Summary
Background
Neonatal acute respiratory distress syndrome (NARDS) was defined in 2017 and the epidemiological data remain unknown. Our objective was to explore aetiological factors, clinical characteristics and outcomes in patients with perinatal NARDS.
Methods
A multicentre, prospective, cross-sectional study was performed in 58 tertiary neonatal intensive care units in China from Jan 1, 2018 to June 30, 2019. Neonates diagnosed with NARDS were included. Primary outcomes were aetiological factors, clinical characteristics and outcomes. Binary logistic regression and multivariate cox proportional regression were performed to identify independent predictors for bronchopulmonary dysplasia (BPD) and/or death or single death. This study was registered with ClinicalTrials.Gov, NCT03311165.
Findings
Among 70,013 admitted neonates, the incidence of NARDS was 1.44% (1005). The cumulative incidences were 65.6%, 86.7%, 94.1% within one, two and three days after birth. The median gestational age and birth weight were 36.4 weeks and 2700 g. Three main aetiological triggers included pneumonia (58.1%), asphyxia (24.3%) and early-onset sepsis (EOS) (21.3%). BPD and/or death was observed in 213 (21.2%) infants, consisting 104 (10.3%) BPD and 126 (12.6%) deaths. The numbers of mild, moderate and severe NARDS were 537 (53.4%), 286 (28.4%) and 182 (18.2%). Two or more doses of surfactant was associated with increased mortality as compared with one or less doses of surfactant (odds ratio [OR] 1.93, 95% confidence interval [CI] 1.20–3.10, P = 0.006). Similarity also appeared in the comparison between EOS and non-EOS triggers (OR 1.57, 95% CI 1.06–2.33, P = 0.023).
Interpretation
NARDS incidence was 1.44% and the three main aetiologies were pneumonia, asphyxia and EOS. The cumulative incidences were 65.6%, 86.7%, and 94.1% within one, two and three days after birth. Our results suggested that two or more doses of surfactant increased mortality compared with one or less doses of surfactant.
Funding
The National Clinical Research Center of China and Clinical Medical Study Program of Children's Hospital of Chongqing Medical University (NCRC-2019-GP-13) and Natural Science Foundation of Chongqing (cstc2020jcyj-msxmX0197).
Keywords: Neonate, Acute respiratory distress syndrome, Bronchopulmonary dysplasia, Mortality, Epidemiology
Abbreviations: ARDS, acute respiratory distress syndrome; NARDS, neonatalacute respiratory distress syndrome; BPD, bronchopulmonary dysplasia; GA, gestational age; IVF, in vitro fertilization; PROM, premature rupture of the membrane; GDM, gestational diabetes mellitus; HDCP, hypertensive disorder complicating pregnancy; ICP, intrahepatic cholestasis of pregnancy; NIV, noninvasive ventilation; NIV-I, intubation after NIV failure; IV, invasive ventilation; HFOV, high-frequency oscillatory ventilation; CMV, conventional mechanical ventiation; NIPPV, nasal intermittent positive pressure ventilation; NHFOV, nasal high-frequency oscillatory ventilation; NCPAP, nasal continuous positive airway pressure; BIPAP, bi-level positive airway pressure; IQR, interquartile range; OR, odds ratio; CI, confidence interval; MAS, meconium aspiration syndrome; PH, pulmonary hemorrhage; PPHN, persistent pulmonary hypertension of newborn; iNO, inhaled nitric oxide
Research in context.
Evidence before this study
PubMed and Google Scholar were searched without language restrictions for published articles between Jan 1, 1980 and June 30, 2022 using the search terms "acute respiratory distress syndrome (ARDS)" AND "neonate" AND "epidemiology" AND "mortality" AND "Bronchopulmonary dysplasia (BPD)". No study reports the epidemiological data for the condition including aetiological triggers, clinical characteristics and outcomes in neonates with ARDS.
Added value of this study
Our findings suggested that the incidence of neonatal ARDS was 1.44%. The cumulative incidences were 65.6%, 86.7%, 94.1% within one, two, and three days after birth. The median gestational age and birth weight were 36.4 weeks and 2700 g. Three main triggers included pneumonia (58.1%), asphyxia (24.3%) and early-onset sepsis (EOS) (21.3%). BPD and/or death were observed in 213 (21.2%) infants, consisting 104 (10.3%) BPD and 126 (12.6%) deaths. The numbers of mild, moderate and severe NARDS were 537 (53.4%), 286 (28.4%) and 182 (18.2%). Two or more doses of surfactant was associated with increased mortality as compared with one or less dose of surfactant. Similarity also appeared in the comparison between EOS and non-EOS triggers.
Implications of all the available evidence
Perinatal neonatal ARDS shares several features with adult and pediatric ARDS.
Introduction
Acute respiratory distress syndrome (ARDS) is a leading cause of respiratory mortality and morbidity, which was first reported by Ashbaugh and colleagues in 1967.1 Since then, the diagnostic criteria of adult and pediatric ARDS are defined in the Berlin Conference and Pediatric Acute Lung Injury Consensus Conference (PALICC),2,3 respectively. However, the two criteria do not cover neonatal perinatal considerations. In 2017, the international neonatal ARDS (NARDS) collaborative group provides the first consensus definition of NARDS (Montreux definition) during the first phase of NARDS project.4 There are consistent themes in the definition of NARDS when compared with adult and pediatric ARDS which stem from similarities in pathophysiology and historical features. However, the two definitions of older ARDS tend to differ with the inclusion of perinatal triggers in NARDS.
According to the NARDS project timelines, the second phase of the project is to carry out a cross-sectional study in patients with perinatal NARDS and to describe clinical characteristics and outcomes, as well as identifying a list of aetiological triggers.4 Therefore, the aims of the present study are: (1) to explore aetiological triggers, (2) to explore clinical characteristics, and (3) to explore outcomes in neonates with NARDS.
