Acute respiratory distress syndrome (ARDS) is lung injury caused by either direct or indirect insults, and leads to severe respiratory failure that is refractory to conventional oxygen therapy.1,2 Hospital mortality in patients with severe ARDS ranges from 45% to 60%.2,3 Lung protective ventilation strategies using low tidal volume and higher levels of positive end-expiratory pressure (PEEP) are widely accepted approaches,4,5 although rescue therapies may still be required in refractory cases.

Prone positioning improves oxygenation by increasing lung homogeneity and counteracting gravitational forces.6 Prolonged prone positioning (≥16h) in ARDS patients with PaO2/FiO2 ratio ≤150 showed positive results.7 Meanwhile, extracorporeal membrane oxygenation (ECMO) can provide adequate blood carbon dioxide removal and oxygenation, allowing a reduction in mechanical ventilation (MV) and minimization of ventilator-induced lung injury. Recent clinical trials in severe ARDS have shown positive results of venovenous-ECMO,8,9 although there are no absolute criteria for ECMO implementation timing in ARDS. Given the lack of definite evidence for ECMO and promising favorable trials of prone positioning, prone positioning may be considered before ECMO implementation in patients with severe ARDS. Thus, knowing the outcome of prone positioning then ECMO would provide guidance to clinicians on which rescue therapy to choose first in severe ARDS patients. However, to date, there is little information on the use of prone positioning before ECMO.

In this study, we analyzed the clinical outcomes of patients with severe ARDS who underwent prone positioning before ECMO and compared them with those who did not undergo prone positioning before ECMO.

Of the 223 patients in the initial cohort, 161 were not included for the following reasons: met specific exclusion criteria (n=90); ECMO provided for an acute respiratory diagnosis other than ARDS (n=68); and pre-ECMO arterial blood gas unavailable for analysis (n=3) (Fig. 1). Thus, our study group consisted of 62 severe ARDS patients who received ECMO as a rescue therapy. There were 28 patients (45%) in the prone group and 34 (55%) in the no prone group.

Figure 1.

Study flow diagram. ECMO: extracorporeal membrane oxygenation; BTT: bridge to transplant; ARDS: acute respiratory distress syndrome.

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Clinical outcomes

The primary outcome, 30-day mortality, was observed in 6 of the 28 patients (21%) in the prone group and 14 of the 34 (41%) in the no prone group (P=0.098) (Table 2). There was a trend toward lower 30- and 60-day mortality rates in the prone group, but not to a statistically significant degree. Moreover, ECMO weaning failure rate was numerically lower, and MV weaning success rate and MV-free days at day 60 were numerically higher in the prone group than in the no prone group, although the results were not statistically significant. Fig. 2 shows the Kaplan–Meier survival curves of the study patients.

Table 2.

Clinical outcomes of the study patients.

Variable	Prone group (n=28)	No prone group (n=34)	P
ECMO duration, d	9.0 (5.5–17.0)	9.0 (6.0–23.0)	0.99
ECMO weaning failure	8 (29)	14 (41)	0.30
Tracheostomy	15 (54)	17 (52)	0.87
MV weaning success	13 (46)	12 (35)	0.37
MV-free days at day 60a	20.5±25.2	15.2±22.4	0.40
Mortality
30-day	6 (21)	14 (41)	0.098
60-day	11 (39)	18 (53)	0.28
90-day	12 (43)	18 (53)	0.43

Data are presented as median (interquartile range) or number (percentage) of patients. ECMO: extracorporeal membrane oxygenation; MV: mechanical ventilation.

a

Data are presented as mean±standard deviation.

Figure 2.

Kaplan–Meier survival curves of the study patients. ECMO: extracorporeal membrane oxygenation.

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Changes of respiratory compliance

Fig. 3 shows the changes in the dynamic compliance between the prone group and the no prone group during a 24-h study period. No change in median dynamic compliance was observed in the prone group. In the no prone group, median dynamic compliance was 23 (range: 21–37)mL/cmH2O before ECMO and marginally decreased to 21 (range: 10–26) mL/cmH2O after 4h (P=0.15 vs. pre-ECMO) and 23 (range: 6–38)mL/cmH2O after 24h (P=0.06 vs. pre-ECMO). Supplementary Fig. 1 shows the changes in dynamic compliance between the study groups stratified according to survival status. In both groups, compared with survivors, non-survivors exhibited a lower median dynamic compliance until 24h.

Figure 3.

Effect of prone positioning before ECMO on dynamic compliance during a 24-h study period. Boxplots show median, 25th and 75th percentiles. Whiskers show 5th and 95th percentiles. aP=0.06 vs. pre-ECMO. ECMO: extracorporeal membrane oxygenation.

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The main findings of the present study are that (i) the use of prone positioning before ECMO was not associated with increased mortality and (ii) prone positioning before ECMO tended to be protective. The 47% 60-day mortality in our study patients (where the median RESP score at ECMO implementation was 2) is comparable with the mortality rates reported in previous studies of similar ECMO-treated ARDS patients.11,13 To the best of our knowledge, this is one of the few studies to evaluate the use of prone positioning before ECMO implementation in patients with severe ARDS.

