STUDY PROTOCOL

TITLE
Volume-Targeted Ventilation versus PressureLimited Ventilation in Respiratory Distress
Syndrome in Prematurely Born Infants- Randomized Controlled Trial.
INTRODUCTION
Invasive mechanical ventilation is a life-saving modality which is largely used in neonatal
intensive care units, particularly in very premature newborn infants. Maintenance of adequate
gas exchange is the primary goal of ventilator support and must be achieved with minimum lung
injury and least possible degree of hemodynamic impairment, while avoiding injury to distant
organs such as the brain.
In neonates there is evidence that excessive tidal volume, rather than high inspiratory
pressure, is the primary determinant of lung injury. With the application of microprocessor
controlled volume guaranteed pressure-limited, time cycled ventilation which combines the
advantages of pressure-limited ventilation (PLV) with guaranteed volume its able to deliver a
more consistent VT breath compared to pressure-limited ventilation alone.
REVIEW OF LITERATURE
In 1997 Sinha et al studied VTV Vs PLV and found volume targeted ventilation was both safe
and efficacious, who weighed more than 1200 g and also volume controlled ventilation achieved
successful outcome criteria sooner and had fewer complications. In 2013 Chowdhury et al done
similar study on PLV vs VTV in acute respiratory Failure in prematurely born infants and
concluded that VTV did not reduce the time to reach weaning criteria but was associated with a
reduction in episodes of hypocarbia. In 2010 Wheeler k et al done a Cochrane study on Volume
-targeted versus pressure-limited ventilation in the neonate. Reviewed twelve randomised trials
(nine parallel trials (629 infants) and three crossover trials (64 infants) they concluded that
Infants ventilated using VTV modes had reduced death and chronic lung disease compared with
infants ventilated using PLV modes. They also recommended further studies are needed to
identify whether VTV modes improve neurodevelopmental outcomes and to compare and refine
VTV strategies.

NEED OF THE STUDY

There is always a need to reduce the number of hours of invasive ventilation due to the known
complications it causes. This study focusses to compare the duration of either modalities in the
specified population as recent literature support there is a difference.
AIM OF THE STUDY
To determine whether volume targeted ventilation compared with pressure limited ventilation
reduced the time to reach weaning criteria in prematurely born infants with Respiratory Distress
Syndrome.
HYPOTHESIS
Volume targeted ventilation(VTV) reduces the time to reach weaning criteria compared to
pressure limited ventilation(PLV) in prematurely born infants diagnosed with respiratory distress
syndrome
NULL HYPOTHESIS
Volume targeted ventilation(VTV) and pressure limited ventilation(PLV) does not have any
difference in the time to reach weaning criteria prematurely born infants diagnosed with
respiratory distress syndrome
METHODOLOGY
Study population
All preterm neonates of 27- 34 weeks ventilated within first day of life, admitted to the Neonatal
Intensive Care Unit (NICU), Kasturba Hospital, Manipal, Udupi District,
Inclusion criteria
1. All preterm neonates of 27- 34 weeks ventilated within first day of life.
Exclusion criteria

1. Neonates with congenital cyanotic heart diseases.

2. Neonates with major congenital malformations.
3. Neonates with air leak syndromes.
4. Neonates requiring High Frequency Oscillatory Ventilation (HFOV)
Study period
March 2016 to July 2017
Study design
Randomized controlled trial
All the Infants included in the study will be stratified into two groups by block randomization,
Group 1 born within the gestational week from 27-30 and Group 2 born at gestational week of
31-34. Sealed opaque envelope will be used to randomize into two treatment modalities.

Preterm
Neonates
(27-34 wks)

Gestational
age 27-30
weeks

A
PLV

Gestational
age 31-34
weeks

B
VTV

A
PLV

Figure 1 Flow chart representing stratified random sampling

B
VTV

Sample size
Sample size is calculated based on expert dependent sample size formula which we calculated as
130, 65 each in both arms.
Infant details like date of birth, admission, gestational age, birth weight, gender, APGAR score,
prenatal steroid administration, mode of delivery, basic vitals on admission are to be recorded.
Monitoring devices used will be Phillips Intellivue MP20 for monitoring vitals, Phillips
M11193A for SpO2 monitoring, Phillips ETCO2 device for monitoring end tidal carbon dioxide.
The ventilators that would be used are Drager Babylog 8000. Ventilatory modes used are SIMVVG and SIMV-PC. Sponsorship for the study was asked with Drager ventilator company and
from SOAHS college.
Prophylactic early surfactant administration will be given based on severity of RDS, surfactant
administration based on the birth weight, infants born with birth weight 1000 gm. given
curosurf (2ml vial) containing 150 mg phospholipid, and infants born with >1000gm given
survanta (4ml vial) containing 100 mg phospholipid.
All the babies intubated with approximate size endotracheal tube based on Neonatal
Resuscitation Program (NRP) guidelines.
WEIGHT(g)

Gestational Age (wks.)

