High-frequency Ventilation: Lessons Learned and Future Directions - Civetta, Taylor, & Kirby's: Critical Care, 4th Edition

Civetta, Taylor, & Kirby's: Critical Care, 4th Edition

Section XIII - Respiratory Disorders

Chapter 133 - High-frequency Ventilation: Lessons Learned and Future Directions

Niall D. Ferguson

Arthur S. Slutsky

Mechanical ventilation practices continue to evolve. In particular, the ventilatory care of patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) has been refocused on avoiding or minimizing further damage to the fragile, injured lung. Conventional ventilators have been used successfully to limit this ventilator-induced lung injury (VILI) (1,2,3), but questions remain regarding the optimal method for lung protection during mechanical ventilation. The recognition of the critical role that VILI can play in the outcome of adults with ALI/ARDS has, in part, spawned a renewed interest in alternative modes of ventilation that may be more lung protective.

High-frequency ventilation (HFV) is just such a modality. In this chapter, we briefly review the different subtypes of HFV and then concentrate on high-frequency oscillation as the mode with the most supporting data and promise. As will be seen, a great deal of experience with HFV has been accrued in the neonatal and pediatric settings. We will draw on this knowledge where relevant, but focus this chapter from the viewpoint of HFV as an emerging therapy in the adult intensive care unit (ICU).

Definitions, Terminology, and Subtypes of High-frequency Ventilation

High-frequency ventilation is a collection of ventilatory modes, grouped together by their common property of employing high respiratory rates, all greater than 60 breaths per minute (4,5). In addition to high-frequency oscillation (HFO), other modes in this group include high-frequency jet ventilation (HFJV) and high-frequency percussive ventilation (HFPV).

High-frequency Jet Ventilation

HFJV is a mode of ventilation in which gas is delivered through a small-bore catheter into the lungs at rates of 100 to 150 breaths per minute (5,6). Delivered tidal volume is still small, but higher than just the volume exiting the jet, as the jets entrain an additional flow of gas by the Venturi effect. Exhalation is passive during HFJV, and gas trapping or dynamic hyperinflation can be an issue. In practice, a conventional ventilator is set up as a “slave” to the jet to provide positive end-expiratory pressure, along with basic monitoring and alarms.

HFJV is a very efficient mode for removing CO₂. Additionally, because of HFJV's very high flow rates and the differing pulmonary time constants in the clinical setting of bronchopleural fistulae, this mode of ventilation is purported to have beneficial effects in the presence of this disorder; however, these benefits have not been verified during objective testing (7,8). Concerns with HFJV relate to the delivery of high pressures (10–50 pounds per square inch), unpredictable tidal volumes, and the development of dynamic hyperinflation, all of which may worsen VILI rather than minimize it. In addition, problems with adequate humidification of inspired gas and the subsequent risks of tracheobronchitis have been noted and documented.

High-frequency Percussive Ventilation

HFPV is the newest and least well studied of the HFV modes. It combines a high-frequency rate of 200 to 900 breaths per minute superimposed on a conventional pressure mode of ventilation (9). HFPV is reported to enhance the clearance of respiratory secretions and has been successfully used in this regard in patients with burns and inhalational injury (9).

High-frequency Oscillation

HFO is a mode of mechanical ventilation that delivers very small tidal volumes around a set mean airway pressure at high respiratory rates of 3 to 15 Hz (equivalent to 180–900 breaths per minute, as 1 Hz = 60 breaths per minute) (10). HFO has been widely and effectively used in neonates and children for close to 20 years (11,12,13,14,15), but only recently has become available in the adult ICU; previous versions of this ventilator were only capable of generating sufficient flow so as to provide adequate CO₂ elimination in patients under 35 kg. In contrast to other HFV modes, humidification is less of an issue during HFO, as a continuous bias flow of humidified gas is passed in front of an oscillating membrane (Fig. 133.1). This oscillating membrane pushes the humidified gas into the patient and also provides active expiration, a factor that likely accounts for the lack of important gas trapping that is observed when HFO is employed at adequate airway pressures (16). The elegance of HFO is that it allows for “decoupling” of oxygenation and ventilation. Alveolar ventilation, and thus carbon dioxide elimination, are dependent on the frequency and tidal volume but are relatively independent of lung volume (17). In contrast, oxygenation is proportional to mean airway pressure and lung volume (18,19).

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Figure 133.1. Schematic overview of the high-frequency oscillation (HFO) circuit. (Reused with permission from Ferguson ND, Stewart TE. New therapies for adults with acute lung injury: high-frequency oscillatory ventilation. Crit Care Clin. 2002;18:91–106.)

