Journal Pre-proof

Minimally Invasive Surfactant Therapy versus Intubation for Surfactant Administration

in Very Low Birth Weight Infants with Respiratory Distress Syndrome

Xing-An Wang, Lih-Ju Chen, Shan-Ming Chen, Pen-Hua Su, Jia-Yuh Chen

PII: S1875-9572(19)30542-X
DOI: https://doi.org/10.1016/j.pedneo.2019.11.002
Reference: PEDN 980

To appear in: Pediatrics & Neonatology

Received Date: 2 April 2019

Revised Date: 22 July 2019
Accepted Date: 5 November 2019

Please cite this article as: Wang X-A, Chen L-J, Chen S-M, Su P-H, Chen J-Y, Minimally Invasive
Surfactant Therapy versus Intubation for Surfactant Administration in Very Low Birth Weight
Infants with Respiratory Distress Syndrome, Pediatrics and Neonatology, https://doi.org/10.1016/
j.pedneo.2019.11.002.

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Copyright © 2019, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. All rights reserved.
 PEDN_2019_207_After Eng edited_final

Original Article

Minimally Invasive Surfactant Therapy versus Intubation for Surfactant

Administration in Very Low Birth Weight Infants with Respiratory

Distress Syndrome

Xing-An Wangb,1, Lih-Ju Chena,c,1, Shan-Ming Chenb, Pen-Hua Sub,c, Jia-Yuh Chena,c,*

a
Division of Neonatology, Department of Pediatrics, Changhua Christian Children’s

Hospital, Changhua city, Taiwan

b
Division of Neonatology, Department of Pediatrics, Chung-Shan Medical University

Hospital, Taichung, Taiwan

c
Institute of Medicine, Chung-Shan Medical University, Taichung, Taiwan

Running title: Minimally invasive surfactant therapy

*Corresponding author. Department of Pediatrics, Changhua Christian Children’s

Hospital , No. 320 Xuguang Road, Changhua City, Changhua 50050, Taiwan.

Fax: +886 4 7238847

E-mail address: 182288@cch.org.tw (J.Y. Chen)

1
The first two authors contributed equally to this article.
Background: Minimally invasive surfactant therapy (MIST) is a new mode of

surfactant administration without intubation to spontaneously breathing preterm

infants with respiratory distress syndrome (RDS). The aims of this study were to

assess the feasibility, efficacy and safety of using MIST to give surfactant for very low

birth weight (VLBW) infants with RDS.

Methods: In total, 53 VLBW infants who were born before 32 gestational weeks with

spontaneous breathing, respiratory distress, and requiring surfactant therapy were

divided into two groups. The infants in group A (n = 29) were intubated and received

surfactant replacement therapy via endotracheal tube, followed by mechanical

ventilation (MV). The infants in group B (n = 24) received tracheal instillation of

surfactant via a semirigid vascular catheter during spontaneous breathing under

nasal continuous positive airway pressure (nCPAP). After surfactant instillation, the

infants in group B were still placed on nCPAP.

Results: Our data showed that infants in group B (MIST group) had significantly lower

rate (P <0.05) of composite outcome of death or bronchopulmonary dysplasia (BPD),

duration of intermittent positive airway pressure ventilation (IPPV) or MV, drug

treatment of patent ductus arteriosus (PDA), and surgical ligation of PDA than group

A.
Conclusion: MIST is feasible, safe and it may reduce the composite outcome of death

or BPD for VLBW infants with RDS requiring surfactant replacement therapy.

Key Words:

bronchopulmonary dysplasia;

minimally invasive surfactant therapy;

respiratory distress syndrome;

surfactant
1. Introduction

Administration of endotracheal surfactant is potentially the main treatment for

preterm infants with RDS, which is followed by mechanical ventilation (MV).1 The

American Academy of Pediatrics (AAP) has recommended that using CPAP

immediately after birth with subsequent selective surfactant administration may be

considered as an alternative to routine intubation with prophylactic or early

surfactant administration in preterm infants.2 The AAP has also recommended that

preterm infants born at <30 weeks’ gestation who need mechanical ventilation

because of severe RDS should be given surfactant after initial stabilization.3 INSURE

