High Frequency Oscillatory Ventilation Combined With Intermittent Sigh Breaths in Neonate: Effect on Carbon Dioxide Level
Phase: NA
Conditions: High-Frequency Ventilation
Sponsor: Prince of Songkla University

Effective date: 29 Jan 2021  
NCT05682937 28/Dec/2022 
AP-001 
Protocol version 03, 28/Dec/2022 
หน้า 1 จาก 14 หน้า 
PROTOCOL 
 
TITLE 
High Frequency Oscillatory Ventilation Combined with 
Intermittent Sigh Breaths in Neonate: Effect on Carbon Dioxide 
Level 
NCT number 
NCT05682937 
Principal 
Investigator 
Mr. Anucha Thatrimontrichai 
Co-investigator 
Ms Kulthida Baingam 
 
Ms. Waricha Janjindamai 
 
Ms. Supaporn Dissaneevate 
 
Ms. Gunlawadee Maneenil 
 
Ms. Manapat Praditaukrit 
All investigator  
Division of Neonatology, Department of Pediatrics, Faculty of 
Medicine, Prince of Songkla University, Songkhla, Thailand 
Keywords 
Carbon Dioxide, High-Frequency Ventilation, Sigh Breath, 
Newborn 
 
 

Effective date: 29 Jan 2021  
NCT05682937 28/Dec/2022 
AP-001 
Protocol version 03, 28/Dec/2022 
หน้า 2 จาก 14 หน้า 
Background and rationale 
 
Pulmonary disease continues to be the major cause of morbidity and mortality in very preterm 
infants.(1) Neonatal intensive care units (NICU) across the world have successfully used conventional 
ventilation (CV), high-frequency oscillatory ventilation (HFOV), and high-frequency jet ventilation (which is 
currently not available in Thailand) to manage respiratory failure in newborn.(2) Non-synchronized CV, the 
earliest mode of ventilation used in neonates, was designed to emulate tidal respirations typical of 
newborns.(3) Synchronized ventilation improves gas exchange; increases patient comfort with decreased need 
for sedation and muscle relaxation; reduces airway pressures; decreases work of breathing, risk of 
barotrauma and volutrauma; and provides faster weaning from mechanical ventilation.(4) 
 
In order to avoid distortion of the lung caused by the large swings in pulmonary pressures during CV 
at rates of 30 to 80 breaths per minute, HFOV at rates of 600 to 800 breaths per minute with very small tidal 
volume (TV) was developed (Figure 1). HFOV allows for low TV, and minimizing volutrauma and shear force 
injury by using of TVs that are smaller than physiologic dead space (<3 mL/kg) that oscillate around a set 
mean airway pressure (MAP) at rates ranging from 300 to 900 breaths per minute (5–15 Hz).(4) Gas 
exchange occurs from multiple processes, including Taylor dispersion, molecular diffusion, regional variation 
in turbulent and laminar flow, and pendelluft movement of air. Exhalation on HFOV is active, in contrast to 
the passive exhalation seen with high-frequency jet ventilation, and adjustments in amplitude, frequency, and 
MAP can modulate infant oxygenation and ventilation.(4)  
 
 
 
Fig. 1 Schematic representation of the purported waveforms of HFOV and conventional pressure-controlled 
ventilation in the distal airways. The large pressure swings present in the proximal circuit during HFOV 
(perhaps up to twice the mean airway pressure, depending on the set ΔP) are significantly attenuated in the 
distal airways. The degree of attenuation is dependent on frequency, ETT size, and inspiratory/expiratory 
time ratio. 
 