Rationale for the Use of High-frequency Ventilation in Acute Lung Injury

Ventilator-induced Lung Injury

Mechanisms of Ventilator-induced Lung Injury

VILI is histologically indistinguishable from ARDS; three decades of experimental research has shown it to occur through a number of mechanisms, including (a) overdistention injury (volutrauma) (20,21,22,23,24,25,26,27,28), (b) collapse–reopening injury (atelectrauma) (1,2,20,29,30,31,32,33,34), and (c) oxygen toxicity (35,36,37). Each of these can lead, in turn, to further injury—termed biotrauma, the release of inflammatory mediators that may worsen pulmonary injury and propagate systemically to harm distant organs (1,2,31,32,38,39,40,41,42,43,44,45).

Numerous studies, performed using both small and large animals, consistently show that ventilatory high end-inspiratory stretch can cause a clinical and histologic picture similar to ARDS even in the absence of any other noxious stimulus (20,21,22,23,24,25,26,27,28). Patients with ARDS are at increased risk of regional lung overdistention because of the patchy nature of ARDS (46,47); the small areas of relatively normal lung (the so-called “baby lung”) receive the bulk of the tidal volume and are at particular risk of volutrauma (48,49). Repeated opening and closing of alveolar units can also cause VILI. In the injured lung, alveolar damage and absolute, or qualitative, deficiencies in alveolar surfactant lead to alveolar instability and localized lung unit collapse. Through each respiratory cycle, these unstable alveoli undergo collapse and reopening, a process that generates injurious mechanical forces and causes further lung injury. There is a substantive body of animal evidence showing that efforts to limit lung unit closing on expiration by maintaining an adequate positive end-expiratory pressure (PEEP) are relatively protective against atelectrauma (1,2,20,30,31,32,33,34). Here, the paradigm is one of “opening the lung and keeping it open,” thereby avoiding cyclic collapse and recruitment/derecruitment (2,50).

The major cause of death among ARDS patients is not refractory hypoxemia, as one might expect, but rather multiorgan dysfunction syndrome (MODS) (51). One hypothesis to explain the link between VILI and multiorgan failure is biotrauma (38,39)—the release of inflammatory mediators in response to injurious ventilation; these mediators may enter the systemic circulation, and hence lead to the development of MODS. Inflammatory mediators, such as interleukins, tumour necrosis factor-β, and platelet-activating factor, are released in response to VILI, oxygen-free radicals, and alveolar shearing. These mediators perpetuate the cascade of lung inflammation and worsen lung injury (31,32). Additionally, injurious ventilation has been shown to increase these inflammatory mediators in the peripheral blood of patients with ARDS (44,52). Through a variety of mechanisms, this inflammatory injury can lead to nonpulmonary organ dysfunction (41,42,43).

With an increased appreciation of the mechanisms of VILI, the next logical step is to employ ventilatory strategies that attempt to decrease overdistention, minimize shear injury, and limit oxygen toxicity (53,54,55). However, these aims may be competing; increasing PEEP may increase the risks of regional alveolar overdistention, while lowering tidal volumes can result in progressive alveolar collapse, a reduction in total lung volume, and higher oxygen requirements. The goals of mechanical ventilation in a patient at risk of VILI therefore should be to ventilate and oxygenate the patient while staying within a “safe window,” avoiding both overdistention and derecruitment—collapse—as illustrated in the volume–pressure curve of the lung shown in Figure 133.2 (56).

Impact of Limiting Ventilator-induced Lung Injury with Conventional Ventilation

In the mid-1990s, given the expanding animal data on VILI outlined above and in light of initial promising, but uncontrolled, human studies of lung-protective ventilation (57,58), a call was made for randomized trials (53). Initial trials focused on avoiding volutrauma, comparing strategies that limited tidal volumes and inspiratory pressures with traditional strategies, both using conventional ventilation. Three smaller studies did not find mortality differences between these approaches (59,60,61). However, a large, methodologically rigorous, and adequately powered trial conducted by the National Institutes of Health (NIH) ARDS Network did show important differences in mortality (3). In this study, 861 patients were randomly assigned to receive a low-stretch strategy with a targeted tidal volume of 6 mL/kg predicted body weight (PBW) and a plateau pressure limit of 30 cm H₂O, or to a higher-stretch strategy using a targeted tidal volume of 12 mL/kg PBW and a plateau pressure limit of up to 50 cm H₂O. The low-stretch strategy was associated with a mortality reduction from 40% in the control group to 31% in the experimental group (relative risk [RR] 0.78; 95% confidence interval [CI] 0.65–0.93). This trial clearly indicates that avoiding volutrauma saves lives in patients with acute lung injury. The trial has subsequently generated significant discussion regarding its mechanisms of benefit (62) and its choice of control strategy (63,64,65,66), but nevertheless, 6 mL/kg PBW has emerged as a standard for tidal volume limitation against which other strategies are compared (67,68).

