Volume Targeted Mask Ventilation Versus Pressure Ventilation in Preterm Infants
Phase: NA
Conditions: Neonatal Respiratory Distress
Sponsor: University of Alberta

EDITED BY  
Qiuping Li,  
Bayi Children’s Hospital, China
REVIEWED BY  
Lingyue Gong,  
Rush University Medical Center, Chicago, 
United States  
Dushyant Batra,  
Nottingham University Hospitals NHS Trust, 
United Kingdom
*CORRESPONDENCE  
Georg M. Schmölzer  
georg.schmoelzer@me.com
RECEIVED 10 November 2025 
REVISED 23 November 2025 
ACCEPTED 03 December 2025 
PUBLISHED 06 January 2026
CITATION 
Law BHY, Yaskina M, Davis PG, Polglase G, 
Dunn M, Mukerji A and Schmölzer GM (2026) 
Study protocol for the volume targeted mask 
ventilation versus pressure ventilation in 
preterm infants—the VOLT-trial.  
Front. Pediatr. 13:1743460. 
doi: 10.3389/fped.2025.1743460
COPYRIGHT 
© 2026 Law, Yaskina, Davis, Polglase, Dunn, 
Mukerji and Schmölzer. This is an open- 
access article distributed under the terms of 
the Creative Commons Attribution License 
(CC BY). The use, distribution or reproduction 
in other forums is permitted, provided the 
original author(s) and the copyright owner(s) 
are credited and that the original publication 
in this journal is cited, in accordance with 
accepted academic practice. No use, 
distribution or reproduction is permitted 
which does not comply with these terms.
Study protocol for the volume 
targeted mask ventilation versus 
pressure ventilation in preterm 
infants—the VOLT-trial
Brenda H. Y. Law
1,2, Maryna Yaskina
3, Peter G. Davis
4,  
Graeme Polglase
5, Michael Dunn
6, Amit Mukerji
7 and  
Georg M. Schmölzer
1,2*
1Centre for the Studies of Asphyxia and Resuscitation, Royal Alexandra Hospital, Edmonton, AB, 
Canada, 2Department of Pediatrics, University of Alberta, Edmonton, AB, Canada, 3Women and 
Children’s Health Research Institute (WCHRI), University of Alberta, Edmonton, AB, Canada, 
4Department of Neonatology, The Royal Women’s Hospital, University of Melbourne, Melbourne, VIC, 
Australia, 5The Ritchie Centre, Department of Paediatrics, Monash University, Hudson Institute of 
Medical Research, Melbourne, VIC, Australia, 6Department of Paediatrics, University of Toronto, 
Toronto, ON, Canada, 7Department of Pediatrics, McMaster University, Hamilton, ON, Canada
Background: The rapid establishment of gas exchange after birth is vital for 
survival and long-term health. When newborn infants fail to initiate 
spontaneous breathing, positive pressure ventilation (PPV) is the cornerstone 
of respiratory support immediately after birth. The aim of PPV is to inﬂate the 
lungs, create a functional residual capacity, deliver an adequate tidal volume 
(VT), facilitate gas exchange, and stimulate breathing, without causing lung or 
brain injury. In the delivery room, PPV is routinely provided via a pressure- 
limited device (called a T-Piece resuscitator), where an arbitrary peak inﬂation 
pressure (PIP) is set, with the assumption an adequate and safe VT will be 
delivered. An alternative approach would be using a ventilator to deliver 
volume-targeted ventilation (VTV), whereby the PIP is adjusted to target a set 
VT measured by an inline ﬂow sensor. While several trials have evaluated the 
use of respiratory function monitors to adjust the delivered VT during PPV, no 
trial has compared PPV with VTV-PPV in the delivery room.
Methods: A randomized trial of VTV-PPV vs. PPV during neonatal resuscitation 
in preterm infants at birth to assess feasibility of a deﬁnitive trial for the 
intervention. Preterm infants born between 230/7 to 286/7 weeks’ gestation 
will be eligible. Patients will be randomized to either the intervention (VTV- 
PPV) or the comparator (PPV) during respiratory support in the delivery room. 
The sample size will be 50 preterm infants. The primary outcome will be 
percentage of eligible participants (=infants requiring PPV) who have the 
intervention performed correctly without protocol deviation (=cross over to 
control group when randomized to VTV-group). Secondary outcomes will 
include 
neonatal 
morbidities 
(e.g., 
death, 
severe 
brain 
injury, 
bronchopulmonary dysplasia; and severe retinopathy of prematurity).
Discussion: The VOLT-trial aims to assess feasibility of VTV-PPV and will 
address gaps in the evidence regarding the optimal approach to the 
establishment of ventilation in the delivery room. We aim to use to results of 
this trial to inform the design of a large multi-centre trial. 
Study Protocol Registration:
https://clinicaltrials.gov/study/NCT05144724, 
identiﬁer NCT05144724.
