The Journal of Maternal-Fetal & Neonatal Medicine
ISSN: 1476-7058 (Print) 1476-4954 (Online) Journal homepage: http://www.tandfonline.com/loi/ijmf20
Oxygen administration at birth in preterm infants: a retrospective analysis Maria Pierro, Fabrizio Ciralli, Mariarosa Colnaghi, Mara Vanzati, Domenica Mercadante, Dario Consonni & Fabio Mosca To cite this article: Maria Pierro, Fabrizio Ciralli, Mariarosa Colnaghi, Mara Vanzati, Domenica Mercadante, Dario Consonni & Fabio Mosca (2015): Oxygen administration at birth in preterm infants: a retrospective analysis, The Journal of Maternal-Fetal & Neonatal Medicine, DOI: 10.3109/14767058.2015.1100161 To link to this article: http://dx.doi.org/10.3109/14767058.2015.1100161
Published online: 30 Oct 2015.
Submit your article to this journal
Article views: 48
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ijmf20 Download by: [New York University]
Date: 15 March 2016, At: 03:10
http://informahealthcare.com/jmf ISSN: 1476-7058 (print), 1476-4954 (electronic) J Matern Fetal Neonatal Med, Early Online: 1–6 ! 2015 Taylor & Francis. DOI: 10.3109/14767058.2015.1100161
ORIGINAL ARTICLE
Oxygen administration at birth in preterm infants: a retrospective analysis Maria Pierro1, Fabrizio Ciralli1, Mariarosa Colnaghi1, Mara Vanzati1, Domenica Mercadante1, Dario Consonni2, and Fabio Mosca1 1
Downloaded by [New York University] at 03:10 15 March 2016
NICU, Department of Clinical Sciences and Community Health, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Universita` Degli Studi Di Milano, Milan, Italy and 2Epidemiology Unit, Fondazione IRCCS Ca’ Granda – Ospedale Maggiore Policlinico, Milan, Italy
Abstract
Keywords
Objective: The aim of the study was to retrospectively investigate the association between initial oxygen concentration in delivery room and short-term outcomes in preterm infants. Methods: Data from infants needing neonatal resuscitation, born at our department between January 2008 and December 2011, were analyzed. Patients were divided into three groups based on gestational age: between 32 and 36 weeks, between 31 and 28 weeks, and below 28 weeks. Results: The administration of each additional unit of oxygen up to 50% showed an association with a 5% increased need for mechanical ventilation (MV) in the neonatal intensive care unit in infants between 32 and 36 weeks [adjusted odds ratio 1.1, 95% confidence interval (CI) 1.04– 1.1] and infants between 28 and 31 weeks (adjusted odds ratio 1.12, 95% CI 1.08–1.44). On the contrary, in infants below 28 weeks, increasing initial concentration of supplementary oxygen did not show any association with MV. Conclusions: Initial oxygen concentration seems to be associated with increased MV in the NICU. Our observations further stress the need for randomized controlled studies in order to obtain definitive recommendations for the optimal initial oxygen concentration during neonatal resuscitation of preterm infants.
Guidelines, mechanical ventilation, neonatal resuscitation, oxygen, preterm
Introduction Neonatal resuscitation includes sequential interventions executed in order to achieve a correct transition to extrauterine life, whenever adaptation does not happen spontaneously. Annually, 136 million babies are born worldwide and, of these, around 10 million (5–10%) require some assistance to start breathing [1], making neonatal resuscitation one of the most frequently practiced procedures in neonatology. Based on evolving scientific evidence, neonatal resuscitation guidelines have been revised and implemented systematically over the past decades [2–4]. One of the major controversial issues amongst these advances is the use of oxygen in the delivery room (DR). Administration of 100% oxygen during positive pressure ventilation, as opposed to any other concentration of oxygen therapy, has been strongly advised [2], although there were some reports that room air could be at least as effective as 100% oxygen in asphyxiated term infants [5,6]. The use of room air had to be proven to
Address for correspondence: Maria Pierro, MD, NICU, Department of Clinical Sciences and Community Health, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Universita` degli Studi di Milano, Via Della Commenda 12, 20122 Milano, Italy. Tel: +39 0255032907. Fax: +39 0255032429. E-mail: [email protected]
History Received 11 April 2014 Revised 15 November 2014 Accepted 22 September 2015 Published online 22 October 2015
reduce the rate of mortality and neurological complications in order to be accepted as the optimal strategy in term infants [7–11]. Conversely, optimal oxygen concentrations during neonatal resuscitation of preterm infants have not yet been determined. Standardization of care regarding oxygen therapy in the DR for preterm infants remains an urgent need in neonatology. The aim of this retrospective study was to investigate the consequences of initial oxygen concentrations, used in resuscitation of preterm infants in the DR, on short-term outcomes.
Methods Study design We retrospectively analyzed data of infants below 37 weeks of gestational age born at the Department of Clinical Sciences and Community Health, University of Milan, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico (Milan, Italy) between January 2008 and December 2011. We divided patients into three groups based on gestational age: between 32 and 36 weeks, between 31 and 28 weeks, and below 28 weeks. Infants with major malformations, chromosomic anomalies and fetal hydrops were excluded.
2
M. Pierro et al.
The primary objective of the study was to assess the association between the initial oxygen concentration administered in the DR and mechanical ventilation (MV) in the NICU. The secondary objective was analyzed the association between the initial oxygen concentration and the need for intubation in the DR. For infants below 32 weeks of gestation, the main complications of prematurity were also analyzed: bronchopulmonary dysplasia, defined as oxygen dependency at 36 weeks post menstrual age [12]; intraventricular hemorrhage defined as stage 2 or higher [13]; patent ductus arteriosus defined by cardiac ultrasound study; retinopathy of prematurity by stage of severity defined as stage 2 or higher [14]; necrotizing enterocolitis defined as stage 2 or higher as per modiEed Bell criteria [15] and cystic periventricular leukomalacia [16].
