Treatment of severe meconium aspiration syndrome with porcinesurfactant: A multicentre, randomized, controlled trial

CHINESE COLLABORATIVE STUDY GROUP FOR NEONATAL RESPIRATORY DISEASES

AbstractAim: A randomized, controlled clinical trial was performed in 19 Chinese neonatal intensive care units to evaluate thesafety and efficacy of exogenous surfactant replacement therapy for severe meconium aspiration syndrome (MAS) in term andnear-term neonates. Methods: Sixty-one term infants with severe MAS were randomly assigned to either a surfactant or acontrol group within 36 h after birth. The infants in the surfactant group (n=31) received an initial dose of porcine lung-

derived surfactant (Curosurf1) at 200 mg/kg, and repeated doses of 200, 100 and 100 mg/kg were given at 6–12 h intervals toa maximum of four doses if oxygenation index (OI) deteriorated by42 from baseline. The primary outcomes were a reductionof OI to less than 10 and an increase of the pre-treatment a/A PO2 ratio of 100% over baseline 24 h after surfactant treatment.The secondary outcomes were duration of mechanical ventilation, incidence of complications and survival to discharge fromhospital. Results: The general demographic characteristics of the study subjects were similar. There was a trend for surfactant-treated infants to have an improvement in arterial oxygenation compared to the control group. In comparison with the controlgroup at 24 h, the surfactant group had a lower mean OI (8.1 vs 10.9), more infants with a 100% increase of a/A PO2 (83%vs 48%, p50.01) over baseline, and a larger area under the curve for PaO2/FiO2 over baseline (3762+1877 vs 2715+1644 mmHg.h, p50.05). Repeated measures of these parameters were also in favour of the surfactant group during 24 hto 3 and 7 d compared to the baseline ( p50.05). No differences were found in mean duration of mechanical ventilation,incidence of major complications and number of survivors between the two groups.

Conclusion: Surfactant replacement therapy improved oxygenation in the study subjects, suggesting that surfactant may havea role in the treatment of severe MAS in term and near-term infants.

Key Words: Meconium aspiration syndrome, pulmonary surfactants, term or near-term neonates, respiratory therapy

Introduction

Meconium aspiration syndrome (MAS) is a severe

and complex neonatal respiratory disorder. Despite

airway suctioning at birth and improved respiratory

care, MAS affects about 5–10% of all infants born

through meconium-stained amniotic fluid and remains

a serious clinical problem associated with consider-

able morbidity and mortality [1]. There is no specific

therapy for MAS, and conventional therapy includes

oxygen supplementation, positive pressure mechanical

ventilation and general supportive intensive care. Some

cases of severe MAS have to be treated with extra-

corporeal membrane oxygenation (ECMO), which is

costly and currently not available in areas of limited

resource.

The pathophysiological mechanisms involved in

the development of MAS may be related not only to

mechanical obstruction of the airways and chemical

injury to the respiratory epithelium but also to surfac-

tant inactivation by meconium [2–4]. Constituents of

meconium, including free fatty acids, cholesterol, bile

salts, bilirubin, blood and proteolytic enzymes, may

contribute to surfactant dysfunction. Since the early

1990s, attempts have been made to treat severe MAS

with exogenous surfactant with variable success. Some

animal studies have reported that treatment with pul-

monary surfactant improves oxygenation and venti-

lation efficiency in animals with respiratory failure

induced by aspirated meconium [5–7]. Several reports

also demonstrated that surfactant replacement

therapy could attenuate or reverse the clinical sequelae

of meconium aspiration, but most of them were retro-

spective and uncontrolled studies [8–10]. There have

been two randomized trials of a bovine surfactant for

treatment of MAS [11,12]. A systematic review, which

included these two studies, concluded that surfactant

treatment may reduce the severity of respiratory illness

and decrease the number of infants needing ECMO

[13].

