Feasibility of combining two individualized lung recruitment maneuvers at birth for very low gestational age infants: a retrospective cohort study

doi:10.21203/rs.2.16455/v1

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Feasibility of combining two individualized lung recruitment maneuvers at birth for very low gestational age infants: a retrospective cohort study

https://doi.org/10.21203/rs.2.16455/v1

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published 01 Apr, 2020

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BACKGROUND Lung recruitment at birth has been advocated as an effective method of improving the respiratory transition at birth. Sustained inflations (SI) and dynamic positive end-expiratory pressure (PEEP) were assessed in clinical and animal studies to define the optimal level. Our working hypothesis was that very low gestational age infants (VLGAI) < 32 weeks’ gestation require an individualized lung recruitment based on combining both manoeuvers.

METHODS Between 2014 and 2016, 100 and 102 inborn VLGAI were enrolled before and after introducing these manoeuvers based on progressive increase in SI up to 15 seconds, with simultaneous gradual increase in PEEP up to 15 cmH2O, according to the cardiorespiratory response. Retrospective comparisons of the rate of mechanical ventilation (MV) < 72h of life, short- and mid-term morbidity were then performed.

RESULTS Among extremely low gestational age infants (ELGAI) < 29 weeks’ gestation, MV and its mean duration < 72h of life, consumption of a 2 nd dose of surfactant, and postnatal corticosteroids decreased significantly from 92 to 71%, 42 to 12h, 35 to 12%, and 49 to 24%, respectively. Among VLGAI, most of these results, and the rate of bronchopulmonary dysplasia (decreasing from 14 to 6%), were significant after a multivariate analysis. Neonatal mortality and morbidity were not different.

CONCLUSIONS In our setting, combining two individualized lung recruitment maneuvers at birth was feasible and may be beneficial on short- and mid-term pulmonary outcomes, especially in ELGAI < 29 weeks’ gestation. A randomized controlled trial is needed to confirm these results.

Pediatrics

Neonatal resuscitation

lung recruitment

dynamic PEEP

sustained inflation

bronchopulmonary dysplasia.

Resuscitating premature infants at birth aims to stimulate spontaneous breathing and establish an optimal functional residual capacity without harming the lungs [1]. To this end, lung recruitment maneuvers have been under investigation over the past two decades [2–6]. To date, despite numerous studies, no clear definition of the optimal inflation duration, nor of positive end-expiratory pressure (PEEP) optimal level exists. According to current knowledge on the respiratory transition at birth [7], sustained inflation (SI) aerates homogeneously the fluid-filled lungs during the initial fetal-neonatal transition phase, and thereafter, adequate PEEP helps to maintain the fluid in the interstitial tissue.

Current international guidelines recommend starting resuscitation of premature infants with intermittent positive pressure ventilation, using a PEEP of 5 cmH2O with the first insufflations of 2–3 s (but not greater than 5 s) [8,9]. However, these measures are probably not sufficient for recruiting the optimal functional residual capacity.

Lung recruitment (LR) at birth using SI of 15–20 s was assessed in numerous randomized controlled trials (RCTs) summarized in 2 recent meta-analyses [10,11]. Despite encouraging results such as a reduced need for intubation, no benefit was found for reduction of mortality or bronchopulmonary dysplasia (BPD). However, studies in the premature lamb have shown better oxygenation, lung mechanics, and end-expiratory global lung volume after a dynamic PEEP strategy based on a step-by-step PEEP increase far beyond 5 cmH2O compared with a nonoptimized SI strategy [4,5]. However, none of these differences were observed when the dynamic PEEP strategy was compared with a SI strategy optimized by real time electrical impedance tomography for the duration of the inflation [6]. We hypothesized that individualized LR maneuvers combining dynamic PEEP and gradually extended SI, as needed, would lower the rate of mechanical ventilation (MV) in the first 72 hours, without increasing neonatal complications. To this end, we retrospectively compared short- and mid-term outcomes, before and after introducing LR maneuvers in very low gestational age infants (VLGAI) < 32 weeks of gestation and especially in the subgroup of extremely low gestational age infants (ELGAI) < 29 weeks of gestation, with higher morbidity and mortality rates.

