INTRODUCTION: Despite recent modifications, the clinical definition of the acute respiratory distress syndrome (ARDS) remains non-specific, leading to under-diagnosis and under-treatment. This study was designed to test the hypothesis that a biomarker panel would be useful for biologic confirmation of the clinical diagnosis of ARDS in patients at risk of developing ARDS due to severe sepsis. METHODS: This was a retrospective case control study of 100 patients with severe sepsis and no evidence of ARDS compared to 100 patients with severe sepsis and evidence of ARDS on at least two of their first four ICU days. A panel that included 11 biomarkers of inflammation, fibroblast activation, proteolytic injury, endothelial injury, and lung epithelial injury was measured in plasma from the morning of ICU day two. A backward elimination model building strategy on 1,000 bootstrapped data was used to select the best performing biomarkers for further consideration in a logistic regression model for diagnosis of ARDS. RESULTS: Using the five best-performing biomarkers (surfactant protein-D (SP-D), receptor for advanced glycation end-products (RAGE), interleukin-8 (IL-8), club cell secretory protein (CC-16), and interleukin-6 (IL-6)) the area under the receiver operator characteristic curve (AUC) was 0.75 (95% CI: 0.7 to 0.84) for the diagnosis of ARDS. The AUC improved to 0.82 (95% CI: 0.77 to 0.90) for diagnosis of severe ARDS, defined as ARDS present on all four of the first four ICU days. CONCLUSIONS: Abnormal levels of five plasma biomarkers including three biomarkers generated by lung epithelium (SP-D, RAGE, CC-16) provided excellent discrimination for diagnosis of ARDS in patients with severe sepsis. Altered levels of plasma biomarkers may be useful biologic confirmation of the diagnosis of ARDS in patients with sepsis, and also potentially for selecting patients for clinical trials that are designed to reduce lung epithelial injury.

Rationale

The contribution of air pollution to the risk of acute respiratory distress syndrome (ARDS) is unknown.

Methods

We studied 1,558 critically ill patients enrolled in a prospective observational study at a tertiary medical center who lived less than 50 km from an air quality monitor and had an ARDS risk factor. Pollutant exposures (ozone, NO2, SO2, particulate matter < 2.5 μm, particulate matter < 10 μm) were assessed by weighted average of daily levels from the closest monitors for the prior 3 years. Associations between pollutant exposure and ARDS risk were evaluated by logistic regression controlling for age, race, sex, smoking, alcohol, insurance status, rural versus urban residence, distance to study hospital, and Acute Physiology and Chronic Health Evaluation II.

Measurements and main results

The incidence of ARDS increased with increasing ozone exposure: 28% in the lowest exposure quartile versus 32, 40, and 42% in the second, third, and fourth quartiles (P < 0.001). In a logistic regression model controlling for potential confounders, ozone exposure was associated with risk of ARDS in the entire cohort (odds ratio, 1.58 [95% confidence interval, 1.27-1.96]) and more strongly associated in the subgroup with trauma as their ARDS risk factor (odds ratio, 2.26 [95% confidence interval, 1.46-3.50]). There was a strong interaction between ozone exposure and current smoking status (P = 0.007). NO2 exposure was also associated with ARDS but not independently of ozone exposure. SO2, particulate matter less than 2.5 μm, and particulate matter less than 10 μm were not associated with ARDS.

Conclusions

Long-term ozone exposure is associated with development of ARDS in at-risk critically ill patients, particularly in trauma patients and current smokers. Ozone exposure may represent a previously unrecognized environmental risk factor for ARDS.

Abstract Introduction Despite recent modifications, the clinical definition of the acute respiratory distress syndrome (ARDS) remains non-specific, leading to under-diagnosis and under-treatment. This study was designed to test the hypothesis that a biomarker panel would be useful for biologic confirmation of the clinical diagnosis of ARDS in patients at risk of developing ARDS due to severe sepsis. Methods This was a retrospective case control study of 100 patients with severe sepsis and no evidence of ARDS compared to 100 patients with severe sepsis and evidence of ARDS on at least two of their first four ICU days. A panel that included 11 biomarkers of inflammation, fibroblast activation, proteolytic injury, endothelial injury, and lung epithelial injury was measured in plasma from the morning of ICU day two. A backward elimination model building strategy on 1,000 bootstrapped data was used to select the best performing biomarkers for further consideration in a logistic regression model for diagnosis of ARDS. Results Using the five best-performing biomarkers (surfactant protein-D (SP-D), receptor for advanced glycation end-products (RAGE), interleukin-8 (IL-8), club cell secretory protein (CC-16), and interleukin-6 (IL-6)) the area under the receiver operator characteristic curve (AUC) was 0.75 (95% CI: 0.7 to 0.84) for the diagnosis of ARDS. The AUC improved to 0.82 (95% CI: 0.77 to 0.90) for diagnosis of severe ARDS, defined as ARDS present on all four of the first four ICU days. Conclusions Abnormal levels of five plasma biomarkers including three biomarkers generated by lung epithelium (SP-D, RAGE, CC-16) provided excellent discrimination for diagnosis of ARDS in patients with severe sepsis. Altered levels of plasma biomarkers may be useful biologic confirmation of the diagnosis of ARDS in patients with sepsis, and also potentially for selecting patients for clinical trials that are designed to reduce lung epithelial injury.

