–20)
Quality of psychometric evidence
(based on weighted scores)
N/A = not applicable; VL = very low; L = low; M = moderate; VG = very good.
aWeighted score range (0–20): Very good psychometric properties (VG): 15–20; Good psychometric properties (M): 12–14.9; Some acceptable psychometric
properties, but remain to be replicated in other studies (L): 10–11.9; Very few psychometric properties reported, or unacceptable results (VL): < 10.
(237). The overall quality of evidence evaluating the relation-
evaluating the depth and quality of sedation in adult ICU
ship between depth of ICU sedation and post-ICU psychologi-
patients: 1) Observer's Assessment of Alertness/Seda-
cal stress is low, and these study results are conflicting. Thus,
tion Scale (OAA/S); 2) Ramsay Sedation Scale (Ramsay);
the overall benefits of maintaining a light sedation level in ICU
3) New Sheffield Sedation Scale (Sheffield); 4) Sedation
patients appear to outweigh the risks.
Intensive Care Score (SEDIC); 5) Motor Activity Assess-
2. Monitoring Depth of Sedation and Brain Function
ment Scale (MAAS); 6) Adaptation to the Intensive Care
a. Sedation scales
Environment (ATICE); 7) Minnesota Sedation Assess-
Question: Which subjective sedation scales are the most
ment Tool (MSAT); 8) Vancouver Interaction and Calm-
valid and reliable in the assessment of depth and qual-
ness Scale (VICS); 9) SAS; and 10) RASS. We reviewed
ity of sedation in mechanically ventilated adult ICU
27 studies including 2,805 patients (2, 239–264): 26 were
patients? (descriptive)
observational studies and one used a blinded and ran-
Answer: The Richmond Agitation-Sedation Scale
domized format to evaluate videos of previously scored
(RASS) and Sedation-Agitation Scale (SAS) are the
patient sedation levels (253). Table 7 summarizes the psy-
most valid and reliable sedation assessment tools for
chometric scores for all ten sedation scales.
measuring quality and depth of sedation in adult ICU
The RASS and SAS yielded the highest psychomet-
patients (B).
ric scores (i.e., inter-rater reliability, convergent or dis-
Rationale: Several subjective sedation scales exist for
criminant validation) and had a robust number of study
monitoring depth of sedation and agitation in adult
participants. Both scales demonstrated a high degree of
ICU patients, and their psychometric properties are well
inter-rater reliability, which included ICU clinicians
described. But the cumulative degree of psychometric
(240, 262, 263). Both scales were able to discriminate
properties tested and the quality of evidence vary widely
different sedation levels in various clinical situations
among scales. We reviewed the psychometric proper-
(246, 250, 258, 261). Moderate to high correlations were
ties of ten subjective sedation scales, each developed for
found between the sedation scores of these scales and
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either electroencephalogram (EEG) or bispectral index
seizures, or to titrate electrosuppressive medication
(BIS) values (244, 246, 258). In addition, the RASS con-
to achieve burst suppression in adult ICU patients
sistently provided a consensus target for goal-directed
with elevated intracranial pressure (+1A).
delivery of sedative agents, demonstrating feasibility of
Rationale: We reviewed 18 studies comparing
its usage (2, 246, 254).
objective monitors of sedation to sedation scoring
We found that the ATICE, MSAT, and VICS had
systems in adult ICU patients (244, 248, 258, 265–
good quality of psychometric evidence, but some psy-
279). Objective monitors included both raw and
chometric properties (e.g., convergent or discrimi-
processed EEG and AEP monitors. Processed EEG
nant validation) have not been tested (242, 243, 249,
monitors (i.e., conversion of a raw EEG signal to an
259, 260). The MAAS, SEDIC, Sheffield, Ramsay, and
index by an algorithm) included the Bispectral Index
OAA/S scales had a lower quality of evidence; replica-
(BIS) and Bispectral Index XP (BIS-XP SE), NI, and
tion studies and psychometric testing of reliability and
the PSI. The overall evidence is conflicting. Fifteen
validity for determining the depth and quality of seda-
studies of moderate quality found that objective
tion in ICU patients are needed (239, 241, 242, 245,
sedation monitors based on either AEP or processed
247–249, 251–253, 255, 261, 262, 264).
EEG signals, including BIS, NI, SE, and PSI, may be
In summary, our comparative assessment of the psy-
useful adjuncts to subjective sedation assessments in
chometric properties of sedation scales revealed RASS
critically ill patients (244, 248, 258, 266, 267, 271–
and SAS to be the most valid and reliable for use in
273, 276, 278–283). However, most of these studies
critically ill patients, whereas ATICE, MSAT, and VICS
reported that electromyographic signals negatively
are moderately valid and reliable. Additional testing of
affected the correlation between the objective measure
the remaining scales is needed to better assess their reli-
in question and sedation scores. Five additional
ability and validity in determining depth of sedation in
studies of moderate quality found no benefit in using
critically ill patients.
objective monitors over subjective scoring systems
b. Neurologic monitoring
to assess depth of sedation (268–270, 277, 284). In
Question: Should objective measures of brain func-
most studies, objective monitors distinguished only
tion (e.g., auditory evoked potentials [AEPs], bispec-
between deep and light levels of sedation, but their
tral index [BIS], Narcotrend Index [NI], Patient
values correlated poorly with specific sedation scores
State Index [PSI], or state entropy [SE]) be used to
and were negatively influenced by electromyographic
assess depth of sedation in noncomatose, adult ICU
signal artifact. Several studies demonstrated that
patients who are not receiving neuromuscular block-
continuous EEG monitoring is useful for detecting
ing agents? (actionable)
nonconvulsive seizure activity in ICU patients either
Answer: We do not recommend that objective mea-
with known seizure activity or who are at risk for
sures of brain function (e.g., AEPs, BIS, NI, PSI,
seizures (e.g., traumatic brain injury, intracerebral
or SE) be used as the primary method to monitor
hemorrhage, cerebral vascular accidents, patients
depth of sedation in noncomatose, nonparalyzed
with an unexplained depressed level of consciousness)
critically ill adult patients, as these monitors are
(275, 281). Continuous EEG monitoring may also be
inadequate substitutes for subjective sedation scor-
useful in titrating electrosuppressive medications to
ing systems (–1B).
achieve burst suppression in critically ill patients with
ii. Question: Should objective measures of brain function
increased intracranial pressure (275, 281).
(e.g., AEPs, BIS, NI, PSI, or SE) be used to measure
3. Choice of Sedative
depth of sedation in adult ICU patients who are receiv-
Question: Should nonbenzodiazepine-based seda-
ing neuromuscular blocking agents? (actionable)
tion, instead of sedation with benzodiazepines, be
Answer: We suggest that objective measures of brain
used in mechanically ventilated adult ICU patients?
function (e.g., AEPs, BIS, NI, PSI, or SE) be used as
an adjunct to subjective sedation assessments in
Answer: We suggest that sedation strategies using
adult ICU patients who are receiving neuromuscular
nonbenzodiazepine sedatives (either propofol or dex-
blocking agents, as subjective sedation assessments
medetomidine) may be preferred over sedation with
may be unobtainable in these patients (+2B).
benzodiazepines (either midazolam or lorazepam) to
iii. Question: Should EEG monitoring be used to detect
improve clinical outcomes in mechanically ventilated
nonconvulsive seizure activity and to titrate electro-
adult ICU patients (+2B).
suppressive medication to obtain burst suppression
Rationale: In general, the choice of sedative agent
in adult ICU patients with either known or suspected
used in ICU patients should be driven by: 1) specific
seizures? (actionable)
indications and sedation goals for each patient; 2)
Answer: We recommend that EEG monitoring be
the clinical pharmacology of the drug in a particular
used to monitor nonconvulsive seizure activity in
patient, including its onset and offset of effect and its
adult ICU patients with either known or suspected
side effect profile; and 3) the overall costs associated
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January 2013 • Volume 41 • Number 1
with using a particular sedative. Outcomes studies
We reviewed 13 studies of 1,551 ICU patients comparing
of the effects of sedative agents in ICU patients typi-
clinical outcomes in patients sedated with either benzodiazepines
cally compare a benzodiazepine (either midazolam or
(midazolam or lorazepam) or nonbenzodiazepines (propofol or
lorazepam) to a nonbenzodiazepine (either propofol
dexmedetomidine) and found no consistent differences in ICU
or dexmedetomidine) for sedation. At the time of our
LOS (183, 197, 220, 222, 285, 286, 292–298). However, our meta-
literature review, only two low-quality studies had
analysis of six trials ranked as moderate to high quality suggested
been published comparing clinical outcomes in ICU
that sedation with benzodiazepines may increase ICU LOS by ap-
patients receiving propofol vs. dexmedetomidine proximately 0.5 days compared with nonbenzodiazepine sedation
for sedation (285, 286). No studies have compared
(p = 0.04) (Fig. 1) (183, 197, 220, 222, 292, 295–297). Limited data
clinical outcomes in ICU patients sedated with either ketamine or other sedative agents. Several studies we
suggested that mechanical ventilation is prolonged with benzodiaz-
reviewed suggested that the sustained use of benzo-
epine-based sedation (183, 220, 292, 298). There was no apparent
diazepine-based sedative regimens is associated with
difference in mortality with benzodiazepine vs. nonbenzodiazepine
adverse clinical outcomes, such as prolonged depen-
sedation (220, 222, 285, 295). Six trials evaluated the influence of
dence on mechanical ventilation, increased ICU benzodiazepine-based sedation on the cost of ICU care (194, 222, LOS, and the development of delirium (29, 183, 220,
286, 294, 299, 300); only one study found that benzodiazepine-
286–293). These findings had not been consistently
based sedation (i.e., midazolam infusion) was associated with high-
reported, however (197, 222, 285, 294–297).
er ICU costs than sedation with dexmedetomidine (300).
