Gilles L. Fraser

Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult

Judith Jacobi, PharmD, FCCM, BCPS; Gilles L. Fraser, PharmD, FCCM; Douglas B. Coursin, MD; Richard R. Riker, MD; Dorrie Fontaine, RN, DNSc, FAAN; Eric T. Wittbrodt, PharmD; Donald B. Chalfin, MD, MS, FCCM; Michael F. Masica, MD, MPH; H. Scott Bjerke, MD; William M. Coplin, MD; David W. Crippen, MD, FCCM; Barry D. Fuchs, MD; Ruth M. Kelleher, RN; Paul E. Marik, MDBCh, FCCM; Stanley A. Nasraway, Jr, MD, FCCM; Michael J. Murray, MD, PhD, FCCM; William T. Peruzzi, MD, FCCM; Philip D. Lumb, MB, BS, FCCM. Developed through the Task Force of the American College of Critical Care Medicine (ACCM) of the Society of Critical Care Medicine (SCCM), in collaboration with the American Society of Health-System Pharmacists (ASHP), and in alliance with the American College of Chest Physicians; and approved by the Board of Regents of ACCM and the Council of SCCM and the ASHP Board of Directors

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.

Prospective evaluation of the Sedation-Agitation Scale for adult critically ill patients.

OBJECTIVE Subjective scales to assess agitation and sedation in adult intensive care unit (ICU) patients have rarely been tested for validity or reliability. We revised and prospectively tested the Sedation-Agitation Scale (SAS) for interrater reliability and compared it with the Ramsay scale and the Harris scale to test construct validity. DESIGN A convenience sample of ICU patients was simultaneously and independently examined by pairs of trained evaluators by using the revised SAS, Ramsay, and Harris Scales. SETTING Multidisciplinary 34-bed ICU in a nonuniversity, academic medical center. PATIENTS Forty-five ICU patients (surgical and medical) were examined a total of 69 times by evaluator pairs. MEASUREMENTS AND MAIN RESULTS The mean patient age was 63.2 yrs, 36% were female, and 71% were intubated. When classified by using SAS, 45% were anxious or agitated (SAS 5 to 7), 26% were calm (SAS 4), and 29% were sedated (SAS 1 to 3). Interrater correlation was high for SAS (r2 = .83; p < .001) and the weighted kappa score for interrater agreement was 0.92 (p < .001). Of 41 assessments scored as Ramsay 1, 49% scored SAS 6, 41% were SAS 5, 5% were SAS 4, and 2% each were SAS 3 or 7. SAS was highly correlated with the Ramsay (r2 = .83; p < .001) and Harris (r2 = .86; p < .001) scales. CONCLUSIONS SAS is both reliable (high interrater agreement) and valid (high correlation with the Harris and Ramsay scales) in assessing agitation and sedation in adult ICU patients. SAS provides additional information by stratifying agitation into three categories (compared with one for the Ramsay scale) without sacrificing validity or reliability.

Assessing sedation during intensive care unit mechanical ventilation with the Bispectral Index and the Sedation-Agitation Scale.

OBJECTIVE To describe the level of sedation for a cohort of mechanically ventilated adult intensive care unit (ICU) patients using validated subjective and objective tools. DESIGN Prospective convenience sample. SETTING Multidisciplinary 34-bed ICU at Maine Medical Center, a 599-bed nonuniversity, academic medical center. PATIENTS Sixty-three adult ICU patients were monitored during 64 episodes of ventilatory support. MEASUREMENTS AND MAIN RESULTS Patients were prospectively evaluated by one trained investigator using the revised Sedation-Agitation Scale (SAS) and were simultaneously monitored for 1 to 5 hrs using the Bispectral Index (BIS), a numeric scale from 0 to 100 derived from the electroencephalogram. BIS values were assigned to baseline, stimulated, and average conditions for each patient by a separate investigator blinded to SAS scores. Ventilator settings, medications, and the lung injury severity (LIS) score were also recorded. Sedation levels varied from very deep sedation (SAS score = 1, BIS score = 43) to mild agitation (SAS score = 5, BIS score = 100). Heavily sedated patients (SAS score = 1-2, n = 20) had higher FIO2 (0.52 vs. 0.42, p = .008), oxygenation index (9.4 vs. 5.4, p = .03), and LIS scores (1.3 vs. 0.7, p = .004) and lower baseline (66 vs. 78, p = .01), average (66 vs. 81, p < .001), and stimulated (89 vs. 96, p = .016) BIS scores compared with more awake patients. Patients with intermittent neuromuscular blockade use (n = 4) had higher FIO2 (0.65 vs. 0.44, p = .006), minute ventilation (14.6 vs. 9.9 L/min, p = .005), positive end-expiratory pressure (7.5 vs. 4.8 cm H2O, p = .05), oxygenation index (15.7 vs. 6.0, p < .001), and LIS scores (3.3 vs. 1.0, p = .036) and were more sedated, with higher suppression ratios (3.5 vs. 0.6, p = .05) and lower SAS scores (1.5 vs. 4, p = .035). The average BIS values correlated well with SAS (r2 = .21, p < .001). CONCLUSIONS SAS and BIS work well to describe the depth of sedation for ventilated ICU patients. Deeper sedation and intermittent neuromuscular blockade were used for patients with greater ventilatory requirements and more severe lung disease. The correlation between subjective and objective scales varied in medical, surgical, and trauma patients. Further research with SAS and BIS may facilitate the development of quantitative sedation guidelines for the ICU.

Continuous infusion of haloperidol controls agitation in critically ill patients.