Population

Our tertiary level hospital covers the Saint-Denis area in the north of Paris, France, with a rate of ~ 4500 deliveries/year. Inborn VLGAI requiring pulmonary resuscitation born from July 2014 to June 2015 (n = 100) and for all of 2016 (n = 102) were included in this retrospective cohort study. A 6-month gap between both periods was needed to introduce LR maneuvers to the NICU team. Data were collected from patients’ medical records and reports.

A total of 244 VLGAI were managed during these periods (120 during 2014/2015 and 124 during 2016). We excluded infants transferred from other hospitals (n = 11) and (n = 14), infants suffering from major congenital anomalies (n = 2) and (n = 3), and newborns requiring no respiratory support beyond a PEEP value of 5 cmH2O (n = 7) and (n = 5) in 2014/2015 and 2016, respectively. Respiratory support was started based on currently used international guidelines (figure 1).

Data collection was approved by the local area ethics committee on human research which allowed a waiver of informed consent for this retrospective study (Protocol No. CLEA–2017–031).

Intervention

The intervention was the introduction of the LR strategy. In the 2014/2015 period, the respiratory assistance of VLGAI was conducted according to international recommendations (PEEP of 5 cm H2O, inflation duration of 2–3 s, peak inspiratory pressure of 20–25 cmH2O) using a face mask with a T-piece resuscitator (Neopuff, Fisher & Paykel, Auckland, New-Zealand), followed by intubation if the baby remained apneic or cyanotic with a pulse oxygen saturation (SpO2) < 75% at 5 min of life whatever the fraction of inspired oxygen (FiO2), or with a heart rate (HR) < 100/min or an FiO2 > 0.4 at 10 min of life in order to achieve an SpO2 > 85%. During 2016, respiratory support was changed to gradual increase in inflations duration (from 3 to 5, to 10, then 15 seconds), as needed, and performed with a simultaneous increase in PEEP every 1 to 2 SI from 5 to 8, 10, 12, then 15 cmH2O, according to the clinical response, which included persistent bradycardia, apnea or gasping. A gradual decrease in PEEP was performed when FiO2 reached 0.4, while SIs were stopped when regular spontaneous breathing was observed.

Monitoring in the DR

Postnatal hypothermia was prevented by using radiant heaters and warmed blankets. After drying, extremely low gestational age infants (ELGAIs) < 29 weeks were immediately wrapped in a sterile, transparent plastic bag. The head was covered by a warmed cap. Temperature was monitored via a cutaneous sensor. An SpO2 sensor was placed at the right hand.

Transport to the neonatal intensive care unit (NICU)

A preheated neonatal transport incubator was used for the transfer to the NICU. During both periods, infants were ventilated (invasively or not) using a Babylog 8000 (Dräger, Lübeck, Germany). Continuous positive airway pressure (CPAP) or noninvasive ventilation (NIV) was provided during the transfer by using nasal cannula (Neotech RAM Cannula^TM, Valencia, CA, USA).

Co-Interventions

Obstetric Management

Some changes in obstetric treatment were introduced in October 2016: antibiotic therapy duration after preterm premature rupture of membrane was shortened from 5 to 3 days [12]; and magnesium sulfate was infused to pregnant women prior to the preterm birth of infants <33 weeks’ gestation [13].

NICU Management

Neonatal management was as follows:

-Intubation criteria did not change: (i) in the DR, they remained as stated above; (ii) in the NICU, the criteria were an FiO2 > 0.4, frequent (> 6 occurrences during 6 hours) or severe apneas (> 1 per 6 hours requiring bag-mask ventilation).

-CPAP or NIV was maintained using the InfantFlow® biphasic nCPAP device (SEBAC, Gennevilliers, France). The synchronized mode was used in case of hypercapnia or moderate apnea despite caffeine treatment.

-During 2016, permissive hypercapnia was introduced with a maximal tolerated pCO2 limit of 65 mmHg (vs 55 mmHg during 2014/2015).