Figure 1. ICU length of stay meta-analysis of high and moderate-quality studies comparing benzodiazepine to nonbenzodiazepine sedation. CI = confidence
interval; IQR = interquartile range. L/D = lorazepam vs. dexmedetomidine; L/P = lorazepam vs. propofol; M/P = midazolam vs. propofol; M/D = midazolam vs.
dexmedetomidine; SD = standard deviation.
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When we compared outcome studies in ICU patients sedated
were seen. These results are consistent with both our analysis
with propofol vs. either midazolam or lorazepam, we found sev-
of previously published data and subsequent recommendation
eral studies demonstrating that propofol use may be associated
for benzodiazepine-based vs. nonbenzodiazepine-based
with a shorter duration of mechanical ventilation, but this effect
varied across patient populations (183, 197, 291, 292, 294–297),
In summary, the current literature supports modest dif-
and did not necessarily translate into a shorter ICU LOS. There
ferences in outcomes with benzodiazepine-based vs. nonben-
was no apparent difference in the incidence of self-extubation
zodiazepine-based sedation. Our meta-analysis of moderate
with propofol vs. benzodiazepine sedation (183). A separate sys-
to high-quality trials indicates that benzodiazepine sedation
tematic review evaluated 16 randomized, controlled trials com-
is associated with an increased ICU LOS. Moderate to high-
paring clinical outcomes in ICU patients receiving either propo-
quality data favor using propofol over lorazepam (183) and
fol or another sedative agent (291). When this meta-analysis was
dexmedetomidine over midazolam (220) to limit the duration
restricted to a comparison of propofol and midazolam, there
of mechanical ventilation. The clinical significance of the com-
was no difference in mortality, a slight reduction in the dura-
parative deliriogenic effects of benzodiazepines remains uncer-
tion of mechanical ventilation with propofol, but no difference
tain, with one high-quality trial indicating benzodiazepines
in ICU LOS. The relationship between using either propofol or
pose higher risks than dexmedetomidine (220). Additional
benzodiazepines for sedation and the development of delirium
recommendations to prevent or treat delirium can be found
is unclear. Only two relevant studies have been published com-
in the Delirium section of these guidelines. Dexmedetomidine
paring the incidence of delirium in ICU patients receiving pro-
may offer an advantage in ICU resource consumption com-
pofol vs. benzodiazepines for sedation (285, 286). In both stud-
pared to midazolam infusions in health care institutions that
ies, patients were randomized to receive propofol, midazolam,
are efficient in transferring patients out of the ICU (300).
or dexmedetomidine for sedation, and the incidence of delirium
Despite the apparent advantages in using either propofol or
was similar in patients receiving either propofol or midazolam,
dexmedetomidine over benzodiazepines for ICU sedation,
but the quality of evidence was low.
benzodiazepines remain important for managing agitation
We reviewed five studies comparing outcomes in ICU patients
in ICU patients, especially for treating anxiety, seizures, and
receiving either dexmedetomidine or a benzodiazepine (either
alcohol or benzodiazepine withdrawal. Benzodiazepines are
midazolam or lorazepam) for sedation (220, 222, 285, 286, 293).
also important when deep sedation, amnesia, or combination
Three of the four studies evaluating duration of mechanical venti-
therapy to reduce the use of other sedative agents is required
lation showed no difference between these groups (222, 285, 286).
However, the largest study did demonstrate a significant reduc-tion in the time to liberation from mechanical ventilation with
dexmedetomidine (3.7 days) compared with midazolam (5.6 Epidemiology of Delirium in ICU Patients. Delirium is a syn-
days) (220). Dexmedetomidine was not associated with a lower
drome characterized by the acute onset of cerebral dysfunction
incidence of self-extubation compared with benzodiazepines with a change or fluctuation in baseline mental status, inat-(222). Four of the five studies showed no difference in ICU LOS
tention, and either disorganized thinking or an altered level of
(220, 222, 285, 286). Five studies, including a subgroup analysis
consciousness (303–309). The cardinal features of delirium are:
from the Maximizing Efficacy of Targeted Sedation and Reduc-
1) a disturbed level of consciousness (i.e., a reduced clarity of
ing Neurological Dysfunction trial, evaluated the development
awareness of the environment), with a reduced ability to focus,
of delirium in patients receiving either dexmedetomidine or a
sustain, or shift attention; and 2) either a change in cognition
benzodiazepine for sedation (220, 222, 285, 286, 298). Delirium
(i.e., memory deficit, disorientation, language disturbance),
was reported in terms of frequency of occurrence, prevalence,
or the development of a perceptual disturbance (i.e., halluci-
and delirium-free days. Three studies favored dexmedetomidine
nations, delusions) (310). A common misconception is that
(286, 288, 300), although only one was of high quality (220). The
delirious patients are either hallucinating or delusional, but
subgroup analysis trial favored dexmedetomidine over lorazepam
neither of these symptoms is required to make the diagnosis.
in septic patients only (298). One trial showed no relationship
Other symptoms commonly associated with delirium include
between benzodiazepine use and delirium (222). One very low-
sleep disturbances, abnormal psychomotor activity, and emo-
quality trial suggested a higher rate of delirium with dexmedeto-
tional disturbances (i.e., fear, anxiety, anger, depression, apathy,
midine, but suffered from serious methodological flaws including
euphoria). Patients with delirium may be agitated (hyperactive
imprecision in the measurement of delirium (285).
delirium), calm or lethargic (hypoactive delirium), or may fluc-
The results of two high-quality, randomized, double-blind,
tuate between the two subtypes. Hyperactive delirium is more
comparative trials of dexmedetomidine vs. either midazolam
often associated with hallucinations and delusions, while hypo-
or propofol for ICU sedation were published after the active delirium is more often characterized by confusion and guideline task force had completed its voting and developed
sedation, and is often misdiagnosed in ICU patients.
its recommendations (301). The relevant outcomes in both
Delirium in critically ill patients is now recognized as a
studies included duration of mechanical ventilation, and ICU
major public health problem, affecting up to 80% of mechani-
and hospital LOS. Except for a longer duration of mechanical
cally ventilated adult ICU patients, and costing $4 to $16 bil-
ventilation with midazolam use, no differences between groups
lion annually in the United States alone (311–314). Over the
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January 2013 • Volume 41 • Number 1
past decade, the study of delirium in ICU patients has expand-
Delirium due to Drug and/or Alcohol Withdrawal. During
ed significantly (315–319). But the underlying pathophysiol-
their ICU stay, critically ill patients may develop a subcategory
ogy of delirium in critically ill patients remains poorly under-
of delirium related to either drug or alcohol withdrawal, which
stood (320–322).
usually manifests as a hyperactive type of delirium. Withdrawal
Impact of Delirium on ICU Patient Outcomes. Delirium, as
symptoms may result from abrupt discontinuation of: 1) illicit
a manifestation of acute brain dysfunction, is an important inde-
or prescription drugs that patients were taking chronically; 2)
pendent predictor of negative clinical outcomes in ICU patients,
sedatives or opioids administered as part of routine ICU care; or
including increased mortality, hospital LOS, cost of care, and
3) chronic ethanol use. An exhaustive review of the pathophysi-
long-term cognitive impairment consistent with a dementia-like
ology, diagnosis, and treatment of drug and alcohol withdrawal
state (313, 320–324). ICU team practices affect the incidence of
is beyond the scope of these guidelines. Clinicians are referred
delirium and its consequences (220, 222, 325–329). Critical care
to other clinical practice guidelines for more detail (341–343).
professionals strive to understand which aspects of delirium are
Patients with long-term exposure to high-dose opiates or
predictable, preventable, detectable, and treatable.
sedatives may develop physiologic dependence, and abrupt discontinuation may cause drug withdrawal symptoms (344).
