Effects of prone positioning on lung mechanical power components in patients with acute respiratory distress syndrome: a physiologic study

Consecutive patients with moderate to severe ARDS (defined by the ratio of arterial partial pressure of oxygen to the fraction of inspired oxygen [PaO₂/FiO₂] ≤ 150 mmHg according to the Berlin definition [15]) were enrolled between July 2019 and June 2023. Informed consent was obtained from the legal representative of each patient before enrollment. Exclusion criteria were age < 18 years, pregnancy, end-stage chronic organ failure, inherited cardiac malformations, severe head injury, and severe hemodynamic instability.

All patients were sedated with sufentanil (20–30 μg/h) and midazolam (10–20 mg/h) to achieve a score of − 5 on the Richmond Agitation-Sedation Scale, and complete neuromuscular blockade was maintained throughout the study period with cisatracurium. An esophageal balloon catheter (NutriVent nasogastric catheter; Sidam, Mirandola, Italy) was advanced into the stomach, inflated, and withdrawn into the esophagus until the appearance of cardiac artifacts on the pressure tracing [16]. The balloon was inflated with the lowest volume to obtain the largest swings in P_eso during tidal ventilation. P_eso measurements were considered reliable if the ratio of change in P_eso to change in airway pressure was 0.8–1.2 during an end-expiratory occlusion test [17, 18].

A thermodilution catheter (5F Pulsiocath, Pulsion Medical Systems, Munich, Germany) was inserted via the femoral artery in all patients included in the study to allow hemodynamic measurements with a pulse contour cardiac output monitor (PiCCOplus; Pulsion Medical Systems, Munich, Germany). Norepinephrine was administered if the mean arterial pressure (MAP) was < 65 mmHg despite preload optimization. Dobutamine was administered if the cardiac index measured by transpulmonary thermodilution was < 2.0 L/min/m² despite sufficient cardiac pre- and afterload.

Patients were passively ventilated in a horizontal position with 0° body inclination throughout the study period with an Engström Carescape R860 ventilator in a volume-controlled ventilation mode using a tidal volume (V_T) of 6 mL/kg of predicted body weight and a respiratory rate (RR) and fraction of inspired oxygen (FiO₂) according to recent guidelines [19]. V_T and RR were modified only if ΔP_RS was greater than 14 cmH₂O and pH_a was < 7.25.

The study protocol included three steps (Fig. 1A): (1) baseline measurement in SP using a ventilation strategy with PEEP based on the lower PEEP/FiO₂ table (baseline) [19, 20]; (2) P_eso-guided ventilation strategy with PEEP targeting an end-expiratory P_TP of 0 to 2 cmH₂O in SP [5]; (3) P_eso-guided ventilation strategy with PEEP targeting an end-expiratory P_TP of 0 to 2 cmH₂O in PP. To standardize lung volume history and allow for comparisons between ventilation strategies and positioning, a dynamic recruitment maneuver was performed before each ventilation strategy, as detailed in Additional file 1: Fig. S1. Therefore, a recruitment maneuver was performed before baseline ventilation with PEEP based on the lower PEEP/FiO₂ table, esophageal pressure-guided PEEP in SP, and esophageal pressure-guided PEEP in PP [21].

In SP, patients were ventilated in a volume-controlled mode after the recruitment maneuver starting with a PEEP of 25 cmH₂O. PEEP was decreased stepwise by 2 cmH₂O every 2 min, and end-expiratory P_eso was measured during a 2-s expiratory hold. The lowest PEEP to achieve an end-expiratory P_TP of 0 to 2 cmH₂O was used for the P_eso-guided ventilation strategy (Additional file 1: Fig. S1). After completing the measurements for the P_eso-guided ventilation strategy in SP, patients were placed in PP with unchanged ventilator settings. A recruitment maneuver was then performed, and PEEP was titrated to end-expiratory P_eso targeting an end-expiratory P_TP of 0 to 2 cmH₂O. Physiologic measurements were obtained after a 30-min equilibration period with each ventilation strategy.