ObjectiveTo evaluate the safety and efficacy of continuous infusion of haloperidol in treating agitated critically ill adult patients. DesignCase series of patients treated with continuous infusion of haloperidol and followed to hospital discharge, during a 6-month period. SettingA 34-bed multidisciplinary intensive care unit (ICU) in a 598-bed nonuniversity, tertiary care teaching hospital. PatientsConsecutive sample of eight patients requiring mechanical ventilation who had severe agitation which was refractory to intermittent bolus treatment with benzodiazepines, narcotics, and haloperidol. InterventionsContinuous infusions of haloperidol (range 3 to 25 mg/hr) were supplemented, as required, to maintain adequate sedation. Measurements and Main ResultsThe four men and four women averaged 47 yrs of age, and the average length of hospitalization was 33 days, with 25 days spent in the ICU. On the day continuous infusion of haloperidol was initiated, the average Acute Physiology and Chronic Health Evaluation (APACHE) II and Therapeutic Intervention Scoring System (TISS) scores were 24 and 47, respectively. The Sedation-Agitation Scale score averaged +2.4 (maximum agitation score being +3) before continuous infusion of haloperidol decreasing to +1.8 after 1 day (p = .38) and to +0.8 after 2 days (p = .06) of continuous infusion of haloperidol. The average daily haloperidol dose increased from 68 mg before continuous infusion of haloperidol to 269 mg (p < .008) after 1 day. The daily total of nonhaloperidol sedatives decreased from 18.3 to 10.9 sedation-equivalent units (p = .15) and the daily number of bolus administrations of sedatives decreased from 23 to 7 (p = .01) after 1 day of continuous infusion of haloperidol. Estimated nursing time to prepare, administer, and monitor these bolus medications decreased from 320 to 96 mins per 24 hrs (p = .01). Of the five patients discharged alive (37.5% mortality rate), four were successfully weaned from assisted ventilation during continuous infusion of haloperidol. Two of these four patients were difficult to wean because of agitation and oversedation. Four possible complications were noted: minor tremors (n = 2), atrial dysrhythmias with intermittent third-degree atrioventricular block and QT interval prolongation (n = 1), and ventricular tachycardia (n = 1). ConclusionsContinuous infusion of haloperidol effectively controls severe agitation in critically ill patients, reduces requirements for bolus administration of sedatives and nursing time lost to that task, and may facilitate ventilator weaning. Parenteral administration of haloperidol was associated with few complications in > 1,340 patient-hours of continuous administration. (Crit Care Med 1994; 22:433–440)

Antibiotic optimization. An evaluation of patient safety and economic outcomes.

BACKGROUND Although numerous reports have described interventions designed to influence antibiotic utilization, to our knowledge none have been evaluated in a randomized study. METHODS Adult inpatients receiving 1 or more of 10 designated parenteral antibiotics for 3 or more days during a 3-month period were randomized to an intervention (n = 141) and a control (n = 111) group using an unblocked, computer-generated random number table. Obstetric patients and those seen in infectious disease consultation were excluded. The intervention group received antibiotic-related suggestions from a team consisting of an infectious disease fellow and a clinical pharmacist. Both groups were evaluated for clinical and microbiological outcomes as well as antibiotic utilization via prospective chart reviews and analysis of the hospitals administrative database. RESULTS Sixty-two (49%) of the intervention group patients received a total of 74 suggestions. Sixty-three (84%) of these suggestions were implemented; the majority involved changes in antibiotic choice, dosing regimen, or route of administration. Per patient antibiotic charges were nearly

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

400 less in the intervention group vs controls (P = .05). Almost all the savings were related to lower intravenous antibiotic charges. Clinical and microbiological response, antibiotic-associated toxic effects, in-hospital mortality, and readmission rates were similar for both groups. Multiple linear regression analysis identified randomization to the intervention group and female sex as the sole predictors of lower antibiotic charges. There was a trend toward a shorter length of stay for the intervention group (20 vs 24.7 days, P = .11). CONCLUSIONS This is the first randomized study to evaluate whether antibiotic choices can be influenced in a cost-effective fashion without sacrificing patient safety. We demonstrate that 50% of patients initially treated with expensive parenteral antibiotics can have their regimens refined after 3 days of therapy and that these modifications result in good clinical outcomes with a substantial reduction in antibiotic expense.

Frequency, severity, and treatment of agitation in young versus elderly patients in the ICU.

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.

Adverse events associated with sedatives, analgesics, and other drugs that provide patient comfort in the intensive care unit.

Study Objective. To study the frequency, duration, severity, and treatment of agitation in patients in the intensive care unit (ICU) to determine if the elderly represent a distinct population.

Antimicrobial stewardship programs as a means to optimize antimicrobial use. Insights from the Society of Infectious Diseases Pharmacists.

Since the 2002 publication of multidisciplinary clinical practice guidelines for intensive care unit (ICU) sedation and analgesia, additional information regarding adverse drug events has been reported. Our understanding of the risks associated with these sedative and analgesic agents promises to improve outcomes by helping clinicians identify and respond to therapeutic misadventures sooner. This review focuses on many issues, including the potentially fatal consequences associated with the propofol infusion syndrome, the evolving understanding of propylene glycol intoxication associated with parenteral lorazepam, new data involving high‐dose and long‐term dexmedetomidine therapy, haloperidol‐ and methadone‐related prolongation of QTc intervals on the electrocardiogram, adverse events associated with atypical antipsychotics, and the potential for nonsteroidal antiinflammatory drugs to interfere with bone healing.