Tube
diameter)

<1000

<28

2.5

1000-2000

28-34

3.0

2000-3000

34-38

3.5

Criteria for Invasive ventilation

DOWN SCORE 4-7

size(mm)

(inner

Administration of surfactant therapy

Arterial blood gas sampling showing respiratory acidosis (pH7.2, PaCO 2 55mmHg,
PaO2 50mmHg with FiO2 40% on non-invasive ventilation

Block randomization technique is used, each of the eligible infant were randomized to either
VTV or PLV mode of ventilation.
The initial settings for the subject on VTV were volume target (VT) of 5ml/kg, PEEP of 46cmH2O, Ti of 0.35-0.45sec, respiratory rate (RR) of 35-45bpm and flow rate of 5-7 L/min and
fraction of inspired oxygen (FiO2) of 21-100%.
The initial settings for the subject on PLV were PIP of 14-18cmH 2O, PEEP of 4-6cmH2O, Ti of
0.35-0.45sec, respiratory rate 35-45bpm and flow rate of 5-7 L/min and FiO2 of 21-100%.
Monitoring

Ventilatory parameters such as Peak inspiratory pressure (PIP) and mean airway pressure
(MAP) in VTV and exhaled tidal volume and MAP in PLV.

Alveolar to arterial oxygen tension monitoring 12 th hourly.

Inflammatory markers at 24 hrs. 48 hrs. and 72 hrs. interval such as

STA-343:

OxiSelect Hydrogen Peroxide Assay Kit (Colorimetric): Cell Bio labs STA-318:
OxiSelect AOPP Assay Kit: Cell Bio labs.

End tidal carbon dioxide monitoring (ETCO2) every 2nd hourly

Cranial ultrasound within 24 hrs. of admission and at 4th week of admission or prior to
discharge.

Time to reach weaning criteria (hrs.)

Weaning criteria

In PLV group weaning criteria is met when PIP reaches 14cmH 2O, Fraction of Inspired
oxygen (FiO2) 0.3 and PEEP of 4-5cmH2O, Respiratory rate of 30 bpm.

In VTV group weaning criteria is met when PIP is 14cmH 2O targeting VT level of
5ml/kg, FiO2 0.3 and PEEP of 4-5cmH2O, Respiratory rate of 30 bpm.

Once the weaning criteria were met methylxanthines were administered aminophylline or
caffeine as per NICU protocol. (Aminophylline 5mg/kg bolus, after hr. 1.5 mg/kg till 34 weeks
of gestational age (GA) or caffeine 20 mg/kg bolus and after 5 mg/kg once a day till 34 weeks of
GA) and the neonate was extubated.
OUTCOME MEASURES
Primary outcome is to compare the time required to reach the weaning criteria by volume
targeted ventilation to pressure limited ventilation in prematurely born infants.
Weaning criteria is defined as

In PLV group when PIP reaches 14 cmH2O, FiO2 0.3 and PEEP of 4-5cmH2O.

In VTV group when PIP is 14 cmH 2O targeting VT level of 5ml/kg, FiO2 0.3 and
PEEP of 4-5cmH2O with Pulsatile saturation (SPO2) of 90- 95% and Heart rate (HR) of
120-140bpm within normal range.

The secondary outcome of the study is to compare VTV to PLV in relation to

Rate of failure
Oxygenation Index at 6th hourly
FiO2 to SpO2 ratio
PaO2 to FiO2 ratio
Episodes of hypocarbia at 2nd hourly
Duration of mechanical ventilation
Oxygen radicals
Complications such as
Broncho pulmonary dysplasia(BPD)
Periventricular leukomalacia(PVL)
Air leak syndrome
Intraventricular Hemorrhage (IVH)
Retinopathy of Prematurity (ROP)
Mortality

Failure criteria

Requirement of higher MAP of greater than 15 cmmH2O

OI of >15 for 3 consecutive hours.
Requirement of scaling up the ventilation strategy with high frequency ventilation of

inhaled nitric oxide upon treating physician decision.

Cross over to high frequency ventilation.