To our knowledge this is the first study in animals that compares the effects of two HFOV regimens on systemic hemodynamics, gas exchange, and lung aeration; one in which the continuous distending pressure (CDP) was adjusted according to mean airway pressure (HFOVcon), and one adjusted to the corresponding mean transpulmonary pressure (HFOV PLmean).
The main finding of the present study is that transpulmonary pressure-guided HFOV with high PEEP values has less impact on systemic hemodynamics than conventional HFOV and does not compromise oxygenation. The reduction in distending pressures (CDP) associated with transpulmonary pressure-guided HFOV resulted in less pulmonary overdistension, but increased the percentage of non-aerated lung tissue (Figs. 3, 4 and 5). Furthermore on comparison between VCV and transpulmonary pressure-guided HFOV there was higher MAP and ITBI and a lower percentage of normal and poor ventilated lung tissue, but less pulmonary overdistension at high PEEP levels in HFOV PLmean.
In previous studies of conventional HFOV, the CDP was based on the mean airway pressure at each PEEP level [4, 7, 8, 11, 15]. This universally established procedure of setting CDP as airway pressure + 5cmH20 is merely an empirical convention that is not underpinned by experimental evidence. It is known that one cannot equate mean airway pressure and transpulmonary pressure, particularly not in patients with ARDS, because of the changes in chest wall and lung elastance. Using Paw or plateau pressure as the reference point would most likely yield a CDP that was too high and could cause overdistension of the lung and, in the end, ventilator-induced lung injury (VILI).
For the sake of comparison in the present study, CDP was set at 5 cmH2O above the mean transpulmonary pressure at each corresponding PEEP level. This is also an empirical approach, albeit it an approach that induces only one modification and not the additional factor of a different pressure increment over the reference point.
Talmor et al. [12] have already shown that HL-guided ventilation is superior to conventional mechanical ventilation. In this study the CDP levels based on PLmean were approximately 40% than those based on mean airway pressures at both employed PEEP levels.
The lesser degree of adverse circulatory effects compared to those observed in the conventionally ventilated animals or described in recently published studies on HFOV is possibly due to the lower CDP used in HFOV PLmean [15, 16]. These circulatory effects are probably caused by an intrathoracic pressure-related preload reduction or by direct impairment of right ventricular function [15, 17]. Most HFOV studies in the past did not take the hemodynamic instability of patients with ARDS into account, which was the consequence of the strict fluid reduction in ARDS therapy [18]. HFOV employed under conditions of hypovolemia will reduce pulmonary perfusion and affect oxygenation. This was confirmed in a study by Ursulet et al. [19], who showed that HFOV indeed caused a significant reduction in cardiac index, but not in arterial blood pressure in hypovolemic patients. Echocardiography or hemodynamic evaluation should therefore be performed before HFOV is started in order to reduce the potential negative circulatory effects. An animal study by Songqiao and coworkers [20] demonstrated that almost no hemodynamic depression actually occurs if the CDP is carefully titrated.
The lower CDP in our study resulted in a higher percentage of non-aerated lung tissue because the higher distending pressures in conventional HFOV are comparable to high PEEP levels. High PEEP levels and a correspondingly high CDP can recruit lung tissue but on the other hand it can also lead to lung overdistension [21]. Fu et al. showed that lung overdistension triggered by an increase in transpulmonary pressure produced a significant increase in the number of epithelial and endothelial breaks [22], which can cause pulmonary edema. Parker et al. are confident that microvascular permeability might be actively modulated by a cellular response due to overdistension [23]. The authors assumed that this cellular response might be initiated by stretch-activated cation channels. The 3.7-fold increase in the capillary filtration coefficient found in their study is a strong argument for avoiding overdistension. It is noteworthy that there was no difference in oxygenation between the two groups, although the animals in the PLmean group had a greater percentage of non-ventilated lung tissue. This might be explained by the fact that the young animals had a more robust hypoxic pulmonary vasoconstriction (HPV) reflex [24] so that perfusion was reduced in the lung areas that were no longer ventilated. The situation in patients in intensive care might be a different one.
