Crh.arizona.edu


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: barrj@stanford.edu 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 www.ccmjournal.org 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 www.ccmjournal.org 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 www.ccmjournal.org 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 www.ccmjournal.org 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 www.ccmjournal.org 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 Critical Care Medicine www.ccmjournal.org 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 www.ccmjournal.org 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.
Critical Care Medicine www.ccmjournal.org 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 www.ccmjournal.org 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 www.ccmjournal.org 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- www.ccmjournal.org 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 www.ccmjournal.org 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- www.ccmjournal.org 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 www.ccmjournal.org 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- www.ccmjournal.org 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 for his invaluable contributions to these guidelines. Mr. Kish- sedation protocol on the duration of mechanical ventilation. Crit Care Med 1999; 27:2609–2615 man was instrumental in helping us to develop our search 11. De Jonghe B, Bastuji-Garin S, Fangio P, et al: Sedation algorithm in strategies, creating and maintaining the large Web-based critically ill patients without acute brain injury. Crit Care Med 2005; guidelines database, and for creating and managing the guide- lines bibliography. Additional thanks to Christopher D. Stave, 12. 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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

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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

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