-Oxygen level was adjusted to obtain an SpO2 target range of 87–93% during 2016 instead of 85–95% during 2014/2015.

-During 2016, the maintenance dose of caffeine (5 mg/kg/day) was doubled in case of moderate apnea.

-During the second period, the first surfactant administration (200 mg/kg of Curosurf, Chiesi, Parma, Italy) was indicated when FiO2 exceeded 0.25 and 0.30 in ELGAIs and VLGAIs respectively, instead of 0.4 during the first period, whatever the gestational age (GA). During both periods, a second dose (100 mg/kg) was administered when FiO2 exceeded 0.4. If the infant was not intubated, the intubation-surfactant-extubation (INSURE) procedure was performed, and considered successful (without MV) if the extubation was carried out less than one hour later.

-Postnatal corticosteroid therapy criteria remained the same for premature infants more than 21 days old: persistent need for MV with FiO2 exceeding 0.4, or after failure of extubation.

-Early-rescue high frequency oscillation (HFO) and volume guarantee ventilations were introduced during 2016, with a change from a systematic sedation-analgesia toward an individualized approach based on the EDIN scale [14].

-No major changes in the nutrition protocol occurred, except for probiotics (Lactobacillus casei and Lactobacillus rhamnosus) introduced in April 2016.

Primary and Secondary Outcomes

The primary outcome was the rate of MV in the first 72 hours. Secondary outcomes were the rate of intubation in the DR; Apgar score at 5 min; surfactant use; ventilator days; postnatal corticosteroids; mortality and morbidity including physiologic BPD [15]; pneumothorax; intraventricular hemorrhage (IVH) > grade 2 [16]; periventricular leukomalacia [17]; treated patent ductus arteriosus (PDA); necrotizing enterocolitis (NEC) > stage 2a [18]; and retinopathy of prematurity (ROP) > stage 2 [19].

Statistical Analysis

Data are summarized as median and interquartile range for quantitative data and as count and percentage for categorical data. Statistical analyses were performed using chi-squared test or Fisher’s exact test for categorical variables and the t-test or Mann-Whitney U-test for continuous variables. All outcomes with p < 0.10 were analyzed with multiple logistic regression. Adjustments were made for confounding, such as sex, birth weight, GA, mode of delivery and low Apgar score (< 5) at 1 minute. Similar analyses were performed for the infants of GA between 29 and 31 weeks and ELGAI subgroup. No adjustment of P values was performed to account for multiple comparisons because subgroups analyses are considered exploratory. All tests were two-sided at a 0.05 significance level. Analyses were carried out using R statistical software version 3.3.2.

Comparability of Study Groups (Table 1)

Although both periods were similar regarding all baseline population characteristics, the cesarean section rate increased from 60 to 72% without reaching significance (p = 0.10).

Intervention

As stated above, in 2016, 5 newborns requiring no respiratory support beyond a PEEP value of 5 cmH2O were excluded from the study. Data concerning the LR maneuvers in 2016 were available for 67/102 patients: 28 (42%) infants required inflations with a peak inspiratory pressure of 20 cmH2O but without any recruitment maneuvers, 14 (21%) required an SI = 5 s with a PEEP = 8 cmH2O, 18 (27%) required an SI = 10 s with a PEEP = 10–12 cmH2O, while only 7 (10%) required an SI = 15 s with a PEEP = 15 cmH2O.

DR Management Data (Table 2)

The rate of the Apgar score < 5 at 5 min decreased by 73% in VLGAI and 79% in ELGAI but without reaching significance (p = 0.1 and p = 0.17, respectively). However, the rate of intubation in the DR significantly decreased by 30% in VLGAI (p < 0.01) and 36% in ELGAI (p < 0.001). The multivariate analysis did not change the results.

