John W. Devlin

Clinical Practice Guidelines for the Management of Pain, Agitation, and Delirium in Adult Patients in the Intensive Care Unit

Objective:To revise the “Clinical Practice Guidelines for the Sustained Use of Sedatives and Analgesics in the Critically Ill Adult” published in Critical Care Medicine in 2002. Methods:The American College of Critical Care Medicine assembled a 20-person, multidisciplinary, multi-institutional task force with expertise in guideline development, pain, agitation and sedation, delirium management, and associated outcomes in adult critically ill patients. The task force, divided into four subcommittees, collaborated over 6 yr in person, via teleconferences, and via electronic communication. Subcommittees were responsible for developing relevant clinical questions, using the Grading of Recommendations Assessment, Development and Evaluation method (http://www.gradeworkinggroup.org) to review, evaluate, and summarize the literature, and to develop clinical statements (descriptive) and recommendations (actionable). With the help of a professional librarian and Refworks® database software, they developed a Web-based electronic database of over 19,000 references extracted from eight clinical search engines, related to pain and analgesia, agitation and sedation, delirium, and related clinical outcomes in adult ICU patients. The group also used psychometric analyses to evaluate and compare pain, agitation/sedation, and delirium assessment tools. All task force members were allowed to review the literature supporting each statement and recommendation and provided feedback to the subcommittees. Group consensus was achieved for all statements and recommendations using the nominal group technique and the modified Delphi method, with anonymous voting by all task force members using E-Survey (http://www.esurvey.com). All voting was completed in December 2010. Relevant studies published after this date and prior to publication of these guidelines were referenced in the text. The quality of evidence for each statement and recommendation was ranked as high (A), moderate (B), or low/very low (C). The strength of recommendations was ranked as strong (1) or weak (2), and either in favor of (+) or against (–) an intervention. A strong recommendation (either for or against) indicated that the intervention’s desirable effects either clearly outweighed its undesirable effects (risks, burdens, and costs) or it did not. For all strong recommendations, the phrase “We recommend …” is used throughout. A weak recommendation, either for or against an intervention, indicated that the trade-off between desirable and undesirable effects was less clear. For all weak recommendations, the phrase “We suggest …” is used throughout. In the absence of sufficient evidence, or when group consensus could not be achieved, no recommendation (0) was made. Consensus based on expert opinion was not used as a substitute for a lack of evidence. A consistent method for addressing potential conflict of interest was followed if task force members were coauthors of related research. The development of this guideline was independent of any industry funding. Conclusion:These guidelines provide a roadmap for developing integrated, evidence-based, and patient-centered protocols for preventing and treating pain, agitation, and delirium in critically ill patients.

Motor Activity Assessment Scale: A valid and reliable sedation scale for use with mechanically ventilated patients in an adult surgical intensive care unit

OBJECTIVE To establish the validity and reliability of a new sedation scale, the Motor Activity Assessment Scale (MAAS). DESIGN Prospective, psychometric evaluation. SETTING Sixteen-bed surgical intensive care unit (SICU) of a 937-bed tertiary care, university-affiliated teaching hospital. PATIENTS Twenty-five randomly selected, adult, mechanically ventilated, nonneurosurgical patients who were admitted to the SICU > or = 12 hrs after surgery and were not receiving neuromuscular blockers. INTERVENTION Four hundred assessments (eight per patient) were completed consecutively but independently, in pairs, at standardized times (both day and night) by two nurses who were preselected for each assessment from a pool of 32 pretrained SICU nurses. MEASUREMENTS AND MAIN RESULTS To estimate validity, paired assessments (four/patient) compared the MAAS result with the subjective assessment using a 10-cm visual analog sedation scale, the percent change in blood pressure and heart rate from the previous 4-hr baselines, and the number of recent agitation-related sequelae. To estimate reliability, paired assessments (four/patient) measured correlation between assessments of the same type (e.g., MAAS-MAAS). Generalized estimating equations, which accounted for the four repeated measures in each patient, supported MAAS validity by finding a linear trend between MAAS and the visual analog scale (p < .001), blood pressure (p < .001), heart rate (p < .001), and agitation-related sequelae (p < .001) end points. The MAAS (kappa = 0.83 [95% confidence interval, 0.72 to 0.94]) was found to be more reliable than subjective assessment using the visual analog scale (intraclass correlation coefficient = 0.32 [95% confidence interval, 0.05 to 0.55]). CONCLUSIONS The MAAS is a valid and reliable sedation scale for use with mechanically ventilated patients in the SICU. Further studies are warranted regarding the effect of MAAS implementation in our SICU on patient outcomes, such as quality of sedation and length of mechanical ventilation, as well as the use of the MAAS in other patient populations (e.g., medical).

