Diurnal sedative changes during intensive care: impact on liberation from mechanical ventilation and delirium.

OBJECTIVE: To determine whether benzodiazepine and propofol doses are increased at night and whether daytime and nighttime sedative doses are associated with delirium, coma, and delayed liberation from mechanical ventilation. DESIGN: Single-center, prospective cohort study nested within the Awakening and Breathing Controlled randomized trial. SETTING: Saint Thomas Hospital in Nashville, TN, from 2004 to 2006. PATIENTS: Adult patients receiving mechanical ventilation for >12 hrs with continuous recording of hourly sedation dosing. INTERVENTIONS: We measured hourly doses of benzodiazepine and propofol exposure during the daytime (7 AM to 11 PM) and nighttime (11 PM to 7 AM) for 5 days. We quantified nighttime dose increases by subtracting the average hourly daytime dose on the preceding day from subsequent average hourly nighttime dose. We used multivariable logistic regression to determine whether daytime and nighttime dose increases were independently associated with delirium, coma, and delayed liberation from mechanical ventilation. MEASUREMENTS AND MAIN RESULTS: Among 140 patients, the median Acute Physiology and Chronic Health Evaluation II score was 27 (interquartile range 22-33). Among those receiving the sedatives, benzodiazepine and propofol doses were increased at night on 40% and 41% of patient-days, respectively. Of 485 patient-days, delirium was present on 160 (33%) and coma on 206 (42%). In adjusted models, greater daytime benzodiazepine dose was independently associated with failed spontaneous breathing trial and extubation, and subsequent delirium (p<.02 for all). Nighttime increase in benzodiazepine dose was associated with failed spontaneous breathing trial (p<.01) and delirium (p=.05). Daytime propofol dose was marginally associated with subsequent delirium (p=.06). CONCLUSIONS: Nearly half of mechanically ventilated intensive care unit patients received greater doses of sedation at night, a practice associated with failed spontaneous breathing trials, coma, and delirium. Over the first 5 days in our study, patients spent 75% of their time in coma or delirium, outcomes that may be reduced by efforts to decrease sedative exposure during both daytime and nighttime hours in the intensive care unit.

Age-, sex-, and race-based differences among patients enrolled versus not enrolled in acute lung injury clinical trials.

OBJECTIVE: Little is known about the participation of racial/ethnic minorities, women, and the elderly into critical care clinical trials. We sought to characterize the representation of racial and ethnic minorities, women, and older patients in clinical trials of patients with acute lung injury and to determine the reasons for nonenrollment. DESIGN, SETTING, AND PATIENTS: We performed a cross-sectional analysis of pooled screening logs from 44 academic hospitals participating in three multicentered, randomized, controlled trials conducted by the Acute Respiratory Distress Syndrome Network from 1996 to 2005. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We calculated odds ratios of enrollment for age, sex, racial groups, and the odds ratio for the presence of each exclusion criterion by age, sex, and race adjusted for demographics, acute lung injury risk factor, study, and study center. A total of 10.4% of 17,459 screened patients with acute lung injury were enrolled. The median (range) enrollment by center was 15% (2% to 88%). Older patients of both sexes were less likely to be enrolled, but older women were more likely to be enrolled than older men. The adjusted odds ratio (95% confidence interval) for enrollment among men > or =75 yrs of age was 0.59 (0.45 to 0.77) and for women > or =75 yrs of age was 0.45 (0.32 to 0.62) compared with men <35 yrs of age. There were no differences in the likelihood of enrollment among all racial/ethnic groups. Older patients and men were less likely to be enrolled because of medical comorbidity. Among all patients who were not enrolled, black patients and their families refused participation more often than white patients. CONCLUSIONS: Older patients are less likely to be enrolled in acute lung injury clinical trials. There is no evidence that women or racial/ethnic minorities are underrepresented in acute lung injury clinical trials.

Cost-effectiveness of implementing low-tidal volume ventilation in patients with acute lung injury.