MV and Respiratory Outcomes (Table 3)

The primary outcome, MV in the first 72 h, showed a statistically significant 23% decrease in the ELGAI subgroup (p = 0.012). Adjusting for sex, birth weight, GA, mode of delivery and Apgar score < 5 at 1 min showed a significant 19% decrease for VLGAI (OR = 0.41; 95% CI: 0.2–0.83; p = 0.01), whereas the decrease was not significant in a univariate analysis (p = 0.053). Analyzing the primary outcome as a continuous variable showed a decrease in MV duration from 12.5 to 6 h (p = 0.064) and from 42 to 12 h (p < 0.01) in VLGAI and ELGAI, respectively. Significantly more infants from 29- to 31-weeks GA were ventilated by HFO while it was not the case in the ELGAI subgroup. The rate of two-dose surfactant consumption decreased by more than half in both the VLGAI (p = 0.052) and ELGAI subgroups (p < 0.01). Adjusting for birth weight, GA and sex showed a significant decrease in VLGAI (OR = 0.25; 95% CI: 0.09–066; p = 0.005). The INSURE practice increased from 1 to 6.9% in VLGAI without reaching significance (p = 0.052). Postnatal corticosteroid therapy decreased significantly by half in both subgroups.

Neonatal Morbidity and Mortality (Table 4)

BPD decreased by more than half in both subgroups. Adjusting for birth weight, treated PDA and infection status showed a statistically significant decrease in VLGAI (OR = 0.28; 95% CI: 0.09–0.86; p = 0.03) without reaching significance in any subgroups. No statistically significant difference in mortality was shown between the two periods and subgroups (p = 0.53 and p = 0.57, respectively). Similarly, the combined BPD/mortality rate did not show a statistically significant difference in VLGAI (p = 0.55) nor in the ELGAI subgroup (p = 0.65).

No statistically significant difference of neonatal morbidities during both periods and subgroups was observed. Moreover, the same small incidence of pneumothorax was observed in both periods (one per year only).

This retrospective cohort study compared the short- and mid-term neonatal morbidity and mortality of a new LR strategy combining individualized increase in PEEP and SI. This LR policy is retrospectively associated with a decrease in i) endotracheal intubation in the DR, ii) rate and duration of mechanical ventilation in the first 72 hours, iii) surfactant use and iv) postnatal corticosteroids consumption. These results were more pronounced in infants < 29 weeks GA. Moreover, this strategy was not associated with any significant increase in neonatal morbidity or mortality.

Our significant decrease in endotracheal intubation rate in the DR is in accordance with other retrospective studies [20,21] and 3 RCTs [22–24] on SI. However, in our study as in all retrospective studies in the DR, it is difficult to ascertain whether this decrease was related to our individualized LR maneuvers or to a longer time allowed to the infants to stabilize without intubation. Nevertheless, in favor of our LR maneuvers we observed a decrease intubation rate in the DR with all physicians, not only the “early intubators”. Nonetheless, only an RCT could add any definitive evidence on this subject. Laryngeal closure is described as the main cause of airway obstruction [25] impeding NIV in the DR in about 26% of VLGAI [26]. In our 2016 cohort, apneic airway obstructions were also observed but only 18% of our VLGAIs were intubated for this reason in the DR, that is, on average in our medical team, twice a year per physician.

Although the total MV duration did not reach a statistically significant decrease, pulmonary morbidity was reduced, as witnessed by a lessened surfactant and postnatal corticosteroids consumption. However, early-rescue HFO, the INSURE procedure, an increased caffeine dosing in the case of moderate apnea, and sedation-analgesia as needed were practiced more often during 2016 and, thus, might have contributed to some pulmonary protection.

A more-than-halved BPD rate was observed in both subgroups but without reaching significance except for a multivariate analysis in the whole population of VLGAIs. We propose two explaining hypotheses. First, our relatively low prevalence of BDP makes a significant decrease more difficult to achieve. Second, the multifactorial origin of BPD [27] might make any effect of our very early intervention difficult to show without a large multicentric RCT.