Preventing, Detecting, and Treating Delirium in ICU Signs and symptoms of acute opiate withdrawal include sweat-
Patients. Delirium may be a disease-induced syndrome (e.g.,
ing, piloerection, mydriasis, lacrimation, rhinorrhea, vomit-
organ dysfunction in severe sepsis), for which timely manage-
ing, diarrhea, abdominal cramping, tachycardia, hypertension,
ment of the cause or causes is essential in order to reduce the
fever, tachypnea, yawning, restlessness, irritability, myalgias,
incidence, severity, and duration of delirium. Iatrogenic (e.g.,
increased sensitivity to pain, and anxiety. The onset of symp-
exposure to sedative and opioid medications) or environmental
toms can occur < 12 hrs following discontinuation of opioids,
(e.g., prolonged physical restraints or immobilization) factors
or be precipitated by either the administration of the opioid
may also contribute to delirium in ICU patients. ICU patients
antagonist, naloxone, or mixed agonist/antagonists such as
should be evaluated for identifiable and avoidable risk factors,
nalbuphine (345, 346). Prolonged benzodiazepine use in ICU
and therapeutic interventions should be assessed in terms of
patients may lead to withdrawal symptoms when the drug is
their likelihood of either causing or exacerbating delirium in
abruptly discontinued, manifesting as anxiety, agitation, trem-
individual patients. Delirium prevention strategies can be cat-
ors, headaches, sweating, insomnia, nausea, vomiting, myoclo-
egorized as nonpharmacologic (e.g., early mobilization), phar-
nus, muscle cramps, hyperactive delirium, and occasionally sei-
macologic, and combined pharmacologic/nonpharmacologic
zures (344). Reversing the sedative effects of benzodiazepines
approaches. Monitoring critically ill patients for delirium with
following long-term exposure with the benzodiazepine recep-
valid and reliable delirium assessment tools enables clinicians
tor antagonist flumazenil may induce symptoms of benzodi-
to potentially detect and treat delirium sooner, and possibly
azepine withdrawal (347, 348). Adult ICU patients receiving
improve outcomes.
dexmedetomidine infusions for up to 7 days have developed
Patients are frequently given various medications to reduce
withdrawal symptoms, most commonly nausea, vomiting, and
the severity and duration of delirium once it has occurred.
agitation, within 24–48 hrs of discontinuing dexmedetomidine
Although no double-blind, randomized, placebo-controlled (349). In the largest study to date looking prospectively at the
trials which are adequately powered have established the effi-
effects of sedation of ICU patients with dexmedetomidine vs.
cacy or safety of any antipsychotic agent in the management
midazolam, the incidence of withdrawal following discontinu-
of delirium in ICU patients, administration of antipsychotic
ation of dexmedetomidine was 4.9% vs. 8.2% in midazolam-
medications is endorsed by various international guidelines
treated patients (p = 0.25) (220). Signs and symptoms of opi-
(330–339), and most critical care specialists use these medi-
oid and sedative withdrawal in critically ill patients may be
cations to treat delirious patients (164). In the previous ver-
overlooked or attributed to other causes, such as alcohol or
sion of these guidelines, the recommended use of haloperidol
illicit drug withdrawal.
for the treatment of delirium was a Level C recommendation
In the past decade, little was published on the pathophysiology
based only on a case series. These data did not meet the evi-
and incidence of drug withdrawal from opioids and sedative
dence standard for this version of the guidelines. No recent
agents administered to adult ICU patients. Most studies are
prospective trials have verified the safety and efficacy of halo-
retrospective and include patients who have received a variety
peridol for the treatment of delirium in adult ICU patients.
of sedative and analgesic agents, making it difficult to determine
Data on the use of other antipsychotics in this patient popula-
specific incidences and risk factors for drug withdrawal in these
tion are similarly sparse. A recent Cochrane Review on using
patients (344, 350). One small prospective study assessed adult
antipsychotics for the treatment of delirium did not address
ICU patients for signs and symptoms of withdrawal following
the issue of antipsychotic use in ICU patients (340). Robust
discontinuation of sufentanil infusions used concurrently with
data on haloperidol in non-ICU patients that could potentially
either midazolam or propofol infusions (351). Patients in the
be applied to the ICU patient population are lacking. Further
sufentanil/midazolam group were sedated for 7.7 days vs. 3.5
research is needed to determine the safety and efficacy of using
days for the sufentanil/propofol group. Withdrawal symptoms
antipsychotics in general, including haloperidol, to treat delir-
occurred more frequently in the midazolam group (35% vs.
ium in ICU patients.
28% with propofol). Although specific recommendations
Critical Care Medicine
www.ccmjournal.org
are lacking for the prophylaxis or treatment of opioid or
ICU discharge (n = 5), hospital discharge (n = 4), 30 days
sedative withdrawal in ICU patients, opioids and/or sedatives
(n = 1), 3 months (n = 1), 6 months (n = 3), and 12 months
administered for prolonged periods (i.e., days) should be
(n = 1) (318, 319, 321, 322, 359–365). All studies classified
weaned over several days in order to reduce the risk of drug
delirium as present on one or more ICU days; three studies
also examined the relationship between delirium duration
Ethanol (ETOH) dependence is present in 15%–20% of all
and mortality (320, 321, 366). Delirium was an indepen-
hospitalized patients (352). Between 8% and 31% of hospital-
dent predictor of mortality in 11 of 15 studies, including
ized patients with ETOH dependence, especially surgical and
the three studies with a high quality of evidence (320, 321,
trauma patients, will go on to develop Alcohol Withdrawal
366). Duration of delirium (after adjusting for coma and in
Syndrome (AWS) during their hospital stay, with signs and
some cases psychoactive medication exposure) was signifi-
symptoms of neurologic and autonomic dysfunction (353–
cantly associated with 6- and 12-month mortality rates. In
355). Symptoms of AWS range from mild to life-threatening
two cohort studies, duration of delirium consistently por-
(356). Up to 15% of hospitalized patients with AWS experi-
tended a 10% increased risk of death per day (after adjust-
ence generalized tonic-clonic seizures, and 5% develop delir-
ing for covariates and appropriately treating delirium as a
ium tremens (DTs), a life-threatening combination of central
time-dependent covariate) (320, 321).
nervous system excitation (agitation, delirium, and seizures)
Nine prospective cohort studies examined the relation-
and hyperadrenergic symptoms (hypertension, tachycardia,
ship between one or more days of delirium in the ICU and
arrhythmias) (357). ICU patients with severe AWS may exhibit
ICU and/or hospital LOS, as well as duration of mechani-
prolonged ventilator dependence and extended ICU stays as a
cal ventilation (318, 319, 322, 323, 360, 361, 363, 364,
result of persistent delirium (353–355).
367). Delirium was an independent predictor of duration
Prior ethanol dependence is often underestimated in ICU
of mechanical ventilation in four studies (360, 363, 364,
patients, making identification of patients at risk for AWS or
367) and of ICU LOS in four studies (318, 319, 364, 367).
DTs difficult. Screening tools for AWS or DTs have not been
Both of these outcome variables are particularly at risk for
fully validated in the critical care setting. Differentiating
immortal time bias, which is introduced when the expo-
between delirium due to alcohol withdrawal vs. other causes
sure to a treatment or independent variable (in this case,
may be difficult. Symptom-oriented treatment of AWS symp-
delirium) can change daily during the actual outcome
toms with drug dosing as needed to specifically target agita-
measurement (in this case, either duration of mechanical
tion, psychosis, and autonomic hyperactivity decreases the
ventilation or ICU LOS) (368). It is therefore important
severity and duration of AWS, and medication requirements
that the predictive relationship between delirium and hos-
in ICU patients (358). Benzodiazepines are considered the
pital LOS was also strong in seven of nine studies (318, 319,
mainstay of alcohol withdrawal treatment, despite uncertainty
322, 323, 361, 364, 367), including three high-quality stud-
about their effectiveness and safety (320). To date, no pub-
ies that accounted for immortal time bias (318, 322, 368).
lished studies have compared the safety and efficacy of treating
Two prospective cohort studies examined the relationship
symptoms of severe AWS with dexmedetomidine vs. benzodi-
between delirium in the ICU and subsequent cognitive
azepines. Diagnosis and management of delirium due to AWS
impairment. One study of moderate quality described an
in ICU patients remains challenging. It is beyond the scope of
association between the presence of delirium on one or
these guidelines to describe the validity of alcohol withdrawal
more ICU days and a higher incidence of cognitive dys-
measurement tools, of alcohol withdrawal prevention, or of its
function at hospital discharge (322). In a recent prospec-
treatment in the critical care setting.
tive cohort study of moderate quality, increasing duration
Delirium: Questions, Statements, and Recommendations.
of delirium in ICU patients was associated with signifi-cantly greater cognitive impairment in these patients at 3
1. Outcomes Associated With Delirium in ICU Patients
and 12 months (324).