Perceived barriers to the use of sedation protocols and daily sedation interruption: a multidisciplinary survey.

BACKGROUND Although use of sedation protocols and daily sedation interruption (DSI) improve outcome, their current use and barriers affecting their use are unclear. METHODS We designed a multidisciplinary, Web-based survey to determine current use of sedation protocols and DSI and the perceived barriers to each, and administered it to members of the Society of Critical Care Medicine. RESULTS The 904 responders were physicians (60%), nurses (14%), or pharmacists (12%); 45% worked in a university hospital. Of 64% having a sedation protocol, 78% used it for >or=50% of ventilated patients. Reasons for lack of protocol use included no physician order (35%), lack of nursing support (11%), and a fear of oversedation (7%). Daily sedation interruption was used by only 40%. Barriers to DSI included lack of nursing acceptance (22%), concern about risk of patient-initiated device removal (19%), and inducement of either respiratory compromise (26%) or patient discomfort (13%). Clinicians who prefer propofol were more likely to use DSI than those who prefer benzodiazepines (55% vs 40, P < .0001). CONCLUSIONS Current intensive care unit sedation practices are heterogeneous, and the barriers preventing the use of both sedation protocols and DSI are numerous. These barriers should be addressed on an institutional basis to boost the use of these evidence-based practices.

A systematic review of risk factors for delirium in the ICU.

Objective:Although numerous risk factors for delirium in the ICU have been proposed, the strength of evidence supporting each risk factor remains unclear. This study systematically identifies risk factors for delirium in critically ill adults where current evidence is strongest. Data Sources:CINAHL, EMBASE, MEDLINE, the Cochrane Central Register for Controlled Trials, and the Cochrane Database of Systematic Reviews. Study Selection:Studies published from 2000 to February 2013 that evaluated critically ill adults, not undergoing cardiac surgery, for delirium, and used either multivariable analysis or randomization to evaluate variables as potential risk factors for delirium. Data Extraction:Data were abstracted in duplicate, and quality was scored using Scottish Intercollegiate Guidelines Network checklists (i.e., high, acceptable, and low). Using a best-evidence synthesis each variable was evaluated using 3 criteria: the number of studies investigating it, the quality of these studies, and whether the direction of association was consistent across the studies. Strengths of association were not summarized. Strength of evidence was defined as strong (consistent findings in ≥2 high quality studies), moderate (consistent findings in 1 high quality study and ≥1 acceptable quality studies), inconclusive (inconsistent findings or 1 high quality study or consistent findings in only acceptable quality/low quality studies) or no evidence available. Data Synthesis:Among 33 studies included, 70% were high quality. There was strong evidence that age, dementia, hypertension, pre-ICU emergency surgery or trauma, Acute Physiology and Chronic Health Evaluation II score, mechanical ventilation, metabolic acidosis, delirium on the prior day, and coma are risk factors for delirium, that gender is not associated with delirium, and that use of dexmedetomidine is associated with a lower delirium prevalence. There is moderate evidence that multiple organ failure is a risk factor for delirium. Conclusions:Only 11 putative risk factors for delirium are supported by either strong or moderate level of evidence. These factors should be considered when designing delirium prevention strategies or controlling for confounding in future etiologic studies.

Benzodiazepine versus nonbenzodiazepine-based sedation for mechanically ventilated, critically ill adults: a systematic review and meta-analysis of randomized trials.

Background:Use of dexmedetomidine or propofol rather than a benzodiazepine sedation strategy may improve ICU outcomes. We reviewed randomized trials comparing a benzodiazepine and nonbenzodiazepine regimen in mechanically ventilated adult ICU patients to determine if differences exist between these sedation strategies with respect to ICU length of stay, time on the ventilator, delirium prevalence, and short-term mortality. Methods:We searched CINAHL, MEDLINE, the Cochrane databases, and the American College of Critical Care Medicine’s Pain, Agitation, Delirium Management Guidelines’ literature database from 1996 to 2013. Citations were screened for randomized trials that enrolled critically ill, mechanically ventilated adults comparing an IV benzodiazepine-based to a nonbenzodiazepine-based sedative regimen and reported duration of ICU length of stay, duration of mechanical ventilation, delirium prevalence, and/or short-term mortality. Trial characteristics and results were abstracted in duplicate and independently, and the Cochrane risk of bias tool was used for quality assessment. We performed random effects model meta-analyses where possible. Results:We included six trials enrolling 1,235 patients: midazolam versus dexmedetomidine (n = 3), lorazepam versus dexmedetomidine (n = 1), midazolam versus propofol (n = 1), and lorazepam versus propofol (n = 1). Compared to a benzodiazepine sedative strategy, a nonbenzodiazepine sedative strategy was associated with a shorter ICU length of stay (n = 6 studies; difference = 1.62 d; 95% CI, 0.68–2.55; I2 = 0%; p = 0.0007) and duration of mechanical ventilation (n = 4 studies; difference = 1.9 d; 95% CI, 1.70–2.09; I2 = 0%; p < 0.00001) but a similar prevalence of delirium (n = 2; risk ratio = 0.83; 95% CI, 0.61–1.11; I2 = 84%; p = 0.19) and short-term mortality rate (n = 4; risk ratio = 0.98; 95% CI, 0.76–1.27; I2 = 30%; p = 0.88). Conclusions:Current controlled data suggest that use of a dexmedetomidine- or propofol-based sedation regimen rather than a benzodiazepine-based sedation regimen in critically ill adults may reduce ICU length of stay and duration of mechanical ventilation. Larger controlled studies are needed to further define the impact of nonbenzodiazepine sedative regimens on delirium and short-term mortality.