BACKGROUND: Despite widespread guidelines recommending the use of lung-protective ventilation (LPV) in patients with acute lung injury (ALI), many patients do not receive this lifesaving therapy. We sought to estimate the incremental clinical and economic outcomes associated with LPV and determined the maximum cost of a hypothetical intervention to improve adherence with LPV that remained cost-effective. METHODS: Adopting a societal perspective, we developed a theoretical decision model to determine the cost-effectiveness of LPV compared to non-LPV care. Model inputs were derived from the literature and a large population-based cohort of patients with ALI. Cost-effectiveness was determined as the cost per life saved and the cost per quality-adjusted life-years (QALYs) gained. RESULTS: Application of LPV resulted in an increase in QALYs gained by 15% (4.21 years for non-LPV vs 4.83 years for LPV), and an increase in lifetime costs of $7,233 per patient with ALI ($99,588 for non-LPV vs $106,821 for LPV). The incremental cost-effectiveness ratios for LPV were $22,566 per life saved at hospital discharge and $11,690 per QALY gained. The maximum, cost-effective, per patient investment in a hypothetical program to improve LPV adherence from 50 to 90% was $9,482. Results were robust to a wide range of economic and patient parameter assumptions. CONCLUSIONS: Even a costly intervention to improve adherence with low-tidal volume ventilation in patients with ALI reduces death and is cost-effective by current societal standards.

Implementation and impact of a translational research training program in pulmonary and critical care medicine.

BACKGROUND: The translation of basic research advances to the clinical arena has been slow and inefficient. With the goal of improving interactions and collaboration between basic science and clinical investigators, we instituted a Translational Research Training Program (TRTP) in acute lung injury to complement our basic science and clinical research training programs in pulmonary and critical care medicine. METHODS: We developed a TRTP in which trainees select a primary research discipline for rigorous development of skills in either basic science research or clinical research. This primary foundation is complemented by cross-training in the other discipline through a specifically designed program of study. To measure the impact of the program, we analyzed publication rates, coauthorship to reflect collaboration between research disciplines, and publication of papers with a translational focus by members of our division before and after the institution of the TRTP. RESULTS: We describe our new training program, including modifications to our preexisting program and development of new components. We found significant increases in multidisciplinary authorship and translational articles following institution of TRTP. CONCLUSIONS: An explicit TRTP appears to increase collaboration between basic and clinical investigators. Our goal is to share our experiences and provide a template for other pulmonary and critical care programs interested in developing similar curricula. We speculate that this training will improve the translation of basic research findings into clinical advances, thus increasing the probability that successful treatments will be developed for patients with lung diseases.

Intensive care unit-acquired neuromyopathy and corticosteroids in survivors of persistent ARDS.

OBJECTIVES: To determine the incidence and outcomes of intensive care unit-acquired neuromyopathy and to investigate the role of methylprednisolone in survivors of persistent acute lung injury. DESIGN: Secondary analysis of completed randomized placebo-controlled trial. SETTING: Twenty-five hospitals in the NHLBI ARDS Network. PATIENTS AND PARTICIPANTS: Patients enrolled in the ARDS Network study of methylprednisolone versus placebo for persistent ARDS who survived 60 days or to hospital discharge. MEASUREMENTS AND RESULTS: One hundred and twenty-eight study patients survived 60 days. Forty-three (34%) of these patients had evidence by chart review of ICU-acquired neuromyopathy, which was associated with prolonged mechanical ventilation, return to mechanical ventilation, and delayed return to home after critical illness. Treatment with methylprednisolone was not significantly associated with an increase in risk of neuromyopathy (OR 1.5; 95% CI 0.7-3.2). CONCLUSIONS: ICU-acquired-neuromyopathy is common among survivors of persistent ARDS and is associated with poorer clinical outcomes. We did not find a significant association between methylprednisolone treatment and neuromyopathy. Limitations of this study preclude definitive conclusions about the causal relationship between corticosteroids and ICU-acquired neuromuscular dysfunction.

The effect of an intensive care unit staffing model on tidal volume in patients with acute lung injury.