KEYWORDS
infant, extremely preterm, neonatal intensive care, delivery room, respiratory function 
tests, neonatal mortality
TYPE Study Protocol 
PUBLISHED 06 January 2026 
DOI 10.3389/fped.2025.1743460
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Introduction
Background and rationale
Limitations of current positive pressure 
ventilation practices in the delivery room
When newborn infants fail to initiate spontaneous breathing 
at birth, positive pressure ventilation (PPV) remains the 
cornerstone of respiratory support immediately (1–3). The 
purpose of PPV is to inﬂate and create functional residual 
capacity in the lung, deliver an adequate tidal volume (VT), 
facilitate gas exchange, and stimulate breathing, all while 
minimizing lung and brain injury (4). Positive pressure 
ventilation (PPV) in the delivery room is usually provided via a 
face mask with a T-piece resuscitator, where peak inﬂation 
pressure (PIP) is selected without measuring the actual tidal 
volume (VT) delivered. Instead, adequacy is judged by heart rate 
and chest wall movement, though studies show healthcare 
providers often cannot reliably assess chest wall movement (5–7).
Tidal volume variability and Its link to lung and 
brain injury at birth
Preterm infants are susceptible to ventilation-induced lung 
injury, as the volume difference between functional residual 
capacity and total lung capacity is small in this population (8). 
Delivery room studies reported that VT during mask PPV 
ranges between 0 and 31 mL/kg (6, 9–13). This is concerning as 
animal studies demonstrated that lung injury was predominantly 
caused by high VT ventilation (>8 mL/kg) and if VT was 
controlled to avoid lung over-distention, little or no injury 
occurred (14–22).
Similarly, studies in preterm lambs reported that PPV with VT 
>8 mL/kg causes brain injury through increased inﬂammation, 
hemodynamic instability, and oxidative stress (17–19). Polglase 
et al. showed that preterm lambs ventilated with higher VT (10– 
12 mL/kg) for the ﬁrst 15 min after birth had highly variable 
cerebral oxygenation, as measured by near-infrared spectroscopy 
(NIRS), compared to preterm lambs ventilated with a protective 
strategy (VT < 8 mL/kg) (19). Disruption of the blood-brain 
barrier was observed in 60% of preterm lambs ventilated with 
high VT, as evidenced by vascular protein extravasation, but was 
not observed in preterm lambs ventilated with a protective 
strategy. 
These 
preclinical 
ﬁndings 
are 
supported 
by 
observational studies in the delivery room, which reported a 
four-fold increase in rates of severe intraventricular hemorrhage 
(IVH) in preterm infants (<29 weeks’ gestation) when VT 
>6 mL/kg was delivered during PPV (23, 24). Therefore, 
approached which could improve VT delivery might reduce lung 
and brain injury.
Adjusting tidal volume to protect the preterm 
lung and brain
Randomized trials in the delivery room utilizing a Respiratory 
Function Monitor (RFM) during PPV, which allows the 
resuscitator to target VT, has been associated with a lower rate 
of excessive (>8 mL/kg) VT delivery (9–11). A systematic review 
of randomized trials comparing RFM visible vs. masked 
demonstrated conﬁrmed that the proportion of infants receiving 
VT >8 mL/kg can be reduced with an RFM visible (25). 
However, rates of bronchopulmonary dysplasia were unchanged 
in all trials. Interestingly, brain injury (deﬁned as any IVH and/ 
or periventricular leukomalacia) can be reduced by 35% and any 
grade IVH by 32% with an RFM visible (25). Unfortunately, 
none of the randomized trials was powered to examine 
differences in brain injury (only reported as secondary 
outcomes), and therefore these results might have only occurred 
by chance.
Neonatologists are increasingly careful in the neonatal 
intensive care unit (NICU) to apply ventilation strategies that 
are gentle to the lungs (26, 27). Volume-targeted ventilation 
(VTV), where ventilators algorithmically adjust PIPs to target a 
set VT as detected through in an inline ﬂow sensor, is routinely 
used in the NICU (26–28). A meta-analysis of VTV in the 
NICU showed a reduction in a number of adverse clinical 
endpoints, including (i) the incidence of pneumothorax (typical 
RR [95%CI] 0.46 [0.25–0.84], numbers needed to treat [95%CI] 
17 [10–100]), (ii) hypocarbia (typical RR [95%CI] 0.56 [0.33– 
0.96], numbers needed to treat [95%CI] 4 [2–25]), (iii) 
combined outcome of death or bronchopulmonary dysplasia 
(typical RR [95%CI] 0.73 [0.57–0.93], numbers needed to treat 
[95%CI] 8 [5–33]), and (iv) the combined outcome of 
periventricular leukomalacia (PVL) or grade 3–4 IVH (typical 
RR [95%CI] 0.48 [0.28–0.84], numbers needed to treat [95%CI] 
11 [7–50]) (27). However, despite the general acceptance of 
VTV in the NICU, clinicians appear less aware that the same 
gentle approach should be applied to PPV in the delivery room 
to reduce lung and brain injury immediately after birth [36,43].
Unanswered question: does VTV improve 
outcomes compared to PPV in the delivery room?