Question: What outcomes are associated with delirium in
2. Detecting and Monitoring Delirium
adult ICU patients? (descriptive)
a. Question: Should ICU patients be monitored routinely
Answer: Delirium is associated with increased mortality
for delirium with an objective bedside delirium instru-
(A), prolonged ICU and hospital LOS (A), and develop-
ment? (actionable)
ment of post-ICU cognitive impairment in adult ICU
Answer: We recommend routine monitoring for delir-
patients (B).
ium in adult ICU patients (+1B).
Rationale: Numerous prospective cohort studies have
Rationale: Delirium is common in both mechanically
demonstrated that patients who develop delirium are at
ventilated (14, 220, 222, 308, 360, 369, 370) and
increased risk for adverse outcomes both in the ICU and
nonmechanically ventilated ICU patients (309, 359,
after discharge. This risk is independent of preexisting
371–379). ICU personnel often underestimate the
comorbidities, severity of illness, age, and other covari-
presence of delirium in patients because it frequently
ates that might be merely associative. Eleven prospective
presents as hypoactive rather than hyperactive
cohort studies examined the relationship between delir-
delirium (372, 380). Delirium can be detected in both
ium while in the ICU and mortality at various time points:
intubated and nonintubated ICU patients using valid
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January 2013 • Volume 41 • Number 1
TABLE 8. Psychometric Scores for Delirium Monitoring Tools
Delirium Monitoring Tools
Confusion
Intensive
Assessment
Care Delirium
Cognitive
Delirium
Delirium
Method for
Screening
Screening
Detection
Psychometric Criteria Scored
Item selection description
Content validation
Limitations presented
Interrater reliability
Interrater reliability tested with
Interrater reliability tested if interrater
reliability is low or inconsistent
Total number of participants
Criterion validation: sensitivity
Criterion validation: specificity
Predictive validation
Directives of use
Relevance of scale in practice
Total score (range: 0–19 or 21)
Weighted scorea (range: 0–20)
Quality of psychometric evidence (based
on weighted scores)
VG, very good; M = moderate; VL = very low; NA = not applicable.
aWeighted score range (0–20): Very good psychometric properties (VG): 15–20; Good psychometric properties (M): 12–14.9; Some acceptable psychometric
properties, but remain to be replicated in other studies (Low): 10–11.9; Very few psychometric properties reported, or unacceptable results (VL): < 10.
and reliable tools. In most studies, delirium detection
monitored, at least once per nursing shift, for the
was improved when caregivers used a valid and reliable
development of delirium using a valid and reliable
delirium assessment tool (367), also allowing them
delirium assessment tool.
to reassure frightened and disoriented patients (381).
b. Question: Which instruments available for delirium
Delirium monitoring rationale includes: 1) most
monitoring have the strongest evidence for validity and
informed patients at moderate to high risk want to
reliability in ventilated and nonventilated medical and
be monitored for delirium; 2) high-quality cohort
surgical ICU patients? (descriptive)
data relating delirium to critical outcomes shows high
Answer: The Confusion Assessment Method for the
delirium "miss rates" in the absence of monitoring;
ICU (CAM-ICU) and the Intensive Care Delirium
3) clinicians have successfully implemented ICU
Screening Checklist (ICDSC) are the most valid
delirium monitoring programs on a large-scale, using
and reliable delirium monitoring tools in adult ICU
assessment tools recommended in these guidelines;
patients (A).
and 4) policy makers can adopt delirium assessment
Rationale: Five delirium monitoring tools were evalu-
as part of routine, high-quality care in most ICUs (254,
ated for use in ICU patients: Cognitive Test for Delir-
372, 374, 382, 383). Based on moderate evidence, we
ium (CTD), CAM-ICU, Delirium Detection Score
issue a strong recommendation that ICU patients at
(DDS), ICDSC, and Nursing Delirium Screening Scale
moderate to high risk for delirium (e.g., patients: with
(Nu-DESC). Table 8 compares their psychometric
a baseline history of alcoholism, cognitive impairment,
properties. Both the CAM-ICU (308, 359, 371–374,
or hypertension; with severe sepsis or shock; on
384–387) and ICDSC (309, 371) demonstrate very
mechanical ventilation; or receiving parenteral
good psychometric properties (i.e., validity and reli-
sedative and opioid medications) should be routinely
ability), and are explicitly designed for use in ICU
Critical Care Medicine
www.ccmjournal.org
patients both on and off mechanical ventilation. Trans-
ing ICU culture (316). A more recent study of delirium
lated into over 20 languages, these tools are currently in
monitoring implementation (published after evidence
use worldwide (315). The CAM-ICU and ICDSC have
was graded for this topic), that included over 500 ICU
shown high inter-rater reliability when tested by ICU
patients (medical, surgical, and cardiac) and over 600
nurses and intensivists (308, 309, 373). They both dem-
ICU nurses over a 3-yr period, reinforces the conclusion
onstrated high sensitivity and specificity when tested
that routine delirium monitoring is feasible in clinical
against the American Psychiatric Association's criteria
practice (394).
for delirium (319, 359, 379). Predictive validation of
3. Delirium Risk Factors
the presence of delirium, as detected with the CAM-
a. Question: What baseline risk factors are associated with
ICU or ICDSC, was associated with clinical outcomes
the development of delirium in the ICU? (descriptive)
such as increased ICU and hospital LOS (318, 319, 322,
Answer: Four baseline risk factors are positively and
323, 360, 361, 363, 364, 367) and higher risk of mortal-
significantly associated with the development of
ity (318, 319, 321, 322, 359–365). Based on our review
delirium in the ICU: preexisting dementia; history of
of the literature, both the CAM-ICU and ICDSC are
hypertension and/or alcoholism; and a high severity
valid, reliable, and feasible tools to detect delirium in
of illness at admission (B).
ICU patients (254, 309). While the CTD (388–390)
Rationale: The following baseline risk factors have
and Nu-DESC (379) reached the minimum weighted
been reported as significant in two or more multivari-
psychometric score of 12 in our analysis, some psycho-
able analyses: preexisting dementia (329, 375, 396);
metric properties remain to be tested for these tools,
history of baseline hypertension (318, 397); alco-
including inter-rater reliability in a nonresearch setting
holism, defined as ingestion of two to three or more
and clinical feasibility. Further psychometric testing of
drinks daily (318, 396); and a high severity of illness at
the DDS (347) is needed in order to better assess its
admission (318, 328, 329, 398). Although age has been
overall validity, reliability, and feasibility as a delirium
identified as one of the most significant risk factors for
monitoring tool in critically ill patients.
delirium outside the ICU, only two studies reported it
Since completing our review and analysis of the
to be significant in ICU patients (328, 398), while four
literature in 2010 on delirium monitoring tools, sev-
studies reported it as insignificant (318, 375, 396, 399).
eral additional studies have been published analyzing
More research is needed to confirm the relationship
the sensitivity, specificity, and reliability of delirium
between age and the development of delirium in ICU
assessment tools in clinical practice (391–394). A meta-
analysis of five ICU delirium screening tools found that
b. Question: Is coma a risk factor for the development of
the CAM-ICU and ICDSC were the most sensitive and
delirium in the ICU? (descriptive)
specific tools for detecting delirium, consistent with
Answer: Coma is an independent risk factor for the
our recommendation (392). A separate meta-analysis
development of delirium in ICU patients. Establish-
of studies comparing the CAM-ICU to the ICDSC
ing a definitive relationship between various sub-
also found a high degree of sensitivity and specificity
types of coma (i.e., medication-related, structural,
for both tools (393). Additional studies are needed to
neurological, medical) and delirium in ICU patients
assess the performance of delirium monitoring tools in
will require further study (B).
routine clinical practice across different types of ICU
Rationale: Several reports have shown coma to be an
patients (391, 394).
independent risk factor for delirium in ICU patients
c. Question: Is implementation of routine delirium moni-
(318, 399). One st
udy further classified coma
toring feasible in clinical practice? (descriptive)
into three categories: medical coma (i.e., due to a pri-
Answer: Routine monitoring of delirium in adult ICU
mary neurological condition), sedative-induced coma,
patients is feasible in clinical practice (B).
and multifactorial coma (both medical and sedative-
Rationale: Moderate-quality evidence suggests that
induced coma) (318). In this study, sedative-induced
routine monitoring of delirium is feasible in clinical
coma and multifactorial coma were significantly asso-
practice. Numerous implementation studies including
ciated with the development of delirium, but medical
over 2,000 patients across multiple institutions showed
coma was not (318).