Methods
Study design
A prospective, multicentre, cross-sectional study was performed in 58 tertiary neonatal intensive care units (NICU) in 26 provinces, autonomous regions and municipalities of China from Jan 1, 2018 to June 30, 2019. The project launch meeting was hold in Dec 16, 2017 in Harbin, China and 72 hospitals were screened. Finally, the neonatologists of 58 hospitals passed the exam of qualification and were included. These included hospitals are the regional centres of critical ill neonates in every provinces, autonomous regions and municipalities, and the included neonatologists of these hospitals also are the main members of Neonatal Professional Committee of Chinese Medical Doctor Association of China. Therefore, the included neonatologists, hospitals and the final analysed sample of patients in the study can be considered to be representative of the wider population in China. Furthermore, according the project launch meeting, twenty neonates with NARDS should be admitted at least before the site was qualified. Once the neonatologists and their hospitals were qualified to recruit patients with NARDS, the numbers of patients with NARDS in the hospital were not restricted. The study was approved by the institutional review boards of Children's Hospital of Chongqing Medical University (201822), and registered at ClinicalTrials.Gov (NCT03311165). The protocol was published in Chinese Journal of Evidence-based Pediatrics.5 All authors reviewed the protocol and vouched for adherence of the study to the protocol. Informed parental written consents were obtained. The trial was performed in accordance with the approved guidelines and regulations of the participating institutions.
Inclusion and exclusion criteria
All newborn infants diagnosed with NARDS were eligible if they met the inclusion and exclusion criteria. The diagnosis of NARDS was accordance with the Montreux definition.4 Newborn infants diagnosed with at least one of the following criteria were not eligible: (1) Severe congenital heart diseases, (2) chromosomal abnormalities, (3) Upper respiratory tract abnormalities, or pulmonary hypoplasias; (4) Parents' rejection to participate the study.
Primary and secondary outcomes
The primary outcomes were etiological factors, clinical characteristics, bronchopulmonary dysplasia (BPD)6 and/or death and single death. The secondary outcomes were the other outcomes, including BPD, air leak, haemodynamically significant patent ductusarteriosus (hsPDA), retinopathy of prematurity (ROP) > 2nd stage,7 necrotising enterocolitis (NEC) ≥ 2nd stage,8 intraventricular haemorrhage (IVH) > 2nd grade,9 and periventricular leukemalacia (PVL),10 ventilation length and ventilator-free days.
Termination of the study
The study would end if one of the following conditions was reached: 1. Death; 2. Parents' decision not to continue the participation; 3. Discharge according to doctors' suggestions.
Data collection
The medical records for all enrolled infants were collected into a database according to the protocol.5 The web site of the database is http://nasone.rxcngo.com/admin/Login/login.
To assess the independent risk factors of BPD and/or death and single death, the epidemiological data of the infants and pregnant women were selected as the covariates based on the literature on older ARDS and neonatal considerations.11, 12, 13, 14
Sample size estimation
The sample size estimation was calculated by PASS 2008 v8.0.3 (NCSS, Kaysville, Utah, USA). According to the previous single-centre data in Children's Hospital of Chongqing Medical University,15 27.0% (55/204) of infants with NARDS was diagnosed with BPD and/or death (41 of death, 26 of BPD, and 55 of BPD and/or death), A reasonable hypothesis was that the allowable error was 3.0%, with a 2-sided significance level of 0.05, a total of 841 neonates with perinatal NARDS would be needed at least. According to the sample size estimation, every hospital needed about 15 (841/58) neonates with NARDS.
Statistical analysis
Quantitative variables would be firstly checked for normality using Kolmogorov–Smirnov test and were presented as mean ± standard deviation and compared using 2-tailed student's t test/one way-ANOVA, or median [interquartile range (IQR)] and compared with Mann–Whitney test. Qualitative variables were present as numbers and compared using the χ2 test or the Fisher's test.
First, the epidemiological data of the enrolled population were univariate analysed between BPD and/or death and survival without BPD groups. Then these variables with a P < 0.20 were entered in stepwise binary logistic regression model after the selected predictor variables being checked for multicollinearity. The analysis of multicollinearity would be performed considering condition index of Eigenvalues and variables inserted in the model would have to carry a Variance Inflation Factor < 2.16 When the variables were correlated, the variable with the highest association with BPD and/or death was retained. The probability of stepwise was 0.05 for entry and 0.1 for removal. Results were presented as odds ratio (OR) and 95% confidence interval (CI). Model goodness-of-fit was evaluated with Hosmer–Lemeshow test (P > 0.05). Predefined comparison of subgroup was ≦ 32 weeks’ gestational age (GA).
The in-hospital mortality was analysed with Kaplan–Meier curves and contrasted with a log-rank test and multivariate cox proportional regression model was performed with the same method above. Results were presented as OR and 95% CI. The likelihood ratio test was used to assess the model goodness-of-fit (P > 0.05). Predefined comparisons of the six subgroups were direct vs indirect triggers,17 early-onset sepsis (EOS) vs non-EOS, perinatal vs late in onset, NARDS severities (mild vs moderate vs severe),17 respiratory supporting modes [successful primary noninvasive ventilation (NIV) vs invasive ventilation after failing of noninvasive ventilation (NIV-I) vs invasive ventilation on admission (IV)], and NARDS plus NARD vs NARDS.
We used SPSS 16.0 (SPSS, Chicago, IL, USA) and Graphpad Prism 6.0 (GraphPad Software, La Jolla, CA, USA) for statistical analysis and graph drawing. For all analyses, a P-value < 0.05 was regarded as significant.
Role of the funding source
The study was funded by National Clinical Research Center of China and Clinical Medical Study Program of Children's Hospital of Chongqing Medical University (NCRC-2019-GP-13), and Natural Science Foundation of Chongqing (cstc2020jcyj-msxmX0197), including the study design and set/maintenance of the database. All authors had full access to the data in the present study and accept responsibility to submit for publication.
Results
Demographic characteristics
Seventy-two NICUs were screened in the project initiating meeting and 58 tertiary level NICUs completed the training plan and were included. From Jan 1, 2018 to June 30, 2019, 70,013 infants were hospitalised and 1021 infants were diagnosed with NARDS. We excluded 16 infants, including 12 with incomplete data and 4 repeated data. Finally, 1005 (1.44%) met the diagnosis criteria, ranging from 0.3% to 6.9% in each center and included in the final analysis (Fig. 1 and Supplement Table S1).
Fig. 1.
