Indications for and Timing of HFOV

The indications for HFOV are ill-defined and are usually dictated by personal preferences of the attending physician and institutional bias. In general, HFOV is only considered as a rescue approach when CMV fails, but it could be argued that it should be considered earlier in the PARDS trajectory to minimize VILI and prevent exposure to noxious ventilator settings. There is virtually no pediatric data supporting this concept, except for one small observational study of 26 patients reporting significantly higher 30-day survival rates (58.8 vs. 12.5%) when HFOV was employed within 24 hours rather than as rescue [45]. OSCILLATE attempted to study the effects of early HFOV within 72 hours of ARDS diagnosis. However, in that study, patients could have been on the ventilator for up to 14 days prior to randomization, making it less clear what the true effects of early HFOV are [40].

Some authors have proposed the use of a specific oxygenation index (OI) or the PaO₂ /FiO₂ ratio as threshold in deciding when to transition a patient to HFOV. Two pediatric trials used, respectively, an OI > 13 and 15 as cut-off values [26, 27]. A recent re-evaluation of the OSCILLATE trial showed that a mortality benefit of HFOV could only be expected in adults with severe ARDS (i.e., PaO₂ /FiO₂ less than 100) [46], suggesting that HFOV as a rescue intervention should only be considered in the sickest of patients.

Lung Volume Optimization Maneuvers

Lung volume is the main determinant of oxygenation in diffuse alveolar disease during HFOV. Simply put, PaO₂ increases linearly with lung volume up to a certain point when alveoli become overdistended [47]. This suggests that an open-lung strategy (i.e., opening up the lung and keeping it open) by (repeated) recruitment maneuvers (RMs) should be considered when switching from CMV to HFOV. Remarkably, RMs seem not to be the standard of care when initiating HFOV [48]. This may be explained by a lack of clinical studies reporting beneficial effects of RMs, or even the best approach to RMs in HFOV, and the presumed enhancement of the underlying inflammatory process [49]. The only guidance comes from one neonatal lamb model study investigating four different RM approaches: a stepwise pressure increase over 6 minutes, a 20 second dynamic sustained inflation either one or repeated six times, and a standard approach (setting CDP directly at start) [50]. This study showed that a stepwise pressure increase produced the greatest gain in lung volume and resolution of atelectasis. A sustained inflation of 30–35 cmH₂O for 20–30 seconds was used in the small study by Samransamruajkit et al, whereas the adult OSICLLATE study applied 40 cmH₂O for 40 seconds [28, 40]. However, such a nonindividualized approach to lung volume optimization does not take the patient’s respiratory system mechanics into account, thereby leading to overdistension or not fully recruited lung units in a clinically unidentifiable group of patients [44]. We have adopted an individualized, staircase incremental–decremental CDP titration as part of an open-lung approach to HFOV (Fig. 7.2). Such an approach is feasible and safe in terms of hemodynamic consequences while allowing for sufficient gas exchange [51].

Additional benefits of optimization of the end-expiratory lung volume include a better distal dampening of the pressure oscillations. This is because pressure oscillations are less dampened in lungs with ongoing atelectasis, thus exposing the conducting airways and alveoli to injurious higher pressure swings (Fig. 7.2) [24]. With reduced compliance in unresolved atelectasis, there is a marked increase in transmission of the peak-to-trough ∆P to the alveoli and bronchi. Another, at least theoretical, benefit of RMs is that it allows oscillating the patient on the deflation limb of the P–V curve, thereby avoiding, at least in part, injurious hyperinflation and atelectasis [20, 52–54]. By doing so, a lower CDP is needed to maintain the same amount of EELV than on the inflation limb because of the hysteresis of the respiratory system.

Achieving the Lowest Tidal Volume

The delivered Vt during HFOV is determined by numerous factors, including resistance of the respiratory system (Rrs) and oscillator settings such as oscillatory power (magnitude of membrane displacement), F in Hertz (Hz), I:E ratio, position of the membrane, endotracheal tube (ETT) length and diameter, and presence of ETT leakage [55–59]. The ETT constitutes the major work load to the oscillator and is an important determinant of Vt [60]. Vt is proportional to the ETT inner cross-sectional area because the impedance of the ETT exceeds the impedance of the lung [61, 62].