Lung lavage using dilute surfactant is a novel, but

investigational treatment approach for MAS. Some

Correspondence: Bo Sun, Children’s Hospital of Fudan University, 183 Feng Lin Road, Shanghai 200032, People’s Republic of China. Tel: +86 21 54524666,

ext. 4038. Fax: +86 21 64047017. E-mail: bsun@shmu.edu.cn/qyang75@yahoo.com.cn

(Received 30 October 2004; accepted 17 December 2004)

Acta Pædiatrica, 2005; 94: 896–902

ISSN 0803-5253 print/ISSN 1651-2227 online # 2005 Taylor & Francis Group Ltd

DOI: 10.1080/08035250510028344

animal and clinical studies reported that surfactant

lavage seemed to be an effective and safe method for

the treatment of severe MAS [14–18], but so far there

is no evidence showing that this approach is superior in

safety to either conventional bolus surfactant therapy

or general supportive care [18].

We hypothesized that, in severe MAS, meconium-

induced lung injury and impaired gas exchange may

be improved by exogenous surfactant, and in circum-

stances where the use of ECMO is limited there would

be benefits for this population of infants. Therefore we

conducted a multicentre, randomized, controlled trial

in China to assess the safety and efficacy of a porcine-

derived surfactant in term and near-term neonates with

severe MAS.

Methods

Study population

Nineteen neonatal intensive care units collaborated

in the trial (Table I). The study was approved by the

Chinese Food and Drug Administration and each

institutional ethics committee. Criteria for enrolment

were: (1) diagnosis of MAS by the presence of meco-

nium in the airways and/or meconium-stained amniotic

fluid at delivery, typical chest X-ray findings, onset of

respiratory distress, and abnormal blood gas findings

indicating respiratory failure and acidosis; (2) birth-

weight 42500 g; (3) postnatal age 536 h; (4) arterial-

to-alveolar oxygen tension ratio (a/A PO2) 50.22

and oxygenation index (OI) 415; (5) treatment with

endotracheal intubation and mechanical ventilation for

1–2 h without improvement. Exclusion criteria: (1)

lethal congenital anomalies including severe congenital

heart disease; (2) intraventricular haemorrhage grade

II–IV; (3) Apgar score 53 at 10 min; (4) clinically

unstable.

Randomization

After parental consent was obtained, the investigators

informed the relevant randomization centre (Chil-

dren’s Hospital of Fudan University, Shanghai, or

Capital Institute of Paediatrics Children’s Hospital,

Beijing) by direct telephone call. Surfactant or control

therapy was randomly assigned by the randomization

centre staff according to sequentially numbered ran-

domization cards, provided in sealed randomization

envelopes, based on an expected total enrolment of 64

patients. The sequence of randomization was in blocks

of four. The attending physician completed basic

information for each enrolled infant on the inclusion

sheet and mailed it to the coordinating centre.

Surfactant administration

All enrolled infants received standard care including

mechanical ventilation, adequate fluids, antibiotics

and other medicines. Infants randomized to the sur-

factant treatment group received 200 mg/kg porcine

surfactant (Curosurf, Chiesi Farmaceutici, Parma,

Italy). Repeated doses of 200 (2nd dose) and 100 (3rd

and 4th doses) mg/kg at 6–12-h intervals, to a maxi-

mum of four doses, were administered if one or more of

the following occurred: deterioration of OI by 42 from

baseline; aspiration of meconium-stained liquid from

the airways with no improvement of OI from baseline;

intercurrent complications such as air leaks that were

not related to surfactant administration. Surfactant

was instilled intratracheally by a sterile feeding tube

up to the proximal end of the endotracheal tube. The

infants were ventilated manually with 100% oxygen

for 1–2 min after each surfactant instillation. No

suctioning of the airways was performed during the

first 2 h after treatment unless signs of airway ob-

struction occurred. Surfactant administration was not

conducted in a blind manner because that would have

required a separate dosing team for each clinic centre.

Data collection

Data from the collaborating units were sent to the trial

coordination centre in Shanghai soon after collection.

