The current strategy for conventional mechanical ventilation (CMV) in patients with acute respiratory distress syndrome (ARDS) is to prevent further lung injury which is a result of alveolar over-distension and the repetitive collapse and reopening of damaged alveoli 123. Lung-protective ventilation using low tidal volume (VT) has been shown to reduce ventilator-induced lung injury (VILI) and mortality in patients with ARDS 245. Theoretically high-frequency oscillatory ventilation (HFOV) achieves all goals of a lung-protective ventilatory mode. It provides the application of extremely small VTs combined with a relatively high mean airway pressure (mPaw). Thereby a more uniform lung recruitment can be achieved while the risk of tidal overdistension is minimized 67. In adults with ARDS, HFOV can be safely applied and may improve gas exchange compared with CMV 8. During HFOV, VT and thus carbon dioxide (CO₂)-elimination are directly related to the applied pressure amplitude (ΔP) and the inspiratory/expiratory ratio and are inversely related to the oscillatory frequency- in other words: The lower the oscillatory frequency, the higher the resulting VT 9.

In adult HFOV trials the applied frequencies varied from 3–6 Hz and, in an attempt to maximize CO₂-elimination, a ΔP from 60–90 cmH₂O was used 1011. In these settings the resulting VTs resemble those during conventional lung-protective ventilation, thereby antagonizing the potential advantages of HFOV 912. Although it was shown that higher oscillatory frequencies (15 Hz) might result in less neutrophil infiltration compared with lower frequencies (5 Hz) in a small animal model of respiratory distress, in adults the application of higher frequencies may lead to insufficient CO₂-elimination with severe respiratory acidosis 131415.

Recently, a new pumpless arteriovenous extracorporeal lung assist system (av-ECLA) has been introduced into clinical practice. It consists of a low-resistance membrane lung (iLA, NovaLung^®, Hechingen, Germany) interposed into a simple arteriovenous shunt between the femoral artery and vein 16. Depending on the diameter of the cannulas, the cardiac output (CO) and the mean arterial pressure (MAP), the transmembraneous blood flow equals 20–30% of the CO 17. With these flow rates near total extracorporeal CO₂-removal could be achieved in animal models of respiratory failure, thereby allowing a more lung protective conventional ventilation strategy 1819.

While significant reductions in minute ventilation and VTs can be obtained during the combination of av-ECLA and conventional mechanical ventilation, optimal oscillatory frequencies remain to be determined. The current study was performed to evaluate the effects of different oscillatory frequencies on CO₂-elimination with and without av-ECLA in a large-animal model of ARDS. We hypothesized that the application of high oscillatory frequencies, and thereby minimization of VT and alveolar stretch, requires the combination of HFOV with av-ECLA in order to maintain or re-establish normocapnia.

All animals survived the complete study period. Gas exchange and hemodynamic parameters did not differ between the animals randomized for the incremental or decremental oscillatory trial before and after lung injury. After saline lavage, all animals developed severe respiratory failure (Table 1, Fig. 2, 3, and 4). Detailed data regarding gas exchange, respiratory parameters, hemodynamics and av-ECLA related parameters, are presented in Tables 1 and 2.

The major findings of this study are twofold: (1) With oscillatory frequencies from 9–15 Hz normocapnia could only be maintained if HFOV was combined with av-ECLA. (2) After lung recruitment and setting the mPaw 3 cmH₂O above Plow, a sustained improvement in oxygenation was detectable even when oscillatory frequencies up to 15 Hz were used.

Conventional mechanical ventilation during severe ARDS can aggravate the progress of lung damage, especially when high tidal volumes are applied and repeated tidal collapse and reopening of damaged lung units occur. Limitation of the VT to 6 ml/kg of the predicted body weight, while keeping the lungs open with sufficient positive end-expiratory pressure (PEEP) can significantly reduce mortality in ARDS 34. Further minimization of the VT combined with the application of high mean airway pressures may be achieved using HFOV 6. Thereby, inspiratory overdistension and expiratory de-recruitment can be avoided 21. Recently, it has been shown in a large-animal model of ARDS, that HFOV reduces histological signs of lung inflammation and messenger RNA expression of interleukin-1-beta in lung tissue compared to conventional lung-protective ventilation 22. In most clinical studies using HFOV in adults, oscillatory frequencies between 3–6 Hz and pressure amplitudes between 60–90 cmH₂O have been used 1011. If hypercapnia was evident during HFOV then oscillatory frequencies were decreased to 3 Hz and amplitudes were increased up to 90–100 cmH₂O. However, oscillatory frequencies below 4 Hz combined with maximum pressure amplitudes resulted in tidal volumes comparable to conventional lung-protective ventilation, thereby antagonizing the potential advantages of HFOV 12.

