Background
The concept of prone positioning of patients on mechanical ventilation for ARDS was proposed in the 1970s and has been regarded as a rescue strategy. Prone position (PP) has been shown to improve oxygenation [
1‐
4] and survival [
5‐
7] in patients with ARDS. Despite the clinical benefits of proning a patient, the mechanism of improvement is not completely understood. The differences in the supine position (SP) versus PP might be related to some anatomical and physiological parameters. From the gravity oriented SP gradients in lung expansion and the considerable reduction in this gradient, not just the reversal of the expansion gradient, in PP allows one to deduce that pleural pressure gradient from nondependent to dependent regions are less in the PP, in part by gravitational effects, reducing the superimposed pressure of both the heart and possibly the abdomen. In a comparative physiology study, the authors concluded that the support of the heart by the lungs in the SP versus support of the heart by the sternum in the PP, rather than shape changes in the rib cage and diaphragm, may be responsible for the differences in resting, recumbent lung expansion gradients [
8]. More recent works in humans have confirmed the reversal and considerable reduction in resting gradient in ventral-dorsal lung expansion when shifting a human from the supine to the prone body posture [
9,
10]. In contrast to effects on lung aeration, pulmonary blood flow is constantly directed dorsally in normal and injured lungs in both the SP and the PP [
3,
11]. Therefore, the PP improves ventilation-perfusion matching [
12], and contributes to improvement in oxygenation. During mechanical ventilation, the more uniform distribution of lung strain allows for recruitment at lower positive pressure, a reduction in regional shear strain, and thus less ventilator-induced lung injury (VALI) [
13,
14].
On the basis of these observations, the analysis of regional heterogeneity of aeration and strain, taking advantage of advances in CT technologies, is crucial for understanding the mechanism of the clinical benefit of the PP. Advances in quantitative computed tomography (CT) imaging and data analysis techniques allow clinicians to assess regional functional and mechanical metrics such as ventilation and regional lung deformation in considerably greater detail [
15‐
17], and these techniques provide maps of regional ventilation and lung stretch between pairs of inspiratory and expiratory images in three-dimension [
18,
19]. To obtain objective results of CT quantitative analysis, a method of automated lung CT segmentation is needed. However, the segmentation of ARDS involvement requires time and experience because consolidation or atelectasis of the lung limits structural reference contrast against the chest wall [
18,
20]. Furthermore, transport of critically ill patients to a CT scanner is problematic [
21]. Although density-based CT quantification of the SP versus PP has been explored in experimental [
22] and human studies [
13,
23‐
25], functional and mechanical CT metrics have not been used to compare the differences between the SP and the PP.
Therefore, we hypothesized that through the use of three-dimensional (3D) CT image registration in healthy subjects, quantification of regional ventilation metrics and visualization of the regional lung motion could clarify the benefit of the PP demonstrated in ARDS. The purpose of this study was to quantitatively compare the regional characteristics of lung functions on a lobar basis between PP and SP with the use of paired inspiratory and expiratory CT scans.
Discussion
In this study, we performed a quantitative analysis to compare regional characteristics of lung functions between the SP and PP by using image registration applied to matched pairs of inspiratory and expiratory CT scans. We derived functional CT metrics by quantifying lung deformation and computed the regional tissue deformation and mechanics on a lobar basis. This study visualized that PP induced more uniform contributions of regional lung ventilation on RRAVC maps and a shift of 3D s* toward anterior regions on the 3D motionography. We calculated the ratio of functional measures in each lobe and found that the PP minimized the lobar differences in lung functions.
In several previous studies, researchers attempted to develop a hypothesis of homogeneous ventilation in the PP by using density-based CT analysis. Studies with standard CT volumetry showed that the vertical gradient CT density was attenuated when patients with ARDS were in PP [
8,
24], and the cephalocaudal gradient was reduced in experimental animal models [
22]. These results indicate that the PP induces a more uniform distribution of gas and tissue by reducing anteroposterior and cephalocaudal gradients. Other studies showed that the volume of overinflated lung mass decreased, whereas the volume of nonaerated or poorly aerated lung mass increased in the PP, which suggests that lung recruitment and homogeneity were enhanced in the PP [
13,
23]. In this study, we computed tissue fractions (TF
IN and TF
EX) rather than the CT density-based volumetry to quantify the regional homogeneity.