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Figure 133.2. Volume–pressure curve of the injured lung. (Reused with permission from Froese AB. High-frequency oscillatory ventilation for adult respiratory distress syndrome: let's get it right this time. Crit Care Med. 1997;25[6]:906–908.)

Another early randomized controlled trial (RCT) published in the late 1990s demonstrated dramatic reductions in mortality using a lung-protective strategy whose goal was to limit both volutrauma and atelectrauma using low tidal volumes and higher PEEP compared with traditional ventilation (69). Amato et al. found a statistically significant reduction in 28-day mortality (11/29 [38%] vs. 17/24 [71%] deaths; RR 0.53; 95% CI 0.31–0.91) favoring patients exposed to the lung-protective strategy. In light of the subsequent positive ARDS Network trial noted above, interpretation of this trial is confounded by the use of both lower PEEP levels and higher tidal volumes and inspiratory pressures in the control group; the relative contribution of efforts to avoid cyclic collapse and reopening is unclear.

Drawing on the promise of the Amato trial, three RCTs have now been completed analyzing the effects of higher versus lower levels of PEEP, while limiting tidal volumes in all study patients. Two of these—the ExPress trial by Mercat et al. and the Lung Open Ventilation Study conducted by Meade et al.—are very recently completed and not yet published; both were presented at the 2006 European Society of Intensive Care Meeting. The one fully published trial, the ALVEOLI study, was conducted by the NIH ARDS Network investigators (70) and was stopped early, which likely contributed to the large baseline imbalance in age favoring the lower PEEP group. When we consider the relative risk after adjusting for baseline imbalances in prognostic factors (including age) from this trial, along with the preliminary findings from the two recent trials, a consistent trend favoring higher PEEP begins to emerge. Therefore, while no single trial has definitively shown an incremental mortality benefit with higher PEEP and attempts to limit atelectrauma while already avoiding overdistention injury, when viewed together, these trials suggest that this benefit may well exist. They also suggest that a higher level of PEEP with or without other maneuvers to open the lung, along with limited tidal volumes and inspiratory pressures, may be considered a very reasonable comparison strategy in future ventilation trials; this approach may be superior, and there is no suggestion of harm compared with lower PEEP levels. These studies clearly demonstrated that ventilatory strategy is important in patients with ARDS, and that lung-protective strategies can minimize VILI and decrease mortality in humans with ARDS. As such, and given the proposed mechanisms of lung protection (Fig. 133.2), a strategy that minimizes overdistention and allows the use of high PEEP should be the ideal mode in patients with ARDS. This is where HFO may have great clinical benefit.

Animal Studies Comparing Conventional Ventilation to High-frequency Oscillation in Acute Lung Injury

The very small delivered tidal volumes are the key to the lung-protective potential of HFO. Because cyclic alveolar stretch is minimal, clinicians are able to set the mean airway pressure (mP_AW) on HFO significantly higher than they are able to set PEEP on conventional ventilation, thereby avoiding cyclic collapse and atelectrauma—and yet they are still able to avoid very high peak inspiratory pressures and subsequent volutrauma (Fig. 133.3). This should allow a larger margin of error and make it easier to stay within the “safe window” of lung protection (Fig. 133.2) (56). Since the first descriptions of HFO (71,72), numerous studies have examined the lung-protective potential of HFO using animal models (Table 133.1) (73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89). Perhaps not surprisingly, earlier studies that compared HFO with potentially injurious conventional ventilation uniformly found improvements in physiology, decreased inflammatory markers, and/or improved histology in animals treated with HFO (73,74,75,76,77,78,79,80,81,82,83). More relevant today, however, are recent studies that have compared HFO with lung-protective conventional ventilation, the majority of which continue to favor HFO in terms of physiology, inflammation, and pathology (Table 133.1) (86,87,88,89).

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Figure 133.3. Pressure–time curve contrasts tidal variations in airway pressure associated with conventional ventilation (dashed line) and high-frequency oscillation (solid line). HFOV, high-frequency oscillation ventilation; CMV, conventional mechanical ventilation. (Reused with permission from Ferguson ND, Stewart TE. New therapies for adults with acute lung injury: high-frequency oscillatory ventilation. Crit Care Clin. 2002;18:91–106.)