Arterial blood gas determinations were done immedi-

ately before (0 h as baseline) and 1, 6, 12 and 24 h and

3, 7 and 14 d after surfactant replacement. Ventilator

settings [peak inspiratory pressure (PIP), mean airway

pressure (MAP), positive end-expiratory pressure

(PEEP) and fraction of inspired oxygen (FiO2)] and

Table I. Numbers of patients randomized in each collaborating unit.

Collaborative Units Control Surfactant Total

Children’s Hospital of Fudan

University

2 2 4

Shanghai Children’s Hospital 5 6 11

Xin Hua Hospital of Shanghai

Second Medical University

0 1 1

Nanjing Children’s Hospital 4 5 (1a) 9 (1a)

Nanjing Maternity Hospital 0 2 (1a) 2 (1a)

Wuxi Children’s Hospital 1 0 1

Suzhou Maternity Hospital 3 1 4

Suzhou Children’s Hospital 2 (1a) 1 3 (1a)

Children’s Hospital of Zhejiang

University

4 3 7

Shaoxing Maternity Hospital 1 4 5

Wenzhou Yuying Children’s

Hospital

0 2 2

Beijing Children’s Hospital 2 4 6

First Hospital of Beijing

University

4 1 5

Beijing Peking Union Hospital 0 2 (2a) 2 (2a)

Capital Institute for Paediatric

Research

3 1 4

Total cases 31 35 66

Total cases after exclusion 30 31 61

a Excluded cases.

Severe MAS and porcine surfactant 897

vital signs at these time points were noted. The primary

outcomes were improvements in oxygenation and

ventilation over baseline 24 h after surfactant treat-

ment, evaluated by the following variables: (1) reduc-

tion of OI to less than 10 [OI=mean airway pressure

(in cmH2O)rFiO2r100/PaO2 (in mmHg)]; (2) a

100% increase of the pre-treatment arterial-to-alveolar

oxygen tension ratio (a/A PO2) [a denotes PaO2, and

A PO2=(713rFiO2)7PaCO2, in which the local

mean barometric pressure minus 47 was substituted

for 713 in the formula]. PaO2/FiO2 were derived from

blood gas values and corresponding FiO2 from venti-

lators. Area under the curve for PaO2/FiO2 (AUCp/f)

in the first 24 h after treatment was integrated for

comparison of overall improvement in oxygenation.

The secondary outcomes were duration of mechanical

ventilation, incidence of complications and survival

to discharge from hospital. Chest radiographs, echo-

cardiograms and head ultrasound examinations were

done before treatment and as clinically indicated

to diagnose pulmonary and extrapulmonary compli-

cations. In addition, all possible adverse events were

collected, analysed and reported to the coordinator.

Statistical analysis

On the basis of previous reports, approximately 70%

of infants with severe MAS were estimated to have

an OI above 10 after 72 h of mechanical ventilation.

We aimed to reduce this from 70% to 40% after

surfactant treatment. Assuming a power of 80% and

a significance level of 5% (two tailed), we estimated

that at least 32 infants in each group (64 infants in

total) had to be enrolled. Data are presented as

means+SD for continuous variables, and as numbers

with percentages for incidence. Differences between

and within the two groups for continuous variables

were evaluated by Wilcoxon Mann-Whitney test, or

Wilcoxon signed-rank test, or repeated measures with

Dunn’s multiple comparisons, respectively, wherever

applicable. Differences between proportions were

assessed by w2 test or Fisher’s exact test. A p-value

50.05 was regarded as statistically significant.

Results

Sixty-six subjects were enrolled in this trial. Five

infants, four in the surfactant group and one in the

control group, were excluded from the final analysis

because of violation of the entry criteria. Six of 31

infants treated with surfactant received one additional

dose and four had two additional doses. The number

of infants randomized by each unit varied because of

differences in the size of the population from which

they were recruited, admission policies and the dur-

ation of trial participation (Table I).

