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The FLARE Four

  • High frequency oscillatory ventilation (HFOV) and airway pressure release ventilation (APRV) are non-conventional modes of ventilation for ARDS that are designed to achieve recruitment and avoid atelectrauma
  • It has been suggested that these non-traditional modes are better suited to COVID-19 associated ARDS than traditional lung protective ventilation
  • Unlike traditional lung protective ventilation, neither HFOV nor APRV has ever been shown to reduce mortality in ARDS. One large trial of HFOV actually suggested an increase in mortality
  • Traditional lung protective ventilation, by which we mean low tidal volume and minimal driving pressure, remains the best approach to mechanical ventilation in COVID-19 and in ARDS more generally

Many people are's time to revive outdated modes of ventilation such as APRV and HFOV for COVID-19 associated ARDS.

HFOV, APRV, Increased Airway Pressure and Morality

A high percentage of critically ill patients with COVID-19 are requiring mechanical ventilation. Mortality for mechanically ventilated patients with COVID-19 varies widely among currently published reports from less than 20% (Grasselli et al. 2020; Goyal et al. 2020) to greater than 80% (Richardson et al. 2020). The poor outcomes in some series have led to speculation that a new approach to mechanical ventilation in these patients is needed. Some are calling for a “paradigm shift” and propose that the critical care community reconsider using HFOV, a non-conventional form of mechanical ventilation. Similarly, some (EMCrit and Farkas 2020) have called for the reconsideration of airway pressure release ventilation (APRV) out of a desire to minimize sedation and paralysis (both of which are associated with increased morbidity and/or mortality in critical illness) (Aragón et al. 2019; National Heart, Lung, and Blood Institute PETAL Clinical Trials Network et al. 2019).

HFOV and APRV are, in at least one respect, perverse choices for alternative approaches to mechanical ventilation in COVID-19. They have in common a relatively high mean airway pressure, which is postulated to increase recruitment and decrease shunt. A key piece of the argument against using standard ARDS approaches in COVID-19 is that patients are not recruitable and their hypoxemia is not primarily due to alveolar collapse and shunt.

ARDS patients, including those with COVID-19, do of course have some areas of impaired ventilation and/or shunt. However, aggressive attempts at alveolar recruitment via the application of increased airway pressures have, in fact, never been shown to decrease mortality in unselected ARDS patients (Brower et al. 2004). In at least one case recruitment maneuvers have been associated with increased mortality (Writing Group for the Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial (ART) Investigators et al. 2017). These issues were reviewed in a prior FLARE (April 2, 2020). Similarly, in contrast to traditional lung protective ventilation, APRV and HFOV have never been associated with a reduced mortality in ARDS. In the case of HFOV, there is one large trial that suggests an increase in mortality (see below).

What Is APRV and How Does it Work?

Figure 1: illustration of pressure versus time in APRV. Slide courtesy of Dean Hess, PhD, RRT.

APRV is a form of pressure targeted, intermittent mandatory ventilation with an inverse I:E ratio. As a pressure targeted mode it can be more comfortable for patients and thus potentially is associated with less sedation. APRV can be thought of as a variation of bi-level positive pressure ventilation in which there is a high pressure (Phigh, analogous to the inspiratory pressure) and a low pressure (Plow, analogous to the expiratory pressure on bi-level). Switches between Phigh and Plow, essentially mandatory breaths, are time-cycled (controlled by Thigh and Tlow, the time spent at high and low pressures, respectively). Spontaneous breaths may occur both during and between mandatory breaths (Daoud, Farag, and Chatburn 2012). Alveolar recruitment, and thus improved oxygenation, is achieved by appropriate choice of Phigh. At the same time, transpulmonary pressure is, in theory, limited.

A concern arises because, as a pressure targeted mode, the tidal volume is not limited. This is because spontaneous effort by the patient (during Tlow, for example) will result in an increase in transpulmonary pressure (Ptp) and increase in delivered flow (Ptp = Pairway opening - Ppleural, so that if the patient decreases pleural pressure, even if the ventilator limits pressure at the airway opening, the transpulmonary pressure will increase). Large tidal volumes, of course, are associated with increased mortality in ARDS (Acute Respiratory Distress Syndrome Network et al. 2000).