Effective date: 29 Jan 2021  
NCT05682937 28/Dec/2022 
AP-001 
Protocol version 03, 28/Dec/2022 
หน้า 3 จาก 14 หน้า 
 
Fig. 2 Results from meta-analysis compared clinical outcomes between elective high-frequency oscillatory 
ventilation (HFOV) versus conventional ventilation (CV) 
 
 
Recent a meta-analysis in 2015, 19 eligible studies involving 4096 preterm infants were included in 
Figure 2. Meta-analysis comparing elective HFOV with CV, bronchopulmonary dysplasia (BPD) and severe 
retinopathy of prematurity in survivors at term equivalent gestational age or discharge was significantly 
reduced with the use of HFOV. There was no evidence of effect on mortality at 28 to 30 days of age or at 
approximately term equivalent age. Pulmonary air leaks, defined as gross air leaks or pulmonary interstitial 
emphysema, occurred more frequently in the HFOV group but no difference in only gross air leaks. However, 
pulmonary air leaks were not different between HFOV and CV when subgroup analyses by age at 
randomization, routine surfactant use or not, type of high frequency ventilator (oscillator versus flow 
interrupter), inspiratory to expiratory (I:E) ratio of high frequency ventilator (1:1 versus 1:2) and CV strategy 
(lung protective or not).(1)  
 
 

Effective date: 29 Jan 2021  
NCT05682937 28/Dec/2022 
AP-001 
Protocol version 03, 28/Dec/2022 
หน้า 4 จาก 14 หน้า 
 
Previous physiologic studies in non-intubation, Sighs are spontaneous deep inspirations 
characterized in infants by a biphasic pattern with an inspiratory reinforcement occurring at the end of an 
inspiration (‘breath on the top of a breath’). Sighs were more frequent in preterm than in term infants and 
more so during Rapid eye movement (REM) sleep than non-REM sleep.(5) Sighs in the preterm infant without 
lung disease were similar frequency in normal full-term infants (1.5 sighs per 10 minutes).(6, 7) Therefore, sigh 
frequency in preterm infants increased with the degree of prematurity at birth and severity of BPD.(6) Sigh 
breaths were much more frequent in infants than in adults.(8)  
 
3A  
 
3B 
 
Fig. 3 True oscillation generated by the HFO option is sinusoidal; expiration is supported by active expiration 
to prevent air trapping. The result is smooth, precise, and gentle oscillation (3A). HFO-Sigh helps avoid 
atelectasis and can be triggered at preset intervals or performed manually as required, following suctioning 
maneuvers for example (3B). 
 
Previous physiologic studies in intubated adults, sigh may improve lung function through improved 
lung elastance (increased gas exchange and lung volume, and decreased the respiratory drive)(9) and 
enhance regional lung protection (decreased regional lung strain and intra-tidal ventilation heterogeneity).(10) 
In an animal study, large inflations or sighs increased release of active surfactant.(11) 
 
 
In intubated animal study, rat took a spontaneously deep (sigh) breath which resulted in a rapid fall 
of pCO2 (from 30 to 26 mm Hg).(12) In intubated pediatric patients after major surgery, arterial pCO2 

Effective date: 29 Jan 2021  
NCT05682937 28/Dec/2022 
AP-001 
Protocol version 03, 28/Dec/2022 
หน้า 5 จาก 14 หน้า 
decreased from pressure support ventilation (PSV, 39.3 ± 3.3 mm Hg) to “PSV + sigh” group (34.3 ± 4.6 mm 
Hg; p <0.001)(13) while arterial pCO2 was not significantly different in neonatal patients (PSV vs. PSV + sigh, 
mean ± SD 42.3 ± 3.7 vs 40.4 ± 5)(14) and adult patients (PSV vs. PSV + sigh, median [interquartile ranges] 
44 [38, 49] vs. 43 [39, 47] mm Hg, p = 0.70).(15)  
 