Therefore, alternate methods of providing tight VT control 
during PPV in the delivery room resuscitation of preterm 
infants is needed, given the complex interaction of mask leak, 
lung compliance, PIP, and resuscitator skill. Using VTV 
immediately after birth would provide continuity from the 
delivery room into the NICU. Tracy et al. compared mask PPV 
with a T-Piece or VTV during simulated neonatal resuscitation 
and reported a lower coefﬁcient of variations and lower VT 
delivery with ventilator driven VTV compared PPV with a 
T-Piece (29). Similarly, Jain et al. compared VTV via a 
mechanical ventilator to manual T-Piece PPV and reported 
improved volume targeting at different compliance settings and 
a reduction in mask leak during simulated mask ventilation 
Abbreviations  
WCHRI, women and children’s health research institute; PPV, positive pressure 
ventilation; VT, tidal volume; PIP, peak inﬂation pressure; VTV, volume- 
targeted ventilation; RFM, respiratory function monitor; HIE, hypoxic- 
ischemic 
encephalopathy; 
IVH, 
intraventricular 
hemorrhage; 
PVL, 
periventricular leukomalacia; NICU, neonatal intensive care unit; ROP, 
retinopathy of prematurity; SAE, severe adverse event; DSMB, data safety 
monitoring board; SURG-TLX, surgery task load index; VOLT, volume 
targeted mask ventilation versus pressure ventilation in preterm infants trial.
Law et al.                                                                                                                                                                
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(30). These studies suggest that VTV is feasible at least during 
animal 
or 
simulated 
neonatal 
resuscitation. 
Furthermore, 
Menakaya et al. compared VTV with a PPV using a Flow- 
Inﬂating bag and reported that preterm infants be safely and 
effectively resuscitated using a ventilator (31). However, no study 
has compared VTV with T-Piece resuscitator during neonatal 
resuscitation of preterm infants in the delivery room. Thus, a 
clinical trial using VTV in the delivery room is urgently needed to 
determine if (a) this method can be feasibly used in the delivery 
room and (b) can potentially improve outcomes by reducing 
bronchopulmonary dysplasia and brain injury in preterm infants.
Objectives
Primary objective
To determine feasibility and safety of a trial comparing VTV- 
PPV to PPV in extremely preterm infants.
Secondary objectives
To evaluate clinical outcomes and HCP experience of the 
VTV-PPV.
Primary research question
Population: In preterm infants born at 230–286 weeks’ 
gestation is a trial of Intervention: mask ventilation using a 
mechanical ventilator (VTV-PPV) Comparison: compared to 
mask ventilation using a T-Piece Resuscitator (PPV) Outcome: 
feasible during mask ventilation in the delivery room, which will 
be assessed by percentage of eligible participants (=infants 
requiring PPV) randomized to the VTV group and receive the 
allocated intervention without protocol deviation (i.e., without 
crossover to the control group) Timeline: during the ﬁrst 10 min 
after birth?
Secondary research questions
1. In preterm infants born at 230–286 weeks of gestation, does 
mask ventilation using a mechanical ventilator compared to 
mask ventilation using a T-Piece Resuscitator reduce neonatal 
morbidities 
(severe 
brain 
injury, 
bronchopulmonary 
dysplasia; and severe retinopathy of prematurity) and reduce 
the number of infants requiring intubation in the delivery 
room by transitioning more successfully to CPAP.
2. What qualitative feedback do HCPs have on the experience of 
using VTV-PPV in the delivery room?
3. How does VTV-PPV compared with PPV affect subjective 
workload reported by HCPs performing mask ventilation?
Trial design
A single centre randomized controlled trial.
Methods: participants, interventions, 
outcomes
Study setting
Royal Alexandra Hospital, Edmonton, Canada, a tertiary 
perinatal center admitting ∼140 infants born between 23+0 to 28+6 
weeks’ gestation annually. The trial is registered on clinicaltrials. 
gov (https://clinicaltrials.gov/study/NCT05144724) (Table 1).
Eligibility criteria
Inclusion criteria (all must be satisﬁed)
- Born between 230/7 to 286/7 weeks’ gestation based on best 
obstetrical estimates
- Considered suitable for full resuscitation, i.e., no parental 
request or antenatal decision to forego resuscitation
- Deferred parental consent post-intervention
Exclusion criteria
- Major congenital or chromosomal malformation
- Conditions that might have an adverse effect on breathing or 
ventilation (e.g., high risk for lung hypoplasia, congenital 
diaphragmatic hernia)
- Antenatally detected congenital heart disease requiring 
intervention in the neonatal period
- Antenatally diagnosed Hydrops requiring intervention in the 
neonatal period
- Neonatal resuscitation initiated before NICU team arrival
- Infants who are born outside of study center and transported to 
center after delivery
Consent or assent: who will take informed 
consent?