Expiratory and inspiratory airway pressures and P_eso were measured during a 2-s inspiratory and 2-s expiratory hold at zero flow to compute end-inspiratory and end-expiratory P_TP (airway pressure − P_eso), respectively. ΔP_RS was calculated as airway plateau pressure (P_platRS) − PEEP, and transpulmonary driving pressure (ΔP_TP) as end-inspiratory P_TP − end-expiratory P_TP. Static respiratory system and lung elastance were calculated as ΔP_RS/V_T and ΔP_TP/V_T, respectively. Chest wall elastance was calculated as end-inspiratory − end-expiratory P_eso/V_T. The elastance ratio of the lung to the respiratory system (E_L/E_RS) was used to calculate lung MP components.

Lung MP was calculated as

Lung total elastic power was calculated as [22, 23]

The elastic static (related to PEEP) and dynamic (related to ΔP_RS) components of lung elastic power (Fig. 1B) were calculated asand, respectively [23]. Resistive power (related to the resistance of the airway) [23] was calculated as

Lung total elastic power and elastic static and dynamic power components were normalized to EELV to describe the energy transfer relative to the aerated lung volume (Additional file 1) [10, 11]. Lung stress was calculated using the elastance-derived method as P_platRS × (E_L/E_RS) [18]. EELV was measured with a modified nitrogen wash-out (20% FiO₂ increase)/wash-in (20% FiO₂ decrease) technique [24, 25]. At the end of the equilibration period, the alveolar dead space fraction was calculated, and arterial blood gas was analyzed. Hemodynamic parameters were obtained using transpulmonary thermodilution, and oxygen delivery was calculated. Vascular pressure transducers were zeroed to ambient pressure after changes in positioning and aligned with the phlebostatic axis corresponding to the right atrium and aortic root. For this purpose, pressure transducers were placed in the midaxillary line of the 4th intercostal space in both SP and PP to obtain comparable measurements of hemodynamic variables.

The effect of PP on total elastic power transmitted to the lung has not been studied in patients with ARDS. Based on the results of the previous study by our group [8], an estimated sample size of 55 patients was required to measure a change in lung total elastic power (primary endpoint of the study) between SP and PP with a power of 0.8 and a significance level of 0.05. The effect size was calculated based on the change in lung total elastic power when using a P_eso-guided ventilation strategy during SP and PP. Fifty-five patients underwent the current study protocol, which was part of a multipurpose study. Of these, forty patients had also been enrolled in a prior study [8], but with a different research question and study protocol. The normality of the data was tested by the Shapiro–Wilk test and subsequently analyzed using the Wilcoxon matched-pairs test for non-normally distributed data. The results are expressed as medians (interquartile range) with a level of significance set at P < 0.05. Statistical analyses were performed using GraphPad Prism 8 (GraphPad Software, San Diego, CA).

PP resulted in lower PEEP and P_platRS compared with SP, but end-inspiratory and end-expiratory P_TP as well as EELV did not differ by positioning (Table 2).

Lung total elastic power was lower during PP compared with SP (6.7 [4.9–10.6] versus 11.0 [6.6–14.8] J/min; P < 0.001) (Fig. 2A). PP also resulted in lower lung total elastic power normalized to EELV compared with SP (3.2 [2.1–5.0] versus 5.3 [3.3–7.5] J/min/L; P < 0.001) (Fig. 2B).

PP reduced lung elastic static power compared with SP (4.2 [3.2–7.4] versus 8.5 [4.8–10.7] J/min; P < 0.001) (Fig. 3A) and lung elastic static power normalized to EELV (2.1 [1.4–3.8] versus 4.2 [2.7–6.0] J/min/L; P < 0.001) (Fig. 3B). PP did not affect lung elastic dynamic power non-normalized and normalized to EELV (Fig. 4A, B). Compared with SP, PP reduced E_L/E_RS and lung stress and increased chest wall elastance when using P_eso-guided ventilation (Table 2).

PaO₂/FiO₂ increased and the shunt fraction and the alveolar dead space fraction decreased during PP compared with SP with P_eso-guided ventilation (Table 3). PP resulted in higher MAP and cardiac output and increased oxygen delivery compared with SP. Further details regarding the effect of PP on respiratory parameters, gas exchange, and hemodynamic parameters are shown in Tables 2, 3, and Additional file 1: Tables S2 and S3.

