Long-term cognitive and psychological outcomes in the awakening and breathing controlled trial.

RATIONALE: Studies have shown that reducing sedation of critically ill patients shortens time on the ventilator and in the intensive care unit (ICU). Little is known, however, of how such strategies affect long-term cognitive, psychological, and functional outcomes. OBJECTIVES: To determine the long-term effects of a wake up and breathe protocol that interrupts and reduces sedative exposure in the ICU. METHODS: In this a priori planned substudy conducted at one tertiary care hospital during the Awakening and Breathing Controlled Trial, a multicenter randomized controlled trial, we assessed cognitive, psychological, and functional/quality-of-life outcomes 3 and 12 months postdischarge among 180 medical ICU patients randomized to paired daily spontaneous awakening trials with spontaneous breathing trials (SBTs) or to sedation per usual care plus daily SBTs. MEASUREMENTS AND MAIN RESULTS: Cognitive impairment was less common in the intervention group at 3-month follow-up (absolute risk reduction, 20.2%; 95% confidence interval, 1.5-36.1%; P = 0.03) but not at 12-month follow-up (absolute risk reduction, -1.9%; 95% CI, -21.3 to 27.1%; P = 0.89). Composite cognitive scores, alternatively, were similar in the two groups at 3-month and 12-month follow-up (P = 0.80 and 0.61, respectively), as were symptoms of depression (P = 0.59 and 0.82) and posttraumatic stress disorder (P = 0.59 and 0.97). Activities of daily living, functional status, and mental and physical quality of life were similar between groups throughout follow-up. CONCLUSIONS: In this trial, management of mechanically ventilated medical ICU patients with a wake up and breathe protocol resulted in similar cognitive, psychological, and functional outcomes among patients tested 3 and 12 months post-ICU. The proven benefits of this protocol, including improved 1-year survival, were not offset by adverse long-term outcomes. Clinical trial registered with www.clinicaltrials.gov (NCT 00097630).

Efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (Awakening and Breathing Controlled trial): a randomised controlled trial.

BACKGROUND: Approaches to removal of sedation and mechanical ventilation for critically ill patients vary widely. Our aim was to assess a protocol that paired spontaneous awakening trials (SATs)-ie, daily interruption of sedatives-with spontaneous breathing trials (SBTs). METHODS: In four tertiary-care hospitals, we randomly assigned 336 mechanically ventilated patients in intensive care to management with a daily SAT followed by an SBT (intervention group; n=168) or with sedation per usual care plus a daily SBT (control group; n=168). The primary endpoint was time breathing without assistance. Data were analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00097630. FINDINGS: One patient in the intervention group did not begin their assigned treatment protocol because of withdrawal of consent and thus was excluded from analyses and lost to follow-up. Seven patients in the control group discontinued their assigned protocol, and two of these patients were lost to follow-up. Patients in the intervention group spent more days breathing without assistance during the 28-day study period than did those in the control group (14.7 days vs 11.6 days; mean difference 3.1 days, 95% CI 0.7 to 5.6; p=0.02) and were discharged from intensive care (median time in intensive care 9.1 days vs 12.9 days; p=0.01) and the hospital earlier (median time in the hospital 14.9 days vs 19.2 days; p=0.04). More patients in the intervention group self-extubated than in the control group (16 patients vs six patients; 6.0% difference, 95% CI 0.6% to 11.8%; p=0.03), but the number of patients who required reintubation after self-extubation was similar (five patients vs three patients; 1.2% difference, 95% CI -5.2% to 2.5%; p=0.47), as were total reintubation rates (13.8%vs 12.5%; 1.3% difference, 95% CI -8.6% to 6.1%; p=0.73). At any instant during the year after enrolment, patients in the intervention group were less likely to die than were patients in the control group (HR 0.68, 95% CI 0.50 to 0.92; p=0.01). For every seven patients treated with the intervention, one life was saved (number needed to treat was 7.4, 95% CI 4.2 to 35.5). INTERPRETATION: Our results suggest that a wake up and breathe protocol that pairs daily spontaneous awakening trials (ie, interruption of sedatives) with daily spontaneous breathing trials results in better outcomes for mechanically ventilated patients in intensive care than current standard approaches and should become routine practice.

Clinical sedation scores as indicators of sedative and analgesic drug exposure in intensive care unit patients.