Flow chart of studied neonates. ARDS: acute respiratory distress syndrome; NICU: neonatal intensive care unit.
Etiological factors
The aetiological factors included 58.1% (592) pneumonia, 24.3% (244) asphyxia, 21.3% (214) EOS, 14.3% (144) pulmonary hemorrhage (PH), 11.0% (111) meconium aspiration, 3.7% (37) milk aspiration, 2.9% (29) biliary aspiration and 1.5% (15) LOS, respectively. Two and more etiologies could be simultaneously presented at a patient, with a percentage of 29.0%. Of patients with asphyxia, EOS, PH, MAS and biliary aspiration also appeared in 6.2% (62), 5.6% (56), 5.3% (53) and 0.7% (7) patients, respectively. There was no virus-related perinatal NARDS. Other results were also shown in Table 1.
Table 1.
The aetiological factors of NARDS.a
| LOS | Biliary aspiration | Milk aspiration | MAS | PH | EOS | Asphyxia | Pneumonia | |
|---|---|---|---|---|---|---|---|---|
| Pneumonia (n, %) | – | – | – | – | – | – | 592 (58.1) | |
| asphyxia (n, %) | – | 7 (0.7) | – | 53 (5.3) | 56 (5.6) | 62 (6.2) | 244 (24.3) | |
| EOS(n, %) | – | 3 (0.3) | – | 28 (2.8) | 50 (5.0) | 214 (21.3) | ||
| PH(n, %) | – | 4 (0.4) | – | 27 (2.7) | 144 (14.3) | |||
| MAS (n, %) | – | 1 (0.1) | – | 111 (11.0) | ||||
| Milk aspiration (n, %) | – | – | 37 (3.7) | |||||
| Biliary aspiration (n, %) | – | 29 (2.9) | ||||||
| LOS(n, %) | 15 (1.5) |
NARDS, neonatal acute respiratory distress syndrome; EOS, early-onset sepsis; PH, pulmonary hemorrhage; MAS, meconium aspiration syndrome; LOS, late-onset sepsis.
Clinical characteristics
The clinical characteristics and outcomes measures of the newborn infants were shown in Table 2. The median GA and birth weight were 36.4 weeks (IQR 33.0–38.1, 24.0–42.3) and 2700 g (IQR 1900–3260, 650–5800). A total of 67.2% were male. Of 1005, neonates were diagnosed with NARDS in 659 (65.6%) within one day, 871 (86.7%) within two days, 946 (94.1%) within three days, and 979 (97.4%) within seven days after birth, respectively. 1.1% (11) of neonates were diagnosed between 8 and 10 days after birth. 15 (1.5%) of neonates (9 of mild, 2 of moderate and 4 of severe NARDS) were diagnosed after 10 days induced by late-onset sepsis (LOS).
Table 2.
Clinical features and outcomes of neonates with perinatal NARDS between BPD and/or death or not and death or survival.a
| Clinical features | Total (n = 1005) | BPD and/or death (n = 213) | Non-BPD and/or death (n = 792) | 95% CI | P-value | Death (n = 126) | Survival (n = 879) | 95% CI | P-value |
|---|---|---|---|---|---|---|---|---|---|
| Maternal age (years) | 30.0 (27.0–34.0) | 30.0 (26.0–34.0) | 30.0 (27.0–34.0) | – | 0.392 | 30.0 (26.0–34.0) | 30.0 (27.0–34.0) | – | 0.263 |
| Gestational age (weeks) | 36.4 (33.0–38.6) | 36.5 (31.5–39.0) | 36.4 (33.2–38.6) | – | 0.368 | 34.1 (31.2–38.5) | 37.0 (33.2–39.0) | – | 0.002 |
| Gender (male, %) | 675 (67.2) | 149 (70.0) | 526 (66.4) | 0.85–1.63 | 0.329 | 84 (66.7) | 591 (67.2) | 0.66–1.45 | 0.899 |
| Birth weight (g) | 2700 (1900–3260) | 2700 (1735–3300) | 2700 (1995–3250) | – | 0.530 | 2175 (1355–3085) | 2700 (2000–3300) | – | <0.001 |
| Apgar 5 min | 9.0 (8.0–10.0) | 9.0 (8.0–10.0) | 9.0 (8.0–10.0) | – | 0.086 | 8.7 (8.0–10.0) | 9.0 (8.0–10.0) | – | <0.001 |
| Twins (yes, %) | 87 (8.7) | 19 (8.9) | 68 (8.6) | 0.61–1.78 | 0.878 | 15 (11.9) | 72 (8.2) | 0.84–2.73 | 0.166 |
| IVF (yes,%) | 99 (10.0) | 22 (10.3) | 77 (9.7) | 0.65–1.76 | 0.792 | 17 (13.5) | 82 (9.3) | 0.87–2.65 | 0.142 |
| PROM (yes,%) | 222 (22.1) | 54 (25.4) | 168 (21.2) | 0.88–1.80 | 0.196 | 27 (21.4) | 195 (22.2) | 0.61–1.51 | 0.848 |
| antenatal corticoids (yes,%) | 216 (21.5) | 45 (21.1) | 171 (21.6) | 0.67–1.41 | 0.884 | 36 (28.6) | 180 (20.5) | 1.02–2.36 | 0.039 |
| Caesarean (yes, %) | 696 (69.3) | 142 (66.7) | 554 (69.9) | 0.62–1.19 | 0.357 | 76 (60.3) | 620 (70.5) | 0.43–0.93 | 0.020 |
| GDM (yes, %) | 144 (14.3) | 33 (18.8) | 111 (13.1) | 0.74–1.72 | 0.585 | 20 (15.9) | 124 (14.1) | 0.69–1.92 | 0.597 |
| HDCP (yes,%) | 129 (12.8) | 26 (12.2) | 103 (13.0) | 0.59–1.47 | 0.757 | 20 (15.9) | 109 (12.4) | 0.79–2.24 | 0.276 |
| ICP (yes, %) | 29 (2.9) | 7 (3.3) | 22 (2.8) | 0.50–2.82 | 0.694 | 4 (3.2) | 25 (2.8) | 0.38–3.27 | 0.836 |