Mechanisms of Gas Transport during High-frequency Oscillation

Tidal volumes are extremely small with HFO, often smaller than the anatomic dead space, in the range of 1 to 2 mL/kg (90). In addition to relying on bulk flow, adequate CO₂ removal during HFO is achieved through a number of alternative mechanisms including convective streaming due to asymmetric velocity profiles, Pendelluft, cardiogenic mixing, and diffusion (Fig. 133.4). A full explanation of these physiologic principles is outside the scope of this chapter; the reader is referred to a number of papers reviewing this physiology in detail (5,91,92,93,94,95,96,97,98,99). The major message from these theoretical and experimental studies is that CO₂ elimination—which is inversely proportional to PaCO₂—is described by the relationship f^aV_T^b, where a = ~1 and b = ~2. This is important clinically in that it indicates that increases in frequency may lead to increased PaCO₂ if V_T falls (see below).

Implementing and Optimizing High-frequency Oscillation in Adults

Because of the lack of an appropriate surrogate end point that correlates with mortality (3,100), a large multicenter trial will be needed to definitively determine the relative effects of HFO compared with conventional mechanical ventilation (CMV) in terms of lung protection and mortality (101,102). Similarly, when making decisions regarding the best methods for applying HFO, we must draw inferences from multiple alternate sources (including animal studies, neonatal RCTs, and adult case series), since large RCTs comparing different HFO strategies are unavailable and would be, frankly, difficult to justify ethically in the absence of demonstrable efficacy over conventional ventilation.

Animal Studies

Too many animal studies have been conducted on high-frequency ventilation to list them in this review (4). Rather, in Table 133.2, we outline a number of these studies that are informative when considering how best to employ HFO in adults (72,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118). Several key messages for HFO can be gleaned from these studies, including the following:

1. At adequate mP_AW, gas trapping is not an issue despite very high respiratory rates.

2. Increasing mP_AW leads to improved oxygenation through lung recruitment.

3. Tidal pressure swings measured in the trachea can be increased with either underrecruitment or overdistention of the lung.

4. Recruitment maneuvers (sustained inflations) may be required to adequately recruit severely injured lungs.

Taken together, and in keeping with the current understanding of VILI mechanisms, these studies suggest that HFO in adults should be employed using an open-lung strategy, facilitated by higher mean airway pressures and lung recruitment maneuvers (56,119,120).

Neonatal Studies

The longest clinical experience and the most rigorous evaluation of HFO have both been in the neonatal population (121,122,123,124,125,126,127,128,129,130). The initial large RCT evaluating HFO in this setting raised safety concerns, but it later became evident that here, too, the safe and effective application of HFO requires lung volume recruitment (121,131,132). Subsequent RCTs of HFO with an open-lung approach have demonstrated HFO to be safe and effective in improving oxygenation and, as indicated by the current Cochrane systematic review, may reduce the risk of death or chronic lung disease (15). Interpreting the neonatal HFO literature is challenging due to differences in study populations (preterm vs. term), interventions (degree of lung recruitment targeted), the timing of HFO (immediately after birth vs. later), and by the introduction of exogenous surfactant as a standard therapy in the 1990s. In addition, it is important to realize that the baseline mortality rate in infant respiratory distress syndrome is an order of magnitude less than that seen in adults with severe ARDS. All of these factors mean that results from neonatal studies cannot be directly extrapolated to adult populations. Important lessons can be learned from the neonatal HFO literature, however, including the importance of thoroughly understanding the underlying physiologic mechanisms of the therapy, and the recognition that a learning curve may exist in the initiation of an HFO program (131,132).

