Dynamic driving pressure associated mortality in acute respiratory distress syndrome with extracorporeal membrane oxygenation
Our study analyzed the serial ventilator settings changes in severe ARDS patients after ECMO support and found that increased dynamic driving pressure during the first 3 days was independently associated with higher mortality. In addition, immunocompromised status, APACHE II score and the duration of ARDS before ECMO initiation were also significantly associated with survival.
Amato and colleagues analyzed nine randomized controlled trials in ARDS patients and concluded that driving pressure was most strong predictor of mortality [17]. Recent study also demonstrated decreased respiratory system and transpulmonary driving pressure were associated with improved 28-day mortality in ARDS patients [18]. A prospective multicenter study in 15 moderate ARDS patients with low-flow extracorporeal carbon dioxide removal (ECCO2R) demonstrated that driving pressure was significantly reduced during the first two days compared to baseline [19, 20]. However, the role of driving pressure on the severe ARDS patients requiring ECMO was uncertain, and a clinical review recommended that driving pressure is important determinant of outcome during ECMO [6]. The present study in severe ARDS patients receiving ECMO revealed that dynamic driving pressure from day 1 to 3 on ECMO was independently associated with mortality (Table 2).
Driving pressure was inversely proportional to compliance of respiratory system and had two common definitions: the difference between plateau pressure and PEEP and the difference between peak inspiratory pressure and PEEP [21]. There was no study compared different modes of ventilation during ECMO, and pressure-controlled mode appears to be advocated [12]. With pressure-controlled ventilation, pressure is maintained constant throughout inspiration, and flow decreases during inspiration and is often followed by a period of zero flow at end inspiration. Peak inspiratory pressure and peak alveolar pressure (plateau pressure) may be equal during no flow status [22]. Therefore, we used the difference between peak inspiratory pressure and PEEP as calculation of “dynamic” driving pressure. In fact, the most correct form can be obtained using transpulmonary driving pressure by esophageal manometry, but it is not easy to use in clinical practice. Reduction in dynamic driving pressure were found after ECMO initiation, and the values of survivors continued decreasing and exhibited significantly lower than nonsurvivors until day 7 (Fig. 2). Better lungs compliance and larger proportion of recovered functional lung size could have benefitted the survivors. Manipulation of driving pressure could be applied for ventilator management beside by adjusting the tidal volume and PEEP [18]. Although standardized ventilation protocol for ARDS patients before and after ECMO was followed, it remains unclear from our observational study to definitely conclude that driving pressure was causally related to outcome or simply another marker for ARDS severity and it needed further randomized controlled trials to confirm our findings.
Although ECMO facilitates the use of lung-protective ventilation, the optimal mechanical ventilation management is unknown [4, 6, 11–14]. The lowering levels of plateau pressure and tidal volume have been related to decreased mortality [16]. Therefore, an ultra-protective ventilation strategy with low tidal volume reduction (4 ml/kg, PBW), airway pressure reduction and adequate PEEP was suggested to mitigate further VILI [4, 11–14]. Mechanical ventilation during ECMO may have an important impact on mortality. A cohort study of influenza A (H1N1)-induced ARDS patients receiving ECMO revealed that higher plateau pressure on the first day under ECMO was significantly associated with increased ICU mortality [23]. Another retrospective study demonstrated that higher PEEP levels during the first 3 days on ECMO were independently associated with lower ICU mortality [24]. A systemic review summarized ventilation practices in ARDS patients with ECMO, and mortality was lower among patients who had lower ventilation intensity following ECMO initiation [14]. Our present study found that pre-ECMO ventilator settings exhibited no significant difference. After ECMO initiation, tidal volume, peak inspiratory pressure and dynamic driving pressure were all decreased, while PEEP levels were relative maintained. Dynamic driving pressure during first 3 days of ECMO support was independently related to ICU mortality. Whether these mechanical settings affected the outcome was not well known, and more information will be obtained from an ongoing study in the future (SOLVE ARDS: Strategies for Optimal Lung Ventilation in ECMO for ARDS; clinicaltrials.gov identifier NCT01990456).
Several studies had investigated the predictors of mortality for severe ARDS patients treated with ECMO [10, 23–27]. Our study found that the duration of ARDS, APACHE II score and immunocompromised status before ECMO were independently associated with ICU mortality. The optimal timing for ECMO initiation had not been established, and mechanical ventilation may cause substantial VILI even under lung-protective strategy, which is worsened by delaying ECMO application for refractory hypoxemia [4, 13, 26–28]. Previous studies manifested duration of mechanical ventilation prior to ECMO support was correlated with mortality [10, 24–27]. Our study found that survivors had significantly shorter ARDS duration before ECMO. Several studies reported that degree of systemic organ failure was correlated with outcome for ARDS patients before ECMO initiation [6, 24–26, 29, 30], and we found that APACHE II score was significantly associated with ICU mortality. Furthermore, recent report included 2355 patients with severe ARDS receiving ECMO from multiple countries over a 13-year period concluded that immunocompromised status was independently associated with hospital survival [10]. Immunocompromised status was independently associated with long-term outcomes form severe ARDS patients with ECMO [25]. Our study also found that immunocompromised status was significantly related to ICU mortality.
There were several limitations of our study. First, this study is a retrospective analysis in one referral medical center, which may limit the generalization to other ICUs or hospitals. Besides, there might be residual and unmeasured confounding variables not included in our study and other biases during long period of study from 2006 to 2015 that could influence outcome. Second, APACHE II score was assessed only on the day of ICU admission and may not really reflect the dynamics of critical illness and treatment response. Serial evaluation of organ dysfunction during study period may be a better predictor of prognosis. Third, early application of prolonged prone position for severe ARDS patients as rescue therapy had survival benefit, but only a small number of our patients (n = 2) underwent prone position before ECMO. Finally, although ultra-protective ventilation strategy with ECMO based on a tidal volume reduction (4 ml/kg, PBW), our study showed relatively higher tidal volume (around 6 ml/kg, PBW) after ECMO support.