Our data showed an increased trend in mortality and high grade IVH. The large multicentric “Sustained Aeration of Infants Lungs” (SAIL) trial comparing SI with conventional ventilation in the DR was recently cancelled (after 426 infants analyzed) because of a significant excess of deaths at less than 48 hours of age in the intervention arm without any reduction in BPD rates in preterm infants < 27 weeks GA [28]. Our speculative explanation of this harmful finding could be that the most immature infants may require an individualized and gentler support than a 15 s SI from the outset, explaining the initial persistent bradycardia observed in the SI group of the SAIL trial, and reflecting potential lung overdistention. In fact, our available data in preterm infants < 27 weeks GA show that only 19% required an SI = 15 s with a PEEP = 15 cmH2O. In our case, the mortality increase was related to an outbreak of first week late-onset septic shock during 2016 (i.e., 6 septic shock cases, including 2 complicated by high grade IVH) instead of 2 during the first period while the overall rate of culture-proven sepsis remained steady (8 then 9 cases per year). We speculate that this mortality increase, although nonsignificant, might be related to some delay in sepsis management among medical and nurse teams unaccustomed to early NIV.

Our results are in accordance with all other retrospective studies [20,29,21,30] assessing SI. Only one [20] showed a decrease in BPD and severe IVH, but these results could be related to other interventions in the DR such as an individualized approach to intubation, more CPAP use, and novel thermoregulation interventions. Four RCTs showed no benefits at all [31,32,22,33]. However, according to the meta-analysis of Bruschettini et al. [10], a decreased duration of MV was found (mean difference: –5.37 days; 95% CI: –6.31 to –4.43), but without differences in the rate of BPD nor combined mortality/BPD. Whether our positive results could be explained only by the adjunction of the possibly more protective dynamic PEEP LR manoeuver [34] should be addressed in a specific RCT.

Two studies using a prophylactic approach with a fixed duration of SI [33,35] have shown a nonsignificant increase in the rate of pneumothorax from 1 to 6% (OR = 4.57; 95% CI: 0.97–21.5; p = 0.06) [33] and from 0 to 3% (p = 0.08) [35]. This side-effect was not found in our study, despite the application of repeated SIs associated with much higher PEEPs. To explain this discrepancy, we postulate that our individualized approach might play a fundamental role. The rate of treated PDA was slightly but significantly increased in the meta-analysis of Schmölzer et al (RR = 1.27 (1.05–1.54)) [36], but our data do not support this observation.

A nonsignificant 20% increase in the rate of cesarean sections was observed during 2016 (p = 0.10). Paradoxically, our results show immediate benefits of the LR strategy, despite the absence of improved clearance of lung fluid that occurs during vaginal delivery [37]. Until recently, one of the described mechanisms of airway liquid clearance at birth was Na⁺ uptake across the airway epithelium. However, this cellular mechanism develops only in late gestation [38], and is too slow to clear the volume of liquid to be expelled within seconds to minutes after birth from airways. Therefore, the airway liquid clearance after birth is thought to result from an increase in the transepithelial pressure gradient, occurring during inspiration, which is incompletely effective in premature neonates [7]. Thus, our results might validate that personalized LR maneuvers helped to clear the fluid-filled airways and initiate gas exchange.

This study shares the limitations of monocentric retrospective cohort studies. Thus, the steady high rate of IUGR observed in our population (~24%) could account for a greater rate of morbidities. Given the changes that occurred in our neonatal management, confounding factors were introduced such as lowering the FiO2 threshold for surfactant administration, volume guarantee ventilation, early-rescue HFO, permissive hypercapnia, individualized doubling of the caffeine maintenance dose, and individualized sedation-analgesia. Moreover, the multiple secondary statistical analyses made in this study limit the value of significant results. Therefore, the beneficial pulmonary outcomes must be interpreted cautiously except probably for the intubation in the DR which could not be impacted by the subsequent management changes.

In conclusion, this retrospective study, shows the feasibility of an individualized LR strategy based on a stepwise increase in PEEP and SI with potentially beneficial short-term neonatal outcomes, especially in the ELGAI. A large RCT is needed to confirm these results.

ETHICS APPROVAL

Data collection was approved by the local area ethics committee on human research which allowed a waiver of informed consent for this retrospective study (Protocol No. CLEA–2017–031).