P_eso-guided ventilation in SP resulted in higher PEEP and P_platRS compared with an oxygenation-guided ventilation strategy using the PEEP/FiO₂ table (baseline). This increased end-inspiratory and end-expiratory P_TP as well as EELV (Table 2).

P_eso-guided ventilation during SP compared with baseline increased lung total elastic power (11.0 [6.6–14.8] versus 8.1 [5.4–11.0] J/min; P < 0.001) (Fig. 2A), but lung total elastic power normalized to EELV did not differ according to the ventilation strategy during SP (5.3 [3.3–7.5] versus 5.1 [3.6–6.9] J/min/L; P = 0.538) (Fig. 2B). Lung elastic static power was higher with P_eso-guided ventilation during SP compared with baseline (8.5 [4.8–10.7] versus 5.5 [3.1–7.3] J/min; P < 0.001) (Fig. 3A). Similarly, P_eso-guided ventilation increased lung elastic static power normalized to EELV compared with baseline (4.2 [2.7–6.0] versus 3.3 [2.3–5.5] J/min/L; P = 0.006) (Fig. 3B). P_eso-guided ventilation during SP compared with baseline decreased ΔP_TP, lung elastic dynamic power (2.5 [1.8–3.5] versus 2.9 [1.9–3.7] J/min; P = 0.029) (Fig. 4A) and lung elastic dynamic power normalized to EELV (1.2 [0.7–1.9] versus 1.7 [1.3–2.7] J/min/L; P < 0.001) (Fig. 4B), but lung stress was higher (Table 2).

PaO₂/FiO₂ increased and the shunt fraction decreased with P_eso-guided ventilation in SP compared with baseline (Table 3). P_eso-guided ventilation resulted in lower MAP and cardiac output during SP compared with baseline but did not affect oxygen delivery (Table 3).

Total MP, which combines static and dynamic parameters of ventilation, has been investigated to quantify the invasiveness of ventilation and may be related to the risk of VILI [26, 27]. Thus, the present study compared elastic power and its components (static and dynamic), to estimate lung stress and strain, according to different positioning and ventilation strategies [22].

However, the role of MP, its static and dynamic components, and the relevance in comparison with simpler bedside indices, e.g., 4 × ΔP_RS + RR, or any other predictor of VILI remains unclear [23, 28]. Despite the debate about the importance of each MP component, high MP per se, which combines different ventilator variables, increases the risk of VILI in patients with ARDS. Moreover, reducing only one variable may be insufficient to significantly modify MP [26]. MP, compared to single-ventilator variables or simpler indices, may thus provide a holistic picture on the invasiveness of different ventilation strategies and the effect of positioning. Normalizing MP transfer to the size of the aerated lung may be the essential step for the clinical use of MP and definition of safety thresholds [11, 27]. This has been shown to correlate power transfer with lung stress and strain [29] and further improve the prediction of mortality in patients with ARDS [30]. However, estimating energy transfer per aerated lung volume in clinical practice may be hindered by the requirement to measure EELV. Although normalization to body weight or compliance has been suggested, the optimal method remains unclear [27].

Another method to measure global lung stress is to isolate the fraction of airway pressure applied to the lung (P_TP) using P_eso measurements [5]. This can provide relevant information regarding the invasiveness of ventilation in situations with altered chest wall mechanics such as PP [8, 14, 31]. In this situation, P_eso-guided ventilation with PEEP titrated to maintain a positive end-expiratory P_TP may be clinically useful to balance lung recruitment and overdistension in patients with ARDS [32].

Thus, utilizing the P_eso measurement to quantify lung MP and normalizing to EELV may add important information regarding the invasiveness of ventilation in patients with ARDS managed with PP, because PP modifies chest wall elastance and increases EELV and lung homogeneity [27, 33]. We modified PEEP in PP to account for the reduced vertical pleural pressures and the accompanying regional changes in lung mechanics in each individual patient [7, 12‐14, 34] and to avoid the influence of inadequate (excessive or insufficient) PEEP on total elastic power transmitted to the lung [6]. In our study, V_T and RR were comparable between ventilation strategies and positioning; thus, changes in lung total elastic power and its components were due to changes in respiratory mechanics addressed by individualized ventilation strategies.