Clinical practice guidelines for the maintenance of patient physical safety in the intensive care unit: Use of restraining therapies— American College of Critical Care Medicine Task Force 2001-2002

ObjectiveTo develop clinical practice guidelines for the use of restraining therapies to maintain physical and psychological safety of adult and pediatric patients in the intensive care unit. ParticipantsA multidisciplinary, multispecialty task force of experts in critical care practice was convened from the membership of the American College of Critical Care Medicine (ACCM), the Society of Critical Care Medicine (SCCM), and the American Association of Critical Care Nurses (AACN). EvidenceThe task force members reviewed the published literature (MEDLINE articles, textbooks, etc.) and provided expert opinion from which consensus was derived. Relevant published articles were reviewed individually for validity using the Cochrane methodology (http://hiru.mcmaster.ca/cochrane/ or www.cochrane.org). Consensus ProcessThe task force met as a group and by teleconference to identify the pertinent literature and derive consensus recommendations. Consideration was given to both the weight of scientific information within the literature and expert opinion. Draft documents were composed by a task force steering committee and debated by the task force members until consensus was reached by nominal group process. The task force draft then was reviewed, assessed, and edited by the Board of Regents of the ACCM. After steering committee approval, the draft document was reviewed and approved by the SCCM Council. ConclusionsThe task force developed nine recommendations with regard to the use of physical restraints and pharmacologic therapies to maintain patient safety in the intensive care unit.

Incidence of propofol-related infusion syndrome in critically ill adults: a prospective, multicenter study

IntroductionWhile propofol is associated with an infusion syndrome (PRIS) that may cause death, the incidence of PRIS is unknown. Determining the incidence of PRIS and the frequency of PRIS-related clinical manifestations are key steps prior to the completion of any controlled studies investigating PRIS. This prospective, multicenter study sought to determine the incidence of PRIS and PRIS-related clinical manifestations in a large cohort of critically ill adults prescribed propofol.MethodsCritically ill adults from 11 academic medical centers administered an infusion of propofol for [>/=] 24 hours were monitored at baseline and then on a daily basis until propofol was discontinued for the presence of 11 different PRIS-associated clinical manifestations and risk factors derived from 83 published case reports of PRIS.ResultsAmong 1017 patients [medical (35%), neurosurgical (25%)], PRIS (defined as metabolic acidosis plus cardiac dysfunction and [>/=] 1 of: rhabdomyolysis, hypertriglyceridemia or renal failure occurring after the start of propofol therapy) developed in 11 (1.1%) patients an average of 3 (1-6) [median (range)] days after the start of propofol. While most (91%) of the patients who developed PRIS were receiving a vasopressor (80% initiated after the start of propofol therapy), few received a propofol dose >83 mcg/kg/min (18%) or died (18%). Compared to the 1006 patients who did not develop PRIS, the APACHE II score (25 +/- 6 vs 20 +/- 7, P = 0.01) was greater in patients with PRIS but both the duration of propofol use (P = 0.43) and ICU length of stay (P = 0.82) were similar.ConclusionsDespite using a conservative definition for PRIS, and only considering new-onset PRIS clinical manifestations, the incidence of PRIS slightly exceeds 1%. Future controlled studies focusing on evaluating whether propofol manifests the derangements of critical illness more frequently than other sedatives will need to be large. These studies should also investigate the mechanism(s) and risk factors for PRIS.