| placenta previa (yes, %) | 88 (8.0) | 15 (7.0) | 73 (9.2) | 0.42–1.33 | 0.319 | 13 (10.3) | 75 (8.5) | 0.66–2.30 | 0.507 |
| Albumin (g/L) | 31 (28–34) | 31 (28–34) | 31 (28–34) | – | 0.568 | 30.0 (26.0–32.0) | 31.0 (29.0–34.0) | – | 0.000 |
| Hemoglobin (g/L) | 166 (151–184) | 163 (150–182) | 167 (151–185) | – | 0.092 | 161.5 (142.8–178.3) | 167.0 (151.0–185.0) | – | 0.004 |
| Platelet (∗109/L) | 238 (187–288) | 241.6 ± 80.8 | 235.7 ± 76.6 | (-5.78)-17.71) | 0.319 | 225.0 ± 85.7 | 238.6 ± 76.2 | (-28.10)-0.88 | 0.066 |
| Surfactant (yes, %) | 701 (68.8) | 154 (72.3) | 547 (69.1) | 0.84–1.64 | 0.362 | 74 (58.7) | 627 (71.3) | 0.39–0.87 | 0.004 |
| Surfactant ≥2 times | 225 (22.4) | 48 (22.5) | 177 (22.3) | 0.0.70–1.45 | 0.954 | 37 (29.4) | 188 (21.4) | 1.01–2.32 | 0.045 |
| NARDS (mild:moderate:severe) | 537:286:182 | 93:68:52 | 444:218:130 | – | 0.003 | 59:26:41 | 478:260:141 | <0.001 | |
| Modes (NIV:NIV-I:IV) | 198:254:553 | 32:47:134 | 166:207:419 | – | 0.028 | 25:26:75 | 173:228:478 | – | 0.415 |
| MAS (yes, %) | 111 (11.0) | 28 (13.1) | 83 (10.5) | 0.82–2.04 | 0.271 | 21 (16.7) | 90 (10.2) | 1.05–2.94 | 0.031 |
| PH (yes, %) | 153 (15.2) | 46 (21.6) | 107 (13.5) | 1.20–2.59 | 0.004 | 50 (39.7) | 103 (11.7) | 3.28–7.48 | <0.001 |
| PPHN (yes, %) | 261 (26.0) | 63 (29.6) | 198 (25.0) | 0.90–1.76 | 0.176 | 54 (42.9) | 207 (23.5) | 1.66–3.58 | <0.001 |
| Heart failure (yes, %) | 108 (10.7) | 34 (16.0) | 74 (9.3) | 1.19–2.86 | 0.006 | 45 (35.7) | 63 (7.2) | 4.61–11.24 | <0.001 |
| EOS (yes, %) | 214 (21.3) | 44 (20.7) | 170 (21.5) | 0.66–1.38 | 0.798 | 48 (38.1) | 166 (18.9) | 1.78–3.93 | <0.001 |
| RBC transfusion (yes, %) | 331 (32.9) | 79 (37.1) | 252 (31.8) | 0.92–1.73 | 0.146 | 67 (53.2) | 264 (30.0) | 1.81–3.86 | <0.001 |
| Outcomes | |||||||||
| LOS (yes, %) | 93 (9.3) | 29 (13.6) | 64 (8.1) | 1.12–2.86 | 0.013 | 20 (15.9) | 73 (8.3) | 1.22–3.56 | 0.006 |
| IVH (yes, %) | 267 (26.6) | 65 (30.5) | 202 (25.5) | 0.90–1.79 | 0.142 | 49 (38.9) | 218 (24.8) | 1.31–2.85 | 0.001 |
| 3 or 4 grades | 33 (3.3) | 5 (2.3) | 28 (3.5) | 0.25–1.72 | 0.388 | 8 (6.3) | 25 (2.8) | 1.02–5.25 | 0.039 |
| ROP (yes, %) | 68 (6.8) | 24 (11.3) | 44 (5.6) | 1.28–3.64 | 0.003 | 24 (19.0) | 44 (5.5) | 2.61–7.65 | <0.001 |
| ≥2 stage | 21 (2.1) | 4 (1.9) | 17 (2.1) | 0.29–2.62 | 0.808 | 0 | 21 (2.4) | 0.96–0.98 | 0.080 |
| NEC (yes, %) | 61 (6.1) | 25 (11.7) | 36 (4.5) | 1.64–4.77 | <0.001 | 25 (19.8) | 36 (4.1) | 3.34–10.05 | <0.001 |
| ≥2nd | 18 (1.8) | 6 (2.8) | 12 (1.5) | 0.70–5.08 | 0.203 | 6 (4.8) | 12 (1.4) | 1.33–9.80 | 0.007 |
| hsPDA (yes, %) | 393 (39.1) | 88 (41.3) | 305 (38.5) | 0.83–1.53 | 0.457 | 61 (48.4) | 332 (37.8) | 1.06–2.25 | 0.022 |
| PDA Closure after Ibuprofen | 152 (15.3) | 42 (19.7) | 110 (13.9) | 1.03–2.26 | 0.035 | 24 (19.0) | 128 (14.6) | 0.85–2.24 | 0.189 |
| Air leak (yes, %) | 119 (11.8) | 34 (16.0) | 85 (10.7) | 1.03–2.43 | 0.036 | 29 (23.0) | 90 (10.2) | 1.64–4.19 | <0.001 |
| PVL (yes, %) | 70 (7.0) | 23 (10.8) | 47 (5.9) | 1.14–3.24 | 0.013 | 23 (18.3) | 47 (5.3) | 2.31–6.78 | <0.001 |
| ventilation length (day) | 3 (1–6) | 4 (1–7) | 3 (1–6) | – | 0.005 | 3 (2–6) | 3 (1–6) | – | 0.493 |
| ventilator-free days (days) | 0 (0–6) | 0 (0–0) | 0 (0–7) | – | <0.001 | 0 (0–0) | 0 (0–7) | – | 0.000 |
NARDS: neonatal acute respiratory distress syndrome; BPD: bronchopulmonary dysplasia; CI: confidence interval; IVF: in vitro fertilization; PROM: premature rupture of the membrane; GDM: gestational diabetes mellitus; HDCP: hypertensive disorder complicating pregnancy; ICP: intrahepatic cholestasis of pregnancy; NIV: noninvasive ventilation; NIV-I: intubation after NIV failure; IV: endotracheal tube and invasive mechanical ventilation; MAS: meconium aspiration syndrome; PH: pulmonary hemorrhage; PPHN: persistent pulmonary hypertension of newborn; EOS: early onset sepsis; LOS: late onset sepsis; RBC: red blood cells; IVH: intraventricular hemorrhage; ROP: retinopathy of prematurity; NEC: necrotizing enterocolitis; hsPDA: haemodynamically significant patent ductusarteriosus; PVL: periventricular leukomalacia.