delirium monitoring compliance rates in excess of 90%.
c. Question: Which ICU treatment-related (acquired) risk
Practicing ICU nurses and physicians demonstrated
factors (i.e., opioids, benzodiazepines, propofol, and
high inter-rater reliability with trained experts using
dexmedetomidine) are associated with the develop-
several of the recommended delirium monitoring tools
ment of delirium in adult ICU patients? (descriptive)
(254, 372, 374, 382, 383). Although studies show that
Answer: Conflicting data surround the relationship
implementation of delirium monitoring is feasible in
between opioid use and the development of delirium
the ICU, lack of physician buy-in is a significant bar-
in adult ICU patients (B). Benzodiazepine use may be
rier (395). Successful strategies for overcoming this
a risk factor for the development of delirium in adult
hurdle requires a focus on human factors and chang-
ICU patients (B). There are insufficient data to deter-
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January 2013 • Volume 41 • Number 1
mine the relationship between propofol use and the
pharmacologic protocols have shown favorable results
development of delirium in adult ICU patients (C).
in non-ICU hospitalized patients (402), such multifac-
In mechanically ventilated adult ICU patients at risk
eted interventions have not been adequately studied in
for developing delirium, dexmedetomidine infusions
the ICU setting.
administered for sedation may be associated with a
b. Question: Should a pharmacologic delirium prevention
lower prevalence of delirium compared to benzodi-
protocol be used in the ICU to reduce the incidence or
azepine infusions administered (B).
duration of delirium? (actionable)
Rationale: Study designs including opioids varied
Answer: We provide no recommendation for using a
greatly. Some reported individual medications used
pharmacologic delirium prevention protocol in adult
(288, 328, 397, 398), while others provided only the
ICU patients, as no compelling data demonstrate that
medication class (363), and still others combined opi-
this reduces the incidence or duration of delirium in
oids with sedatives or other analgesics (318, 329, 396).
these patients (0, C).
Study results also varied considerably. Most studies
Rationale: One prospective, unblinded, randomized
reported either an increased risk of delirium with opi-
controlled trial assessed a nocturnal pharmacologic
oids or no association (288, 318, 328, 329, 363, 396–
regimen for maintaining sleep-wake cycles in hospital-
398). One study (400) found that opioids reduced the
ized patients following gastrointestinal surgery, with
risk of delirium in burn patients. Only one high-quality
questionable value and applicability to critical care
study explicitly addressed the association between pro-
practice (403). A more recent prospective, placebo-
pofol and delirium risk in ICU patients, and found no
controlled, blinded, randomized study did show benefit
significant relationship (328). Benzodiazepines were
to administering low doses of haloperidol prophylac-
included in several delirium risk factor studies. As with
tic to elderly surgical ICU patients in order to prevent
opioids, study designs varied greatly. Some moderate-
delirium (404). However, these patients were not very
quality studies reported a strong relationship between
ill, and most were not mechanically ventilated. More
benzodiazepine use and the development of delirium
study is needed to determine the safety and efficacy of
(288, 328), while others found no significant relation-
using a pharmacologic delirium prevention protocol in
ship (318, 363, 396–399). Two randomized controlled
ICU patients.
trials comparing sedation with benzodiazepines vs. c. Question: Should a combined nonpharmacologic and
dexmedetomidine reported a lower prevalence of
pharmacologic delirium prevention protocol be used in
delirium ( 20%) in patients randomized to receive
the ICU to reduce the incidence or duration of delir-
dexmedetomidine (220, 298). Although these data do
ium? (actionable)
not prove that benzodiazepines are causal or that dex-
Answer: We provide no recommendation for the use
medetomidine is protective, this literature suggests that benzodiazepines may be a risk factor for the develop-
of a combined nonpharmacologic and pharmacologic
ment of delirium in the ICU. Whether dexmedetomi-
delirium prevention protocol in adult ICU patients,
dine reduces the risk of ICU patients developing delir-
as this has not been shown to reduce the incidence of
ium is now under study.
delirium in these patients (0, C).
4. Prevention of Delirium
Rationale: One before/after study evaluated the impact
a. Question: Should a nonpharmacologic delirium proto-
of a multidisciplinary protocol for managing PAD in
col be used in the ICU to reduce the incidence or dura-
ICU patients. Patients managed with this protocol had
tion of delirium? (actionable)
a reduced incidence of subsyndromal delirium but not
Answer: We recommend performing early mobilization
delirium, improved pain control, and a 15% reduc-
of adult ICU patients whenever feasible to reduce the
tion in their total ICU costs (327, 405). Subsyndromal
incidence and duration of delirium (+1B).
delirium in ICU patients is defined as patients who
Rationale: Early mobilization was initially studied in
have less than four points on the ICDSC; patients with
the critical care setting as a nonpharmacologic inter-
subsyndromal delirium have worse clinical outcomes
vention aiming to improve functional outcomes. In the
than those without delirium (319). Further research
first multicenter randomized controlled trial of early
is needed to determine whether a combined nonphar-
mobility (326), and in a subsequent implementation
macologic and pharmacologic protocol reduces the
study (401), investigators also noted striking reductions
incidence or duration of full-blown delirium in ICU
in the incidence of delirium, depth of sedation, and
hospital and ICU LOS, with an increase in ventilator-
d. Question: Should haloperidol or atypical antipsychot-
free days. These studies suggest that early and aggres-
ics be used prophylactically to prevent delirium in ICU
sive mobilization is unlikely to harm ICU patients, but
patients? (actionable)
may reduce the incidence and duration of delirium,
Answer: We do not suggest that either haloperidol or
shorten ICU and hospital LOS, and lower hospital
atypical antipsychotics be administered to prevent
costs. While more broadly targeted, high-quality non-
delirium in adult ICU patients (–2C).
Critical Care Medicine
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Rationale: No high-quality studies with sufficient sam-
were allowed to receive IV haloperidol 1–10 mg every
ple size or effect size demonstrate a benefit of admin-
2 hrs as needed. The use of haloperidol was not sig-
istering prophylactic antipsychotics to the general ICU
nificantly different between the groups. Comparable
population. A recent moderate-quality trial demon-
data are not available for treatment with haloperidol
strated that low-dose IV haloperidol prophylaxis may
alone. Sufficiently powered, carefully designed, multi-
reduce the prevalence of delirium in low acuity elderly
center, placebo-controlled trials are needed to address
postoperative patients who are admitted to the ICU
the hypothesis that antipsychotics are beneficial in the
(404). Whether these data can be applied to a more
treatment of delirium in critically ill patients.
diverse population of sicker ICU patients is uncertain.
c. Question: Should treatment with cholinesterase inhibi-
A well-designed, but underpowered, multicenter, ran-
tors (rivastigmine) be used to reduce the duration of
domized controlled trial of delirium prophylaxis with
delirium in ICU patients? (actionable)
either haloperidol or ziprasidone vs. placebo did not
Answer: We do not recommend administering riv-
show any benefit with either treatment group as com-
astigmine to reduce the duration of delirium in ICU
pared to placebo (370). One moderate-quality study
patients (–1B).
suggested that a single dose of sublingual risperidone
Rationale: Rivastigmine, a cholinesterase inhibitor,
administered immediately postoperatively to cardiac
may be useful in treating delirium in demented elderly
surgery patients reduced the incidence of delirium
patients. However, rivastigmine was compared to pla-
(406). Further research is needed to better define the
cebo in critically ill patients in an investigation stopped
safety and efficacy of typical and atypical antipsychot-
for futility and potential harm (409) This multicenter
ics for delirium prevention in ICU patients.
trial was halted after 104 patients were enrolled because
e. Question: Should dexmedetomidine be used prophylac-
the rivastigmine-treated patients had more severe and
tically to prevent delirium in ICU patients? (actionable)
longer delirium, with a trend toward higher mortality.
