Transpulmonary Pressure–guided Ventilation to Attenuate Atelectrauma and Hyperinflation in Acute Lung Injury

The inherent appeal of using esophageal manometry to guide positive end-expiratory pressure (PEEP) titration lies in its ability to distinguish lung from chest wall mechanics. Transpulmonary pressure (Pl) is calculated as the pressure measured at the airway opening minus the pleural pressure, which is typically estimated via esophageal manometry. Lung injury termed “atelectrauma” may occur from high regional forces generated repeatedly during cyclic closure and reopening of small airways during tidal ventilation (1, 2). Negative Pl values (in which pleural pressure exceeds airway pressure) predispose to small airways closure and cause lung injury that in preclinical models, is attenuated with higher PEEP (3, 4).

In this issue of the Journal, Bastia and colleagues (pp. 969–976) highlight the potential for esophageal manometry to estimate Pl even in asymmetric lung injury (5). In their study, invasively ventilated pigs were subjected to unilateral lung injury via surfactant lavage and high tidal stretch instituted with temporary endobronchial blockade, occluding the contralateral lung. After injury was established, the bronchial blocker was removed, and respiratory mechanics were assessed in both hemithoraces at different amounts of PEEP. Pleural pressure was measured directly using air-filled balloon catheters inserted into the ventral and dorsal pleural spaces of the left and right hemithoraces, and it was also estimated with esophageal manometry. Electrical impedance tomography was used to evaluate heterogeneous insufflation.

Vertical pleural pressure gradients were observed as previously described (6, 7), but no significant difference in pleural pressure of the left versus the right hemithorax was found, regardless of which lung was injured. These findings are expected given that lung injury induced via the airway should not alter chest wall mechanical properties. Normally, mechanical coupling of the left and right hemithoracic pleural spaces occurs via 1) mechanical coupling of the left and right rib cages with symmetrical movement during respirations and 2) compliance of mediastinal structures separating the hemithoraces. In contrast to unilateral lung injury, decreased mediastinal compliance can create asymmetric hemithoracic chest wall mechanics, as may occur with mediastinal fibrosis resulting from thoracic surgery or chest radiation therapy, for example (8).

In their swine model, esophageal pressure corresponded closely with posterior pleural pressure. However, in humans, esophageal pressure approximates the midthoracic pleural pressure, a contrast explained by differences in swine versus human chest wall shape and anatomic position of the esophagus in the thorax (9).

Bastia and colleagues also demonstrated asymmetric insufflation of injured versus noninjured lungs, a direct result of differences in lung compliance created by unilateral injury. Importantly, heterogeneous insufflation was attenuated with higher PEEP at the expense of increasing hyperinflation, which was most pronounced in the noninjured lung. Intriguingly, PEEP titrated to achieve Pl near 0 cm H₂O appeared to minimize the competing effects of end-expiratory lung collapse and hyperinflation. Pronounced collapse occurred particularly in the injured lung when end-expiratory Pl was negative (<0 cm H₂O), presumably because of gravitational effects on increased lung mass from cell-rich edema infiltration, as well as effects of surfactant depletion. The noninjured lung, being more compliant, was more susceptible to hyperinflation particularly when end-expiratory Pl was positive (>0 cm H₂O).

The surfactant depletion model employed in this study might amplify the degree of collapse observed with negative Pl, and no measures of lung injury were reported. Also, reports of regional Pl should be viewed skeptically because of small airway closure and flooded alveoli, as discussed previously in this journal (10). Nevertheless, these findings highlight the potential folly of aggressive PEEP titration without regard for lung stress or strain, particularly in heterogeneous lung injury. The preponderance of existing human and preclinical data indicates that lung injury from overdistension is far more detrimental than that from atelectrauma. Thus, any potential lung-protective benefit from higher PEEP might only be evident when the risk of end-tidal overdistension is minimized simultaneously.

One could envision that an ideal PEEP titration strategy in acute lung injury might begin by targeting Pl near 0 cm H₂O at end-expiration to attenuate atelectrauma (Figure 1). Some measure of inspiratory stress or strain (e.g., airway or transpulmonary driving pressure, end-inspiratory Pl, or electrical impedance tomography–derived strain) (11) might then be used to determine whether protective ventilation can be attained at a Vt of 6 ml/kg predicted body weight without significant hyperinflation. If hyperinflation persists, Vt would be lowered until hyperinflation abates. If gas exchange impairment precludes further reduction in Vt despite increasing respiratory rate, then either 1) PEEP would be lowered, and negative end-expiratory Pl would tolerated in recognition of the greater contribution of hyperinflation to clinically significant lung injury or 2) if deemed appropriate, extracorporeal gas exchange could be considered to enable further reduction in Vt when appropriate.

Figure 1.

Transpulmonary pressure (Pl) to guide lung-protective ventilation. (A) Theoretical relationship of Pl with the competing risks of ventilation-induced lung injury (VILI) from overdistension and atelectrauma. The risk of clinically meaningful injury from overdistension exceeds that of atelectrauma. (B) Ventilator titration ideally would seek to attenuate both overdistension and atelectrauma in at-risk patients. Maximal lung protection may occur when positive end-expiratory pressure is set to achieve an end-expiratory Pl near 0 cm H₂O and Vt is targeted to a driving Pl of ≤10–12 cm H₂O. Boxes reflect the range of Pl during tidal ventilation in a theoretical patient with severe acute respiratory distress syndrome. Red, yellow, and green colored boxes denote high, moderate, and low risk of VILI, respectively. In practice, patient susceptibility to biophysical injury may be a key determinant of the numerical threshold at which the risk of lung injury from overdistension exceeds that of atelectrauma. For reference, in the lean, healthy, spontaneously breathing adult, Pl is ∼0 cm H₂O at FRC, 10 cm H₂O at end-inspiration during normal tidal breathing, and 20–25 cm H₂O at TLC. Reported Vt is in ml/kg predicted body weight, and ∆P is in cm H₂O. *If gas exchange permits; ^†if Vt cannot be lowered. ∆P = driving pressure; End-Insp. = end-inspiration.

Such a PEEP strategy has not been tested in a clinical trial. In the EPVent-2 trial of moderate to severe acute respiratory distress syndrome (12), esophageal pressure–guided PEEP was targeted to an end-expiratory Pl between 0 cm H₂O and +6 cm H₂O depending on the Fi_O2 requirement. Although speculative, it is conceivable that some patients in this protocol experienced overdistension that countered the protective effects against atelectrauma. The EPVent-2 protocol did prescribe limits to “peak stress,” prohibiting end-inspiratory Pl from exceeding 20 cm H₂O, but increasing evidence suggests that a lower end-inspiratory Pl might attenuate overdistension further (11, 13).

Although translation to demonstrable clinical benefit has proven elusive, preclinical studies continue to suggest a protective role for precise PEEP titration in severe acute lung injury. Competing effects of overdistension and atelectrauma with higher and lower PEEP, respectively, almost certainly have contributed to past unsuccessful trials. So too has phenotypic heterogeneity, including but not limited to differences in mechanical and biological susceptibility to ventilation-induced lung injury (14, 15). Future trials should explicitly confront the competing effects of PEEP and the inherent phenotypic heterogeneity of acute respiratory distress syndrome to provide the best chance for identifying the optimal PEEP titration strategy to maximize clinical benefit.