This study analyzed consecutive changes in the ventilator settings for patients with severe ARDS receiving ECMO. The primary insight in this research was that MP alone, MP normalized to PBW, and MP normalized to compliance during the first 3 days of ECMO were all independently associated with hospital mortality. Among the ventilator variables, mechanical power normalized to compliance during the first 3 days of ECMO had the greatest predictive value for mortality.
We hypothesized that excessive MP may contribute to the development of VILI and thereby influence clinical outcomes . At the time of this study, there was no clearly defined threshold indicating safe MP values for patients with critical illness or ARDS. One experimental study reported on the development of lung edema and other forms of lung damage when MP exceeded 12 J/min . It has been shown that in-hospital mortality is independently associated with higher MP among critically ill patients, which increases consistently in cases where MP exceeds 17 J/min . In another study using a standardized screening program, 28-day hospital mortality and 3-year mortality were higher in ARDS cases where MP exceeded 22 J/min . However, none of the studies mentioned above considered the effects of changes in MP over time.
ECMO facilitates the use of ultra-protective ventilation, which allows reductions in the contributors of energy load (i.e., MP) to promote lung healing, mitigate further lung injury [1, 2]. Previous studies have reported that during the first 3 days of ECMO, higher PEEP  and lower driving pressure [12, 18] were independently associated with lower mortality. However, there was no clearly defined threshold indicating safe ventilator settings and MP values for patients with severe ARDS undergoing ECMO .
In the current study, we found that higher MP values during ECMO (but not before ECMO) were associated with increased mortality. We observed a significant difference between patients in the low and high MP groups in terms of mortality but not in terms of baseline MP nor ventilator settings. In a Cox regression models, MP during the first 3 days of ECMO was independently associated with hospital mortality, and the predictive power of MP during ECMO exceeded that of all other individual ventilator variables. MP >14.4 J/min during the first 3 days of ECMO was significantly positively correlated with 90-day hospital mortality and showed greater hazard of death (Adjusted HR, 2.340; 95% CI, 1.358-4.031; p = 0.002). Overall, our findings revealed that MP (indicating a conjunction of ventilator settings parameters) during ECMO could be considered a predictor of survival and should be taken into account in optimizing ventilation.
The energy load (MP) delivered to the lungs is not necessarily evenly distributed. The effects of MP on the respiratory system depend not only on the energy load itself but also on the pathophysiology of the lungs (e.g., functional lung size, proportion of inhomogeneity, and the recruitability) [4, 5]. Therefore, MP should be normalized, at least adjusted for functional lung size to reflect the actual amount of energy expected to be delivered to the lungs. Respiratory system compliance is correlated directly with the amount of aerated lung available for tidal ventilation (functional lung size) in patients with ARDS . Zhang et al. reported that MP normalized to PBW was far more accurate than the absolute value of MP in predicting mortality . Coppola et al. reported no causal relationship between MP alone and mortality, whereas both MP and transpulmonary MP normalized to respiratory system compliance or to the amount of well-aerated tissue were independently associated with ICU mortality . However, the above studies were predicated on baseline MP values, they did not account for serial changes in MP during the ICU stay and did not seek to determine whether the link between MP and mortality was independent from other ventilator settings.
Patients with severe ARDS requiring ECMO tended to have more noninflated tissue (i.e., lower functional lung size), greater inhomogeneity, and greater lung recruitability . There have been relatively few studies examining the effects of MP normalized to functional lung size on mortality in severe ARDS patients receiving ECMO. Cox regression models in our study revealed that the risk of death estimates obtained using MP normalized to compliance were higher than those of MP alone or MP normalized to PBW, despite the fact that all three factors were independently associated with mortality (HR 2.289, 1.060, and 1.004, respectively, all p < 0.05). It indicated that functional lung size in ARDS patients is not always proportional to body weight , and is generally determined by the severity of the disease and is therefore better quantified by compliance . MP normalized to compliance higher than 0.53 J/min/ml/cm H2O during the first 3 days on ECMO was significantly associated with greater hazard of death (Adjusted HR, 2.238; 95% CI, 1.224-4.094; p = 0.009). Our findings demonstrated that MP normalized to compliance is a superior representation of the actual amount of energy transmitted to the lungs. Precisely defining the safety limits of MP will require further randomized controlled trials to evaluate the correlations between mortality and MP normalized to functional lung size, lung inhomogeneity, and recruitability.