INTRODUCTION: Little is known about the mechanisms through which intensivist physician staffing influences patient outcomes. We aimed to assess the effect of closed-model intensive care on evidence-based ventilatory practice in patients with acute lung injury (ALI). METHODS: We conducted a secondary analysis of a prospective population-based cohort of 759 patients with ALI who were alive and ventilated on day three of ALI, and were cared for in 23 intensive care units (ICUs) in King County, Washington. RESULTS: We compared day three tidal volume (VT) in open versus closed ICUs adjusting for potential patient and ICU confounders. In 13 closed model ICUs, 429 (63%) patients were cared for. Adjusted mean VT (mL/Kg predicted body weight (PBW) or measured body weight if height not recorded) for patients in closed ICUs was 1.40 mL/Kg PBW (95% confidence interval (CI) = 0.57 to 2.24 mL/Kg PBW) lower than patients in open model ICUs. Patients in closed ICUs were more likely (odds ratio (OR) = 2.23, 95% CI = 1.09 to 4.56) to receive lower VT (or= 12 mL/Kg PBW) compared with patients cared for in open ICUs, independent of other covariates. The effect of closed ICUs on hospital mortality was not changed after accounting for delivered VT. CONCLUSIONS: Patients with ALI cared for in closed model ICUs are more likely to receive lower VT and less likely to receive higher VT, but there were no other differences in measured processes of care. Moreover, the difference in delivered VT did not completely account for the improved mortality observed in closed model ICUs.

Predictors of hospital mortality in a population-based cohort of patients with acute lung injury.

OBJECTIVE: Studies describing predictors of mortality in patients with acute lung injury were primarily derived from selected academic centers. We sought to determine the predictors of mortality in a population-based cohort of patients with acute lung injury and to characterize the performance of current severity of illness scores in this population. DESIGN: Secondary analysis of a prospective, multicenter, population-based cohort. SETTING: Twenty-one hospitals in Washington State. PATIENTS: The cohort included 1,113 patients with acute lung injury identified during the year 1999-2000. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We evaluated physiology, comorbidities, risk factors for acute lung injury, and other variables for their association with death at hospital discharge. Bivariate predictors of death were entered into a multiple logistic regression model. We compared Acute Physiology and Chronic Health Evaluation (APACHE) II, APACHE III, and Simplified Acute Physiology Score II to the multivariable model using area under the receiver operating characteristic curve. The model was validated in an independent cohort of 886 patients with acute lung injury. Modified acute physiology score, age, comorbidities, arterial pH, minute ventilation, PaCO2, PaO2/FiO2 ratio, intensive care unit admission source, and intensive care unit days before onset of acute lung injury were independently predictive of in-hospital death (p < .05). The area under the receiver operating characteristic curve for the multivariable model was superior to that of APACHE III (.81 vs. .77, p < .001) but was no different after external validation (.71 vs. .70, p = .64). CONCLUSIONS: The predictors of mortality in patients with acute lung injury are similar to those predictive of mortality in the general intensive care unit population, indicating disease heterogeneity within this cohort. Accordingly, APACHE III predicts mortality in acute lung injury as well as a model using variables selected specifically for patients with acute lung injury.

Effect of intensive care unit organizational model and structure on outcomes in patients with acute lung injury.

RATIONALE: Prior studies supported an association between intensive care unit (ICU) organizational model or staffing patterns and outcome in critically ill patients. OBJECTIVES: To examine the association of closed versus open models with patient mortality across adult ICUs in King County (WA). METHODS: Cohort study of patients with acute lung injury (ALI). MEASUREMENTS AND MAIN RESULTS: ICU structure, organization, and patient care practices were assessed using self-administered mail questionnaires completed by the medical director and nurse manager. We defined closed ICUs as units that required patient transfer to or mandatory patient comanagement by an intensivist and open ICUs as those relying on other organizational models. Outcomes were obtained from the King County Lung Injury Project, a population-based cohort of patients with ALI. The main endpoint was hospital mortality. Of 24 eligible ICUs, 13 ICUs were designated closed and 11 open. Complete survey data were available for 23 (96%) ICUs. Higher physician and nurse availability was reported in closed versus open ICUs. A total of 684 of 1,075 (63%) of patients with ALI were cared for in closed ICUs. After adjusting for potential confounders, patients with ALI cared for in closed ICUs had reduced hospital mortality (adjusted odds ratio, 0.68; 95% confidence interval, 0.53, 0.89; P = 0.004). Consultation by a pulmonologist in open ICUs was not associated with improved mortality (adjusted odds ratio, 0.94; 95% confidence interval, 0.74, 1.20; P = 0.62). These findings were robust for varying assumptions about the study population definition. CONCLUSIONS: Patients with ALI cared for in a closed-model ICU have reduced mortality. These data support recommendations to implement structured intensive care in the United States.

