Feasibility of an alternative, physiologic, individualized open-lung approach to high-frequency oscillatory ventilation in children

High-frequency oscillatory ventilation (HFOV) is considered as a rescue intervention in children suffering from acute lung injury when conventional mechanical ventilation (CMV) fails [1, 2]. However, there are scarce paediatric scientific data supporting its use. The only paediatric randomized controlled trial (RCT) that evaluated the effects of HFOV on patient outcome was published in 1994 and found no differences in mortality rates between HFOV and CMV [3]. Continued use of HFOV in paediatrics became even more controversial following two negative clinical trials in adult ARDS and two recent paediatric observational reports failing to show any benefit of HFOV on patient outcome [4–7]. Gupta et al. reported increased mortality and prolonged duration of mechanical ventilation associated with early or late HFOV in a database analysis study using propensity score matching, although there were serious methodological issues related to this study [6, 8, 9]. Bateman and co-workers performed a post hoc analysis of paediatric patients enrolled into a large protocolized paediatric sedation trial using propensity matching with clinically relevant variables [7]. When patients managed with early HFOV were compared with those supported with late HFOV or CMV, mortality was unchanged, but duration of mechanical ventilation was prolonged in the early HFOV group.

It remains unclear whether the outcomes of these studies confirm that HFOV is not beneficial, or even harmful, or that patient outcome was determined by the oscillator management strategy [10–12]. Most paediatric HFOV studies make no mention of recruitment manoeuvres (RM) and reported frequencies (F) in the range of 5–8 Hz. Yet, optimizing lung volume by means of a RM seems physiologically necessary when transitioning to HFOV to recruit collapsed, atelectatic lung units being exposed to larger, potentially more injurious pressure swings [13]. Furthermore, use of low oscillatory F is not in line with the concept of the corner frequency (Fc) [2]. Fc is the F at which the pressure cost of ventilation is the lowest, in other words the F that is the least injurious to the lung [14]. In disease conditions with reduced respiratory system compliance (Crs), such as ARDS, Fc is increased indicating that the highest oscillatory F that still allows for adequate ventilation might be preferable.

We started using an individualized, physiology-driven strategy to HFOV as an alternative mode of ventilation for PARDS rather than the more traditional size/age-based approach as a rescue intervention. Our strategy is centred on an open-lung concept using an initial staircase incremental–decremental mean airway pressure (mPaw) titration manoeuvre, a high F (12 Hz), and high power to initially target a proximal pressure amplitude (∆P_proximal) of 70–90 cm H₂O, irrespective of age or weight. Here, we report our first experiences with this alternative approach to HFOV in a heterogeneous group of patients with moderate-to-severe acute lung injury. We studied the feasibility of our strategy and examined the level and time course of metrics for oxygenation and ventilation and hemodynamic parameters as well as the use of sedative-analgesic medications and neuromuscular blocking agents (NMBA).

To the best of our knowledge, this is the first study reporting that an individualized, physiology-based open-lung HFOV approach characterized by high F and high initial ∆P_proximal in paediatric patients is feasible and does not impair gas exchange or haemodynamics, irrespective of age or PARDS severity.

HFOV is traditionally considered as rescue therapy in case of refractory hypoxemia, although there are some paediatric reports supporting earlier use [6, 20]. Our liberal criteria for transitioning to HFOV may be interpreted as lack of full optimization of CMV. Indeed, we employ HFOV early in the disease trajectory when a patient meets pre-defined criteria rather than using it as a rescue intervention as proposed in international consensus statements in order to prevent ventilator settings from becoming toxic [21, 22]. Inherently, the number of patients managed with HFOV might be higher than in comparable centres including a wider patient spectrum not limited to only patients with severe lung disease. Our liberal use may therefore explain the observed differences in improvement in OI and PaO₂/FiO₂ ratio between PARDS severity strata. The greatest improvement in these metrics was observed in patients with severe PARDS, confirming previous observations [20].

Importantly, our study was not designed to examine superiority of HFOV over CMV. At the same time, when interpreting our results, it cannot be ruled out that, at least in a proportion of patients in our population, similar effects on oxygenation and ventilation could have been achieved if a (ultra-)lung protective ventilation strategy (i.e., lower Vt in combination with RM) continued, and NMBA administration, prone positioning, and/or higher PEEP were used, potentially in combination. It must be acknowledged that the best strategy to optimize CMV in children with severe PARDS remains uncertain [22]. Recommendations for ventilator management and use of (non-)pulmonary-specific ancillary treatments in PARDS have been made, but these are largely based on expert opinion rather than scientific evidence [21, 23, 24]. Paediatric observational studies have reported use of higher levels of PEEP in PARDS than in our cohort, although it is common among the paediatric critical care community to tolerate higher FiO₂ [25–29]. To date, there is no specific PEEP strategy shown to be beneficial nor are there RCT data demonstrating that higher PEEP is better than lower PEEP in PARDS, although there are some suggestions that lower PEEP in PARDS may be associated with increased mortality [29]. We also do not know the optimal Vt in (severe) PARDS [30]. To date, prone positioning has not been shown to improve patient outcome in PARDS, although this may also be explained by not restricting its use to severe PARDS [31]. Short-term use of NMBA early in the course of MV has been shown to improve outcome in adults with ARDS, but this remains unclear in paediatrics [32]. Thus, when it comes to paediatric MV, many unknowns remain [33]. Our study underscores the need for systematic testing our HFOV approach on patient outcome. This can only be done in a well-designed RCT.