The present study demonstrates that, in the PP, TF
IN and TF
EX were increased in the right middle lobe but decreased in the lower lobes in the PP (
P < 0.05; Table
1). In addition, UM/L ratios of TF
IN and TF
EX were all near unity in the PP, and were significantly greater than those in the SP (
P < 1.0 × 10
− 7). These findings corroborate the previous results from density-based CT volumetry studies with regard to homogeneity in the PP. This improvement in ventilatory homogeneity in ARDS leads to a decrease in the shunt fraction [
3,
4], and in approximately 70% of patients, ventilation-perfusion mismatching and oxygenation were markedly improved in the PP [
3,
4]. However, improvement in oxygenation in the PP does not fully explain the decreased mortality of ARDS [
29]. Thus, the survival benefit observed with the PP is assumed to be more related to a protective effect against VALI [
10,
30]. Indeed, recent data indicate that the paradigm of ARDS management has shifted from improving gas exchange to minimizing VALI and ensuring lung protection [
31].
ARDS is characterized by a massive loss of lung aeration for tidal ventilation, which predominates in dorsal regions in the SP [
32]. Hence, the mechanical distortion and regional overdistension caused by tidal ventilation develop in “ventral aerated lungs” in the SP, which is the most important determinant of VALI [
33]. The PP has been reported to delay and attenuate the progression of VALI in animal studies [
14,
30], and a CT volumetric study in patients with ARDS also revealed that PP was an effective lung protective strategy that could possibly alleviate VALI [
13]. However, these studies did not provide evidence of CT metrics with regard to reduced strain in the PP. A more recent experimental study with inspiratory and expiratory CT scans revealed that the PP alleviated lung injury by minimizing the patterns with suboptimal aeration and large tidal swings (termed “unstable inflation”) [
34]. The investigators employed parametric response maps, which have an advantage of spatial localization compared with simple density maps, and can depict regional heterogeneity. However, simple density difference measures are confounded by the effect of the baseline inflation of the target lung region. Therefore, we used the functional CT metrics of regional ventilation and tissue mechanics including
s*,
J, and RRAVC, which enable us to detect additional heterogeneity of lung strain and stress over CT density map [
16,
35].
Our results showed that UM/L and U/ML ratios of RRAVC and
J were all near unity in the PP and significantly higher in the PP than in the SP (
Ps < 0.001; Table
2). Moreover, the regional displacement gradient was reduced and shifted toward the anterior regions in the PP (Fig.
3). Because the loss of lung aeration is distributed mainly in the dorsal and caudal lungs in the SP [
36,
37], these results together suggest that regional differences in strain between lung regions are reduced in the PP. Given that it is a crucial step to decrease lung strain in ARDS to prevent VALI, the PP could be an effective strategy of recruiting nonaerated lung and preventing overinflation. Nonetheless, the PP has been shown to be effective and is recommended in only severe ARDS [
6,
38]. It is speculated that the PP benefits more hypoxemic patients with ARDS, who have more severe and heterogeneous lung injury and greater ventilation–perfusion mismatch. However, with increasing understanding of the heterogeneous pathophysiology of ARDS, identifying patients who will most benefit from the PP remains elusive [
10]. Recently, lung morphology, assessed by CT images, has been suggested as a predictor of benefit from the PP, which indicates that gravity dependent ARDS is more likely to respond to the PP than is diffuse ARDS [
13,
39]. Of note was that a lobar analysis in our study showed a trend for RRAVC and
J to increase in the right middle and upper lobes and to decrease in the lower lobes in the PP (Table
3). Moreover, our study included the 3D motionography and mapping of the regional lung homogeneity and strain. In the real-life clinical practice for ARDS, lung morphology assessments are not readily available and frequently misclassified [
31], and so the visual information provided in this study could serve as a surrogate to apply personalized PP therapy in patients with gravity dependent ARDS.
This study had some limitations that need to be considered. First, a comparison of CT measures between the SP and PP was performed mostly in different subjects. Thus, intersubject variability may have affected CT measures. However, we included only subjects with normal lungs. In addition, the distributions of specific volume change and density have been demonstrated to be more homogeneous in healthy subjects than in patients with lung disease [
40]. Second, this quantitative analysis was in healthy subjects with normal lungs, not in patients with ARDS. In addition, inspiratory scans were taken at TLC, i.e., with a volume excursion several times larger than the tidal volume used during mechanical ventilation. Hence, the effect of CT metrics extracted from homogeneous normal lungs taken at TLC could be a little different in heterogeneous ARDS during mechanical ventilation. Indeed, the PP is known to be effective only in severe ARDS, and identifying patients who would most benefit from the PP remains a clinical challenge [
38]. Therefore, further research into the comparison of these regional ventilation and lung mechanics between the SP and PP in ARDS is warranted.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.