Downloaded by [New York University] at 03:10 15 March 2016
Setting In our unit, neonatal resuscitation is performed following the American Academy of Pediatrics (AAP) guidelines. As no initial oxygen concentration is recommended by the AAP guidelines and no evidence of the optimal initial oxygen concentration is available for preterm infants, the initial oxygen concentration in our unit is chosen by the attending neonatologist. The oxygen blender is set between 21% and 90% by the neonatologist before the baby is born, independently from the clinical conditions, based on the personal interpretation of the available evidence. Oxygen is then tailored to maintain oxygen saturation (SpO2) between 10th and 90th percentile at birth [17]. FiO2 is usually increased by 10% increments when the infant’s SpO2 is below the 10th percentile for 1 min and decreased by 10% increments when the SpO2 is above the 90th percentile for 1 min. Before the SpO2 nomograms were published in 2010, oxygen was tailored to keep SpO2 between 85% and 92%. In case of chest compressions, FiO2 is increased straight to 100% according to current AAP guidelines [4]. A neonatal resuscitation team composed of neonatologists and neonatology nurses with specialized training is present for complicated deliveries and all C-sections. Available devices for neonatal resuscitation are detailed in the Online Supplement. Respiratory assistance in the NICU is administered following standard operating procedures, which are revised on a regular basis. Briefly, in newborns receiving nasal continuous positive airway pressure (NCPAP), the need for MV is determined by one or more of the following criteria: (i) requirement of more than 0.4 fraction inspired oxygen (FiO2) for longer than 30 min (unless sudden deterioration) to maintain partial saturation of oxygen (SpO2) in the range 88–95%; (ii) intractable apnea (deEned as 4 episodes of apnea, a respiratory pause lasting at least 20 s, or a pause accompanied by bradycardia, cyanosis or pallor [18], per hour or 2 episodes of apnea per hour requiring mask ventilation) and (iii) pH 7.2 and/or arterial pressure of carbon dioxide (PaCO2) 65 mmHg on arterial or capillary blood gas sample. Surfactant treatment (Curosurf–Chiesi Farmaceutici, Parma, Italy), either in the DR or in the NICU, is administrated in cases of FiO2 dependency40.4. MV is discontinued when effective respiratory drive, FiO2
J Matern Fetal Neonatal Med, Early Online: 1–6
requirement50.4 to maintain SpO2 88–95%, mean airway pressure57, pH47.25 and PaCO2560 mmHg are present. NCPAP is suspended when FiO2 is50.3, in the absence of apnea for at least a 24-h period. Data collection In our unit, a system of computerized charting (Neocare, i&t group, Italy) has consistently been in use since 2007. The system allows collection of any neonatal data. No diagnostic and therapeutic actions can be initiated without entering DR resuscitation data and providing complete information. Retrospective retrieval of information can be requested through the computerized chart archives in the form of an Excel file. Statistical analysis Odds ratios and 95% confidence intervals (CIs) were calculated with the use of generalized-estimating-equation log-binomial regression models with robust variance estimates to adjust for clustering of twins. We constructed separate models for each outcome. In adjusted analyses, each model included gestational age, Apgar score at 1 min, gender, intubation in the DR, prenatal steroids, mode of delivery and initial oxygen concentration. Cord pH, birth weight and year of birth were not included in the model, since they never showed any difference in the univariate analysis. Initial oxygen concentration during resuscitation showed a non-linear relationship with MV and also with intubation in DR and complications of prematurity with the same cut-off at 50%. Regression analysis was performed using restricted splines for initial oxygen concentration as an alternative to inappropriate linearity assumptions, with 50% cut-off. We show representative pictures in the entire population in the Supplemental material (Figure 1S). Data were analyzed with the use of SAS software, version 9 (SAS Institute, Cary, NC).
Results Characteristics of the study population Throughout the 4-year time frame of the study, 26 083 babies were born at our center. Infants included from the analysis are listed in Figure 2S. Neonatal resuscitation in the DR was required for 1474 infants (5.3%), of these, 863 were premature (58.5%). Maneuvers performed during neonatal resuscitation are detailed in Table 1. All infants with gestational age below 28 weeks (141) and 230 of 289 infants between 28 and 31 of gestational age (79.5%) required neonatal resuscitation. The need for neonatal resuscitation drastically decreased to 17% (463 of 2707) for infants of gestational age between 32 and 36 weeks (Table 1). Need for MV In any class of infants, Apgar score was inversely related to MV in the NICU, and intubation in the DR was strongly associated with MV. Male gender and C-section were risk factors only in infants between 32 and 36 weeks. Restricted splines analysis, with a cut-off at oxygen concentration of 50%, showed that increasing initial oxygen delivery up to 50% raised the odds of MV in infants between 32 and 36 weeks
Oxygen and neonatal resusciation
DOI: 10.3109/14767058.2015.1100161
Table 1. Neonatal resuscitation in the DR.
