Rationale for High-Frequency Oscillation as a Primary Lung-Protective Mode in Patients with ALI/ARDS

Lung-Protective Mode in Patients with ALI/ARDS

H. Quiroz-Martinez and N.D. Ferguson

Introduction

Clinicians and researchers are becoming increasingly conscious of the potentially harmful effects of mechanical ventilation, and more attention is being focused on methods of ventilation that may reduce these complications. Indeed the paradigm for mechanical ventilation in patients with acute lung injury (ALI) and acute respi- ratory distress syndrome (ARDS) has evolved in the last 10 years from a goal of nor- malizing blood gases to one of avoiding ventilator-induced lung injury (VILI) while maintaining adequate gas exchange. Lung protection during mechanical ventilation begins with limitation of tidal volume on conventional ventilation, but the optimal method remains to be determined [1]. One potential modality that may be useful in the avoidance of VILI is high-frequency oscillation (HFO). In this chapter, we will introduce HFO, provide a brief discussion of ARDS and VILI, and focus on the pre- clinical and clinical data available to date supporting the use of HFO as a primary modality to avoid VILI in adults.

Basics of HFO

HFO Mechanics and Physiology

During the second half of the 20

century, different researchers documented that ventilation (i.e., adequate CO

clearance) was possible for variable periods of time employing tidal volumes that were under dead space volume at high respiratory rates; observations that were theorized as long ago as 1915 [2, 3]. HFO did not appear as an alternative mode of mechanical ventilation until the early 1980s after Bohn et al. published their findings showing they could effectively ventilate dogs using a piston-driven oscillator at low mean airway pressure and tidal volumes less than anatomic dead space using variable frequencies [4, 5].

Conceptually, this mode of mechanical ventilation uses high respiratory cycle fre-

quencies (3 – 15 Hz) with very low tidal volumes, maintaining a relatively constant

mean airway pressure (Paw). This is achieved with rapid oscillations of a reciprocat-

ing diaphragm driven by a piston, which creates pressure waves in the ventilator cir-

cuit that ultimately determine the tidal volume. The oscillator-patient system has no

intrinsic source of fresh gas; to provide adequate gas exchange a bias flow of fresh,

heated and humidified gas (20 – 60 l/min) is incorporated as part of the ventilator

circuit, and passes between the oscillating membrane and the patient (Fig. 1). This

provides the desired FiO

and clears CO

from the system. During HFO the oscillat-

ing diaphragm actively pulls outward during expiration; a process that may promote

Fig. 1. Schematic overview of the high frequency oscillation (HFO) cir- cuit. From [50] with permission.

CO

clearance, and help prevent gas trapping and alveolar overdistention. The oscil- latory pressure amplitude ( 2 P; the peak-to-peak pressure gradient generated by the membrane) is measured in the ventilator circuit; it does not reflect the pressure oscillations in the distal airways. These pressures are greatly attenuated by the endo- tracheal tube and high-caliber airways so the actual pressure swings in the alveoli are much lower.

During HFO, oxygenation depends on the mean airway pressure, the resultant lung volume and the FiO

[6, 7]. In contrast, ventilation is determined by the power set on the ventilator (and the resultant 2 P), the frequency, and the bias flow rate [8, 9]. Because frequency and tidal volume are not independent in HFO (higher fre- quencies lead to smaller tidal volumes because of reduced inspiratory times), and because alveolar ventilation depends more on tidal volume and less on the fre- quency (V

V

·f) [9], during HFO we have a phenomenon known as ‘negative fre- quency dependence’. This means that during HFO a decrease in the respiratory fre- quency leads to an increase in the tidal volume with a consequent increase in CO

clearance.

Gas Exchange during HFO

During spontaneous ventilation and conventional ventilation, convection and

molecular diffusion are the principal mechanisms of gas movement to and in the

alveoli. During HFO, the tidal volume is lower than the dead space volume so the

mechanisms of gas transport in the airways are different. A number of different

mechanisms have been proposed to account for the observation of adequate ventila-

tion despite such small tidal volumes (Fig. 2) [10]. First, the most proximal alveoli

may receive ventilation as usual through direct bulk convection. Second, in the con-

ducting airways (bronchi, bronchioles, and terminal bronchioles), gas mixing and

movement takes place because of differences in flow velocity profiles that occur dur-

ing inspiration and expiration because of the shape of the airways, so-called asym-

metric velocity profiles, with resultant net movement of fresh gas into the lung and

