Discussion
Our study represents one of the first published ARDS studies to use target trial emulation. In our exploratory investigation, we used data from a ‘real world’ setting to emulate a clinical trial comparing the effect of adding limited ∆P to conventional LTVV protective lung ventilation on mortality in adults with C-ARDS. This approach serves as a reliable method to estimate the causal effect of an intervention when only observational data are available, given it accounts for daily intervention adherence and both baseline and daily factors affecting both intervention adherence and primary outcome occurrence.34 35 48
While our sample is relatively small, our exploratory results suggest that limiting ∆P when LPV is already employed may not improve survival in patients C-ARDS. Our results highlight the need to conduct future prospective RCTs comparing limited ∆P to LTVV in IMV adults with ARDS. This study also demonstrates that target trial emulation approaches are feasible to use, particularly where RCTs are lacking and data are collected prospectively and rigorously.
Results from published studies evaluating the association between a limited ∆P and survival among adults with non-COVID ARDS have varied. Calls to limit ∆P are derived from studies that have associated ΔP with increased mortality from VILI, lung stress, strain or biotrauma.7 17 49 50 In one study, an initial ΔP of >15 cm H2O was shown to be a stronger predictor of mortality than the traditional LPV approach.7 However, ΔP data were evaluated only once in the first 24 hours of IMV and only in patients without any respiratory efforts; the effect of a sustained ∆P over time on survival remained unclear. A secondary analysis of two previous trials demonstrated the limited prognostic value of IMV day 1 Δp≤13 cm H2O on survival.44 The SIESTA Investigators reported a ∆P cut-off ≤19 cm to be a slightly better predictive value of mortality than Pplat,51 whereas the results from the Lung Safe study showed a linear increase in mortality with an increase with ΔP with no threshold value identified.52 The alveolar recruitment for acute respiratory distress syndrome trial (ART) has raised concerns about limiting ΔP.53 An emulated pragmatic clinical trial using a large observational registry of patients without COVID ARDS posited that early and sustained ∆P reduction is associated with survival benefit.6 However, this benefit was primarily influenced by adherence to protective lung ventilation rather than maintenance of a low ∆P.
The recent ESICM ARDS guidelines26 highlight the trade-off between adjusting VT and respiratory rate in attempting to control the overall intensity of MV23 and emphasise the need for further examination of the merits of additional lung-protective strategies (eg, ΔP) and personalised ventilator targets. Clinicians often consider the initial ∆P to reflect the initial lung compliance and adjust ∆P in response to changes in lung compliance over time. Our results explored mortality outcomes with static ∆P for the duration of the IMV period.
Multiple studies have compared patient characteristics, treatments and outcomes between patients with and without C-ARDS .54–57 While patients with C-ARDS are generally older, heavier and more likely to have diabetes, the respiratory mechanics and response to treatment have been similar.26 54 56 Bain et al found key demographic and physiological parameters, biomarkers and clinical outcomes between C-ARDS and non-coronavirus 19 viral ARDS, but the delivered minute ventilation to be lower C-ARDS compared with bacterial and culture-negative ARDS.54 In the study by Brault et al, the driving pressures, respiratory system compliance and oxygenation responses to recruitment manoeuvres and prone position therapies were similar between C-ARDS and non-C-ARDS.56 However, there was heterogeneity in ventilator response, which underscores the importance of considering a personalised ventilator strategy that is independent of the underlying ARDS phenotype. This highlights the importance of future research on LPV strategy, for example, limited ∆P and the role of personalised ventilator targets.26
Our data suggest that in the routine care of spontaneously breathing patients with ARDS, maintaining LPV using low Pplat should be prioritised over limiting ∆P. Our exploratory findings inform the feasibility of conducting future target trial emulation studies in larger cohorts to inform ARDS management strategies. Our results will also help inform the design of future prospective randomised trials evaluating a ∆P limitation strategy and offer insights into the real-world experiences for different ARDS subphenotypes where the application of typical syndromic definitions is challenging.19 21 22 58–62 The misclassification of ARDS subphenotypes in the LIVE trial was reported to be a large factor in the lack of demonstrable benefit associated with the use of personalised treatment strategy.58 Our results urge the need to examine the role of personalised LPV on outcomes among the various ARDS phenotyping.26 58 It remains unclear whether selecting different ventilatory strategies or precision treatment strategies based on ARDS subphenotypes will influence outcomes.63