Informed parental/guardian consent will be obtained after the 
study intervention for ongoing data collection. The consent 
approach of obtaining individual consent after birth for data 
inclusion in the trial, will strengthen the number being 
recruited. Furthermore, this approach has been reviewed and 
approved by our local human ethics review board and is 
supported by the local Neonatal Family Advisory Care Team. 
For this important study to be feasible, and enroll a 
representative sample, an informed consent obtained after the 
study intervention for ongoing data is important, as obtaining 
consent prior to delivery can be difﬁcult (32, 33). Guidelines for 
this approach as laid down by Tri-Council Policy Statement 
state that any study wishes to use deferred consent needs (34): 
a) “A serious threat to the prospective participant requires 
immediate intervention.” Infants participating in this trial 
will require respiratory support, which in most cases was 
unforeseen prior to delivery; hence these infants will all 
need PPV and using mask ventilation will be therapeutic. 
Although the pressure limited PPV method (PPV group) is 
the routinely used method at the participating site, it would 
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not be feasible for a neonatal resuscitation study to ask 
permission prior to delivery from every parent delivering 
within the participating site.
b) “either no standard efﬁcacious care exists or the research 
offers a realistic possibility of direct beneﬁt to the 
participant in comparison with standard care.” The 
currently used approach in the delivery room is pressure 
limited PPV. However, in the NICU, VTV is standard of 
care 
for 
providing 
mechanical 
ventilation, 
not 
for 
resuscitation on NICU. The available animal evidence and 
limited neonatal data suggest that the interventional 
approach has the potential to improve standards of care.
c) “either the risk is not greater than that involved in standard 
efﬁcacious care, or it is clearly justiﬁed by the prospect for direct 
beneﬁts to the participant.” Resuscitation is therapeutic and the 
currently available evidence suggest that the interventional 
approach (VTV-PPV group) has no higher risk of harm 
compared to the current standard of care (PPV group). 
Furthermore, the intervention approach is routine standard 
practice in the NICU, and has been shown to decrease 
combined outcomes of death/bronchopulmonary dysplasia and 
brain injury.
d) “the prospective participant is unconscious or lacks capacity to 
understand the risks, methods and purposes of the research 
project.” A person in labor cannot give a valid informed 
consent to a research study. Thus, the parents will be 
informed as soon as possible after stabilization of the infant 
about the study and asked to consent to the use of data that 
have been collected on their child.
e) “third party authorization cannot be secured in sufﬁcient time, 
despite diligent and documented efforts to do so;” The parents 
will be informed as soon as possible after birth about the study 
and asked to consent to the use of data that have been 
collected on their child.
f) “No relevant prior directive by the participant is known to exist.”
g) There is an increasing use of the deferred consent approach 
within delivery room research. The steering committee of 
this application has ample experience with using this 
approach during neonatal resuscitation studies.
Consent or assent: ancillary studies
Parents of participating infants will be asked if they agree to 
use of their data should they choose to withdraw from the trial. 
Participants will also be asked for permission for the research 
team to share relevant data with people from the Universities 
taking part in the research where relevant. This trial does not 
involve collecting biological specimens for storage.
Interventions
Choice of comparators
In the delivery room, PPV is routinely provided via a T-Piece 
resuscitator, where a PIP is arbitrarily chosen, with the 
assumption it will deliver an adequate VT. However, the delivered 
VT is not measured and therefore PIP is not adjusted to optimize 
VT 
delivery. While a lung-protective strategy must start 
immediately after birth, this has not been studied in detail. Lung 
compliance and the corresponding PIP needed to deliver an 
appropriate VT vary between infants depending on gestational age, 
disease state and delivery mode (C-section vs. vaginal). In 
addition, the optimal PIP and VT for an individual infant change 
in the ﬁrst minutes after birth as lung ﬂuid is cleared and the 
lung aerated. Therefore, relying on a ﬁxed PIP and subjective 
assessment of chest rise may result in harm by either under- or 
over-ventilation. It may be beneﬁcial to measure and adjust the 
VT delivered during PPV in the minutes after birth, especially in 
very preterm infants at the greatest risk of lung and brain injury. 
Delivery room studies reported that VT during PPV ranges 
between 0 and 31 mL/kg, which is concerning as animal studies 
reported that lung injury was predominantly caused by high VT 
ventilation (>8 mL/kg). This led to the utilization of RFMs during 
TABLE 1 Trial timeline.