Downloaded by [New York University] at 03:10 15 March 2016
32–36 weeks N¼463 Tactile stimulation, n (%) NCPAP only, n (%) Mask ventilation, n (%) Endotracheal intubation, n (%) Positive pressure ventilation, n (%) Respiratory assistance, n (%) Surfactant administration, n (%) Initial oxygen concentration, mean ± SD Maximum oxygen concentration, mean ± SD Whole resuscitation in room air, n (%)* Cardiac massage, n (%) Adrenaline, n (%) Crystalloid solution, n (%) Sodium bicarbonate, n (%) Blood, n (%) SpO2 monitor, n (%)
424 21 363 55
(91.5) (4.6) (78.4) (11.1)
Discussion 28–31 weeks N¼230 221 14 200 64
(61.1) (6) (85.8) (27.5)
528 weeks N¼141 118 1 94 100
(83.7) (0.3) (66.2) (70.6)
374 (80.7)
206 (88.4)
140 (95.8)
395 (88.3)
220 (94.4)
141 (100)
9 (2)
22 (9.4)
50 (35)
25 (10.2)
27 (11.8)
32 (19)
30 (13.5)
33 (16.1)
45 (25)
77 (33)
29 (19)
182 (46) 13 4 6 8 1 278
(2.8) (0.9) (1.3) (1.8) (0.2) (60)
3
11 6 5 2 1 220
(4.7) (2.6) (2.1) (0.9) (0.4) (94.4)
17 10 10 7 1 141
(11.9) (7) (7) (4.9) (0.7) (100)
*Out of patients needing respiratory resuscitation. (adjusted odds ratio 1.1, 95% CI 1.04–1.11) and in infants between 28 and 31 weeks (adjusted odd ratio 1.12, 95% CI 1.08–1.44). On the contrary, in infants below 28 weeks, MV was not related in any way to initial oxygen concentration in the DR (Table 2). Increasing oxygen concentration from 50% to 100% further increased the risk for MV in the NICU for any of the different gestational age groups; however, it did not reach significance. Intubation in DR In any class of preterm infants, Apgar score was inversely related to intubation in DR, while gestational age was inversely related to intubation in the DR only in infants below 28 weeks. Restricted splines analysis, with a cut-off at oxygen concentration of 50%, showed that increasing initial oxygen delivery up to 50% raised the odds of intubation in the DR in infants between 32 and 36 weeks (adjusted odds ratio 1.05, 95% CI 1.01–1.09) and in infants between 28 and 31 weeks (adjusted odds ratio 1.05, 95% CI 1.01–1.06) (Table 3). On the contrary, in infants below 28 weeks, need for intubation in the DR was not influenced by initial oxygen concentration. Increasing oxygen concentration from 50% to 100% further increased the risk for MV in the NICU for any of the different gestational age groups; however, it did not reach significance (Table 3). Complications of prematurity Initial concentration of oxygen was not associated with any complication of prematurity except for intraventricular hemorrhage, in infants below 28 weeks of gestation (data described in the Supplemental material, Table 1S).
We found that higher initial oxygen concentrations during resuscitation at birth seem to be associated with an increased need for intubation in the DR and MV in the NICU in preterm infants between 28 and 36 weeks, but not below 28 weeks. From our analysis, each additional unit of oxygen, up to 50%, was associated with a 10% increased risk of MV in the NICU in preterm infants between 28 and 31 weeks and between 32 and 36 weeks. Accordingly, beginning neonatal resuscitation with 50% oxygen concentration instead of 21% may increase by 15.8-fold the risk for MV in the NICU. These observations may be explained by the known effect of oxidative stress and subsequent impairment of lung fluid balance resulting in respiratory distress syndrome and transient tachypnea of the newborn [19]. In our data, among infants between 32 and 36 and between 28 and 31 weeks, each additional unit of oxygen, up to 50%, was associated with about a 5% increased risk of intubation in the DR. This suggests that beginning neonatal resuscitation with 50% instead of 21% oxygen may increase the risk for intubation in the DR by 4.2-fold. This finding is consistent with previous studies showing that resuscitation with oxygen delayed the onset of spontaneous breathing compared to room air [6,20]. We found that 79.4% of infants below 28 weeks and 65% of infants between 28 and 31 weeks needed supplemental oxygen during resuscitation. These proportions are slightly lower compared to previous published data [21–23]. These studies regarding the use of oxygen in preterm infants during the transition to extrauterine life suggest that most preterm infants require supplemental oxygen to achieve expected oxygenation levels. However, the target SpO2 levels differed from one study to the other and from the nomogram currently in use [17]. Moreover, the study population varied as well in different studies. One limitation of our study is that the computerized chart can automatically record neither the actual SpO2 monitoring nor the FiO2 delivered. The initial and highest values of FiO2 needed to maintain SpO2 within the ranges are entered by the neonatologist once the resuscitation is completed. The SpO2 monitoring was performed in all infants below 32 weeks and in 60% of infants between 32 and 36 weeks. The patients that did not receive the monitoring were the ones that needed a very brief period of mask ventilation with no time to start the monitoring. A second limitation of the study is that we do not have a standard method of selecting the initial oxygen concentration. The attending neonatologist always chooses the initial oxygen concentration by setting the oxygen blender before the baby is born, independently from the clinical conditions. However, there may be subjectivity and potential bias in taking resuscitation decisions that could have been affected by personal preferences, perceived severity of each case and/or different antenatal and delivery conditions. In order to reduce the inherent bias of the severity of clinical conditions on initial oxygen concentration, we performed univariate analysis in including possible indicators of severity at birth (details in the ‘‘Methods’’ section). Then, we performed a multivariate analysis with these factors. In our multivariate analysis, initial oxygen concentration was shown to be an independent risk factor for MV and intubation in the