Fig. 2. Alternative mechanisms of gas exchange with high frequency oscillation (HFO). From [10] with per- mission.

exhaled gas moving out. Third, different alveolar units have different resistance and compliance values, and thus different time constants and rates of filling and empty- ing at a given pressure gradient. These differences result in asynchronous filling of contiguous alveoli, so gas can swing from rapid filling alveoli to slow filling alveoli improving the gas mixture. This mechanism of gas exchange is called Pendelluft. As usual, the principal mechanism of gas transport in the alveoli is molecular diffusion where the intermixing of molecules is due to Brownian motion. In HFO the high flow rates, turbulence and combination of convection and molecular diffusion results in enhanced molecular dispersion. Finally, transmitted cardiac oscillations also play a role in HFO gas exchange, having been shown to improve gas mixing five-fold by enhancing the molecular diffusion in the alveoli [11].

Rationale for HFO in Adults Acute Respiratory Failure and ARDS

Acute respiratory failure is one of the leading causes of admission to the intensive

care unit (ICU), and the most frequent organ dysfunction found in the critically ill

patient [12]. ARDS is the most severe and life-threatening form of acute respiratory

failure. ARDS is an important clinical problem for intensivists both because of its

relatively common incidence (with recent reports of 65 cases per 100,000 population

per year [13]), and because of its high associated mortality rate (ranging from

30 – 65 % depending on the specific population included). Despite our improved

understanding of the pathophysiologic changes in ARDS and the advances in life support technology, the mortality rates have generally remained high in unselected populations [14]. Notwithstanding numerous laboratory and clinical investigations, no pharmacological therapy has yet been demonstrated to have an impact on mor- tality.

Ventilator-Induced Lung Injury

Positive-pressure ventilation is the cornerstone for support of the patient with ALI/

ARDS, but it has well documented potential deleterious effects on respiratory mechanics, hemodynamics, and immune response. Indeed, since the demonstration that the manner in which mechanical ventilation is delivered directly affects mortal- ity in patients with ALI/ARDS [1,15], our goals for ventilation have clearly changed.

Today the aim is to oxygenate and ventilate without causing further VILI. VILI is thought to occur primarily through two major mechanisms: Cyclic alveolar overdis- tention, and repetitive alveolar collapse and reopening [16].

Gross barotrauma is defined as the presence of extra-alveolar air due to alveolar rupture; this correlates with high levels of peak airway pressure and positive end- expiratory pressure (PEEP), high tidal volume and gas trapping. More subtly, volu- trauma results from the cyclic overdistention of lung units that leads to mechanical disruption of the alveolar-capillary barrier and inflammation, ultimately creating a histological picture that is indistinguishable from primary ARDS. Dreyfuss et al.

found that high tidal volume ventilation induced pulmonary edema by causing increases in both epithelial and endothelial permeability, and that transpulmonary pressure (Pplateau – Ppleural) was the major determinant [17]. Similarly, Hernandez et al. demonstrated in immature rabbits that volume distension of the lung, rather than high peak inspiratory pressure (PIP) caused microvascular damage [18].

Meanwhile, ventilation at low lung volumes can also cause parenchymal damage due to alveolar collapse, termed atelectrauma [19]. The repetitive opening and clos- ing of these atelectatic alveoli, provoked by conventional mechanical ventilation, can cause excessive alveolar wall strain that triggers the inflammatory cascade.

All forms of mechanical trauma to the alveoli may lead to surfactant dysfunction, epithelial and endothelial cell injury (necrosis/apoptosis) with increased alveolar- capillary permeability, inflammatory mediator release, neutrophil infiltration, lung macrophage activation, and bacterial translocation. Each of these mechanisms can in turn exacerbate the local injury and initiate or potentiate a systemic inflamma- tory response, a process known as biotrauma [20, 21].