 
Besides pCO2 level, sigh breaths improved oxygenation and lung mechanics in neonate. In 
crossover randomized controlled trial (RCT) from 11 neonates (median age 11.5 [8.7–74] days) after cardiac 
surgery, PSV + sigh mode significantly increased PaO2/FiO2, inspiratory time and tidal volumes, and 
decreased oxygenation index and respiratory rate compared to PS mode.(14) In 48 healthy preterm infants 
(weight at study 2,042 ± 316 g and postconceptional age 36.6 ± 2.0 weeks), mean ± SD. functional residual 
capacity (FRC) after sigh breaths, after apneic pauses, and neither a sigh nor an apneic pause was found 
26.0 ± 6.9, 20.0 ± 6.8, and 24.0 ± 7.7 mL/kg, respectively, FRC after sigh breaths and neither a sigh nor an 
apneic pause was significantly higher than after apneic pauses.(16)   
Knowledge gap  
Due to the lack of data and complexity of ventilator management trials, a clear consensus for the 
optimum mode of initial mechanical ventilation for neonate does not exist. The ventilation strategies used for 
this population vary significantly. However, HFOV is increase used as an initial ventilatory strategy especially 
in preterm infants including our center. Study in HFOV combined with intermittent sigh breaths in neonate is 
limited especially on arterial carbon dioxide level. 
There were only two active but not recruiting studies which compared between HFOV with 
intermittent sigh breaths (HFOV-sigh) and HFOV in ClinicalTrial.gov 
(https://clinicaltrials.gov/ct2/results?cond=High+frequency+oscillatory+ventilation+with+intermittent+sigh+breath
s+&term=&cntry=&state=&city=&dist=, Figure 4)(17, 18) Both registered trials focus on preterm neonates 
(gestational age 24–36 weeks), sigh PIP 30 cm H2O for 1 hour, and measured lung mechanics (electric 
tomography impedance) and blood oxygenation.(17, 18) While this study fulfils this intervention by enrolled 
preterm and term infants (gestational age 24–41 weeks), lower sigh PIP (MAP+5, maximum sigh PIP 30 cm 
H2O; usually MAP in HFOV 8–25 cm H2O) for 2 hours, and focus on blood ventilation.  
 
Fig. 4 Studies registered in ClinicalTrial.gov which compared “High frequency oscillatory ventilation with 
intermittent sigh breaths (HFOV-sigh)” with “High frequency oscillatory ventilation (HFOV)” 

Effective date: 29 Jan 2021  
NCT05682937 28/Dec/2022 
AP-001 
Protocol version 03, 28/Dec/2022 
หน้า 6 จาก 14 หน้า 
Objectives 
Comparing the pCO2 level after 2 hours of HFOV-sigh mode (after intervention) compared with HFOV mode 
(before intervention) 
 
Conceptual framework 
 
Fig. 5 Factors affect arterial pCO2 level in ventilated neonates  
(HFOV = High frequency oscillatory ventilation; PIP = Peak inspiratory pressure; RR = Respiratory Rate; Ti = 
inspiratory time) 
 
pCO2
Ventilator 
setting
Invasive
Conventional
HFOV
HFOV-only
HFOV-volume 
guarantee
HFOV-sigh
Sigh PIP
Sigh RR
Sigh Ti
Non-invasive
Sedation
Secretion 
Underlying 
lung disease

Effective date: 29 Jan 2021  
NCT05682937 28/Dec/2022 
AP-001 
Protocol version 03, 28/Dec/2022 
หน้า 7 จาก 14 หน้า 
Literature review 
 
 
High-frequency oscillatory ventilation (HFOV) is a type of ventilator that can reduce barotrauma, 
achieve adequate alveolar ventilation with small tidal volumes. In recent years, HFOV versus conventional 
ventilation for acute pulmonary dysfunction in preterm infants had has been highly debated issue about 
effectiveness in many systemic reviews, meta-analyses, and randomized controlled trials.(1, 19, 20) From meta-
analysis, It revealed HFOV could reduce chronic lung disease or death rather than conventional ventilation.(1) 
 
 
Sighs are spontaneous deep inspirations characterized in infants by a biphasic pattern with an 
inspiratory reinforcement occurring at the end of an inspiration (‘breath on the top of a breath’). Sighs were 
more frequent in preterm than in term infants and more so during Rapid eye movement (REM) sleep than 
non-REM sleep.(5) Sighs in the preterm infant without lung disease were similar frequency in normal full-term 
infants (1.5 sighs per 10 minutes).(6, 7) Therefore, sigh frequency in preterm infants increased with the degree 
of prematurity at birth and severity of bronchopulmonary dysplasia.(6) Sigh breaths were much more frequent 
in infants than in adults.(8)  
 