CONSENT FOR PUBLICATION

Not applicable.

AVAILABILITY OF DATA AND MATERIALS

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

COMPETING INTERESTS

The authors have no competing interests relevant to this article to disclose.

FUNDING

No external funding for this manuscript.

AUTHORS’ CONTRIBUTIONS

PW conceptualized and designed the study, supervised data collection, analyzed and interpreted data, reviewed and revised the manuscript. ZK collected data, carried out the initial statistical analysis, drafted the initial manuscript, reviewed and revised the manuscript. MB carried out statistical analyses, contributed to analysis and interpretation of data, reviewed and revised the manuscript. PB, CB-Q and VL contributed to analysis and interpretation of data, reviewed and revised the manuscript. All authors read and approved the final manuscript.

ACKNOWLEDGMENTS

The authors gratefully acknowledge the members of the Delafontaine Hospital Neonatal Intensive Care Unit’s medical team (by alphabetical order): Drs. F. Abouassi, M. Alchaar, C. Allioux, O. Girard, F. Harbi, F. Imestouren-Goudjil, A. Saïd-Idrissi, and N. Semaan.

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Table 1 Very Low Gestational Age Infants < 32 weeks GA Population Characteristics
	Period 1 (2014/2015) N=100	Period 2 (2016) N=102
Female, n (%)	47 (47)	41 (40)
Gestational age, weeks (median) [1^st Qu; 3^rd Qu]	29 [27;30]	28 [27;30]
Birth weight, g (median) [1^st Qu; 3^rd Qu]	1075 [850;1365]	1022 [888;1361]
IUGR, n (%)	25 (25)	23 (22)
Cesarean Section, n (%)	60 (60)	73 (72)
Premature birth causes, n (%)
Chorioamnionitis	30 (30)	23 (22)
Pre-eclampsia + abnormal FHR	44 (44)	54 (53)
Other	12 (12)	13 (13)
Idiopathic	14 (14)	12 (12)
Antenatal corticosteroids, n (%):
None	15 (15)	11 (11)
One dose	21 (21)	20 (19)
Two doses	64 (64)	71 (70)
GA: gestational age; IUGR: intrauterine growth restriction (< 3^rd percentile); FHR: fetal heart rate; No significant difference between period 1 and 2.

Table 2 Delivery Room Management Data
	VLGAI		29- to 31-wk stratum		ELGAI
	Period 1 N=100	Period 2 N=102	Period 1 N = 51	Period 2 N = 43	Period 1 N=49	Period 2 N=59
1 min Apgar score < 5, n (%)	38 (38)	43 (42)	13 (25)	21 (49)	25(51)	22 (37)
3 min Apgar score < 5, n (%)	23 (23)	22 (21)	7 (14)	11 (26)	16 (33)	11 (19)
5 min Apgar score < 5, n (%)	7 (7)	2 (2)	3 (6)	1 (2)	4 (8)	1 (1.7)
10 min Apgar score < 5, n (%)	1 (1)	1 (1)	0 (0)	0 (0)	1 (2)	1 (1.7)
Intubation in the delivery room, n (%)	69 (69)	50 (49)*##	25 (49)	16 (37)	44 (90)	34 (58)*##
VLGAI: very low gestational age infants < 32 weeks; ELGAI: extremely low gestational age infants < 29 weeks; *##: p and adjusted p < 0.01