Answer: We provide no recommendation for the use
In another study (published after the evidence analysis
of dexmedetomidine to prevent delirium in adult ICU
for this recommendation), perioperative rivastigmine
patients, as there is no evidence regarding its effective-
was administered for delirium prophylaxis in patients
ness in these patients (0, C).
undergoing elective cardiac surgery (n = 120, patients >
Rationale: One cardiovascular ICU study (n = 306)
65 yr), and had no effect on the incidence of postopera-
addressed the issue of dexmedetomidine and delirium
tive delirium in these patients (410).
prophylaxis in ICU patients (407). Delirium lasted 2
d. Question: Should haloperidol and atypical antipsychot-
days in the dexmedetomidine group compared with 5
ics be withheld in patients at high risk for torsades de
days in the morphine group (p = 0.03), but delirium
pointes? (actionable)
prevalence was not significantly reduced (9% vs. 15%,
Answer: We do not suggest using antipsychotics in
respectively, p = 0.09). Until more data become avail-
patients at significant risk for torsades de pointes (i.e.,
able, we provide no recommendation for delirium
patients with baseline prolongation of QT interval,
prophylaxis with dexmedetomidine, given the risks of
patients receiving concomitant medications known to
treatment without clear benefit.
prolong the QT interval, or patients with a history of
5. Treatment of Delirium
this arrhythmia) (–2C).
a. Question: Does treatment with haloperidol reduce the
Rationale: Torsades de pointes is a dangerous complica-
duration of delirium in adult ICU patients? (descriptive)
tion associated with antipsychotic administration. Orig-
Answer: There is no published evidence that treatment
inal case reports warned of this arrhythmia in patients
with haloperidol reduces the duration of delirium in
receiving IV haloperidol (411, 412) and its association
adult ICU patients (No Evidence).
with a prolonged QT interval (413, 414). Although tor-
b. Question: Does treatment with atypical antipsychotics
sades has also been described without QT prolongation
reduce the duration of delirium in adult ICU patients?
(415, 416). Torsades has also occurred in patients receiv-
ing atypical antipsychotics, such as ziprasidone (417)
Answer: Atypical antipsychotics may reduce the dura-
and risperidone (418), and recent reports have warned
tion of delirium in adult ICU patients (C).
of drug interactions that could heighten this risk (419).
Rationale: In a single small prospective, randomized,
Although the quality of evidence is low, the morbidity
double-blind, placebo-controlled study (n = 36), ICU
and mortality associated with this complication is high.
patients with delirium who received quetiapine had
e. Question: For mechanically ventilated, adult ICU
a reduced duration of delirium (408). Patients with
patients with delirium who require continuous IV
delirium who were being treated with haloperidol were
infusions of sedative medications, is dexmedetomidine
randomized to additionally receive either quetiapine
preferred over benzodiazepines to reduce the duration
50 mg or placebo every 12 hrs. The quetiapine dose
of delirium? (actionable)
was increased by 50 mg if more than one dose of halo-
Answer: We suggest that in adult ICU patients with
peridol was given in the previous 24 hrs. All patients
delirium unrelated to alcohol or benzodiazepine with-
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January 2013 • Volume 41 • Number 1
drawal, continuous IV infusions of dexmedetomidine
But this strategy leads to increased mortality, prolonged
rather than benzodiazepine infusions be administered
duration of ventilation and ICU LOS, and possibly long-term
for sedation in order to reduce the duration of delir-
neuropsychological dysfunction and functional decline of
ium in these patients (+2B).
patients (75, 238, 287, 318, 424–426). In spite of the published
Rationale: Two randomized controlled trials compar-
benefits of ICU sedation strategies that minimize the use of
ing sedation with benzodiazepines vs. dexmedetomi-
sedatives and depth of sedation in patients, adoption of these
dine reported a significant daily reduction ( 20%) sedation practices is not widespread.
in delirium prevalence in patients receiving dexme-
ICU protocols that combine routine pain and sedation
detomidine (220, 370, 420). These data are incon-
assessments, with pain management and sedation-minimiz-
clusive about whether benzodiazepines raised the ing strategies (i.e., daily sedative interruption or protocols risk of delirium, or dexmedetomidine reduced the that otherwise target light levels of sedation), along with risk, and further investigations are needed to address
delirium monitoring and prevention, may be the best strate-
this question. But data from these two clinical trials
gy for avoiding the complications of over sedation. Protocols
(which included a high percentage of patients at risk
can also facilitate communication between bedside nurses
for delirium), coupled with delirium risk factor data
and other members of the ICU team, helping them to define
from observational trials, suggest that benzodiazepines
appropriate pain and sedation management goals, and to
may be a risk factor for the development of delirium
assess the effectiveness of treatment strategies for each indi-
in the ICU. These findings led to this recommendation
vidual patient (3, 14, 62, 259, 427, 428). Although the impact
for using dexmedetomidine rather than benzodiaz-
of routine delirium monitoring on ICU outcomes has never
epines for sedation in ICU patients with delirium not
been rigorously evaluated, early recognition of delirium may
due either to benzodiazepine or ethanol withdrawal.
nevertheless facilitate patient reassurance, help to identify
There are insufficient data to make recommendations
reversible causative factors, and permit implementation of
regarding the risks and benefits of using other non-
effective delirium treatments. Early detection and treatment
benzodiazepine sedatives, such as propofol, to reduce
of delirium may in turn allow for a patient to be conscious,
the duration of delirium in ICU patients.
yet cooperative enough to potentially participate in ventila-tor weaning trials and early mobilization efforts. However,
Management of PAD to Improve ICU Outcomes
delirium can only be assessed in patients who are able to suf-
Use of Integrated PAD Protocols to Optimize ICU Patient
ficiently interact and communicate with bedside clinicians.
Care. Our ability to effectively manage PAD in critically ill
Optimal pain management and a light level of sedation are
patients enables us to develop potential management strat-
essential for this to occur.
egies that reduce costs, improve ICU outcomes, and allow
Defining Depth of Sedation. Although there are obvi-
patients to participate in their own care (9–13, 16–20). Yet
ous benefits to minimizing sedation in critically ill patients,
the application of these guideline recommendations poses
no clear consensus exists on how to define "light" vs. "deep"
significant challenges to critical care practitioners. A suc-
sedation. The overarching objectives for the management of
cessful strategy is to implement an evidence-based, insti-
pain, agitation, and delirium in ICU patients should be to
tutionally-specific, integrated PAD protocol, and to assess,
consistently focus on patient safety and comfort, while avoid-
treat and prevent PAD, using an interdisciplinary team ing short- and long-term complications associated with either approach. Protocols facilitate the transfer of evidence-
excessive or inadequate treatment. Traditionally, the goals of
based "best practices" to the bedside, limit practice varia-
ICU analgesia and sedation have been to facilitate mechanical
tion, and reduce treatment delays (2, 3). A protocolized
ventilation, to prevent patient and caregiver injury, and to avoid
approach can also significantly improve patient outcomes
the psychological and physiologic consequences of inadequate
and serve as a guide for quality assurance efforts (13, 327,
treatment of pain, anxiety, agitation, and delirium. Avoiding
complications of over-sedation, such as muscle atrophy and
In spite of these recognized advantages, widespread weakness, pneumonia, ventilator dependency, thromboembol-
adoption of integrated PAD protocols is lagging. Only 60% of
ic disease, nerve compression, pressure sores, and delirium, are
ICUs in the United States have implemented PAD protocols,
also important (11, 325, 326, 429). A more precise definition
and even when instituted, protocol adherence is low, which
of light vs. deep sedation is offered to guide the creation and
negatively impacts patient outcomes (163, 199). Despite implementation of sedation protocols that provide sufficient > 20 yr of emphasis on the importance of systematic pain
patient comfort without inducing coma.
assessment and management, data suggest that: 1) preemptive
Central to these guidelines are the principles that: 1) pain,
analgesia for painful procedures is used only 20% of the depth of sedation, and delirium should be frequently moni-time in ICU patients; 2) pain and discomfort remain leading
tored using valid and reliable assessment tools; 2) patients
sources of patient stress; and 3) at least 40% of ICU patients
should receive adequate and preemptive treatment for pain; 3)
still report experiencing moderate to severe pain (2, 60, 73,
patients should receive sedation only if required; and 4) that
423). Medication-induced coma has long been thought sedatives should be titrated to allow patient responsiveness and of as a "humane" therapeutic goal for many ICU patients.
awareness that is demonstrated by their ability to purposefully
Critical Care Medicine
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respond to commands (i.e., a combination of any three of the
investigating the efficacy and safety of this strategy in sur-
following actions upon request: open eyes, maintain eye con-
gical, trauma, neurologic, and neurosurgical patients are
tact, squeeze hand, stick out tongue, and wiggle toes) (15, 16,
needed. Protocolized management strategies (e.g., hourly
326). This degree of responsiveness and awareness goes beyond
titration) to avoid deep sedation are also associated with
patients being merely "sleepy but arousable" and is essential for
clinical benefit, but it remains unclear whether combin-
the evaluation of pain through patient self-report, for assessing
ing sedation protocolization with daily sedative interrup-
patients' readiness to wean and extubate, for performing delir-
tion would lead to additional benefits (16).
ium assessments, and for implementing early mobility efforts.
Question: Should analgesia-first sedation (i.e., analgose-
It remains unclear as to whether it's better to titrate sedation
dation) or sedative-hypnotic-based sedation be used in
to a goal that allows patients to be consistently awake, coop-
mechanically ventilated ICU patients? (actionable)
erative, and calm, or to provide deeper sedation with a daily
Answer: We suggest that analgesia-first sedation be used
awakening trial (16, 430). In the final analysis, both strategies
in mechanically ventilated adult ICU patients (+2B).
have been shown to reduce the incidence of deep sedation and
Rationale: Providing analgesia-first sedation for many
its associated risks (431).