4
M. Pierro et al.
J Matern Fetal Neonatal Med, Early Online: 1–6
Table 2. MV in the NICU in preterm resuscitated infants. 32–36 weeks
Downloaded by [New York University] at 03:10 15 March 2016
N ¼ 94
GA, mean ± SD, weeks Apgar 1 min, median (range) Female gender, n (%) C-section, n (%) Prenatal steroids, n (%) Intubation in DR, n (%) Initial oxygen spline 21–50%, mean ± SD Initial oxygen spline 50–100%, mean ± SD
528 weeks
28–31 weeks
N ¼ 369 Adjusted odds ratio (95% CI)
N ¼ 125
N ¼ 105
MV
No MV
Adjusted odds ratio (95% CI)
N ¼ 110
N ¼ 31
MV
No MV
Adjusted odds ratio (95% CI)
MV
No MV
33.8 ± 1.4
34.1 ± 1.4
0.84 (0.688–1.03)
30.2 ± 0.8
30.04 ± 0.7
0.67 (0.43–1.05)
25.1 ± 1.3
25 ± 1.3
0.79 (0.71–0.88)
5 (1–8)
6 (4–9)
0.76 (0.66–0.88)z
4 (0–7)
6 (5–8)
0.64 (0.56–0.79)z
3 (0–5)
5 (2–8)
0.77 (0.68–0.88)z
63 (63.2)
168 (46.6)
0.46 (0.27–0.8)y
39 (36.8)
64 (51.2)
0.86 (0.18–1.2)
13 (40.8)
50 (45)
0.8 (0.49–1.29)
91 (93.7)
291 (80.3)
116 (89.3)
100 (93.6)
28 (83.6)
155 (44.4)
98 (71.1)
84 (80.2)
0.86 (0.36–3.92) 1.18 (0.48–2.85)
91 (87.5)
45 (47.4)
3.1 (1.14–8.37)* 1.15 (0.64–2.05)
24 (75)
70 (65.4)
0.84 (0.36–1.92) 1.04 (0.58–1.85)
41 (42.7)
16 (4.5)
10 (2.3–20.05)z
64 (50)
13 (7)
4.2 (2.03–8.67)z
83 (75.5)
18 (56.3)
5 (2.33–10.67)z
24 ± 5
22 ± 4
1.1 (1.04–1.11)z
30 ± 14
24 ± 6
1.12 (1.08–1.44)*
33 ± 10
31 ± 17
1.01 (0.98–1.04)
60 ± 18
56 ± 16
1 (0.95–1.07)
65 ± 21
58 ± 14
1.01 (0.96–1.06)
69 ± 20
55 ± 10
1.01 (0.96–1.06)
MV, mechanical ventilation. *p50.05. yp50.01. zp50.001. Table 3. Intubation in the DR in preterm resuscitated infants. 32–36 weeks
GA, mean ± SD, weeks Apgar 1 min median (range) Female gender, n (%) C-section, n (%) Prenatal steroids, n (%) Initial oxygen spline 21–50%, mean ± SD Initial oxygen spline 50–100%, mean ± SD
N ¼ 369
Intubation n ¼ 55
Spontaneous breathing n ¼ 408
Adjusted odds ratio (95% CI)
34 ± 1.4
34 ± 1.5
4 (2–8)
6 (4–10)
35 (58)
196 (49)
52 (94)
330 (86)
16 (29)
184 (48)
24 ± 5
23 ± 4
63 ± 20
55 ± 15
MV, mechanical ventilation. *p50.05. yp50.01. zp50.001.
528 weeks
28–31 weeks
N ¼ 94
N ¼ 125
N ¼ 105
N ¼ 110
N ¼ 31
Intubation n ¼ 64
Spontaneous breathing n ¼ 166
Adjusted odds ratio (95% CI)
Intubation n ¼ 100
Spontaneous breathing n ¼ 41
Adjusted odds ratio (95% CI)
0.84 (0.64–1.11) 0.5 (0.4–0.61)z 0.83 (0.41–1.63) 2.23 (0.69–7.24) 0.42 (0.19–0.92)* 1.05 (1.01–1.09)*
30.13 ± 0.8
30.18 ± 0.7
1.02 (0.57–1.87) 0.43 (0.13–0.59)z 1.08 (0.42–2.77) 0.52 (0.08–3.34) 0.45 (0.14–1.19) 1.05 (1.01–1.06)*
24.5 ± 1.3
26 ± 0.9
3 (0–5)
6 (2–7)
20 (48.8)
43 (42)
35 (80.1)
87 (86.2)
30 (65.6)
64 (64.4)
34 ± 21
27 ± 11
0.67 (0.58–0.77)y 0.47 (0.38–0.57)z 1.08 (0.6–1.99) 1.64 (0.58–4.62) 1.07 (0.52–2.19) 1 (0.97–1.04)
4 (1–7)
6 (5–8)
23 (35.9)
80 (47.2)
59 (93.4)
157 (92.3)
50 (75.7)
133 (80.2)
31 ± 16
25 ± 7
1.03 (0.95–1.07)
67 ± 24
58 ± 10
1.03 (0.95–1.08)
66 ± 22
53 8
1 (0.94–1.07)
Oxygen and neonatal resusciation
Downloaded by [New York University] at 03:10 15 March 2016
DOI: 10.3109/14767058.2015.1100161
DR. However, given the retrospective character of the data, we describe measures of association and not causality. We found that mean maximum oxygen concentration rarely reached 50% even in infants below 28 weeks (mean 45%±25). As previously shown by different authors [21–23], initiating resuscitation with 100% oxygen frequently exposes preterm infants to excessively high SpO2. There is evidence that even brief exposures to high oxygen at birth can cause oxidative stress and inflammation, and increase the need for MV and risk of bronchopulmonary dysplasia [24]. Surveys of neonatal resuscitation practices with regards to oxygen administration in very low birth weight infants showed wide variability according to different centers and countries, but also amongst neonatologists at the same center [25–27]. Further studies are needed to determine the optimal initial concentration comparing room air and other oxygen concentrations, considering 100% is likely too high for preterm infants as well as term infants. In the AAP guidelines and in several studies, infants below 32 weeks are usually grouped together. We divided infants below 28 weeks and between 28 and 31 weeks of gestation, according to the established knowledge regarding lung development. Between the 16th and 26th weeks of fetal development, the canalicular stage takes place and the exchanging portion of the lung is formed and vascularized. However, the terminal sac and production of surfactant starts around 26 weeks during the saccular stage that encompasses the period from 26 weeks until term [28]. We found that, in infants below 28 weeks, initial oxygen concentration was not related in any way to the respiratory outcomes or complications of prematurity. On the contrary, in infants with gestational age between 28 and 31 weeks, each additional unit of oxygen up to 50% was associated with an increased rate of MV and intubation in the DR similar to late preterm infants. Based on these data, we suggest the need for the establishment of subcategories of infants below 32 weeks of gestational age for the purpose of providing recommendations for neonatal resuscitation. The finding that oxygen concentration up to 50% seemed to be associated with poor short-term outcomes in infants between 32 and 36 weeks of gestational age, in which no recommendations regarding initial oxygen concentration are currently available [2], seems noteworthy. Almost 50% of these infants could complete the entire resuscitation in room air, and the maximum oxygen concentration required was 30%±13.5. Studies on late preterm infants are urgently needed in order find optimal initial oxygen concentration in DR.
