Timothy D. Girard

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.

Delirium as a predictor of long-term cognitive impairment in survivors of critical illness

Objective:To test the hypothesis that duration of delirium in the intensive care unit is an independent predictor of long-term cognitive impairment after critical illness requiring mechanical ventilation. Design:Prospective cohort study. Setting:Medical intensive care unit in a large community hospital in the United States. Patients:Mechanically ventilated medical intensive care unit patients who were assessed daily for delirium while in the intensive care unit and who underwent comprehensive cognitive assessments 3 and 12 mos after discharge. Measurements and Main Results:Of 126 eligible patients, 99 survived ≥3 months after critical illness; long-term cognitive outcomes were obtained for 77 (78%) patients. Median age was 61 yrs, 51% were admitted with sepsis/acute respiratory distress syndrome, and median duration of delirium was 2 days. At 3-mo and 12-mo follow-up, 79% and 71% of survivors had cognitive impairment, respectively (with 62% and 36% being severely impaired). After adjusting for age, education, preexisting cognitive function, severity of illness, severe sepsis, and exposure to sedative medications in the intensive care unit, increasing duration of delirium was an independent predictor of worse cognitive performance—determined by averaging age-adjusted and education-adjusted T-scores from nine tests measuring seven domains of cognition—at 3-mo (p = .02) and 12-mo follow-up (p = .03). Duration of mechanical ventilation, alternatively, was not associated with long-term cognitive impairment (p = .20 and .58). Conclusions:In this study of mechanically ventilated medical intensive care unit patients, duration of delirium (which is potentially modifiable) was independently associated with long-term cognitive impairment, a common public health problem among intensive care unit survivors. (Crit Care Med 2010; 38:1513–1520

Delirium in the intensive care unit.

Delirium, an acute and fluctuating disturbance of consciousness and cognition, is a common manifestation of acute brain dysfunction in critically ill patients, occurring in up to 80% of the sickest intensive care unit (ICU) populations. Critically ill patients are subject to numerous risk factors for delirium. Some of these, such as exposure to sedative and analgesic medications, may be modified to reduce risk. Although dysfunction of other organ systems continues to receive more clinical attention, delirium is now recognized to be a significant contributor to morbidity and mortality in the ICU, and it is recommended that all ICU patients be monitored using a validated delirium assessment instrument. Patients with delirium have longer hospital stays and lower 6-month survival than do patients without delirium, and preliminary research suggests that delirium may be associated with cognitive impairment that persists months to years after discharge. Little evidence exists regarding the prevention and treatment of delirium in the ICU, but multicomponent interventions reduce the incidence of delirium in non-ICU studies. Strategies for the prevention and treatment of ICU delirium are the subjects of multiple ongoing investigations.

Delirium and sedation in the intensive care unit: survey of behaviors and attitudes of 1384 healthcare professionals.

Objective:A 2001 survey found that most healthcare professionals considered intensive care unit (ICU) delirium as a serious problem, but only 16% used a validated delirium screening tool. Our objective was to assess beliefs and practices regarding ICU delirium and sedation management. Design and Setting:Between October 2006 and May 2007, a survey was distributed to ICU practitioners in 41 North American hospitals, seven international critical care meetings and courses, and the American Thoracic Society e-mail database. Study Participants:A convenience sample of 1384 healthcare professionals including 970 physicians, 322 nurses, 23 respiratory care practitioners, 26 pharmacists, 18 nurse practitioners and physicians’ assistants, and 25 others. Results:A majority [59% (766 of 1300)] estimated that more than one in four adult mechanically ventilated patients experience delirium. More than half [59% (774 of 1302)] screen for delirium, with 33% of those respondents (258 of 774) using a specific screening tool. A majority of respondents use a sedation protocol, but 29% (396 of 1355) still do not. A majority (76%, 990 of 1309) has a written policy on spontaneous awakening trials (SATs), but the minority of respondents (44%, 446 of 1019) practice spontaneous awakening trials on more than half of ICU days. Conclusions:Delirium is considered a serious problem by a majority of healthcare professionals, and the percent of practitioners using a specific screening tool has increased since the last published survey data. Although most respondents have adopted specific sedation protocols and have an approved approach to stopping sedation daily, few report even modest compliance with daily cessation of sedation.

Effect of dexmedetomidine versus lorazepam on outcome in patients with sepsis: an a priori-designed analysis of the MENDS randomized controlled trial

IntroductionBenzodiazepines and α2 adrenoceptor agonists exert opposing effects on innate immunity and mortality in animal models of infection. We hypothesized that sedation with dexmedetomidine (an α2 adrenoceptor agonist), as compared with lorazepam (a benzodiazepine), would provide greater improvements in clinical outcomes among septic patients than among non-septic patients.MethodsIn this a priori-determined subgroup analysis of septic vs non-septic patients from the MENDS double-blind randomized controlled trial, adult medical/surgical mechanically ventilated patients were randomized to receive dexmedetomidine-based or lorazepam-based sedation for up to 5 days. Delirium and other clinical outcomes were analyzed comparing sedation groups, adjusting for clinically relevant covariates as well as assessing interactions between sedation group and sepsis.ResultsOf the 103 patients randomized, 63 (31 dexmedetomidine; 32 lorazepam) were admitted with sepsis and 40 (21 dexmedetomidine; 19 lorazepam) without sepsis. Baseline characteristics were similar between treatment groups for both septic and non-septic patients. Compared with septic patients who received lorazepam, the dexmedetomidine septic patients had 3.2 more delirium/coma-free days (DCFD) on average (95% CI for difference, 1.1 to 4.9), 1.5 (-0.1, 2.8) more delirium-free days (DFD) and 6 (0.3, 11.1) more ventilator-free days (VFD). The beneficial effects of dexmedetomidine were more pronounced in septic patients than in non-septic patients for both DCFDs and VFDs (P-value for interaction = 0.09 and 0.02 respectively). Additionally, sedation with dexmedetomidine, compared with lorazepam, reduced the daily risk of delirium [OR, CI 0.3 (0.1, 0.7)] in both septic and non-septic patients (P-value for interaction = 0.94). Risk of dying at 28 days was reduced by 70% [hazard ratio 0.3 (0.1, 0.9)] in dexmedetomidine patients with sepsis as compared to the lorazepam patients; this reduction in death was not seen in non-septic patients (P-value for interaction = 0.11).ConclusionsIn this subgroup analysis, septic patients receiving dexmedetomidine had more days free of brain dysfunction and mechanical ventilation and were less likely to die than those that received a lorazepam-based sedation regimen. These results were more pronounced in septic patients than in non-septic patients. Prospective clinical studies and further preclinical mechanistic studies are needed to confirm these results.Trial RegistrationNCT00095251.

