The relationship between ventilatory function and cognitive and behavioral impairment in ALS.

Objective: To study the association between ventilatory function and cognitive and behavioral impairment in ALS patients accounting for the effects of pertinent covariates. Methods: Four hundred and eighty-one patients were identified from the Mayo Clinic Florida ALS registry who had concurrent forced vital capacity (FVC) and cognitive and behavioral testing using the ALS Cognitive Behavioral Screen (ALS-CBS). Multiple linear regression analysis was used to study the effects of FVC and relevant covariates on the ALS-CBS cognition score, subscores, and caregiver behavioral inventory. Results: FVC was positively correlated to the cognitive and behavioral subscores on the ALS-CBS (p < 0.001), and the correlation was independent of the effects of site of ALS onset, age, and years of education. Conclusion: Cognitive and behavioral function may be adversely affected by ventilatory impairment in ALS. The presence of cognitive and behavioral impairment warrants a detailed assessment of ventilatory function.

Adjuvant Inhaled Corticosteroids in Community-Acquired Pneumonia: A Review Article.

Community-acquired pneumonia is still a major cause of morbidity and mortality worldwide. Since the inflammatory response induced by the immune system is often a major contributor to the lung injury, it becomes reasonable to assess the potential benefit of anti-inflammatory agents in treating community-acquired pneumonia. The role of corticosteroids as adjunct anti-inflammatory agents in treating community-acquired pneumonia is still controversial. Several studies have assessed the benefit of their use in patients with community-acquired pneumonia. In most of those studies, the route of corticosteroids administration was systemic. The aim of this article is to provide a concise review of the role of corticosteroids in treating community-acquired pneumonia when administered via inhalational route, with the potential benefit of avoiding systemic side effects of corticosteroids while exerting the same anti-inflammatory effects on the lungs. Conclusion: the use of inhaled corticosteroids may be of benefit in certain patient subsets with community-acquired pneumonia. Further randomized controlled trials are needed for better determination of such patient subsets.

The ARREST Pneumonia Clinical Trial. Rationale and Design.

Patients hospitalized for pneumonia are at high risk for mortality. Effective therapies are therefore needed. Recent randomized clinical trials suggest that systemic steroids can reduce the length of hospital stays among patients hospitalized for pneumonia. Furthermore, preliminary findings from a feasibility study demonstrated that early treatment with a combination of an inhaled corticosteroid and a bronchodilator can improve oxygenation and reduce risk of respiratory failure in patients at risk of acute respiratory distress syndrome. Whether such a combination administered early is effective in reducing acute respiratory failure (ARF) among patients hospitalized with pneumonia is unknown. Here we describe the ARREST Pneumonia (Arrest Respiratory Failure due to Pneumonia) trial designed to address this question. ARREST Pneumonia is a two-arm, randomized, double-blinded, placebo-controlled trial designed to test the efficacy of a combination of an inhaled corticosteroid and a ß-agonist compared with placebo for the prevention of ARF in hospitalized participants with severe pneumonia. The primary outcome is ARF within 7 days of randomization, defined as a composite endpoint of intubation and mechanical ventilation; need for high-flow nasal cannula oxygen therapy or noninvasive ventilation for >36 hours (each alone or combined); or death within 36 hours of being placed on respiratory support. The planned enrollment is 600 adult participants at 10 academic medical centers. In addition, we will measure selected plasma biomarkers to better understand mechanisms of action. The trial is funded by the U.S. National Heart Lung and Blood Institute.Clinical trial registered with www.clinicaltrials.gov (NCT04193878).

Rapid, multimodal, critical care knowledge-sharing platform for COVID-19 pandemics.

In many areas of the world, critical care providers caring for COVID-19 patients lacked specific knowledge and were exposed to the abundance of new and unfiltered information. With support from the World Health Organization, we created a multimodal tele-education intervention to rapidly share critical care knowledge related to COVID-19 targeting providers in a region of Southeastern Europe. We delivered 60-minute weekly interactive tele-education sessions over YouTubeTM between March 2020 and May 2020, supplemented by a dedicated webpage. The intervention was reinforced using a secure social media platform (ViberTM), providing continuous rapid knowledge exchange among faculty and learners. A high level of engagement was observed, with over 2000 clinicians participating and actively interacting over a 6-week period. Surveyed participants were highly satisfied with the intervention. Tele-education interventions using social media platforms are feasible, low-cost, and effective methods to share knowledge during the COVID-19 pandemic.