The idea of decoupling ventilation and oxygenation was introduced by Gattinoni et al 232425: Extracorporeal CO₂-elimination was provided by a veno-venous perfusion route with 20–30% of the cardiac output, whereas oxygenation was maintained by mechanical ventilation. Several animal and human trials showed the feasibility of reducing ventilator requirements during pump-driven extracorporeal CO₂-removal 23242627. However, despite technical advances of these systems, several side-effects and complications impede its benefits, e.g., pump-induced traumatisation of blood cells, plasma leakage of oxygenator membranes and activation of the coagulation and inflammatory system.

Pumpless extracorporeal lung assist became feasible with the introduction of low-resistance membrane lungs that could be interposed into a simple arteriovenous shunt between the femoral artery and vein 28. With the patient's heart as the driving force, the transmembranous blood flow is up to 25–30% of the CO, thereby allowing comparable CO₂-elimination and reductions in ventilatory support achieved during pumpdriven extracorporeal CO₂-removal 19. In an adult sheep model of respiratory failure, av-ECLA allowed significant reductions in VTs (from 15 ± 1.6 to 3 ± 1.5 ml/kg), peak inspiratory pressures (40 ± 2.1 to 20 ± 7.5 cmH₂O) and minute ventilation (10 ± 1.4 to 0.5 ± 0 L/min) 19.

The goal of this large-animal study of ARDS was to evaluate the effects of HFOV during different oscillatory frequencies on CO₂-elimination with and without the application of av-ECLA. Our results clearly demonstrate that normocapnia was not achieved and respiratory acidosis developed if higher oscillatory frequencies (> 9 Hz) were used without av-ECLA. Although 'permissive hypercapnia' might be one element of a lung-protective ventilation strategy because of its potential beneficial effects, such as suppression of lung inflammation, the safe level of hypercapnia and the respiratory acidosis remains unknown 29. In addition, there are clinical situations where hypercapnia is contraindicated, e.g. in patients with decreased cerebral compliance 30.

It has now been accepted, that VT-reduction is the key factor to improving outcome and to protecting the lungs from further damage, whereas the optimal VT remains unclear 431. In our study, the implementation of av-ECLA allowed the use of maximal oscillatory frequencies (up to 15 Hz), similar to those applied during neonatal HFOV, without the risk of hypercapnia or respiratory acidosis. Although not measured in this study, with the settings chosen, the resulting VTs can safely be assumed to be below 1 ml/kg of the predicted body weight 1632. Nevertheless, mere VT-reduction during conventional ventilation leads to low peak pressure ventilation favouring further lung de-recruitment 33. Very recently, Dembinski and co-workers compared the use of av-ECLA and VT-reduction to 3 ml/kg with a conventional low-tidal volume (6 ml/kg) ventilation strategy in a large-animal model of ARDS 34. After 24 hours, the VT-reduction in the av-ECLA group resulted in a significant impairment of oxygenation and an increase of the pulmonary shunt fraction compared with the CMV group. However, the PEEP levels used in this study were very low and insufficient in preventing lung de-recruitment. In ARDS patients ventilated with low tidal volumes, de-recruitment is usually reversed by a recruitment manoeuvre or prevented by an adequate PEEP level 33. Adjusting the mPaw level for optimal lung recruitment remains difficult during HFOV. Usually mPaw during HFOV is set 3 to 5 cmH₂O higher than the mPaw used during CMV 21. In an animal model of respiratory distress, it was shown that setting the mPaw 6 cmH₂O above the lower inflection point of the pressure-volume curve yielded the best oxygenation 21. Using a similar recruitment strategy, we found sustained improvements of oxygenation, even with maximum oscillatory frequencies. Since VT can be minimized when HFOV is combined with av-ECLA, an optimal recruitment of lung volume appears to be essential in this setting.

