Do spontaneous and mechanical breathing have similar effects on average transpulmonary and alveolar pressure? A clinical crossover study

In recent years, conflicting data have been published concerning the beneficial or detrimental effect of preserved spontaneous breathing (SB) compared with fully controlled mechanical ventilation (CMV) during acute respiratory failure [1‐5]. SB has been credited with having several beneficial effects, such as improved hemodynamics [6], improved ventilation-to-perfusion matching [7], decreased ventilator-induced lung injury (VILI) [8, 9], and decreased muscle atrophy [10]. However, SB can also cause or aggravate lung injury during mechanical ventilation, as shown by experimental evidence [11‐13], by mechanisms that include negative intrathoracic and alveolar pressure (causing interstitial or alveolar edema), loss of control over tidal volume (V_T), and inhomogeneous regional stretch. Abolition of SB might be one of the mechanisms by which the use of neuromuscular blocking agents in the first hours after intubation may improve patient outcome [14]. For this reason, greater attention is now being paid to better understanding of the pressure across the lung (i.e., transpulmonary pressure [P_L]).

While airway pressure (Paw) is usually lower during SB than during CMV, this does not necessarily translate into a lower pressure across the lung (i.e., a lower P_L). By convention, P_L is the difference between the pressure at the airway opening and the pleural or esophageal pressure [15]. Our hypothesis was that, for a given inspired volume and flow, and for the same mechanical properties (i.e., compliance and resistance) of the lung, the amplitude of the change in P_L (ΔP_L) during assisted SB and during CMV should not differ, regardless of the level of inspiratory effort, whereas the absolute value of airway and esophageal pressure should differ. To our knowledge, however, despite the major implication of understanding the mechanisms of VILI, this has not been directly verified in patients. For instance, the net effect on local transmural vascular pressures may significantly impact the generation of VILI [16]. The total P_L can be divided into the pressure generated to overcome the resistance to airflow between the airway opening and the alveoli, and the pressure needed to expand the terminal airways (i.e., the transalveolar pressure). Only the latter part of the P_L, which equals the product of lung elastance and volume, is dissipated across the alveolus and is commonly considered to cause VILI [17]. At the same time, the pathophysiological relevance of the pressure needed to generate the airflow across the airway will be substantially different between CMV and assisted SB, which may have clinical consequences. The absolute value of the pressure surrounding the lungs, as well as that of the alveolar pressure (Palv), will change in a positive direction related to atmosphere during controlled ventilation and in a more negative direction for increasing levels of breathing effort. Airflow generation in the presence of elevated airflow resistance may lead to an extremely high P_L during both fully controlled and spontaneously assisted ventilation, but accompanied in the latter case by very negative pressure around and even inside the alveoli.

The purpose of the present study was to compare the ΔP_L during spontaneous assisted breathing and fully controlled ventilation, trying to match similar conditions of airflow and volume, in a group of patients undergoing different levels of pressure support ventilation (PSV) followed by a phase of CMV. Moreover, we investigated the role of the resistive pressure in the generation of negative intrathoracic and intraalveolar pressure during spontaneous assisted breathing. Finally, we reasoned that if the transalveolar pressure is similar during CMV and PSV, then plateau pressure (Pplat) during PSV, obtained in the absence of flow and during patient’s muscle relaxation, should provide similar information as during CMV. For this reason, we evaluated the reliability of the measurement of Pplat during PSV compared with that obtained during CMV.

This is a secondary analysis of data collected in a previous study, where the methods are described in more detail [18].

The main demographic and clinical variables of the patients are reported in Table 1. All patients completed the protocol and had data available for all study phases, except for 9.5 % of the inspiratory holds, which were discarded (see below). Inspiratory flows and V_T did not significantly differ overall during the three levels of PSV and the CMV phases (Table 2), with a slight decrease during PSV-low. V_T in PSV and CMV were tightly correlated (r ² = 0.93, data not shown), but the correlation was loose for inspiratory flow (r ² = 0.23, data not shown), suggesting that, while on average there were no differences between PSV and CMV at an individual breath level, the conditions might not be comparable.

Our data show that, in a mixed population of patients undergoing spontaneous assisted breathing, neither transpulmonary nor transalveolar pressure changes differed between controlled and spontaneous assisted ventilation for comparable volumes and flows. When the breaths were matched for inspired volume and inspiratory flow, the values were almost identical. This was also the case in static conditions, suggesting that Pplat can be measured reliably also during PSV. By contrast, the absolute Palv value could markedly differ during inspiration, frequently becoming lower than PEEP during PSV.

A first consequence is that if SB has any role (protective or detrimental) in modulating VILI, this cannot be mediated by a pure, isolated difference in the ΔP_L. Moreover, it has to be considered that only part of the P_L is dissipated across the alveoli; this is called the transalveolar pressure and equals the product of lung elastance and volume. The remaining pressure determines a gradient between the airway opening and the alveoli, which yields an inspiratory flow. This gradient will be the same, regardless of the amount of pressure generated by the patient and by the ventilator, as shown by our data (Fig. 3), and it depends on the airflow profile and inspiratory Raw. For example, Yoshida et al. defined the “total alveolar stretching pressure” (P_L) as Pplat + ΔPes (ΔPes being measured during inspiration), but this pressure extends across the entire lung (alveoli + airways) and is not specific for “alveoli” [11]. As a matter of fact, the increased P_L in the presence of a strong inspiratory effort is associated with an increased resistive pressure [11].

These concepts are illustrated in the figure E2 in Additional file 1, which shows the respective meaning of transpulmonary and transalveolar pressure under assisted SB and CMV. For the same mechanical properties (compliance and resistance) of the respiratory system, the ΔP_L will differ between controlled and SB only if flow and/or lung volume differ, and transalveolar pressure will differ only if lung volume changes. As shown by our data, in the presence of similar volumes and inspiratory flows, transpulmonary and transalveolar pressure do not differ between controlled and spontaneous ventilation, regardless of the inspiratory effort.

