Richard R. Riker

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.

Dexmedetomidine vs Midazolam for Sedation of Critically Ill Patients: A Randomized Trial

CONTEXT Gamma-aminobutyric acid receptor agonist medications are the most commonly used sedatives for intensive care unit (ICU) patients, yet preliminary evidence indicates that the alpha(2) agonist dexmedetomidine may have distinct advantages. OBJECTIVE To compare the efficacy and safety of prolonged sedation with dexmedetomidine vs midazolam for mechanically ventilated patients. DESIGN, SETTING, AND PATIENTS Prospective, double-blind, randomized trial conducted in 68 centers in 5 countries between March 2005 and August 2007 among 375 medical/surgical ICU patients with expected mechanical ventilation for more than 24 hours. Sedation level and delirium were assessed using the Richmond Agitation-Sedation Scale (RASS) and the Confusion Assessment Method for the ICU. INTERVENTIONS Dexmedetomidine (0.2-1.4 microg/kg per hour [n = 244]) or midazolam (0.02-0.1 mg/kg per hour [n = 122]) titrated to achieve light sedation (RASS scores between -2 and +1) from enrollment until extubation or 30 days. MAIN OUTCOME MEASURES Percentage of time within target RASS range. Secondary end points included prevalence and duration of delirium, use of fentanyl and open-label midazolam, and nursing assessments. Additional outcomes included duration of mechanical ventilation, ICU length of stay, and adverse events. RESULTS There was no difference in percentage of time within the target RASS range (77.3% for dexmedetomidine group vs 75.1% for midazolam group; difference, 2.2% [95% confidence interval {CI}, -3.2% to 7.5%]; P = .18). The prevalence of delirium during treatment was 54% (n = 132/244) in dexmedetomidine-treated patients vs 76.6% (n = 93/122) in midazolam-treated patients (difference, 22.6% [95% CI, 14% to 33%]; P < .001). Median time to extubation was 1.9 days shorter in dexmedetomidine-treated patients (3.7 days [95% CI, 3.1 to 4.0] vs 5.6 days [95% CI, 4.6 to 5.9]; P = .01), and ICU length of stay was similar (5.9 days [95% CI, 5.7 to 7.0] vs 7.6 days [95% CI, 6.7 to 8.6]; P = .24). Dexmedetomidine-treated patients were more likely to develop bradycardia (42.2% [103/244] vs 18.9% [23/122]; P < .001), with a nonsignificant increase in the proportion requiring treatment (4.9% [12/244] vs 0.8% [1/122]; P = .07), but had a lower likelihood of tachycardia (25.4% [62/244] vs 44.3% [54/122]; P < .001) or hypertension requiring treatment (18.9% [46/244] vs 29.5% [36/122]; P = .02). CONCLUSIONS There was no difference between dexmedetomidine and midazolam in time at targeted sedation level in mechanically ventilated ICU patients. At comparable sedation levels, dexmedetomidine-treated patients spent less time on the ventilator, experienced less delirium, and developed less tachycardia and hypertension. The most notable adverse effect of dexmedetomidine was bradycardia. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00216190 Published online February 2, 2009 (doi:10.1001/jama.2009.56).

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.

Efficacy and safety of quetiapine in critically ill patients with delirium: A prospective, multicenter, randomized, double-blind, placebo-controlled pilot study*

Objective: To compare the efficacy and safety of scheduled quetiapine to placebo for the treatment of delirium in critically ill patients requiring as-needed haloperidol. Design: Prospective, randomized, double-blind, placebo-controlled study. Setting: Three academic medical centers. Patients: Thirty-six adult intensive care unit patients with delirium (Intensive Care Delirium Screening Checklist score ≥4), tolerating enteral nutrition, and without a complicating neurologic condition. Interventions: Patients were randomized to receive quetiapine 50 mg every 12 hrs or placebo. Quetiapine was increased every 24 hrs (50 to 100 to 150 to 200 mg every 12 hrs) if more than one dose of haloperidol was given in the previous 24 hrs. Study drug was continued until the intensive care unit team discontinued it because of delirium resolution, therapy ≥10 days, or intensive care unit discharge. Measurements and Main Results: Baseline characteristics were similar between the quetiapine (n = 18) and placebo (n = 18) groups. Quetiapine was associated with a shorter time to first resolution of delirium [1.0 (interquartile range [IQR], 0.5–3.0) vs. 4.5 days (IQR, 2.0–7.0; p =.001)], a reduced duration of delirium [36 (IQR, 12–87) vs. 120 hrs (IQR, 60–195; p =.006)], and less agitation (Sedation-Agitation Scale score ≥5) [6 (IQR, 0–38) vs. 36 hrs (IQR, 11–66; p =.02)]. Whereas mortality (11% quetiapine vs. 17%) and intensive care unit length of stay (16 quetiapine vs. 16 days) were similar, subjects treated with quetiapine were more likely to be discharged home or to rehabilitation (89% quetiapine vs. 56%; p =.06). Subjects treated with quetiapine required fewer days of as-needed haloperidol [3 [(IQR, 2–4)] vs. 4 days (IQR, 3–8; p = .05)]. Whereas the incidence of QTc prolongation and extrapyramidal symptoms was similar between groups, more somnolence was observed with quetiapine (22% vs. 11%; p = .66). Conclusions: Quetiapine added to as-needed haloperidol results in faster delirium resolution, less agitation, and a greater rate of transfer to home or rehabilitation. Future studies should evaluate the effect of quetiapine on mortality, resource utilization, post-intensive care unit cognition, and dependency after discharge in a broader group of patients.

