We read the article by Turan et al.  with great interest and would like to congratulate the authors on conducting this large, important, factorial trial. The authors found that neither a “high” (8 cm H2O) positive end-expiratory pressure (PEEP), nor a low (6 ml/kg) tidal volume strategy or a combination impacted postextubation hypoxemia or postoperative pulmonary complications. As such, the trial confirms findings of previous studies that nonindividualized PEEP levels do not improve patient outcomes. It corroborates findings from a large study by Karalapillai et al. that simply randomizing to high versus low tidal volumes does not seem to confer benefit for patients undergoing mechanical ventilation for general anesthesia.

We would like to add two important observations based on recent literature to the discussion of the study by Turan et al.  First, Neto et al.  and others have shown that it is not tidal volume per se that is the critical component of lung protection, but rather the resulting driving pressure, i.e., the interaction of the applied tidal volume with the individual patient’s respiratory system compliance, which is a more accurate determinant of perioperative lung injury and postoperative pulmonary complications. Our group recently corroborated these findings in a cohort of 197,474 surgical patients where higher intraoperative tidal volumes (greater than 8 ml/kg) were associated with increased risk of postoperative respiratory failure only in patients with a low compliance, and this effect was completely mediated by the resulting driving pressure.  In addition to lowering the applied tidal volume, modification of PEEP, which was the second factor in the trial by Turan et al.  can reduce driving pressure through shifting tidal ventilation toward the high-compliance part of the pressure or volume loop. However, even in patients with “healthy” lungs undergoing general anesthesia, PEEP requirements are heterogeneous, and a “standard” PEEP is often inadequate.  To better understand the effect of the study intervention, it would be helpful if the driving pressure per group could be provided by Turan et al. to understand group differentiation regarding this crucial factor. Based on previous literature  it may be hypothesized that the interventions in the present study were effective when they resulted in a reduction in driving pressure, which might be tested in a post hoc analysis. In addition, it would be informative to analyze the effects of lowering tidal volume in patients with a lower respiratory system compliance.  It is highly likely that lung-protective ventilation in the operating room is effective only in patients with impaired compliance. A study that lumps those patients with a mass of healthy patients is bound to show a “negative” result.

Second, it is a classic phenomenon that physicians increase the respiratory rate when lowering tidal volume to maintain minute ventilation and end-tidal carbon dioxide.  This is relevant because it has been shown that increasing repetition of stress and strain might be equally damaging and therefore negates the effect of lowering tidal volume (and, subsequently, driving pressure).  Indeed, in the study by Turan et al., the respiratory rate in the low tidal volume groups was more than 30% higher. Therefore, randomly assigning patients on the basis of factorial clusters with low versus high tidal volumes omitted the weight of impactful components like respiratory rate. Measures have been proposed to quantify this interaction of PEEP, tidal volume, and respiratory rate by estimating the intensity of ventilation. In a cohort of 230,767 surgical patients, we recently observed that an increased intraoperative ventilation intensity quantified by mechanical power was associated with higher odds of postoperative respiratory failure.  This was corroborated by a secondary analysis of the study by Karalapillai et al.  who found that not tidal volume, but ventilation intensity, measured as mechanical power, incorporating the respiratory rate explained the variance in the risk of postoperative pulmonary outcomes. 

There is an impressive success in completing such a large trial in a 2-yr period. Based on the findings from Turan et al. and recent literature, we should move away from studies focusing on single, “standard” ventilator parameters, and we propose that the era of trials of mechanical ventilation in unselected patients in the operating room is over.