Time-varying Intensity of Mechanical Ventilation and Outcomes of Patients with Acute Respiratory Failure

Background: Mortality in acute respiratory failure remains high despite treatment with lung-protective mechanical ventilation. Strategies focusing on limiting driving pressure (∆P) during mechanical ventilation have been proposed to mitigate ventilator-associated lung injury and to further reduce mortality. However, the effectiveness of such sustained interventions in terms of patient-important outcomes remains unclear. Methods: The association between daily dynamic ∆P and ICU mortality was measured using Bayesian joint models in mechanically ventilated patients recorded in the Toronto Intensive Care Observational Registry. In addition, the causal effects of sustained interventions on static or dynamic ∆P on ventilator mortality compared to usual care were estimated under full adherence using the parametric g-formula. Using data from the COVID-19 Critical Care Consortium registry, the treatment effectiveness of extracorporeal life support (ECMO) – a rescue therapy to maintain gas exchange while minimizing exposure to higher intensities of mechanical ventilation – was investigated using marginal structural models with inverse probability weighting in patients with COVID-19-related, acute respiratory failure. Results: Each daily increment in dynamic ∆P was associated with a significant increase in the hazard of death. Ventilator mortality (95% CI) of patients with acute respiratory failure would have been reduced by 0.6% (95% CI: 0.3% to 1.2%) or 1.9% (95% CI: 1.7% to 2.2%) had either daily static or dynamic ∆P been limited ≤ 15 cmH2O, compared to usual care where tidal volumes and plateau pressures were already controlled (risk ratio 0.90, 95% CI 0.89 to 0.92). Secondary analyses showed that early and sustained interventions on ∆P were more effective than brief or later limitations. For patients with COVID-19-related acute respiratory failure, ECMO therapy reduced mortality by 7.1% (8.2% to 6.1%) compared to conventional mechanical ventilation (risk ratio 0.78, 95% CI 0.75 to 0.82). ECMO therapy was most effective if provided early during mechanical ventilation to patients with age < 65 years and PaO2/FiO2 < 80 mmHg or with static ∆P > 15 cmH2O. Conclusion: Early and sustained interventions to limit exposure to higher intensities of mechanical ventilation represent a promising strategy to reduce mortality of patients with acute respiratory failure and should be investigated in future clinical trials.

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