Background There is no effective pharmacotherapy for the acute respiratory distress syndrome (ARDS), and mortality remains high. Preclinical studies support the efficacy of mesenchymal stem (stromal) cells (MSCs) in the treatment of lung injury. The aim of this phase one clinical trial was to test the safety of a single dose of allogeneic bone marrow-derived MSCs in patients with moderate-to-severe ARDS. Methods The STem cells for ARDS Treatment (START) trial was a multi-center, open-label, dose-escalation phase one clinical trial of a single dose of intravenous MSCs in patients with moderate-to-severe ARDS. The trial is registered with clinicaltrials.gov number [NCT01775774]. The first three patients were treated with low dose MSCs (1million cells/kg predicted body weight (PBW)); the next three patients received intermediate dose MSCs (5 million cells/kg PBW); and the final three patients received high dose MSCs (10 million cells/kg PBW). Primary outcomes included the incidence of pre-specified infusion associated events and serious adverse events. Secondary outcomes included standard respiratory and systemic endpoints, 28- and 60-day mortality, and measurement of biologic markers of inflammation and endothelial and epithelial injury. The trial completed enrollment in January 2014. Findings There were no pre-specified infusion associated events or treatment-related adverse events in any of the nine patients in this trial. Serious adverse events (SAEs) were subsequently observed in three patients during in the weeks following the infusion: two patients expired >seven days after the MSC infusion, and one patient was discovered to have multiple embolic infarcts of the spleen, kidneys, and brain that were age-indeterminate but thought to have occurred prior the MSC infusion based on MRI results. None of these SAEs were thought to be MSC-related. Interpretation A single intravenous infusion of allogeneic, bone marrow-derived human MSCs was well tolerated in 9 patients with moderate to severe ARDS. Based on this phase one experience, we have proceeded to phase two testing of MSCs for moderate to severe ARDS. Funding The trial was funded by the National Heart, Lung and Blood Institute (NHLBI U01HL10871301).

Background-Treatment with bone-marrow-derived mesenchymal stromal cells (MSCs) has shown benefits in preclinical models of acute respiratory distress syndrome (ARDS). Safety has not been established for administration of MSCs in critically ill patients with ARDS. We did a phase 2a trial to assess safety after administration of MSCs to patients with moderate to severe ARDS.Methods-We did a prospective, double-blind, multicentre, randomised trial to assess treatment with one intravenous dose of MSCs compared with placebo. We recruited ventilated patients with

Rationale: Accurate, early identification of patients at risk for developing acute lung injury (ALI) provides the opportunity to test and implement secondary prevention strategies. Objectives: To determine the frequency and outcome of ALI development in patients at risk and validate a lung injury prediction score (LIPS). Methods: In this prospective multicenter observational cohort study, predisposing conditions and risk modifiers predictive of ALI development were identified from routine clinical data available during initial evaluation. The discrimination of the model was assessed with area under receiver operating curve (AUC). The risk of death from ALI was determined after adjustment for severity of illness and predisposing conditions. Measurements and Main Results: Twenty-two hospitals enrolled 5,584 patients at risk. ALI developed a median of 2 (interquartile range 1-4) days after initial evaluation in 377 (6.8%; 148 ALI-only, 229 adult respiratory distress syndrome) patients. The frequency of ALI varied according to predisposing conditions (from 3% in pancreatitis to 26% after smoke inhalation). LIPS discriminated patients who developed ALI from those who did not with an AUC of 0.80 (95% confidence interval, 0.78-0.82). When adjusted for severity of illness and predisposing conditions, development of ALI increased the risk of in-hospital death (odds ratio, 4.1; 95% confidence interval, 2.9-5.7). Conclusions: ALI occurrence varies according to predisposing conditions and carries an independently poor prognosis. Using routinely available clinical data, LIPS identifies patients at high risk for ALI early in the course of their illness. This model will alert clinicians about the risk of ALI and facilitate testing and implementation of ALI prevention strategies. Clinical trial registered with www.clinicaltrials.gov (NCT00889772).

Background: The relationship between body mass index (BMI) and development of acute respiratory distress syndrome (ARDS) is unknown. Methods: A cohort study of critically ill patients at risk for ARDS was carried out. BMI was calculated from admission height and weight. Patients were screened daily for AECC (American European Consensus Committee)-defined ARDS and 60-day ARDS mortality. Results: Of 1795 patients, 83 (5%) patients were underweight (BMI ,18.5 kg/m 2 ), 627 (35%) normal (BMI 18.5-24.9), 605 (34%) overweight (BMI 25-29.9), 364 (20%) obese (BMI 30-39.9) and 116 (6%) severely obese (BMI >40). Increasing weight was associated with younger age (p,0.001), diabetes (p,0.0001), higher blood glucose (p,0.0001), lower prevalence of direct pulmonary injury (p,0.0001) and later development of ARDS (p = 0.01). BMI was associated with ARDS on multivariate analysis (OR adj 1.24 per SD increase; 95% CI 1.11 to 1.39). Similarly, obesity was associated with ARDS compared with normal weight (OR adj 1.66; 95% CI 1.21 to 2.28 for obese; OR adj 1.78; 95% CI 1.12 to 2.92 for severely obese). Exploratory analysis in a subgroup of intubated patients without ARDS on admission (n = 1045) found that obese patients received higher peak (p,0.0001) and positive end-expiratory pressures (p,0.0001) than non-obese patients. Among patients with ARDS, increasing BMI was associated with increased length of stay (p = 0.007) but not with mortality (OR adj 0.89 per SD increase; 95% CI 0.71 to 1.12). Conclusion: BMI was associated with increased risk of ARDS in a weight-dependent manner and with increased length of stay, but not with mortality. Additional studies are needed to determine whether differences in initial ventilator settings may contribute to ARDS development in the obese.