ICU patients is supported by the high frequency of
Outcomes: Questions, Statements, and Recommendations.
pain and discomfort as primary causes of agitation and by reports implicating standard hypnotic-based
1. Sedation Strategies to Improve Clinical Outcomes
sedative regimens as having negative clinical and qual-
Question: Should a protocol that includes either daily
ity-of-life outcomes. Four unblinded studies includ-
sedative interruption or a light target level of sedation
ing 630 medical and surgical ICU patients examined
be used in mechanically ventilated adult ICU patients?
an analgesia-first approach (436–439). Data from one
moderate-quality study suggested that analgesia-first
Answer: We recommend either daily sedation interrup-
sedation is associated with longer ventilator-free time
tion or a light target level of sedation be routinely used
during a 28-day period, and shorter ICU LOS (439).
in mechanically ventilated adult ICU patients (+1B).
Otherwise, no consistent advantages of analgesia-first
Rationale: Five unblinded randomized controlled trials
sedation over sedative-hypnotic-based sedation were
involving 699 patients evaluated daily sedation interrup-
found. Optimal analgesia and sedation were achieved
tion (14–16, 432, 433). All but one (432) were restricted
during 97% of the time with either strategy (436, 438).
to medical ICU patients; a single pilot trial targeted light
One trial did not demonstrate any harm from the
sedation as the comparator (16). One low-quality trial
intervention on rates of self-extubation or VAP, but
suggested harm, but suffered from serious methodologi-
the incidence of agitated delirium was higher in the
cal issues (433). Data suggest daily sedation interruption
analgesia-first sedation group (439). Data on delirium,
reduces the time that patients spend on the ventilator (or
self-extubation, VAP, mortality, or cost of ICU care are
increases ventilator-free days in survivors) and ICU LOS.
insufficient to draw firm conclusions about the influ-
An alternative strategy using protocols to maintain
ence of this intervention.
light sedation (without daily sedation interruption) High-quality study data are scarce in support of was described in 11 unblinded studies involving 3,730
using one opiate over another in ICU patients receiv-
patients. The data suggest this approach reduces the
ing analgesia-first sedation (127, 134, 407). Clinicians
amount of time that patients spend on the ventilator (or
should rely on pharmacology, safety, and cost-effective-
increases ventilator-free days for survivors) (7–13, 18,
ness when making opioid treatment decisions (440).
19, 434). The effect of protocolization on ICU LOS was
Analgesics that are short-acting and easily titratable
inconsistent with little data suggesting any detrimental
may offer an advantage by facilitating frequent neuro-
effect (7–13, 17–19, 327, 434). Conflicting data in two
logic evaluations.
studies were likely related to the similarity of control
The benefits of analgesia-first approach must be
group sedation practices to those offered by the inter-
balanced by the potential for opiates to interfere with
vention (18, 19). Healthcare systems that employ bedside
respiratory drive, reduce gastric motility, and compli-
care models with 1:1 nurse-to-patient ratios or institu-
cate the provision of enteral nutrition (134, 441). Pos-
tions where sedation minimization is a goal may not
sible pain recurrence and withdrawal upon analgesic
benefit (435). Data are insufficient to draw firm conclu-
discontinuation should be anticipated (130). Further-
sions on the effect of either daily sedation interruption
more, 18% to 70% of patients treated with analgesia-
or protocolization to maintain a level of light sedation
first strategies will require supplementation with other
on ventilator-associated pneumonia (VAP), delirium
traditional sedative agents (436–439).
prevalence, patient comfort, or cost of ICU care.
Although data suggest potential additional benefits
In summary, daily sedation interruption is associated
with analgesia-first sedation, the ultimate role of this
with clinical benefit in medical ICU patients, but the ben-
strategy remains unclear because one moderate-quality
efits remain uncertain in those who are alcohol-depen-
study (439) required a 1:1 nurse-to-patient ratio and
dent or not admitted to a medical ICU service. Studies
the availability of patient "sitters," and no rigorous pub-
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January 2013 • Volume 41 • Number 1
lished studies have specifically compared analgesia-first
daytime light exposure may affect a hospitalized
sedation with conventional GABA-based sedation strate-
elderly patient's quality and consolidation of sleep at
gies. Preliminary data suggest that analgesia-first seda-
night (460). These findings must be validated in an
tion strategies do not have a negative impact on long-
ICU patient population. Further research is needed
term psychological function (442). These data should
to support the positive effects of using eye patches
be confirmed and expanded to explore the influence of
or ear plugs to limit the aversive effects of noise
analgesia-first sedation on outcomes such as delirium,
and light (461). High doses of sedative agents and
self-extubation, VAP, mortality, and cost of ICU care,
mechanical ventilation disrupt sleep patterns in crit-
and on long-term cognitive function. Although these
ically ill patients (459, 462). There is no evidence that
studies administered an opioid as the primary analgesic,
light levels of sedation promote sleep in the ICU.
future studies in critically ill patients should evaluate a
ii. Question: Should specific modes of mechanical ven-
multimodal analgesic approach using a combination of
tilation be used to promote sleep in ventilated ICU
opioids and nonopioid analgesics (52).
patients? (actionable)
c. Sleep promotion in ICU patients
Answer: We provide no recommendation for using spe-
i. Question: Should nonpharmacologic interventions
cific modes of mechanical ventilation to promote sleep
be used to promote sleep in adult ICU patients?
in adult ICU patients, as insufficient evidence exists for
the efficacy of these interventions (0, No evidence).
Answer: We recommend promoting sleep in adult
Rationale: Two small studies (n < 30) have demon-
ICU patients by optimizing patients' environments,
strated that modes of mechanical ventilation that
using strategies to control light and noise, clustering
reduce the risk of central apnea events may improve
patient care activities, and decreasing stimuli at night
the quality of sleep in adult ICU patients (463, 464).
to protect patients' sleep cycles (+1C).
Larger, well-designed prospective clinical trials are
Rationale: Sleep deprivation is detrimental in humans,
needed to validate these findings.
and sleep disruption is common in ICU patients (443,
2. Strategies to Facilitate Implementation of ICU Analgesia,
444). They have few complete sleep cycles, numerous
Seda tion, and Delirium Guidelines
awakenings due to environmental disruptions (noise,
Question: Should an interdisciplinary educational and
light, and physical stimulation), and infrequent rapid-
behavioral strategy be used to facilitate the implementa-
eye-movement sleep (443, 445–448). Sleep depri-
tion of sedation protocols and guidelines in adult ICUs?
vation impairs tissue repair and cellular immune
function, and may affect the healing response (449).
Answer: We recommend using an interdisciplinary ICU
In critically ill patients, sleep deprivation may con-
team approach that includes provider education, preprinted
tribute to the development of delirium (450–454) and
and/or computerized protocols and order forms, and qual-
increased levels of physiologic stress (455, 456).
ity ICU rounds checklists to facilitate the use of PAD man-
Sleep science in the ICU has not advanced in the past
agement guidelines or protocols in adult ICUs (+1B).
decade. Because few studies identify pharmacologic
Rationale: The bulk of data from 12 unblinded stud-
effects of sedatives on sleep in critically ill patients, we
ies involving 2,887 patients suggests that one or more
focused on nonpharmacologic interventions to pro-
interventions, along with the protocol implementation
mote sleep in the ICU. Two recently published studies
to provide patient comfort in the ICU, reduces the dura-
(n > 30, prospective cohort, before/after study design)
tion of mechanical ventilation (or increases ventilator-
demonstrated that implementing quiet time on both
free days for survivors (7–10, 12, 13, 18, 19, 159–162)).
day and night shifts and clustering patient care activi-
Interventions to implement protocols had inconsistent
ties reduce disturbances and promote both observed
impact on ICU LOS, with little data suggesting harm
and perceived sleep in adult ICU patients (457, 458).
within the 11 studies involving 2,707 patients (7–10,
Another descriptive study further confirmed that
12, 13, 18, 19, 159, 160, 162). There was no evidence
mechanically ventilated ICU patients do not have
for harm with this intervention when the incidence of
uninterrupted periods for sleep to occur (459). From
self-extubation was examined. Lastly, data were insuf-
these findings, we hypothesized that nurses should
ficient to support a recommendation based on the time
select time periods to promote sleep by avoiding rou-
patients spent within their defined sedation goal or on
tine ICU care activities (such as the daily bath), turn-
patient or nurse satisfaction. Data suggest that the pri-
ing down the lights, and reducing ambient noise dur-
mary benefit of using one or more interventions (e.g.,
ing these periods. In three studies suggesting scheduled
education, additional staff, electronic reminders) is
rest periods, the periods most likely to be uninter-
to limit time on mechanical ventilation, but the over-
rupted in the ICU were 2–4 AM (458), 12–5 AM (457), and
all benefit is uncertain. Low risk and minimal cost are
around 3 AM (459).