Systemic and Inhaled Corticosteroids, with or without Beta Agonists, as Adjuvant Therapy in Community Acquired Pneumonia.

The aim is to provide a narrative review of the role of corticosteroids, with and without inhaled beta agonist, in communityacquired pneumonia. Community and health-care associated pneumonia remain leading causes of morbidity and mortality despite appropriate antibiotic therapy. The pneumonia-associated adverse outcomes are not only related to the infectious organism, but also to a dysfunctional host-immune response resulting in overwhelming inflammation. Use of systemic corticosteroids as adjuvant therapy in pneumonia remains controversial. Multiple randomized clinical trials evaluating corticosteroids in patients with community acquired pneumonia have found discrepant results in terms of benefits and adverse effects. Inhaled delivery of corticosteroids offer the potential advantage of providing therapeutic benefits directly to the lung, with minimal to no adverse systemic effects. CONCLUSION: Although meta-analyses suggest potential benefits in a select group of patients with more severe pneumonia, the ideal timing, dose, route of delivery, duration, and patient selection remain to be established. A smaller body of literature suggests benefit of inhaled corticosteroids, with or without inhaled beta agonists, but future large scale clinical trials are needed to establish clinical benefit with inhaled delivery.

Hypotension after intensive care unit drop-off in adult cardiac surgery patients.

BACKGROUND: Hypotension is a frequent complication in the intensive care unit (ICU) after adult cardiac surgery. AIM: To describe frequency of hypotension in the ICU following adult cardiac surgery and its relation to the hospital outcomes. METHODS: A retrospective study of post-cardiac adult surgical patients at a tertiary academic medical center in a two-year period. We abstracted baseline demographics, comorbidities, and all pertinent clinical variables. The primary predictor variable was the development of hypotension within the first 30 min upon arrival to the ICU from the operating room (OR). The primary outcome was hospital mortality, and other outcomes included duration of mechanical ventilation (MV) in hours, and ICU and hospital length of stay in days. RESULTS: Of 417 patients, more than half (54%) experienced hypotension within 30 min upon arrival to the ICU. Presence of OR hypotension immediately prior to ICU transfer was significantly associated with ICU hypotension (odds ratio = 1.9; 95% confidence interval: 1.21-2.98; P < 0.006). ICU hypotensive patients had longer MV, 5 (interquartile ranges 3, 15) vs 4 h (interquartile ranges 3, 6), P = 0.012. The patients who received vasopressor boluses (n = 212) were more likely to experience ICU drop-off hypotension (odds ratio = 1.45, 95% confidence interval: 0.98-2.13; P = 0.062), and they experienced longer MV, ICU and hospital length of stay (P < 0.001, for all). CONCLUSION: Hypotension upon anesthesia-to-ICU drop-off is more frequent than previously reported and may be associated with adverse clinical outcomes.

New Diagnosis of Obstructive Sleep Apnea Following Anterior Cervical Discectomy Complicated by Rheumatoid Arthritis: A Case Report.

Obstructive sleep apnea (OSA) is the most common variant of sleep-disordered breathing that often goes undiagnosed. OSA is characterized mainly by anatomical obstruction or partial collapse of upper airways during sleep. The obstruction is multifactorial, and a lesser-known fact is that damage to the pharyngeal plexus during head and neck procedures or placement of hardware in the cervical area can lead to narrowing or collapse of the upper airway. We present such a case of a 59-year-old female who developed new-onset OSA after undergoing anterior cervical discectomy and fusion (ACDF). The severity of OSA worsened with the progression of her rheumatoid arthritis (RA) in the cervical region. This case report aims to raise awareness of such an association among clinicians to enable them to screen appropriate patients for sleep-disordered breathing and treat them accordingly.

Acute pulmonary embolism in patients with obstructive sleep apnea: frequency, hospital outcomes, and recurrence.