Table 133.1 Animal studies comparing VILI with HFO vs. CMV

Author	Animal	Lung injury	HFO	CMV	LRM at onset	Duration	HFO effects on physiology	HFO effects on inflammation	HFO effects on pathology
HFO vs. potentially injurious (high volume/pressure) CMV
Hamilton 1983	Rabbits	Saline lavage	mP_AW = 15, f = 15 Hz	PEEP 6, PIP 25	Both	5–20 h	↑ O₂	↓ Mortality in 20-h model	↓ Hyaline membranes
Tamura 1985	Rabbits	IV starch particle emboli	f = 15 Hz, V_T 1–2 mL/kg	PEEP 2, PIP 20	No	3 h	↑ O₂	↓ EVLW, ↓ protein leak
McCulloch 1988	Rabbits	Saline lavage	High EELV	PEEP 8, PIP for CO₂	Both	7 h	↑ O₂, ↑ compliance		↓ Hyaline membranes
Bond 1993	Rabbits	Saline lavage	mP_AW = 15 Intermittent LRM	PEEP 8 PIP for CO₂	Both	6 h	↑ O₂, ↑ compliance
Imai 1994	Rabbits	Saline lavage	mP_AW = 15, f = 15 Hz	mP_AW = 15, PIP 25, PEEP 5	Both	4 h	↑ O₂, ↑ compliance	↓ PMN, PAF, TXB₂ in BAL
Matsuoka 1994	Rabbits	Saline lavage	mP_AW = 15, f = 15 Hz	PEEP 5, PIP 25	Both	2–4 h	↑ O₂	↓ BAL PMN # and activation	↓ Intra-alveolar cellularity
Sugiura 1994	Rabbits	Saline lavage	mP_AW = 15 Hz Intermittent LRM	PEEP 5, PIP 23	Both	4 h	↑ O₂, ↑ compliance	↓ BAL PMN # and activation	↓ Lung injury
Takata 1997	Rabbits	Saline lavage	mP_AW = 13, f = 15 Hz	PEEP 5, PIP 28	Both	1–4 h	↑ O₂, ↑ compliance	↓ TNF-β mRNA, ↓ PMN in BAL	↓ Hyaline membranes
Gommers 1999	Rabbits	Saline lavage	f = 10 Hz mP_AW for PaO₂	PEEP 6, PIP 26	HFO only	5 h	↑ O₂		↓ Lung injury
Kerr 2001	Rabbits	NNMU lavage	f = 15 Hz mP_AW = PIP-7	PEEP 4, V_T = 10 mL/kg	No	1–2 h	↑ O₂, ↓ resp. acidosis	↓ LA surfactant conversion/loss
Noda 2003	Rabbits	Saline lavage	mP_AW = 15, f = 15 Hz	PEEP 5, PIP 25	Both	4 h	↑ O₂	↓ TNF-α mRNA, ↓ BAL PMN #
HFO vs. lung-protective CMV
Vazquez de Anda 1999	Rats	Saline lavage	f = 10 Hz mP_AW for PaO₂	PEEP for PaO₂, V_Tfor CO₂	Both	3 h	Similar O₂	Similar BAL protein levels
Rimensberger 2000	Rabbits	Saline lavage	f = 15 Hz mP_AW = CCP + 4	V_T = 5 mL/kg PEEP > CCP	Both	4 h	Similar O₂ and compliance	Similar MPO levels	Similar histology score
Rotta 2001	Rabbits	Saline lavage	mP_AW = 16, f = 10 Hz	PEEP > P_flex, V_T = 6 mL/kg	Both	4 h	↓ resp. acidosis, ↓inotropes	Similar, elastase in BAL	↓ MDA in lung homogenate
Imai 2001	Rabbits	Saline lavage	mP_AW = 15, f = 15 Hz	PEEP 10, V_T = 6 mL/kg	Both	4 h	↑ O₂, ↓ CO₂ ↑compliance	↓ TNF-β, ↓ PMN in BAL	↓ Alveolar path. score
Sedeek 2003	Sheep	Saline lavage	f = 8 Hz mP_AW = PMC	PIP <35; PEEP = PMC	Both; repeated	6 h	Similar O₂	Similar to ↓ cytokine mRNA	↓ Lung injury
Von der Hardt 2004	Piglets	Saline lavage	mP_AW = 18, f = 15 Hz	PEEP 4, PIP 20	No	8 h	↑ O₂	↓ mRNA of IL-8, IL-1β IL-6, etc.	↓ Macrophage IL-8 gene expr.
VILI, ventilator-induced lung injury; HFO, high-frequency oscillation; CMV, conventional mechanical ventilation; LRM, lung recruitment manoeuvre; mP_AW, mean airway pressure; f, frequency; PEEP, positive end-expiratory pressure; PIP, peak inspiratory pressure on CMV; EVLW, extravascular lung water; V_T, tidal volume; EELV, end-expiratory lung volume; PMN, polymorphonuclear cells; PAF, platelet-activating factor; TXB₂, thromboxane B₂; BAL, bronchoalveolar lavage; TNF, tumor necrosis factor; NNMU, N-nitroso-n-methylurethane; resp., respiratory; MDA, malondialdehyde (marker of lipid peroxidation); LA, large aggregate surfactant (i.e., functionally active surfactant); CCP, critical closing pressure (i.e., pressure on deflation limb of volume–pressure curve corresponding to 50% of total lung capacity); MPO, myeloperoxidase; PMC, point of maximal curvature (on the deflation limb of the volume–pressure curve); IL, interleukin; gene expr., gene expression; exog surf., exogenous surfactant. Study selection criteria: Population: Animal models (excluding preterm animals) of acute lung injury; intervention: HFO vs. conventional ventilation, no additional cointerventions; outcome: any marker(s) of lung injury (not gas exchange alone); therefore, not crossover studies.

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Figure 133.4. Alternative mechanisms of gas exchange with high-frequency oscillation (HFO). (Reused with permission from Slutsky AS, Drazen JM. Ventilation with small tidal volumes. N Engl J Med. 2002;347[9]:630–631.)