Prone positioning may prevent lung injury by recruiting the dorsal regions of lung, improving respiratory mechanics, and clearing pulmonary secretions. Increasing the chest wall elastance, offloading the weight of the heart, and minimizing the weight of the abdominal contents on the diaphragm may enhance respiratory mechanics and increase recruitable lung units.6,14,15 Recent meta-analysis and randomized controlled trial showed that prone positioning can improve survival when applied early in the course of severe ARDS.7,16 Moreover, the use of prone positioning has been shown to significantly reduce the need for ECMO in severe ARDS patients.7 Meanwhile, early application of ECMO in patients with less severe ARDS may be beneficial by further reducing ventilator-induced lung injury,17 reducing hypoxic pulmonary vasoconstriction and unloading the right ventricle,18 and facilitating early rehabilitation.19 Failure of prone positioning may be associated with a delay in starting early ECMO. Therefore, there is controversy over which rescue therapy to choose first in severe ARDS patients. Although our study was based on a limited number of selected patients, it shows that the treatment outcome of the prone group was comparable or better to that of the no prone group, suggesting that prone positioning may be considered before ECMO implementation in patients with severe ARDS.

Several studies have evaluated the impact of prone positioning before or during ECMO in ARDS patients.13,20–23 Prone positioning before ECMO was shown to be a protective factor in two studies.13,20 In the study conducted by Schmidt et al.,13 refractory hypoxemia occurred despite prone positioning in approximately two-thirds of severe ARDS patients, although prone-positioned patients had significantly lower plateau pressures and driving pressures before ECMO. In our study, the prone group tended to have lower peak inspiratory pressure and dynamic driving pressure before ECMO implementation. In addition, pre-ECMO peak inspiratory pressure and dynamic driving pressure were lower in survivors compared with non-survivors in the prone group (data not shown). These findings are in line with the results of Schmidt et al.’s study, supporting the notion that prone positioning before ECMO might have the advantage of protecting lungs from further MV-induced lung injuries. The combination of prone positioning and ECMO has been recently studied in three trials.21–23 These studies demonstrated a clear benefit in terms of oxygenation and lung compliance and the absence of serious adverse events. Using ultra-protective ventilation with low plateau pressures during ECMO could develop the formation of poorly aerated areas in dependent lung regions.24 The aforementioned findings suggest that by recruiting the dorsal regions of the lungs, prone positioning could exert beneficial effects during ECMO. Meanwhile, we found that dynamic compliance decreased shortly after ECMO implementation in the no prone group, but compliance was kept constant in the prone group. Based on our findings, prone positioning might also be helpful in the pre-ECMO setting for preventing lung de-recruitment caused by ultra-protective ventilation. Albeit preliminary, our results do warrant further studies to confirm its applicability to clinical settings.

Inhaled NO is a selective pulmonary vasodilator that acts by dilating pulmonary vascular beds in those areas of the lungs where ventilation is preserved, thereby leading to a reduction in ventilation/perfusion mismatch and pulmonary vascular pressures. Despite a transient improvement in oxygenation in adults with ARDS, the recent meta-analysis has demonstrated no survival benefit associated with NO use regardless of severity.25 Moreover, it was even associated with a higher mortality within the RESP score.11 The present results, in which pre-ECMO inhaled NO was significantly associated with 30- and 60-day mortality, are consistent with those of previous studies. The underlying mechanism for this phenomenon is not clear, although the use of NO appears to increase the incidence of renal failure.25

This multicenter study had several limitations. First, its non-randomized design was prone to selection bias, and the low power due to relatively small sample sizes of our study are likely to be responsible for some of the non-significant results. Second, the data prior to prone positioning were not collected in this study. We do not know what prompted physicians to use prone positioning before ECMO for patients in the prone group. Third, we were not able to specify the timing and the duration of prone positioning before ECMO in our study, although the median time from intubation to ECMO was about 1 day in both groups. It is likely that prone positioning sessions were performed insufficiently before ECMO, which may have affected the treatment outcomes. Moreover, we were unable to ascertain whether such findings were due to excessive severity of patients, or because other rescue therapies had been used instead of prone positioning. Fourth, criteria for assessing ECMO for ARDS, MV on ECMO, and weaning from ECMO were not standardized among the participating centers. Thus, it is possible that the two groups were not treated with the exact same modalities across institutions. Lastly, we used the difference between the peak inspiratory pressure and PEEP to calculate the “dynamic” driving pressure12 because most patients were on pressure-controlled ventilation during the evaluation of ventilator settings. However, the ventilation variable that best stratifies risk in ARDS patients is driving pressure, calculated as the end-inspiratory pressure minus PEEP.26

In conclusion, our results indicate that prone positioning before ECMO was not associated with increased mortality in patients with severe ARDS. Prone positioning before ECMO tended to be protective, even if it failed. These findings suggest that prone positioning may be applied as a first line therapy in patients with severe hypoxemia, and also highlight the need to understand when to use other potential rescue therapies before ECMO implementation. Further studies are required to clearly demonstrate the effect of prone positioning prior to ECMO implementation.

WYK participated in the literature search, analysis of data, and manuscript preparation. BJK participated in the data collection and analysis of data. CRC, SHP, JYO, SYP, WHC, YSS, YJC, SP, and JHK participated in the data collection and helped to review the manuscript for important intellectual content. SBH participated in the study design and helped to review the manuscript for important intellectual content. All authors read and approved the final manuscript.

This research was supported by a grant of the Korean Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HC15C1507). The funders had no role in study design, data collection and analysis, preparation of the manuscript, or decision to publish.

The authors declare no conflict of interest.