Patients with ALI/ARDS are at particularly high risk of VILI since their lungs are

already inflamed and heterogeneously damaged; regions of injured lung can be adja-

cent to relatively normal parenchyma. The injured alveolar regions may be filled

with fluid and collapsed during the entire respiratory cycle, collapsed at the end of

expiration but re-expanded during inspiration, or aerated throughout the respira-

tory cycle and susceptible to overdistention. The relatively healthy zones of the lung

that have higher compliance tend to receive the bulk of delivered tidal volumes and

are, therefore, submitted to more stress and strain than the consolidated alveoli. In

this way, contiguous acini might be in danger of different types of ventilator-induced

injury, making it more difficult to ventilate without causing further damage. In addi-

tion, using conventional ventilation, strategies to minimize volutrauma and atelec-

trauma can directly compete. Increasing end-expiratory volumes (with high PEEP)

can predispose to high end-inspiratory volumes and volutrauma. Meanwhile small

tidal volumes to limit volutrauma can predispose to alveolar collapse and atelec- trauma. For these reasons, patients with ARDS are more susceptible to develop VILI at traditional positive pressure ventilation settings.

Laboratory Data

With an understanding of the mechanisms of VILI, we can appreciate that in order to minimize VILI, we should limit tidal overdistention and resultant volutrauma, while simultaneously keeping the lung open and avoiding cyclic collapse and atelec- trauma. HFO is theoretically ideally suited to these goals. The key is the very small tidal volumes that are delivered during HFO. These should allow for the setting of a high mean airway pressure aimed at keeping the lung open, while still being able to avoid the tidal overdistention that would be inevitable even using small conventional tidal volumes. Tidal volumes are not measured routinely during HFO, and some concerning measurements in sheep raised the issue of whether the use of lower fre- quencies in adults (3 – 6 Hz compared with 10 – 15 Hz used in neonates) would still result in very small tidal volumes [22]. Very recently, however, Hager et al. have measured tidal volumes in adults receiving HFO at their usual settings, documenting that delivered tidal volumes are indeed low, in the range of 1 – 2 ml/kg predicted body weight [23].

During the 1980s and ’90s several animal studies compared the effects of HFO vs.

traditional (high volume/pressure) conventional ventilation in saline-lavage lung injury models. Many of these studies supported HFO as an attractive alternative to preserve adequate oxygenation, maintain ventilation, optimize lung mechanics, and minimize VILI. Almost universally, compared with what are now known to be inju- rious settings of conventional ventilation, HFO resulted in improved gas exchange, decreased levels of inflammatory markers, and improved pulmonary pathology scores [24, 25].

More relevant today, however, are more recent studies comparing HFO with lung- protective conventional ventilation using lower tidal volumes (6 ml/kg) with or without increased PEEP, again in saline lavage models. As expected, these investiga- tions do not show such a dramatic benefit for HFO. Of six studies published from 1999 to 2004, two showed similar oxygenation, inflammation, and pathology between the two groups, while four favored HFO in these categories; none suggested a benefit for conventional ventilation [26 – 31]. Taken collectively, these animal stud- ies still provide a strong physiological rationale for a potential benefit from HFO in terms of VILI reduction compared with optimal conventional ventilation.

Clinical Data: Neonates

With the promising results gathered from animal models, HFO was implemented in the management of hyaline membrane disease in human neonates as a ventilatory modality that could reduce VILI and promote adequate gas exchange. In 1987, Fro- ese et al. proved sufficient efficacy and safety with HFO to warrant further investiga- tions in this population [32]. Initial enthusiasm quickly waned when the HiFi study showed no benefits in outcomes and an increase in intracranial complications [33];

it was subsequently realized that this was likely due to a strategy targeting lower air-

way pressures and higher fraction of inspired oxygen (FiO

), along with a dispropor-

tionate number of complications at less experienced centers [34]. None of the more

than a dozen neonatal randomized controlled trials (RCTs) that have followed has

shown similar concerns with harm. In general, those that employed a lung recruit- ment strategy in the HFO arm showed better oxygenation and lung mechanics in the HFO group, with some showing significant improvement in outcomes such as chronic lung disease [35]. Despite a lack of a definitive effect on outcome, HFO remains widely used in neonatal ICUs, but is most often employed in the early man- agement of patients with moderate to severe preterm respiratory distress syndrome who require alveolar recruitment with lung-protective ventilation at high mean air- way pressures.

Clinical Data: Adults

In adults there are comparatively few data about HFO in ARDS. This is largely because until the mid-1990s commercially available oscillators were not capable of ventilating patients over 35 kg in weight, and the adult version of the neonatal/pedi- atric machine did not receive regulatory approval in the United States until 2001.