Time point
Enrolment Allocation
Post-allocation
Hospital 
discharge
Antenatal
At birth
7–10 days of 
age
Enrolment
Eligibility screen
X
X
Informed consent
X
X
Maternal demographic and pregnancy data
X
Randomization data
X
Baseline infant data
X
X
Interventions
Intervention
X
Outcome assessments
Safety Assessment In-hospital Mortality (Part of primary outcome)
X
X
X
Safety Assessment Intraventricular hemorrhage
X
Completion of admission data
X
Primary Outcome: Feasibility to recruit 50 preterm infants requiring PPV over a 
2-year period
X
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PPV to target VT. Three trials compared an RFM visible to adjust 
the delivered VT to RFM masked, which resulted in a reduction 
of VT >8 mL/kg being delivered, but failed to reduce rates of 
bronchopulmonary dysplasia. Therefore, alternate methods of 
providing tight VT control during PPV in the delivery room 
resuscitation of preterm infants is needed. In the NICU, VTV 
ventilators which algorithmically adjust PIPs to target a set VT are 
routinely used. A meta-analysis of trials comparing VTV with 
pressure guided ventilation in the NICU showed a reduction in 
pneumothorax, 
combined 
outcome 
of 
death 
or 
bronchopulmonary dysplasia, combined outcome of PVL or grade 
3–4 IVH. However, despite the general acceptance of VTV in the 
NICU, this approach is not used in the delivery room to reduce 
lung and brain injury immediately after birth. The trials will 
compare VTV-PPV with PPV during respiratory support 
immediately after birth to assess the feasibility of VTV-PVV.
Intervention description
Treatment arms
PPV group
The clinical team will proceed through all steps of the neonatal 
resuscitation algorithm, as per current neonatal resuscitation 
guideline (1–3) and local hospital policy (standard hospital 
practice guideline). Mask ventilation in the delivery room will 
be provided as per local hospital policy (standard hospital 
practice guideline). At the Royal Alexandra Hospital, mask 
ventilation is delivered with a T-piece device with initial settings 
of PIP of 24 cmH2O, a peak expiratory pressure PEEP of 
6 cmH2O, a max PIP of 40 cmH2O and a gas ﬂow rate of 8– 
10 L/min. Resuscitators are trained to use a ventilation rate of 
40–60 inﬂations/min. The clinical team will determine if/when 
ventilation pressures (both PEEP and PIP) should be increased, 
as per local hospital policy (standard hospital practice 
guideline), using clinical assessments (heart rate, oxygen 
saturation, auscultation, chest raise) (Figure 1).
VTV-PPV group
Initial ventilation settings for VTV-PPV will be a VT of 5 mL/ 
kg, a ventilation rate of 50 inﬂations/min, a maximum PIP of 
40 cmH2O, and a PEEP of 6 cmH2O. For VTV-PPV, a size 9.0 
endotracheal tube connector will be inserted into the facemask 
to allow secure attachment of the ﬂow sensor and ventilator 
circuit. Ventilation will be delivered using PC-CMV with 
Volume Guarantee, beginning at 5 mL/kg and adjustable up to 
6 mL/kg if required. The trigger sensitivity will be set at 0.2 L/ 
min to enable infant-triggered breaths, and the inspiratory time 
FIGURE 1 
VOLT study algorithm.
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will be set at 0.3 s, with the option to increase to 0.5 s based on 
clinical response. To minimize leak, clinicians will use a two- 
hand mask-hold technique, as the ventilator tubing is heavier 
than a T-piece and may otherwise create downward pull. The 
clinical team will proceed through all steps of the neonatal 
resuscitation algorithm, as per current neonatal resuscitation 
guidelines (1–3) and local hospital policy but will replace 
standard 
pressure-limited 
PPV 
with 
VTV-PPV 
in 
the 
intervention group. The clinical team will determine if and 
when VT, ventilation rate, and/or PEEP should be increased, 
using clinical assessments (heart rate, oxygen saturation, 
auscultation, chest rise). In addition, the clinical team will be 
trained to troubleshoot ventilator alarms such as low minute 
ventilation (e.g., airway obstruction) and disconnect alarms (e.g., 
mask leak) (Figure 1). No CO2 monitoring (end-tidal or 
transcutaneous) will be used due to feasibility limitations in the 
delivery room.
Duration of treatment period
The study intervention will be applied for the ﬁrst 10 min 
after birth.
Criteria for discontinuing or modifying 
allocated interventions
In any cases where the resuscitation team believes, that VTV- 
PPV is not working, the resuscitation team can revert to standard 
hospital practice guideline of administering PPV using a T-Piece 
resuscitator at any time.
If HR <60 at any time despite 30 s of effective ventilation, the 
resuscitation guidelines state to use an alternate airway and start 
chest compression. At that time, the VTV-PPV approach must 
be abandoned and a T-Piece must be used.
Strategies to improve adherence to 
interventions
Training logs and continuing engagement during daily clinical 
huddles to remind about the study.
Relevant concomitant care permitted or 
prohibited during the trial
Other than providing PPV with either a ventilator 
(intervention) or a T-Piece (standard of care), all delivery room 
interventions will follow the center’s local hospital policy 
(standard hospital practice guideline) and the current neonatal 
resuscitation guidelines (1–3).
Provisions for post-trial care
Care during the primary hospitalization will adhere to local 
practice guidelines.
Outcomes
Primary outcome
Percentage of eligible participants (=infants requiring PPV) 
who have the intervention performed correctly without protocol 
deviation (=cross over to control group when randomized to 
VTV-group).