Although our approach to HFOV may not be considered novel, it is not uniformly used in children [20, 34–37]. It is more custom to set F and ∆P_proximal according to age, mPaw, and observation of chest wiggle [2, 20]. However, such an approach ignores the respiratory system mechanics of the underlying disorder. Furthermore, a RM after switching to HFOV is not routinely performed. We have adopted a physiology-based and individualized approach to HFOV that: a) makes use of a high F that allows for sufficient gas exchange and a high initial ∆P_proximal with a fixed power setting, and b) a staircase incremental–decremental mPaw titration aimed at finding the lowest mPaw on the deflation limb of the P–V loop after switching to HFOV. The rationale behind choosing the highest possible F is based on the concept of the corner frequency (Fc), which is influenced by the resistance and compliance of the respiratory system [14]. Fc identifies the point of the lowest pressure cost of ventilation, i.e. the point that should be the least injurious to the lung. Fc is increased when there is reduced Crs, suggesting targeting F ≥ 8 Hz [2, 14]. Our data show that we were able to achieve F > 8 Hz, irrespective of age or severity of PARDS. We did not find impaired CO₂ elimination despite these higher F. Despite the “high” initial ∆P_proximal, PaCO₂ and pH levels normalized within 6 hours after transitioning to HFOV, especially in patients with moderate or severe PARDS. Although it cannot be ruled out that normalization of the pH was also partially due to our liberal use of furosemide, our data also suggest that even higher F may be used to accept higher PaCO₂. We arbitrarily choose the initial ∆P_proximal not to exceed 90 cm H₂O as higher values may theoretically expose the proximal airways to injurious pressures. Reassuringly, dampening of the pressure swings among the endotracheal tube is much greater when high F is used, thereby diminishing the likelihood of proximal airway injury [38].

We always perform a lung optimization manoeuvre after switching to HFOV to optimize end-expiratory lung volume (EELV) as the PaO₂ is linearly correlated with EELV [39]. Aside from optimizing lung volume to improve oxygenation, pressure oscillations are less dampened in regions with poor compliance, thereby causing larger pressure swings [13]. One group of investigators found that a stepwise mPaw increase produced the greatest increase in lung volume and resolution of atelectasis compared with a 20-s sustained dynamic inflation (either once or repeated 6 times) or a standard approach (i.e. random setting of mPaw) in a neonatal lamb model [40]. We have adopted such a stepwise increase–decrease mPaw titration as a RM strategy. This allows us to individualize the mPaw setting and oscillate on the deflation limb of the P–V loop where there is less continuous recruitment and decruitment of alveoli [41]. Nonetheless, there is a need for comparing various types of RM for determining optimal EELV as the best RM in HFOV still needs to be identified. Furthermore, there appeared to be a slow decrease in mPaw during the first 3 days after start of HFOV. This could mean that we did not wean HFOV aggressively enough, calling for a better protocolization of HFOV weaning instead of a gradual reduction of the mPaw when oxygenation was satisfactorily.

Although the number of patients put on vasoactive drugs increased over time, the vasoactive score (which includes dosages of vasoactive drugs) did not increase. Furthermore, the cumulative amount of fluid boluses remained low in our patient population. This suggests that there was no haemodynamic instability in our study population despite the delivery of a higher mPaw. We did note an increase in NMBA use during the first 48 h of HFOV, especially in children > 60 months, possibly reflecting work of breathing in these patients when breathing spontaneously due to the fixed bias flow of HFOV [42].

A key strength of this study is that we used a protocolized approach to paediatric HFOV in terms of patient selection and management, taking disease trajectory into account. This has not been previously reported. At the same time, there are limitations that should be considered. Although we describe one of the largest cohorts of paediatric HFOV patients, our study represents a single-centre experience with a liberal use of HFOV thereby including a subgroup of patients with less severe disease [2]. Furthermore, practice variability may have influenced our findings, but this is inherent to the study design and can only be overcome by a RCT [43]. Last, from a theoretical perspective, HFOV seems to be a suitable mode for lung-protective ventilation (LPV). The effect of our alternative approach on the development of ventilator-induced lung injury (VILI) cannot be deducted from the present study and warrants further investigations. Our approach is currently being tested in a 2-by-2 factorial randomized controlled trial comparing the effects of ventilation strategy (CMV vs. HFOV) with or without prone positioning on patient outcome (www.prospect-network.org).

In summary, we report the feasibility in terms of oxygenation, ventilation, and haemodynamics of using an alternative, individualized, physiology-based open-lung approach to HFOV that targets high F and high ∆P_proximal. Further research including multisite dissemination and systematic evaluation compared to CMV on both short- and long-term outcomes in paediatric practice is warranted.