BACKGROUND: It is unclear how best to measure sedative/analgesic drug exposure in the clinical care of critically ill patients. Large doses and prolonged use of sedatives and analgesics in the intensive care unit (ICU) may lead to oversedation and adverse effects, including delirium and long-term cognitive impairment. These issues are of particular concern in elderly patients (aged > or =65 years), who account for at least half of all ICU admissions and nearly two thirds of ICU days. OBJECTIVE: This pilot study explored the relationships between clinical sedation scores, sedative/analgesic drug doses, and plasma drug concentrations in critically ill patients, the majority of whom were elderly. METHODS: This was a prospective, observational study conducted in a 500-bed, tertiary care community hospital. Study patients included a cohort of mechanically ventilated, medical ICU patients who were admitted to the hospital between April and June 2004 who required use of fentanyl, lorazepam, or propofol. Sedative/analgesic medications were administered according to clinical guidelines. Patients' sedation levels were measured twice daily using the Richmond Agitation-Sedation Scale (RASS). Dosing of fentanyl, lorazepam, and propofol was recorded. Blood was sampled twice daily for up to 5 days to analyze plasma drug concentrations. To specifically evaluate the effects of acute, extended (rather than chronic) sedative and analgesic exposure, the study focused on an ICU population receiving these agents for at least 48 hours but <2 weeks. RESULTS: Eighteen medical ICU patients (11 females, 7 males; mean [SD] age, 66.1 [18.1] years) on mechanical ventilation comprised the study cohort. Fifteen patients were aged >62 years, and 11 of those were aged > or =71 years. Plasma drug concentrations (median and interquartile range) were as follows: fentanyl--2.1 ng/mL, 0.9-3.4 ng/mL; lorazepam--266 ng/mL, 112-412 ng/mL; and propofol--845 ng/mL, 334-1342 ng/mL. Maximum concentrations were 3- to 12-fold higher than medians (fentanyl, 7.3 ng/mL; lorazepam, 3108 ng/mL; propofol, 10,000 ng/mL). Medication doses were only moderately correlated with RASS scores (Spearman rho): fentanyl--rho = -0.39, P = 0.002; lorazepam--rho = -0.28, P = 0.001; and propofol--rho = -0.46, P < 0.001. Plasma drug concentrations of fentanyl and lorazepam demonstrated moderate correlations with sedation scores (fentanyl--rho = -0.46, P = 0.002; lorazepam: rho = -0.49, P < 0.001), while propofol concentrations correlated poorly with sedation scores (rho = -0.18, P = 0.07). Associations between interval drug doses and plasma concentrations were as follows: fentanyl, rho = 0.84; lorazepam, rho = 0.76; and propofol, rho = 0.61 (all, P < 0.001). Instructive examples of discrepant dose versus plasma concentration profiles and drug interactions are provided, including 3 cases with patients aged > or =64 years. CONCLUSIONS: Elderly patients are commonly encountered in the ICU setting. Only moderate correlations existed between clinical sedation levels and dose or plasma concentration of sedative/analgesic medications in this study population. Further work is needed to understand appropriate and feasible measures of exposure to sedatives/analgesics relating to clinical outcomes.

Delirium and its motoric subtypes: a study of 614 critically ill patients.

OBJECTIVES: To describe the motoric subtypes of delirium in critically ill patients and compare patients aged 65 and older with a younger cohort. DESIGN: Prospective cohort study. SETTING: The medical intensive care unit (MICU) of a tertiary care academic medical center. PARTICIPANTS: Six hundred fourteen MICU patients admitted during a process improvement initiative to monitor levels of sedation and delirium. MEASUREMENTS: MICU nursing staff assessed delirium and level of consciousness in all MICU patients at least once per 12-hour shift using the Confusion Assessment Method for the Intensive Care Unit and the Richmond Agitation-Sedation Scale. Delirium episodes were categorized as hypoactive, hyperactive, and mixed type. RESULTS: Delirium was detected in 112 of 156 (71.8%) subjects aged 65 and older and 263 of 458 (57.4%) subjects younger than 65. Mixed type was most common (54.9%), followed by hypoactive delirium (43.5%) and purely hyperactive delirium (1.6%). Patients aged 65 and older experienced hypoactive delirium at a greater rate than younger patients (41.0% vs 21.6%, P<.001) and never experienced hyperactive delirium. Older age was strongly and independently associated with hypoactive delirium (adjusted odds ratio=3.0, 95% confidence interval=1.7-5.3), compared with no delirium in a model that adjusted for other important determinants of delirium including severity of illness, sedative medication use, and ventilation status. CONCLUSION: Older age is a strong predictor of hypoactive delirium in MICU patients, and this motoric subtype of delirium may be missed in the absence of active monitoring.