Two trials have compared APRV with traditional low tidal volume ventilation. One, in trauma patients, (Maxwell et al. 2010) showed a decrease in ventilator free-days, an increase in ICU length of stay and an increase in incidence of ventilator associated pneumonia in the APRV group. A more recent, single center open label study found an increase in ventilator free days associated with APRV, but no difference in mortality (Zhou et al. 2017). Patients on APRV did receive less sedation and were weaned from the ventilator earlier, but these findings are made difficult to interpret in light of the open-label design. In sum, the only ventilation strategy in ARDS for which there is high grade clinical evidence indicating a decrease in mortality is traditional low tidal volume ventilation.

What is HFOV and How Does it Work?

HFOV is a form of invasive mechanical ventilation that provides high-frequency (3-15Hz), low-amplitude (i.e., 1-3cc/kg, often less than the anatomic dead space) oscillations around a relatively high mean airway pressure. The high mean airway pressure is set to optimize recruitment, while the small amplitude of the oscillations limits tidal recruitment, overdistention and atelectrauma. The mechanisms of gas exchange in HFOV are distinct from those in conventional mechanical ventilation. For example, the cyclic volumes provided by the HFO ventilator are typically less than anatomic dead space. As such, gas exchange does not occur primarily by straightforward convection as in conventional modes (Lunkenheimer et al. 1972; Bohn et al. 1980).

HFOV requires a specialized ventilator built for this purpose. As shown in Figure 2, the oscillator is essentially a piston in a cylinder. Air flow, called “bias flow,” passes between the cylinder and the patient, at a controlled rate (typically 20-60 LPM) and oxygen concentration (FiO2). This flow results in a mean airway pressure (mPaw). The oscillations stir the air in the patient’s lungs around the mPaw. At a typical frequency of 3-5 Hz (3-5 breaths/second), the oscillator delivers 180-300 “breaths” per minute, but can even deliver up to 15 Hz, or 900 “breaths” per minute. In order to provide HFOV, patients are typically heavily sedated and paralyzed (Daoud, Farag, and Chatburn 2012).

Figure 2. Anatomy of HFOV ventilation (Facchin and Fan 2015).

A pressure-time plot in Figure 3 demonstrates how fixed regular cycles enable tight control of mPaw in HFOV as compared to volume-controlled ventilation.

Figure 3. Pressure-time curve of HFOV vs. continuous mandatory ventilation, a conventional mode of mechanical ventilation (Augason et. al.).

So how can tidal volumes smaller than the anatomic dead space effectively remove CO2?

Several proposed mechanisms likely play a role in gas exchange in HFOV. These are visualized and described in Figure 4. Among these, the most important are Taylor dispersion in the central airways, molecular diffusion in the lung periphery and Pendelluft.

In conventional ventilation, the majority of CO2 transport occurs via convection (transport of a substance along a fluid flow). In the lungs, there is a pressure gradient which exists between the airway opening and the alveoli and a bulk flow of gas down this gradient. Since in HFOV there isn’t much of a pressure gradient, the question is: how do you get any net transport from the alveolus to the airway opening? You could get a net transport of CO2 by diffusion because there is a higher concentration of CO2 in the alveolus than the airway opening, but pure diffusion across the length of the airway tree is not sufficiently efficient.

Though other mechanisms, as outlined in Figure 4. likely play a role, three primary mechanisms account for the majority of gas exchange during HFOV (Fredberg 1980).

1) Taylor turbulent dispersion - in the presence of turbulent flow, which likely occurs in the lung at the high instantaneous velocities associated with HFOV, diffusion is augmented by the random motion of individual gas molecules caused by turbulent eddies. This augmented diffusion results in enhanced axial transfer of gas (i.e. along the length of the airway).

2) Molecular diffusion - in the lung periphery, where distances are smaller, molecular diffusion down concentration gradients may result in significant gas transport.

3) Pendelluft - because different lung units may have different compliances and resistances, they will have different time constants. This will cause an exchange of gas among these units.

Figure 4. Mechanisms of ventilation in HFOV (Slutsky and Drazen, 2002).