Uncontrolled Adult Studies

The studies reporting the clinical experience with HFO in adults, which are summarized in Table 133.3 (133,134,135,136,137,138,139,140,141,142,143), are also informative for optimizing an HFO protocol. Almost all of them studied HFO as rescue therapy for patients with extremely severe disease who were “failing” conventional ventilation. Despite being limited by their uncontrolled nature and by selection bias, consistent messages that arise from these rescue series include:

1. HFO is usually effective in improving oxygenation.

2. HFO appears safe, with no obvious increased rates of complications.

3. Both baseline oxygenation index and duration of CMV prior to HFO are associated with increased mortality.

One prospective, multicentered study from our group is unique in that it tested an explicit protocol for applying HFO early in the course of ARDS, incorporating lung recruitment maneuvers (RMs) and a descending titration of mean airway pressure to optimize lung volumes for gas exchange and lung protection (140). RMs—sustained inflation maneuvers with 30 to 40 cm H₂O pressures for 30 to 40 seconds—have been found to be safe in adults on CMV, but studies have shown mixed results in terms of efficacy and duration of their oxygenation effects (144,145,146,147,148,149,150,151,152). Because of the small tidal volumes generated with HFO, there is very little tidal recruitment of the lung, creating a more compelling rationale for RMs during HFO compared with CMV (19,50,102,153,154). The main finding from a physiologic standpoint in our study was that the combination of HFO and RMs was well tolerated and resulted in rapid and sustained lung recruitment (140). Furthermore, the explicit HFO protocol appeared feasible; adherence was excellent, and the method for weaning HFO and transitioning to CMV appeared practical and safe.

Tidal volume during HFO has always been assumed to be very low, but it is not routinely measured with currently available oscillators. Tidal volume is known to be inversely related to frequency due to a decreasing inspiratory time with increasing frequency (17), and in adults, typical frequencies have been significantly lower than those used in neonates (3–6 vs. 12–15 Hz) (132,139). Sedeek et al. explored this issue in a lung-injured sheep model, measuring tidal volumes of up to 4 mL/kg at high-pressure amplitudes and low frequencies (Table 133.2) (118). These tidal volume measurements may be overestimated because of technical reasons (155), but they do highlight the importance of efforts to minimize delivered tidal volumes with adult HFO, and they have spurred further investigation. Tidal volumes on HFO measured in adults using a very accurate device (156) were small—1.1 to 2.5 mL/kg—and strongly influenced by frequency (90). Cumulatively, these data are reassuring in that HFO in adults can be set to deliver very small tidal volumes, but at the same time they highlight the potential importance of targeting the lowest tidal volume possible (155). This could be achieved by increasing frequency as high as tolerated while avoiding severe respiratory acidosis, a strategy that has been proposed as physiologically sensible (157) and recently shown to be feasible in most patients (158).