Hemodynamic monitoring in shock and implications for management. International Consensus Conference, Paris, France, 27-28 April 2006.

OBJECTIVE: Shock is a severe syndrome resulting in multiple organ dysfunction and a high mortality rate. The goal of this consensus statement is to provide recommendations regarding the monitoring and management of the critically ill patient with shock. METHODS: An international consensus conference was held in April 2006 to develop recommendations for hemodynamic monitoring and implications for management of patients with shock. Evidence-based recommendations were developed, after conferring with experts and reviewing the pertinent literature, by a jury of 11 persons representing five critical care societies. DATA SYNTHESIS: A total of 17 recommendations were developed to provide guidance to intensive care physicians monitoring and caring for the patient with shock. Topics addressed were as follows: (1) What are the epidemiologic and pathophysiologic features of shock in the ICU? (2) Should we monitor preload and fluid responsiveness in shock? (3) How and when should we monitor stroke volume or cardiac output in shock? (4) What markers of the regional and micro-circulation can be monitored, and how can cellular function be assessed in shock? (5) What is the evidence for using hemodynamic monitoring to direct therapy in shock? One of the most important recommendations was that hypotension is not required to define shock, and as a result, importance is assigned to the presence of inadequate tissue perfusion on physical examination. Given the current evidence, the only bio-marker recommended for diagnosis or staging of shock is blood lactate. The jury also recommended against the routine use of (1) the pulmonary artery catheter in shock and (2) static preload measurements used alone to predict fluid responsiveness. CONCLUSIONS: This consensus statement provides 17 different recommendations pertaining to the monitoring and caring of patients with shock. There were some important questions that could not be fully addressed using an evidence-based approach, and areas needing further research were identified.

The association between body mass index and clinical outcomes in acute lung injury.

BACKGROUND: The association between body mass index (BMI) and outcomes in critically ill patients is unclear. Our objective was to determine the association between BMI and outcomes in a population-based cohort of patients with acute lung injury (ALI). METHODS: In a prospective cohort study of all ICU patients in King County, Washington, with ALI in 1 year (1999 to 2000), 825 patients had a BMI recorded. Using multivariate analysis, patients in the abnormal BMI groups were compared to normal patients in the following areas: mortality, hospital length of stay (LOS), ICU LOS, duration of mechanical ventilation, and discharge disposition. RESULTS: There was no mortality difference in any of the abnormal BMI groups compared to normal-weight patients. Severely obese patients had longer hospital LOS than normal-weight patients (mean increase, 10.5 days; 95% confidence interval [CI], 4.8 to 16.2 days; p < 0.001); this was accentuated when analysis was restricted to survivors (mean increase, 14.3 days; 95% CI, 7.1 to 21.6 days; p < 0.001). ICU LOS and duration of mechanical ventilation were also longer in the severely obese group when analysis was restricted to survivors (mean increase, 5.6 days; 95% CI, 1.3 to 9.8 days; p = 0.01; and mean increase, 4.1 days; 95% CI, 0.4 to 7.7 days, respectively; p = 0.03). Severely obese patients were more likely to be discharged to a rehabilitation or skilled nursing facility than to home. CONCLUSIONS: BMI is not associated with mortality in patients with ALI, but severe obesity is associated with increased morbidity and resource utilization in the hospital and after discharge.

Therapy for late-phase acute respiratory distress syndrome.

