American Journal of Respiratory and Critical Care Medicine

Rationale: There is increasing evidence for a clinical benefit of noninvasive high-frequency oscillatory ventilation (nHFOV) in preterm infants. However, it is still unknown whether the generated oscillations are effectively transmitted to the alveoli.

Objectives: To assess magnitude and regional distribution of oscillatory volumes (VOsc) at the lung level.

Methods: In 30 prone preterm infants enrolled in a randomized crossover trial comparing nHFOV with nasal continuous positive airway pressure, electrical impedance tomography recordings were performed. During nHFOV, the smallest amplitude to achieve visible chest wall vibration was used, and the frequency was set at 8 hertz.

Measurements and Main Results: Thirty consecutive breaths during artifact-free tidal ventilation were extracted for each of the 228 electrical impedance tomography recordings. After application of corresponding frequency filters, Vt and VOsc were calculated. There was a signal at 8 and 16 Hz during nHFOV, which was not detectable during nasal continuous positive airway pressure, corresponding to the set oscillatory frequency and its second harmonic. During nHFOV, the mean (SD) VOsc/Vt ratio was 0.20 (0.13). Oscillations were more likely to be transmitted to the non–gravity-dependent (mean difference [95% confidence interval], 0.041 [0.025–0.058]; P < 0.001) and right-sided lung (mean difference [95% confidence interval], 0.040 [0.019–0.061]; P < 0.001) when compared with spontaneous Vt.

Conclusions: In preterm infants, VOsc during nHFOV are transmitted to the lung. Compared with the regional distribution of tidal breaths, oscillations preferentially reach the right and non–gravity-dependent lung. These data increase our understanding of the physiological processes underpinning nHFOV and may lead to further refinement of this novel technique.

Scientific Knowledge on the Subject

Noninvasive high-frequency oscillatory ventilation (nHFOV) is a relatively new technique designed to augment the effectiveness of nasal continuous positive airway pressure in neonates. Current evidence suggests that nHFOV may be a promising alternative to other noninvasive modes for supporting ventilation and avoiding endotracheal intubation in preterm infants, although the mechanisms by which these clinical benefits are achieved are largely unknown.

What This Study Adds to the Field

This study provides the first evidence of substantial transmission of oscillatory volumes into the lung of preterm infants on nHFOV support. Compared with the regional distribution of tidal breaths, oscillations are more likely to reach the right and the non–gravity-dependent areas of the lung.

The use of noninvasive high-frequency oscillatory ventilation (nHFOV) as respiratory support for preterm infants is increasing, owing to potential benefits over the standard noninvasive respiratory support, nasal continuous positive airway pressure (nCPAP) (13). Clinical studies suggest that nHFOV may be superior to nCPAP for carbon dioxide (CO2) clearance and may improve respiratory stability, particularly in preterm infants with evolving bronchopulmonary dysplasia (47). However, the physiological effects within the lung accounting for these findings are poorly understood.

Because of the heterogeneous pattern of lung disease in these infants, ventilation distribution and regional lung volumes cannot be assumed to be uniform throughout all lung units, especially in gravity-dependent lung regions (8, 9). This is particularly so during HFOV where ventilation is maintained using complex gas flow mechanisms (1013). Animal data during invasive (endotracheal) HFOV suggest that oscillations are shifted toward the non–gravity-dependent lung at higher frequencies (14). During facemask-delivered nHFOV in 1-year-old infants, oscillations resulted in only marginal thoracic movements when measured with respiratory inductance plethysmography (15). Because oscillations are known to be dampened by the ventilator circuit, the nasal interface, and leaks around the nose and mouth, the magnitude and regional distribution of oscillatory volumes (VOsc) that are actually transmitted to the alveoli remain unknown (1013, 15).

Conventional tools for monitoring the regional behavior of the neonatal lung expose the infant to radiation or procedures that are unacceptably invasive (16). Electrical impedance tomography (EIT) is a noninvasive, radiation-free method that measures the regional ventilation distribution in a cross-sectional slice of the lung (17). This continuous assessment of regional lung function has been shown to be representative of the whole lung in ventilated preterm infants (18).