(intubation, surfactant administration and extubation) method has been reported to

decrease the need for mechanical ventilation.4,5 The European consensus guidelines

on the management of RDS have recommended that MIST as an alternative to

INSURE if your unit has appropriate expertise.6 MIST or less invasive surfactant

administration (LISA) in preterm infants with RDS has been reported to lead fewer

complications.7—26 Avoiding endotracheal ventilation has also been reported to

prevent BPD.27

The aims of this study were to evaluate the feasibility, efficacy and safety of

using MIST to deliver surfactant for VLBW infants with RDS requiring surfactant

administration.
2. Materials and methods

2.1. Study design

We conducted a retrospective analysis of data from VLBW infants with spontaneous

breathing and respiratory distress requiring surfactant replacement therapy.

Between July 2015 and July 2018, in total 53 VLBW infants who were born before 32

gestational weeks were enrolled in this study. All 53 VLBW infants received nCPAP 4-8

cmH2O initially; however, respiratory distress (including intercostal retractions, nasal

flaring, tachypnea and cyanosis) was persistent. Chest radiographs had positive

findings of air bronchograms and diffuse reticular-granular infiltrates, often

progressing to severe bilateral opacity. All 53 VLBW infants required a fraction of

inspired oxygen (FiO2) ≧0.4 to maintain oxygen saturation above 90 percent. In

total, 29 preterm infants (group A) were intubated and received surfactant (Survanta,

AbbVie Inc. North Chicago, Illinois, USA, 100 mg/kg; 4 ml/kg) replacement therapy

via endotracheal tube, followed by mechanical ventilation (Babylog VN 500, Dräger,

Lübeck, Germany). In total, 24 infants (group B) received tracheal instillation of

surfactant (Survanta, AbbVie Inc., North Chicago, Illinois, USA, 100 mg/kg; 4 ml/kg)

via a semirigid 16-gauge vascular catheter (Angiocath, BD, Sandy, Utah, USA) during

spontaneous breathing under nCPAP. The depth of catheter insertion beyond the

vocal cords was 1 cm for infants 25—26 weeks, 1.5 cm for infants 27—28 weeks, and
2 cm for infants 29—32 weeks. MIST procedure was performed with direct

visualization of the vocal cords with a laryngoscope. After catheter placement, the

laryngoscope was removed and surfactant was instilled intratracheally for 1—3

minutes. After instillation, the catheter was immediately removed and infant was still

placed on nCPAP. The patterns of surfactant instillation were decided by

neonatologists of our neonatal intensive care unit (NICU). Surfactant instillation via a

vascular catheter was performed by two neonatologists (Dr. Xing-An Wang and Dr.

Jia-Yuh Chen), because these two neonatologists were familiar with the procedure of

MIST. Our NICU was a level-III NICU.

2.2 Study population

Between July 2015 and July 2018, in total 53 VLBW infants with RDS requiring

surfactant replacement therapy were enrolled in this study. All infants had birth

weight (BW) < 1500 grams and gestational age (GA) < 32 weeks. The mean BW was

1140.52 ± 176.72 grams (ranging from 580 to 1450 grams) and the mean GA was

28.66 ± 1.42 weeks (ranging from 23 + 3/7 to 31 + 5/7 weeks) in group A. The mean

BW was 1239.92 ± 197.41 grams (ranging from 610 to 1450 grams) and the mean

GA was 29.41 ± 1.58 weeks (ranging from 24 + 1/7 to 31 + 6/7 weeks) in group B.

Infants with BW > 1500 grams or GA > 32 weeks or infants with congenital

malformation or infants intubated immediately after birth were excluded from this
study.