associated with implementing one or more strategies to
Another study, using indirect evidence from nurs-
improve the use of an integrated sedation protocol in
ing home patients, suggested that the amount of
Critical Care Medicine
www.ccmjournal.org
Tools for Facilitating the Application of the These
recommendations supported by clinical practice guidelines
Recommendations to Bedside Care
should be adapted to local practice patterns and resource
Closing the gap between the evidence highlighted in these
availability, and used as a template for institution-specific
guidelines and ICU practice will be a significant challenge
protocols and order sets. Successful implementation will
for ICU clinicians (465, 466) and is best accomplished us-
require augmentation with education, engagement of local
ing a multifaceted, interdisciplinary approach (4, 467). The
thought leaders, point-of-use reminders, and caregiver-spe-
Figure 2. A, Pocket card operationalizing the PAD guideline recommendations (front side). (Continued.)
www.ccmjournal.org
January 2013 • Volume 41 • Number 1
Figure 2 (Continued). B, Pocket card summarizing specific pain, agitation, and delirium (PAD) guideline statements and recommendations (back side).
BPS = Behavioral Pain Scale; CPOT = Critical-Care Pain Observation Tool; RASS = Richmond Agitation and Sedation Scale; SAS = Sedation-Agitation
Scale; EEG = electroencephalography; CAM-ICU = Confusion Assessment Method for the ICU; ICDSC = ICU Delirium Screening Checklist; ETOH =
ethanol; LOS = length of stay; HTN = hypertension.
cific practice feedback, together with continuous protocol
transfer and application (465, 466). To support this effort,
evaluation and modification (7–10, 12, 13, 18, 19, 159–162,
we have developed a pocket card summarizing these guide-
468). Incorporating electronically based guidelines into clin-
line recommendations (Fig. 2) and a template for a PAD care
ical decision-support tools may facilitate bedside knowledge
bundle (Fig. 3) (469).
Critical Care Medicine
www.ccmjournal.org
Figure 3. A, ICU pain, agitation, and delirium (PAD) care bundle (469). B, ICU PAD care bundle metrics; NRS = Numeric Rating Scale; BPS = Be-
havioral Pain Scale; CPOT = Critical-Care Pain Observation Tool; nonpharmacologic therapy = relaxation therapy, especially for chest tube removal; IV
= intravenous; AAA = abdominal aortic aneurysm; NMB = neuromuscular blockade; RASS = Richmond Agitation and Sedation Scale; SAS = sedation-
Agitation Scale; brain function monitoring = auditory evoked potentials (AEP), Bispectral Index (BIS), Narcotrend Index (NI), Patient State Index (PSI),
or State Entropy (SE); DSI = daily sedation interruption (also referred to as Spontaneous Awakening Trial [SAT]); ETOH = ethanol; nonbenzodiazepines,
propofol (use in intubated/mechanically ventilated patients), dexmedetomidine (use in either intubated or nonintubated patients); SBT = spontaneous
breathing trial; EEG = electroencephalography; ICP = intracranial pressure; CAM-ICU = Confusion Assessment Method for the ICU; ICDSC = ICU
Delirium Screening Checklist.
www.ccmjournal.org
January 2013 • Volume 41 • Number 1
Care bundles have facilitated translation of practice guide-
cal Center, Seattle, WA); and to Kathy Ward and Laura Kolinski
lines to the bedside to manage a number of complex ICU prob-
(Society of Critical Care Medicine, Mount Prospect, IL) for
lems, including VAP, catheter-associated bloodstream infec-
their technical assistance with these guidelines.
tions, and sepsis (470, 471). A care bundle includes elements most likely to improve patient outcomes. Elements should be:
easy to implement, beneficial, supported by sound scientific
1. Jacobi J, Fraser GL, Coursin DB, et al; Task Force of the American
and clinical reasoning, and relevant across patient populations
College of Critical Care Medicine (ACCM) of the Society of Critical
and healthcare systems (31). Adherence to each bundle element
Care Medicine (SCCM), American Society of Health-System Phar-
macists (ASHP), American College of Chest Physicians: Clinical
should be measurable and linked to one or more specific
practice guidelines for the sustained use of sedatives and analgesics
patient outcomes. Quality assurance data should facilitate care-
in the critically ill adult. Crit Care Med 2002; 30:119–141
giver feedback and allow rapid-cycle improvement to further
2. Chanques G, Jaber S, Barbotte E, et al: Impact of systematic evalu-
customize bundles. This PAD Care Bundle is based on system-
ation of pain and agitation in an intensive care unit. Crit Care Med
2006; 34:1691–1699
atically identifying and managing PAD in an integrated fashion,
3. Payen JF, Bosson JL, Chanques G, et al; DOLOREA Investigators:
and assessing the effectiveness of these strategies (Fig. 3).
Pain assessment is associated with decreased duration of mechani-
cal ventilation in the intensive care unit: A post Hoc analysis of the
DOLOREA study. Anesthesiology 2009; 111:1308–1316
4. Vasilevskis EE, Ely EW, Speroff T, et al: Reducing iatrogenic risks:
The goal of these guidelines is to define best practices for opti-
ICU-acquired delirium and weakness—Crossing the quality chasm.
Chest 2010; 138:1224–1233
mizing the management of PAD in adult ICU patients. These
5. Riker RR, Fraser GL: Altering intensive care sedation paradigms to
guidelines were developed by performing a rigorous, objective,
improve patient outcomes. Crit Care Clin 2009; 25:527–538, viii
transparent, and unbiased assessment of the relevant published
6. Arnold HM, Hollands JM, Skrupky LP, et al: Optimizing sustained use
evidence based on the GRADE methodology. Statements and
of sedation in mechanically ventilated patients: Focus on safety. Curr
Drug Saf 2010; 5:6–12
recommendations were developed by taking into consideration
7. Arabi Y, Haddad S, Hawes R, et al: Changing sedation practices in
not only the quality of the evidence but also important clinical
the intensive care unit—Protocol implementation, multifaceted mul-
outcomes and the values and preferences of ICU stakeholders.
tidisciplinary approach and teamwork. Middle East J Anesthesiol
We believe that these guidelines provide a practical roadmap
2007; 19:429–447
for developing evidence-based, best practice protocols for inte-
8. Arias-Rivera S, Sánchez-Sánchez Mdel M, Santos-Díaz R, et al: Effect
of a nursing-implemented sedation protocol on weaning outcome.
grating the management of PAD in critically ill patients.
Crit Care Med 2008; 36:2054–2060
9. Brattebø G, Hofoss D, Flaatten H, et al: Effect of a scoring system
and protocol for sedation on duration of patients' need for ven-
tilator support in a surgical intensive care unit. BMJ 2002; 324:
Special thanks to Charles P. Kishman, Jr, MSLS, Information
Services Librarian (University of Cincinnati, Cincinnati, OH),
10. Brook AD, Ahrens TS, Schaiff R, et al: Effect of a nursing-implemented
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Clinical Epidemiology and Biostatistics, Hamilton, Ontario,
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www.ccmjournal.org
January 2013 • Volume 41 • Number 1
Source: http://crh.arizona.edu/sites/default/files/u35/Pain,%20Agitation,%20Delirium.pdf
October 2007, Volume 16, No.1 Current Issues in Medical Management Varenicline: The Newest Pharmacotherapy for Smoking CessationAndrew L. Pipe, CM, MD, Robert Reid, PhD, MBA, Bonnie Quinlan, RN, BScN, APN Minto Prevention and Rehabilitation Centre, University of Ottawa Heart Institute, Ottawa, Ontario Smoking cessation is deemed to be the most powerful of all the is essential, in all professional settings, that systematic approaches to
Organic Anion Transporter 3 Contributes to theRegulation of Blood Pressure Volker Vallon,*†‡ Satish A. Eraly,* William R. Wikoff,§ Timo Rieg,*‡ Gregory Kaler,*David M. Truong,* Sun-Young Ahn,* Nitish R. Mahapatra,* Sushil K. Mahata,*‡Jon A. Gangoiti,储 Wei Wu,* Bruce A. Barshop,储 Gary Siuzdak,§ and Sanjay K. Nigam*储¶ Departments of *Medicine, †Pharmacology, 储Pediatrics, and ¶Cellular and Molecular Medicine, University ofCalifornia, San Diego, ‡Department of Medicine, San Diego VA Healthcare System, and §Department of MolecularBiology and the Center for Mass Spectrometry, Scripps Research Institute, La Jolla, California