Low PEEP combined with low VT, plateau pressure and Transpulmonary pressure minimizes lung injury
Recently, experimental studies challenged the common belief that atelectasis might be detrimental to protective ventilation, provided lungs are kept at rest. This protective strategy includes the following elements: 1) a minimal PEEP level to assure adequate gas exchange (a certain level of ‘permissive hypoxemia’ to allow for an oxygen saturation not below 88%) associated with low VT or a VT able to ventilate only the aerated lungs, while minimizing any detrimental effect on the collapsed alveoli and peripheral airways; and 2) the respiratory rate should be set to keep pHa within physiologic ranges, or even to allow a certain degree of permissive hypercapnia. This strategy of so-called “permissive atelectasis” should combine protective effects on the lungs as well as mitigate possible hemodynamic impairment. In endotoxin-induced lung ARDS, Samary et al. [32] investigated the impact of different mechanical ventilation strategies combining different VT and PEEP, aiming to reach different driving transpulmonary pressures (∆P): 1) low ∆P (VT = 6 ml/kg, PEEP = 3 cmH2O); high ∆P (VT = 22 ml/kg, PEEP = 3 cmH2O) and mean ∆P with a VT to reach a mean between low and high ∆P (VT = 13 ml/kg, PEEP = 3 cmH2O). Other groups, with low VT and moderate (9.5 cmH2O) and high (11 cmH2O) PEEP, were also investigated. In these experimental settings, PEEP was adjusted to obtain an inspiratory plateau pressure of the respiratory system similar to that achieved with mean and high ∆P while using high VT. This was the first experimental study to evaluate the individual effects of VT, PEEP, plateau pressure (Pplat) and ∆P on lung inflammation, fibrogenic response, endothelial and epithelial cell injury, and activation of cell stress. Ventilation with low VT and low PEEP was associated with greater atelectasis, while increased VT and low PEEP reduced the amount of atelectasis and low VT and higher PEEP promoted a progressive increase in hyperinflation, to similar degrees as with high VT with low PEEP.
The first question is, therefore, whether it is more injurious to the lungs to adopt a ventilation strategy with more atelectasis but lower inspiratory pressures with low VT, designed to ventilate only the aerated lungs without promoting excessive opening and closing of alveolar units or stressing the peripheral airways? In agreement with our primary hypothesis, ventilation with low VT, low PEEP and low ∆P resulted in reduced expression of interleukin (IL)-6, receptor for advanced glycation end products (RAGE), and amphiregulin. Interestingly, mechanical ventilation with low VT and higher PEEP combined with higher ∆P and plateau pressure, a situation in which lungs were fully open, resulted in reduced expressions of IL-6 and RAGE, but was associated with increased amphiregulin expression and lung hyperinflation. Therefore, our data suggest that a ventilation strategy aimed to keep the lung fully open and then gently ventilated with low VT might effectively reduce lung inflammation, However, mechanical ventilation with low VT but a PEEP level not high enough to keep the lung fully open induced alveolar instability, thus resulting in increased expression of IL-6, RAGE and amphiregulin. Overall, IL-6 and amphiregulin expressions correlated better with plateau pressure and ∆P, highlighting the major influence of inspiratory stress as compared to other pressures in determining VILI. In a secondary analysis of these data, we investigated the impact of energy and power on VILI. IL-6 and amphiregulin expressions correlated better with power compared to energy of mechanical ventilation [33]. In conclusion, in experimental pulmonary ARDS, both mechanical ventilation strategies – 1) low VT and PEEP, yielding low transpulmonary ∆P, plateau pressure, energy, and power, and 2) low VT combined with a PEEP level sufficient to keep the lungs fully open – mitigated VILI. It is noteworthy that non-optimal PEEP might have negative effects on lung injury (Fig. 1).
