Academic Editor: Luca Roncati
Background: Recently, non-invasive ventilation has been widely used due to the reduction of adverse effects of endotracheal intubation. Nevertheless nearly no researches have compared the efficacy of non-invasive respiratory support between preterm twins. The objective of this study was to determine if there is a decreased non-invasive ventilation (NIV) failure from bi-level positive airway pressure (Bi-PAP) vs nasal continuous positive airway pressure (NCPAP) in preterm twins as initial ventilation. Methods: This prospective cohort study enrolled 100 pairs preterm twins who were admitted to the NICU at Yunnan Qujing Maternity and Child Health Care Hospital from 2017.10 to 2020.09 for respiratory distress syndrome. One of the twin was randomly assigned to Bi-PAP, meanwhile another to NCPAP. The primary outcome was the incidence of NIV failure. Secondary outcomes was the occurrence rate of side-effects of NIV. Results: A total of 100 pairs preterm twins were included in statistical analysis. No distinct differences were found in NIV failure between groups (NCPAP vs Bi-PAP, 5% vs 2%, p = 0.248). We did not find any statistical difference in secondary outcome between Bi-PAP and NCPAP. Conclusions: In this prospective cohort study, among preterm twins with RDS, NCPAP was noninferior to Bi-PAP with respect to the reduction of the need for invasive mechanical ventilation (IMV).
Respiratory distress syndrome (RDS) is the leading cause of death among preterm
in NICU, with extensive alveolar collapse and decreased pulmonary compliance due
to pulmonary surfactant (PS) deficiency [1, 2]. The death rate of preterm infants
greatly reduced due to the introduction of mechanical ventilation. However it was
followed by a series of acute complications and chronic complications such as air
leak syndrome, abdomen distends, subglottic stenosis, bradycardia, infection,
bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP) and
intraventricular hemorrhage (IVH) [3, 4, 5]. In the treatment of RDS, non-invasive
ventilation (NIV) was recommended by European Consensus Guidelines and American
Academy of Pediatrics [6, 7]. Continuous positive airway pressure (CPAP) is the
most widely used non-invasive respiratory supports. CPAP is a ventilation
technique that provides a constant positive pressure for the inhalation and
exhalation phases of preterm infants with spontaneous breathing, which can
increase functional residual capacity (FRC) and oxygen partial pressure (PaO
We conducted a prospective cohort study of 100 pairs preterm twins who were admitted to the NICU at Yunnan Qujing Maternity and Child Health Care Hospital from 2017.10 to 2020.09 for respiratory distress syndrome requiring respiratory support. Each of the twins involved were randomly assigned to the NCPAP group or the Bi-PAP group in a 1:1 ratio. In other words, one of a pair was randomly distributed to Bi -PAP, meanwhile another to NCPAP. The study was approved by the local ethics committees and registered at www.chictr.org.cn Number: ChiCTR2100045680 (registration date, 23 April 2021). All parents of the newborns signed the written informed consent form before participation in the study.
Patients meeting the following criteria were included in the study: (1)
gestational age(GA)
Exclusion criteria included: intubation for any reason; congenital abnormality of the airway, esophagus or lungs, congenital heart disease, pneumorrhagia, inherited disease, intraventricular hemorrhages or sepsis.
Clinical manifestations and chest X-ray findings are the main basis for diagnosis of RDS. The main clinical manifestations of RDS are nasal flaring, respiratory distress, tachypnea, and cyanosis and grunting showing up within the first 24 h of life. Grain shadow, air bronchogram or white lung were the typical X-ray picture of RDS [20].
Noninvasive respiratory support criteria were defined as follows [21]: (1) Early
prophylactic use in the delivery room for the extremely premature infants
(gestational age 25–28 weeks) with spontaneous breathing; (2) Preterm infants
who are at high risk for RDS (gestational weeks
Continuous positive airway pressure system provides for NCPAP (CareFusion,
Stephan, Fabian). Infants on NCPAP received positive end expiratory pressure
(PEEP) of 6 cm H2O initially, which was adjusted between 6 and 8 cm H2O according
to the condition of infant’s respiratory. FiO
Bi-PAP was provided by Infant Flow-driver device (CareFusion, Fabian). Infants
on Bi-PAP received higher CPAP level (Phigh) of 8 cm H2O initially, which was
adjusted to between 8–9 cm H2O. Lower CPAP level (Plow) was 5 cm H2O initially
and adjusted to be between 4–6 cm H2O. T High (Time upper level): 0.6–0.7 s,
rate: 30–40 breaths/min. FiO
Criteria for intubation or NIV failure: There was no improvement or persistent
aggravation after the use of non-invasive respiratory support (shortness of
breath, groaning, three depressions and cyanosis without relief), accompanied by
the following conditions: (1) PaO
Surfactant (Curosurf; 200 mg/kg) treatment was conducted by the INSURE
(intubation, surfactant, extubation) technique in the case of FiO
Caffeine (Caffeine Citrate Injection) was recommended for RDS to avoid apnea. 20 mg/kg was for an initial dose, 5–10 mg/kg was for a maintenance dose [22].