Background

Given the persistent shortage of organs for transplantation, new donor management strategies to improve both organ utilization and quality of procured organs are needed. Current management protocols for the care of the deceased donor before organ procurement are based on physiological rationale, experiential reasoning, and retrospective studies without rigorous testing. Although many factors contribute to the lack of controlled clinical trials in donor management, a major factor is the unique challenges posed by research in the brain-dead organ donor.

Methods and results

This article describes the study design and the challenges faced during implementation of the Beta-agonists for Oxygenation in Lung Donors (BOLD) study, a randomized, placebo-controlled clinical trial of nebulized albuterol vs. placebo in 500 organ donors. The study design and implementation are described with emphasis on aspects of the study that are unique to research in brain-dead organ donors.

Conclusions

Experience gained during the design and implementation of the BOLD study should be useful for investigators planning future clinical trials in the brain-dead donor population and for intensivists who are involved in the care of the brain-dead organ donor.

Background and objective

Quality measures used in pay-for-performance systems are intended to address specific quality goals, such as safety, efficiency, effectiveness, timeliness, equity, and patient-centeredness. Given the small number of narrowly focused measures in prostate cancer care, we sought to determine whether adherence to any of the available payer-driven quality measures influences patient-centered outcomes, including health-related quality of life (HRQOL), patient satisfaction, and treatment-related complications.

Methods

The Comparative Effectiveness Analysis of Surgery and Radiation study is a population-based, prospective cohort study that enrolled 3708 men with clinically localized prostate cancer during 2011 and 2012, of whom 2601 completed the 1-year survey and underwent complete chart abstraction. Compliance with 6 quality indicators endorsed by national consortia was assessed. Multivariable regression was used to determine the relationship between indicator compliance and Expanded Prostate Cancer Index Composite (EPIC-26) instrument summary scores, satisfaction scale scores (service satisfaction scale for cancer care), and treatment-related complications.

Results

Overall rates of compliance with these quality measures ranged between 64% and 88%. Three of the 6 measures were weakly associated with 1-year sexual function and bowel function scores (β=-4.6, 1.69, and 2.93, respectively; P≤0.05), whereas the remaining measures had no significant relationship with patient-reported HRQOL outcomes. Satisfaction scores and treatment-related complications were not associated with quality measure compliance.

Conclusions

Compliance with available nationally endorsed quality indicators, which were designed to incentivize effective and efficient care, was not associated with clinically important changes in patient-centered outcomes (HRQOL, satisfaction, or complications) within 1-year.

Background

While randomized controlled trials represent the highest level of evidence we can generate in comparative effectiveness research, there are clinical scenarios where this type of study design is not feasible. The Comparative Effectiveness Analyses of Surgery and Radiation in localized prostate cancer (CEASAR) study is an observational study designed to compare the effectiveness and harms of different treatments for localized prostate cancer, a clinical scenario in which randomized controlled trials have been difficult to execute and, when completed, have been difficult to generalize to the population at large.

Methods

CEASAR employs a population-based, prospective cohort study design, using tumor registries as cohort inception tools. The primary outcome is quality of life after treatment, measured by validated instruments. Risk adjustment is facilitated by capture of traditional and nontraditional confounders before treatment and by propensity score analysis.

Results

We have accrued a diverse, representative cohort of 3691 men in the USA with clinically localized prostate cancer. Half of the men invited to participate enrolled, and 86% of patients who enrolled have completed the 6-month survey.

Conclusion

Challenging comparative effectiveness research questions can be addressed using well-designed observational studies. The CEASAR study provides an opportunity to determine what treatments work best, for which patients, and in whose hands.

Rationale

Exposure to air pollution has molecular and physiologic effects on the lung that may increase the risk of acute respiratory distress syndrome (ARDS) after injury.

Objectives

To determine the association of short- and long-term air pollutant exposures and ARDS risk after severe trauma.

Methods

We analyzed data from a prospective cohort of 996 critically ill patients presenting with acute trauma and an injury severity score greater than 15. Exposures to ozone, nitrogen dioxide, sulfur dioxide, carbon monoxide, and particulate matter less than 2.5 μm were assessed by weighted averages of daily levels from all monitors within 50 km of the geocoded location of a patient's residence. Patients were followed for 6 days for the development of ARDS according to Berlin Criteria. The association between each exposure and ARDS was determined via multivariable logistic regression adjusting for potential confounders.

Measurements and main results

ARDS developed in 243 (24%) patients. None of the short-term exposures averaged over the 3 days before presentation was associated with ARDS, except sulfur dioxide, which demonstrated a nonlinear association. Nitrogen dioxide, sulfur dioxide, and particulate matter less than or equal to 2.5 μm in aerodynamic diameter exposure over the 6 weeks before presentation was significantly associated with ARDS (P < 0.05). All long-term exposures (3 yr) were associated with ARDS (P < 0.01) in adjusted models, despite exposure levels largely below U.S. and European Union air quality standards.