Conclusions Cautionary notes about our data include that, as for all retrospective studies, our findings cannot prove causality. Our observations further stress that randomized studies are urgently needed to arrive at definitive recommendations for the optimal initial oxygen concentration during neonatal resuscitation. In infants between 32 and 36 weeks of gestational age, in which no recommendations regarding initial oxygen concentration are currently available, our data suggest that lower initial oxygen concentrations may
5
contribute to improve short-term respiratory outcomes. In infants below 32 weeks of gestational age, it may be necessary to establish subcategories of infants for the purpose of providing recommendations for neonatal resuscitation.
Acknowledgements We thank Dr. Fabio Candotti, MD (National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA), Dr. Bernard The´baud, MD, PhD (Professor of Pediatrics, Department of Pediatrics, Children’s Hospital of Eastern Ontario) and Dr. Stefano Ghirardello, MD (Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan) for the scientific revision of our manuscript. We thank Dr. Ashraf Kharrat, MD (Children Hospital of Eastern Ontario) the English revision of the manuscript.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.
References 1. Lee AC, Cousens S, Wall SN, et al. Neonatal resuscitation and immediate newborn assessment and stimulation for the prevention of neonatal deaths: a systematic review, meta-analysis and Delphi estimation of mortality effect. BMC Public Health 2011;11:S3–12. 2. International Guidelines for Neonatal Resuscitation: an excerpt from the guidelines 2000 for cardiopulmonary resuscitation and emergency cardiovascular care: International Consensus on Science. Pediatrics 2000;67:293–303. 3. International Liaison Committee on Resuscitation. 2005 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations. Part 7: Neonatal resuscitation. Resuscitation 2005;67:293–303. 4. Wyllie J, Perlman JM, Kattwinkel J, et al. Part 11: Neonatal resuscitation: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations. Resuscitation 2010;81:e260–87. 5. Ramji S, Ahuja S, Thirupuram S, et al. Resuscitation of asphyxic newborn infants with room air or 100% oxygen. Pediatr Res 1993; 34:809–12. 6. Saugstad OD, Rootwelt T, Aalen O. Resuscitation of asphyxiated newborn infants with room air or oxygen: an international controlled trial: the Resair 2 study. Pediatrics 1998;102:e1. 7. Tan A, Schulze A, O’Donnell CP, Davis PG. Air versus oxygen for resuscitation of infants at birth. Cochrane Database Syst Rev 2005; 2:CD002273. 8. Saugstad OD, Ramji SS, Vento M. Resuscitation of depressed newborn infants with ambient air or pure oxygen: a meta-analysis. Biol Neonate 2005;87:27–34. 9. Davis PG, Tan A, O’Donnell CP, Schulze A. Resuscitation of newborn infants with 100% oxygen or air: a systematic review and meta-analysis. Lancet 2004;364:1329–33. 10. Rabi Y, Rabi D, Yee W. Room air resuscitation of the depressed newborn: a systematic review and meta-analysis. Resuscitation 2007;72:353–63. 11. Saugstad OD. Resuscitation of newborn infants with 21% or 100% oxygen: an updated systematic review and meta-analysis. Neonatology 2008;94:176–82. 12. Jobe A, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med 2001;163:1723–9. 13. Papile L, Burstein J, Burstein R, et al. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J Pediatr 1978;92:529–34. 14. The Committee for the ClassiEcation of Retinopathy of Prematurity. An international classiEcation of retinopathy of prematurity. Arch Ophthalmol 1984;102:1130–4.
6
M. Pierro et al.
Downloaded by [New York University] at 03:10 15 March 2016
15. Bell MJ, Ternberg JL, Feigin RD, et al. Neonatal necrotizing enterocolitis: therapeutic decision based upon clinical staging. Ann Surg 1978;187:1–7. 16. de Vries LS, Eken P, Dubowitz LM. The spectrum of leukomalacia using cranial ultrasound. Behav Brain Res 1992;49:1–6. 17. Dawson JA, Kamlin CO, Vento M, et al. Defining the reference range for oxygen saturation for infants after birth. Pediatrics 2010; 125:e1340–7. 18. Task Force on Prolonged Apnea: prolonged apnea. Pediatrics 1978; 61:651. 19. Gitto E, Reiter RJ, Karbownik M, et al. Respiratory distress syndrome in the newborn: role of oxidative stress. Intensive Care Med 2001;27: 1116–23. 20. Vento M, Asensi M, Sastre J, et al. Resuscitation with room air instead of 100% oxygen prevents oxidative stress in moderately asphyxiated term neonates. Pediatrics 2001;107:642–7. 21. Wang CL, Anderson C, Leone TA, et al. Resuscitation of preterm neonates by using room air or 100% oxygen. Pediatrics 2008;121: 1083–9. 22. Rabi Y, Singhal N, Nettel-Aguirre A. Room-air versus oxygen administration for resuscitation of preterm infants: the ROAR study. Pediatrics 2011;128:e374–38.