In the current study, EIT data from our randomized crossover trial on the effect of nHFOV on preterm infants were analyzed (7). We tested the hypothesis that, in preterm infants born at <30 weeks of gestation, nHFOV would result in a significant transmission of VOsc to the lungs. We speculated that VOsc would be evenly distributed between the right and the left lung but greater in the non–gravity-dependent regions.

The trial was registered with the Australian and New Zealand Clinical Trials Registry (ACTRN12616001516471) and approved by the local ethics committee. All parents provided written informed consent.

Population and Intervention

Preterm infants born before 30 weeks’ gestation who were 1) extubated for more than 24 hours, 2) older than 7 days, 3) between 26 and 34 completed weeks of gestation, and 4) clinically stable while receiving nCPAP support at the time of study were randomized to receive nHFOV or nCPAP first, each for 120 minutes. Infants were managed on the assigned therapy for an additional 30 minutes before each study period. This was considered a washout period and not included in the analysis. A Babylog VN500 ventilator (Dräger Medical System) and short binasal prongs (Hudson Respiratory Care) were used for both intervention periods. The bias gas flow rate was 6 L/min. During the study, the nCPAP level (CPAP phase) and mean airway pressure (nHFOV phase) were set at the same level as that used before study commencement. Frequency (8 Hz), positive end-expiratory pressure, mean airway pressure, and inspiratory-to-expiratory ratio (1:1) were not adjusted. The oscillatory amplitude was set at 20 cm of water (cm H2O) at the outset of the study and modified to maintain transcutaneous carbon dioxide levels between 40 and 60 mm of mercury. If the infant was normocapnic, the smallest amplitude to achieve visible chest wall vibration was used. Because infants were nursed in a prone position throughout the study, dorsal lung regions were considered non–gravity dependent.

Data Collection

An ultrasound gel–coated textile electrode belt with 32 electrodes was fastened at the nipple level (19). During each intervention period, four 10-minute EIT sequences were recorded with the SenTec BB2 EIT device (SenTec AG) at a frame rate of 48 Hz in a custom-built infant imaging package (19, 20). For each sequence, the first 30 stable consecutive breaths of artifact-free tidal ventilation were identified and data extracted. Recordings were excluded from analysis if more than three electrodes had insufficient skin contact or if fewer than 30 consecutive breaths could be identified.

Data Analysis

Data were extracted and analyzed using ibeX (version 1.1; SenTec AG) and Matlab software (version 2019a; Mathworks). First, predefined anatomical lung regions based on the vendor-provided human model chest atlas were projected into the EIT image and EIT signals outside of these regions excluded (21, 22). Second, two bandpass filters were applied on all recordings (nHFOV and nCPAP) to split the unfiltered ventilation signal (∆Z) into a signal for tidal breathing (∆ZSpon) and a signal for oscillations (∆ZOsc). A low-pass frequency of 3 Hz was used to isolate ∆ZSpon from ∆Z, being three harmonics of the median respiratory rate of 59 breaths per minute during the recordings (23, 24). We isolated the oscillatory signal (∆ZOsc) by applying two band-pass filters with a width of ±0.2 Hz around 8 Hz (corresponding to the set frequency during nHFOV) and 16 Hz (the second harmonic of the nHFOV frequency). Third, for each of the two filtered signals, the amplitudes were extracted, averaged over the selected 30-breaths sequence, and normalized for body weight. Depending on the applied filter, this corresponded to the relative Vt or the VOsc (expressed in AU/kg), respectively. Next, the VOsc/Vt ratio was calculated for each recording. Fourth, regional ventilation distributions were quantified by assessing VOsc, Vt, and the VOsc/Vt ratio separately for the gravity-dependent, non–gravity-dependent, right, and left lung. These relative changes in regional ventilation were then weighted to the known pixel contribution of each region to normalize for differences in lung size (25, 26). Finally, functional EIT images (per patient and overall) were generated to visualize differences in the regional ventilation distribution between the tidal breathing signal and the oscillatory signal. The regional ventilation pattern of the tidal breathing signal was generated by subtracting the EIT signal at the start of inspiration from the signal at the end of inspiration. For the oscillatory signal, functional EIT images were generated using the SD of the impedance time course (17).