However, there are strong data in the literature showing that, under some conditions, SB efforts can be detrimental. In keeping with our findings, this can be explained by at least three mechanisms that do not imply a different transpulmonary or transalveolar pressure change. First, in all the pressure-targeted ventilatory modes, the control over V_T is lost and, consequently, the patient might develop nonprotective V_T even if airway pressures are not high. This is possibly one of the mechanisms explaining the report of Bruells et al. [20], who found a more severe degree of VILI if negative pressure ventilation (similar in some aspects to SB) was used, as compared with positive pressure ventilation. Since in this elegant experiment the V_T was not controlled, it was probably higher in the negative pressure ventilation group, as suggested by the lower arterial PaCO₂. In such circumstances, the ΔP_L will be higher during negative pressure (spontaneous) ventilation, albeit, as emphasized before, this is simply due to the higher V_T reached [15].

Second, absolute values of esophageal, pleural, alveolar, and intrathoracic pressure will be progressively lower during strenuous breathing efforts, leading, in some cases, to values below PEEP for the entire respiratory cycle, as shown by our data. The consequences of these negative pressure swings can be profound, particularly regarding the hemodynamic profile. In fact, while during CMV the resistive pressure drop does not have major physiological consequences, during assisted SB the inspiratory resistive pressure drop (unlikely to be compensated by the expiratory pressure drop of opposite sign, usually passive and driven mainly just by the elastic pressure recoil of the chest wall) causes major physiological consequences. It increases the filling of the right heart, impairs the function of the left ventricle, and causes a negative interstitial pressure in the lung, which can in turn lead to fluid accumulation in the pulmonary interstitium. Moreover, the increased cardiac output usually associated with SB [6] will necessarily lead to an increased perfusion of lung capillaries, the latter being a known factor contributing to VILI [21], even in the absence of increased vascular pressures [22]. During inspiration, the fall in pleural pressure is larger than the fall in intravascular pressure in the pulmonary circulation, explaining the increase in transmural pressure increases [23]. This increase in vascular pressure in the pulmonary circulation has been shown to favor the development of VILI [16].

Toumpanakis and coworkers [24] imposed a resistive load on spontaneously breathing animals, causing important negative inspiratory pressure swings, and they found severe lung injury. It is worth noting that, in this model, even if the V_T were not measured, this was likely normal; thus, the transalveolar pressure (product of inspired volume and elastance) was normal, but with very negative absolute alveolar and intrathoracic pressures. Similarly, Stalcup and Mellins previously demonstrated that, during asthma, negative pleural pressure swings cause alveolar fluid accumulation [25].

Finally, the pleural pressure during SB might be uneven due to the action of diaphragmatic contraction, leading to “regional” overinflation and or pendelluft, as recently shown by electrical impedance tomography [12].

In this study, we focused on PSV, a ventilatory form that (except during asynchronies) implies a relative stereotyped interaction between patient and ventilator: The ventilator delivers flow simultaneously with the patient’s demand. However, patient-ventilator interaction can be more complex during other ventilatory modes allowing SB, such as synchronized intermittent mandatory ventilation, bilevel ventilation, and airway pressure release ventilation [26]. In these conditions, P_L and Palv changes can be greatly amplified. As an example, while breath stacking [27] will lead to increased P_L, an inspiratory effort occurring during expiration will cause a profound negative Palv.

This study has some limitations. First, it was originally designed not to specifically test this hypothesis but to evaluate the relationship between diaphragmatic electromyogram and muscle pressure. However, the data collected (Pes and Paw during controlled and spontaneously assisted ventilation) are reliable and allowed us to design this independent study. The sample size was relatively small (ten patients) and had some heterogeneity. Thanks to the crossover study design, we calculated (based on the standard deviation of P_L during CMV) that the minimum detectable difference of P_L between two steps was 3.6 cmH₂O, with an α of 0.05 (two-tailed) and a power of 80 %.

A second limitation is that our calculations were based on a single value of Pes and on the assumption of a single compartment model. This is a simplification, since it is known that, particularly in the presence of lung disease, pleural pressure is not uniform and parenchymal compliance and resistance can have regional heterogeneities. As a consequence, our results should be regarded as “average” values for the lungs, but we have to keep in mind that, for some lung regions, P_L (or transalveolar) pressures can be considerably higher (or lower). The same reasoning also applies to the end-inspiratory occluded pressure during pressure support, which represents an average of the pressures distending the alveoli.

A third limitation resides in the fact that we applied two fixed squared flow rates in CMV without a prospective match with PSV for airflow value and shape. Consequently, while V_T was very similar during the two ventilation modes, airflow was not, without a systematic direction. To overcome this limitation in part, we performed ex post facto matching by focusing part of the analysis on the breaths with similar airflow values. Moreover, also based on previous data from our group [28], we did not expect that Raw would present relevant differences between these two conditions, and we assumed them to be identical.

Finally, we assumed that compliance and resistance of the respiratory system did not change between CMV and PSV, but different volume history or the use of sedation (which was difficult to avoid, however) might have affected respiratory mechanics.

We show that ΔP_L under similar conditions of inspiratory flow and volume is similar between fully controlled and assisted mechanical ventilation. However, in the latter condition, the Pes and Palv can have remarkable negative swings that are in part required to overcome the airflow resistive pressure. Negative Palv values and their consequences on fluid shifts are potential mechanisms by which SB might induce lung injury. Finally, we show that by performing an inspiratory hold, it is possible to obtain a good estimate of the total pressure distending the respiratory system (or the lung) also during PSV.