A recent study by Morais et al. evaluated respiratory mechanics in SP and PP over a range of PEEP levels in patients with ARDS and found a variety of responses in global and regional mechanics induced by PP, suggesting the need to individualize PEEP according to the positioning [35]. On the contrary, a study by Mezidi et al. found no significant differences in PEEP titrated according to end-expiratory P_TP when patients were turned from SP to PP [36]. Of note and in contrast to our study with 0° body inclination for both SP and PP, the study compared SP with 30° to PP with 0° to 15° body inclination [36]. Body inclination has been shown to affect respiratory mechanics and EELV in mechanically ventilated patients with ARDS due to changes in chest wall elastance and P_TP [37, 38].

The effect of PEEP in patients with ARDS is critically dependent on lung recruitability [39]; however, the large vertical pleural pressure gradient present in supine patients with ARDS [17] may not allow for significant recruitment without concomitant overdistension due to differences in regional P_TP [40]. In our study, PP resulted in a significant reduction of lung total elastic power and lung total elastic power normalized to EELV compared with SP. Although the role of static and dynamic MP components in the pathogenesis of VILI is debated [23, 28], excessive MP, regardless of the constituents, causes similar lung injury [26, 27]. PP decreases pleural pressure gradients and homogenizes ventilation [7], reducing the risk of VILI [4, 41] by limiting regional lung strain due to overdistension and tidal recruitment [3].

In moderate to severe ARDS patients with recruitable lung parenchyma, PP increases end-expiratory P_TP and EELV [8, 39]. As demonstrated in the present physiologic study, PP may therefore be a part of a lung-protective ventilation strategy aimed at reducing lung total elastic power transmission per aerated lung volume. This may reduce damaging ventilation above the proposed parenchymal stress threshold by decreasing lung strain while increasing the size of the aerated lung [10, 42]. Our results expand the mechanistic understanding of the effects of PP to improve lung protection by reducing energy transfer per aerated lung volume, which has been discussed as a major factor for improved survival in the PROSEVA trial [2‐4].

On the other hand, in our study, PP did not reduce lung elastic dynamic power non-normalized and normalized to EELV with P_eso-guided ventilation. The dynamic component of lung MP is exponentially affected by V_T [9] and may lead to increased inspiratory lung strain, as indicated by the resulting ΔP_TP [43]. High MP due to excessive V_T causing damaging lung stress and strain is clinically indicated by altered respiratory mechanics with sharply increased P_platRS and ΔP_TP when EELV is kept constant [26]. Although the decrease in ΔP_TP and lung elastance with comparable EELV during PP compared to SP was non-significant, this trend may signify the opening of new lung units and/or improved mechanical properties of previously ventilated lung units [44]. Consequently, V_T is evenly distributed between dependent and non-dependent lung regions during PP and overdistension is limited [7], as reflected by reduced end-inspiratory lung stress and total elastic power normalized to EELV. Prolonged periods of PP may further reduce total elastic power transfer per aerated lung volume, as EELV has been shown to increase over time in PP [36].

The key message of our study for clinical practice is that PP allows for a reduction in lung elastic power transmission per aerated lung volume because comparable P_TP and EELV can be achieved at lower airway pressures. This may have important implications for the ventilator management during PP.

In our study, compared with baseline, P_eso-guided ventilation in SP resulted in higher PEEP, P_platRS, and EELV, thereby improving PaO₂/FiO₂ due to a reduced pulmonary shunt. However, this ventilation strategy increased lung total elastic power and lung stress. This is consistent with the results of the EPVent-2 trial, where P_eso-guided ventilation resulted in PEEP levels similar to ours and did not reduce ΔP_TP compared with a ventilation strategy using the higher PEEP/FiO₂ table [45]. Although there was no significant difference in lung total elastic power normalized to EELV when using P_eso-guided ventilation in SP compared with baseline, higher PEEP and P_platRS may have resulted in overdistension of non-dependent lung regions, despite improving dependent lung aeration by maintaining positive end-expiratory P_TP and increasing EELV [18]. Our study demonstrates that PP compared to SP can offset the need for higher airway pressures to maintain positive end-expiratory P_TP and reduce pulmonary shunt. This results in a reduction in total elastic and elastic static power transmission per aerated lung volume compared to SP.