Predictors of mortality in patients with suspected propofol infusion syndrome

Objectives:To identify predictors of mortality in patients with suspected propofol infusion syndrome and to develop a simple scoring system to identify patients with suspected propofol infusion syndrome who are most at risk of death. Design:Retrospective, database analysis. Setting:MEDWATCH system. Participants:Reports (1989–2005) where propofol was associated with ≥1 of 24 published propofol infusion syndrome clinical manifestations. Interventions:None. Measurements and Main Results:After comparison of demographic and clinical manifestations between survivors and nonsurvivors, a multivariate logistic regression model was built through a stepwise selection process and then used to develop a simplified mortality scoring system. Of 1139 patients with suspected propofol infusion syndrome, 342 (30%) were fatal. Death was more likely if patients were ≤18 yrs (odds ratio [95% confidence interval], 2.3 [1.7–3.2]), male (1.3 [1.1–1.7]), received a vasopressor (1.8 [1.3–2.5)]), or had the following clinical manifestations: cardiac (3.8 [2.88–4.91]), metabolic acidosis (3.7 [2.7–5.0]), renal failure (1.9 [1.4–2.6]), hypotension (1.8 [1.3–2.3]), rhabdomyolysis (1.8 [1.3–2.3]), or dyslipidemia (2.0 [1.2–3.4]). The multivariable modeling process found that cardiac symptoms, rhabdomyolosis, hypotension, metabolic acidosis, renal failure, and age each affected survival, although significant interactions existed between some of these factors. Based on the combination of the presence or absence of the six factors in the multivariate model, a propofol infusion syndrome mortality risk score of 0 to 4 resulted in a predicted %/observed % mortality for each score of 0 (10%/10%), 1 (24%/24%), 2 (47%/44%), 3 (72%/81%), and 4 (89%/83%). Conclusions:A number of characteristics are independently associated with higher mortality in patients with suspected propofol infusion syndrome, only some of which are currently reflected in the package insert. Further research should focus on prospectively evaluating the mortality scoring system in patients with suspected propofol infusion syndrome.

N-acetylcysteine improves indocyanine green extraction and oxygen transport during hepatic dysfunction

OBJECTIVES To investigate whether the beneficial systemic hemodynamic effects of N-acetylcysteine, an agent that increases cyclic guanosine monophosphate (cGMP) concentration in fulminant hepatic failure, are present in a range of liver disorders and what concurrent effect this agent has on the hepatic-splanchnic circulation. SETTING Liver Failure Unit, Kings College Hospital, London, UK. PATIENTS Fifteen patients with hepatic dysfunction who were mechanically ventilated, either after liver transplantation or during an acute or decompensated chronic liver disorder. INTERVENTIONS Prostacyclin was administered at a continuous infusion rate of 5 ng/kg/min for 60 mins. After a washout period, the hemodynamic effects of this infusion were compared with the effects present during infusion of N-acetylcysteine at 150 mg/kg in 250 mL of 5% dextrose in water over 15 mins and then 50 mg/kg in 250 mL of 5% dextrose for 45 mins at an infusion rate of 62.5 mL/hr. MEASUREMENTS AND MAIN RESULTS Following N-acetylcysteine infusion, the baseline oxygen delivery (DO2) increased from 667 +/- 154 to 751 +/- 166 (SD) mL/min/m2, and oxygen consumption (VO2) improved in 13 of 15 patients (150 +/- 30 to 169 +/- 25 mL/min/m2) (p< .01). Indocyanine green clearance, as determined by a fiberoptic physiologic monitoring system, also improved in 13 of 15 patients (7.3 +/- 4.2% to 11.8 +/- 4.0% [mean change 100%, 95% confidence interval 9 to 256]) (p = .002). Patients who were defined as responders in relation to systemic hemodynamics (VO2 of >10% from baseline [n = 6; 40%]) had a significantly lower baseline consumption compared with that of nonresponders (133 vs. 162 mL/min/m2, p = .04). No clear relationship between the increments in VO2 and indocyanine green clearance was observed (r2 = .21; p = .08). Prostacyclin resulted in moderate improvements in systemic DO2 (but not VO2) and a nonsignificant increase in indocyanine green clearance. CONCLUSION N-acetylcysteine increases systemic VO2 in a proportion of patients with a wide variety of hepatic disorders. In addition, N-acetylcysteine elicits an improvement in indocyanine green clearance. These properties may be clinically useful in a range of critical illnesses where systemic or hepatic-splanchnic circulations are compromised.

Pharmacology of commonly used analgesics and sedatives in the ICU: benzodiazepines, propofol, and opioids.

Opioids, benzodiazepines, and propofol remain the mainstay by which to optimize patient comfort and facilitate mechanical ventilation in patients who are critically ill. Unfortunately none of these agents share all of the characteristics of the ideal sedative or analgesic agent: rapid onset, rapid recovery, a predictable dose response, a lack of drug accumulation, and no toxicity. To optimize care, critical care clinicians should be familiar with the many pharmacokinetic, pharmacodynamic, and pharmacogenetic variables that can affect the safety and efficacy of these sedatives and analgesics.