Secondary outcomes
Secondary outcomes include: 
1. All-cause in-hospital mortality
2. Severe brain injury on cranial ultrasound: Severe grade 3 and 
4 intraventricular or intraparenchymal hemorrhage according 
to 
Papile 
(35), 
periventricular 
leukomalacia, 
or 
ventriculomegaly based on neuroimaging studies (timing 
and frequency of imaging based on local site practices)
3. Severe retinopathy of prematurity (stage 3 or higher) as 
deﬁned in the International Classiﬁcation of ROP, and/or 
ROP treated with laser, cryotherapy, or intraocular injection 
therapy (36)
4. Bronchopulmonary dysplasia at 36 weeks corrected age and at 
40 weeks corrected age, deﬁned as receiving any supplemental 
oxygen or any form of respiratory support (including invasive 
mechanical 
ventilation, 
non-invasive 
ventilation 
with 
continuous positive airway pressure, nasal intermittent 
positive pressure ventilation, or high-ﬂow nasal canula)
5. Total duration of mechanical ventilation via an endotracheal 
tube in days
6. Discharge home on oxygen
7. Duration of any respiratory support (invasive mechanical 
ventilation, 
non-invasive 
ventilation 
with 
continuous 
positive airway pressure, nasal intermittent positive pressure 
ventilation, or non-invasive neural assist ventilation or non- 
invasive high frequency ventilation, or high-ﬂow nasal 
cannula) in days
8. Duration of supplemental oxygen in days
9. Length of hospital stay in days
10. Rate of intubation in the delivery room
11. Rate of chest compression in the delivery room
12. Rate of pneumothorax (diagnosed by chest x-ray or lung 
ultrasound) and interventions (e.g., needle drainage or chest 
drain)
13. Necrotizing enterocolitis, Modiﬁed Bell’s criteria stage 2 or 
greater (37)
14. Duration of positive pressure ventilation at birth (within the 
ﬁrst 10 min)
15. Resuscitators 
subjective 
workload 
performing 
mask 
ventilation, as evaluated by Surgery Task Load Index 
(SURG-TLX)-questionnaire.
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16. Resuscitators qualitative feedback on using VTV-PPV in the 
delivery room, provided through free text responses.
Participant timeline
Sample size
This will be a trial to assess the feasibility of VTV-PPV in the 
delivery room. Our primary outcome will assess the percentage of 
eligible participants (=infants requiring PPV) who have the 
intervention performed correctly without protocol deviation 
(=cross over to control group when randomized to VTV-group). 
We aim to recruit a sample of 50 infants (25 per arm) 
randomized 1:1 to VTV-PPV or PPV. The proposed sample size 
should be reached within 24 months. This study will be an 
initial trial for a large multi-center trial.
Recruitment
The study will be carried out at the Royal Alexandra Hospital, 
Edmonton, Canada, a tertiary perinatal center with ∼6,000 
deliveries annually admitting ∼140 infants born between 23+0 to 
28+6 weeks’ gestation annually. Approximately 60% of babies 
born between 23 and 28 weeks’ gestation require PPV at birth. 
The study site has a long history of conducting randomized 
trials and has the proven capability of enrolling the required 
number of infants. The number of infants being recruited will 
be 50, as per sample size. The overall recruitment period is a 
maximum of 24 months. There will be 50 infants recruited in 
Canada.
Assignment of interventions
Allocation
Sequence generation
The Biostatistics Unit at Women and Children’s Health 
Research Institute (WCHRI), University of Alberta, Edmonton, 
Canada, will prepare the randomization schedule. Before trial 
initiation, a statistician will generate the 1:1 allocation sequence 
with computer-generated random numbers, which a second 
statistician will independently validate.
Concealment mechanism
The site’s allocation sequence is password-protected, with 
access restricted to the independent statistician.
Implementation
Before the start of the trial, the statistician will use computer- 
generated random numbers to prepare the allocation sequence by 
producing the codes and allocation table. Clinical staff attending 
neonatal deliveries will open an envelope with the group 
assignment and will enroll participants.
Assignment of interventions: blinding
Who will be blinded
Blinding will not be feasible in the delivery room, as the 
healthcare providers will use two different ventilation devices 
including the VN 500 Ventilator (VTV-PPV Group) and the 
Neopuff T-Piece (PPV Group). The outcome assessor will be 
unaware of the group allocation. This blinding will be 
maintained until the data is locked for the ﬁnal analysis, which 
will be performed blinded to group analysis and then un-blinded.
Procedure for unblinding if needed
Members of the Data Safety Monitoring Board (DSMB) will 
access unblinded treatment allocations to determine causality for 
any severe adverse events (SAEs) or other serious trial- 
related events.
Data collection and management
Plans for assessment and collection of outcomes
The VOLT investigators and research nurses will collect data 
from maternal and infant paper or electronic medical records. 
Data will be entered into a REDCapTM (Vanderbilt University) 
electronic database, designed and managed at the University of 
Alberta. REDCap is a secure, web-based application that 
supports data capture for research studies, including database 
management, survey design, and audit trails to ensure 
data integrity.
