Evaluating tidal volume stability in extremely preterm infants on high-frequency oscillatory ventilation with volume guarantee

Abstract

Background

High Frequency Oscillatory Ventilation (HFOV) combined with volume guarantee (HFOV-VG) represents an innovative ventilation mode designed for managing respiratory failure in neonates. This study aimed to assess the stability of High Frequency tidal volume (VThf) in extremely preterm infants ventilated on HFOV with VG during the first 48 h of life. Additional objectives included examining the correlations between VThf, Diffusion Coefficient of Carbon Dioxide (DCO₂) and key respiratory markers.

Methods

This retrospective, single-center study included 22 extremely preterm infants treated with HFOV-VG as the primary mode of ventilation at King Abdulaziz Medical City. Data were collected directly from the ventilator every minute for the first 48 h of life. Blood gases were analyzed every 4–6 h to maintain normocapnia (PCO₂ 40–55 mmHg). The distribution of continuous variables was assessed using the Shapiro-Wilk test for normality. As most data were found to be non-normally distributed, results are presented as medians with interquartile ranges (IQR). The Kruskal-Wallis test was used to compare non-normally distributed continuous variables across groups. The Spearman’s rank correlation coefficient (Spearman’s rho) was used to evaluate correlations between key clinical and ventilatory variables. All statistical analyses were conducted using Stata software (version 17; StataCorp LLC, College Station, TX), with statistical significance set at p < 0.05.

Results

Twenty-two infants had a median gestational age of 26.5 weeks (IQR 24–28) and a median birth weight of 830 g (IQR 600–1300). The median set VThf per kilogram was 2.2 mL/kg [IQR 2,2.6], which was consistent with the measured VThf. Significant correlations were observed between weight-corrected DCO₂ and VThf (spearman rho = 0.8089, p < 0.0001), and between measured amplitude and weight corrected DCO₂ (spearman rho = 0.6497p < 0.0001). Raw DCO₂ correlated with measured amplitude (spearman rho = 0.1364, p < 0.0001). PCO₂ showed no significant correlation with raw DCO₂ (p = 0.4813) and weight-corrected DCO₂ (p = 0.4845). Notable variations in FiO₂, frequency, and MAP were identified between different PCO₂ levels (p < 0.01) as well as the weight corrected DCO₂ (p = 0.04).

Conclusions

HFOV-VG effectively stabilized VThf in extremely preterm infants with fluctuations in amplitude, providing consistent ventilation support during the early critical period. The weight-corrected DCO₂ correlated strongly with VThf and measured amplitude, underscoring its potential as a reliable marker for CO₂ clearance. These findings highlight the utility of HFOV-VG in managing respiratory needs in extreme preterm infant.

Introduction

Although the use of non-invasive ventilation methods is increasing, a considerable proportion of extremely preterm infants with respiratory distress syndrome (RDS) still require intubation and mechanical ventilation. High-frequency oscillatory ventilation (HFOV) is commonly used in treating infants with respiratory distress syndrome (RDS) [1, 2]. One of the potential benefits of HFOV compared to conventional mechanical ventilation is its use of smaller tidal volumes and the ability to safely maintain higher mean airway pressures than what is typically applied in conventional ventilation methods [3]. Although several mechanisms contribute to gas exchange in HFOV, the tidal volume generated during HFOV (VThf) plays a critical role in carbon dioxide removal. This VThf is primarily produced by fluctuations in the pressure (ΔPhf) around the mean airway pressure, as well as the oscillation frequency [4]. Factors such as endotracheal tube size and lung compliance also influence the VThf [5]. These factors can cause significant variations in VThf and CO₂ clearance, which may impact the overall effectiveness of HFOV [6].

