Our understanding of the mechanisms and importance of ventilator-induced lung injury (VILI) has advanced over the past three decades, in large part because of carefully conducted animal experiments [1–4]. The principles derived and knowledge gained from these studies has subsequently been applied and tested in the clinical arena, leading to reductions in mortality in adults with the acute respiratory distress syndrome (ARDS) [5, 6]. While significant progress has been made, mortality of ventilated patients with disease processes, such as ARDS, remains very high, and despite the advances, it is likely that this high mortality is still due partly to VILI. Many experimental and clinical questions related to VILI remain unanswered; one such area is the impact of high-frequency oscillation (HFO) on VILI in ARDS.

HFO should theoretically be an ideal mode to limit VILI. It delivers pressure oscillations around a relatively constant mean airway pressure, producing very small tidal volumes (often less than the anatomic dead space). In 1915, based on observations of panting dogs, Henderson and colleagues first suggested that adequate gas exchange could take place with tidal volumes smaller than dead space [7]. Another example of naturally occurring high-frequency ventilation is seen in hummingbirds, which breathe at a rate of 250/min at rest. Measurements of respiratory rates per unit mitochondrial volume, however, reveal no significant differences between hummingbirds and mammals [8]. Many investigators have subsequently shown – and explained why – it is possible to ventilate dogs, cats, rabbits, rats, pigs, sheep, monkeys, and humans with tidal volumes significantly less than dead space [9–11].

These minimal tidal excursions should allow us to set HFO in such a way as to keep the lung open, avoiding atelectrauma, while simultaneously limiting tidal overdistension, avoiding volutrauma. Indeed, many studies have demonstrated beneficial effects on gas exchange, pulmonary inflammation, and histology with HFO, compared with injurious conventional ventilation. More importantly, recent studies have suggested that HFO may still reduce VILI compared with lung-protective strategies using conventional ventilation [12–14], although this finding is not universal [15, 16].

Extrapolating these and other animal HFO data directly to adults with ARDS has limitations: most of these studies are short-term (typically 4–6 h) studies performed in small animals (mostly rabbits), conducted with HFO settings that are commonly used in the neonatal intensive care unit. Although the ventilators are very similar, important differences exist between the application of HFO in the adult and neonatal clinical settings. These differences could markedly impact this mode's effects on VILI. In adults, lower frequencies are usually used to facilitate gas exchange (4–6 vs 10–12 Hz in neonates). In addition, more power is needed to oscillate an adult, resulting in higher peak-to-peak pressure gradients (ΔP), and finally endotracheal tubes in adults are obviously larger than in rabbits or neonates. Each of these factors will lead to larger tidal volumes being delivered in adult HFO settings. Since the very small tidal volumes are the key to the lung-protective potential of HFO, this might suggest that adult HFO is not as effective in reducing VILI, compared with the neonatal setting; however, the critical issue is not the absolute size of the tidal volume but the relative size in relation to lung volume. Exactly how small animal studies scale to human patients with ARDS is not entirely clear.

The study by Muellenbach and colleagues in this issue of “Intensive Care Medicine” attempts to address many of these issues. They studied a large-animal model of lung injury using pigs with an average weight of 55 kg, and compared the effects of low-tidal volume conventional ventilation vs HFO with adult settings on lung pathology and inflammatory biomarkers [17]. Their main finding was that semi-quantitative lung histology scores (scored by pathologists blinded to group assignment) were lower in the inflammation subcategory with HFO; pulmonary mRNA for IL1-beta was also significantly lower in the HFO animals. These differences were seen even with the use of a typical adult HFO frequency (6 Hz) and ΔP (60–80 cm H2O), delivered through an 8.5-mm endotracheal tube.

There are important limitations to this study, however, that we must consider when interpreting and applying these findings. Firstly, the lung injury model used, saline lavage, is known to be a relatively mild and easily recruitable form of lung injury. This is evident in the present study by the adequate oxygenation in both groups using a relatively low FiO2 and relatively low mean airway pressures that are substantially lower than required for adults with severe ARDS. Indeed, in most studies of HFO in adults with ARDS, the mean airway pressures on HFO are higher than the values on conventional ventilation. It is not clear whether the observed differences in these results would be amplified or diminished in the setting of more severe lung injury. Secondly, there are differences in the lungs of pigs and those of humans. For example, pigs have minimal collateral ventilation compared with humans [18]. Whether this could impact gas transport, and hence change the relative ventilatory settings required to achieve adequate gas exchange, is unknown. Thirdly, although the authors are to be commended for performing what may be considered to be a relatively long study (24 h) compared with most studies in small animals, most patients with ARDS are ventilated for many days, weeks, or even months. Finally, we should be cognizant of the fact that multiple comparisons of end points were made between groups. Other components of the lung pathology score and other inflammatory markers were not significantly different. This may be because of the sampling time frame (e.g., an early difference in TNF-α may have been attenuated by 24 h), or alternatively might suggest that some positive findings were seen by chance alone.

In conclusion, high-frequency oscillation is an exciting ventilatory technique that, from a theoretical perspective, should be very lung protective. The limitations discussed herein notwithstanding, the study by Muellenbach and colleagues [17] suggests that the attenuation of VILI seen with HFO in small animal models with neonatal settings may also be present when HFO is applied in larger animals using typical adult settings. How these findings will translate to clinical studies of adults with ARDS remains to be determined.