STUDY OBJECTIVES: The objectives of this study were to assess the effect of obstructive sleep apnea (OSA) on the risk of acute pulmonary embolism (PE), hospital outcomes including mortality, and PE recurrence. METHODS: We retrospectively enrolled adult patients, admitted to Mayo Clinic Hospital in Rochester, Minnesota, within a 5-year period (2009-2013). We compared frequency of PE, hospital mortality, and secondary outcomes in patients with OSA versus patients without OSA. We assessed risk of PE recurrence in relation to compliance with OSA therapy. RESULTS: Of 25,038 patients, 3,184 (13%) had OSA and 283 (1.1%) experienced PE. Frequency of PE in patients with and without OSA was 2.4% versus 0.9% (odds ratio [OR], 2.51; 95% confidence interval [CI], 1.9-3.3; P < .001). OSA was independently associated with increased risk of PE after adjusting for demographics and comorbidities (OR, 1.44; 95% CI, 1.07-1.9; P = .017). Adjusted hospital mortality was increased in patients with PE (OR, 2.88; 95% CI, 1.7-4.9; P < .001) but not in patients with OSA (OR, 0.98; 95% CI, 0.7-1.4, P = .92). OSA was not a significant determining factor for mortality in patients who experienced a PE (OR, 0.56; 95% CI, 0.1.1-2.78; P = .47), adjusting for demographics, PE severity, and Charlson comorbidity index. Adjusted risk of PE recurrence was greater in patients with OSA compared with patients without OSA (OR, 2.21; 95% CI, 1.05-4.68; P < .04). The patients compliant with OSA therapy had a lower rate of PE recurrence (16% vs 32%; P = not significant). CONCLUSIONS: Although OSA significantly increases risk of acute PE occurrence and recurrences, related hospital mortality was not greater in patients with OSA compared with those without OSA. OSA therapy might have a modifying effect on PE recurrence.

Impact of weekly case-based tele-education on quality of care in a limited resource medical intensive care unit.

BACKGROUND: Limited critical care subspecialty training and experience is available in many low- and middle-income countries, creating barriers to the delivery of evidence-based critical care. We hypothesized that a structured tele-education critical care program using case-based learning and ICU management principles is an efficient method for knowledge translation and quality improvement in this setting. METHODS AND INTERVENTIONS: Weekly 45-min case-based tele-education rounds were conducted in the recently established medical intensive care unit (MICU) in Banja Luka, Bosnia and Herzegovina. The Checklist for Early Recognition and Treatment of Acute Illness (CERTAIN) was used as a platform for structured evaluation of critically ill cases. Two practicing US intensivists fluent in the local language served as preceptors using a secure two-way video communication platform. Intensive care unit structure, processes, and outcomes were evaluated before and after the introduction of the tele-education intervention. RESULTS: Patient demographics and acuity were similar before (2015) and 2 years after (2016 and 2017) the intervention. Sixteen providers (10 physicians, 4 nurses, and 2 physical therapists) evaluated changes in the ICU structure and processes after the intervention. Structural changes prompted by the intervention included standardized admission and rounding practices, incorporation of a pharmacist and physical therapist into the interprofessional ICU team, development of ICU antibiogram and hand hygiene programs, and ready access to point of care ultrasound. Process changes included daily sedation interruption, protocolized mechanical ventilation management and liberation, documentation of daily fluid balance with restrictive fluid and transfusion strategies, daily device assessment, and increased family presence and participation in care decisions. Less effective (dopamine, thiopental, aminophylline) or expensive (low molecular weight heparin, proton pump inhibitor) medications were replaced with more effective (norepinephrine, propofol) or cheaper (unfractionated heparin, H2 blocker) alternatives. The intervention was associated with reduction in ICU (43% vs 27%) and hospital (51% vs 44%) mortality, length of stay (8.3 vs 3.6 days), cost savings ($400,000 over 2 years), and a high level of staff satisfaction and engagement with the tele-education program. CONCLUSIONS: Weekly, structured case-based tele-education offers an attractive option for knowledge translation and quality improvement in the emerging ICUs in low- and middle-income countries.

Correlation Between Oxygen Saturation and Pulse Tracing Patterns on Overnight Oximetry With Normal Desaturation Index Is an Independent Predictor of Obstructive Sleep Apnea.