Demographic characteristics

The general demographic characteristics of the study

infants are shown in Table II. There were no differ-

ences in sex, gestational age, birthweight, Apgar score,

age at randomization and mode of delivery between

the two groups. More male than female infants were

enrolled in the trial, but the two groups were com-

parable for the proportion of male and female infants.

Oxygenation variables

Treatment with surfactant resulted in a rapid improve-

ment in oxygenation in the early phase of treatment

which was poorly sustained from 6 h. At 7, 14 and

28 d, data collection was completed in only a few cases

and there were no significant differences in oxygen-

ation between the two groups. The surfactant group

showed a decrease in OI from a mean of 19.1 before

treatment to a mean of 11.6 at 1 h after surfactant

treatment, while the control group did not show a

significant decrease of OI until 6 h (both p50.01 vs

baseline) (Figure 1). Twenty-four hours after treat-

ment, a reduction of mean OI to 8.1 was found in

the surfactant group compared to 10.9 in the control

group. At subsequent assessments OI was lower than

10 in both groups. At 1, 6, 12 and 24 h, more infants

in the surfactant group than in the control group had

an OI 510. At 24 h, 20/27 (74%) infants treated with

surfactant had an OI 510 compared to 11/22 (50%)

in the control group (Table III), but this difference

was not statistically significant.

The changes of a/A PO2 over time are shown in

Figure 1. Surfactant significantly improved a/A PO2

from 0.12+0.06 to 0.19+0.12 after 1 h (p50.01

vs baseline), while in the control group the difference

did not become significant until 6 h (0.10+0.04 vs

0.16+0.14, p50.05). An increase of a/A PO2 4100%

over baseline at 6 h was observed in 17/31 (55%) of

surfactant-treated infants and in 5/20 (25%) of control

group infants (p50.05) (Table III). The difference in

Table II. Demographic characteristics of infants whose data were

analysed.

Characteristics

Surfactant

(n=31)

Control

(n=30)

Sex (male/female)a 22/9 21/9

Gestational age (wk)b 40.0+1.4 39.6+1.7

Birthweight (g)b 3444+534 3359+506

Apgar at 5 minb 7.4+2.1 7.0+2.4

Age at randomization (h)b 14.3+10.1 15.6+13.6

Type of birth (%)a

Spontaneous 16 (51.6) 12 (40.0)

Induction 1 (3.2) 1 (3.3)

Caesarean section 14 (45.2) 17 (56.7)

a Values are presented as numbers and percentages; b values are

presented as mean+SD; no differences were found in any demo-

graphic characteristics between surfactant and control group.

898 Chinese Collaborative Study Group for Neonatal Respiratory Diseases

the distribution of infants according to improvements

of a/A PO2 between groups was more prominent at

24 h: 24/29 (83%) vs 12/25 (48%) in the surfactant

and control group, respectively (p=0.007). When

analysing the values of PaO2/FiO2, a similar trend was

found compared to a/A PO2 curves of the two groups

in the first 3 d after the randomized treatment

(Figure 1). There were significantly more infants with

50-mmHg increments of PaO2/FiO2 at 6 and 24 h

of treatment (data not shown). At 24 h, AUCp/f was

significantly higher in the surfactant-treated infants

(3762+1877 mmHg.h) compared to the controls

(2715+1644 mmHg.h, p50.05). After repeated

measurement for within-group differences (Dunn’s

multiple comparisons), a/A PO2, OI and PaO2/FiO2 in

the surfactant-treated group were significantly im-

proved at 24 h, 3 and 7 d compared to the baseline

(p50.05). In the control group, improvements were

found only at 3 and 7 d. No significant differences were

found between the groups at the other two time points.

Only six of 31 infants treated with surfactant met the

criteria for repeat dosing and received one additional

dose, with four receiving two additional doses. Com-

pared to single dose, no substantial improvements in

OI and a/A PO2 were found in infants treated with

multiple doses.