Plans to promote participant retention and 
complete follow-up
We are anticipating a <5% loss to follow-up until hospital 
discharge. The center has conducted more than 20 neonatal 
trials in the delivery room with lost-to-follow-up rates for the 
primary outcome of <5%.
Data management
VOLT investigators and research nurses will collect maternal 
and infant data from paper or electronic records and enter it 
into REDCapTM (Vanderbilt University), a secure, web-based 
research database designed and managed by the University of 
Alberta (38, 39).
Conﬁdentiality
Participant data will be handled in compliance with applicable 
data protection and privacy regulations. All data will be securely 
stored, with electronic records accessible only to authorized 
research team members via password protection. Data will be 
de-identiﬁed, and participant anonymity will be maintained in 
all scientiﬁc publications and presentations.
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Biological specimens
There will be no biological specimens collected.
Statistical methods
Statistical methods for primary and 
secondary outcomes
WCHRI will handle, verify, and analyze VOLT-trial data, with 
statistical methods aligned to standard randomized trial practices. 
Results will be reported in compliance with CONSORT guidelines.
The primary analysis will be conducted using an “intention- 
to-treat” approach. The primary analysis will focus on feasibility 
deﬁned as percentage (75% or greater) of eligible participants 
(=infants requiring PPV) who have the intervention performed 
correctly without protocol deviation (=cross over to control 
group when randomized to VTV-group). Analysis of secondary 
outcomes will include the above-mentioned secondary outcomes 
using descriptive statistics. Summary statistics will be presented 
for baseline and clinical characteristics; continuous data by 
mean, two-sided 95%CI of the mean, standard deviation, 
median, interquartile range (ﬁrst and third quartiles), minimum 
and maximum. Categorical data will be presented by absolute 
and relative frequencies. The clinical characteristics and outcome 
parameters will be compared using Student’s t-test for 
parametric and Mann–Whitney U-test for nonparametric 
comparisons of continuous variables, and χ2 for categorical 
variables. The analysis will be 2-sided and p-value <0.05 will be 
considered statistically signiﬁcant.
Interim safety analyses
The DSMB will conduct one interim safety analyses 
throughout the trial to assess in-hospital mortality and SAEs 
after 24 (50%) infants recruited.
Methods for additional analyses (e.g., 
subgroup analyses)
At the end of each intervention, the clinician’s workload will 
be assessed using the Surgery Task Load Index (SURG-TLX)- 
questionnaire (40). 
The 
SURG-TLX- 
questionnaire is 
a 
multidimensional workload measure to assess the impact of six 
various sources of stress on the perceived demands of trained 
healthcare professionals. These six aspects are then combined 
into a total workload score.
The SURG-TLX- questionnaire will assess: 
1. Task complexity (How complex was the procedure?)
2. Physical demands (How physically fatiguing was the 
procedure?)
3. Mental demands (How mentally fatiguing was the procedure?)
4. Distraction (How distracting was the operating environment?)
5. Situational stress (How anxious did you feel while performing 
the procedure?)
6. Temporal demands (How hurried or rushed was the pace of the 
procedure?)
Furthermore, clinicians will be asked about their experience of 
using VTV-PPV by completing a short survey to solicit their 
feedback on switching between CPAP and PPV with the 
ventilator, not directly manipulating airway pressures during 
VTV-PPV, and performing ventilation corrective steps during 
VTV-PPV.
Analysis population and missing data
There will be no analysis for missing data will be reported and 
sensitivity analyses considered.
Plans to give access to the full protocol, 
participant level-data and statistical code
Trial information is publicly available on ClinicalTrials.gov
(NCT05144724) and the Research4Babies website. The protocol 
will be shared and submitted for publication, and the de- 
identiﬁed VOLT dataset will be released 6 months after the 
primary outcome is published; data requests can be emailed to 
georg.schmoelzer@me.com and will be decided by the VOLT 
Trial Steering Committee.
Oversight and monitoring
Composition of the coordinating center 
and trial steering committee
The trial management team is based at the Royal Alexandra 
Hospital, 
Edmonton, 
Canada, 
includes 
the 
Principal 
Investigators (GMS), and the Trial coordinators (Caroline Fray 
and Erin Perla), and meets weekly (Table 2).
Trial steering committee
The Trial Steering Committee detailed below meets 
approximately quarterly, chaired by GMS.
Composition of the data monitoring 
committee, its role, and reporting structure
The DSMB, composed of three independent members (Chair, 
neonatal clinician, and biostatistician), is guided by a pre-ﬁnalized 
Charter to safeguard participants, monitor trial conduct, advise 
investigators, and oversee interim safety reviews. It will meet 
about every six months and for interim safety analyses, with no 
pre-speciﬁed stopping criteria (Table 3).
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Adverse event reporting and harms
Safety reporting from the VOLT-Trial will follow standards 
from the University of Alberta Human Research Ethics Board 
and the Tri-Council Policy Statement: Ethical Conduct for 
Research Involving Humans (34).