STUDY OBJECTIVES: Overnight pulse oximetry (OPO) is commonly used as a screening test for obstructive sleep apnea. Heart rate variability (HRV) correlates well with apnea-hypopnea index during polysomnography (PSG). We hypothesized that visual correlation of episodic increase in HRV with minimal oxygen desaturations on normal OPO (oxygen desaturation index less than 5 events/h) is predictive of OSA. METHODS: A retrospective analysis of patients undergoing OPO and PSG in 1 year was performed. We included only OPO performed on room air and interpreted as normal. Visual correlation between simultaneous increase in HRV and minimal oxygen desaturation was independently assessed by three raters, resulting in the consensus agreement. The primary outcome was presence of OSA on the subsequent PSG. RESULTS: Of 936 patients with OPO and PSG, 109 patients had normal overnight oximetry study on room air. Of these, 65 (60%) were females, median (interquartile range) age was 54 years (44, 67), body mass index was 29 kg/m2 (25, 32), and the median oxygen desaturation index was 1.8 events/h (1, 2.7). Consensus agreement identified 54 patients with visual correlation between pulse and minimal oxygen desaturations. Thirty-two patients (29%) were found to have OSA on PSG, of which 24 (75%) could have been accurately predicted by the consensus agreement (odds ratio 4.70, 95% confidence interval 1.87-11.8, P < .001). When adjusted for pertinent clinical and demographic variables, consensus agreement was independently associated with diagnosis of OSA on subsequent PSG (odds ratio 5.6, 95% confidence interval 1.76-20.9, P = .003). CONCLUSIONS: Visual correlation between episodic increase in HRV and minimal oxygen desaturations on OPO is an independent predictor of OSA, and promising marker for clinical use.

Early Machine-Human Interface around Sepsis Severity Identification: From Diagnosis to Improved Management?

OBJECTIVE: To investigate the statistical measures of the performance of 2 interventions: a) early sepsis identification by a computerized sepsis "sniffer" algorithm (CSSA) in the emergency department (ED) and b) human decision to activate a multidisciplinary early resuscitation sepsis and shock response team (SSRT). METHODS: This study used a prospective and historical cohort study design to evaluate the performance of two interventions. INTERVENTION: A computerized sepsis sniffer algorithm (CSSA) to aid in early diagnosis and a multidisciplinary sepsis and shock response team (SSRT) to improve patient care by increasing compliance with Surviving Sepsis Campaign (SSC) bundles. RESULTS: The CSSA yielded a sensitivity of 100% (95% CI, 99.13-100%) and a specificity of 96.2% (95% CI, 95.55-96.45%) to identifying sepsis in the ED (Table 1). The SSRT resource was activated appropriately in 34.1% (86/252) of patients meeting severe sepsis or septic shock criteria; the SSRT was inappropriately activated only three times in sepsis-only patients. In 53% (134/252) of cases meeting criteria for SSRT activation, the critical care team was consulted as opposed to activating the SSRT resource. CONCLUSION: Our two-step machine-human interface approach to patients with sepsis utilized an outstandingly sensitive and specific electronic tool followed by more specific human decision-making.

Sleep Apnea in Patients Hospitalized With Acute Ischemic Stroke: Underrecognition and Associated Clinical Outcomes.

STUDY OBJECTIVES: To evaluate clinical recognition of sleep apnea and related outcomes in patients hospitalized with acute ischemic stroke. METHODS: A retrospective study of all patients hospitalized with acute ischemic stroke from April 2008 to December 2014. The primary predictor and outcome variables were sleep apnea and hospital mortality, respectively. Secondary outcomes were mechanical ventilation, hospital length of stay, and the survivor's functional level by the modified Rankin scale. A sensitivity multivariate regression analysis included the propensity score for cardiovascular comorbidities and sleep apnea. RESULTS: Of 989 patients, 190 (19%) were considered to have sleep apnea. Only 42 patients (22%) received any treatment for sleep apnea during the hospital stay. Despite higher prevalence of cardiovascular comorbidities, the patients with sleep apnea had lower hospital mortality, 1% versus 5.6% in patients without sleep apnea (odds ratio [OR] 0.18; 95% confidence interval [CI], 0.03-0.58, P = .002). Only the National Institutes of Health Stroke Scale (NIHSS) and the Glasgow coma scale (GCS) were significant predictors of adjusted hospital mortality (OR 1.06, 95% CI 1.01-1.11, P = .01 and OR 0.61, 95% CI 0.51-0.69, P ≤ .001, respectively). A composite clinical propensity score for sleep apnea and cardiovascular comorbidities was significantly associated with decreased mortality, independent to either NIHSS (OR 0.11, 95% CI 0.017-0.71; P = .02) or GCS (OR 0.07, 95% CI 0.01-0.52; P = .01). CONCLUSIONS: Prevalence of sleep apnea in our study was low, likely because of clinical underrecognition. Despite having more cardiovascular disease, the patients with acute stroke and sleep apnea had less severe neurological injury and lower unadjusted mortality than those without a history of sleep apnea.

