High-frequency oscillatory ventilation (HFOV) can be used as either a primary (failing noninvasive ventilation [NIV]) or rescue (failing conventional mechanical ventilation [CMV]) ventilation mode in neonates [1]. Physiologically, HFOV has been considered a lung-protective ventilation method that minimizes ventilator-induced lung injury due to the very small delivery tidal volumes (less than the anatomical dead space) [1]. During HFOV, oxygenation is controlled by the mean airway pressure (MAP) and fraction of inspired oxygen (FiO₂), while ventilation is controlled by the oscillatory pressure amplitude (delta pressure, dP) and frequency. The inspiratory-to-expiratory ratio (I:E) affects both oxygenation and ventilation. According to one prior meta-analysis, the application of elective HFOV results in a small reduction in the risk of bronchopulmonary dysplasia (BPD), death, and severe retinopathy of prematurity compared with CMV; however, these effects have been inconsistent across trials [2].

Spontaneous periodic sigh breaths, deep and interspersed breaths of larger tidal volumes than the preceding or following breaths, occur more frequently in newborns than in adults [3]. Sigh breaths in preterm and term infants are much larger than those in adults [4]. These large augmented breaths in infants are often followed by apnea and hypoventilation, likely occurring secondary to the increased activity of peripheral chemoreceptors in neonates [4]. Sigh frequency in preterm infants increases with the degree of prematurity at birth and the severity of BPD [5]. Sigh breaths more commonly precede periodic epochs during non-rapid eye movement (59%) compared to rapid eye movement (18%) during sleep (P<0.005) [6]. Spontaneous sigh breaths may augment functional residual capacity, increase lung compliance, and recruit atelectatic alveoli [3,7]. In animal studies, sigh increases the release of active surfactants [8], and transiently decreases the partial pressure of carbon dioxide (PaCO₂) [9].

In mechanical ventilation with spontaneous breathing, automated sustained inflations or sigh breaths (Sighs) are brief cyclic recruitment maneuvers. In intubated adults with acute hypoxemic respiratory failure or acute respiratory distress syndrome (RDS) undergoing pressure support ventilation (PSV), a randomized clinical trial (RCT) have shown that Sighs may improve lung function by improving the PaO₂/FiO₂ (P/F) ratio [10], while non-RCTs have shown that Sighs function by decreasing regional heterogeneity [11], improving gas exchange and lung volume, and decreasing respiratory drive [12]. A recent multicenter RCT among traumatic adults with Sighs showed increased ventilator-free days (VFDs; 18.4 days vs. 16.1 days) and reduced 28-day mortality rate (11.6% vs. 17.6%) in patients with Sighs compared to those without, with no differences in nonfatal adverse events [13].

In one before-after study, 19 children undergoing PSV after a major surgery received PSV alone or with Sighs. The Sighs group showed an improved P/F ratio (394.2±127.0 vs. 312.6±137.4, P<0.01) and indexed to body weight compliance (1.01±0.30 mL/kg/cmH₂O vs. 0.85±0.35 mL/kg/cmH₂O, P<0.01), and a decreased PaCO₂ level (34.3±4.6 mmHg vs. 39.3±3.3 mmHg, P<0.001) from baseline [14].

In a neonatal non-RCT, 30 infants with very low birth weight (VLBW) were divided into 2 NIV groups (continuous positive airway pressure [CPAP] and high-flow nasal cannula therapy). This study found that spontaneously occurring Sighs on noninvasive respiratory support due to RDS do not increase end-expiratory lung impedance, or alter the delta Z [15]. However, data regarding neonatal respiratory outcomes in the invasive mode, particularly in the primary HFOV mode, are still lacking. Although the HFOV may reduce ventilator-induced lung injury and improve gas exchange, it does not induce neonatal breathing. Thus, Sighs may improve ventilation, avoid atelectasis, and facilitate the transition into neonatal breathing.