The bulk of the published experience with adult HFO comes from observational studies where HFO was used as rescue therapy in patients who failed to improve with conventional ventilation (Table 1) [36 – 44]. The baseline characteristics of these study groups vary, but most of them were receiving conventional ventilation for rel- atively long periods of time (1.7 to 10 days) before being switched to HFO. The deci- sion to switch a patient from conventional ventilation to HFO was generally made based on oxygenation failure (PaO

‹ 65 despite FiO

8 60 %) and the requirement of high airway pressures to recruit and maintain the adequate lung volumes (peak inspiratory pressures and/or high PEEP). After the switch to HFO, oxygenation, ven- tilation, and lung mechanics improved over all, and there were few severe or lethal complications reported. The most frequent complications were pneumothorax and hypotension. The mortality rates in these reports ranged from 31 to 81 %, with most of the deaths due to multiple organ failure (MOF). As a relevant finding, the delay in the initiation of HFOV was an independent predictor of mortality. Based on these results, HFO in adults appears to be an effective and safe rescue modality for patients with ARDS who fail to improve with conventional mechanical ventilation (Table 1) [36 – 44].

To our knowledge only two RCTs of HFO in adults with ARDS have been carried out [45, 46]. Both of these were conceived and started prior to the landmark results of the first ARDSNet trial. As such, they compared HFO with conventional ventila- tion, which, by today’s standards, would not be considered optimally lung-protec- tive. The control groups in both of these studies received tidal volumes of 6 – 10 ml/

kg of actual body weight. The primary objective of both studies was to demonstrate

safety; they were both underpowered to detect mortality differences. That said, the

first and largest of these studies enrolled 148 patients and showed an encouraging

trend towards an HFO mortality reduction with 30-day mortalities of 37 % vs. 52 %

(p = 0.10) [45]. The second smaller study was stopped early because of slow enrol-

ment (N = 61) and overall showed no difference between groups (RR [95 %CI]: 1.29

[0.66 – 2.55]) [46]; in a post-hoc analysis, patients with the most severe baseline lung

disease (highest oxygenation index) may have received more benefit from HFO. Nei-

ther trial suggested any concerns with harm during HFO; both concluded that HFO

was a safe and effective mode of ventilation for adults with severe ARDS. The RCT

data available to date are clearly not definitive when it comes to assessing the utility

of HFO as a primary lung-protective mode. Not only are the patient numbers too

small to create precise estimates, but they are confounded by the use of now out-

Table 1. Summary of clinical experience with high frequency oscillation (HFO) in adults Reference Design Patients APACHE II (SD

or IQR)

CV prior to HFO Mortality

Fort 1997 [36]

Prospective 17 23.3 (7.5) 5.12 „ 4.3 days 30 day: 53%

Claridge 1999 [44]

Prospective 5 29 20 %

Mehta 2001 [38]

Prospective 24 21.5 (6.9) 5.7 „ 5.6 days 30 day: 66 %

Andersen 2002 [37]

Retrospective 16 27 7.2 days 3 months: 31 %

David 2003 [43]

Prospective 42 28 (IQR 24 – 37) 3.0 (0.7 – 9.1) days

30 day: 43 %

Mehta 2004 [39]

Retrospective 156 24 5.6 days 30 day: 61.7 %

Cartotto 2004 [40]

Retrospective 6 16 4.8 days Hospital: 83 %

David 2005 [42]

Retrospective 5 trauma patients with brain injury

25 10 days 20 %

Finkielman 2006 [41]

Retrospective 14 36 1.7 days 30 day: 57 %

Ferguson 2005 [48]

Prospective 25 24 (19 – 32) 13 (6 – 51) hours ICU mortality 44 %

Derdak 2002 [45]

RCT 148

75 HFO 73 CV

22 (6) HFO 22 (9) CV

2.7 (3) days HFO 4.4 (8) days CV

37 % HFO vs. 52 % CV 30-day mortality (p = 0.102) Bollen

1997 – 2001 [46]

RCT 61

37 HFO 24 CV

21 (8) HFO 20 (9) CV

2.1 (3) days HFO 1.5 (2) days CV

43 % HFO vs. 33 % CV 30-day mortality (p = 0.59) RCT: randomized controlled trial; CV: conventional mechanical ventilation

dated conventional strategies, and by the inclusion of some patients who had already been exposed to a significant duration of conventional ventilation.