Table 3 Mechanical Ventilation and Respiratory Outcomes
	VLGAI		29- to 31-wk stratum		ELGAI
	Period 1 N=100	Period 2 N=102	Period 1 N = 51	Period 2 N = 43	Period 1 N=49	Period 2 N=59
MV in the first 72 h, n (%)	75 (75)	60 (61)#	30 (59)	19 (48)	45 (92)	41 (69)*
Duration of MV within the first 72 h, h (median) [1^st Qu; 3^rd Qu]	12.5 [1.5-48]	7 [0-41]	6 [0-19]	0 [0-14]	42 [9-72]	12** [0-48]
Duration of MV, d (median) [1^st Qu; 3^rd Qu]	1 [0-5]	1 [0-7]	0 [0-1]	0 [0-2]	5 [1-20]	4 [0-10]
Duration of NIV, d (median) [1^st Qu; 3^rd Qu]	17.5 [4-38]	23 [7-33]	10 [3-19]	10 [5-23]	35 [17-42]	29 [15-38]
HFO, n (%)	26 (26)	34 (33)	2 (4)	15 (35)*##	24 (49)	19 (32)
2^nd dose of Surfactant, n (%)	18 (18)	8 (8)##	1 (2)	1 (2)	17 (35)	7 (12)*##
INSURE Procedure, n (%)	1 (1)	7 (7)	0 (0)	3 (7)	1 (2)	4 (7)
Postnatal Corticosteroids, n (%)	29 (29)	16 (15)*##	5 (10)	2 (5)	24 (49)	14 (24)*##
VLGAI: very low gestational age infants < 32 weeks; ELGAI: extremely low gestational age infants < 29 weeks; MV: mechanical ventilation; NIV: noninvasive ventilation; HFO: high frequency oscillation; INSURE: intubation-surfactant-extubation; : p < 0.05; : p < 0.01; #: adjusted p < 0.05; ##: adjusted p < 0.01; ##: p and adjusted p < 0.01.

Table 4 Neonatal Mortality and Morbidity
	VLGAI		29- to 31-wk stratum		ELGAI
	Period 1 N=100	Period 2 N=102	Period 1 N = 51	Period 2 N = 43	Period 1 N=49	Period 2 N=59
Physiologic BPD at 36 weeks GA, n (%)	14 (14)	6 (6)#	4 (8)	1 (2)	10 (20)	5 (8.5)
Mortality, n (%)	9 (9)	13 (13)	2 (4)	1 (2)	7 (14)	12 (20)
BPD and/or mortality, n (%)	23 (23)	19 (19)	6 (12)	2 (4.6)	17 (35)	17 (29)
Pneumothorax, n (%)	1 (1)	1(1)	0 (0)	0 (0)	1 (2)	1 (1.7)
Treated PDA, n (%)	15 (15)	21 (21)	0 (0)	4 (9)	15 (31)	17 (29)
NEC > grade 2a, n (%)	4 (4)	5 (5)	1 (2)	1 (2)	3 (6)	4 (7)
IVH > grade 2, n (%)	2 (2)	6 (6)	0 (0)	0 (0)	2 (4)	6 (10)
Periventricular leukomalacia, n (%)	4 (4)	1 (1)	2 (4)	0 (0)	2 (4)	1 (1.7)
ROP > grade 2, n (%)	1 (1)	0 (0)	0 (0)	0 (0)	1 (2)	0 (0)
VLGAI: very low gestational age infants < 32 weeks; BPD: bronchopulmonary dysplasia; PDA: patent ductus arteriosus; NEC: necrotizing enterocolitis; IVH: intraventricular hemorrhage; ROP: retinopathy of prematurity. #: adjusted p < 0.05.

BPD: bronchopulmonary dysplasia

CPAP: continuous positive airway pressure

CPR: cardiopulmonary resuscitation

DR: delivery room

ELGAI: extremely low gestational age infants

FiO2: fraction of inspired oxygen

GA: gestational age

HR: heart rate

HFO: high frequency oscillation

INSURE: intubation-surfactant-extubation

IUGR: intrauterine restriction growth

IVH: intraventricular hemorrhage

LR: lung recruitment

MV: mechanical ventilation

NEC: necrotizing enterocolitis

NICU: neonatal intensive care unit

NIV: noninvasive ventilation

PDA: patent ductus arteriosus

PEEP: positive end-expiratory pressure

RCT: randomized controlled trial

ROP: retinopathy of prematurity

SI: sustained inflation

SpO2: pulse oxygen saturation

VLGAI: very low gestational age infants

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Feasibility of combining two individualized lung recruitment maneuvers at birth for very low gestational age infants: a retrospective cohort study

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