Intensive care unit delirium is an independent predictor of longer hospital stay: a prospective analysis of 261 non-ventilated patients.

INTRODUCTION: Delirium occurs in most ventilated patients and is independently associated with more deaths, longer stay, and higher cost. Guidelines recommend monitoring of delirium in all intensive care unit (ICU) patients, though few data exist in non-ventilated patients. The study objective was to determine the relationship between delirium and outcomes among non-ventilated ICU patients. METHOD: A prospective cohort investigation of 261 consecutively admitted medical ICU patients not requiring invasive mechanical ventilation during hospitalization at a tertiary-care, university-based hospital between February 2002 and January 2003. ICU nursing staff assessed delirium and level of consciousness at least twice per day using the Confusion Assessment Method for the ICU (CAM-ICU) and Richmond Agitation-Sedation Scale (RASS). Cox regression with time-varying covariates was used to determine the independent relationship between delirium and clinical outcomes. RESULTS: Of 261 patients, 125 (48%) experienced at least one episode of delirium. Patients who experienced delirium were older (mean +/- SD: 56 +/- 18 versus 49 +/- 17 years; p = 0.002) and more severely ill as measured by Acute Physiology and Chronic Health Evaluation II (APACHE II) scores (median 15, interquartile range (IQR) 10-21 versus 11, IQR 6-16; p < 0.001) compared to their non-delirious counterparts. Patients who experienced delirium had a 29% greater risk of remaining in the ICU on any given day (compared to patients who never developed delirium) even after adjusting for age, gender, race, Charlson co-morbidity score, APACHE II score, and coma (hazard ratio (HR) 1.29; 95% confidence interval (CI) 0.98-1.69, p = 0.07). Similarly, patients who experienced delirium had a 41% greater risk of remaining in the hospital after adjusting for the same covariates (HR 1.41; 95% CI 1.05-1.89, p = 0.023). Hospital mortality was higher among patients who developed delirium (24/125, 19%) versus patients who never developed delirium (8/135, 6%), p = 0.002; however, time to in-hospital death was not significant the adjusted (HR 1.27; 95% CI 0.55-2.98, p = 0.58). CONCLUSION: Delirium occurred in nearly half of the non-ventilated ICU patients in this cohort. Even after adjustment for relevant covariates, delirium was found to be an independent predictor of longer hospital stay.

Monitoring sedation status over time in ICU patients: reliability and validity of the Richmond Agitation-Sedation Scale (RASS).

CONTEXT: Goal-directed delivery of sedative and analgesic medications is recommended as standard care in intensive care units (ICUs) because of the impact these medications have on ventilator weaning and ICU length of stay, but few of the available sedation scales have been appropriately tested for reliability and validity. OBJECTIVE: To test the reliability and validity of the Richmond Agitation-Sedation Scale (RASS). DESIGN: Prospective cohort study. SETTING: Adult medical and coronary ICUs of a university-based medical center. PARTICIPANTS: Thirty-eight medical ICU patients enrolled for reliability testing (46% receiving mechanical ventilation) from July 21, 1999, to September 7, 1999, and an independent cohort of 275 patients receiving mechanical ventilation were enrolled for validity testing from February 1, 2000, to May 3, 2001. MAIN OUTCOME MEASURES: Interrater reliability of the RASS, Glasgow Coma Scale (GCS), and Ramsay Scale (RS); validity of the RASS correlated with reference standard ratings, assessments of content of consciousness, GCS scores, doses of sedatives and analgesics, and bispectral electroencephalography. RESULTS: In 290-paired observations by nurses, results of both the RASS and RS demonstrated excellent interrater reliability (weighted kappa, 0.91 and 0.94, respectively), which were both superior to the GCS (weighted kappa, 0.64; P<.001 for both comparisons). Criterion validity was tested in 411-paired observations in the first 96 patients of the validation cohort, in whom the RASS showed significant differences between levels of consciousness (P<.001 for all) and correctly identified fluctuations within patients over time (P<.001). In addition, 5 methods were used to test the construct validity of the RASS, including correlation with an attention screening examination (r = 0.78, P<.001), GCS scores (r = 0.91, P<.001), quantity of different psychoactive medication dosages 8 hours prior to assessment (eg, lorazepam: r = - 0.31, P<.001), successful extubation (P =.07), and bispectral electroencephalography (r = 0.63, P<.001). Face validity was demonstrated via a survey of 26 critical care nurses, which the results showed that 92% agreed or strongly agreed with the RASS scoring scheme, and 81% agreed or strongly agreed that the instrument provided a consensus for goal-directed delivery of medications. CONCLUSIONS: The RASS demonstrated excellent interrater reliability and criterion, construct, and face validity. This is the first sedation scale to be validated for its ability to detect changes in sedation status over consecutive days of ICU care, against constructs of level of consciousness and delirium, and correlated with the administered dose of sedative and analgesic medications.