As our understanding and experience with adult HFO expands, our concept of

the optimal application of HFO in the population continues to evolve [47]. Extrapo-

lating from both the neonatal literature and adult rescue series, most experts agree

that for optimal lung protection, HFO should be applied early and in combination

with a strategy to recruit the lung. Our group conducted a multinational pilot study

in which HFO was used in conjunction with recruitment maneuvers as a lung-pro-

tective strategy for adult patients with early ARDS. The goals were to assess safety,

feasibility, and physiologic response to this HFO strategy. The main baseline differ-

ences from previous studies was the short duration of conventional ventilation prior

to HFO (13 [6 – 51] hours), and the use of standardized ventilatory settings to judge

severe hypoxemia [48]. HFO combined with recruitment maneuvers provided rapid and significant improvements in oxygenation and respiratory mechanics. After twelve hours of HFO, the mean FiO

was significantly reduced compared with pre- study levels (0.5 „ 0.2 vs. 0.9 „ 0.1, p ‹ 0.001). The pressure cost of oxygenation, determined by the oxygenation index (FiO

× mean Paw × 100/PaO

) was also sig- nificantly decreased over the same interval. Only 3 % of the maneuvers were aborted (due primarily to transient hypotension) and good protocol adherence was demon- strated [48]. These results are promising and suggest that it is indeed feasible to enrol patients into an early trial of protocolized HFO. The other factor that we now believe is important to consider when implementing adult HFO is an effort to deliver the lowest tidal volume possible, taking advantage of the alternative mechanisms of gas exchange. To achieve this we now routinely use high power settings and titrate frequency to the maximal level that will allow a reasonable pH (e.g., above 7.25) [23, 47]. Emerging data suggest that when applied systematically it is often possible to oscillate adults at significantly higher frequencies (and therefore with lower tidal volumes) than previously believed [49].

Conclusion

In this chapter we have attempted to outline the basic physiology of high-frequency oscillation, and explain why, given our understanding of VILI, HFO is theoretically ideally suited as a lung-protective mode. Collectively, we are still on the learning curve with HFO in adults. While promising, the use of HFO as a primary mode for lung-protection in ARDS patients needs further investigation before it is widely adopted as routine clinical practice. At the current time the usual indication for HFO in adults should be as rescue therapy for patients with severe hypoxemic respi- ratory failure who are not responding to conventional ventilation.

References

1. The Acute Respiratory Distress Syndrome Network (2000) Ventilation with lower tidal vol- umes as compared with traditional tidal volumes for acute lung injury and the acute respira- tory distress syndrome. N Engl J Med 342:1301 – 1308

2. Henderson Y, Chillingsworth F, Whitney J (1915) The respiratory dead space. Am J Physiol 38:1 – 19

3. Lunkenheimer PP, Rafflenbeul W, Keller H, Frank I, Dickhut HH, Fuhrmann C (1972) Appli- cation of transtracheal pressure oscillations as a modification of “diffusion respiration”. Br J Anaesth 44:627

4. Bohn DJ, Miyasaka K, Marchak BE, Thompson WK, Froese AB, Bryan AC (1980) Ventilation by high-frequency oscillation. J Appl Physiol 48:710 – 716

5. Bryan AC (2001) The oscillations of HFO. Am J Respir Crit Care Med 163:816 – 817 6. Kolton M, Cattran CB, Kent G, Volgyesi G, Froese AB, Bryan AC (1982) Oxygenation during

high-frequency ventilation compared with conventional mechanical ventilation in two mod- els of lung injury. Anesth Analg 61:323 – 332

7. Suzuki H, Papazoglou K, Bryan AC (1992) Relationship between PaO2 and lung volume dur- ing high frequency oscillatory ventilation. Acta Paediatr Jpn 34:494 – 500

8. Slutsky AS, Drazen FM, Ingram RH Jr et al (1980) Effective pulmonary ventilation with small-volume oscillations at high frequency. Science 209:609 – 671

9. Slutsky AS, Kamm RD, Rossing TH, et al (1981) Effects of frequency, tidal volume, and lung volume on CO2 elimination in dogs by high frequency (2 – 30 Hz), low tidal volume ventila- tion. J Clin Invest 68:1475 – 1484