Conclusions

Long-term low- to moderate-level air pollutant exposure is associated with a greater risk of developing ARDS after severe trauma and represents a novel and potentially modifiable environmental risk factor for ARDS.

Objective

To provide population-based estimates of other-cause mortality by age and comorbidity in men with prostate cancer for use at the point of care in shared decision making.

Materials and methods

We sampled 3183 men with nonmetastatic prostate cancer from the Prostate Cancer Outcomes Study, a US population-based prospective cohort. Survival analysis accounting for competing risks was used to provide predictions of other-cause and cancer-specific mortality by age, comorbidity, and tumor risk through 14 years of follow-up.

Results

Older men had a higher absolute risk of other-cause mortality associated with comorbidity. For men with comorbidity counts of 0, 1, 2, and 3+, cumulative incidence of other-cause mortality at 14 years was 9%, 18%, 30%, and 35% for those younger than 60 years; 26%, 26%, and 48%, and 52% for those aged 60-70 years; and 49%, 57%, 66%, and 74% for those older than 70 years. Prostate cancer mortality at 14 years was 5%, 8%, and 23% for men with low-, intermediate-, and high-risk disease. Competing risk pictograms for each age/comorbidity/tumor-risk pair provide visual characterization of these risks over time.

Conclusion

Our survival tables may be used at the point of care as part of shared decision making. Men aged >60 years with multiple comorbidities have substantial risk of other-cause mortality within 15 years of diagnosis and should consider conservative management for low-risk disease, given its low incidence of cancer-specific mortality. Men with high-risk disease, regardless of age or comorbidity, are at greater risk for cancer mortality and may still be appropriate candidates for aggressive treatment.

OBJECTIVE: To evaluate the safety, feasibility, and efficacy of combined adrenergic blockade with propranolol and clonidine in patients with severe traumatic brain injury (TBI). BACKGROUND: Administration of adrenergic blockade after severe TBI is common. To date, no prospective trial has rigorously evaluated this common therapy for benefit. METHODS: This phase II, single-center, double-blinded, pilot randomized placebo-controlled trial included patients aged 16-64 years with severe TBI (intracranial hemorrhage and Glasgow Coma Scale score ≤ 8) within 24 h of ICU admission. Patients received propranolol and clonidine or double placebo for 7 days. The primary outcome was ventilator-free days (VFDs) at 28 days. Secondary outcomes included catecholamine levels, hospital length of stay, mortality, and long-term functional status. A planned futility assessment was performed mid-study. RESULTS: Dose compliance was 99%, blinding was intact, and no open-label agents were used. No treatment patient experienced dysrhythmia, myocardial infarction, or cardiac arrest. The study was stopped for futility after enrolling 47 patients (26 placebo, 21 treatment), per a priori stopping rules. There was no significant difference in VFDs between treatment and control groups [0.3 days, 95% CI (- 5.4, 5.8), p = 1.0]. Other than improvement of features related to sympathetic hyperactivity (mean difference in Clinical Features Scale (CFS) 1.7 points, CI (0.4, 2.9), p = 0.012), there were no between-group differences in the secondary outcomes. CONCLUSION: Despite the safety and feasibility of adrenergic blockade with propranolol and clonidine after severe TBI, the intervention did not alter the VFD outcome. Given the widespread use of these agents in TBI care, a multi-center investigation is warranted to determine whether adrenergic blockade is of therapeutic benefit in patients with severe TBI. Trial Registration Number NCT01322048.

BACKGROUND: Prior studies have shown significant variability in the quality of prostate cancer care in the US with questionable associations between quality measures and patient reported outcomes. We evaluated the impact of compliance with nationally recognized radiation therapy (RT) quality measures on patient-reported health-related quality of life (HRQOL) outcomes in the Comparative Effectiveness Analysis of Surgery and Radiation (CEASAR) cohort. METHODS: CEASAR is a population-based, prospective cohort study of men with localized prostate cancer from which we identified 649 who received primary RT and completed HRQOL surveys for inclusion. Eight quality measures were identified based on national guidelines. We analyzed the impact of compliance with these measures on HRQOL assessed by the 26-item Expanded Prostate Index Composite at pre-specified intervals up to 5 years after treatment. Multivariable analysis was performed controlling for demographic and clinicopathologic features. RESULTS: Among eligible participants, 566 (87%) patients received external beam radiation therapy and 83 (13%) received brachytherapy. Median age was 69 years (interquartile range: 64-73), 33% had low-, 43% intermediate-, and 23% high-risk disease. 28% received care non-compliant with at least one measure. In multivariable analyses, while some statistically significant associations were identified, there were no clinically significant associations between compliance with evaluated RT quality measures and patient reported urinary irritative, urinary incontinence, bowel, sexual or hormonal function. CONCLUSIONS: Compliance with RT quality measures was not meaningfully associated with patient-reported outcomes after prostate cancer treatment. Further work is needed to identify patient-centered quality measures of prostate cancer care.