Prolonged hypoxemic respiratory failure and evidence of lung organization and fibrosis are features of an ARDS subgroup that is variably identified as "late," "persistent," or "fibroproliferative" ARDS. Early reports suggested that patients with late ARDS had a high mortality unless treated with corticosteroids. A large recent study with improved methodology has demonstrated that despite improvements of pulmonary physiology, corticosteroids do not change mortality of patients who continue to meet ARDS criteria 7 to 28 days after onset of acute lung injury. Additionally, there is no compelling evidence that persistent ARDS confers a higher mortality than that of ALI/ARDS. Observational and interventional studies are needed to increase understanding of the incidence, best management, and outcomes of patients with persistent ARDS.

Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome.

BACKGROUND: Persistent acute respiratory distress syndrome (ARDS) is characterized by excessive fibroproliferation, ongoing inflammation, prolonged mechanical ventilation, and a substantial risk of death. Because previous reports suggested that corticosteroids may improve survival, we performed a multicenter, randomized controlled trial of corticosteroids in patients with persistent ARDS. METHODS: We randomly assigned 180 patients with ARDS of at least seven days' duration to receive either methylprednisolone or placebo in a double-blind fashion. The primary end point was mortality at 60 days. Secondary end points included the number of ventilator-free days and organ-failure-free days, biochemical markers of inflammation and fibroproliferation, and infectious complications. RESULTS: At 60 days, the hospital mortality rate was 28.6 percent in the placebo group (95 percent confidence interval, 20.3 to 38.6 percent) and 29.2 percent in the methylprednisolone group (95 percent confidence interval, 20.8 to 39.4 percent; P=1.0); at 180 days, the rates were 31.9 percent (95 percent confidence interval, 23.2 to 42.0 percent) and 31.5 percent (95 percent confidence interval, 22.8 to 41.7 percent; P=1.0), respectively. Methylprednisolone was associated with significantly increased 60- and 180-day mortality rates among patients enrolled at least 14 days after the onset of ARDS. Methylprednisolone increased the number of ventilator-free and shock-free days during the first 28 days in association with an improvement in oxygenation, respiratory-system compliance, and blood pressure with fewer days of vasopressor therapy. As compared with placebo, methylprednisolone did not increase the rate of infectious complications but was associated with a higher rate of neuromuscular weakness. CONCLUSIONS: These results do not support the routine use of methylprednisolone for persistent ARDS despite the improvement in cardiopulmonary physiology. In addition, starting methylprednisolone therapy more than two weeks after the onset of ARDS may increase the risk of death. (ClinicalTrials.gov number, NCT00295269.).

Hypercapnic acidosis and mortality in acute lung injury.

OBJECTIVE: We tested the hypothesis that hypercapnic acidosis is associated with reduced mortality rate in patients with acute lung injury independent of changes in mechanical ventilation. DESIGN: Secondary analysis of randomized clinical trial data using hypothesis-driven multivariate logistic regression. SETTING: Randomized, multiple-center trial (n = 861) comparing 12 mL/kg to 6 mL/kg predicted body weight tidal volumes previously published by the National Institutes of Health Acute Respiratory Distress Syndrome (ARDS) Network. PATIENTS: Acute lung injury patients enrolled in a randomized, multiple-center trial (n = 861). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The adjusted odds ratio and 95% confidence intervals (CI) for 28-day mortality rate associated with hypercapnic acidosis defined as day 1 pH <7.35 and Pa(CO2) >45 mm Hg were 0.14 (95% CI 0.03-0.70, p = .016) in the 12 mL/kg predicted body weight tidal volume group and 1.18 (95% CI 0.59-2.35, p = .639) in the 6 mL/kg predicted body weight tidal volume group. Other definitions of hypercapnic acidosis spanning a range of magnitudes suggest a dose-response association between hypercapnic acidosis and 28-day mortality in the 12 mL/kg predicted body weight tidal volume group. None of our definitions of hypercapnic acidosis were associated with reduction in 28-day mortality in the 6 mL/kg predicted body weight tidal volume group. CONCLUSIONS: Hypercapnic acidosis was associated with reduced 28-day mortality in the 12 mL/kg predicted body weight tidal volume group after controlling for comorbidities and severity of lung injury. These results are consistent with a protective effect of hypercapnic acidosis against ventilator-associated lung injury that was not found when the further ongoing injury was reduced by 6 mL/kg predicted body weight tidal volumes.

