Overall, 35 of 520 patients were excluded from analysis: 32 (6%) had no eligible ventilator settings and three (<1%) had missing data on height required for calculating predicted body weight and adherence to lung protective ventilation (fig 1). Thus data from 485 patients, with 6240 eligible ventilator settings and 12
202 total ventilator settings, were available for analysis. For the secondary analysis of complete data, 30 (6%) of the 485 eligible patients were excluded owing to missing ventilator variables required for measuring the primary exposure, leaving 455 patients with 4938 eligible ventilator settings and 10
321 total ventilator settings.
Fig 1Flow of patients through study
Tables 1 and 2 present the patients’ characteristics, ventilator variables, and other covariates related to the intensive care unit, by adherence to lung protective ventilation and by two year mortality status. Of 485 patients, 274 (57%) were male and the median age (years) was 53 (interquartile range 42-63). Patients were predominantly admitted to a medical (compared with surgical) intensive care unit, with a median severity of illness (acute physiology and chronic health evaluation II) score of 27 (interquartile range 20-33, table 1). The median number of eligible ventilator settings per patient was 8 (interquartile range 3-15). The median duration (days) of mechanical ventilation was 9 (interquartile range 5-17), stay in the intensive care unit was 13 (8-22), and hospital stay was 21 (13-36).
Table 1 Patients’ characteristics, by ventilator adherence and mortality status at two years. Values are numbers (percentages) unless stated otherwise
Table 2 Mechanical ventilation variables by adherence to lung protection and mortality status at two years.* Values are median (interquartile range) unless stated otherwise
Of 6240 eligible ventilator settings, 2548 (41%) were adherent to lung protective ventilation, with no significant temporal trends in adherence observed over the three year study period. Of the 485 patients, 417 (86%) received 50% or less and 68 (14%) received more than 50% of their twice daily ventilator settings adherent to lung protective ventilation. A total of 180 (37%) patients never received lung protective ventilation during any of their twice daily ventilator settings. Patients who were ever (versus never) exposed to lung protective ventilation were younger, and a significantly greater proportion were male and received neuromuscular blockers (table 1).
Overall, 311 (64%) of the 485 patients died during the two years after onset of acute lung injury. Mortality status at two years was not available for 29 (6.0%) of the 485 patients, and these patients were censored in the analysis. The mortality rate increased over time, particularly over the first year of follow-up, from 44% at 30 days to 52% at 90 days and 62% at one year (fig 2). Those who were alive after two years were significantly younger with lower comorbidity, severity of illness, and organ failure scores (table 1).
Fig 2Unadjusted Kaplan-Meier survival curve, with 95% confidence limits, for 485 patients with acute lung injury in primary analysis
During the two year follow-up, survival was independently associated with several covariates: younger age; lower comorbidity, organ failure scores, cumulative fluid balance, and days with neuromuscular blockers; and a greater number of high frequency oscillation or airway pressure release ventilator settings (table 3). After adjusting for the total duration of mechanical ventilation and all other covariates, for each additional adherent ventilator setting measured twice daily, the risk of mortality over two years decreased by 3% (hazard ratio 0.97, 95% confidence interval 0.95 to 0.99, P=0.002). For a prototypical patient, this finding equates to an estimated absolute risk reduction in two year mortality of 4.0% (95% confidence interval 0.8% to 7.2%, P=0.012) for 50% ventilator adherence and 7.8% (1.6% to 14.0%, P=0.011) for 100% adherence compared with a 49.7% baseline mortality under the assumption of no adherence to lung protective ventilation (fig 3).
Table 3 Predictors of two year survival for patients with acute lung injury
Fig 3Predicted absolute risk reduction in mortality by adherence to lung protective ventilation. Estimates based on Cox proportional hazards regression model with time varying covariates used to predict survival estimates for a prototypical patient (more ...)
The results of the primary analysis of 485 patients were robust to varying both the tidal volume and the plateau pressure thresholds used to define adherence to lung protective ventilation. In addition, the primary results using multiple imputation for missing data were similar when replicated in the secondary analysis of 455 patients, which excluded those with complete missing data for the primary exposure, with a hazard ratio for each additional adherent ventilator setting of 0.96 (95% confidence interval 0.94 to 0.99, P=0.001). Finally, results of the post hoc propensity score analyses were consistent with results from the primary analysis.
Compared with a mean tidal volume <6.5 mL/kg predicted body weight, the adjusted hazard ratios for two year mortality for a mean tidal volume of 6.5 to 8.5 mL/kg predicted body weight was 1.59 (1.19 to 2.14, P=0.001) and for >8.5 mL/kg predicted body weight was 1.97 (1.23 to 3.16, P=0.004). Moreover, when tidal volume was modelled as a continuous variable, no evidence supported a non-linear relation between two year survival and mean tidal volume (fig 4; P=0.182 for the non-linear terms of a cubic spline model), with an adjusted hazard ratio of 1.18 (1.07 to 1.31, P=0.001), indicating an 18% relative increase in mortality for each 1 mL/kg predicted body weight increase in average tidal volume.
Fig 4Predicted change in hazard of mortality for increasing mean tidal volume, based on multivariable Cox model, across 485 patients with acute lung injury. A more flexible non-linear Cox model for mean tidal volume (cubic spline with three degrees (more ...)