In clinical practice, it is common to set F and power according to the patient’s age, ventilator settings, and observation of chest wiggle. However, from a physiological perspective, it seems more appropriate to use the highest possible F in PARDS. First, the higher the F, the smaller is the Vt because changes in F are inversely proportional to the distal oscillatory pressure amplitude [63]. It will subsequently be easier to stay within the limits of the safe zone (i.e., the zone with the smallest risk of injurious hyperinflation or atelectasis) of the P–V loop. Second, collapsed lung regions are more easily opened at higher F [64]. Third, the delivered Vt is more equally distributed as it becomes less dependent on regional compliance at higher F [23]. However, finding the best F can be challenging. Venegas et al have proposed that setting the oscillatory F is dictated by the corner frequency (Fc) of the lung, Fc = 1/(2πRC), where R is resistance and C compliance [65]. Fc defines the optimal frequency at which there is adequate gas transport during HFOV in combination with the least injurious pressures and is influenced by the underlying disease (Fig. 7.3). It is increased in lung diseases characterized by short time constants and low compliance such as in PARDS. Importantly, F is intimately linked with ∆P. Basically, the higher the ∆P, the larger is the Vt. Yet, we (unpublished data) and others have observed in bench test studies that Vt was smaller when combining high F (15 Hz) and high power (set to achieve a ∆P of 90) compared with low F (5 Hz) and low power settings as the distal pressure amplitude was much lower but still associated with a sufficient CO₂ elimination [66].

Description of APRV

Airway Pressure Release Ventilation (APRV) was first described in 1987 as a mode to deliver two levels of continuous positive airway pressure (CPAP) while allowing for spontaneous breathing throughout the respiratory cycle [67]. Unlike traditional CPAP, both oxygenation and ventilation are supported during APRV. A continuous high flow is delivered to the patient, only interrupted by intermittent opening of the expiratory valve, resulting in a decrease in circuit pressure allowing gas outflow and thereby enhanced CO₂ removal from the lungs as well as emptying of the anatomic dead space. Unlike CMV, the breath begins at an elevated baseline and ends with the deflation from high pressure to a low pressure. This driving pressure gradient establishes the delivered Vt allowing for ventilation, which is (as with PCV) affected by Crs and Rrs. Hence, APRV is considered a time-triggered, pressure-limited, and time-cycled intermittent mode of ventilation with an inversed inspiratory-to-expiratory ratio [68]. Of note, APRV is in fact an inverse ratio mode of PCV if spontaneous breathing is absent.

The operator has to set the high (Phigh) and low (Plow) pressure as well as the time (T) intervals of these pressures (Thigh and Tlow). Oxygenation is determined by the FIO₂ and Thigh. Usually, Phigh is set to match the plateau pressure (Pplat) during CMV (targeting Pplat <30 cmH₂O), but the approach to setting Plow and Thigh and Tlow is highly variable [68]. Thigh can be set somewhere between 4 and 10 seconds and is dictated by oxygenation. For Plow and Tlow, there are roughly two concepts: (a) using a constant Tlow and nonzero Plow to prevent complete end-expiratory lung deflation and a Thigh that is approximately 90% of the total cycle time, or (b) setting Tlow dictated by lung mechanics (to achieve an end-expiratory flow: peak expiratory flow (PEF) ratio of ±50–75%), Plow at zero and Thigh >90% of the total cycle time – the inherent short Tlow thus prevents complete end-expiratory lung emptying [69, 70]. How both are ultimately set is dictated by the desired level of CO₂ elimination. The combination of these settings results in a mPaw calculated by ((Phigh ∗ Thigh) + (Plow ∗ Tlow)) / (Thigh + Tlow). The prolonged inspiratory time may lead to the development of intrinsic PEEP (PEEPi), which should be avoided because of its adverse cardiovascular effects.