2.3. Ventilation strategy

During the acute phase of illness, infants with mechanical ventilation were placed in

the assist/control (A/C) mode. Initial setting: were rate 30—40 breaths per minute

(bpm), inspiratory time (i-time) 0.4 seconds, positive end-expiratory pressure (PEEP)

4—8 cmH2O, and peak inspiratory pressure (PIP) 12—25cmH2O adapted to babies’

chest movement and CO2 elimination. Once the infants were recovering from their

acute illness (PIP < 18 cmH2O and FiO2 < 0.3), the ventilatory mode was changed

from A/C to synchronized intermittent mandatory ventilation (SIMV) mode. The

target arterial blood gases were to keep pH from 7.20 to 7.45, PaO2 from 50 to

80mmHg, PaCO2 from 35 to 60mmHg, and SpO2 from 90 to 95%. If the following

ventilatory settings were reached, extubation was considered: PIP <16cmH2O, PEEP

<5cmH2O, rate ≦20bpm, and FiO2 ≦0.3. After extubation, the infants were placed

on nasal bubble CPAP, using 4 to 6 cmH2O delivered through short binasal prongs.

Infants in MIST group (group B) received nasal bubble CPAP 4 to 8 cmH2O. If infants in

group B could not tolerate nasal bubble CPAP, nasal intermittent positive pressure

ventilation (nIPPV) would be used. If infants could not tolerate nIPPV, then intubation

with mechanical ventilation would be used.

2.4. Definitions
RDS was diagnosed on the basis of radiologic and clinical findings. BPD was defined

as treatment with fraction of inspired oxygen (FiO2) >0.21 for at least 28 days plus

failure of room air challenge test with or without support at 36 weeks’ postmenstrual

age. Sepsis was defined as a positive blood culture and treatment for at least 7 days

with antibiotics. Intraventricular hemorrhage (IVH) was defined as either IVH with or

without ventricular dilatation or intracerebral (parenchymal) hemorrhage on cranial

ultrasound.28 Pulmonary hemorrhage was defined as detecting blood in the

endotracheal tube and positive chest radiographic finding of focal or diffuse

ground-glass opacities. NEC was defined as infants diagnosed with NEC≧stage IIA

(Bell’s classification). ROP was defined according to international classification.29 This

study was approved by the Ethics Committee at Chung Shan Medical University

Hospital.

2.5. Statistical analysis

IBM SPSS, Version 22 for Windows software package (IBM SPSS Inc., Chicago, IL, USA)

was used for recording data and analyzing results. Means were compared by

Student’s t-test, Chi-square test or Fisher’s exact test for categorical data as

appropriate. A two-sided p-value of <0.05 was considered as statistically significant.

3. Results

Characteristics of the study infants are summarized in Table 1. There was no

significant difference (P >0.05) in birth weight, gestational age, gender, Apgar scores,

type of delivery, multiple births, premature rupture of the membrane (PROM),

meconium stained amniotic fluid, serum glucose levels, initial arterial blood gas

(PaO2, PaCO2, pH), age of initial surfactant administration, intrauterine growth

restriction (IUGR) and doses of surfactant administration between group A

(intubated group) and group B (MIST group). Outcomes of the study infants are

summarized in Table 2. There was no significant difference (P >0.05) in the duration

of oxygen therapy between these two groups. The duration of mechanical ventilation

was significantly longer (P <0.001) in group A than group B and the duration of nCPAP

was significantly longer (P <0.001) in group B than group A. However, there was no

significant difference (P >0.05) in total duration of MV and nCPAP between these two

groups. Only 2 patients in MIST group required intubation and they received MV later

in group B (MIST group). Seven patients in group B received nIPPV therapy later, and

the other 15 patients in group B received nCPAP only after MIST. Significantly fewer

(P = 0.036) infants received drug treatment of PDA and significantly fewer (P = 0.006)

infants received PDA ligation in group B than group A. Although the incidence of BPD
or death did not reach statistically significant difference (P >0.05), the composite

outcome of death or BPD was significantly lower (P = 0.038) in group B than group A.

There was no significant difference (P >0.05) in the incidence of IVH grade 1—2, IVH

grade 3—4, Retinopathy of prematurity (ROP) stage 1—2, ROP stage 3, ROP with

laser therapy, sepsis, metabolic bone disease, or necrotizing enterocolitis (NEC)

between these two groups. There was a trend in which more infants (P = 0.056) in

group A developed pulmonary hemorrhage than group B.