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.

Delirium duration and mortality in lightly sedated, mechanically ventilated intensive care patients*

Objectives:To determine the relationship between the number of delirium days experienced by intensive care patients and mortality, ventilation time, and intensive care unit stay. Design:Prospective cohort analysis. Setting:Patients from 68 intensive care units in five countries. Patients:Three hundred fifty-four medical and surgical intensive care patients enrolled in the SEDCOM (Safety and Efficacy of Dexmedetomidine Compared with Midazolam) trial received a sedative study drug and completed at least one delirium assessment. Interventions:Sedative drug interruption and/or titration to maintain light sedation with daily arousal and delirium assessments up to 30 days of mechanical ventilation. Measurements and Main Results:The primary outcome was all-cause 30-day mortality. Multivariable analysis using Cox regression incorporating delirium duration as a time-dependent variable and adjusting for eight relevant baseline covariates was conducted to quantify the relationship between number of delirium days and the three main outcomes. Overall, delirium was diagnosed in 228 of 354 patients (64.4%). Mortality was significantly lower in patients without delirium compared to those with delirium (15 of 126 [11.9%] vs. 69 of 228 [30.3%]; p < .001). Similarly, the median time to extubation and intensive care unit discharge were significantly shorter among nondelirious patients (3.6 vs. 10.7 days [p < .001] and 4 vs. 16 days [p < .001], respectively). In multivariable analysis, the duration of delirium exhibited a nonlinear relationship with mortality (p = .02), with the strongest association observed in the early days of delirium. In comparison to 0 days of delirium, an independent dose-response increase in mortality was observed, which increased from 1 day of delirium (hazard ratio, 1.70; 95% confidence interval, 1.27–2.29; p < .001), 2 days of delirium (hazard ratio, 2.69; confidence interval, 1.58–4.57; p < .001), and ≥3 days of delirium (hazard ratio, 3.37; confidence interval, 1.92–7.23; p < .001). Similar independent relationships were observed between delirium duration and ventilation time and intensive care length of stay. Conclusions:In ventilated and lightly sedated intensive care unit patients, the duration of delirium was the strongest independent predictor of death, ventilation time, and intensive care unit stay after adjusting for relevant covariates.

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)

Adverse events and their relation to mortality in out-of-hospital cardiac arrest patients treated with therapeutic hypothermia.

Objectives:To investigate the association between adverse events recorded during critical care and mortality in out-of-hospital cardiac arrest patients treated with therapeutic hypothermia. Design:Prospective, observational, registry-based study. Setting:Twenty-two hospitals in Europe and the United States. Patients:Between October 2004 and October 2008, 765 patients were included. Interventions:None. Measurements and Main Results:Arrhythmias (7%–14%), pneumonia (48%), metabolic and electrolyte disorders (5%–37%), and seizures (24%) were common adverse events in the critical care period in cardiac arrest patients treated with therapeutic hypothermia, whereas sepsis (4%) and bleeding (6%) were less frequent. Sustained hyperglycemia (blood glucose >8 mmol/L for >4 hrs; odds ratio 2.3, 95% confidence interval 1.6–3.6, p < .001) and seizures treated with anticonvulsants (odds ratio 4.8, 95% confidence interval 2.9–8.1, p < .001) were associated with increased mortality in a multivariate model. An increased frequency of bleeding and sepsis occurred after invasive procedures (coronary angiography, intravascular devices for cooling, intra-aortic balloon pump), but bleeding and sepsis were not associated with increased mortality (odds ratio 1.0, 95% confidence interval 0.46–2.2, p = .91, and odds ratio 0.30, 95% confidence interval 0.12–0.79, p = .01, respectively). Conclusions:Adverse events were common after out-of-hospital cardiac arrest. Sustained hyperglycemia and seizures treated with anticonvulsants were associated with increased mortality. Bleeding and infection were more common after invasive procedures, but these adverse events were not associated with increased mortality in our study.

Consensus summary statement of the International Multidisciplinary Consensus Conference on Multimodality Monitoring in Neurocritical Care: A statement for healthcare professionals from the Neurocritical Care Society and the European Society of Intensive Care Medicine

Neurocritical care depends, in part, on careful patient monitoring but as yet there are little data on what processes are the most important to monitor, how these should be monitored, and whether monitoring these processes is cost-effective and impacts outcome. At the same time, bioinformatics is a rapidly emerging field in critical care but as yet there is little agreement or standardization on what information is important and how it should be displayed and analyzed. The Neurocritical Care Society in collaboration with the European Society of Intensive Care Medicine, the Society for Critical Care Medicine, and the Latin America Brain Injury Consortium organized an international, multidisciplinary consensus conference to begin to address these needs. International experts from neurosurgery, neurocritical care, neurology, critical care, neuroanesthesiology, nursing, pharmacy, and informatics were recruited on the basis of their research, publication record, and expertise. They undertook a systematic literature review to develop recommendations about specific topics on physiologic processes important to the care of patients with disorders that require neurocritical care. This review does not make recommendations about treatment, imaging, and intraoperative monitoring. A multidisciplinary jury, selected for their expertise in clinical investigation and development of practice guidelines, guided this process. The GRADE system was used to develop recommendations based on literature review, discussion, integrating the literature with the participants’ collective experience, and critical review by an impartial jury. Emphasis was placed on the principle that recommendations should be based on both data quality and on trade-offs and translation into clinical practice. Strong consideration was given to providing pragmatic guidance and recommendations for bedside neuromonitoring, even in the absence of high quality data.