HFOV combined with volume guarantee (HFOV-VG) represents an innovative ventilation mode designed for managing respiratory failure in neonates. Theoretically, HFOV-VG is anticipated to lower the risk of lung injury by minimizing fluctuations in VThf. It also aims to reduce out-of-target PCO₂ levels and decrease episodes of hypoxia compared to traditional HFOV [7, 8]. With HFOV-VG, clinicians are able to set a target VThf, and the ventilator automatically adjusts the amplitude pressure to deliver the desired VThf. This precise regulation of VThf, combined with automatic amplitude adjustments, is especially advantageous in situations where respiratory mechanics change quickly [7, 9]. Research has shown that during HFOV-VG, VThf may fluctuate momentarily, but overall, it remains consistently close to the set target over time [10]. The Diffusion Coefficient of Carbon Dioxide (DCO₂) is recognized as an essential marker for tracking CO₂ clearance, but the level needed to maintain normocapnia can differ between individuals. Weight-corrected DCO₂ ([mL/kg] ²/s) has been proposed as a method to minimize variability between patients [8].

This study builds upon existing literature by specifically evaluating the stability of VThf over the first 48 h in extremely preterm infants ventilated with HFOV with VG. While previous studies have explored the general performance of HFOV-VG, there remains a gap in understanding how VThf fluctuations relate to key respiratory markers such as weight-corrected DCO₂, PCO₂, and measured amplitude. By examining these relationships, this study offers new insights into the effectiveness of HFOV-VG in maintaining stable ventilation and optimizing CO₂ clearance in extremely preterm infants.

The primary aim of this study was to evaluate the stability of VThf over the first 48 h in extremely preterm infants ventilated with HFOV using VG. Additionally, the study aimed to explore the correlations between VThf and key respiratory markers, including the weight-corrected DCO₂, PCO₂, and measured amplitude. Furthermore, the study aimed to examine the differences in ventilatory settings across varying levels of PCO₂, to provide insights into optimizing respiratory support in this high-risk population.

Methodology

This retrospective, single-center study was conducted on twenty-two extremely preterm infants born at less than 28 weeks’ gestation between January 2024 to October 2024. The study was conducted at King Abdulaziz Medical City, and ethical approval was obtained from the King Abdullah International Medical Research Centre (KAIMRC) before the commencement of the study. The inclusion criteria were infants born at less than 28 weeks gestational age who were ventilated on HFOV with VG and inborn at the facility. The exclusion criteria included infants who were outborn or had major congenital anomalies or congenital heart disease.

In this study, all 22 infants included in this study were intubated at birth for respiratory distress syndrome (RDS) and remained ventilated for at least 48 h. HFOV-VG was initiated soon after admission to the NICU as the primary mode of ventilation. No infants were intubated later for other indications, ensuring a uniform study population. The ventilator used was the Dräger VN600, specifically chosen for its HFOV-VG capabilities. The VN600 ventilator produces a sinusoidal pressure waveform centered around a designated mean airway pressure (MAP), incorporating both active inspiration and expiration phases. In volume-guarantee (VG) mode, this ventilator targets a specific VThf by using a microprocessor that monitors the VThf of the previous breath—adjusted for any air leak—and then modulates the delta pressure to maintain the set VThf target. For these infants, the MAP was initially set at 10 mbar, and then gradually increased in increments of 2 mbar every 2–3 min until an optimal pressure for lung recruitment was achieved. This critical pressure point was defined by improved oxygenation or a fraction of inspired oxygen (FiO₂) requirement below 40% with an arterial oxygen saturation target of 90–94%. Once the optimal opening pressure was identified, the MAP was reduced stepwise by 2 mbar to find the closing pressure, followed by re-opening the lung to the critical pressure level. Finally, the MAP was set 2 mbar above the closing pressure to maintain continuous lung inflation and stability, allowing for optimal respiratory function. In this approach, the lung recruitment maneuver was tailored and carefully monitored to prevent overdistension and ensure minimal lung injury, offering a protective strategy in the early respiratory management of these preterm infants. Surfactant was administered soon after admission to the NICU for all infants included in the study.