Statistical Analysis

Analyses were performed on the averages of each EIT recording. Normally distributed data are presented as mean with SD or 95% confidence interval (CI). Nonparametric data are presented as median and interquartile range. Because each subject was measured four times during each mode of ventilation, comparisons between nHFOV and nCPAP were performed using a mixed model ANOVA controlling for within-subjects variance (using the “afex” package in R statistics, version 3.6.2) (27). Correlation was assessed using Pearson’s correlation coefficient. P values < 0.05 were considered statistically significant.

Population

Among 30 infants, 228 EIT recordings containing 6,840 breaths were analyzed, 112 recordings during nHFOV and 116 during nCPAP (Figure 1). Demographic and clinical characteristics of the included infants are provided in Table 1.

Table 1. Baseline Demographics and Clinical Characteristics

CharacteristicsMedian (IQR)*
Perinatal 
 Gestational age at birth, wk26.6 (25.6 to 27.3)
 Birth weight, g870 (772 to 1,020)
 Male, n (%)16 (53)
 Antenatal glucocorticoids, n (%)26 (87)
 Apgar score at 5 min8 (6 to 8)
 Exogenous surfactant, n (%)29 (97)
Before randomization 
 Endotracheal ventilation, n (%)29 (97)
 Duration of endotracheal ventilation, d11 (2 to 31)
 Duration of noninvasive ventilation, d12 (9 to 19)
 Postnatal glucocorticoids, n (%)11 (37)
At randomization 
 Postnatal age, d33 (16 to 45)
 Postmenstrual age, wk31.1 (30.0 to 32.0)
 Weight, g1,271 (1,069 to 1,583)
 Nasal CPAP pressure, cm H2O7 (6 to 8)
 FiO20.30 (0.28 to 0.34)
 SpO2/FiO2300 (263 to 321)
 Capillary blood gas 
  pH7.35 (7.33 to 7.39)
  Pco2, mm Hg53 (48 to 57)
  Base excess, mmol/L2 (−1 to 4)
  HCO3, mmol/L28 (26 to 32)
Respiratory follow-up 
 Bronchopulmonary dysplasia, n (%)21 (70)

Definition of abbreviations: CPAP = continuous positive airway pressure; IQR = interquartile range; SpO2 = oxygen saturation as measured by pulse oximetry.

*Unless otherwise specified.

Bronchopulmonary dysplasia was diagnosed at 36-week corrected gestation according to the modified Walsh criteria (49).

Frequency Spectrum

The unfiltered ventilation signals of one typical infant’s recording and its corresponding frequency spectra are provided in Figure 2. During nHFOV, three frequency ranges can be identified. Areas shaded in green represent tidal breathing and areas shaded in red represent oscillations. The high-frequency spikes were not present during nCPAP.

Tidal and Oscillatory Volumes during nCPAP and nHFOV

The global tidal and oscillatory volumes during both modes of ventilation are provided in Table 2. The filtered ventilation signals ∆ZSpon and ∆ZOsc of one typical nCPAP and nHFOV recording are shown in Figure 3, A1/A2 and B1/B2. During nHFOV, VOsc could be measured within the lungs with a mean (SD) tidal amplitude of 1.7 (1.0) AU/kg. The corresponding mean (SD) Vt was 9.5 (4.8) AU/kg, and the mean (SD) VOsc/Vt ratio was 0.20 (0.13). Reassuringly, there was very little signal within the ∆ZOsc domain during nCPAP. The mean (SD) oscillatory amplitude set at the ventilator was 20 (3.2) cm H2O, which did not correlate with the measured VOsc (r = 0.13, P = 0.18).