A few studies have examined the effect of RR on VILI and clinical outcomes. Experimental studies have shown that reducing RR ameliorates lung inflammation and lung injury  and that the elevated MP resulting from higher RR can induce lung edema and damage . The LUNG SAFE study concluded that increased RR was associated with increased hospital mortality in patients with ARDS . Our study revealed that ECMO had a more pronounced effect on reducing RR than on any other determinants of MP, as mentioned in other recent studies [15, 24, 25]. We also observed that total RR of nonsurvivors was significantly higher than that of survivors during the first 3 days of ECMO.
Besides, the effects of spontaneous breathing could be protective or deleterious, depending on the severity of lung injury and strength of spontaneous activity. This means that lung injury could be worse in cases of severe ARDS, whether receiving ECMO or not, with vigorous spontaneous effort . One recent international study reported mean spontaneous RR of 9 ± 13 breaths/minute before ECMO and 8 ± 11 breaths/minute during the first 2 days of ECMO. This indicated that those patients were not fully sedated and paralyzed, and neuromuscular blocking agents were used in only 41 % of cases . In estimating MP values, patients should be completely relaxed; i.e., without any active inspiratory efforts . In our study, the median spontaneous RR before ECMO was 0 (0-7) breaths/minute and 1 (0-4) breath/minute during the first 3 days of ECMO, indicating that our patients were nearly total sedated and paralyzed. At present, the role of spontaneous effort in patients receiving ECMO for severe ARDS remains unclear, and the benefit or harm were likely depending on the patients’ respiratory pattern, patient-ventilator dyssynchrony, pendelluft, and the phase and duration of ARDS . In many cases, implementing a spontaneous breathing ECMO strategy is difficult or clinically infeasible to apply due to the high respiratory drive associated with severe ARDS and the need for deep sedation to mitigate patient self-inflicted lung injury [2, 27, 28].
The most common cause of death among ARDS patients is multiorgan failure . One international multicenter prospective study reported that extrapulmonary organ failure (elevated lactate levels and positive fluid balance) during ECMO had a significantly negative impact on 6-month mortality for patients with ARDS . Our findings revealed that there was no significant difference between survivors and nonsurvivors in terms of MP and SOFA score before ECMO; however, MP and SOFA score were shown to decrease during the first 3 days of ECMO. SOFA score during the first 3 days of ECMO remained independently associated with hospital mortality. These findings indicated that ECMO could facilitate a further reduction in ventilator load (i.e., MP) in order to alleviate VILI by reducing the proinflammatory biotrauma response, thereby preventing multi-organ failure and improving survival [2, 30, 31]. Besides, an immunocompromised status was associated with lower survival, as reported in previous studies in which the 6-month survival rate was only 30 % to 37 % [15, 32]. The timing of ECMO initiation for severe ARDS with refractory hypoxemia has yet to be defined ; however, recent studies have also reported a link between ARDS duration before ECMO and mortality [15, 31]. This is perhaps due to the fact that ECMO promotes lung-protective ventilation, such that any delay in initiating ECMO would increase the likelihood of VILI and subsequent mortality.
This study was hindered by a number of limitations. First, this retrospective study was conducted in one tertiary care referral center with a high annual volume of patients requiring ECMO, thereby limiting generalizability. Second, ventilatory variables were recorded only once a day (at approximately 10 a.m.) during the stay in the ICU and therefore do not necessarily represent dynamic changes in ventilator status, including fluctuations in MP during 24-hour intervals. Third, ultra-protective ventilation with VT below 4 ml/kg PBW has been recommended for patients with ARDS undergoing ECMO [1, 2]. Nonetheless, mean VT value in the current study was 6 ml/kg PBW after ECMO, due perhaps to the fact that ultra-protective ventilation was not widely implemented between 2006 and 2015. Fourth, we assessed functional lung size by means of PBW and compliance due to the retrospective study, but computed tomography scan of the lungs may be more accurate way to estimate amount of aerated remaining functional lung, lung inhomogeneity or the recruitability [6, 20]. However, computed tomography scan requires intra-hospital patient transfer from ICU to radiology department and the use of ECMO preclude widespread clinical use. Finally, our objective in this observational study was to identify the factors associated with mortality without considering issues pertaining to causality. Any number of residual or confounding variables that were not measured may have influenced the results.