J Matern Fetal Neonatal Med, Early Online: 1–6
23. Dawson JA, Kamlin CO, Wong C, et al. Oxygen saturation and heart rate during delivery room resuscitation of infants530 weeks’ gestation with air or 100% oxygen. Arch Dis Child Fetal Neonatal Ed 2009;94:F87–91. 24. Vento M, Moro M, Escrig R, et al. Preterm resuscitation with low oxygen causes less oxidative stress, inflammation, and chronic lung disease. Pediatrics 2009;124:e439–49. 25. Trevisanuto D, Doglioni N, Ferrarese P, et al. Neonatal resuscitation of extremely low birthweight infants: a survey of practice in Italy. Arch Dis Child Fetal Neonatal Ed 2006;91: F123–4. 26. El-Naggar W, McNamara PJ Delivery room resuscitation of preterm infants in Canada: current practice and views of neonatologists at level III centers. J Perinatol 2012;32: 491–7. 27. Leone TA, Rich W, Finer NN. A survey of delivery room resuscitation practices in the United States. Pediatrics 2006;117: e164–75. 28. Schoenwolf GC, Larsen WJ. Development of the respiratory system and body cavities, in Larsen’s human embryology. 4th ed. New York, Edinburgh: Churchill Livingstone; 2009.
ISSN: 1476-7058 (Print) 1476-4954 (Online) Journal homepage: http://www.tandfonline.com/loi/ijmf20
Oxygen administration at birth in preterm infants: a retrospective analysis Maria Pierro, Fabrizio Ciralli, Mariarosa Colnaghi, Mara Vanzati, Domenica Mercadante, Dario Consonni & Fabio Mosca To cite this article: Maria Pierro, Fabrizio Ciralli, Mariarosa Colnaghi, Mara Vanzati, Domenica Mercadante, Dario Consonni & Fabio Mosca (2015): Oxygen administration at birth in preterm infants: a retrospective analysis, The Journal of Maternal-Fetal & Neonatal Medicine, DOI: 10.3109/14767058.2015.1100161 To link to this article: http://dx.doi.org/10.3109/14767058.2015.1100161
Published online: 30 Oct 2015.
Submit your article to this journal
Article views: 48
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ijmf20 Download by: [New York University]
Date: 15 March 2016, At: 03:10
http://informahealthcare.com/jmf ISSN: 1476-7058 (print), 1476-4954 (electronic) J Matern Fetal Neonatal Med, Early Online: 1–6 ! 2015 Taylor & Francis. DOI: 10.3109/14767058.2015.1100161
ORIGINAL ARTICLE
Oxygen administration at birth in preterm infants: a retrospective analysis Maria Pierro1, Fabrizio Ciralli1, Mariarosa Colnaghi1, Mara Vanzati1, Domenica Mercadante1, Dario Consonni2, and Fabio Mosca1 1
Downloaded by [New York University] at 03:10 15 March 2016
NICU, Department of Clinical Sciences and Community Health, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Universita` Degli Studi Di Milano, Milan, Italy and 2Epidemiology Unit, Fondazione IRCCS Ca’ Granda – Ospedale Maggiore Policlinico, Milan, Italy
Abstract
Keywords
Objective: The aim of the study was to retrospectively investigate the association between initial oxygen concentration in delivery room and short-term outcomes in preterm infants. Methods: Data from infants needing neonatal resuscitation, born at our department between January 2008 and December 2011, were analyzed. Patients were divided into three groups based on gestational age: between 32 and 36 weeks, between 31 and 28 weeks, and below 28 weeks. Results: The administration of each additional unit of oxygen up to 50% showed an association with a 5% increased need for mechanical ventilation (MV) in the neonatal intensive care unit in infants between 32 and 36 weeks [adjusted odds ratio 1.1, 95% confidence interval (CI) 1.04– 1.1] and infants between 28 and 31 weeks (adjusted odds ratio 1.12, 95% CI 1.08–1.44). On the contrary, in infants below 28 weeks, increasing initial concentration of supplementary oxygen did not show any association with MV. Conclusions: Initial oxygen concentration seems to be associated with increased MV in the NICU. Our observations further stress the need for randomized controlled studies in order to obtain definitive recommendations for the optimal initial oxygen concentration during neonatal resuscitation of preterm infants.
Guidelines, mechanical ventilation, neonatal resuscitation, oxygen, preterm
Introduction Neonatal resuscitation includes sequential interventions executed in order to achieve a correct transition to extrauterine life, whenever adaptation does not happen spontaneously. Annually, 136 million babies are born worldwide and, of these, around 10 million (5–10%) require some assistance to start breathing [1], making neonatal resuscitation one of the most frequently practiced procedures in neonatology. Based on evolving scientific evidence, neonatal resuscitation guidelines have been revised and implemented systematically over the past decades [2–4]. One of the major controversial issues amongst these advances is the use of oxygen in the delivery room (DR). Administration of 100% oxygen during positive pressure ventilation, as opposed to any other concentration of oxygen therapy, has been strongly advised [2], although there were some reports that room air could be at least as effective as 100% oxygen in asphyxiated term infants [5,6]. The use of room air had to be proven to
Address for correspondence: Maria Pierro, MD, NICU, Department of Clinical Sciences and Community Health, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Universita` degli Studi di Milano, Via Della Commenda 12, 20122 Milano, Italy. Tel: +39 0255032907. Fax: +39 0255032429. E-mail: [email protected]
History Received 11 April 2014 Revised 15 November 2014 Accepted 22 September 2015 Published online 22 October 2015
reduce the rate of mortality and neurological complications in order to be accepted as the optimal strategy in term infants [7–11]. Conversely, optimal oxygen concentrations during neonatal resuscitation of preterm infants have not yet been determined. Standardization of care regarding oxygen therapy in the DR for preterm infants remains an urgent need in neonatology. The aim of this retrospective study was to investigate the consequences of initial oxygen concentrations, used in resuscitation of preterm infants in the DR, on short-term outcomes.