What Is the Theory Behind the Idea That HFOV May Be Useful in ARDS?

There was hope that HFOV could be useful in adult ARDS patients similarly to how it is used in respiratory distress syndrome in infants. It was theorized that such a means of ventilation would reduce ventilator associated lung injury (VILI) while still delivering adequate oxygenation to patients.

Major types of VILI include barotrauma, volutrauma, atelectrauma, and biotrauma (Beitler, Malhotra, and Thompson 2016) and are defined in Table 1.

Table 1. Types of ventilator-induced lung injury (Beitler et al., 2016).

Excessive strain or distention is termed volutrauma (Dreyfuss et al. 1988; Fu et al. 1992). Interestingly, in vitro studies have found that cyclic (versus tonic) distention results in more cell death (Tschumperlin, Oswari, and Margulies 2000; Ye et al. 2012). In a pig model, Protti and colleagues ventilated pigs using various combinations of tidal volume and PEEP to produce dynamic and static strain, respectively. This showed that static lung strain (versus dynamic lung strain) led to improved mortality, oxygenation and lung mechanics (Protti et al. 2013). This suggests that minimizing tidal volume and variations in airway pressure might be beneficial in humans. To that end, since HFOV can deliver significantly lower tidal volumes than conventional ventilation, there may be less cyclical lung distention, and more static lung distension.

Edematous lung and surfactant dysfunction in ARDS also higher critical opening pressures for diseased lung units may lead to tidal recruitment - repetitive opening and closing of alveoli during the respiratory cycle. This can lead to lung injury and is termed atelectrauma (Taskar et al. 1997; Albert 2012). Since HFOV causes only minimal lung collapse with each expiration, HFOV might, in theory, cause less atelectrauma than conventional ventilation even with carefully titrated PEEP.

Barotrauma is injury caused by high pressure application (alveolar rupture, pneumothorax, air leaks, etc.), often in areas of regional overdistention (Slutsky and Ranieri 2014). As discussed below, HFOV can be run at relatively high mean airway pressures (> 30 cmH2O). The avoidance of barotrauma will depend on careful selection of mPaw.

What Do We Know About HFOV in Adults With ARDS?

Early studies of HFOV vs. conventional ventilation, notably the MOAT and EMOAT trials, revealed no significant difference in mortality between HFOV and conventional ventilation (Derdak et al. 2002; Bollen et al. 2005). However, both studies were plagued with significant limitations: (1) they were small, with fewer than 200 patients, and more importantly, (2) the conventional ventilation control group was using now outdated protocols (up to 10cc/kg of tidal volume in MOAT, and tidal volume adjusted to peak inspiratory pressure < 45cm H2O in EMOAT). Recruitment maneuvers were not used in either trial.

A 2010 meta-analysis of 8 trials (pooled n = 419) found a seeming mortality benefit to HFOV over conventional ventilation (RR 0.77, 95% CI 0.61 to 0.98, P=0.03) but acknowledged substantial heterogeneity between the samples studied and an overall small sample size (Sud et al. 2010). And again, the control groups were not using what we now accept as lung protective ventilation.

To settle the matter, two large, multicenter, randomized controlled trials compared HFOV vs. conventional ventilation using low tidal volume ventilation and were published simultaneously in the New England Journal of Medicine.

In OSCILLATE (Ferguson et al. 2013), a planned total of 1,200 patients with moderate to severe ARDS at 39 centers in 5 countries were to be randomized to HFOV vs. conventional ventilation. Mean P:F was 114-121. HFOV was initiated with a mPaw of 30cm H2O, and adjusted according to a protocol to achieve a specified PaO2 range. This trial was stopped early, after 548 patients were randomized, because of significantly higher mortality in the HFOV group (47% vs. 35%, RR 1.33, 95% CI 1.09-1.64, p = 0.005, See Figure 4 below). Patients on HFOV more frequently required vasopressors (up to 78% vs. 58% the day after protocol initiation, p = 0.01) and neuromuscular blockade (46% vs. 26% the day after protocol initiation, p< 0.001), and had a higher (but not significantly so) rate of barotrauma (18% vs. 13%, p = 0.13). The HFOV group also used more fentanyl and midazolam vs. the control, although the propofol use was higher in the control group on most days.