The amplitude limit was set approximately 10–15% higher than the required average amplitude to achieve target VThf, which was adjusted in increments of 0.1–0.2 mL/kg to maintain the target PaCO₂ range. Blood gas analyses were performed at regular intervals (4–6 h or as needed) to ensure the infants maintained normocapnia, defined as PaCO₂ levels between 40 and 55 mmHg. These blood gas results guided ventilator setting adjustments, ensuring that each infant received individualized respiratory support based on their physiological needs. FiO₂ levels were adjusted to maintain oxygen saturation (SpO₂) between 90 and 94%, using pulse oximetry for continuous monitoring.

Data were continuously collected for the first 48 h of life. Key ventilatory parameters—including set and measured VThf, amplitude, MAP, frequency, and the FiO₂—were recorded directly from the ventilator every minute. For each infant, 2,880 ventilator measurements were captured over the study period, resulting in a detailed dataset for in-depth analysis. In addition to the ventilatory parameters, the study monitored the diffusion coefficient of carbon dioxide (DCO₂), which is a critical measure of the efficiency of CO₂ removal. To allow for accurate comparisons, DCO₂ and VThf were corrected for each infant’s weight, accounting for variations in weight. The PCO₂ data were paired with ventilator data by extracting ventilator parameters recorded 10 min before each blood gas sampling. This interval was selected to allow for physiological stabilization following any ventilatory adjustments and to ensure that the recorded ventilatory settings accurately reflect the conditions influencing the measured PCO₂.

Maternal characteristics recorded included a history of premature rupture of membranes (PROM) > 18 h, hypertensive disorders (chronic hypertension and pregnancy-induced hypertension), diabetes (gestational and pregestational), chorioamnionitis, and the use of antenatal steroids. Chorioamnionitis was defined clinically based on the presence of maternal fever (≥ 38.0 °C) along with one or more of the following criteria: uterine tenderness, maternal or fetal tachycardia, foul-smelling amniotic fluid, or purulent vaginal discharge, following the guidelines recommended by the American College of Obstetricians and Gynecologists [11]. PROM was defined as rupture of membranes persisting for more than 18 h before delivery. Additionally, antenatal steroid administration was reported for any administration of steroids, including both partial and full courses, with dexamethasone being the corticosteroid of choice at our center. Baseline demographics for each infant included gestational age, birth weight, gender, Apgar scores at 5 min, and mode of delivery. Additionally, the duration of ventilation to extubation and the occurrence of pulmonary air leaks were documented.

Statistical analysis

Data were collected directly from the ventilator every minute for the first 48 h of life, resulting in a total of 2,880 observations per patient. The distribution of continuous variables was assessed using the Shapiro-Wilk test for normality. As most data were found to be non-normally distributed, results are presented as medians with interquartile ranges (IQR). Categorical variables are presented as absolute numbers and percentages.

The Kruskal-Wallis test was used to compare non-normally distributed continuous variables across groups, such as the comparison of PaCO₂ levels (hypocarbia, normocarbia, and hypercarbia). Categorical variables were compared using the chi-square test. The Spearman’s rank correlation coefficient (Spearman’s rho) was used to evaluate correlations between key clinical and ventilatory variables, such as the relationships between measured tidal volume and DCO₂, or between amplitude and PCO₂, due to the non-parametric nature of the data. All statistical analyses were conducted using Stata software (version 17; StataCorp LLC, College Station, TX), with statistical significance set at p < 0.05.

Results

Table 1 Maternal and infant’s characteristics

Table 1 shows that the study population had a median gestational age of 26.5 weeks and birth weight of 830 g. Maternal risk factors included hypertension (23%), premature rupture of membranes (32%), and chorioamnionitis (14%). Antenatal steroids were given in 73% of cases. Most infants (64%) were delivered via cesarean section and all received surfactant. No mortality was reported (Table 1).