The incidences of the mild, moderate and severe NARDS were 53.4% (537), 28.4% (286) and 18.2% (182), respectively. All 1005 patients reached the study endpoint and no patients’ parents refused to continue the participation. BPD and/or death was presented in 213 newborn infants (21.2%), including 10.3% (104) diagnosed with BPD, and 12.6% (126) died. 7-day and 30-day mortality was 9.6% (96) and 11.4% (115), respectively.
NARDS plus RDS was diagnosed in 30.3% (303) neonates. There were no differences in the incidences of death (35 vs 91, OR 0.88, 95% CI 0.58–1.33, P = 0.535) and BPD and/or death (73 vs 140, OR 1.27, 95% CI:0.92–1.76, P = 0.140) between NARDS plus RDS and NARDS. Surfactant was administrated to 701 (68.8%) infants. Of them, 225 (22.4%) were administrated two and more times. Surfactant administration was gradually decreased with the increase of GA, with 90.3% (28/31) at < 28 weeks, 81.2% (56/69) at 28–29 + 6 weeks, 78.5% (73/93) at 30–31 + 6 weeks, 72.0% (77/107) at 32–33 + 6 weeks, 66.7% (142/213) at 34–36 + 6 weeks, 67.4% (163/242) at 37–38 + 6 weeks, 66.3% (136/205) at 39–40 + 6 weeks, and 57.8% (26/45) at ≥ 41 weeks. Other outcomes of different GA were shown in Table 3.
Table 3.
Gestational ages and outcomes in patients with NARDS.a
| Characteristics and outcomes | Gestational ages (weeks, n) |
||||||||
|---|---|---|---|---|---|---|---|---|---|
| <28 (31) | 28-29 + 6 (69) | 30-31 + 6 (93) | 32-33 + 6 (107) | 34-36 + 6 (213) | 37-38 + 6 (242) | 39-40 + 6 (205) | ≥41 (45) | ||
| Surfactant (yes, %) | 28 (90.3) | 56 (81.2) | 73 (78.5) | 77 (72.0) | 142 (66.7) | 163 (67.4) | 136 (66.3) | 26 (57.8) | |
| RDS (yes, %) | 17 (54.8) | 37 (53.6) | 51 (54.8) | 45 (42.1) | 59 (27.7) | 42 (17.4) | 41 (20.0) | 11 (24.4) | |
| NARDS | Mild | 14 (45.2) | 43 (62.3) | 50 (53.8) | 65 (60.7) | 115 (54.0) | 135 (55.8) | 103 (50.3) | 12 (26.7) |
| Moderate | 6 (19.4) | 14 (20.3) | 31 (33.3) | 17 (15.9) | 67 (31.5) | 65 (26.8) | 62 (30.2) | 24 (53.3) | |
| Severe | 11 (35.4) | 12 (17.4) | 12 (12.9) | 25 (23.4) | 31 (14.5) | 42 (17.4) | 40 (19.5) | 9 (20.0) | |
| LOS (yes, %) | 7 (22.6) | 11 (15.9) | 10 (10.8) | 13 (12.1) | 17 (8.0) | 20 (8.3) | 11 (5.4) | 4 (8.9) | |
| Air leak (yes, %) | 1 (3.3) | 7 (10.1) | 9 (9.7) | 8 (7.5) | 25 (11.7) | 34 (14.0) | 27 (13.1) | 8 (17.8) | |
| PH (yes, %) | 9 (29.0) | 9 (13.0) | 17 (18.2) | 13 (12.1) | 25 (21.7) | 35 (14.4) | 34 (16.6) | 11 (24.4) | |
| hsPDA (yes, %) | 19 (61.3) | 25 (36.2) | 35 (37.6) | 41 (38.3) | 90 (42.2) | 91 (37.6) | 75 (36.6) | 17 (37.8) | |
| PDA Closure after Ibuprofen | 7 (22.6) | 13 (18.8) | 19 (20.4) | 19 (17.8) | 34 (16.0) | 36 (14.9) | 16 (7.8) | 8 (17.8) | |
| PPHN (yes, %) | 7 (22.6) | 8 (11.6) | 20 (21.5) | 22 (20.6) | 53 (24.9) | 70 (28.9) | 67 (32.7) | 14 (31.1) | |
| IVH (yes, %) | 19 (61.3) | 32 (46.4) | 46 (49.5) | 31 (29.0) | 54 (25.4) | 39 (16.1) | 38 (18.5) | 8 (17.8) | |
| >2nd | 6 (19.4) | 11 (15.9) | 5 (5.4) | 4 (3.7) | 2 (0.9) | 1 (0.4) | 4 (2.0) | 0 (0) | |
| ROP (yes, %) | 15 (48.4) | 14 (20.2) | 12 (12.9) | 4 (3.7) | 9 (4.2) | 6 (2.4) | 5 (2.4) | 3 (6.7) | |
| ≥2 stage | 10 (32.3) | 5 (7.2) | 5 (5.4) | 0 (0) | 1 (0.5) | 0 (0) | 0 (0) | 0 (0) | |
| NEC (yes, %) | 7 (22.6) | 12 (17.4) | 13 (14.0) | 3 (2.8) | 7 (3.3) | 10 (4.1) | 5 (2.4) | 4 (8.9) | |
| ≥2nd | 5 (16.1) | 6 (8.7) | 4 (4.3) | 1 (0.9) | 1 (0.5) | 1 (0.4) | 0 (0.0) | 0 (0) | |
| Total death (yes, %) | 12 (38.7) | 13 (18.8) | 16 (17.2) | 20 (18.7) | 15 (7.0) | 20 (8.2) | 21 (10.2) | 9 (20.0) | |
| Total BPD and/or death (yes, %) | 30 (96.8) | 43 (62.3) | 34 (36.6) | 28 (26.2) | 18 (8.4) | 24 (9.9) | 26 (12.7) | 10 (22.2) | |
| BPD (yes, %) | 24 (77.4) | 31 (44.9) | 21 (22.6) | 10 (9.3) | 4 (1.9) | 6 (2.4) | 6 (2.9) | 2 (4.4) | |
| Mild | 10 (32.3) | 21 (30.4) | 15 (16.1) | 4 (3.7) | 2 (0.9) | 4 (1.7) | 2 (0.9) | 1 (2.2) | |
| Moderate | 8 (25.8) | 3 (4.3) | 4 (4.3) | 3 (2.8) | 1 (0.5) | 0 (0) | 2 (0.9) | 0 (0) | |
| Severe | 6 (19.4) | 7 (10.1) | 2 (2.1) | 3 (2.8) | 1 (0.5) | 2 (0.8) | 2 (0.9) | 1 (2.2) | |
NARDS, neonatal acute respiratory distress syndrome; RDS, respiratory distress syndrome; LOS, late onset sepsis; PH, pulmonary hemorrhage; hsPDA, haemodynamically significant patent ductusarteriosus; PPHN, persistent pulmonary hypertension of newborn; IVH, intraventricular hemorrhage; ROP, retinopathy of prematurity; NEC, necrotizing enterocolitis; BPD, bronchopulmonary dysplasia.