The primary outcome was the incidence of NIV failure or the need for intubation and IMV, the time of the follow-up was 4 weeks after discharge.
Secondary outcomes included the length of hospital day, intraventricular
hemorrhage (IVH)
Student’s t test was used to determine the statistical significance of differences between groups if the continuous data were normally distributed and described by the means and standard deviations (SDs).The nonparametric H test was used for abnormal distribution. The categorical variable were described as rates and percentages by means of Fisher’s exact test or chi-square analysis. p values were judged significant if they were less than 0.05. All statistical data analyses were accomplished with the use of SPSS statistical software (version 22.0, IBM Corp., Armonk, NY, USA ).
256 patients admitted to NICU at Yunnan Qujing Maternity and Child Health Care Hospital, parents of 234 infants were consented. 16 infants were transferred to another site and 8 patients discharge within 24 hours after admission. 10 infants (3.9%) were excluded from this study. Of the 10 excluded neonates, 2 neonates were diagnosed with congenital malformation. 8 neonates were excluded for congenital heart disease; Thus, a total of 200 preterm infants were enrolled in final (Fig. 1). Of the 200 study-eligible infants (91 females, 109 males),the average gestational age was 33-week (range 27–36 weeks) and a birth weight ranging from 670 g to 2900 g. General clinical characteristics of newborn babies are summarized in Table 1. Baseline characteristic were similar between the two studied groups.
Flow chart of infants’ recruitment.
Parameter | Bi-PAP (n = 100) | NCPAP (n = 100) | p |
GA | 33 (31–34) | 33 (31–34) | 1 |
BW | 1700 (1450–2000) | 1677 (1440–1900) | 0.580 |
Gender (Male) | 59 | 50 | 0.201 |
1 Apgar score | 8 (7–8) | 8 (7–8) | 0.939 |
5 Apgar score | 8 (8–8) | 8 (8–8) | 0.828 |
10 Apgar score | 8 (8–8) | 8 (8–8) | 0.378 |
SNAPPE II | 0 (0–12) | 0 (0–12) | 0.820 |
Caesarean birth | 66 | 66 | 1 |
Premature rupture of membranes | 51 | 51 | 1 |
Antenatal corticosteroids | 51 | 51 | 1 |
Diabetes | 3 | 3 | 1 |
Cholestasis of pregnancy | 1 | 1 | 1 |
Pernicious placenta previa (PPP) | 3 | 3 | 1 |
NCPAP, nasal continuous positive airway pressure; Bi-PAP, Bi-level positive airway pressure; GA, gestational age week; BW, birth weight; p, p-value of Bi-PAP vs NCPAP. |
Primary and secondary outcomes are shown in Table 2.The difference was not
statistically significant in NIV failure between NCPAP and Bi-PAP (NCPAP vs
Bi-PAP, 5% vs 2%, p = 0.248). Secondary outcomes did not differ
significantly between the NCPAP and Bi-PAP groups. No differences were noted in
the incidence of NEC (1% vs 0%), ROP (15% vs 13%), BPD (31% vs 29%), PS
treatment (67% vs 70%), IVH
Parameters | Bi-PAP (n = 100) | NCPAP (n = 100) | p |
IMV | 2 | 5 | 0.248 |
NEC | 0 | 1 | 0.368 |
ROP | 13 | 15 | 0.976 |
PNX | 0 | 0 | 1 |
BPD | 29 | 31 | 0.585 |
PS treatment | 70 | 67 | 0.648 |
Caffeine treatment | 47 | 43 | 0.570 |
Nosocomial infection | 9 | 10 | 0.809 |
IVH | 14 | 15 | 0.934 |
death | 2 | 2 | 1 |
Abdomen distends | 22 | 29 | 0.256 |
HS | 23 (16–38.75) | 24.5 (16.25–40.75) | 0.715 |
expenses | 35578.56 (23962.0–63765.88) | 35355.78 (22945.57–65262.19) | 0.854 |
Neurological function score | 52.27 |
52.17 |
0.918 |
Bi-PAP, Bi-level positive airway pressure; NCPAP, nasal continuous positive airway pressure; NEC, necrotizing enterocolitis; IMV, invasive mechanical ventilation; ROP, retinopathy of prematurity; PNX, pneumothorax; BPD,bronchopulmonary dysplasia; PS, pulmonary surfactant; IVH, intraventricular hemorrhage; HS, hospital stay; p, p-value of Bi-PAP vs NCPAP. |