While our data were not derived from a prospective RCT, and our study cohort was relatively small, our results suggest that when variables that influence ICU survival are considered,26 47 limiting ΔP may not improve survival. It is unclear if limiting ∆P derives benefits from the adjustment of its individual components or is linked to the total driving force.64 65 The effect of modulating ∆P by adjusting tidal volume and PEEP may vary based on disease progression, the nature of the underlying lung and chest wall compliance,65–69 and the possibility of the potentially harmful effect of mechanical power.24 25
In our cohort, the initial VT and PEEP were adjusted according to the current guidelines,26 37 but further interventions to limit ∆P varied and were at the clinicians’ discretion. The absence of the benefit of limited ΔP can be related to the variability in adjusting VT, PEEP or the respiratory rate to limit ∆P and compensate for the low-minute ventilation offsetting potential benefits51 70 and a validated approach to guide ventilator adjustment for a ∆P limitation strategy is needed. A certain ∆P may not have the same protective effects across all ARDS subsets nor across all disease subgroups due to different phenotypical features, specifically in compliance and recruitability.6 20–22 60 69 71 72 The misclassification of ARDS subphenotypes in the LIVE trial was reported to be a large factor in the lack of demonstrable benefit associated with the use of personalised treatment strategy.58 Our results urge the need to examine the role of personalised LPV on outcomes among the various ARDS phenotyping.26 58 Certain subphenotypes have been shown to benefit from certain therapeutics,55 57 but it remains unclear whether selecting different ventilatory strategies or precision treatment strategies based on ARDS subphenotypes will influence outcomes.63 Current literature describes a similar pathophysiology for C-ARDS and ARDS from other etiologies,54 56 57 and recent recommendations for non-pharmacological respiratory support do not recommend the use of a specific ventilatory strategy but recommend implementing evidence-based strategies for patients with ARDS, including ARDS due to COVID-19.26 55 Our findings can be extended to ARDS from other aetiologies, considering the similarities in phenotypes and lung mechanics. While some baseline differences were reported (eg, higher BMI, socioeconomic status, gender, etc), these differences do not merit deviation from evidence-based respiratory support strategies of ARDS from any cause.26
Our exploratory study has several limitations. Emulation analysis provides a novel approach to ARDS research, but it also has inherent limitations. This modelling approach relies on the correct weight specification and the consistency assumption that the weights are correctly specified.73 The stabilised IPW marginal structure model relies on the consistency assumption that the weights are correctly specified and can be sensitive to violations of the positivity assumption (ie, non-zero probability of receiving any treatment sequence).73 While our small sample limited our ability to consider all variables that could influence survival in patients with ARDS (eg, sedation choice and depth or neuromuscular blocker use) and may limit inference, we provided the needed real-world data to explore the use of target trial emulation in patients with ARDS. We included a convenience cohort of patients with C-ARDS and formally evaluated the sample size needed to show a benefit with limiting ΔP’s, should one exist. Although there were missing Pplat, ΔP and covariate values, the incidences were low, and we used a formal approach to address the missingness. Factors such as short inspiratory pauses or auto-PEEP and chest wall stiffness were not collected; thus, misinterpretation of the ΔP may have occurred.74 We made extensive efforts to control for confounders and collected data that were routinely available to clinicians. Our data were prospectively collected, but the computation of pulmonary mechanics was not independently verified. The presence of spontaneous breathing may result in underestimating transpulmonary ∆P, thus limiting its accuracy. Lastly, the lack of observed benefit from limiting ∆P might be related to the variability in ∆P adjustment approaches in the absence of a validated institutional strategy.