Methods Study design We retrospectively analyzed data of infants below 37 weeks of gestational age born at the Department of Clinical Sciences and Community Health, University of Milan, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico (Milan, Italy) between January 2008 and December 2011. We divided patients into three groups based on gestational age: between 32 and 36 weeks, between 31 and 28 weeks, and below 28 weeks. Infants with major malformations, chromosomic anomalies and fetal hydrops were excluded.
2
M. Pierro et al.
The primary objective of the study was to assess the association between the initial oxygen concentration administered in the DR and mechanical ventilation (MV) in the NICU. The secondary objective was analyzed the association between the initial oxygen concentration and the need for intubation in the DR. For infants below 32 weeks of gestation, the main complications of prematurity were also analyzed: bronchopulmonary dysplasia, defined as oxygen dependency at 36 weeks post menstrual age [12]; intraventricular hemorrhage defined as stage 2 or higher [13]; patent ductus arteriosus defined by cardiac ultrasound study; retinopathy of prematurity by stage of severity defined as stage 2 or higher [14]; necrotizing enterocolitis defined as stage 2 or higher as per modiEed Bell criteria [15] and cystic periventricular leukomalacia [16].
Downloaded by [New York University] at 03:10 15 March 2016
Setting In our unit, neonatal resuscitation is performed following the American Academy of Pediatrics (AAP) guidelines. As no initial oxygen concentration is recommended by the AAP guidelines and no evidence of the optimal initial oxygen concentration is available for preterm infants, the initial oxygen concentration in our unit is chosen by the attending neonatologist. The oxygen blender is set between 21% and 90% by the neonatologist before the baby is born, independently from the clinical conditions, based on the personal interpretation of the available evidence. Oxygen is then tailored to maintain oxygen saturation (SpO2) between 10th and 90th percentile at birth [17]. FiO2 is usually increased by 10% increments when the infant’s SpO2 is below the 10th percentile for 1 min and decreased by 10% increments when the SpO2 is above the 90th percentile for 1 min. Before the SpO2 nomograms were published in 2010, oxygen was tailored to keep SpO2 between 85% and 92%. In case of chest compressions, FiO2 is increased straight to 100% according to current AAP guidelines [4]. A neonatal resuscitation team composed of neonatologists and neonatology nurses with specialized training is present for complicated deliveries and all C-sections. Available devices for neonatal resuscitation are detailed in the Online Supplement. Respiratory assistance in the NICU is administered following standard operating procedures, which are revised on a regular basis. Briefly, in newborns receiving nasal continuous positive airway pressure (NCPAP), the need for MV is determined by one or more of the following criteria: (i) requirement of more than 0.4 fraction inspired oxygen (FiO2) for longer than 30 min (unless sudden deterioration) to maintain partial saturation of oxygen (SpO2) in the range 88–95%; (ii) intractable apnea (deEned as 4 episodes of apnea, a respiratory pause lasting at least 20 s, or a pause accompanied by bradycardia, cyanosis or pallor [18], per hour or 2 episodes of apnea per hour requiring mask ventilation) and (iii) pH 7.2 and/or arterial pressure of carbon dioxide (PaCO2) 65 mmHg on arterial or capillary blood gas sample. Surfactant treatment (Curosurf–Chiesi Farmaceutici, Parma, Italy), either in the DR or in the NICU, is administrated in cases of FiO2 dependency40.4. MV is discontinued when effective respiratory drive, FiO2
J Matern Fetal Neonatal Med, Early Online: 1–6
requirement50.4 to maintain SpO2 88–95%, mean airway pressure57, pH47.25 and PaCO2560 mmHg are present. NCPAP is suspended when FiO2 is50.3, in the absence of apnea for at least a 24-h period. Data collection In our unit, a system of computerized charting (Neocare, i&t group, Italy) has consistently been in use since 2007. The system allows collection of any neonatal data. No diagnostic and therapeutic actions can be initiated without entering DR resuscitation data and providing complete information. Retrospective retrieval of information can be requested through the computerized chart archives in the form of an Excel file. Statistical analysis Odds ratios and 95% confidence intervals (CIs) were calculated with the use of generalized-estimating-equation log-binomial regression models with robust variance estimates to adjust for clustering of twins. We constructed separate models for each outcome. In adjusted analyses, each model included gestational age, Apgar score at 1 min, gender, intubation in the DR, prenatal steroids, mode of delivery and initial oxygen concentration. Cord pH, birth weight and year of birth were not included in the model, since they never showed any difference in the univariate analysis. Initial oxygen concentration during resuscitation showed a non-linear relationship with MV and also with intubation in DR and complications of prematurity with the same cut-off at 50%. Regression analysis was performed using restricted splines for initial oxygen concentration as an alternative to inappropriate linearity assumptions, with 50% cut-off. We show representative pictures in the entire population in the Supplemental material (Figure 1S). Data were analyzed with the use of SAS software, version 9 (SAS Institute, Cary, NC).