This study aimed to evaluate the differences in PaCO₂ levels before and after Sighs during invasive HFOV in preterm and term neonates.

Ninety-four infants were assessed for eligibility; of these, 64 were excluded because of previous or current pulmonary air leaks (n=3), heterogeneous lung diseases (n=7), suspected or confirmed grade III–IV intraventricular hemorrhage (n=1), hemodynamic instability despite using an inotrope (n=15), PaCO₂ level<45 mmHg or >70 mmHg before the intervention (n=30), moribund status (n=7), and parents’ decision not to participate (n=1). Thirty participants (neonates) were finally enrolled.

The mean GA and birth weight (BW) were 33.6±4.1 weeks and 2,305±853 g, respectively. The numbers of neonates with GA at 24–31, 32–36, and 37–41 weeks were 9 (30%), 13 (43%), and 8 (27%), respectively. The median (IQR) 1-minute and 5-minute Apgar scores were 7 (5, 8) and 9 (8, 9), respectively. The numbers of neonates who were male, appropriate for GA, and delivered by cesarean section were 17 (57%), 30 (100%), and 23 (77%), respectively. The causes for intubation included RDS in 15 (50%), severe TTN in 11 (37%), congenital heart disease in 3 (10%), and mild to moderate birth asphyxia in 1 (3%).

The median date of intervention was at 1.88 (IQR, 0.87–3.79; range, 0.20–9.55) days of life. The mean body weight and oxygen index were 2,330±880 g and 3.45±1.37, respectively. Before Sighs, the HFOV was set using the following parameters: (1) frequencies of 10 and 12 Hz in 21 and 9 neonates, respectively; (2) MAP values of 7, 8, 9, 10, and 13 cmH₂O in 5, 12, 8, 4, and 1 neonates, respectively; (3) mean dP and FiO₂ of 21.3±5.9 cmH₂O and 0.31±0.08, respectively; and (4) I:E = 1:1. Sighs pressure and frequency were above 5 cmH₂O of MAP and 3 breaths/min, respectively.

Arterial blood gas levels are shown in Table 1. The mean PaCO₂ levels after Sighs during HFOV was found to be significantly decreased compared to HFOV alone (45.2±6.6 mmHg vs. 48.8±3.1 mmHg; mean difference [MD] -3.6±7.3 mmHg; 95% confidence interval [CI], -6.3 to -0.9; P=0.01). Individual PaCO₂ levels before and after Sighs are shown in Fig. 1. Overall, 70% (21 of 30) of neonates achieved decreased PaCO₂ levels after Sighs. In HFOV with Sighs, the range of PaCO₂ levels was 31.9–56.9 mmHg, and PaCO₂<35 mmHg was found in 3 neonates. In the subgroup analysis, the mean PaCO₂ levels after Sighs during HFOV was significantly decreased compared to HFOV alone in neonatal RDS (n=15; 44.8±6.2 mmHg vs. 49.0±3.4 mmHg; MD, -4.2 mmHg; 95% CI, -8.2 to -0.2; P=0.04). No differences were found in pH and PaO₂ (regarding GA and indication of intubation in Table 1), including gas transport coefficient, minute volume, and oxygen index, before and after Sighs during HFOV (Table 2).

During the Sighs intervention, no participants withdrew (for example, due to developing air leak syndrome, changes in the HFOV setting, or the need for a new or increased dose of inotrope). After the intervention, no participants developed air leak syndrome. All patients survived until discharge.

Neonates and premature infants have immature respiratory and central nervous systems, meaning that some require ventilatory support. Based on the concept of neonatal ventilation, gentle invasive ventilation, aggressive extubation, and full NIV support have been implicated in these neonates. However, the exact benefits and disadvantages of CMV and HFOV remain unclear. One prior meta-analysis showed that elective HFOV use resulted in lower BPD and severe retinopathy of prematurity rates than CMV [2]. A small tidal volume from the HFOV may reduce both baro- and volutrauma; however, a knowledge gap exists between the optimal MAP and dP for each GA and BW. Fetal breathing involves a very small diaphragmatic movement, whereas neonatal breathing requires a large movement that is similar to CMV.