Table 2. Global Vt and Oscillatory Volume during Both Modes of Ventilation

 CPAP [Mean (SD)]HFOV [Mean (SD)]Mean Difference (95% CI)Test Statistic*
Vt, AU/kg11.6 (5.0)9.5 (4.8)2.1 (0.8 to 3.4)F = 33, P < 0.001
VOsc, AU/kg0.1 (0.1)1.7 (1.1)−1.6 (−1.4 to −1.8)F = 413, P < 0.001
VOsc/Vt ratio0.01 (0.01)0.20 (0.13)−0.19 (−0.16 to −0.21)F = 333, P < 0.001

Definition of abbreviations: CI = confidence interval; CPAP = continuous positive airway pressure; HFOV = high-frequency oscillatory ventilation; VOsc = oscillatory volume; VOsc/Vt ratio = ratio of oscillatory volume divided by Vt.

Analyses are based on the averages of each electrical impedance tomography recording.

*The F value is the test statistic of the ANOVA and corresponds to the variation between subjects divided by the variation within subjects. P values of the mixed model ANOVA are shown.

Regional Ventilation Patterns during nHFOV

The regional distributions of Vt and VOsc expressed as total volumes, as percentage and as a ratio to account for anatomical sizes of lung regions is shown in Table 3. The non–gravity-dependent and the right lung contributed a greater portion to total Vt (Figure 3, B3 and Table 3). Similarly, oscillations were more likely to be transmitted to the non–gravity-dependent and right-sided lung regions (Figure 3, B4 and Table 3). The mean VOsc/Vt ratio was higher in the non–gravity-dependent compared with the gravity-dependent lung (mean difference [95% CI], 0.041 [0.025–0.058]; P < 0.001) and higher in the right compared with the left lung (mean difference [95% CI], 0.040 [0.019–0.061]; P < 0.001). There was no change in the ventilation homogeneity ratio with different amplitudes in all four lung regions (see Table E1 in the online supplement). Regional oscillation and ventilation maps for each individual patient are available online (see Figure E1).

Table 3. Regional Ventilation Distribution of Vt and Oscillatory Volume during nHFOV

 VtVOsc
EIT Signal (AU/kg)Ventilation Distribution (%)Ventilation Homogeneity Ratio*EIT Signal (AU/kg)Ventilation Distribution (%)Ventilation Homogeneity Ratio*
Overall9.5 (4.8)1.7 (1.1)
Right6.2 (4.0)63 (22)1.14 (0.37)1.1 (0.8)65 (19)1.15 (0.32)
Left3.3 (1.7)37 (15)0.95 (0.38)0.6 (0.4)35 (18)0.90 (0.45)
NGD5.4 (2.7)57 (10)1.04 (0.19)1.0 (0.7)62 (7)1.11 (0.13)
GD4.1 (2.3)43 (13)0.99 (0.29)0.7 (0.4)38 (7)0.87 (0.16)

Definition of abbreviations: EIT = electrical impedance tomography; GD = gravity-dependent; NGD = non–gravity-dependent; nHFOV = noninvasive high-frequency oscillatory ventilation; VOsc = oscillatory volume.

All data are shown as mean (SD).

*The ventilation homogeneity ratio corresponds to the relative changes in regional ventilation, which were weighted to the known pixel contribution of each anatomical lung region: The percentage of Vt and VOsc reaching the respective part of the lung was divided by the anatomical lung size of the right, left, non–gravity-dependent, and gravity-dependent parts of the lung. A value greater than 1 means the amount of Vt or VOsc in that region is greater than the anatomically expected contribution of that region.