Previous physiologic studies in intubated adults, sigh may improve lung function through improved 
lung elastance (increased gas exchange and lung volume, and decreased the respiratory drive)(9) and 
enhance regional lung protection (decreased regional lung strain and intratidal ventilation heterogeneity).(10) In 
an animal study, large inflations or sighs increased release of active surfactant.(11) 
 
Sigh breaths may improve CO2 clearance,(13) oxygenation and lung mechanics(14, 16) in neonate. 
Currently, only 4 studies in HFOV-sigh mode were conducted. The first and second studies were registered 
in Clinical trial.gov.(17, 18) Preterm (gestational age 24–36 weeks) neonates were enrolled to crossover RCT 
between HFV and HFV-sigh groups to compare oxygenation and lung volume in both periods. The sigh peak 
inspiratory pressure (PIP) was set at 30 cm H2O. Both trials have still been active studies and outcome data 
not reported in the clinicaltrial.gov. The third study in Japan was a practical advice in preterm (especially for 
infants born at less than 28-week gestation). They applied sigh breaths (2-3 times per minute, 0.7-1.0 
seconds in duration) with sigh PIP at 5 cm H2O above the current mean airway pressure (MAP).(21) The final 
study compared HFJV with or without sigh breath in neonate with respiratory distress syndrome (RDS) and 
meconium aspiration syndrome (MAS).(22) 
 
 
We hypothesized that sigh breaths augment restoring lung volume and ventilation in intubated 
neonate with HFOV. In neonatal studies, the results from HFOV combined with intermittent sigh breaths have 
never reported (active 2 studies and review 1 study).(17, 18, 21) This study, therefore, was designed to examine 
the short-term effects of sigh breaths during HFOV in neonate undergoing mechanical ventilation.  

Effective date: 29 Jan 2021  
NCT05682937 28/Dec/2022 
AP-001 
Protocol version 03, 28/Dec/2022 
หน้า 8 จาก 14 หน้า 
Methods 
Study design: before-after interventional, non-randomized trial, study  
Study setting: Neonatal Intensive Care Unit (NICU), Songklanagarind Hospital 
Target population: NICU admitted neonate 
Study population: Intubated neonate 
Inclusion criteria: 
• Preterm and term neonate (gestational age 24-41 weeks) with postnatal age less than 28 days 
• Already ventilated with high frequency ventilation at least 1 hours  
• An umbilical or peripheral arterial catheterization was available 
Exclusion criteria 
• Previous or current pulmonary air leaks (pulmonary interstitial emphysema, pneumothorax, 
pneumomediastinum, and pneumopericardium)  
• Heterogeneous lung disease including MAS, congenital diaphragmatic hernia 
• Suspected lung hypoplasia  
• Suspected or confirmed intraventricular hemorrhage grade III-IV  
• Suspected or confirmed hypoxic ischemic encephalopathy or 5-min Apgar score less than 3 
• Hemodynamic instability despite using inotrope(s) 
• Arterial pCO2 level less than 45 mm Hg or more than 70 mm Hg before intervention 
• Need a new arterial puncture for samples both before and after interventions  
• Moribund status 
• Parents’ decision not to participate 
Subject withdrawal criteria 
• Develop air leak syndrome during intervention 
• Worsening respiratory distress with increasing HFO setting (changed Hz, MAP, delta pressure, 
increased FiO2 more than 0.1, and need to suction or positive pressure ventilation via self-inflating 
bag or T-piece resuscitation) during study 
• Hemodynamic instability and need to increase dose or add new inotrope during intervention 
• Parents’ decision not to participate during study 
Study termination criteria 
• During or after intervention within 24 hours, more than 5 neonates will develop new pulmonary air 
leaks (10% of 50 participants; because pulmonary air leaks occurred in HFOV 27.7% [392/1,415] 
in meta-analysis(1) so we use 10% of sample size calculation to terminate study for safety). 
• The second sample after add sigh breath, more than 10 neonates have pCO2 <35 mm Hg 
neonates (20% of 50 participants).  
Sample size calculation   
 