Apolipoprotein E4 polymorphism as a genetic predisposition to delirium in critically ill patients.

OBJECTIVE: To test for an association between apolipoprotein E (APOE) genotypes and duration of intensive care unit delirium. DESIGN: Prospective, observational cohort study. SETTING: A 541-bed, community-based teaching hospital. PATIENTS: Fifty-three mechanically ventilated intensive care unit patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: All patients were managed with standardized sedation and ventilator weaning protocols as part of an ongoing clinical trial and were evaluated prospectively for delirium with the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). DNA was extracted from whole blood samples obtained on enrollment, and APOE genotype was determined using polymerase chain reaction followed by restriction enzyme digestion by investigators blinded to the clinical information. Delirium occurred in 47 (89%) patients at some point during the intensive care unit stay. Of the 53 patients, 12 (23%) had an APOE4 allele (APOE4+) and 41 (77%) had only APOE2 or APOE3 alleles (APOE4-). APOE4+ patients were younger (53.2 +/- 21.9 vs. 65.4 +/- 13.4, p = .08) and less often admitted for pneumonia (0% vs. 29.3%, p = .05) compared with APOE4- patients, yet they had a duration of delirium that was twice as long: median (interquartile range), 4 (3, 4.5) vs. 2 (1, 4) days (p = .05). No other clinical outcomes were significantly different between the APOE4+ and APOE4- patients. Using multivariable regression analysis to adjust for age, admission diagnosis of sepsis or acute respiratory distress syndrome or pneumonia, severity of illness, and duration of coma, the presence of APOE4 allele was the strongest predictor of delirium duration (odds ratio, 7.32; 95% confidence interval, 1.82-29.51, p = .005). CONCLUSIONS: APOE4 allele represents the first demonstrated genetic predisposition to longer duration of delirium in humans.

Current opinions regarding the importance, diagnosis, and management of delirium in the intensive care unit: a survey of 912 healthcare professionals.

OBJECTIVE: Recently published clinical practice guidelines of the Society of Critical Care Medicine recommend monitoring for the presence of delirium in all mechanically ventilated patients because of the potential for adverse outcomes associated with this comorbidity, yet little is known about healthcare professionals' opinions regarding intensive care unit delirium or how they manage this organ dysfunction. The aim of this survey was to assess the medical community's beliefs and practices regarding delirium in the intensive care unit. DESIGN: Survey administration was conducted both without a delirium definition (phase 1) and then with a definition of delirium (phase 2). SETTING: Critical care meetings and continuing medical education/board review courses from October 2001 to July 2002. PARTICIPANTS: A convenience sample of physicians (n = 753), nurses (n = 113), pharmacists (n = 13), physician assistants (n = 12), respiratory care practitioners (n = 8), and others (n = 13). INTERVENTIONS: Survey. MEASUREMENTS AND MAIN RESULTS: Participants completed 912 of the surveys. The majority (68%) of respondents thought that >25% of adult mechanically ventilated patients experience delirium. Delirium was considered a significant or very serious problem in the intensive care unit by 92% of healthcare professionals, yet underdiagnosis was acknowledged by 78%. Only 40% reported routinely screening for delirium, and only 16% indicated using a specific tool for delirium assessment. Delirium was considered important in the outcome of elderly and young patients by 89% and 60% of the respondents, respectively (p <.0001). The most serious complications these professionals associated with delirium were prolonged mechanical ventilation, self-injury, and respiratory difficulties. Delirium was treated with haloperidol by 66% of the respondents, with lorazepam by 12%, and with atypical antipsychotics by <5%. More than 55% administered haloperidol and lorazepam at daily doses of < or =10 mg, but some used >50 mg/day of either medication. CONCLUSIONS: Most healthcare professionals consider delirium in the intensive care unit a common and serious problem, although few actually monitor for this condition and most admit that it is underdiagnosed. Data from this survey point to a disconnect between the perceived significance of delirium in the intensive care unit and current practices of monitoring and treatment.