Radiological findings
All the infants revealed bilateral abnormal results. The most common pattern on admission was ground glass opacity (65.6%) and the "white lung" accounted for 13.4% (135). Of 1005 patients, a reduced trends of 85.4% (169), 72.4% (184) and 55.3% (306) of ground glass opacity were shown in the infants supported by NIV, NIV-I, and IV. In contrast, an increased trends of 3.5% (7) of NIV, 10.6% (27) of NIV-I, and 18.3% (101) of IV were shown the "white lung" among the three respiratory supporting modes. Similar trends were also shown in the infants with mild, moderate and severe NARDS [ground glass opacity: 74.7% (401) vs 57.0% (163) vs 52.2% (95); "white lung": 9.3% (50) vs 11.5% (33) vs 28.6% (52)] (Fig. 2A-2M).
Fig. 2.
Changing trends of chest X-rays in neonates with perinatal NARDS. (2A–2C) 30 + 3 weeks. (2A) The chest X-ray at 5 h after birth after the first administration of surfactant with NCPAP; (2B) The chest X-ray before the second administration of surfactant after invasive ventilation on the second day, OI: 22; now the antibiotic was used; (2C) the chest X-ray before extubation on the fifth day. Diagnosis: EOS related NARDS. (2D–2F) 36 + 6 weeks. (2D) the chest X-ray at 10 h after birth after the first administration of surfactant with NCPAP; (2E) the chest X-ray before the second administration of surfactant on the second day, OI: 10; now the antibiotic was used; (2F) the chest X-ray on the third day. Diagnosis: EOS related NARDS. (2G–2J) 30 + 1 weeks. (2G) the chest X-ray at 2 h after birth before the first administration of surfactant with NIPPV, OI:12; (2H) the chest X-ray on the third day, OI: 3; (2I) the chest X-ray on the eighth day; (2J) the chest X-ray on the fifth day, now the antibiotic was used; Diagnosis: LOS related NARDS. (2K–2M) 26 + 3 weeks. (2K) the chest X-ray at 4 h after birth before the first administration of surfactant with NIPPV, OI:16; (2L) the chest X-ray on the second day before extubation, OI: 4; (2M) the chest X-ray on the tenth day, now the antibiotic was used, OI:15. Diagnosis: LOS related NARDS. NCPAP: nasal continuous positive airway pressure; OI: oxygenation index; EOS: early onset sepsis; NARDS: neonatal acute respiratory distress syndrome; NIPPV: nasal intermittent positive pressure ventilation; LOS: late onset sepsis.
Respiratory support
NIV was used in 452 infants (45.0%) on admission [13 of nasal intermittent positive pressure ventilation (NIPPV), 2 of nasal high-frequency oscillatory ventilation (NHFOV), 412 of nasal continuous positive airway pressure (NCPAP) and 25 of bi-level positive airway pressure (BIPAP)]. Of them, 198 (19.7%) succeeded to avoid IV (12 of NIPPV, 1 of NHFOV, 163 of NCPAP and 22 of BIPAP), and 254 (25.3%) failed to NIV (1 of NIPPV, 1 of NHFOV, 249 of NCPAP and 3 of BIPAP) and need invasive ventilation.
IV was used in 553 (55.0%) infants on admission. Of them, high-frequency oscillatory ventilation (HFOV) was selected in 291 (29.0%) infants, and conventional mechanical ventilation (CMV) in 516 (51.3%). 26 (5.0%) ventilated infants with CMV were converted to HFOV for low oxygen saturation and/or difficult removal of carbon dioxide. None was converted from HFOV to CMV.
The numbers of single death and BPD and/or death among NIV, NIV-I and IV groups were 25 (12.6%) and 32 (16.2%), 26 (10.2%) and 47 (18.5%), 75 (13.6%) and 134 (24.2%). 2 (0.8%) and 17 (3.1%) died before extubation between NIV-I and IV groups, and 24 (9.4%) and 58 (10.5%) died after the first extubation among NIV-I and IV groups.
Persistent pulmonary hypertension of newborn (PPHN) was diagnosed in 261 (26.0%) patients. Of them, death, and BPD and/or death appeared in 54 (20.7%) and 63 (24.1%) infants. Sildenafil and inhaled nitric oxide (iNO) were administrated to 168 (16.7%) (75 in PPHN, 93 in non-PPHN) and 146 (14.5%) (85 in PPHN, 61 in non-PPHN) infants, respectively. Of 261 patients with PPHN, iNO, sildenafil and iNO plus sildenafil were administrated to 36 (3.6%), 46 (4.6%) and 39 (3.9%) infants. Of 146 patients administrated by iNO, death, BPD and/or death appeared in 14 (9.6%), 46 (31.5%) infants. Of 168 patients administrated by sildenafil, death, BPD and/or death appeared in 16 (9.5%), and 47 (28.0%) infants. 393 (39.1%) newborn infants were diagnosed with hsPDA, Of them, 152 (38.7%) were closed after Ibuprofen.