The mechanisms by which the clinical benefits of nHFOV are mediated are largely unknown. With this study, we provide the first evidence of substantial transmission of oscillatory volumes into the lung of preterm infants on nHFOV support. We also demonstrate that compared with the regional distribution of tidal breaths, oscillations are more likely to reach the right and the non–gravity-dependent areas of the lung.

nHFOV was developed to combine the advantages of endotracheal HFOV and noninvasive ventilation (2, 3). It is thought that the oscillations during nHFOV deliver a small Vt, thereby eliminating CO2 mostly from the upper airways and adding to CO2 clearance by tidal breathing from the lower airways (28, 29). During nHFOV, however, gas could theoretically also be transported to the distal parts of the lung by other mechanisms including convective flow, longitudinal dispersion due to turbulence, and pendelluft, depending on the respiratory cycle (1013, 30). Moreover, oscillations during nHFOV are known to be dampened by various mechanisms, which may explain that thoracic movements attributed to oscillations were only marginal in four 1-year-old infants (15, 31). In contrast to these older infants, the highly compliant chest wall in preterm infants facilitates pressure transmission during nHFOV. Furthermore, respiratory inductance plethysmography measures the movement of the chest and abdominal wall and can only approximate the actual oscillatory volume transported to the alveoli. By measuring EIT changes in regional ventilation distribution, we demonstrated that contrary to previous suggestions, nHFOV oscillations are transmitted to the lung level in preterm infants. In fact, the oscillations’ amplitude was approximately one-fifth of the overall Vt during nHFOV, which would correspond to an absolute oscillatory volume of 0.8–1.2 ml/kg with regard to the internationally recommended total Vt for ventilated preterm infants (32). Thus, our data suggest that CO2 removal during nHFOV may also occur in the intrathoracic airways.

We also found that during each inflation, overall Vts within the lung were comparable for both interventions, although Vt was lower during nHFOV. This may support the use of higher mean airway pressures to facilitate gas exchange when escalating infants from nCPAP to nHFOV, but this has not yet been evaluated in adequately powered clinical trials (7). One could speculate that infants on nHFOV may need to work less hard than infants on nCPAP support to achieve the same gas exchange; however, this is difficult to quantify. Furthermore, the lower Vt during nHFOV may provide a potential explanation for the finding in the original trial that infants on nHFOV required more oxygen to remain within the oxygen saturation target.

We did not observe a correlation between the amplitude set at the ventilator and the VOsc reaching the lung. However, the amplitude during the study was increased until there was a visible wiggle of the infant’s thorax. We speculate that because of intrinsic variations in compliance and resistance, different amplitudes may have been required to achieve the same VOsc reaching the infant’s lung (33).

Clinical studies suggest that nHFOV may be better than nCPAP for postextubation support and respiratory stability, particularly in preterm infants with evolving bronchopulmonary dysplasia (47). Our physiological data support these findings and offer potential explanations for the clinical benefits of nHFOV. Because inspiratory glottic dilator activity seems to be maintained during nHFOV (34), we speculate that in contrast to pressure peaks during nonsynchronized noninvasive positive pressure ventilation, oscillations may be transmitted to the lung more consistently (35). This may provide a continuous stimulus and a possible explanation for the clinical benefit of nHFOV.

The regional distribution of oscillations during nHFOV has never been described before. We found that compared with Vt, VOsc are more likely to be transmitted to the right lung. The angle of the tracheal bifurcation is more acute for the left main bronchus compared with the right, and this difference is more pronounced in infants than in adults (3638). The more acute angle might dampen the transmission of oscillations to the left side (11, 12, 39), and this effect may be frequency dependent (14). Altered flow profiles during the higher oscillatory frequency may explain the differences in ventilation distribution compared with frequencies of regular tidal breathing (1012). During tidal breathing, there is mainly quasi-steady flow, whereas during HFOV, there are various factors contributing to gas exchange (10, 40). Miedema and colleagues found that a similar increase in pressure amplitude during endotracheal HFOV resulted in a significantly greater increase of oscillatory volume in the right compared with the left lung (41).