Outcome

The overall duration of mechanical ventilation was

105+81 and 80+40 h in the surfactant and control

group, respectively. The survival rate was 96.8% (30 of

31 infants) in the surfactant and 90% (27 of 30) in the

control group. No differences were found in these

two variables. The incidences of complications in

the survivors are shown in Table IV. There were five

infants (16.7%) with intracranial haemorrhage in the

control group compared to only one case (3.2%) in

the surfactant group. On the other hand, four cases

of patent ductus arteriosus (12.8%) were reported in

infants treated with surfactant and none in the control

group. The occurrence of complications in the two

groups was not significantly different.

Discussion

Exogenous surfactant may improve lung function in

MAS by the following mechanisms: (1) increasing the

endogenous surfactant pool and compensating for

the inhibitory effects of proteins leaking into alveolar

spaces and the decrease of surfactant phospholipid

synthesis and secretion [19,20]; (2) mitigating lung

injury caused by positive airway pressure ventilation

and exposure to high oxygen concentrations [21,22];

and (3) modulating chemically induced inflammation

due to pro-inflammatory cytokine production (inter-

leukin-1, -6, -8, -10, and tumour necrosis factor, etc.)

and down-regulating the expression of nuclear tran-

scription factor-kappa B (NF-kB) [23–25].

Despite advances in neonatal intensive care over

the last two decades, MAS remains one of the most

challenging clinical conditions to manage and is the

most common indication for treatment with ECMO.

Since the early 1990s a number of studies of exogenous

surfactant treatment for MAS has been reported.

Improvement of oxygenation was observed in most

of the experimental and clinical studies. In a small,

uncontrolled clinical study, Auten et al. [8] reported

that a/A PO2 improved from 0.09 before to 0.24 and

OI from 26 before to 10 at 1 h after treatment with

calf lung surfactant extract in seven term infants with

Figure 1. (a) The changes of OI (oxygenation index) over time; (b)

the changes of a/A PO2 over time; and (c) the changes of PaO2/FiO2

over time. Values are presented as mean+SD. *p50.05, **p50.01

vs baseline (0 h, within-group comparisons). There were no signifi-

cant differences between the surfactant group and the control group

at any time. Repeated measurements for within-group differences

(Dunn’s multiple comparisons) show significantly improved OI, a/A

PO2 and PaO2/FiO2 in the surfactant group at 24 h, 3 and 7 d

compared to the baseline. In the control group, improvements were

found only at 3 and 7 d.

Severe MAS and porcine surfactant 899

severe MAS. In a retrospective survey, Halliday et al.

[10] found good, modest and poor responses in 18%,

38% and 44% of Curosurf-treated infants, respec-

tively, with 81% survival at 28 d. Khammash et al. [9]

used bovine lung surfactant extract to treat 20 cases

of MAS using respiratory distress syndrome (RDS) as

reference controls. Their infants were enrolled with a

mean a/A PO2 of 0.07 and OI of 37. This retrospective

analysis revealed a response to single or multiple doses

in 15 infants, and 14 of these survived. All non-

responders died. In the first randomized, controlled

trial reported by Findlay et al. [11], babies with

severe MAS (mean a/A PO2 of 0.09) were treated

with up to four doses of 150 mg/kg Survanta, instilled

every 6 h by continuous infusion for 20 min within 6 h

after delivery; the first dose was given before the age

of 6 h. The results were favourable, with improve-

ment in oxygenation, reduced incidence of air leak

complications, shorter duration of mechanical venti-

lation, and less need for ECMO. Another large

multicentre, randomized, controlled trial by Lotze

et al. [12] demonstrated that the use of Survanta,

particularly in the early phase of respiratory failure,

significantly decreased the need for ECMO in infants

with a primary diagnosis of MAS.