Primary outcome: Compare arterial pCO2 level between HFOV (before) and HFOV-sigh (after)  

Effective date: 29 Jan 2021  
NCT05682937 28/Dec/2022 
AP-001 
Protocol version 03, 28/Dec/2022 
หน้า 9 จาก 14 หน้า 
• No previous study was compared the pCO2 level between neonates who were on HFOV mode 
and HFOV + sigh mode.  
• From Bonacina 2019,(14) neonates who were on invasive PSV and PSV + sigh mode. The pCO2 
levels in PSV and PSV + sigh were 42.3 ± 3.7 mm Hg and 40.4 ± 5.0 mm Hg (Delta = 1.9 mm 
Hg, SD. = 4.35), respectively.   
 
• Study design was before and after intervention. The dependent outcome was pCO2 level 
(continuous variable) In two dependent mean data, the calculated sample size was 42 neonates 
(alpha = 0.05, beta = 0.2, Delta = 1.9, SD. = 4.35), then increase 20% (if possible) for increased 
power. Finally, the targeted sample size was 50 neonates. We plan to recruit for one year, then 
preliminary analysis will do. If the result was significant differences, the study may be considered 
to terminate. 
Operational definition 
• Dependent variable = Arterial pCO2 level 
• Independent variables = Sigh breaths  
Procedure 
• Neonates who were ventilated with HFOV would be informed consent to the parents by the 
neonatal fellow (Dr. Kulthida Baingam). After informed consent, the first arterial blood gas was 
drawn after on HFOV at least 1 hour. Then, participants would be switched on HFOV-sigh mode 
(the same setting of HFOV mode and add only sigh breath). The second arterial blood gas was 
drawn (2 hours to 2 hours 15 minutes after start HFOV-sigh). After that sigh breaths would be 
switched off then on only HFOV mode.  
• The ventilator in NICU had 4 brands (SLE6000, Drager, Fabian, and Sensor medic); however, sigh 
mode was only available in SLE6000 infant ventilators (United Kingdom) and Drager Babylog 
VN500 (Germany).  
• HFOV-sigh setting both SLE6000 and Drager Babylog VN500: setting (Hz, MAP, delta pressure) 
same as HFOV, set sigh RR 3 breath/min, Sigh Ti = 1 sec, Sigh PIP = (MAP+5, maximum 30) cm 

Effective date: 29 Jan 2021  
NCT05682937 28/Dec/2022 
AP-001 
Protocol version 03, 28/Dec/2022 
หน้า 10 จาก 14 หน้า 
H2O, Slope sigh 0.5. No change in Hz, MAP, delta pressure, and increased FiO2 less than 0.1 
occurred between intervention. 
• Currently, only 3 studies in HFOV-sigh mode were conducted (Table 1). We set sigh RR 3 
breath/min and Sigh Ti = 1 sec (similar to previous studies(17, 18, 21)), Sigh PIP = (MAP+5,(21) 
maximum 30(17, 18)) cm H2O. While HFJV combined with higher sigh PIP (set at 27 and 37 cm H2O 
in RDS and MAS) resulted in excessive tidal volume.(22) 
Table 1. Review sigh breaths in neonates, children, and adults with HFOV  
Author 
Population 
Mode of 
ventilator 
Sigh setting 
Sigh 
Duration  
Sigh PIP 
(cm H2O) 
Sigh RR 
(/min) 
Sigh Ti 
(sec.) 
Heiring(17, 18) 
Preterm neonate 
HFOV 
30 
3 
1 
1 h 
Nakanishi(21) 
Preterm neonate 
HFOV+VG 
MAP+5 
2-3 
0.7-1.0 
N/A 
Romo(22) 
Preterm and Term 
neonates 
HFJV 
27 (RDS) 
37 (MAS) 
6 
0.3-0.4 
N/A 
Bonacina(14) 
Neonate and infant 
PSV 
30 
1 
3 
240 
breaths 
Nacoti (13) 
 
