The potentially injurious effect of positive pressure mechanical ventilation on the lungs of patients with ARDS has been broadly recognized for more than 25 years.1 Re-cognizing that the application of high distending pressures to the injured lungs results in lung injury indistinguishable from that observed in patients with ARDS led to the widespread implementation of lung-protective ventilation strategies by using low tidal volumes (VT).2 However, applying lung-protective strategies to patients without ARDS has failed to consistently show a benefit in terms of reducing mortality.3 The key underlying concept here is that high VT does not induce ventilator-induced lung injury (VILI) per se, with the actual driver of VILI being the excessive lung stress and strain that a given VT generates.4 Driving pressure represents the distending pressure of the respiratory system with tidal ventilation and, therefore, is a surrogate of the effect of a given VT on these determinants of VILI.5 Driving pressure was shown to determine the effect of a low VT ventilation strategy on mortality in subjects with ARDS,6 and a driving pressure < 15 cm H2O is proposed as a target when setting the ventilator5 (although this hypothesis has never been evaluated in a clinical trial). Previous studies failed to show an association between driving pressure and mortality in subjects without ARDS.7,8
In this issue of Respiratory Care, Roca et al9 provide evidence that driving pressure is also associated with the risk of developing ARDS, which contributes to the growing literature that suggests that driving pressure is in the causal pathway of VILI. The investigators analyzed data from a multi-center prospective observational study on 1,575 subjects without ARDS who were receiving controlled mechanical ventilation.9 They found that higher driving pressure in the first 2 days of mechanical ventilation was associated with an increased risk of developing ARDS in the subsequent days.9 Importantly, their results were robust across several sensitivity analyses and by using bootstrap validation. Unlike other studies that explored the same question in which an association between driving pressure and mortality was not observed,7,8 this is the first report in which subjects who progressed to ARDS actually had higher driving pressure versus those who did not progress to ARDS (mean ± SD driving pressure, 15 ± 5 cm H2O vs 12 ± 5 cm H2O).9 The study by Roca et al9 is important because it provides evidence that ARDS can be induced in non-injured lungs when injurious mechanical ventilation is applied. These findings have implications for clinical practice and for future research.
Prevention is better than cure. Until now, lung-protective ventilation is recommended for patients with established ARDS. The notion that ARDS can be generated de novo by injurious mechanical ventilation settings can shift the paradigm of lung-protective ventilation to prevention of VILI rather than focusing on mitigating the deleterious effects of positive-pressure ventilation in patients once lung injury is established. If elevated driving pressure causes VILI, then proactive measures to limit driving pressure could be implemented. Given that > 95% of the patients who require mechanical ventilation do not have ARDS at the onset of respiratory support,10 the potential benefit of a reduction in the risk of VILI in this population is substantial.
Importantly, the diagnosis of ARDS is often missed by clinicians.11 The Berlin definition of ARDS12 has moderate inter-observer reliability, and even experienced clinicians disagree with regard to the presence or absence of ARDS in a given patient.13 Interestingly, mortality among patients in which there is consensus in the diagnosis of ARDS is similar to that when expert physicians disagree on ARDS diagnosis,14 which suggests that the biology of ARDS is different than what the Berlin definition says ARDS is.12 Failure to recognize the presence of ARDS could lead to the underutilization of inexpensive, readily available, and lifesaving lung-protective ventilation strategies. Adhering to a driving pressure-limited ventilation strategy in most patients who received mechanical ventilation could ensure that safe mechanical ventilation is delivered regardless of clinician recognition of ARDS,12 which reduces the risk of iatrogenic complications.
Moreover, driving pressure could be used not only as a target to provide safe mechanical ventilation but also as a trigger for escalation to rescue interventions in ARDS. Current recommendations suggest the use of oxygenation thresholds to guide the implementation of adjuvant strategies,15 and the Berlin definition of ARDS does not incorporate any indicator of lung mechanics or of the effect of mechanical ventilation on lung stress and/or strain (respiratory system compliance was originally considered in the draft definition but was later removed from the final criteria because the consensus panel believed that adding this variable did not improve the predictive validity of the definition for mortality). However, a number of considerations support the hypothesis of using driving pressure as a trigger to consider escalation to more complex interventions aimed at enhancing lung protection. In trials that evaluated the effect of a low VT and high PEEP strategy, reductions in driving pressure more accurately reflected the benefit of adopting this strategy compared with changes in /..16 Similarly, in the ARMA trial,17 which evaluated the effect of low versus high VT ventilation in ARDS, oxygenation was worse in the low VT arm throughout the first week, whereas mortality was significantly reduced.