Primary outcomes
These variables were considered to have univariable associations with BPD and/or death including Apgar 5 min, premature rupture of the membrane, hemoglobin, ARDS severities, primary respiratory supporting modes, PH, PPHN, heart failure, and transfusion of red blood cells, with a P value < 0.2 (Table 2). In the binary logistic regression analysis, variables that retained independent associations with the incidence of BPD and/or death were PH (OR 1.57, 95% CI 1.06–2.33, P = 0.026), ARDS severe vs mild (OR 1.83, 95% CI 1.23–2.73, P = 0.003), ARDS moderate vs mild (OR 1.51, 95% CI 1.06–2.16, P = 0.022), and heart failure (OR 1.71, 95% CI 1.09–2.68, P = 0.019) (Table 4). In the neonates less than/equal to 32 weeks, no independent risk factor for BPD and/or death was found, including GA (Supplement Table S2).
Table 4.
Independent risk factors for BPD and/or death and death.
| Independent risk factors for BPD and/or deatha | OR | 95% CI | P-value |
|---|---|---|---|
| Pulmonary hemorrhage | 1.57 | 1.06–2.33 | 0.026 |
| NARDS severe vs mild | 1.83 | 1.23–2.73 | 0.003 |
| NARDS moderate vs mild | 1.51 | 1.06–2.16 | 0.022 |
| Heart failure | 1.71 | 1.09–2.68 | 0.019 |
| Independent risk factors for deathb | OR | 95% CI | P-value |
| Surfactant | 0.40 | 0.26–0.61 | <0.001 |
| surfactant ≥2 times | 1.93 | 1.20–3.10 | 0.006 |
| Pulmonary hemorrhage | 2.45 | 1.66–3.60 | <0.001 |
| Early-onset sepsis | 1.57 | 1.06–2.33 | 0.023 |
| Meconium aspiration syndrome | 2.34 | 1.42–3.86 | 0.001 |
| NARDS severe vs mild | 1.60 | 1.06–2.42 | 0.027 |
| Albumin | 0.96 | 0.92–0.99 | 0.021 |
| Heart failure | 3.13 | 2.13–4.58 | <0.001 |
BPD, bronchopulmonary dysplasia; OR, odds ratio; CI, confidence interval; NARDS, neonatal acute respiratory distress syndrome.
Binary logistic regression.
Multivariate cox proportional regression
In-hospital survival
Kaplan–Meier analyses for the in-hospital survival were performed in six subgroups of NARDS (Fig. 3A–F). Otherwise, in the multivariate cox proportional regression, surfactant ≥2 times (OR 1.93, 95% CI 1.20–3.10, P = 0.006), EOS (OR 1.57, 95% CI 1.06–2.33, P = 0.023), PH (OR 2.45, 95% CI 1.66–3.60, P < 0.001), meconium aspiration syndrome (MAS) (OR 2.34, 95% CI 1.42–3.86, P = 0.001), heart failure (OR 3.13, 95% CI 2.13–4.58, P < 0.001), and NARDS severe vs mild (OR 1.60, 95% CI 1.06–2.42, P = 0.027) were associated with the increased rate of the in-hospital mortality. In contrast, use of surfactant (OR 0.40, 95% CI 0.26–0.61, P < 0.001) and albumin transfusion (OR 0.96, 95% CI 0.92–0.99, P = 0.021) were related to the decreased incidences of the in-hospital mortality.
Fig. 3.
Kaplan–Meier analyses for in-hospital survival for respiratory modes of NIV, NIV-I and IV (Fig 3A) (P = 0.356), mild, moderate and severe NARDS (Fig 3B) (P = 0.032), direct vs indirect insult (Fig 3C) (HR 2.55, 95% CI 1.71–3.58, P < 0.001) and EOS vs non-EOS (Fig 3D) (HR 1.72, 95% CI 1.21–2.91, P = 0.006). ARDS plus RDS vs ARDS (Fig 3E) (HR 0.95, 95% CI 0.64–1.41, P = 0.817) and non-perinatal-onset ARDS vs late-onset ARDS (Fig 3F) (HR 2.89, 95% CI 0.62–6.50, P = 0.259). NIV: noninvasive ventilation; NIV-I: intubation after NIV failure; IV: invasive ventilation; NARDS: neonatal acute respiratory distress syndrome; HR:Hazard ratio; CI:confidence interval; OS: early onset sepsis; ARDS: acute respiratory distress syndrome; RDS: respiratory distress syndrome.
Discussion
A prospective, multicentre, cross-sectional study was performed and the aim was to explore the aetiological factors, clinical characteristics and outcomes in neonates with NARDS. As a result, the incidences of perinatal NARDS was 65.6% within one day, 86.7% within two days, 94.1% within three days and 97.4% within seven days after birth. They were similar to the report by Hudson et al., in which the cumulative incidences within one, two, three, and seven days after onset were about 48–70%, 68–92%, 80–94% and near 100%.18 According to the PALICC, surfactant therapy cannot be recommended as routine therapy in PARDS (strong agreement).19 In adult patients with sepsis-induced ARDS, the continuous administration of aerosolised synthetic surfactant has no significant effect on 30-day survival, length of stay in the intensive care unit, duration of mechanical ventilation, or physiologic function.20 They were consistent with the present study, in which two and more doses of surfactant was associated with the increased mortality as compared with one or zero dose of surfactant. These results demonstrate that perinatal NARDS shares several features with adult and pediatric ARDS, and advancements in older ARDS are also suitable for perinatal NARDS.