Table 2 Ventilatory and blood gas parameters in preterm infants ventilated with HFOV and volume guarantee

Table 2 presents key respiratory parameters measured in 22 extremely preterm infants ventilated on HFOV with VG. The median set amplitude was 27 [IQR 24,30], while the measured amplitude was 16 [IQR 14,20]. Both the set and measured tidal volumes (VThf) were 2.2 mL/kg [IQR 2,2.6]. The median raw DCO₂ was 38 mL²/s [IQR 27,69], and the weight-corrected DCO₂ was 55.5 mL/kg²/s [IQR 41,69.7]. The set frequency was 10 Hz [IQR 9,12], and the set mean airway pressure (MAP) was 12 cmH₂O [IQR 10,14]. (Table 2).

The scatter plot in Fig. 1 demonstrates a strong correlation between Set and Measured VThf with the regression line (y = 0.11 + 0.96x) indicating a near 1:1 relationship. The R² value (0.844) suggests that the majority of the variance in measured VThf is attributed to the set values, highlighting the consistency of VG in HFOV. Most data points cluster tightly along the regression line, indicating that the ventilator effectively maintains tidal volume delivery within the intended range. However, some variability is evident, particularly at lower and mid-range VThf values, where measured values deviate slightly from set values. (Fig. 1).

Fig. 1

Scatter plot pf set and measured VThf (ml/kg)

Figure 2 illustrates a comparison between set and measured VThf (ml/kg) for 22 infants ventilated on HFOV with VG over the first 48 h. The set VThf (ml/kg) (blue bars) generally ranges between 2 and 3 ml/kg for most infants. Overall, the measured VThf (ml/kg) aligns closely with the set VThf (ml/kg), indicating that the volume guarantee function was generally effective in maintaining the targeted VThf across the cohort (Fig. 2).

Fig. 2

Comparison of set and measured tidal volumes per kilogram across 22 infants ventilated on HFOV with VG Over the first 48 h

Table 3 Correlation of ventilatory parameters: DCO2, tidal volume, amplitude, and PCO2 in infants ventilated on HFOV with VG over the first 48 h

Table 3 presents correlations between various respiratory parameters. There was a strong, statistically significant positive correlation between weight-corrected DCO₂ and VThf (spearman rho = 0.8089, p < 0.0001), which aligns with the mathematical relationship between these variables. However, the strength of this correlation in a clinical setting reinforces the role of VThf in CO₂ elimination, supporting the use of weight-corrected DCO₂ as a reliable surrogate for ventilation efficiency in extremely preterm infants. There was also a statistically significant positive correlation between VThf and measured amplitude (spearman rho = 0.2217, p < 0.0001). The PCO₂ did not correlate with VThf (Spearman rho = 0.0304, p = 0.7049), raw DCO₂ (ml²/s) (Spearman rho = -0.0564, p = 0.4813) or weight-corrected DCO₂ (mL/kg²/s) (Spearman rho = 0.0560, p = 0.4845). The lack of correlation between PCO₂ and DCO₂ indicates that CO₂ elimination through the ventilator may not directly correspond to PCO₂ levels. Measured amplitude correlated positively with both weight-corrected DCO₂ (spearman rho = 0.6497, p < 0.0001) and raw DCO2 (spearman rho = 0.1364, p < 0.0001), suggesting that higher amplitude settings are associated with better CO₂ clearance. (Table 3).