Physiologic Benefits

The potential benefits of APRV are linked to a presumed reduced risk of volutrauma inherent to the pressure limitation with this mode, and therefore, the delivered Vt is affected by Crs and Rrs (as with PCV). In line with the open-lung concept, the risk for atelectrauma may be reduced because APRV delivers a higher mPaw than on PCV. Numerous animal studies have shown improved oxygenation and some reduced lung injury with APRV [30]. However, the true potential benefit of APRV is probably linked to spontaneous breathing, which makes it appealing. Critical care practitioners have adopted the philosophy of maintaining spontaneous breathing in mechanically ventilated patients as much as possible. This dogma is based on early work showing that Vt was directed toward the dorsal, well-perfused regions of the lung in anesthetized adults without lung injury when they were in the supine position [71]. These beneficial effects of spontaneous breathing were confirmed in experimental and clinical studies of lung injury [72, 73]. Explanations for these beneficial effects include reduced shunt fraction, improved distribution of Vt toward the dependent lung zones, and less lung inflammation [74–76]. In addition, spontaneous breathing may allow for a better patient–ventilator synchrony and a potential decrease in sedation and analgesia. To date, however, these beneficial effects have not been demonstrated in children.

Clinical Evidence in Children

The pediatric literature on APRV is mainly limited to case reports, case series, and retrospective and prospective observational cohort studies with small sample sizes. In most cases, APRV was employed as rescue intervention and overall results in terms of oxygenation and ventilation were not universally confirmed. In 2018, Lalgudi Ganesan et al reported the outcomes of the first RCT comparing APRV with CMV in Berlin-defined PARDS (Table 7.1) [69]. In this open-label, parallel-designed RCT, children aged 1 month to 12 years were randomized within 24 hours of PARDS diagnosis and 72 hours of ventilation to APRV or CMV. Remarkably, randomization was unbalanced as there were more girls and patients suffering from more severe hypoxia in the APRV arm. In the APRV group, Phigh was set 1–2 cmH₂O above Pplat with a maximum of 30 cmH₂O and subsequently titrated targeting Vt 6–7 mL/kg IBW and Thigh at 4 seconds; Plow was set at 0 cmH₂O and Tlow was terminated when the expiratory flow had decreased to approximately 75% of the peak expiratory flow. Ventilator algorithms used in the two prone positioning trials by Curley et al were used for patients randomized to CMV [77, 78]. HFOV was used as rescue mode when predefined hypoxia criteria were met. Although the study was designed to include 26 patients per randomization arm, it was stopped prematurely at 50% enrollment because of increased mortality in the APRV group (53.8%) compared to CMV (26.9%), yielding a relative risk for death of 2.0 (95% CI 0.97–4.41). Cause of death in these patients was refractory hypoxemia in almost half of the patients, whereas the remaining patients died from MSOF. The primary endpoint VFDs were significantly lower in the APRV arm (9.7 ± 11.1 days) compared to the CMV arm (14.2 ± 10.4 days).

In summary, the available pediatric literature does not support the use of APRV in PARDS.

Current Evidence in Adults

Clinical studies in adults with ARDS have reported improved oxygenation, ventilation, and lung mechanics when comparing APRV with CMV, although most of these studies were not restricted to patients with severe ARDS [30]. However, different results in terms of patient outcome have been reported. Putensen et al found improved cardiovascular performance and arterial oxygenation as well as fewer ventilator and ICU days when comparing APRV with PCV, whereas others found no effect on clinically relevant outcomes in two RCTs [79, 80]. Similarly, conflicting observations have been made in prospective and retrospective cohort studies [81–83].

Why Did APRV Fail to Improve Outcomes?

Although not novel, use of APRV is limited to a certain number of centers and requires greater experience than traditional PCV. As with HFOV, there is no clear understanding of what optimal initial and titration APRV settings are effective. Furthermore, concerns related to APRV must be better understood, and include the effect of high transpulmonary pressures during spontaneous breathing, along with cyclical derecruitment and Vt variability during the release time [69].