According to Montreux definition of NARDS, an important consideration to diagnose NARDS is to exclude infants with RDS. It is very difficult to exclude RDS within the first three days after birth, because 30.3% (303) of 1005 infants were diagnosed with NARDS plus RDS and surfactant was administrated to up to 701 (68.8%) infants in the present study. There are three causes to explain the difficult exclusion of RDS. First, the European Consensus Guideline for the Management of RDS does not define an exact diagnostic criteria for RDS in the 2019 update.21 Second, the triggers inducing RDS could be also the causes of NARDS. An example is that bile acid can lead to RDS or ARDS or both.22,23 Third, the time for the diagnosis of perinatal NARDS and RDS is overlapped within the first 3 days after birth. In the present study, the cumulative incidences of NARDS were 65.6%, 86.7%, and 94.1% within one, two, and three days after birth. It is also consistent with the adult ARDS, which suggest that ARDS will develop within 72 h in the majority of patients at risk for the syndrome and within one week in nearly all patients at risk.18,24 We believe that addressing this issue can further increase the value of Montreux definition.
To date, exogenous surfactant replacement is not recommended in adult and pediatric ARDS.19,20,24 Therefore, its action for perinatal NARDS is needed to be further elucidated. Systematic review indicated that, in the infants with MAS, surfactant reduced the severity of respiratory illness and decreased the number of infants with progressive respiratory failure requiring support with extracorporeal membrane oxygenation (ECMO), but no beneficial effects on mortality [relative risk (RR) 0.98, 95% CI 0.41–2.39].25 Another review included eight randomised controlled trials and the result also demonstrated that surfactant did not reduce the risk of mortality in neonates with MAS (RR 0.38, 95% CI 0.09–1.57; and RR 0.80, 95% CI 0.39–1.66).26 In the present study, ≥ 2 doses of surfactant was associated with the increased mortality as compared with one or zero dose of surfactant. These results indicates no beneficial effect of surfactant on perinatal NARDS, and it is consistent with older ARDS.
Furthermore, perinatal neonatal, pediatric and adult ARDS also share several other features, including triggers, time of ARDS onset after triggers, ARDS severities, chest X-rays, and respiratory supporting modes. They are also similar in ARDS incidence and male (1.44% and 67.2% in the present study vs 3.2% and 61.2% in pediatric ARDS vs 2.3% and 62% in adult ARDS).12,22,27 It was similar to a multicer study by Luca et al. (1.5% and 60.0%).17 Those similarities make NARDS entity meaningful, and benefit infants with perinatal NARDS from the advancements in the basic study and clinical management of older ARDS.
Similar to adult ARDS,18 sepsis was one of the three main etiologic factors in patients with perinatal NARDS (43% vs 21.3% of EOS). Several studies have compared the effects of infectious and non-infectious triggers on mortality in older ARDS, and the results were inconsistent. Compared with patients with non-sepsis-related ARDS, those with sepsis-related had a higher mortality (38.2% vs 22.6%; P = 0.016).28 It was consistent with the present study, in which EOS were associated with the increased rate of the in-hospital death (OR 1.57, 95% CI 1.06–2.33, P = 0.023). In contrast, Nadir Yehya et al. reported that infectious ARDS was presented lower mortality (23% vs 37%, P = 0.013).29 Otherwise, Luca et al. reported that no difference was found between infectious vs noninfectious NARDS (P = 0.429).17 One of the causes may be the viral and/or bacterial infection. In pediatric population, virus infection accounts for about 60% of severe pneumonia, and only 30% are from bacteria trigger.30 In the present study, there was no virus-related perinatal NARDS.
The major limitations of the present study: (1) The study mainly presented data from level three hospitals, it is likely that lower level hospitals might have had worse outcomes. (2) Mild perinatal NARDS might be considered as RDS. Therefore, the incidence of ARDS may be underestimated. (3) Viral-induced perinatal NARDS was not presented. (4) ECMO was not performed in the present study. (5) The present study reported mainly the data of patients with perinatal NARDS and the sample size of LOS-related NARDS was not enough. (6) According to the sample size estimation, every hospitals needed about 15 neonates with NARDS, and the small sample size is difficult to compared by ICU and province, autonomous region and municipality. So we did not consider for clustering by ICU and province, autonomous region, and municipality in the analysis.31 Now we have designed another study to compare these outcomes by ICU and province, autonomous region and municipality in Chinese Neonatal Network, and the results could give us more reasonable explanations.
In summary, the incidence of NARDS was 1.44%, three main aetiologies were pneumonia of 58.1%, asphyxia of 24.3% and EOS of 21.3%. The cumulative incidences were 65.6%, 86.7%, and 94.1% within one, two, and three days after birth. Two or more doses of surfactant was associated with increased mortality as compared with one or zero doses of surfactant. These similarities make NARDS entity meaningful, and benefit newborn infants with perinatal NARDS from the advancements in the basic study and clinical management of pediatric and adult ARDS.
Contributors
Dr Chen contributed to conceptualisation, funding acquisition, project administration and supervision, drafted the initial manuscript and reviewed the manuscript, created Fig. 1, Fig. 2, Fig. 3 and agree to use it in the manuscript, and data interpretation. Dr Li contributed to methodology and formal analysis. Dr Shi conceptualised and designed the study, critically reviewed the manuscript for important intellectual content. The ChiNARDS study group members contributed to the collection of data. All authors revised the manuscript and approved the final manuscript as submitted. Dr Chen, Li, and Shi verified the underlying study data. All authors had full access to the data in the present study and accept responsibility to submit for publication.
Data sharing statement
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
Declaration of interests
No financial disclosure, and the other authors also have no financial disclosures relevant to this article. No financial or non-financial benefits have been received or will be received from any party related directly or indirectly to the individuals of this article.
Acknowledgments
We also thank Sophie Wang (PhD, MD) for their valuable suggestions that greatly improved the writing presentation of this article. The study was funded by the National Clinical Research Center of China and Clinical Medical Study Program of Children's Hospital of Chongqing Medical University (NCRC-2019-GP-13), and Natural Science Foundation of Chongqing(cstc2020jcyj-msxmX0197). We thank the 1005 newborn babies and their parents for supporting this study.
Footnotes
Supplementary data related to this article can be found at https://doi.org/10.1016/j.eclinm.2022.101739.
Appendix A. Supplementary data
The following are the supplementary data related to this article:
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Associated Data
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