4. Discussion

The combination of prenatal corticosteroids and postnatal surfactant in the

prophylaxis and treatment of RDS has significantly improved neonatal outcomes by

reducing both respiratory morbidity and mortality.1,6 The AAP has recommended that

using CPAP immediately after birth with subsequent selective surfactant

administration may be considered as an alternative to routine intubation with

prophylactic or early surfactant administration in preterm infants.2 Noninvasive

ventilation strategies including nCPAP, nIPPV, and bilevel continuous positive airway

pressure (BiPAP) have replaced intubation and mechanical ventilation as the initial

intervention providing positive ventilation to reduce the risk of atelectasis.6,30

However, for some patients who do not adequately respond to nCPAP, nIPPV or BiPAP,

intubation and mechanical ventilation with PEEP may be needed. INSURE method

has been reported to decrease the need for mechanical ventilation; 4,5,31 however,

INSURE method needs intubation for infants with RDS.27 It has been reported that

avoiding endotracheal ventilation can prevent BPD.

It has been reported that MIST or LISA technique for surfactant delivery via a

vascular catheter or a nasogastric tube resulted in a lesser need of mechanical

ventilation for preterm infants with RDS.7—26 In this study, we used a semirigid
16-gauge vascular catheter during spontaneous breathing under nCPAP for surfactant

instillation rather than nasogastric tube. Usually, this semirigid vascular catheter did

not need the aid of Magil forceps to give surfactant instillation.8 In this study, only 2

of the 24 patients in MIST group required intubation and they received MV later.

Seven of the 24 patients in MIST group received nIPPV therapy later, and the other

15 patients in MIST group received nCPAP therapy only after MIST. Both nIPPV and

nCPAP are non-invasive ventilation therapies. The duration of intubation and MV was

significantly shorter (P <0.001) in MIST group than in intubated group. Our data

showed that MIST could decrease the incidence of intubation with MV, drug

treatment for PDA, surgical ligation of PDA, and composite outcome of death or BPD.

The same findings were reported previously.14,17,22,25,26 Strategies aimed at avoiding

endotracheal mechanical ventilation in infants <30 weeks’ GA had a beneficial impact

on preventing BPD as reported by Fisher et al.27 It was reported that MIST resulted in

a rapid and homogenous increase in end-expiratory lung volume, which was

associated with an improvement in oxygenation.32 It was also reported that, in

addition to improved oxygenation, MIST resulted in a decrease in breathing effort

measured by transcutaneous electromyography of the diaphragm activity in preterm

infants with RDS.33 An animal study also showed that the initial lung tissue

association of exogenous surfactant was impaired by mechanical ventilation.34 This

was associated with a reduction of dynamic compliance and evidence of increased

surfactant inactivation.34 In this study, MIST decreased the incidence of PDA, drug

treatment of PDA, and surgical ligation of PDA, as reported elsewhere.23,35 Isayama et

al. reported that the use of LISA was associated with the lowest composite outcome

of death or BPD among noninvasive ventilation strategies.36 Although not reaching

statistically significant difference (P = 0.056), there was a trend of fewer patients in

MIST group developing pulmonary hemorrhage in this study. This might be due to

less pulmonary injury by MIST method than by giving surfactant via endotracheal

tube. No major complications were found in performing MIST in this study.

There are several limitations in this study. First, it is a retrospective study.

Second, it is a single-center study. Finally, the sample size is small.

We conclude that MIST technique is a feasible, safe and efficacious method to

deliver surfactant instillation via a thin vascular catheter during spontaneous

breathing on nCPAP. MIST reduce the duration of mechanical ventilation and may

reduce the composite outcome of death or BPD for VLBW infants with RDS.
Conflict of interest

The authors have no conflicts of interest relevant to this article.

Acknowledgements

The authors thank neonatologists and nursing stuff in our NICU for caring for the

sick preterm infants.

