Background Management of neonatal respiratory distress syndrome (RDS) involves
noninvasive respiratory supports, such as nasal continuous positive airway (nCPAP), and
mechanical ventilation. On the other hand, exogenous surfactant administration is the
other cornerstone for the treatment of RDS. Currently, the decision to administer
surfactant in a non-invasively ventilated newborn is commonly based on cut-off values of
inspired fraction of oxygen (FiO2). Nevertheless, the accuracy of this criterion might be
weak because FiO2 values depend per se by the setting of respiratory support. Moreover,
the American Academy of Pediatrics guidelines do not recommend any FiO2 threshold for
surfactant administration. It has been shown that prompt administration of surfactant
(within the first 3 hours of life) can reduce the risk of bronchopulmonary dysplasia
(BPD). Unfortunately, criteria for surfactant treatment used, often leads to a delayed
administration. The role of lung ultrasound (LU) as a semi-quantitative method for the
decision to give exogenous surfactant has been studied in recent years. Researchers
demonstrated that a LU score (LUS) of RDS severity is able to predict the need for
surfactant therapy, as subsequently confirmed by subsequent studies. After these results,
a first quality improvement study demonstrated that the use of a LUS cut-off for deciding
surfactant treatment allowed a significant increase of early administration. This finding
has been confirmed by a recent single-center randomized controlled trial. However, all
these studies were single-center, and there are not multicenter randomized controlled
trials which can support the wide use of LUS measurement as a standard method for
surfactant replacement therapy.
This study, in addition to investigating the decision-making role of LUS in the
administration of surfactant, also aims to evaluate the possibility of making treatment
with surfactant earlier and more timely, having already been shown in the past that an
early administration improves clinical outcomes.
Aim of the study The investigators hypothesized that the use of a LUS for measuring RDS
severity and deciding surfactant treatment thresholds might decrease the incidence of
early and late sequelae in the study group. Thus, a timely surfactant therapy would
eventually improve short (e.g. Need of mechanical ventilation in the first 3 days) and
more long-term outcomes, such as BPD or death.
To confirm this hypothesis, the investigators planned an international multicenter
randomized controlled study in which preterm infants will be randomized into two groups:
one will be managed deciding surfactant treatment of preterm infants with RDS on the
basis of a cut-off value of FiO2 (CG), and one will be managed deciding surfactant
treatment using a LUS cut-off and FiO2 (LUSG).
Study design The study will be a multicenter randomized open control trial carried out in
Level III-IV neonatal intensive care units (NICUs). The financial outcome of the study is
no profit. The design of the study is of superiority. The enrollment period will be 24
months (starting February 1, 2022).
Study population The study will take place within the NICUs and therefore in a hospital
setting. The study will be multicenter.
The total number of enrolled infants will be 668 (334 per arm). Each center will have to
enroll a minimum of 10 children and a maximum of 70.
An interim analysis will be conducted after 167 infants enrolled in each arm (334 total
infants enrolled).
Management in the delivery room and in the first hour of life Positive pressure with a
neonatal mask and a T-piece system (Neopuff Infant Resuscitator ®, Fisher and Paykel,
Auckland, New Zealand) will be used to stabilize the newborns after birth as per routine
daily practice. If necessary, infants will start mechanical ventilation in agreement with
the European guidelines on neonatal resuscitation. In this latter case the babies will be
excluded from the study (see Exclusion criteria section).
In order to better standardize the timing of care after birth, it is expected that
assistance in the delivery room, transfer of the newborn to the intensive care unit,
stabilization of the newborn and the related procedures (positioning of the vascular
access, stabilization of ventilatory parameters, thermal stabilization, etc.) are
completed within the first hour of life.
