Low tidal volume ventilation is currently the recommended protocol for ARDS patients. However, a single tidal volume may not be appropriate for all patients [
5,
6]. Our study found that respiratory system compliance affected the relationship between tidal volume and strain in ARDS patients. Lung strain did not increase significantly with increasing tidal volumes between 6 and 10 ml/kg PBW in the C
high patients. However, among the C
low ARDS patients, even with ventilation at a tidal volume of 6 ml/kg PBW, the strain was high enough to induce VILI.
The limitations of low tidal volume
When strain exceeds the physiological range, excessive expansion or alveolar recruitment and collapse [
21] induce VILI [
9,
21]. Recently, it was proposed that lung deformation may be one of the key mechanisms of VILI and was therefore defined as a marker to indicate VILI in our study. Our study showed that strain increases gradually with increases in tidal volume and that these parameters are positively correlated. However, in different patients, a given tidal volume will generate different levels of lung strain. Among the patients included in our study, the strain ranged from 0.05 to 1.21 when each patient received mechanical ventilation at a tidal volume of 6 ml/kg PBW.
Furthermore, tidal volume is not the only factor to affect the VILI. Protti and his co-workers reported that a high strain rate, which is the ratio between strain and inspiratory time, is a risk factor for ventilator-induced pulmonary edema [
22]. Cressoni et al. also demonstrated that not only tidal volume but also transpulmonary pressure and respiratory rate could induce VILI if they exceed the safe thresholds [
23]. Therefore, we need to pay attention to not only tidal volume but also other mechanical factors during mechanical ventilation of patients.
The limitations of limiting plateau pressure ventilation
Limiting plateau pressure to below 30 cmH
2O is one key strategy for preventing VILI [
24]. Therefore, to avoid the lung injury, we did not increase the tidal volume if the plateau was greater than 30 cmH
2O. Therefore, some of the strain data at higher tidal volumes were missing for some of the patients. We used the hot-deck imputation to address such missing values to analyze the data.
However, airway plateau pressure is influenced by respiratory system compliance and other factors [
25], and there is no clear threshold value that ensures a safe ventilator strategy [
7]. For example, the same plateau pressure of 30 cmH
2O could result in different strains depending on the chest wall elastance. We found that plateau pressure did not correlate with lung strain, possibly as the result of differences in the pleural pressure. Approximately 56.3% of our patients demonstrated a high strain even when the plateau pressure was less than 30 cmH
2O. This was consistent with findings from previous studies that showed that decreasing the plateau pressure from 29 to 25 cmH
2O enhanced lung protection in ARDS patients [
26]. Our results showed that plateau pressure was not a good index for VILI. In a patient with a fixed compliance, the factor that affects the tidal volume and further affects the strain is the driving pressure not the plateau pressure. Amato et al. demonstrated that decreased driving pressure but not plateau pressure was strongly associated with increased survival. Therefore, setting the tidal volume for an individual based on the driving pressure both in non-ARDS and ARDS patients has been recommended [
20,
27].
Respiratory system compliance affected the effect of tidal volume on driving pressure and strain
Ventilation with a low tidal volume of 6 ml/kg PBW did not improve outcomes for all ARDS patients [
5,
6]. One possible reason may be that in patients with a pronounced form of baby lung, ventilation with 6 ml/kg PBW still carries a serious VILI risk because of the high strain. In contrast, among patients with less pronounced baby lung, 6 ml/kg PBW, which generates low strain, could be unnecessarily low, which would increase the risk of supplementary sedation and atelectasis [
15]. In our study, we found that the EELV was much higher in patents with high respiratory system compliance (Additional file
2: Figure S1). This result was consistent with those of Rylander and colleagues, which showed that FRC decreased along with respiratory system compliance in ARDS patients [
28].
We found that in the patients with low respiratory system compliance, the driving pressure and lung strain could easily exceed the safe thresholds, even when using a tidal volume of 6 ml/kg PBW (Figs.
2 and
3). In addition, our results showed that the strain may exceed the safe range when the tidal volume is increased to 10 ml/kg PBW or higher even in patients with high respiratory system compliance. This result indicated that tidal volumes higher than 10 ml/kg PBW should not be used even in patients with higher respiratory system compliance, which is similar to the recommendations for the use of protective ventilation with lower tidal volumes in non-ARDS patients [
29]. Therefore, setting individual tidal volumes based on respiratory system compliance, which is a similar strategy to that based on driving pressure [
20], may be a better treatment option.