Table 133.2 Animal studies informing optimal HFO implementation

Author	Animal	Lung injury	Intervention	Design	Outcomes	Main findings	Comment
HFO proof of concept and basic settings
Bohn 1980	Dogs	None	HFO at various frequencies	Single cohort	Gas exchange and airway pressures	First description of HFO showing safety and efficacy	HFO capable of supporting adequate gas exchange
Bryan 1986	Rabbits	Saline lavage	HFO at various mP_AW	Single cohort	Occlusion pressures	Gas trapping with HFO only seen at extremely low mP_AW	Gas trapping not an issue with HFO despite high frequencies
Bancalari 1987	Rabbits	Meconium aspiration	HFO (mP_AW = 11–22; f = 10–15 Hz) vs. HFJV	Crossover	Gas exchange, lung volumes (plethys.)	No significant gas trapping with HFO; yes with HFJV	Gas trapping not an issue with HFO despite high frequencies
Courtney 1992	Rabbits	Saline lavage	HFO at various I:E ratios (constant mP_AW, P and f)	Single cohort	Gas exchange and hemodynamics	Varying I:E ratios had no significant effect on PaO₂, PaCO₂, BP, or CO	At constant mP_AW, I:E ratio does not have a large effect on gas exchange
Pillow 1999	Rabbits	None	HFO at various I:E ratios	Single cohort	Airway–alveolar pressure difference	P_ALV was lower than mP_AW at I:E ratios below 1:1	With I:E of 1:2, alveolar pressures may be somewhat lower than set mP_AW
HFO volume-pressure and gas-exchange relationships
Boynton 1991	Rabbits	Saline lavage	HFO at various mP_AW	Single cohort	Gas exchange, lung volumes (plethys.)	↑ mP_AW leads to ↑ O₂ through ↑lung volume; hysteresis present	Oxygenation response is a reasonable surrogate for recruitment
Goddon 2001	Sheep	Saline lavage	HFO at various mP_AW	Single cohort	Gas exchange and mechanics	Best O₂ was at mP_AW of P_FLEX + 6 also equal to PMC on deflation	Oxygenation response is a reasonable surrogate for recruitment
van Genderingen 2002 (ICM)	Pigs	Saline lavage	HFO with stepwise increases in mP_AW	Single cohort	Oxygenation index and shunt fraction	mP_AW with ↑ OI was close to ↑ shunt; large hysteresis	Oxygenation response is a reasonable surrogate for recruitment
Dembinski 2002	Pigs	Oleic acid infusion	HFO vs. CMV titrated to PaO₂	RCT	Airway pressures and shunt fraction	↑ mP_AW needed with HFO to match PaO₂ on CMV	High mP_AW needed for lung opening on HFO—may be reduced subsequently
Luecke 2003	Pigs	Saline lavage	HFO at various mP_AW	Single cohort	Gas exchange and mechanics	Increasing mP_AW mirrored volume on deflation limb of pressure–volume curve; no hysteresis on HFO	Lung opening may occur on HFO without RMs
Intrathoracic tidal pressure swings and lung recruitment during HFO
Sakai 1999	Rabbits	Saline lavage	HFO at various mP_AWand V_T	Single cohort	Pressure swings in airway and pleura	At low mP_AW pressure swings are increased; decreased after an RM	Underrecruited lungs lead to higher pressure swings on HFO
van Genderingen 2002	Pigs	Saline lavage	HFO at various mP_AW	Single cohort	Oscillatory pressure ratio (OPR)^a	OPR is increased when the lung is overdistended OR underrecruited	Underrecruited or overdistended lungs lead to higher pressure swings on HFO
Recruitment maneuver effects with HFO
Byford 1988	Rabbits	Saline lavage + CMV	HFO + RMs with oscillator on and off	Crossover	Gas exchange, lung volumes (plethys.)	RMs with oscillator on yielded ↑ recruitment at ↓ pressures	RMs with oscillator not paused may be more effective
Sznajder 1988	Dogs	Oleic acid	HFO vs. high tidal volume CMV	Crossover	Gas exchange, lung volumes (plethys.)	Full lung recruitment on HFO only achieved after a RM to TLC	RMs on HFO needed for lung recruitment in severe lung injury model
Walsh 1988	Rabbits	Saline lavage	HFO + various RMs	Single cohort	Gas exchange and mechanics	RMs improve gas exchange and compliance on HFO	Lower pressures possible with HFO after RMs
Suzuki 1992	Rabbits	Saline lavage + CMV	HFO ± RMs	Single cohort	Lung volume and gas exchange	HFO without RMs was uniformly fatal; HFO + RMs improved gas exchange	RMs on HFO needed for lung recruitment in severe lung injury model
Delivered tidal volumes with “adult settings” on HFO
Sedeek 2003	Sheep	Saline lavage	HFO at various ΔP and f	Single cohort	Delivered tidal volumes	At very low f and high ΔP, V_T may not be negligible on HFO	Need to target lowest V_T possible with HFO (use highest tolerated frequency)
^aOscillatory pressure ratio is the ratio of pressure swings at the proximal and distal end of the endotracheal tube during HFO. HFO, high-frequency oscillation; mP_AW, mean airway pressure; f, frequency; HFJV, high-frequency jet ventilation; plethys., plethysmography; I:E, inspiratory:expiratory; BP, blood pressure; CO, cardiac output; P_ALV, alveolar pressure; P_FLEX, pressure at the lower inflexion point of the static volume–pressure curve; OI, oxygen index; RCT, randomized controlled trial; PMC, point of maximal curvature on the deflation limb of the static volume–pressure curve; CMV, conventional mechanical ventilation; V_T, tidal volume; RM, recruitment maneuver.