This trial was conducted to compare the efficacy and safety of Bi-PAP to NCPAP as initial support in preterm twins with respiratory distress syndrome. In order to avoid the interaction of maternal pregnancy-related diseases and the influence of disease severity on the outcome, preterm twins was involved in our study. No literature data was reported about the different efficiency of Bi-PAP and NCPAP in preterm twins with RDS. This study shows that NCPAP and Bi-PAP are not significantly different with respect to the rate of NIV failure, rates of complications, in-hospital mortality, neurological function score, and length of hospital stay. These findings suggest that Bi-PAP is not superior to NCPAP as an initial management of respiratory distress in these premature twins.
Consistent with our study, Mi-Ji Lee et al. [17] also found that there
was no statistically significant difference in treatment failure, clinical
effectiveness and safety compared with NCPAP in infants of RDS (n = 93, GA 30–35
weeks). Over 80% of premature babies in our study were also born between 30 and
35 weeks of gestation. We speculate that Bi-PAP might have no advantage on older
gestational age groups. However, a randomized trail (RCT) involved 540 infants
with GA
This study innovatively uses preterm twins to balance many potential mother-related influences and included a neurodevelopmental assessment. As we all know, the outcomes are closely related to many factors, such as the severity of RDS, the birth weight of the child, gestational age, and whether there are other secondary diseases, especially infections. The choice of ventilation mode is based on comprehensive consideration of all factors. The limitations of the study are: (1) the different MAP of the two ventilation (2) we did not discuss the gas blood. (3) In clinical practice, PEEP was adjusted according to the condition of patients, therefore, we cannot promise that the PEEP are the same all the time between the two NIV strategies. (4) Over 80% of premature babies in our study, the gestational age is between 30 and 35 weeks. This was a relatively mature group of preterm infants, Maybe, Bi-PAP have a bigger influence on younger infants. Only 3% patients were born before 28 weeks, so it is hard for us to perform a subgroup analysis due to the small sample size.
This trial provides evidence that there is no clinically significant difference in NIV failure rates between Bi-PAP and NCPAP when used in preterm twins born before 36 weeks. Further investigations are needed to explore the safety and efficiency of Bi-PAP.
BPD, Bronchopulmonary dysplasia; Bi-PAP, Bi-level positive airway pressure; FRC,
Functional residual capacity; IMV, Invasive mechanical ventilation; IVH,
Intraventricular hemorrhage; PS, Pulmonary surfactant; PEEP, Positive
end-expiratory pressure; PaO
XD conceptualized, designed the study and collected the data. HC was a major contributor in analyzing the data and writing the manuscript. CZ collected data and reviewed the manuscript. HY completed the ethics registration and clinical trial registration. YS conceptualized and designed the study, accomplished the article-extracting and data analysis, critically reviewed the manuscript for important intellectual content. FL conceptualized and designed the study, accomplished the article-extracting and data analysis, critically reviewed the manuscript for important intellectual content. CL conceptualized and designed the study. All authors read and approved the final manuscript.
We have got the ethics approval at Medical Theory Committee of Qujing Maternal and Child Health Hospital, Yunnan Province and the reference number is QJFYLL2018-KY001. Consent was obtained by the parents of involved preterm infants.
Not applicable.
This work was supported by National Natural Science Foundation of China (NO.81401236), Natural Science Foundation of Chongqing (cstc2021jcyj-msxmX0257), Science and health project of Chongqing Health Commission (NO.2021MSXM202), project of Chongqing Educational Commission (KJQN201800410).
The authors declare no conflict of interest.