Low static strain is less injurious
Another important and underevaluated effect of PEEP is its possible injurious effects related to excessive static strain. In fact, as discussed above, only dynamic strain (such as ∆P) has been considered as a potential factor determining lung injury. In a study by Güldner et al. [34], pigs that had undergone saline lung lavage were separately ventilated with a double-lumen tube: the left lung with a very low VT (3 ml/kg predicted body weight [PBW]) according to an atelectrauma or volutrauma strategy, while the right lung was ventilated with a continuous positive airway pressure (CPAP) of 20 cmH2O. The volutrauma strategy included high PEEP set above the level where dynamic compliance increased more than 5% during a PEEP trial, and the atelectrauma strategy included low PEEP to achieve driving pressures comparable with those of volutrauma. The potential increase in CO2 and decrease in pHa due to the extremely low VT was controlled by extracorporeal removal. This experiment separated the potential beneficial or detrimental effects of higher or lower static strain on VILI, i.e., higher or lower PEEP. In both conditions, atelectrauma and volutrauma, the tidal breath was extremely low. Regional lung aeration was assessed by computed tomography (CT), and inflammation by FDG-PET. Contrary to general belief regarding ultraprotective ventilation, volutrauma (i.e., higher static strain) yielded higher inflammation as compared to atelectrauma (i.e., lower static strain). Volutrauma decreased the blood fraction at similar perfusion and increased normally and hyperaerated lung compartments and tidal hyperaeration. Atelectrauma yielded more poorly and non-aerated lung compartments, and tidal recruitment, as well as increased ∆P. These data suggested that volutrauma and static strain may promote even greater lung inflammation than atelectrauma at comparable low VT values and lower driving pressures, suggesting again that static stress and strain are major determinants of VILI. Mechanical power was higher in volutrauma compared to atelectrauma groups. However, the intensity, i.e., mechanical power normalized to lung tissue, was comparable between volutrauma and atelectrauma, with negligible differences. Thus, we exclude any influence of differences in intensity to explain our results regarding the potential injurious effects of excessive static strain. In conclusion, higher PEEP increases static strain, thus promoting lung inflammation.
Low PEEP minimally impairs lymphatic drainage
Higher PEEP may also have negative effects on fluid drainage from pulmonary structures. The dynamic of fluids in the pulmonary interstitium is carefully regulated by the pressures inside and outside the capillaries, the extracellular matrix, and pulmonary lymphatics, and differs between spontaneous breathing and mechanical ventilation. The lymphatics collect fluids through three routes: hilar, transpleural, and transabdominal [35]. In normal conditions, a continuous leak of fluids occurs from the capillaries to the interstitium, because of the overall balance between hydrostatic and oncotic pressures in the capillaries and interstitium. The lymphatics maintain a negative pressure in the interstitium, which is important to prevent changes in the mechanical and functional properties of the respiratory system. Furthermore, fluids are also drained from the pleural space to the interstitium in the parietal side through specific foramina or, again, a combination of hydrostatic and oncotic pressures. Finally, drainage occurs through lymphatics positioned in the diaphragm, which play a relevant role during spontaneous breathing and mechanical ventilation.