Our multicentre, randomized, controlled clinical

trial showed that Curosurf improved oxygenation and

ventilation efficacy in infants with severe neonatal

respiratory failure due to MAS. The increase of the

pre-treatment a/A PO2 by 100% over baseline at 6 and

24 h, and significantly higher levels of AUCp/f in the

first 24 h, indicated significant improvement in the

Curosurf-treated group. There were significantly more

infants with 50-mmHg increments of PaO2/FiO2 at 6

and 24 h of treatment and a reduction of OI to less

than 10 at 24 h in the Curosurf-treated group com-

pared to the control group. OI values and a/A PO2 at

entry were lower than those in the study of Khammash

et al. who enrolled infants with more severe disease.

In contrast to rapid and significant improvement in

oxygenation at 1 h after surfactant administration

in RDS, which was not seen in the previous studies

[8–11], we found only modest improvement in

oxygenation at 6 and 24 h. Moreover, improvement of

oxygenation was sustained in the surfactant-treated

group as shown by repeated measurements over time

from 24 h to 3 and 7 d. There were no statistically

significant differences in duration of ventilation or in

the incidence of complications. It appears that treat-

ment response is related to severity of disease, timing

of initial surfactant treatment, dose, dosing frequency,

mode of surfactant delivery and quality of the surfac-

tant preparation. In contrast to the other studies

[8–11], the timing of initiation of treatment was late

(up to 36 h after birth) and single-dose treatment was

used in most infants in our trial. Although the sample

size of the current study was not powered to evaluate

mortality as a major outcome of the study intervention,

a trend toward lower mortality was observed after

Table IV. The incidences of complications observed in the survivors.

Complications Surfactant (n=31) Control (n=30)

Interstitial emphysema 4 (12.8%) 7 (23.3%)

Pneumothorax 6 (19.4%) 6 (20.0%)

Intracranial haemorrhage 1 (3.2%) 5 (16.7%)

Pneumonia 15 (48.4%) 13 (43.3%)

Patent ductus arteriosus 4 (12.8%) 0

Values are presented as numbers and percentages; no differences

were found in the incidence of complications between the surfactant

and control group.

Table III. Categorical changes of OI and a/A PO2 over baseline at each assessment time.

Time OI Surfactant Control

Improvement of

a/A PO2 (%) Surfactant Control

1 h510 15 8 5100 19 18

510 13 15 5100 10 4

p-value 0.180 0.196

6 h510 16 6 5100 14 15

510 13 14 5100 17 5

p-value 0.082 0.036a

12 h510 16 11 5100 13 11

510 11 12 5100 14 11

p-value 0.419 0.897

24 h510 20 11 5100 5 13

510 7 11 5100 24 12

p-value 0.082 0.007b

3 d510 15 17 5100 7 8

510 3 3 5100 15 15

p-value 1.000 0.833

a p50.05, b p50.01 surfactant versus control; values are patient numbers.

900 Chinese Collaborative Study Group for Neonatal Respiratory Diseases

Curosurf treatment (3.2% vs 10%). Taken together,

the studies suggest that, in babies with severe MAS

and clinical evidence of intractable respiratory failure,

early intervention with exogenous surfactant could

improve oxygenation and prevent the need for ECMO

[13]. Further larger and systematic studies of sur-

factant treatment for MAS should be performed

comparing single and multiple doses, and high and

low dose (e.g. 200 or 100 mg/kg) of a specific surfac-

tant preparation in order to develop more precise

recommendations in babies with MAS.

Lung lavage with dilute surfactant is a novel treat-

ment approach for MAS. The lavage manoeuvre may

facilitate airway clearance of meconium by reducing

its tenacity and improving the ventilation/perfusion

relationship. Ogawa et al. [14] and Lam et al. [15]

reported uncontrolled experiences using small volumes

of dilute bovine surfactant to lavage four and six

neonates with MAS, respectively. Both groups noted

clinical improvement in these infants. In two animal

models of MAS, Cochrane et al. [16] and Dargaville

et al. [17] also found that lavage with a large volume

of dilute surfactant was associated with increased

meconium removal and improved lung function.