Risk stratification using SpO2/FiO2 and PEEP at initial ARDS diagnosis and after 24 h in patients with moderate or severe ARDS.

BACKGROUND: We assessed the potential of risk stratification of ARDS patients using SpO2/FiO2 and positive end-expiratory pressure (PEEP) at ARDS onset and after 24 h. METHODS: We used data from a prospective observational study in patients admitted to a mixed medical-surgical intensive care unit of a university hospital in the Netherlands. Risk stratification was by cutoffs for SpO2/FiO2 and PEEP. The primary outcome was in-hospital mortality. Patients with moderate or severe ARDS with a length of stay of > 24 h were included in this study. Patients were assigned to four predefined risk groups: group I (SpO2/FiO2 ≥ 190 and PEEP < 10 cm H2O), group II (SpO2/FiO2 ≥ 190 and PEEP ≥ 10 cm), group III (SpO2/FiO2 < 190 and PEEP < 10 cm H2O) and group IV (SpO2/FiO2 < 190 and PEEP ≥ 10 cm H2O). RESULTS: The analysis included 456 patients. SpO2/FiO2 and PaO2/FiO2 had a strong relationship (P < 0.001, R 2 = 0.676) that could be described in a linear regression equation (SpO2/FiO2 = 42.6 + 1.0 * PaO2/FiO2). Risk stratification at initial ARDS diagnosis resulted in groups that had no differences in in-hospital mortality. Risk stratification at 24 h resulted in groups with increasing mortality rates. The association between group assignment at 24 h and outcome was confounded by several factors, including APACHE IV scores, arterial pH and plasma lactate levels, and vasopressor therapy. CONCLUSIONS: In this cohort of patients with moderate or severe ARDS, SpO2/FiO2 and PaO2/FiO2 have a strong linear relationship. In contrast to risk stratification at initial ARDS diagnosis, risk stratification using SpO2/FiO2 and PEEP after 24 h resulted in groups with worsening outcomes. Risk stratification using SpO2/FiO2 and PEEP could be practical, especially in resource-limited settings.

Neurological outcomes of patients with history of obstructive sleep apnea after a cardiac arrest.

BACKGROUND: Cardiac arrest survivors may have disabilities due to hypoxic brain injury. Patients with obstructive sleep apnea are exposed to intermittent hypoxemia that may lead to ischemic preconditioning. We have hypothesized that patients with obstructive sleep apnea have better neurological outcomes following a cardiac arrest due to preconditioning of the brain. METHODS: We retrospectively analyzed all the survivors of in-hospital cardiac arrest from January 2006 to September 2016. Patients with confirmed or suspected obstructive sleep apnea were selected for further analysis and those without were used as comparison. Primary outcome was neurological functionality on hospital discharge by the Cerebral Performance Category. RESULTS: A total of 739 patients had cardiac arrest within the study period. The immediate mortality rate was 59% (N=43) in patients with obstructive sleep apnea and 94% (N=623) in those without (p<0.001). Approximately 10% (N=73) were discharged alive and these were selected for further analysis. Patients without obstructive sleep apnea had more frequently "Poor" outcomes compared to those with obstructive sleep apnea (OR 2.91; 95% CI, 1.11-7.66; p=0.03). After adjusting in a multivariate analysis, obstructive sleep apnea was "protective" of "Poor" neurological outcomes: adjusted OR 0.21; 95% CI, 0.06-0.64; p=0.01. CONCLUSION: Patients with obstructive sleep apnea had better unadjusted survival rates, and favorable adjusted neurological outcomes at discharge compared to those without obstructive sleep apnea. These results suggest that obstructive sleep apnea patients may tolerate better acute brain ischemia due to preconditioning.

Current challenges in the management of sepsis in ICUs in resource-poor settings and suggestions for the future.