Unlike the situation for more central diaphragmatic lymphatic vessels, optimization of lymphatic drainage through the diaphragm depends on anatomical location and functional physiological properties. In fact, central diaphragmatic lymphatic vessels are passively activated by muscular contraction, and thus become partially ineffective during controlled mechanical ventilation. On the other hand, lymphatic loops located at the extreme diaphragmatic periphery additionally require an intrinsic pumping mechanism to propel lymph centripetally [36]. Such active lymph propulsion is attained by means of a complex interplay among sites and is able to organize lymph flow in an ordered way. More recently, it has been shown that spontaneous contraction of lymphatics located in the extreme diaphragmatic periphery might involve hyperpolarization-activated cyclic nucleotide-gated channels in lymphatics equipped with muscle cells [37]. Hence, the three-dimensional arrangement of the diaphragmatic lymphatic network seems to be finalized to efficiently exploit the stresses exerted by muscle fibers during the contracting inspiratory phase to promote lymph formation in superficial submesothelial lymphatics and its further propulsion in deeper intramuscular vessels [38]. In the presence of diffuse damage of the alveolar capillary membrane, the role of lymphatics is even more important, to avoid progression and provide at least partial cleaning of lung edema. The increase in pressure in the alveoli, with increased inspiratory, mean or end-expiratory pressure, may markedly impair the function of lymphatics, determining a reduction in fluid drainage capability. During spontaneous breathing, the pressure in the interstitium is higher than the pressure in the lymphatics, resulting in a negative gradient (around 3–4 mmHg) which facilitates continuous drainage of fluids [39]. By contrast, during positive pressure, an increase in interstitial and lymphatic pressures occurs, to a similar degree (10 mmHg). In this case, the gradient between the interstitium and lymphatics becomes around zero or even positive, impairing possible fluid drainage. In addition, the increase in pressure in the respiratory system increases pressures in the pulmonary vessels and, as a consequence, on the venous side. This increase in hydrostatic pressures promotes fluid leak from capillaries on the abdominal and diaphragmatic side, thus potentially increasing pressure in the abdomen and further worsening respiratory and circulatory function as well as lymphatic drainage from the lungs (Fig. 2). In conclusion, mechanical ventilation with higher PEEP negatively affects lymphatic drainage from the lung, possibly impairing fluid exchange from the interstitial lung tissue.
Low PEEP improves right ventricular function
Patients with ARDS are characterized by a moderate-to-severe impairment of right ventricular (RV) function, which impacts on systemic hemodynamics [40]. Several devices and modalities, such as echocardiography, are now available to monitor respiratory settings according to RV tolerance. Acute cor pulmonale is defined as a persistent increase in pulmonary vascular resistance and, from an echocardiographic point of view, is characterized by paradoxical septal motion [40]. In patients with ARDS, the severity of the pulmonary disease involving the microvasculature influences development of acute cor pulmonale, which may also be caused or exacerbated by an aggressive ventilatory strategy. In fact, even minor overload in pulmonary vascular resistance may impair RV function. In this context, the use of lower VT has been associated with a decreased rate of RV impairment and acute cor pulmonale, with possible beneficial effects on outcome [41]. However, PEEP may negatively affect RV function [42]. In fact, the decrease in cardiac output is more often associated with a preload decrease and no change in RV contractility, whereas the increased RV volumes with PEEP may be associated with a reduction in RV myocardial performance. Acidosis and hypercapnia induced by VT reduction and increase in PEEP with constant plateau pressure have been found to be associated with impaired RV function despite positive effects on oxygenation and alveolar recruitment [43]. It has been suggested that respiratory system ∆P ≥ 18 cmH2O, PaCO2 ≥ 48 mmHg, and PaO2/FiO2 < 150 mmHg are three factors independently associated with acute cor pulmonale. Thus, extended sessions of prone positioning instead of increasing PEEP have been proposed in patients with moderate to severe ARDS [44]. In conclusion: 1) increased RV afterload during ARDS may induce acute cor pulmonale; 2) higher PEEP and plateau pressure, as well as increased ∆P, worsens RV function and systemic hemodynamics.
PEEP and CT scan
As discussed above, it is likely that it is necessary to keep the lungs fully open to achieve the potential positive effects of the ‘open-lung’ strategy. CT scan studies in ARDS patients have shown that the potential of recruitment in this population varies widely [45]. Moreover, the level of PEEP required to keep the lungs fully open is extremely high, especially in moderate to severe ARDS [46]. Additionally, even 15 cmH2O PEEP has been shown not to be enough to keep the lung open [47] and to be associated with overdistension [48]. In conclusion, therefore, CT scan studies have shown that high PEEP levels (> 15 cmH2O) are needed to keep the lungs fully open and are always associated with increased overdistension and hemodynamic impairment.