Sighs application during HFOV may generate transitional ventilation from a small to large tidal volumes (but at a lower rate than CMV), and has a benefit in recruitable lung diseases and the release of active surfactants [8], particularly RDS. In the present study, Sighs (frequency=3 breaths/min in 2 hours) was found to decrease PaCO₂ levels in the overall GA and RDS groups. In the subgroup analysis, the lower GA group showed a higher CO₂ clearance; however, MDs were insignificant. Therefore, Sighs may be a choice for reducing PaCO₂ levels during HFOV and RDS within a short duration of intervention.

Studies investigating Sighs plus invasive ventilation only in the PSV mode in adults and children, and NIV in neonates are limited. Previous studies have shown that, during the invasive PSV mode, Sighs increased the P/F ratio (in adults with acute RDS [10] and children after major surgery [14,20]), tidal volume (in children [20]), gas exchange and lung volume [12] and VFDs (in adults [13]). Moreover, Sighs have been shown to decrease the PaCO₂ level [14] and oxygen index [20] in children, as well as the regional heterogeneity [11], respiratory drive [12], and mortality rate [13] in adults. In contrast to one study of VLBW neonates with RDS, Sighs on NIV support were found not to increase end-expiratory lung impedance or alter delta Z [15].

This was a pioneering study of ventilator-generated Sighs application during HFOV in both term and preterm neonates. Two active, as yet unpublished, studies from the same principal investigator that compared HFOV-Sighs and HFOV alone were identified in the ClinicalTrial. gov registry (effects on blood oxygenation [17] and lung volume [18]). Currently, early- or primary-mode HFOV use and extubation from HFOV are increasingly used in clinical practice. Sighs may be considered in ventilated neonates who have hypercarbia or are prepared before extubation to familiarize themselves with big breaths and succeed in extubation.

However, this study had some limitations. First, the duration of the intervention was only 2 hours to ensure the safety of fragile participants. For the next step, Sighs are considered to require extubation (a longer period for more information on benefits and safety), and investigation in an RCT. Second, the sigh setting is still inclusive, particularly during the neonatal period. Further studies are required to enroll more participants (increase the power) to determine the optimal Sighs setting in each subgroup population (different GA and BW). Third, most modern (hybrid) ventilators provide the option for simultaneous delivery of CMV and HFOV, thus enabling the application of periodic Sighs during HFOV, which may assist in lung volume recruitment. However, Sighs mode is available in only a few special ventilator brands. Fourth, no severe complications, such as air leak syndrome, respiratory deterioration, or hemodynamic instability, were observed in any patients treated with HFOV plus Sighs. Three neonates had low PaCO₂ levels (30–35 mmHg); therefore, its application should be cautioned and closely monitored. Fifth, overall Sighs in HFOV reduced the PaCO₂ level (70%, 21 of 30); however, respiratory monitoring (gas transport coefficient, minute volume, and P/F ratio in Table 2) did not significantly change after Sighs. As such, it is possible that the difference was only insignificant because the sample size was too small to detect the difference. Similar to Sighs during NIV, end-expiratory lung impedance or altered delta Z did not significantly change after Sighs use [15]. Finally, the wide variation in CO₂ levels may have occurred due to the small sample size, wide range of GA (24 to 40 weeks), or underlying disease, and were not interrupted during study period.

In conclusion, the present study showed that HFOV integrating Sighs functionality can reduce PaCO₂ levels, particularly in patients with recruitable lung disease, such as RDS. However, further studies are required to conclusively determine the effect of Sighs (recruitment maneuvers in general), to better understand their limits, mechanisms, and indications in individual patients, and to determine the optimal Sighs for different BW and lung pathologies.