BACKGROUND: Sepsis is a major reason for intensive care unit (ICU) admission, also in resource-poor settings. ICUs in low- and middle-income countries (LMICs) face many challenges that could affect patient outcome. AIM: To describe differences between resource-poor and resource-rich settings regarding the epidemiology, pathophysiology, economics and research aspects of sepsis. We restricted this manuscript to the ICU setting even knowing that many sepsis patients in LMICs are treated outside an ICU. FINDINGS: Although many bacterial pathogens causing sepsis in LMICs are similar to those in high-income countries, resistance patterns to antimicrobial drugs can be very different; in addition, causes of sepsis in LMICs often include tropical diseases in which direct damaging effects of pathogens and their products can sometimes be more important than the response of the host. There are substantial and persisting differences in ICU capacities around the world; not surprisingly the lowest capacities are found in LMICs, but with important heterogeneity within individual LMICs. Although many aspects of sepsis management developed in rich countries are applicable in LMICs, implementation requires strong consideration of cost implications and the important differences in resources. CONCLUSIONS: Addressing both disease-specific and setting-specific factors is important to improve performance of ICUs in LMICs. Although critical care for severe sepsis is likely cost-effective in LMIC setting, more detailed evaluation at both at a macro- and micro-economy level is necessary. Sepsis management in resource-limited settings is a largely unexplored frontier with important opportunities for research, training, and other initiatives for improvement.

Randomized Clinical Trial of a Combination of an Inhaled Corticosteroid and Beta Agonist in Patients at Risk of Developing the Acute Respiratory Distress Syndrome.

OBJECTIVES: Effective pharmacologic treatments directly targeting lung injury in patients with the acute respiratory distress syndrome are lacking. Early treatment with inhaled corticosteroids and beta agonists may reduce progression to acute respiratory distress syndrome by reducing lung inflammation and enhancing alveolar fluid clearance. DESIGN: Double-blind, randomized clinical trial (ClinicalTrials.gov: NCT01783821). The primary outcome was longitudinal change in oxygen saturation divided by the FIO2 (S/F) through day 5. We also analyzed categorical change in S/F by greater than 20%. Other outcomes included need for mechanical ventilation and development of acute respiratory distress syndrome. SETTING: Five academic centers in the United States. PATIENTS: Adult patients admitted through the emergency department at risk for acute respiratory distress syndrome. INTERVENTIONS: Aerosolized budesonide/formoterol versus placebo bid for up to 5 days. MEASUREMENTS AND MAIN RESULTS: Sixty-one patients were enrolled from September 3, 2013, to June 9, 2015. Median time from presentation to first study drug was less than 9 hours. More patients in the control group had shock at enrollment (14 vs 3 patients). The longitudinal increase in S/F was greater in the treatment group (p = 0.02) and independent of shock (p = 0.04). Categorical change in S/F improved (p = 0.01) but not after adjustment for shock (p = 0.15). More patients in the placebo group developed acute respiratory distress syndrome (7 vs 0) and required mechanical ventilation (53% vs 21%). CONCLUSIONS: Early treatment with inhaled budesonide/formoterol in patients at risk for acute respiratory distress syndrome is feasible and improved oxygenation as assessed by S/F. These results support further study to test the efficacy of inhaled corticosteroids and beta agonists for prevention of acute respiratory distress syndrome.

Sepsis and Shock Response Team: Impact of a Multidisciplinary Approach to Implementing Surviving Sepsis Campaign Guidelines and Surviving the Process.

The Surviving Sepsis Campaign guidelines are designed to decrease mortality through consistent application of a 7-element bundle. This study evaluated the impact of improvement in bundle adherence using a time-series analysis of compliance with the bundle elements before and after interventions intended to improve the process, while also looking at hospital mortality. This article describes interventions used to improve bundle compliance and hospital mortality in patients admitted through the emergency department with sepsis, severe sepsis, or septic shock. Quality improvement methodology was used to develop high-impact interventions that led to dramatically improved adherence to the Surviving Sepsis Campaign guidelines bundle. Improved performance was associated with a significant decrease in the in-hospital mortality of severe sepsis patients presenting to the emergency department.

Effect of Aspirin on Development of ARDS in At-Risk Patients Presenting to the Emergency Department: The LIPS-A Randomized Clinical Trial.