10. Slutsky AS, Drazen JM (2002) Ventilation with small tidal volumes. N Engl J Med 347:630 – 631

11. Slutsky AS, Brown R (1982) Cardiogenic oscillations: a potential mechanism enhancing oxy- genation during apneic respiration. Med Hypotheses 8:393 – 400

12. Vincent JL, Akca S, De Mendonca A, et al (2002) The epidemiology of acute respiratory fail- ure in critically ill patients. Chest 121:1602 – 1609

13. Rubenfeld GD, Caldwell E, Peabody E, et al (2005) Incidence and outcomes of acute lung injury. N Engl J Med 353:1685 – 1693

14. Ferguson ND, Frutos-Vivar F, Esteban A, et al (2005) Airway pressures, tidal volumes and mortality in patients with the acute respiratory distress syndrome. Crit Care Med 33:21 – 30 15. Amato MB, Barbas CS, Medeiros DM, et al (1998) Effect of a protective-ventilation strategy

on mortality in the acute respiratory distress syndrome. N Engl J Med 338:347 – 354 16. Pinhu L, Whitehead T, Evans T, Griffiths M (2003) Ventilator-associated lung injury. Lancet

361:332 – 340

17. Dreyfuss D, Soler P, Basset G, Saumon G (1988) High inflation pressure pulmonary edema.

Respective effects of high airway pressure, high tidal volume, and positive end-expiratory pressure. Am Rev Respir Dis 137:1159 – 1164

18. Hernandez LA, Peevy KJ, Moise AA, Parker JC (1989) Chest wall restriction limits high air- way pressure-induced lung injury in young rabbits. J Appl Physiol 66:2364 – 2368

19. Muscedere JG, Mullen JB, Gan K, Slutsky AS (1994) Tidal ventilation at low airway pressures can augment lung injury. Am J Respir Crit Care Med 149:1327 – 1334

20. Tremblay LN, Slutsky AS (1998) Ventilation-induced lung injury: from barotrauma to bio- trauma. Proc Assoc Am Phys 110:482 – 488

21. Tremblay LN, Slutsky AS (2006) Ventilator-induced lung injury: from the bench to the bed- side. Intensive Care Med 32:24 – 33

22. Sedeek KA, Takeuchi M, Suchodolski K, Kacmarek RM (2003) Determinants of tidal volume during high-frequency oscillation. Crit Care Med 31:227 – 231

23. Hager DN, Fessler HE, Fuld MK, Simon BA, Brower RG (2006) Effects of frequency and pres- sure amplitude on tidal volumes in adults with ards during high-frequency oscillatory venti- lation. Proc Am Thorac Soc 3:A376 (abst)

24. McCulloch PR, Forkert PG, Froese AB (1988) Lung volume maintenance prevents lung injury during high frequency oscillatory ventilation in surfactant-deficient rabbits. Am Rev Respir Dis 137:1185 – 1192

25. Sugiura M, McCulloch PR, Wren S, Dawson RH, Froese AB (1994) Ventilator pattern influ- ences neutrophil influx and activation in atelectasis-prone rabbit lung. J Appl Physiol 77:1355 – 1365

26. Vazquez de Anda GF, Hartog A, Verbrugge SJ, Gommers D, Lachmann B (1999) The open lung concept: pressure-controlled ventilation is as effective as high-frequency oscillatory ven- tilation in improving gas exchange and lung mechanics in surfactant-deficient animals.

Intensive Care Med 25:990 – 996

27. Rimensberger PC, Pache JC, McKerlie C, Frndova H, Cox PN (2000) Lung recruitment and lung volume maintenance: a strategy for improving oxygenation and preventing lung injury during both conventional mechanical ventilation and high-frequency oscillation. Intensive Care Med 26:745 – 755

28. Rotta AT, Gunnarsson B, Fuhrman BP, Hernan LJ, Steinhorn DM (2001) Comparison of lung protective ventilation strategies in a rabbit model of acute lung injury. Crit Care Med 29:2176 – 2184

29. Imai Y, Nakagawa S, Ito Y, Kawano T, Slutsky AS, Miyasaka K (2001) Comparison of lung protection strategies using conventional and high-frequency oscillatory ventilation. J Appl Physiol 91:1836 – 1844

30. Sedeek KA, Takeuchi M, Suchodolski K, et al (2003) Open-lung protective ventilation with pressure control ventilation, high-frequency oscillation, and intratracheal pulmonary ventila- tion results in similar gas exchange, hemodynamics, and lung mechanics. Anesthesiology 99:1102 – 1111