The study design implies the following limitations: First, we used an ARDS model based on surfactant-depletion. In adults, not surfactant deficiency, but alveolar flooding is the predominant mechanism in ARDS development with surfactant-depleted lungs responding better to lung recruitment 35. Second, the Sensormedics 3100 B oscillator is a pressure cycling machine that can neither control nor directly measure VTs. Hence, in this study no direct statement regarding the applied VTs can be made. However, in a recent observational study VT was measured directly during HFOV in ARDS patients: It was shown, that the tidal volumes during HFOV with frequencies between 5 and 12 Hz are between 0.8 and 3.3 ml/kg of the predicted body weight 12. Third, the study protocol did not allow alterations of the pressure amplitude and I:E-ratio in order to improve CO₂-elimination. Both parameter settings refer to previous experimental large-animal studies of HFOV and clinical practice 112236. However, if maximal oscillatory frequencies without av-ECLA were used, only moderate hypercapnia and respiratory acidosis developed. Therefore, one might argue, that without av-ECLA CO₂-elimination could have been improved by adjusting the pressure amplitude and I:E-ratio to 90–100 cmH₂O and 1:2, respectively. On the other hand, with near total CO₂-removal due to extracorporeal lung assist, the applied pressures and accordingly the applied VT could have been further reduced, thereby minimizing VT and alveolar shear stress. Finally, av-ECLA allows for decoupling of ventilation and oxygenation. Therefore, the application of more lung-protective ventilator settings is not only possible, but should also be examined. However, it was not the purpose of this study to examine the effect of higher frequency HFOV on lung damage.

Despite the potential benefits with regard to lung protective ventilation strategies, different complications are described during av-ECLA. These included infections, ischemia of the lower limb after cannulation, bleeding and cannula thrombosis 16. In addition, the device should not be used in patients with cardiogenic shock, heparin-induced thrombocytopenia and severe peripheral arterial occlusive disease.

In conclusion, we demonstrate in a large-animal model of ARDS, that the combination of HFOV and av-ECLA guarantees normocapnia even with maximal oscillatory frequencies of 9 to 15 Hz. In this context, av-ECLA can be interpreted as a tool to unmask the entire lung protective potential of HFOV. Minimization of the applied VT does not only limit tidal overdistension and volutrauma, but also facilitates lung recruitment and prevents the lungs from atelactrauma since the application of higher mean airway pressures is possible. Thereby, oxygenation can be maintained. Histologic and immunologic data are needed in order to prove the lung protective effects of the proposed therapeutic concept.

In a further trial, it should be evaluated whether the combination of HFOV with maximal oscillatory frequencies and the av-ECLA result in further lung-protection when compared to conventional lung-protective ventilation.

ARDS: Acute respiratory distress syndrome; av-ECLA: Arteriovenous extracorporeal lung assist; CMV: Conventional mechanical ventilation; CO: Cardiac output; CO₂: carbon dioxide; CVP: Central venous pressure; DO₂: Oxygen delivery; FiO₂: Inspiratory oxygen fraction; HFOV: High-frequency oscillatory ventilation; HR: Heart rate; I:E: Inspiratory to expiratory ratio; MAP: Mean arterial pressure; mPaw: Mean airway pressure; MPAP: Mean pulmonary artery pressure; PaCO₂: Arterial carbon dioxide tension; PaO₂: Arterial oxygen tension; PCWP: Pulmonary artery wedge pressure; PEEP: Positive end-expiratory pressure; PIP: Peak inspiratory pressure; Plow: Lower inflection point; PRM: Post recruitment measurements; PV: Pressure-volume curve; PVR: Pulmonary vascular resistence; Qs/Qt: pulmonary shunt fraction; RM: Recruitment manoeuvre; RR: Respiratory rate; SvO₂: Mixed venous oxygen tension; SVR: System vascular resistance; VILI: Ventilator-induced lung injury; VO₂: Oxygen consumption; VT: Tidal volume.

The authors declare that they have no competing interests.

RMM designed the study, collected data, and drafted the manuscript. JK collected the data and helped to write the manuscript. MK and AJ performed the statistical analysis. UW collected data. FS participated in the design of the study. CW, PK and NR helped to interpret the results and write the manuscript. JB drafted the manuscript and participated in the design of the study. All authors read and approved the final manuscript.