Studies have shown that volume-controlled ventilation (VCV) with small tidal volumes, adequate positive end-expiratory pressure (PEEP) and low driving pressures (<15cmH₂0) can improve oxygenation and reduce pulmonary morbidity in patients with acute respiratory distress syndrome (ARDS) [1, 2].

High frequency oscillatory ventilation (HFOV) is another approach to lung-protective ventilation, since it employs very low tidal volumes and very small changes in delta pressure [3] applied with higher continuous distending pressure (CDP). Several earlier studies have demonstrated the efficacy of HFOV in patients with ARDS in whom VCV has failed [4–6]. There is also evidence that outcome is improved when HFOV is initiated at an early stage [7, 8]. However, two recent studies showed either no benefit or even a higher mortality rate with HFOV compared to conventional ventilation [9, 10]. One possible explanation is that inappropriate HFOV ventilator settings had cancelled out the positive effects of HFOV.

Until now, HFOV ventilator settings have been guided by the mean airway pressure (Paw_mean), and the CDP has been set at Paw_mean plus 5 cm H₂0 in almost all studies [4, 7, 11]. This approach is more than questionable, because the Paw is not a valid surrogate for transpulmonary pressure (P_L). Since only a positive end-exspiratory P_L can prevent cyclic opening and closing and overdistension of the alveolae, P_L has to be > 0 in order to prevent alveolar collapse.

The potential solution thus lies in choosing HFOV settings based on a more exact approach to the distending pressure applied to the lung. Talmor et al. showed that oxygenation and pulmonary compliance improves when PEEP is adjusted according to esophageal pressure (Pes) [12]. In an earlier study we found that we were able to reduce CDP when it was adjusted according to Pes [13]. It is therefore reasonable to hypothesize that it would be of benefit to set CDP according to P_L and not base it on mean airway pressure (Paw_mean).

The study had the approval of our institution’s animal study review board. The animals were handled according to the Helsinki convention for the use and care of animals.

Experimental protocol

Baseline measurements were performed at 5 cmH₂O PEEP after all parameters had been constant for 30 min, first in healthy lungs and then after ARDS had been induced by the intrabronchial installation of hydrochloric acid (0.1 N, pH 1.1; 2.5 ml kg^− 1 body weight) during inspiration. Equal aliquots were instilled through a suction catheter into the right and left main bronchus. The injury was considered stable if partial pressure of arterial oxygen (PaO₂) remained constantly lower than 300 mmHg at a FiO₂ of 1.0 at 60 min after instillation.

The animals were then ventilated in the study modes at consecutive PEEP levels of 10 and 20 cmH₂O. Measurements were performed after 10 min ventilation at each PEEP level. Mean airway (Paw_mean) and esophageal pressures (Pes) were recorded. End-expiratory esophageal pressure was measured during an end-expiratory hold (PEEP) and the inspiratory esophageal pressure was measured during an inspiratory hold (plateau pressure). The end-expiratory and the end-inspiratory esophageal pressure were then added and divided through the arithmetic mean, in order to calculate the mean esophageal pressure (Pes_mean). The transpulmonary pressures (P_L) were then calculated (Fig. 1):

$$ {\mathsf{P}}_{\mathsf{L}\ \mathsf{mean}}={\mathsf{P}\mathsf{aw}}_{\mathsf{mean}}-{\mathsf{P}\mathsf{es}}_{\mathsf{mean}}. $$

At the end of the measurements at each PEEP level the lungs were allowed to collapse by disconnecting the tracheal tube from the respirator for 30 s. A recruitment maneuver was then performed by inflating the lungs to a pressure of 40 cmH₂O for 40 s after which ventilation was started at the next PEEP level.

VCV was performed as described above. HFOV was performed with a SensorMedics®-Ventilator 3100B (Care Fusion, Yorba Linda, CA, USA). For HFOV_con the CDP was set at 5 cmH₂O above the Paw_mean. For HFOV P_Lmean the CDP was set at 5 cmH₂O over the mean P_L measured during VCV at the corresponding PEEP level as described by Talmor et al. [12] (Fig. 1). The initial ventilator settings were bias flow 20 l min^− 1, power 70%, inspiration time 44%, and frequency 5 Hz. It was not possible to randomize the order of these measurements due to the nature of the study design.

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 (HFOV_con), and one adjusted to the corresponding mean transpulmonary pressure (HFOV P_Lmean).

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 P_Lmean.

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 H_L-guided ventilation is superior to conventional mechanical ventilation. In this study the CDP levels based on P_Lmean 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 P_Lmean [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 P_Lmean 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 P_Lmean there were fewer differences in hemodynamics than on comparison between HFOV_con and HFOV P_Lmean. Only the MAP and the ITBI were higher in HFOV P_Lmean compared to VCV, but SV and CO stayed the same at high PEEP levels in comparison to HFOV_con and HFOV P_Lmean. CT examinations of HFOV P_Lmean and VCV were comparable to HFOV P_Lmean versus HFOV_con, because a higher percentage of non ventilated and poorly ventilated lung tissue was observed, but there was less over distended lung tissue in HFOV P_Lmean.

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.

When treating ARDS, the ventilator settings demand meticulous adjustments and are a compromise between recruiting and stabilizing non-aerated lung tissue while avoiding overdistention and hemodynamic compromise. Our study results showed that HFOV guided by transpulmonary pressure is equal or superior to conventional HFOV with regard to systemic hemodynamics, oxygenation, and lung overdistension in animals. It might therefore be useful as a prophylactic approach to prevent worsening of lung injury in the early phase of ARDS. The promising results of transpulmonary pressure-guided HFOV would justify a clinical trial in which HFOV is initiated immediately after the onset of ARDS.