Children undergoing 
major surgery 
PSV 
30 
1 
0.5 
1 h 
Mauri (10) 
Adult with ARDS 
PSV 
35 
2,1,0.5 
N/A 
20 min 
Mauri(15) 
Adult with ARDS 
PSV 
30 
1 
N/A 
30 min 
Badet(23) 
Adult with ARDS 
A/C 
<40, 2*TV 
2-3 
N/A 
1 h 
A/C= assist controlled, HFJV = high-frequency jet ventilation; HFOV = High frequency oscillatory ventilation; 
VG = Volume guarantee; MAP = Mean airway pressure, MAS = Meconium aspiration syndrome; N/A = not 
available; PIP = peak inspiratory pressure; PSV = pressure support ventilation; RDS = Respiratory distress 
syndrome; RR = Respiratory rate; Ti = Inspiratory time; TV = tidal volume 
• The monitoring during HFOV and HFOV-sigh monitoring was vital signs (systolic, diastolic, mean 
arterial pressure, heart rate, SpO2 were collected every 15 minutes during intervention for 2 h and 
after intervention for 1 h) by neonatal fellow (Dr. Kulthida Baingam) and nurse, clinical 
manifestations, respiratory distress, umbilical arterial blood gas during study, and chest X-ray 
within 24 hours after intervention or immediately if clinical conditions deteriorate. The first blood 
gas was obtained after HFOV mode at least 1 hour with stable participants. After HFOV-sigh, the 
blood gas was obtained after 2 hours (no more than 2 hours 15 minutes) in this setting.  
Data collection 
 Participant’s data and blood gas’s result will be recorded in record form.   
Data management 

Effective date: 29 Jan 2021  
NCT05682937 28/Dec/2022 
AP-001 
Protocol version 03, 28/Dec/2022 
หน้า 11 จาก 14 หน้า 
EpiData entry is used for data entry and data documentation. The data will be safe and private 
collected; moreover, only principal investigator and recorder will access. 
Data analysis 
Parametric continuous variables are presented as mean (standard deviation, SD) and paired t-test 
was used to compare paired samples. Nonparametric continuous variables are presented as median 
(interquartile range, IQR) and the Wilcoxon signed rank test with continuity correction was used to compare 
paired samples. Subgroup analysis for gestational age less than 37 and 32 weeks.  
Ethical issues 
For Safety, the intermittent sigh breaths generated low sigh RR, optimal sigh PIP and Ti from previous 
studies. For 2 hours, neonatal fellow will monitor clinical conditions and then 24 hours after intervention. Risk of 
sigh breath may be air leak syndrome because this mode may increase PIP sigh and ventilation. In meta-
analysis in neonate, neonates who on HFOV mode developed pulmonary air leaks 27.7% (392/1,415).(1) 
However, neonate with risk of air leak syndrome (previous or current pulmonary air leaks e.g., pulmonary 
interstitial emphysema, pneumothorax, pneumomediastinum, and pneumopericardium. Heterogeneous lung 
disease including MAS, congenital diaphragmatic hernia, and suspected lung hypoplasia) will be excluded and 
the participants will be closed-monitored during and 24 hours after intervention (clinical and radiographic 
conditions). Some neonates may expose X-ray (increase 1 time) more than routine care to monitor safety. 
However, some neonate may need follow X-ray by clinical condition of each neonate within 24 hours, this 
neonate will not be repeat more X-ray.     
The blood gases were drawn for 2 times, more than routine care. The arterial blood gases were only 
drawn through umbilical or peripheral arterial catheter for reducing pain from direct artery puncture. Each time 
used approximately 0.2 mL of blood (Total blood 0.4 mL). Arterial blood gases were needed to evaluate 
patient’s ventilation. In case of lowest birth weight 500 g neonate, total blood loss was about 0.8 mL/kg/day (< 
2.5 mL/kg). The methods of arterial blood gas drawing were firstly the doctor would draw blood containing 
heparin from umbilical artery catheter to the first syringe by sterile technique then the tuberculin syringe was 
secondly drawing from umbilical artery catheter to be analyzed for arterial blood gas. Thirdly, the blood from the 
first syringe was returned to the patient and finally the blood was clear from umbilical or peripheral arterial 
catheter by 0.5 mL flushing with normal saline. The maximum allowable blood draw volumes were shown in 
Figure 6.  

