**RATIONALE: **Low-tidal volume ventilation (LTVV; 6 ml/kg) benefits patients with acute respiratory distress syndrome and may aid those with other causes of respiratory failure. Current early ventilation practices are poorly defined.

**OBJECTIVES: **We observed patients with acute respiratory failure to assess the feasibility of a pragmatic trial of LTVV and to guide experimental design.

**METHODS: **We prospectively enrolled consecutive patients with acute respiratory failure admitted to intensive care units expected to participate in the proposed trial. We collected clinical data as well as information on initial and daily ventilator settings and inpatient mortality. We estimated the benefit of LTVV using predictive linear and nonlinear models. We simulated models to estimate power and feasibility of a cluster-randomized trial of LTVV versus usual care in acute respiratory failure.

**RESULTS: **We included 2,484 newly mechanically ventilated patients (31% with acute respiratory distress syndrome) from 49 hospitals. Hospital mortality was 28%. Mean initial tidal volume was 7.1 ml/kg predicted body weight (95% confidence interval, 7.1-7.2), with 78% of patients receiving tidal volumes less than or equal to 8 ml/kg. Our models estimated a mortality benefit of 0-2% from LTVV compared with usual care. Simulation of a stepped-wedged cluster-randomized trial suggested that enrollment of 106,361 patients would be necessary to achieve greater than 90% power.

**CONCLUSIONS: **Use of initial tidal volumes less than 8 ml/kg predicted body weight was common at hospitals participating in the National Heart, Lung, and Blood Institute Prevention and Early Treatment of Acute Lung Injury (PETAL) Network. After considering the size and budgetary requirement for a cluster-randomized trial of LTVV versus usual care in acute respiratory failure, the PETAL Network deemed the proposed trial infeasible. A rapid observational study and simulations to model anticipated power may help better design trials.

**BACKGROUND: **Acute Respiratory Distress Syndrome (ARDS) is an important clinical problem. The definition of ARDS requires an arterial blood gas to define the ratio of partial pressure of arterial oxygen to fraction of inspired oxygen (PaO2/FIO2 ratio). However, many patients with ARDS do not have a blood gas measured, which may result in under-diagnosis of the condition. As a consequence, a method for estimating PaO2 from noninvasive measurements is desirable.

**METHODS: **Using data from three ARDS Network studies, we analyzed the enrollment arterial blood gas to compare non-linear to linear and log-linear imputation methods of estimating PaO2 from hemoglobin percent saturation with oxygen measured by a pulse oximeter (SpO2). We compared mortality on the basis of various measured and imputed PaO2/FIO2 ratio cutoffs to assure clinical equivalence.

**RESULTS: **We studied 1184 patients, of whom 707 had SpO2≤96%. Non-linear imputation from an SpO2/FIO2 ratio resulted in lower error than linear or log-linear imputation (p<0.001) for patients with SpO2≤96% but was equivalent to log-linear imputation in all patients. 90-day hospital mortality was 26-30%, depending on the PaO2/FIO2 ratio, whether non-linearly imputed or measured. On multivariate regression, the association between imputed and measured PaO2 varied by use of vasopressors and SpO2.

**CONCLUSIONS: **A non-linear equation more accurately imputes PaO2/FIO2 from SpO2/FIO2 than linear or log-linear equations, with similar observed hospital mortality of SpO2/FIO2 ratio versus measured PaO2/FIO2 ratios. While further refinement through prospective validation is indicated, a non-linear imputation appears superior to prior approaches to imputation.