Once infants with RDS have been screened, enrolled in the study, and allocated to the CG
or LUSG, LU will be performed as soon as possible between 1 and 3 hours life (<3 h of
life). In the meantime, the newborns will be assisted in noninvasive ventilation (nCPAP,
pressure 6-8 cmH20) and oxygen to maintain preductal oxygen saturation (SpO2) between 90
and 95%. A loading dose of caffeine citrate of 20 mg/kg will be administered in the first
hours of life followed by a maintenance of 5 mg/kg/day, as per routine clinical practice.
Noninvasive ventilation management after the first 3 hours of life or after surfactant
administration After the first three hours of life or after having administered
surfactant, according to the criteria provided by the randomization group, the newborns
can be assisted with non-invasive ventilation other than nCPAP (NIPPV, BiPAP, HFNC)
according to the care protocol of the centers involved in the study.
Lung ultrasound procedure LU will be performed by the attending physician. Centers
participating to the study should be routinely using LU and all the physician are already
trained for the use of the technique.
LUS will be calculated by performing longitudinal scans of the chest in the anterior
(midclavicular line), lateral (anterior axillary line) and posterior (posterior axillary
line) area bilaterally using high-frequency linear or micro linear (hockey stick) probe
between 1 and 3 hour of life. The focus will be located at the level of the pleural line.
A score from 0 to 3 will be assigned to each scan area based on the ultrasound detected
pattern (in case of different score pattern in the same area the worst will be the one
chosen).
LU can be performed keeping the patient in the supine position without the need to rotate
him as the posterior axillary line is accessible from the side of the newborn.
Surfactant replacement therapy should be given if LUS is 9 or more in the babies
recruited to the LUSG.
The LUS group will receive as rescue therapy surfactant administration in case of LUS <
or = 8 but FiO2> 0.30 on nCPAP (pressure 6-8 cmH20) to maintain preductal SpO2 between 90
and 95%.
Surfactant treatment Once criteria for surfactant administration have been reached,
surfactant (Curosurf ®, Chiesi, Parma, Italy) will be given (200 mg/kg) according to the
InSURE (Intubate-SURfactant-Extubate), LISA (Less- Invasive-Surfactant-Administration) or
IN-REC-SURE (INtubate-RECruit-SURfactant-Extubate) technique in both the groups as per
the enrollment center protocol.
Pharmacological premedication with fentanest and/or atropine will be allowed (as per
center protocol) and recorded.
After surfactant administration, the babies of both groups will be extubated if it has
been performed the InSURE or IN-REC-SURE method within 30 min (if satisfactory
respiratory drive is present) and will receive nCPAP (pressure 6-8 cmH2O) as per center
protocol .
Infants of both groups can receive a subsequent dose of surfactant (100 mg/kg of
poractant alfa) using the same method if they meet the non-invasive ventilation failure
criteria again during the following 12 to 24 h.
nCPAP ventilation failure criteria In the NICU, nCPAP will be the standard method of
noninvasive support in all infants recruited to this trial. nCPAP failure is defined if
any of the following criteria are met: FiO2 ≥ 0.30 to maintain a SpO2> 90 for at least 30
min unless rapid clinical deterioration has occurred; respiratory acidosis defined as
pCO2 > 65 mmHg (8.5 kPa) and pH <7.20 on an arterial or capillary blood gas sample; apnea
defined as more than four episodes of apnea per hour or more than two episodes of apnea
per hour when ventilation with bag and mask or Neopuff will be required.
Mechanical ventilation should commence if the patient meets one of the following criteria
after additional dose of surfactant: pCO2 > 65 mmHg and pH <7.20, or paO2 <50 mm Hg, or
FiO2 >0.40 after surfactant administration or in case of apnea (> 4 episodes in 1 hour or
> 2 episodes in 1 hour ventilation with bag and mask or Neopuff ), and should continue
with the aim of maintaining a pCO2 of 55-65 mmHg and a SpO2 of 90-95%, using synchronized
Mechanical Ventilation (MV), volume controlled MV, or high frequency ventilation.
Patients will be extubated as per center protocol.