The change of lung strain with increasing tidal volume depends on the change in EELV. In addition, PEEP is a very important factor that affects the value of EELV. Therefore, the results of the changes of driving pressure and strain were also affected by the PEEP setting rather than purely on the interplay between tidal volume and compliance. In ARDS, a suitable PEEP could recruit the collapsed alveoli, avoid the alveolar overdistension and improve the lung compliance. In contrast, an unsuitable PEEP will decrease the compliance. Therefore, it is important to consider the effect of PEEP when setting the tidal volume during mechanical ventilation.
We found that there was only a relatively low correlation between respiratory system compliance and EELV. However, we found that the EELV was much higher in patents with high respiratory system compliance (Additional file
2: Figure S1). Because the study included only 19 patients, the small sample size could explain the lack of confirmation of a relationship between the compliance and EELV. Interestingly, in the subjects with low compliance and low EELV, we did not find that changes in tidal volume affected the strain more than in the subjects with higher compliance with high EELV. The results showed that the strain decreased more in the C
high group than in the C
low group when the tidal volume was increased from 6 to 8 ml/kg PBW. There are two possible explanations for this result. First, the conditions of patients with low compliance could have been much more severe than those of the patients with high compliance. According to the results of a previous study, patients with severe disease may have a large amount of recruitable lung and require a higher PEEP [
14]. Therefore, when the tidal volume was increased, the mean airway pressure would increase accordingly, which is especially significant in low compliance patients. Furthermore, the increased pressure may recruit the collapsed lung in a gravity-dependent manner and/or induce alveolar overdistension in nondependent areas. These two factors would both increase the EELV and cause smaller changes in the strain as a function of increases in the tidal volume. Second, it is important to note that we did not continue to increase the tidal volume if the plateau exceeded 30 cmH
2O. For this reason, some of the data for the strain values at higher tidal volumes were missing for some of the patients. We used hot-deck imputation to address any missing values to permit analysis of the data. Therefore, the actual strain may have been higher than we reported. However, we did not know how large the volume would need to be for the differences among the strain values to be significant.
Driving pressure and lung strain
Driving pressure might be used as a surrogate of lung strain and has been recommended to guide selection of the ventilator settings [
20,
27]. We found that the strain increased gradually in parallel with the driving pressure. The strain was significantly higher in the patients with high driving pressures compared to the patients with low driving pressures (Fig.
4a). These results may partly validate the concept of the study of Amato and his colleagues [
20]. However, we found only a moderately positive relationship between the driving pressure and the lung strain (Fig.
4b). This result was similar to the relationship between the EELV and respiratory system compliance. It is possible that this result is related to the small sample size. A further study that includes more patients needs to be performed to confirm these results.
Our study had some limitations. First, we did not collect bronchoalveolar lavage fluid from the patients for the measurement of the inflammatory cytokines, so we did not identify a corresponding threshold value for strain in our study. We only showed that there is a risk of exposure to potentially injurious lung strain on the basis of the value of strain that was reported in a previous study. Further study is needed to define a threshold that can indicate VILI.
Second, we calculated respiratory system compliance as the ratio between tidal volume and driving pressure. Actually, compliance is also affected by intra-abdominal pressure, chest wall compliance and other effects [
30]. However, our patients had no obvious abdominal hypertension, thoracic deformities or other factors that could affect chest wall compliance. In addition, we defined a respiratory system compliance of 0.6 ml/(cmH
2O/kg) as the cutoff point for the classification of the patients based on previous studies. Therefore, we believe that these factors had no significant impact on the results.
Third, we calculated only dynamic strain, not static strain, which should also be studied to improve the treatment of ARDS patients. Lung strain is affected by PEEP. With PEEP, lungs are kept tonically inflated above their functional residual capacity, which exposes them to additional static strain [
31]. However, PEEP reduces dynamic strain by re-expanding the collapsed lung tissue. In our study, there was no significant difference in PEEP between the two groups, and therefore, PEEP would not be expected to substantially affect our results.