31. von der Hardt K, Kandler MA, Fink L, et al (2004) High frequency oscillatory ventilation sup- presses inflammatory response in lung tissue and microdissected alveolar macrophages in surfactant depleted piglets. Pediatr Res 55:339 – 346

32. Froese AB, Butler PO, Fletcher WA, Byford LJ (1987) High frequency oscillatory ventilation in

premature infants with respiratory failure: a preliminary report. Anesth Analg 66:814 – 824

33. HIFI Study Group (1989) High-frequency oscillatory ventilation compared with conventional mechanical ventilation in the treatment of respiratory failure in preterm infants. N Engl J Med 320:88 – 93

34. Bryan AC, Froese AB (1991) Reflections on the HIFI trial. Pediatrics 87:565 – 567

35. Henderson-Smart DJ, Bhuta T, Cools F, Offringa M (2003) Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants. Cochrane Database Syst Rev: CD000104

36. Fort P, Farmer C, Westerman J, et al (1997) High-frequency oscillatory ventilation for adult respiratory distress syndrome – a pilot study. Crit Care Med 25:937 – 947

37. Andersen FA, Guttormsen AB, Flaatten HK (2002) High frequency oscillatory ventilation in adult patients with acute respiratory distress syndrome – a retrospective study. Acta Anaes- thesiologica Scand 46:1082 – 1088

38. Mehta S, Lapinsky SE, Hallett DC, et al (2001) A prospective trial of high frequency oscilla- tory ventilation in adults with acute respiratory distress syndrome. Crit Care Med 29:

1360 – 1369

39. Mehta S, Granton J, MacDonald RJ, et al (2004) High-frequency oscillatory ventilation in adults: the Toronto experience. Chest 126:518 – 527

40. Cartotto R, Ellis S, Gomez M, Cooper A, Smith T (2004) High frequency oscillatory ventila- tion in burn patients with the acute respiratory distress syndrome. Burns 30:453 – 463 41. Finkielman JD, Gajic O, Farmer JC, Afessa B, Hubmayr RD (2006) The initial Mayo Clinic

experience using high-frequency oscillatory ventilation for adult patients: a retrospective study. BMC Emerg Med 6:2

42. David M, Karmrodt J, Weiler N, Scholz A, Markstaller K, Eberle B (2005) High-frequency oscillatory ventilation in adults with traumatic brain injury and acute respiratory distress syndrome. Acta Anaesthesiol Scand 49:209 – 214

43. David M, Weiler N, Heinrichs W, et al (2003) High-frequency oscillatory ventilation in adult acute respiratory distress syndrome. Intensive Care Med 29:1656 – 1665

44. Claridge JA, Hostetter RG, Lowson SM, Young JS (1999) High-frequency oscillatory ventila- tion can be effective as rescue therapy for refractory acute lung dysfunction. Am Surg 65:1092 – 1096

45. Derdak S, Mehta S, Stewart TE, et al (2002) High frequency oscillatory ventilation for acute respiratory distress syndrome: A randomized controlled trial. Am J Respir Crit Care Med 166:801 – 808

46. Bollen CW, van Well GT, Sherry T, et al (2005) High frequency oscillatory ventilation com- pared with conventional mechanical ventilation in adult respiratory distress syndrome: a randomized controlled trial. Crit Care 9: R430 – 439

47. Froese AB (2002) The incremental application of lung-protective high-frequency oscillatory ventilation. Am J Respir Crit Care Med 166:786 – 787

48. Ferguson ND, Chiche JD, Kacmarek RM, et al (2005) Combining high-frequency oscillatory ventilation and recruitment maneuvers in adults with early acute respiratory distress syn- drome: The Treatment with Oscillation and an Open Lung Strategy (TOOLS) Trial pilot study. Crit Care Med 33:479 – 486

49. Fessler HE, Hager DN, Brower RG (2006) Feasibility of very high frequencies during high-fre- quency oscillation in adults with acute respiratory distress syndrome. Proc Am Thorac Soc 3:A378 (abst)

50. Ferguson ND, Stewart TE (2002) New therapies for adults with acute lung injury: High-fre-

quency oscillatory ventilation. Crit Care Clin 18:91 – 106