Table 4 Comparison of HFOV/VG settings and PaCO₂ levels in 22 infants over 48 h

Table 4 provides a comparison of ventilatory parameters across three groups of infants ventilated on HFOV with VG categorized by their levels of PCO₂: hypocarbia (PCO₂ < 40mmHg) (n = 53), normocarbia (PCO₂ 40-55mmHg) (n = 55), and hypercarbia (PCO₂ > 55mmHg) (n = 55). The measured amplitude showed no significant difference between the groups (p = 0.97). The FiO₂ demonstrated a statistically significant increase, starting from a median of 40 [30–55] in the hypocarbia group to 45 [35–65] in the normocarbia group and reaching 50 [41–89] in the hypercarbia group (p < 0.01). The frequency also showed significant variation, with the normocarbia group having a higher median frequency of 10 [10, 11, 12, 13] Hz compared to 10 [8, 9, 10, 11] Hz in the hypocarbia group and 10 [9, 10, 11] Hz in the hypercarbia group (p < 0.01). The MAP had no statistically significant difference (p = 0.24). The VThf was also not significantly different between groups (p = 0.53). While the raw DCO₂ values did not show significant differences (p = 0.89), the weight-corrected DCO₂ was significantly different, with medians of 47 [39–66] in the hypocarbia group, 59 [48–70] in the normocarbia group, and 55 [42–80] in the hypercarbia group (p = 0.04) (Table 4).

Discussion

In this study, we retrospectively investigated 22 extremely preterm infants born at less than 28 weeks’ gestation. Our objective was to assess the stability of tidal volume delivery in infants ventilated on HFOV with VG over the first 48 h of life.

Our findings show that the set and measured VThf were highly consistent in both median values and interquartile range (IQR), indicating that the ventilator settings effectively achieved the desired VThf levels. Clinically, the set and measured VThf values were closely aligned, as demonstrated in our scatter plot analysis, confirming that VThf remained stable and within the target range. However, despite this strong correlation, some variation between set and measured VThf was observed. This variability is likely influenced by several factors. First, adjustments in amplitude occur stepwise rather than continuously. The ventilator modifies amplitude in discrete increments in response to deviations from the set VThf, which may result in transient mismatches between the set and measured tidal volume. Second, if the maximum allowable amplitude is set too low, the ventilator may not generate sufficient pressure to fully achieve the set VThf, particularly in cases of increased impedance or airway resistance. Third, the presence of an air leak around the endotracheal tube may lead to a loss of delivered volume, reducing the measured VThf despite automatic ventilator adjustments. These factors may explain the observed minor deviations while demonstrating the overall stability and reliability of VG in HFOV.

In our study, infants were ventilated at a median frequency of 10 Hz, with a set amplitude range of 25–30, while the measured amplitude consistently ranged between 14 and 20. There is evidence from previous studies that the increase in amplitude required to maintain a stable VThf, measured at the airway opening, becomes progressively dampened as it moves through the airways to the alveoli. This attenuation effect is especially pronounced at higher oscillatory frequencies, where the pressure gradually reduces, reaching its lowest point at the system’s resonant frequency, as shown in multiple studies [9, 12, 13]. The ideal frequency is influenced by the lung’s condition; higher frequencies are particularly beneficial for lung diseases with low compliance and short time constants, such as respiratory distress syndrome (RDS) in preterm infants [10, 13]. There is evidence from animal studies that employing very high frequencies (20 Hz) with a reduced VThf significantly decreased histological lung injury when compared to conventional mechanical ventilation (CMV) and HFOV at more typical frequencies (10 Hz) [13, 14]. Recently, Zannin et al. showed that in preterm infants, increasing the oscillatory frequency while adjusting amplitudes to sustain a stable DCO₂ resulted in VThf values that were consistently lower [15].

In this study we have also examined the correlations between DCO₂, VThf, amplitude, and PCO₂. Our findings showed a strong correlation between weight-corrected DCO₂ and VThf, which aligns with the mathematical relationship between these variables. However, the strength of this correlation in a clinical setting reinforces the role of VThf in CO₂ elimination, supporting the use of weight-corrected DCO₂ as a reliable surrogate for ventilation efficiency in extremely preterm infants. The lack of correlation between DCO₂ and PCO₂ in our study suggests that while DCO₂ is a useful marker of ventilation efficiency, it may not fully predict gas exchange adequacy as reflected in blood gas parameters. This discrepancy can be attributed to several factors, including individual variability in lung compliance, dead space ventilation, and pulmonary perfusion, all of which influence the relationship between ventilation and arterial PCO₂. Additionally, metabolic factors such as CO₂ production and perfusion status may impact PCO₂ levels independently of ventilation settings. The timing of blood gas measurements, which provide intermittent assessments, compared to the continuous monitoring of DCO₂, could also contribute to the weak correlation observed. Moreover, ventilator settings are often adjusted based on blood gas results rather than DCO₂ trends alone, further influencing the relationship. These results imply that in clinical practice, reliance on DCO₂ alone might not suffice, and a more individualized approach—potentially incorporating frequent blood gas assessments and real-time ventilator monitoring—may improve outcomes for extremely preterm infants during the critical early phase of respiratory support.