Not only overdistension, but also high oxygen concentrations can cause lung injury. HFOV initiated late in the course of ARDS will require a high FiO2, and high oxygen concentrations in combination with low distending pressures tend to promote airway closure with consequent atelectasis in dependent regions [25]. Derosa et al. showed in a porcine model of ARDS that no alveolar collapse occurred with low FiO2 and low distending pressures. One can therefore safely conclude that the FiO2 of 1.0 in our study increased the amount of non-ventilated lung tissue. High distending pressures can prevent lung collapse but they also cause the cyclical alveolar opening and closing that increases lung injury. HFOV should therefore not be simply regarded as a rescue therapy but rather as an early therapeutic option, because in the early stage of ARDS a low FiO2 and low distending pressures will be sufficient therapy.
Although spontaneous ventilation is a cornerstone of ARDS therapy, muscle relaxation in the early phase can reduce lung injury [26]. Muscle relaxation facilitates ventilator synchronization and thus helps to limit alveolar pressure peaks with overdistension and consecutive pulmonary or systemic inflammation [26]. But it also increases the percentage of non-ventilated tissue. In view of our results, transpulmonary pressure-guided HFOV probably has a similar effect because it reduces overdistension. The results of the OSCILLATE and the OSCAR trials called the safety of HFOV into question [9, 10]. The OSCILLATE trial was terminated before completion because the interim analysis had shown that the use of HFOV resulted in a 12% increase in in-hospital mortality. The patients in the HFOV group had required more vasopressor support, perhaps due to the high intrathoracic pressures used in the OSCILLATE trial. High intrathoracic pressures cause hemodynamic compromise and increased right ventricular afterload. Employing transpulmonary pressure-guided HFOV would have resulted in lower mean airway pressures and hemodynamic compromise would have been less severe. It is also important to select suitable patients because HFOV is probably only a superior method in patients with homogenously damaged lungs [27], which are potentially recruitable for gas exchange. It should also be emphasized that centers with little or no experience in the use of HFOV participated in both trials, so the question arises whether suitable patients had been selected, and if HFOV had been correctly implemented.
The high airway pressures used in conventional ventilation or conventional HFOV induce regional overdistension in healthy lung units, which is probably the reason why the open-lung concept has failed to reduce mortality in ARDS in the past. One should note that the OSCAR trial, in which there was no difference in mortality between HFOV and conventional ventilation, used lower airway pressures than the OSCILLATE trial. Overdistension, and to some degree even recruitment, causes local and systemic inflammation, which leads to the question whether a larger percentage of non-aerated lung tissue, as found in our study, might actually be an advantage. It should be noted that on comparison between VCV and HFOV PLmean there were fewer differences in hemodynamics than on comparison between HFOVcon and HFOV PLmean. Only the MAP and the ITBI were higher in HFOV PLmean compared to VCV, but SV and CO stayed the same at high PEEP levels in comparison to HFOVcon and HFOV PLmean. CT examinations of HFOV PLmean and VCV were comparable to HFOV PLmean versus HFOVcon, because a higher percentage of non ventilated and poorly ventilated lung tissue was observed, but there was less over distended lung tissue in HFOV PLmean.
We propose that HFOV guided by transpulmonary pressure monitoring can be an alternative therapeutic option in the early stage of ARDS because it reduces the amount of overdistension and thereby limits escalation of lung injury.
Limitations
The primary limitation of the study was that it was not possible to randomize the order in which the ventilatory modes were applied, since the transpulmonary pressures used for the HFOV settings were determined during the preceding phase with conventional ventilation. There is the possibility, albeit a small one, that using each animal for both ventilator modes might have induced factors relating to the history of the lung, which as a consequence might have influenced subsequent measurements. However, performing all measurements in a single animal has the major advantage of reducing inter-individual variability and allows the use of paired-data analysis that gives greater statistical power and reduces the risk of type II error. Statistical analysis was exploratory and differences in median and interquartile ranges were reported. Significance was assessed using the paired Wilcoxon test, but was not adjusted for multiple testing in order to avoid false negatives.
Another limitation is the fact that the hemodynamic advantages of HFOV PLmean over HFOVcon were only detectable at a very high PEEP level of 20 cmH2O. The plateau pressures of more than 30 cmH2O associated with this PEEP level would not have been tolerated in a clinical setting. The lower, clinically acceptable Paw would have resulted in a lower CDP during HFOVcon and there might have been no difference detectable at this pressure.
Last, the CDP used for HFOV PLmean was obtained by a method analogous to that used for HFOVcon, i.e. by adding 5 cmH2O to the reference pressure, in this case PL. This is also an empirical approach and has no experimental basis.