Incidence and outcomes of acute lung injury.

BACKGROUND: Acute lung injury is a critical illness syndrome consisting of acute hypoxemic respiratory failure with bilateral pulmonary infiltrates that are not attributed to left atrial hypertension. Despite recent advances in our understanding of the mechanism and treatment of acute lung injury, its incidence and outcomes in the United States have been unclear. METHODS: We conducted a prospective, population-based, cohort study in 21 hospitals in and around King County, Washington, from April 1999 through July 2000, using a validated screening protocol to identify patients who met the consensus criteria for acute lung injury. RESULTS: A total of 1113 King County residents undergoing mechanical ventilation met the criteria for acute lung injury and were 15 years of age or older. On the basis of this figure, the crude incidence of acute lung injury was 78.9 per 100,000 person-years and the age-adjusted incidence was 86.2 per 100,000 person-years. The in-hospital mortality rate was 38.5 percent. The incidence of acute lung injury increased with age from 16 per 100,000 person-years for those 15 through 19 years of age to 306 per 100,000 person-years for those 75 through 84 years of age. Mortality increased with age from 24 percent for patients 15 through 19 years of age to 60 percent for patients 85 years of age or older (P<0.001). We estimate that each year in the United States there are 190,600 cases of acute lung injury, which are associated with 74,500 deaths and 3.6 million hospital days. CONCLUSIONS: Acute lung injury has a substantial impact on public health, with an incidence in the United States that is considerably higher than previous reports have suggested.

Causes and timing of death in patients with ARDS.

BACKGROUND: Since the early 1980s, case fatality of patients with ARDS has decreased, and explanations are unclear. DESIGN AND METHODS: Using identical definitions of ARDS and organ failure, we analyzed consecutive cohorts of patients meeting syndrome criteria at our institution in 1982 (n = 46), 1990 (n = 112), 1994 (n = 99), and 1998 (n = 205) to determine causes and timing of death. RESULTS: Overall case fatality has decreased from 68% in 1981-1982 to a low of 29% in 1996, plateauing since the mid-1990s (p = 0.001 for trend). Sepsis syndrome with multiple organ failure remains the most common cause of death (30 to 50%), while respiratory failure causes a small percentage (13 to 19%) of deaths. The distribution of causes of death has not changed over time. There was no change in the timing of death during the study periods: 26 to 44% of deaths occurred early (< 72 h after ARDS onset), and 56 to 74% occurred late (> 72 h after ARDS onset). However, the increased survival over the past 2 decades is entirely accounted for by patients who present with trauma and other risk factors for their ARDS, while survival for those patients whose risk factor is sepsis has not changed. Additionally, withdrawal of life support in these patients is now occurring at our institution significantly more frequently than in the past, and median time until death has decreased in patients who have support withdrawn. CONCLUSIONS: While these results do not explain the overall case fatality decline in ARDS, they do indicate that sepsis syndrome remains the leading cause of death and suggest that future therapies to improve survival be targeted at reducing the complications of sepsis.

Death rounds: end-of-life discussions among medical residents in the intensive care unit.

PURPOSE: We introduced "Death Rounds," a monthly discussion of the issues and emotions surrounding the care of dying patients, into the intensive care unit (ICU) rotations for medical house staff. We surveyed participating residents to evaluate their satisfaction with these discussions. SUBJECTS AND METHODS: Death Rounds occurred at university-based teaching hospitals in Seattle, Washington and Salt Lake City, Utah, between October 2000 and March 2002. Residents who had attended Death Rounds were surveyed in April 2002. RESULTS: A 10-item survey was distributed by e-mail to 116 residents in Utah and Washington. Of 116 residents, 97 (84%) responded to the survey; 50 of these 97 had attended at least one Death Rounds. Of these 50, the majority reported that Death Rounds were worthwhile (76%) and that sessions should be incorporated into all ICU rotations (76%). CONCLUSIONS: Death Rounds provide a unique opportunity for residents to discuss the issues raised in caring for dying patients. This conference can be easily incorporated into the ICU curriculum. Most residents who participated in the survey indicated that they valued Death Rounds and believed that it should be included in all ICU rotations.