In comparing the infants based on their PCO₂ levels (hypocarbia, normocarbia, and hypercarbia), we found that infants with hypercarbia required significantly higher FiO₂ levels, possibly reflecting compromised gas exchange in hypercarbic states. Frequency settings also differed across the PCO₂ groups, implying that adjusting oscillatory frequency may help in managing CO₂ levels. Additionally, weight-corrected DCO₂ differed significantly across groups, underscoring its value as an indicator of ventilation efficacy in relation to PCO₂ levels. The lower weight-corrected DCO₂ observed in hypocapnic infants may be explained by several factors. Hypocapnia in preterm infants often results from an increased minute ventilation relative to metabolic CO₂ production rather than enhanced ventilatory efficiency. While DCO₂ is a recognized marker of CO₂ elimination in HFOV, it is influenced by both tidal volume and frequency. In hypocapnic states, clinicians may have reduced ventilatory support, particularly by lowering the frequency, leading to a paradoxical reduction in DCO₂ despite lower PCO₂ levels. Additionally, hypocapnic infants might have better lung compliance, allowing for more effective CO₂ elimination at lower ventilatory pressures, thereby requiring less DCO₂ to maintain normocapnia. Another potential explanation is that the relationship between DCO₂ and PCO₂ is not entirely linear, as other factors such as changes in metabolic demand, fluctuations in cardiac output, and alterations in pulmonary perfusion can influence CO₂ clearance. Consequently, in some cases, a lower DCO₂ may still be sufficient to achieve hypocapnia, reinforcing the need for individualized ventilatory adjustments rather than relying solely on DCO₂ as a surrogate for gas exchange adequacy. Interestingly, MAP and tidal volume remained relatively constant across all PCO₂ groups, indicating that these parameters might not require significant adjustments based solely on PCO₂ levels. This could reflect the inherent stability of certain ventilatory settings even as gas exchange requirements change.

In a retrospective study of 53 preterm infants less than 32 weeks’ gestation with severe RDS, researchers evaluated VThf and DCO₂ required to achieve normocapnia during HFOV-VG. The study reported that a VThf of around 1.64 mL/kg was necessary to maintain normocapnia across the cohort. No significant correlation was observed between PCO₂ levels and either VThf or DCO₂corr, though VThf was slightly lower at a frequency of 12 Hz compared to 10 Hz [16]. Compared to our findings, which involved 22 extremely preterm infants under 28 weeks’ gestation, we have also found no correlation between VThf, DCO₂ and PCO₂. Of note that VThf in our study was larger at 2.2 ml/kg. Both studies reinforce the recommendation for individualized HFOV-VG settings to meet patient-specific needs, particularly through continuous PCO₂ monitoring and frequent setting adjustments.

In another prospective, randomized crossover study, researchers compared HFOV with VG to HFOV alone in 20 preterm infants under 32 weeks’ gestation with RDS. Their results indicated that HFOV with VG produced higher VThf and DCO₂ compared to HFOV alone. Additionally, the VG feature allowed for more consistent VThf maintenance within the target range and led to fewer instances of hypo- and hypercarbia compared to HFOV alone. The authors noted that, despite these findings, the study’s small sample size and crossover design limit broader conclusions [7]. Our study differs in its focus and scope, evaluating 22 extremely preterm infants under 28 weeks’ gestation ventilated solely on HFOV with VG over a continuous 48-hour period. Similar to the crossover study, we observed that VG helps stabilize tidal volumes, though our extended tracking allowed for insights into dynamic respiratory parameters across a larger set of minute-by-minute data points.