Effective date: 29 Jan 2021  
NCT05682937 28/Dec/2022 
AP-001 
Protocol version 03, 28/Dec/2022 
หน้า 12 จาก 14 หน้า 
 
Fig.6 Maximum allowable blood draw volumes 
The record form was unidentifiable enrolled patients; therefore, name or hospital number would not be 
filled in the record form. The data would be kept in secret files and only principal investigators and recorders 
could access to these data. 
Enrolled participants may be not directly profitable from this thesis; nevertheless, the enrolled 
participants would be evaluated pCO2 level and ventilation monitoring 
The social benefit was the published study in neonate that evaluate sigh breaths in HFOV that may 
lead to further investigation and application in general practice. 
Informed consent process 
The parents of intubated neonates with available umbilical artery catheter would be pursued to enrolled 
in this study by NICU fellows within a few days after intubation. The parents would receive informative 
documents with explaining the entire data about 30 to 60 minutes or until the parent were crystal clear about 
the study detail by NICU fellows. If the parents allowed the patients to enroll in the study, they would sign the 
signature in the informed consent’s document. 
The resigned data would be recorded in the recorded form and informed consent’s document. It would 
record date of resignment and signature of both parents and doctors.  
 
Time table 1st October 2022 ถึง 30th June 2024 
 
 
 
 

Effective date: 29 Jan 2021  
NCT05682937 28/Dec/2022 
AP-001 
Protocol version 03, 28/Dec/2022 
หน้า 13 จาก 14 หน้า 
References 
1. 
Cools F, Offringa M, Askie LM. Elective high frequency oscillatory ventilation versus conventional 
ventilation for acute pulmonary dysfunction in preterm infants. Cochrane Database Syst Rev. 
2015(3):Cd000104. 
2. 
Ackermann BW, Klotz D, Hentschel R, Thome UH, van Kaam AH. High-frequency ventilation in 
preterm infants and neonates. Pediatr Res. 2022. 
3. 
Delivoria-Papadopoulos M, Swyer PR. Assisted ventilation in terminal hyaline membrane disease. 
Archives of disease in childhood. 1964;39(207):481-4. 
4. 
Elgin TG, Berger JN, Thomas BA, Colaizy TT, Klein JM. Ventilator management in extremely 
preterm infants. NeoReviews. 2022;23(10):e661-e76. 
5. 
Hoch B, Bernhard M, Hinsch A. Different patterns of sighs in neonates and young infants. Biology of 
the neonate. 1998;74(1):16-21. 
6. 
Jost K, Latzin P, Fouzas S, Proietti E, Delgado-Eckert EW, Frey U, et al. Sigh-induced changes of 
breathing pattern in preterm infants. Physiol Rep. 2015;3(11). 
7. 
Davis GM, Moscato J. Changes in lung mechanics following sighs in premature newborns without 
lung disease. Pediatr Pulmonol. 1994;17(1):26-30. 
8. 
Qureshi M, Khalil M, Kwiatkowski K, Alvaro RE. Morphology of sighs and their role in the control of 
breathing in preterm infants, term infants and adults. Neonatology. 2009;96(1):43-9. 
9. 
Patroniti N, Foti G, Cortinovis B, Maggioni E, Bigatello LM, Cereda M, et al. Sigh improves gas 
exchange and lung volume in patients with acute respiratory distress syndrome undergoing pressure 
support ventilation. Anesthesiology. 2002;96(4):788-94. 
10. 
Mauri T, Eronia N, Abbruzzese C, Marcolin R, Coppadoro A, Spadaro S, et al. Effects of sigh on 
regional lung strain and ventilation heterogeneity in acute respiratory failure patients undergoing 
assisted mechanical ventilation. Critical care medicine. 2015;43(9):1823-31. 
11. 
Massaro GD, Massaro D. Morphologic evidence that large inflations of the lung stimulate secretion 
of surfactant. The American review of respiratory disease. 1983;127(2):235-6. 
12. 
Barrington KJ, Finer NN, Wilkinson MH. Progressive shortening of the periodic breathing cycle 
duration in normal infants. Pediatr Res. 1987;21(3):247-51. 
13. 
Nacoti M, Spagnolli E, Bonanomi E, Barbanti C, Cereda M, Fumagalli R. Sigh improves gas 
exchange and respiratory mechanics in children undergoing pressure support after major surgery. 
Minerva Anestesiol. 2012;78(8):920-9. 
14. 
Bonacina D, Bronco A, Nacoti M, Ferrari F, Fazzi F, Bonanomi E, et al. Pressure support ventilation, 
sigh adjunct to pressure support ventilation, and neurally adjusted ventilatory assist in infants after 
cardiac surgery: A physiologic crossover randomized study. Pediatr Pulmonol. 2019;54(7):1078-86. 
15. 
Mauri T, Foti G, Fornari C, Grasselli G, Pinciroli R, Lovisari F, et al. Sigh in patients with acute 
hypoxemic respiratory failure and ARDS: The PROTECTION pilot randomized clinical trial. Chest. 
2021;159(4):1426-36. 
16. 
Poets CF, Rau GA, Neuber K, Gappa M, Seidenberg J. Determinants of lung volume in 
spontaneously breathing preterm infants. Am J Respir Crit Care Med. 1997;155(2):649-53. 