In a secondary analysis of the largest trial that evaluated the effect of prone positioning in ARDS, gas exchange improvement after prone positioning was not associated with increased survival.18 Finally, in a trial on venovenous extracorporeal membrane oxygenation (VV-ECMO) versus standard lung-protective ventilation strategies, the largest benefit of initiating therapy with VV-ECMO was observed in the subgroup of subjects who required VV-ECMO to facilitate lung-protective ventilation (an effect that was not observed in the subgroup of subjects with oxygenation-driven entry criteria).19 In this same trial, only driving pressure, and not , was improved in the intervention arm, in which a benefit in mortality was observed. Taken together, these observations suggest that high stress and/or strain are the key factors that drive mortality in ARDS and strengthen the hypothesis that the goal of these rescue therapies is to enable lung-protective ventilation. A potential algorithm for the management of ARDS incorporating driving pressure is presented in Figure 1.
Finally, driving pressure could be used to guide enrollment in clinical trials that evaluate strategies to enhance lung-protective ventilation in ARDS. Critical care, unfortunately, has been plagued with underpowered studies that provided indeterminate results. One of the main challenges of conducting research in this field is that ARDS is a markedly heterogeneous entity.20 This leads to grouping of diseases with potentially significant biologic and clinical differences that could, in turn, result in different responses to treatments. Grouping subjects based on their baseline susceptibility to benefit from a lung-protective strategy (instead of on their baseline risk of dying) could aid in reducing this heterogeneity.21 Driving pressure provides a simple bedside measurement that could be used to select subjects who may accrue larger benefits from the intervention, improving trial efficiency with a solid mechanistic rationale.
There are plenty of examples throughout the medical literature in which observational studies or post hoc analyses that used strong physiologic rationale showed promising results only to be later debunked by clinical trials that showed no effect or even harm.22,23 Therefore, caution is generally advised when interpreting the results of observational studies in which causality cannot be confirmed. So, what are the potential downsides of putting driving pressure in the frontline of management and research in patients with respiratory failure? First, limiting tidal ventilation commonly hinders spontaneous ventilation. Although there is strong evidence that supports restricting VT in the early stage of ARDS, there is a large knowledge gap with regard to how and, more importantly, when to allow patients to resume spontaneous breathing. On the one hand, the benefits on patient-centered outcomes of minimizing sedation and allowing patients to be awake and breathe spontaneously are clear.24 On the other hand, results of a recent study suggest longitudinal exposure to elevated driving pressure up to 30 d is associated with an increased risk of death.25 It is uncertain how these 2 seemingly contradictory pieces of evidence can be reconciled. Second, low pressure/volume ventilation could lead to hypoventilation. Although moderate respiratory acidosis is considered acceptable in patients with ARDS, the effects of permissive hypercapnia on patients without ARDS have not been described.
However, because using the driving pressure-limited approach will actually lead to variable VT, depending on lung size, it is likely that patients without ARDS (and with theoretically more lung surface available for ventilation) will receive adequate alveolar ventilation. Importantly, these issues pertain to both the accepted standard therapy in ARDS, low VT ventilation and a driving pressure-limited approach. If and by how much a driving pressure-limited ventilation strategy results in different alveolar ventilation than a VT limited one is currently unknown. Finally, driving pressure reflects the distending pressure of the whole respiratory system. Patients with increased chest wall elastance may present elevated driving pressure while lung stress is still within safe limits. In cases in which clinicians suspect chest wall mechanics may be impaired, more precise monitoring of specific lung mechanics may be warranted.26
The diagnosis and management of patients with ARDS remains a major challenge for clinicians. Using driving pressure to guide ventilator settings can help avoid the need to distinguish between patients with injured and uninjured lungs, and simplify the management of patients who receive mechanical ventilation. Under this paradigm, the delivered VT will depend on the actual area of the lungs available for ventilation, and tidal ventilation will remain in the physiologic range of lung stretch, minimizing the risk of inducing further lung injury.
Footnotes
- Correspondence: Eddy Fan MD PhD, Interdepartmental Division of Critical Care Medicine, University of Toronto, 585 University Avenue, PMB 11–123, Toronto, ON M5G 2N2, Canada. E-mail: eddy.fan{at}uhn.ca
See the Original Study on Page 1505
The authors have disclosed no conflicts of interest.
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