In another retrospective study, investigators analyzed the performance of HFOV-VG in 17 infants. They collected approximately 3.2 million seconds of ventilator data, evaluating the stability of the VThf and its effect on ventilation parameters and blood gas measurements. The study found a median VThf of 1.93 mL/kg, with the delivered VThf closely matching the set target within 0.2 mL/kg for 83% of the time. Though there were moment-to-moment fluctuations in VThf, it aligned well with the target value when averaged over 5-minute intervals. A weak inverse correlation was observed between weight-corrected DCO₂ and PaCO₂, while uncorrected values showed no correlation [10]. Our findings align with this study in that HFOV-VG maintained VThf close to target settings. In our study, we did not observe a correlation between PCO2 and both raw and weight-corrected DCO2 contrary to this study. Both studies underscore HFOV-VG’s efficacy in providing consistent tidal volume but also highlight the need for individualized settings for optimal respiratory support in neonates.

Building on the findings of previous studies, this study expands our understanding of HFOV-VG by evaluating VThf stability and its relationship with key respiratory parameters over the first 48 h in extremely preterm infants. While prior research has assessed VThf and DCO₂ in relation to normocapnia or ventilation stability, our study provides a continuous minute-by-minute analysis, offering a more detailed perspective on VThf fluctuations. Additionally, while some studies reported correlations between DCO₂ and PCO₂, we did not observe a significant relationship between PCO₂ and both raw and weight-corrected DCO₂, suggesting that DCO₂ alone may not fully capture ventilation efficiency. Our findings also emphasize variations in ventilatory settings across different PCO₂ levels, particularly in frequency adjustments and FiO₂ requirements. By continuously assessing HFOV-VG performance in extremely preterm infants under 28 weeks’ gestation, this study provides meaningful data to refine respiratory management strategies in this high-risk population.

The study has some strengths and limitations. A key strength is the continuous monitoring of ventilatory parameters every minute over the first 48 h. This detailed dataset allowed us to assess the stability of tidal volume highlighting the capability of HFOV with VG to provide consistent respiratory support in this high-risk group. Additionally, the exclusive focus on infants born at less than 28 weeks’ gestation ensures that the findings are particularly relevant for those at the highest risk of respiratory complications.

The study’s limitations include a relatively small sample size of 22 infants, which may affect the generalizability of the results. Moreover, being a single-center study, the findings may not fully apply to other NICU settings with different equipment or ventilation protocols. Another limitation of this study is the lack of data on endotracheal tube (ETT) leak, which may have influenced the accuracy of volume-targeting. Future studies incorporating continuous monitoring of ETT leak would be valuable in evaluating its effect on volume-targeted high-frequency ventilation and ensuring more precise delivery of set tidal volumes in extremely preterm infants. Lastly, the lack of a control group ventilated without VG limits the ability to make direct comparisons, which could have added further depth to the conclusions. Noteworthy, we acknowledge that the findings of our study are specific to the VN600 ventilator and apply primarily to preterm infants with RDS, a condition characterized by relatively homogeneous lung disease.

Conclusions

In conclusion, this study provides valuable insights into the performance of HFOV-VG in extremely preterm infants, emphasizing its effectiveness in maintaining stable tidal volumes and consistent respiratory support over the first 48 h of life. Our findings showed significant correlations between weight-corrected DCO₂ and tidal volume, indicating that weight-adjusted DCO₂ may serve as a useful indicator of ventilation efficiency in this population. Additionally, the lack of a strong correlation between DCO₂ and PaCO₂ suggests that multiple parameters should be considered when optimizing respiratory support. Overall, HFOV-VG appears to be a promising lung-protective ventilation strategy, with the potential for improved outcomes through individualized monitoring and tailored adjustments based on real-time data. Further multi-center studies with larger sample sizes are needed to validate these findings.