In OSCAR (Young et al. 2013), 795 patients with moderate ARDS (mean P:F 113 mmHg) at 29 hospitals across the UK were randomized to HFOV vs. conventional ventilation. Participants entered the trial on average after two days of mechanical ventilation. HFOV was set at 5 cm H2O above the plateau pressure on enrollment, for a mean of 26.9 ± 6.2 cmH2O (vs. 30.9 ± 11 in conventional ventilation) on study day 1. Achieved mean tidal volumes in the first 3 days were 213-240 cc’s in patients on HFOV (cc/kg not available), and 8.2-8.3 cc/kg for those on conventional ventilation. P/F ratios and PaCo2 were consistently higher in the HFOV group during the first three study days. Overall, this study found no 30-day mortality benefit to using HFOV (41.7% in HFOV vs. 41.1% in conventional ventilation, p = 0.85, see Figure 4 below again). In this trial too, patients on HFOV were exposed to neuromuscular blockade and sedation for a longer period of time (2.0 vs 2.5 days, p = 0.02; 8.5 vs 9.4 days, p = 0.07). There was no difference in the duration of vasopressor exposure (2.8 vs. 2.9 days, p = 0.74).

Putting These Two Studies Together

These two studies effectively deflated hopes of HFOV being superior to conventional ventilation in adults with ARDS. The mortality difference in OSCILLATE is likely multifactorial, though may be related high mPaw and subsequent hemodynamic compromise (hence the need for more vasopressors), increased sedation and NMB in the HFOV arm and effective lung protective ventilation achieved in the control group (particularly given the low mortality rate of 35% in the control group for patients with moderate ARDS). In OSCAR, mPaw was notably lower, and mortality did not significantly differ between groups, but the achieved tidal volumes in the control group were a bit above what we would consider lung protective, and the mean tidal volumes in the low 200s on HFOV likely are well below 6cc/kg. Thus, even though HFOV did deliver significantly lower tidal volumes, and conventional ventilation failed to, HFOV still did not improve mortality by comparison. The increased use of neuromuscular blockade in both studies is to be expected, since patients must be completely passive for HFOV, but this comes at the expense of increased sedation, and potentially increased vasopressor use for sedation-related hypotension. Thus, even if an argument could be made that HFOV were equivalent to conventional ventilation, it may not be worth the added risks of continuous paralysis (or the cost of new ventilators, and training, for the hospital).

Figure 5. Mortality outcomes from large, randomized controlled trials of HFOV vs. conventional ventilation (Ferguson et al. 2013, Young et al. 2013).

Subsequently, a meta-analysis pooling the patients from MOAT, EMOAT, OSCILLATE and OSCAR (n = 1,552) found no differential effect of HFOV based on compliance (p = 0.35), a significantly higher rate of barotrauma (adjusted OR 1.87, 95% CI 1.06 – 3.28, p = 0.03), no improvement in later quartiles on HFOV (a proposed surrogate for increased experience with HFOV as the trials went on), and a signal towards increased mortality when low tidal volumes were achieved in the control group (Meade et al. 2017).


Both HFOV and APRV are non-conventional ventilation strategies which are designed to maximize alveolar recruitment and minimize atelectrauma. However, neither has been shown to improve mortality for patients with ARDS. In fact, HFOV may be harmful, and requires substantial sedation and oftentimes paralysis. Additionally, HFOV also requires specific ventilator equipment, and more importantly, significant training and experience. Furthermore, the use of APRV has not been rigorously studied in ARDS patients, and may allow patients to suffer injurious transpulmonary pressures and large tidal volumes. There is a proven mortality benefit to conventional low-tidal volume ventilation and proning. Therefore, even if there is a theoretical basis of benefit for HFOV of APRV, trialing unconventional ventilation strategies in unselected ARDS patients instead of rigorously evaluated, evidence-based lung protective ventilation is not likely to improve mortality. We therefore do not recommend using HFOV or APRV in adult patients with COVID-19 associated ARDS.


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