Pre-deﬁned SAE are: 
- Death in the delivery room
- Death in the Neonatal Intensive Care Unit
Auditing
The Ethics Committee will review trial conduct annually, 
while the independent DSMB will meet every six months for 
trial oversight and interim safety analyses. The Trial Steering 
Committee 
will 
convene 
quarterly 
to 
monitor 
conduct 
throughout the study.
Plans for communicating important 
protocol amendments to relevant parties
Since trial initiation, there have been no major protocol 
amendments. Minor modiﬁcations have been submitted for 
approval to the relevant ethics committees and subsequently 
distributed and communicated to all participating sites.
Dissemination plans
Trial results
Trial results will be shared at national and international 
conferences, 
submitted 
to 
high-impact 
journals, 
and 
disseminated through media and social media. A lay 
summary, developed in collaboration with the Canadian 
Premature Babies Foundation, will be provided to all 
participating families.
Discussion
The VOLT-trial will evaluate the feasibility of using VTV-PPV 
in the delivery room to reduce brain injury and improve outcomes 
in extremely preterm infants. Findings will address evidence gaps 
in initial ventilation at birth and inform a future large-scale 
deﬁnitive randomized trial.
Trial status
The current Protocol version is 3.5, dated October 4, 2022. 
Recruitment began in October 2024 at Royal Alexandra 
Hospital, Edmonton. Recruitment is expected to be completed 
in 2026 with results expected in 2027.
Author contributions
BL: Conceptualization, Data curation, Formal analysis, 
Funding 
acquisition, 
Investigation, 
Methodology, 
Project 
administration, Resources, Validation, Writing – review & 
editing, Visualization. MY: Conceptualization, Formal analysis, 
Investigation, Methodology, Project administration, Validation, 
Writing 
– 
review 
& 
editing. 
PD: 
Conceptualization, 
Investigation, Methodology, Validation, Writing – review & 
editing, Data curation, Visualization. GP: Conceptualization, 
Data 
curation, 
Investigation, 
Methodology, 
Validation, 
Visualization, 
Writing 
– 
review 
& 
editing, 
Project 
administration. MD: Conceptualization, Methodology, Project 
administration, Validation, Visualization, Writing – review & 
editing. 
AM: 
Conceptualization, 
Methodology, 
Project 
administration, Validation, Visualization, Writing – review & 
editing. 
GS: 
Conceptualization, 
Methodology, 
Project 
administration, Validation, Writing – review & editing, Data 
curation, Formal analysis, Funding acquisition, Investigation, 
Resources, Writing – original draft.
Funding
The author(s) declared that ﬁnancial support was received 
for this work and/or its publication. We would like to 
TABLE 2 Composition of the coordinating center and trial steering 
committee.
Prof Georg M. Schmölzer 
(Nominated Principal Investigator)
Centre for the Studies of Asphyxia and 
Resuscitation, Edmonton, Canada
University of Alberta, Edmonton, Canada
Assistant Prof Brenda Law 
(Principal Investigator)
Centre for the Studies of Asphyxia and 
Resuscitation, Edmonton, Canada
University of Alberta, Edmonton, Canada
Dr. Maryna Yaskina (Senior 
Biostatistician)
Women and Children’s Health Research 
Institute, University of Alberta, Edmonton, 
Canada
Prof Peter G. Davis (Principal 
Investigator)
Melbourne University, Melbourne, Australia
Prof. Graeme Polglase (Principal 
Investigator)
Monash University, Melbourne, Australia
Michael Dunn (Principal 
Investigator)
University of Toronto, Toronto, Canada
Amit Mukerji (Principal 
Investigator)
McMaster University, Hamilton, Canada
Caroline Fray (Trial coordinator)
Centre for the Studies of Asphyxia and 
Resuscitation, Edmonton, Canada
Erin Perla (Trial coordinator)
Centre for the Studies of Asphyxia and 
Resuscitation, Edmonton, Canada
TABLE 3 Data Safety Monitoring Board.
Prof Anup Katheria
Chair
San Diego, USA
Prof Anne Solevåg
Independent Expert
Oslo, Norway
Ben Vandermeer
Statistician
Edmonton, Canada
Law et al.                                                                                                                                                                
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thank 
the 
Women’s 
and 
Children 
Research 
Institute, 
University of Alberta for funding the trial via the Innovation 
Grant scheme.
Acknowledgments
We wish to thank the babies and their families that are taking 
part in the VOLT-trial as well as all healthcare professionals who 
work so hard on the trial.
Conﬂict of interest
The author(s) declared that this work was conducted in the 
absence of any commercial or ﬁnancial relationships that could 
be construed as a potential conﬂict of interest.
Generative AI statement
The author(s) declared that generative AI was not used in the 
creation of this manuscript.
Any alternative text (alt text) provided alongside ﬁgures in this 
article has been generated by Frontiers with the support of 
artiﬁcial intelligence and reasonable efforts have been made to 
ensure accuracy, including review by the authors wherever 
possible. If you identify any issues, please contact us.
Publisher’s note
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or those of the publisher, the editors and the reviewers. Any product 
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manufacturer, is not guaranteed or endorsed by the publisher.
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