Theoretically, the overall effect of a reduction in end-expiratory P_TP on lung MP is less pronounced than the effect of changes in V_T, ΔP_RS, and inspiratory airflow [9]. This suggests that reducing elastic static power may have a minor impact on lung protection; however, a U-shaped relationship between end-expiratory P_TP and the risk of VILI has been discussed, with both insufficient and excessive end-expiratory P_TP causing VILI due to atelectrauma and overdistension, respectively [22, 26, 32, 46]. As shown experimentally, the application of inadequate lung elastic static power can impair lung structural architecture and elastance, and increase extravascular lung water and inflammation [26, 46]. Furthermore, the combination of elastic static and dynamic power, but not elastic static or dynamic power alone, correlated with alveolar collapse and regional overdistension as hallmarks of VILI [22]. This highlights the importance of not reaching a critical lung stress and strain threshold [10].

In SP, P_eso-guided ventilation with higher PEEP and P_platRS resulted in a reduction of cardiac output in comparison with baseline. The results of our study are consistent with the findings in an animal model, where higher elastic static power caused severe hemodynamic impairment [26], which could be translated to the clinical setting. Adverse hemodynamic effects of mechanical ventilation are common in patients with ARDS [47], but may be limited by PP [48]. PP with P_eso-guided ventilation restored cardiac output and increased MAP and oxygen delivery in comparison with SP. Possible mechanisms for this effect of PP in our study may include an increased gradient for venous return by increasing intra-abdominal pressure and reduced lung overdistension with decreased pulmonary vascular resistance and right ventricular afterload, thereby improving right ventricular function [47‐49].

PP improves survival in patients with moderate to severe ARDS, possibly by improving lung protection and reducing VILI [2‐4]. This might be due to a reduction in the pleural pressure gradient with changes in P_TP and EELV that affect the transmission of static and dynamic MP components. The short-term physiologic data from our study suggest that PP may allow for a reduction in lung elastic power without a loss of EELV, thereby minimizing energy transfer per aerated lung volume and improving gas exchange, hemodynamics, and oxygen delivery in patients with moderate to severe ARDS. Furthermore, quantifying lung MP and normalizing it to EELV may be an essential step to describe the energy transfer relative to the aerated lung volume at the bedside to better monitor mechanically ventilated patients with ARDS.

Our study has several limitations. We studied the short-term physiologic effects of PP using P_eso-guided ventilation with similar per protocol V_T and RR; thus, we cannot exclude that the effects of PP on lung MP components differ according to ventilation strategy. In line with the mechanistic understanding of VILI, maintaining a positive end-expiratory P_TP has been associated with lower mortality in a post hoc re-analysis of the EPVent-2 trial [5]; however, the optimal ventilation strategy during PP is unclear.

Individual lung recruitability was not assessed before the study, and the effect of PEEP on lung total elastic power, lung elastic static, and dynamic power components, as well as respiratory and hemodynamic parameters, may depend on recruitability [50]. During protective ventilation, a U-shaped relationship between PEEP and VILI has been suggested by experimental studies [22, 26, 46], but the best method to individualize PEEP is unknown [19].

Our study focused on lung total elastic power including its elastic static and dynamic components to approximate lung stress and strain [22]. We excluded the resistive component of MP [9] because the biological impact of this component in comparison with the elastic power components is unclear [10, 11, 51]. Additionally, estimating energy transfer per aerated lung volume by normalizing MP in clinical practice may be hindered by the requirement to measure EELV, and the optimal method to normalize MP is unclear [27].

Another limitation is the lack of an imaging technology, e.g., electrical impedance tomography, to quantify regional lung aeration, as the physiologic effects of PP may be heterogeneous [35]. Although lung total elastic power, power components normalized to EELV, and lung stress were minimized, we cannot formally exclude regional hyperinflation in PP.