IMPORTANCE: Management of acute respiratory distress syndrome (ARDS) remains largely supportive. Whether early intervention can prevent development of ARDS remains unclear. OBJECTIVE: To evaluate the efficacy and safety of early aspirin administration for the prevention of ARDS. DESIGN, SETTING, AND PARTICIPANTS: A multicenter, double-blind, placebo-controlled, randomized clinical trial conducted at 16 US academic hospitals. Between January 2, 2012, and November 17, 2014, 7673 patients at risk for ARDS (Lung Injury Prediction Score ≥4) in the emergency department were screened and 400 were randomized. Ten patients were excluded, leaving 390 in the final modified intention-to-treat analysis cohort. INTERVENTIONS: Administration of aspirin, 325-mg loading dose followed by 81 mg/d (n = 195) or placebo (n = 195) within 24 hours of emergency department presentation and continued to hospital day 7, discharge, or death. MAIN OUTCOMES AND MEASURES: The primary outcome was the development of ARDS by study day 7. Secondary measures included ventilator-free days, hospital and intensive care unit length of stay, 28-day and 1-year survival, and change in serum biomarkers associated with ARDS. A final α level of .0737 (α = .10 overall) was required for statistical significance of the primary outcome. RESULTS: Among 390 analyzed patients (median age, 57 years; 187 [48%] women), the median (IQR) hospital length of stay was 6 3-10) days. Administration of aspirin, compared with placebo, did not significantly reduce the incidence of ARDS at 7 days (10.3% vs 8.7%, respectively; odds ratio, 1.24 [92.6% CI, 0.67 to 2.31], P = .53). No significant differences were seen in secondary outcomes: ventilator-free to day 28, mean (SD), 24.9 (7.4) days vs 25.2 (7.0) days (mean [90% CI] difference, -0.26 [-1.46 to 0.94] days; P = .72); ICU length of stay, mean (SD), 5.2 (7.0) days vs 5.4 (7.0) days (mean [90% CI] difference, -0.16 [-1.75 to 1.43] days; P = .87); hospital length of stay, mean (SD), 8.8 (10.3) days vs 9.0 (9.9) days (mean [90% CI] difference, -0.27 [-1.96 to 1.42] days; P = .79); or 28-day survival, 90% vs 90% (hazard ratio [90% CI], 1.03 [0.60 to 1.79]; P = .92) or 1-year survival, 73% vs 75% (hazard ratio [90% CI], 1.06 [0.75 to 1.50]; P = .79). Bleeding-related adverse events were infrequent in both groups (aspirin vs placebo, 5.6% vs 2.6%; odds ratio [90% CI], 2.27 [0.92 to 5.61]; P = .13). RESULTS: Among 390 analyzed patients (median age, 57 years; 187 [48%] women), median (IQR) hospital length of stay was 6 (3-10) days. Administration of aspirin, compared with placebo, did not significantly reduce the incidence of ARDS at 7 days (OR, 1.24; 92.6%CI, 0.67-2.31). No significant differences were seen in secondary outcomes or adverse events. [table: see text] CONCLUSIONS AND RELEVANCE: Among at-risk patients presenting to the ED, the use of aspirin compared with placebo did not reduce the risk of ARDS at 7 days. The findings of this phase 2b trial do not support continuation to a larger phase 3 trial. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01504867.

How to improve assessment of balance in baseline characteristics of clinical trial participants-example from PROSEVA trial data?

The randomization process is expected to balance assignment between the groups, independent to the participant and/or investigator, and as such avoids systematic error. However, it is recognized that groups assigned through the randomization process are not completely the same. Generally, a table with baseline characteristics is provided, where investigators report demographic and pertinent clinical variables based on the random group assignment and P values for the each variable in attempt to either support the balanced assignment or to indicate that the balance between groups was not ideal. The recently published PROSEVA trial showed more than 50% relative risk reduction of 28-day mortality among ARDS patients in the prone group compared to the supine group. In order to demonstrate a novel approach and exemplify how imbalance in baseline characteristics between groups could have potentially contributed to the large observed effect, we pooled pertinent baseline clinical variables from the trial in a meta-analysis-like manner. In addition to the quantification, we assigned the variable's "quality" of probable effect on the outcome as likely beneficial or harmful. After pooling pertinent dichotomous variables by the probability of their effect on the outcome, it appeared that approximately 37% (18% to 60%) of the observed PROSEVA trial effect could have been due to differences in baseline clinical characteristics. The main limitation of this approach is that all variables are assumed to have similar weights on the outcome. Interestingly, the weights of beneficial and harmful effects on the outcome were very similar. The proposed method of assessment of potential imbalance between the intervention groups assesses not only the magnitude of the difference, but rather the pooled probability of beneficial or harmful effect towards outcome, as well. As such, it could be useful as a secondary measure for the assessment of imbalance in the trials with the unexpectedly large observed effects.