Interestingly, VOsc were also transmitted predominantly to the non–gravity-dependent parts of the lung, and in fact, this effect was greater than during tidal breathing. As infants were prone throughout our study, the non–gravity-dependent lung regions correspond to the dorsal parts of the lung. The angle of the dorsal diaphragm is steeper compared with the ventral diaphragm, potentially contributing to higher Vt in the dorsal lung. Oscillatory gas flow, however, also consists of diaphragm-independent mechanisms such as pendelluft or turbulent longitudinal dispersion (30). Thus, the predominant transmission of VOsc to the non–gravity-dependent lung region may be due to frequency-dependent effects: recently, it had been shown in sheep that ventilation in the non–gravity-dependent lung was higher with an increasing oscillatory frequency (14). Owing to gravitational forces, the non–gravity-dependent lung has a higher compliance, which leads to more volume delivered to these lung units (42). This effect is even more pronounced for higher frequencies (42, 43). We hypothesize that these mechanisms may contribute to an increased regional ventilation homogeneity, which may ultimately lead to a decrease in preterm lung injury during nHFOV (44, 45). Although our results are intriguing from a physiological perspective, high-quality evidence from larger randomized controlled trials demonstrating a lasting clinical improvement is still lacking. We think that currently, nHFOV may be justified on a case-by-case basis to avoid intubation.

Our study has several limitations. First, we studied a small sample of infants. However, even with only 30 infants, we had 228 separate EIT recordings and 6,840 breaths to evaluate, thus increasing the value of the data set. Importantly, we showed that, in contrast to studies of different populations, oscillations during nHFOV are transmitted to the lung level in stable preterm neonates. The distribution pattern was similar for most infants, strengthening the validity of our results. Second, EIT measures relative changes; thus, we cannot draw conclusions regarding the absolute volume changes in the lung during nHFOV. However, EIT measurements have been proved to correlate well with measured Vts in animal studies (46, 47) and are representative of the whole lung in ventilated preterm infants (18). Third, a single ventilator model was used to deliver nHFOV. Because the type of ventilator may impact the performance of nHFOV, our results cannot be extrapolated to other devices (48).

Conclusions

In preterm infants, oscillatory volumes during nHFOV are transmitted to the lung. Compared with the regional distribution of tidal breaths, oscillations preferentially reach the right and non–gravity-dependent lung. These data increase our understanding of the physiological processes underpinning nHFOV and may lead to further refinement of this novel technique.

The authors thank all the parents and infants who participated in the study and the staff at the neonatal intensive care unit of The Royal Women’s Hospital, Melbourne, Australia.

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Correspondence and requests for reprints should be addressed to Christoph M. Rüegger, M.D., Newborn Research, Department of Neonatology, University Hospital and University of Zurich, Frauenklinikstrasse 10, 8091 Zurich, Switzerland. E-mail: .

Supported by the Victorian Government Operational Infrastructure Support Program (Melbourne, Australia); the National Health and Medical Research Council (Practitioner Fellowship GNT 1059111 [P.G.D.]); the German Research Society (DFG-grant Nr. LO 2162/ 1-1 [L.S.]); the TÜFF Habilitation Program (TÜFF 2459-0-0 [L.S.]); Career Development Fellowships GNT 11123859 and 1057514 [D.G.T.]); the Swiss National Science Foundation (Early Postdoctoral Mobility fellowship P2ZHP3_161749 [C.M.R.]); and the Swiss Society of Neonatology (Milupa Fellowship Award [C.M.R.]). V.D.G. received an Endeavour Research Fellowship (Australia, ERF_RDDH_5276_2016). SenTec AG had no involvement in study design, implementation, analysis, interpretation, and reporting.

Author Contributions: P.G.D., D.B., L.S., D.G.T., and C.M.R. developed the concept and design of the study. L.S., J.T., and C.M.R. were involved in patient recruitment and conducted the electrical impedance tomography (EIT) measurements. A.D.W. developed the EIT analysis software. V.D.G., A.D.W., and C.M.R. performed the EIT analysis. All authors participated in data interpretation. V.D.G. and C.M.R. wrote the first draft, and all authors contributed to redrafting the manuscript.

This article has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org.

Originally Published in Press as DOI: 10.1164/rccm.202007-2701OC on October 23, 2020

Author disclosures are available with the text of this article at www.atsjournals.org.

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