Table 133.3 Uncontrolled studies HFO for adult ARDS

Author	N	Population	Baseline severity of illness	Design	Complications	Main findings	Comment
HFO as “rescue therapy”
Fort 1997	17	ARDS	OI = 49APACHE II = 23	Prospective	Barotrauma 6% ETT obstruction 6%	Improved oxygenation; mortality 53%	Baseline OI and duration of CMV associated with ↑mortality
Claridge 1999	5	ARDS, trauma	P/F = 52 APACHE II = 28	Not reported	Not reported	Improved oxygenation; mortality 20%	HFO appears safe and improves O₂ in rescue setting
Mehta 1997	24	ARDS	OI = 33 APACHE II = 22	Prospective	Barotrauma 8% ETT obstruction 4%	Improved oxygenation; mortality 67%	HFO appears safe and improves O₂ in rescue setting
Andersen 2002	16	ARDS	OI = 28 APACHE II = 27	Retrospective	Barotrauma 6%	Improved oxygenation; mortality 31%	HFO appears safe and improves O₂ in rescue setting
David 2003	42	ARDS	OI = 23 APACHE II = 28	Prospective	Barotrauma 2%	Improved oxygenation; mortality 43%	HFO appears safe and improves O₂ in rescue setting
Cartotto 2004	25	ARDS, burns	OI = 27 APACHE II = 16	Retrospective	Barotrauma 0%	Improved oxygenation; mortality 28%	HFO appears safe and improves O₂ in rescue setting
Mehta 2004	156	ARDS	OI = 31 APACHE II = 24	Retrospective	Barotrauma 21%	Improved oxygenation; mortality 62%	Baseline OI and duration of CMV associated with ↑mortality
Pachl 2006	30	ARDS	Not reported	Prospective	Not reported	Not reported
Finkielman 2006	14	ARDS	OI = 35 APACHE II = 35	Retrospective	Barotrauma 0%	Improved oxygenation; mortality 57%	HFO appears safe and improves O₂ in rescue setting
Weiler 2006	5	ARDS	OI = 28 APACHE II = 25	Retrospective	Barotrauma 0%	Improved oxygenation; mortality not reported	HFO appears safe and improves O₂ in rescue setting
HFO for lung protection
Ferguson 2005	25	Early ARDS	OI = 23 APACHE II = 24	Prospective, consecutive, protocolized	Barotrauma 8%–20%	Rapidly improved oxygenation; mortality 44%; excellent protocol adherence	Pilot study of an explicit protocol including conversion criteria to CMV
HFO, high-frequency oscillation; ARDS, acute respiratory distress syndrome; OI, oxygen index; ETT, endotracheal tube; CMV, conventional mechanical ventilation.

Randomized Controlled Trials of High-frequency Oscillation in Adults

To date, only two RCTs have compared HFO with CMV in adults (101,159). Both of these trials were planned and started prior to the completion of the first ARDS Network study that showed benefit from strict control of tidal volumes (3). Neither RCT demonstrated safety concerns (the primary outcome); rates of barotrauma and other complications were similar between groups in both studies. The larger of the two RCTs shows an impressive trend toward a mortality benefit with HFO (RR 0.72; 95% CI 0.50–1.04) despite more than 10% of the control group crossing over to HFO (101). The second trial, which began accrual at the same time, was stopped because of slow enrollment. In fact, the enrollment rates per center per month were identical in both studies; the latter study simply highlights the need for extensive multicentered collaboration for a successful HFO RCT. Mortality results from the smaller study are less encouraging, but these are significantly confounded by large baseline differences favoring the control group, and by an almost 20% crossover rate. Nevertheless, pooled results from these trials still suggest a potentially important survival benefit with HFO (RR 0.899, 95% CI 0.51–1.58; random effects model). Inferences from these RCTs are limited, however, by their methodology, small sample sizes, and, importantly, by use of now dated, potentially injurious conventional ventilation strategies.

Future Directions

A research focus on the ventilatory care of ARDS patients has, to date, paid significantly greater dividends than the disappointing results of pharmacotherapy testing (160). Following the completion of the three conventional ventilation RCTs comparing a “lung open” approach with a lower PEEP approach, we believe that the study of HFO represents the next logical and important question to be addressed in ARDS research. We ground this belief in:

1. A strong physiologic rationale and database of animal studies

2. Experience from the neonatal and pediatric arenas

3. An expanding clinical experience with adult HFO

4. Promising results from small nondefinitive RCTs

Despite the very strong physiologic rationale and the encouraging clinical data to date, there are potential detrimental consequences of HFO. First, the physiologic benefit of HFO is likely derived from recruitment of the lung with higher mean airway pressures, while still not overdistending alveoli because of the very small tidal volumes. Hence, patients with mild disease and minimal collapsed or consolidated lung may not be good candidates for HFO (151). Second, the high mean airway pressures may negatively impact hemodynamics. Third, because the bias flow rate is insufficient to meet the inspiratory flow demands of adults in respiratory distress, all adults on HFO must have their respiratory efforts suppressed with intravenous sedation. This means that the majority of adults will be heavily sedated, and many may need transient neuromuscular blockade. Due to these concerns, and to target a population in need of recruitment, we believe that future studies should enroll patients with severe ARDS who are likely to have significant lung collapse and who frequently require significant amounts of sedation, with or without paralysis, on conventional ventilators.

In summary, we believe that HFO—and other forms of high-frequency ventilation—should currently be reserved for “rescue therapy” in patients who are failing conventional ventilation. We do not believe that HFO can be recommended for routine use in adults with ARDS at the current time because:

· There are potential detrimental physiologic and clinical consequences as described above

· This would represent premature dissemination of a complex technology without rigorous evaluation of its risks, benefits, and indications

A definitive RCT to establish the impact of HFO versus best current conventional ventilation on mortality is needed.

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