Recently, Salvia-Roiges et al. [26] reported that airway

lavage with diluted surfactant in the first hours of life

combined with an intravenous single dose of dexa-

methasone might be a more effective treatment for

severe MAS compared to bolus surfactant or lavage

with diluted surfactant alone. However, Wiswell and

co-workers [18] found no significant advantage in

oxygenation or duration of ventilation with Surfaxin, a

synthetic peptide-based surfactant, administered by

lavage compared with standard care in a multicentre,

randomized, controlled trial. Moreover, 20% of the

lavaged group had the procedure halted because of

marked hypoxaemia or systemic hypotension. In a

recent review, Kinsella [27] pointed out that large-

volume lung lavage with dilute surfactant may be quite

effective in removing meconium particles from the

lung, but its application in the human newborn with

severe MAS may carry substantial risks. Currently,

early use of exogenous surfactant as a small-volume

bolus remains a more suitable method for surfactant

delivery in babies with severe MAS, and the safety

and the efficacy of surfactant lavage awaits the results

of randomized trials with appropriate sample sizes.

Acknowledgements

This work is a part of Dr Liling Qian’s thesis work for adoctorate degree. The authors thank Prof. Suhua Cao,Department of Statistics and Social Medicine, FudanUniversity, for reviewing the data and statistical analysis.This study was supported by Chiesi Farmaceutici S.p.A.,Parma, Italy, and Grunenthal Pharmaceutical (China), Co.Ltd., Shengzheng, Guangdong, China, and Beijing KangqiaoHealth Consulting Co. Ltd., Beijing.

Participating hospitals and investigators

Shanghai Children’s Hospital, Shanghai (Qi-Wei Huang,Yu-Ming Zhang); Nanjing Children’s Hospital, Jiangsu(Shao-Ming Song, Ling Wu, Ying-Mei Xu, Xiao-Yu Zhou);Children’s Hospital of Zhejiang University, Zhejiang (Li-Zhong Du, Mei-Yue Sun, Li-Ping Shi); Beijing Children’sHospital of Capital Medical University, Beijing (Ke-Hua Li,Xun-Mei Fan); First Hospital of Beijing University, Beijing(Zai-Chen Guo, Ying Wang); Shaoxing Maternity Hospital,Zhejiang (Ye-Jun Jiang); Capital Institute for PediatricResearch, Beijing (Guo-Wei Song, Xiao-Zhuang Gan);Children’s Hospital of Fudan University, Shanghai (ChaoChen, Xiao-Mei Shao, Xu-Dong Zhang, Li-Ling Qian[coordinator], Bo Sun [trial director]); Suzhou MaternityHospital, Jiangsu (Jian Gu, Xiao-Lu Yang); Suzhou Chil-dren’s Hospital of Suzhou University, Jiangsu (Zhi-Hui Xiao,Xiao-Chun Ding); Wenzhou Yuying Children’s Hospitalof Wenzhou Medical College, Zhejiang (Zhen-Lang Lin);Nanjing Maternity Hospital, Jiangsu (Xiao-Qi Gu, Shu-PingHan); Beijing Union Hospital of Peking Union MedicalUniversity, Beijing (Dan-Hua Wang); Xin Hua Hospital andShanghai Children’s Medical Centre of Shanghai SecondMedical University, Shanghai (Jian-Xing Zhu, Jian-HuaSun); Wuxi Children’s Hospital, Jiangsu (Hong-Min Chen);Shanghai International Peace Maternity Hospital, Shanghai(Yue-Hua Shen); Second Hospital of Nanjing MedicalUniversity, Jiangsu (Shu-Ting Li); Maternity Hospital ofZhejiang University, Zhejiang (Ming-Yuan Wu); JiaxinMaternity Hospital, Zhejiang (Jiang-Fan Yang).

International advisory group

Henry L. Halliday (Belfast, UK), Christian P. Speer(Wurzburg, Germany), Bengt Robertson (Stockholm,Sweden), Tore Curstedt (Stockholm, Sweden): trial design,data analysis and interpretation, and manuscript preparation.

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902 Chinese Collaborative Study Group for Neonatal Respiratory Diseases