Risk factors for post-traumatic stress disorder symptoms following critical illness requiring mechanical ventilation: a prospective cohort study

IntroductionPost-traumatic stress disorder (PTSD) has been identified in a significant portion of intensive care unit (ICU) survivors. We sought to identify factors associated with PTSD symptoms in patients following critical illness requiring mechanical ventilation.MethodsForty-three patients who were mechanically ventilated in the medical and coronary ICUs of a university-based medical center were prospectively followed during their ICU admission for delirium with the Confusion Assessment Method for the ICU. Additionally, demographic data were obtained and severity of illness was measured with the APACHE II (Acute Physiology and Chronic Health Evaluation II) score. Six months after discharge, patients were screened for PTSD symptoms by means of the Post-Traumatic Stress Syndrome 10-Questions Inventory (PTSS-10). Multiple linear regression was used to assess the association of potential risk factors with PTSS-10 scores.ResultsAt follow-up, six (14%) patients had high levels of PTSD symptoms. On multivariable analysis, women had higher PTSS-10 scores than men by a margin of 7.36 points (95% confidence interval [CI] 1.62 to 13.11; p = 0.02). Also, high levels of PTSD symptoms were less likely to occur in older patients, with symptoms declining after age 50 (p = 0.04). Finally, although causation cannot be assumed, the total dose of lorazepam received during the ICU stay was associated with PTSD symptoms; for every 10-mg increase in cumulative lorazepam dose, PTSS-10 score increased by 0.39 (95% CI 0.17 to 0.61; p = 0.04). No significant relationship was noted between severity of illness and PTSD symptoms or duration of delirium and PTSD symptoms.ConclusionHigh levels of PTSD symptoms occurred in 14% of patients six months following critical illness necessitating mechanical ventilation, and these symptoms were most likely to occur in female patients and those receiving high doses of lorazepam. High levels of PTSD symptoms were less likely to occur in older patients.

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).

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.

Post-traumatic stress disorder and post-traumatic stress symptoms following critical illness in medical intensive care unit patients: assessing the magnitude of the problem.

IntroductionPost-traumatic stress disorder (PTSD) is a potentially serious psychiatric disorder that has traditionally been associated with traumatic stressors such as participation in combat, violent assault, and survival of natural disasters. Recently, investigators have reported that the experience of critical illness can also lead to PTSD, although details of the association between critical illness and PTSD remain unclear.MethodsWe conducted keyword searches of MEDLINE and Psych Info and investigations of secondary references for all articles pertaining to PTSD in medical intensive care unit (ICU) survivors.ResultsFrom 78 screened papers, 16 studies (representing 15 cohorts) and approximately 920 medical ICU patients met inclusion criteria. A total of 10 investigations used brief PTSD screening tools exclusively as opposed to more comprehensive diagnostic methods. Reported PTSD prevalence rates varied from 5% to 63%, with the three highest prevalence estimates occurring in studies with fewer than 30 patients. Loss to follow-up rates ranged from 10% to 70%, with average loss to follow-up rates exceeding 30%.ConclusionExact PTSD prevalence rates cannot be determined due to methodological limitations such as selection bias, loss to follow-up, and the wide use of screening (as opposed to diagnostic) instruments. In general, the high prevalence rates reported in the literature are likely to be overestimates due to the limitations of the investigations conducted to date. Although PTSD may be a serious problem in some survivors of critical illness, data on the whole population are inconclusive. Because the magnitude of the problem posed by PTSD in survivors of critical illness is unknown, there remains a pressing need for larger and more methodologically rigorous investigations of PTSD in ICU survivors.

The Immunopathogenesis of Sepsis in Elderly Patients

Prominent among the numerous events that contribute to the enhanced susceptibility of elderly patients to infection is the decline of immune function that accompanies aging. Elderly patients experience a marked decline in cell-mediated immune function and reduced humoral immune function. Age-dependent defects in T and B cell function are readily demonstrable in elderly patients, yet the essential elements of innate immunity are remarkably well preserved. The cytokine and chemokine signaling networks are altered in elderly patients and tends to favor a type 2 cytokine response over type 1 cytokine responses. The induction of proinflammatory cytokines after septic stimuli is not adequately controlled by anti-inflammatory mechanisms in elderly persons. This immune dysregulation is accompanied by a more pronounced procoagulant state in older patients. These molecular events function in concert to render elderly patients at excess risk for mortality from severe sepsis and septic shock.