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Table 1 Characteristics of the included patients.
Group A (n = 29) Group B (n = 24) P value
(Intubated group) (MIST group)
BW (g) 1140.52 ± 176.72 1239.92 ± 197.41 0.059
GA (wk) 28.66 ± 1.42 29.41 ± 1.58 0.071
Gender (m/f) 17/12 14/10 0.983
Apgar score (1st min) 4.86 ± 1.41 4.92 ± 1.24 0.872
Apgar score (5th min) 7.46 ± 1.14 7.54 ± 0.98 0.793
Delivery 0.883
NSD (n) 9 (31.0%) 7 (29.2%)
C/S delivery (n) 20 (69.0%) 17 (70.8%)
Multiple births 0.504
Single (n) 22 (75.9%) 20 (83.3%)
Twin (n) 7 (4.1%) 4 (16.7%)
PROM (n) 8 5 0.570
Meconium stained 0 0 1.0
amniotic fluid (n)
Serum glucose (mg/dL) 62.43 ± 23.09 65.83 ± 24.00 0.607
Initial arterial blood gas
PaO2 (mmHg) 70.81 ± 18.27 73.29 ± 14.20 0.432
PaCO2 (mmHg) 45.75 ± 13.99 50.52 ± 12.93 0.444
pH 7.28 ± 0.07 7,27 ± 0.08 0.729
Age of 1st dose surfactant 1.84 ± 1.35 2.33 ± 2.82 0.724
therapy (hrs)
IUGR 0.709
AGA (n) 23 (79.3%) 20 (83.3%)
SGA (n) 6 (20.7%) 4 (16.7%)
Doses of surfactant used 1.39 ± 0.69 1.17 ± 0.38 0.141
1 dose (n) 20 18
2 doses (n) 9 6
Data are expressed as the mean ± standard deviation; MIST: minimally invasive
surfactant therapy; BW: birth weight; GA: gestational age; m: male; f: female; NSD:
normal spontaneous delivery; C/S: cesarean section; PROM: premature rupture of
membrane; IUGR: intrauterine growth restriction; AGA: appropriate for gestational
age; SGA: small for gestational age
Table 2 Outcomes of the included patients.
Group A (n = 29) Group B (n = 24) P value
(Intubated group) (MIST group)
Duration of O2 therapy (d) 23.93 ± 15.34 20.79 ± 10.08 0.394
Duration of MV (d) 15.55 ± 10.50 2.63 ± 5.25 <0.001
Duration of nCPAP (d) 6.31 ± 5.69 14.46 ± 8.21 <0.001
Duration of MV+nCPAP (d) 21.86 ± 12.36 17.08 ± 9.35 0.125
No. of intubation+MV (%)* 29 (100%) 2 (6.9%) <0.001
No. of nIPPV or MV (%)* 29 (100%) 9 (31%) <0.001
No. of drug treatment for PDA (%)* 22 (75.9%) 13 (54.2%) 0.036
No. of PDA ligation (%)* 8 (27.6%) 0 (0) 0.006
BPD (%)* 13 (44.8%) 5 (20.8%) 0.066
Death (%)* 1 (3.4%) 0 (0) 1.000
BPD or death (%)* 14 (48.3%) 5 (20.8%) 0.038
Air leak (%)* 2 (6.9%) 0 (0) 0.495
IVH grade 1—2 (%)* 8 (27.6%) 4 (16.7%) 0.512
IVH grade 3—4 (%)* 2 (6.9%) 0 (0) 0.495
ROP stage 1—2 (%)* 8 (27.6%) 5 (20.8%) 0.570
ROP stage 3 (%)* 2 (6.9%) 1 (4.2%) 1.000
ROP with laser therapy (%)* 1 (3.4%) 1 (4.2%) 1.000
Sepsis (%)* 2 (6.9%) 0 (0) 0.495
Pulmonary hemorrhage (%)* 5 (17.2%) 0 (0) 0.056
Metabolic bone disease (%)* 2 (6.9%) 0 (0) 0.495
NEC (%)* 1 (3.4%) 0 (0) 1.000
*Fisher’s exact test, data are mean ± standard deviation
MV: mechanical ventilation; d: days; nCPAP: nasal continuous positive airway
pressure; No.: number; nIPPV: nasal intermittent positive pressure ventilation; PDA:
patent ductus arteriosus; No: number; BPD: bronchopulmonary dysplasia; IVH:
intraventricular hemorrhage; ROP: retinopathy of prematurity; NEC: necrotizing
enterocolitis.