Effective date: 29 Jan 2021  
NCT05682937 28/Dec/2022 
AP-001 
Protocol version 03, 28/Dec/2022 
หน้า 14 จาก 14 หน้า 
17. 
Heiring C. High Frequency Oscillatory Ventilation Combined With Intermittent Sigh Breaths: Effects 
on Blood Oxygenation and Stability of Oxygenation  [updated October 20, 2020. Available from: 
https://clinicaltrials.gov/ct2/show/NCT01959009?id=NCT01959009+OR+NCT01962818&draw=2&rank
=2&load=cart. 
18. 
Heiring C. High Frequency Oscillatory Ventilation Combined With Intermittent Sigh Breaths: Effects 
on Lung Volume Monitored by Electric Tomography Impedance.  [updated October 20, 2020. 
Available from: 
https://clinicaltrials.gov/ct2/show/NCT01962818?id=NCT01959009+OR+NCT01962818&draw=2&rank
=1&load=cart. 
19. 
Cools F, Askie LM, Offringa M, Asselin JM, Calvert SA, Courtney SE, et al. Elective high-frequency 
oscillatory versus conventional ventilation in preterm infants: a systematic review and meta-analysis 
of individual patients' data. Lancet. 2010;375(9731):2082-91. 
20. 
Courtney SE, Durand DJ, Asselin JM, Hudak ML, Aschner JL, Shoemaker CT. High-frequency 
oscillatory ventilation versus conventional mechanical ventilation for very-low-birth-weight infants. N 
Engl J Med. 2002;347(9):643-52. 
21. 
Sindelar R, Nakanishi H, Stanford AH, Colaizy TT, Klein JM. Respiratory management for extremely 
premature infants born at 22 to 23 weeks of gestation in proactive centers in Sweden, Japan, and 
USA. Semin Perinatol. 2022;46(1):151540. 
22. 
Romo CM, Malone P, Fang T, Crotwell D, DiBlasi R. The Effect of Sigh Breaths on Volume Delivery 
During Simulated Neonatal High Frequency Jet Ventilation. Respir Care. 2019;64(Suppl 
10):3239444. 
23. 
Badet M, Bayle F, Richard JC, Guérin C. Comparison of optimal positive end-expiratory pressure 
and recruitment maneuvers during lung-protective mechanical ventilation in patients with acute lung 
injury/acute respiratory distress syndrome. Respir Care. 2009;54(7):847-54.