Results Characteristics of the study population Throughout the 4-year time frame of the study, 26 083 babies were born at our center. Infants included from the analysis are listed in Figure 2S. Neonatal resuscitation in the DR was required for 1474 infants (5.3%), of these, 863 were premature (58.5%). Maneuvers performed during neonatal resuscitation are detailed in Table 1. All infants with gestational age below 28 weeks (141) and 230 of 289 infants between 28 and 31 of gestational age (79.5%) required neonatal resuscitation. The need for neonatal resuscitation drastically decreased to 17% (463 of 2707) for infants of gestational age between 32 and 36 weeks (Table 1). Need for MV In any class of infants, Apgar score was inversely related to MV in the NICU, and intubation in the DR was strongly associated with MV. Male gender and C-section were risk factors only in infants between 32 and 36 weeks. Restricted splines analysis, with a cut-off at oxygen concentration of 50%, showed that increasing initial oxygen delivery up to 50% raised the odds of MV in infants between 32 and 36 weeks
Oxygen and neonatal resusciation
DOI: 10.3109/14767058.2015.1100161
Table 1. Neonatal resuscitation in the DR.
Downloaded by [New York University] at 03:10 15 March 2016
32–36 weeks N¼463 Tactile stimulation, n (%) NCPAP only, n (%) Mask ventilation, n (%) Endotracheal intubation, n (%) Positive pressure ventilation, n (%) Respiratory assistance, n (%) Surfactant administration, n (%) Initial oxygen concentration, mean ± SD Maximum oxygen concentration, mean ± SD Whole resuscitation in room air, n (%)* Cardiac massage, n (%) Adrenaline, n (%) Crystalloid solution, n (%) Sodium bicarbonate, n (%) Blood, n (%) SpO2 monitor, n (%)
424 21 363 55
(91.5) (4.6) (78.4) (11.1)
Discussion 28–31 weeks N¼230 221 14 200 64
(61.1) (6) (85.8) (27.5)
528 weeks N¼141 118 1 94 100
(83.7) (0.3) (66.2) (70.6)
374 (80.7)
206 (88.4)
140 (95.8)
395 (88.3)
220 (94.4)
141 (100)
9 (2)
22 (9.4)
50 (35)
25 (10.2)
27 (11.8)
32 (19)
30 (13.5)
33 (16.1)
45 (25)
77 (33)
29 (19)
182 (46) 13 4 6 8 1 278
(2.8) (0.9) (1.3) (1.8) (0.2) (60)
3
11 6 5 2 1 220
(4.7) (2.6) (2.1) (0.9) (0.4) (94.4)
17 10 10 7 1 141
(11.9) (7) (7) (4.9) (0.7) (100)
*Out of patients needing respiratory resuscitation. (adjusted odds ratio 1.1, 95% CI 1.04–1.11) and in infants between 28 and 31 weeks (adjusted odd ratio 1.12, 95% CI 1.08–1.44). On the contrary, in infants below 28 weeks, MV was not related in any way to initial oxygen concentration in the DR (Table 2). Increasing oxygen concentration from 50% to 100% further increased the risk for MV in the NICU for any of the different gestational age groups; however, it did not reach significance. Intubation in DR In any class of preterm infants, Apgar score was inversely related to intubation in DR, while gestational age was inversely related to intubation in the DR only in infants below 28 weeks. Restricted splines analysis, with a cut-off at oxygen concentration of 50%, showed that increasing initial oxygen delivery up to 50% raised the odds of intubation in the DR in infants between 32 and 36 weeks (adjusted odds ratio 1.05, 95% CI 1.01–1.09) and in infants between 28 and 31 weeks (adjusted odds ratio 1.05, 95% CI 1.01–1.06) (Table 3). On the contrary, in infants below 28 weeks, need for intubation in the DR was not influenced by initial oxygen concentration. Increasing oxygen concentration from 50% to 100% further increased the risk for MV in the NICU for any of the different gestational age groups; however, it did not reach significance (Table 3). Complications of prematurity Initial concentration of oxygen was not associated with any complication of prematurity except for intraventricular hemorrhage, in infants below 28 weeks of gestation (data described in the Supplemental material, Table 1S).
We found that higher initial oxygen concentrations during resuscitation at birth seem to be associated with an increased need for intubation in the DR and MV in the NICU in preterm infants between 28 and 36 weeks, but not below 28 weeks. From our analysis, each additional unit of oxygen, up to 50%, was associated with a 10% increased risk of MV in the NICU in preterm infants between 28 and 31 weeks and between 32 and 36 weeks. Accordingly, beginning neonatal resuscitation with 50% oxygen concentration instead of 21% may increase by 15.8-fold the risk for MV in the NICU. These observations may be explained by the known effect of oxidative stress and subsequent impairment of lung fluid balance resulting in respiratory distress syndrome and transient tachypnea of the newborn [19]. In our data, among infants between 32 and 36 and between 28 and 31 weeks, each additional unit of oxygen, up to 50%, was associated with about a 5% increased risk of intubation in the DR. This suggests that beginning neonatal resuscitation with 50% instead of 21% oxygen may increase the risk for intubation in the DR by 4.2-fold. This finding is consistent with previous studies showing that resuscitation with oxygen delayed the onset of spontaneous breathing compared to room air [6,20]. We found that 79.4% of infants below 28 weeks and 65% of infants between 28 and 31 weeks needed supplemental oxygen during resuscitation. These proportions are slightly lower compared to previous published data [21–23]. These studies regarding the use of oxygen in preterm infants during the transition to extrauterine life suggest that most preterm infants require supplemental oxygen to achieve expected oxygenation levels. However, the target SpO2 levels differed from one study to the other and from the nomogram currently in use [17]. Moreover, the study population varied as well in different studies. One limitation of our study is that the computerized chart can automatically record neither the actual SpO2 monitoring nor the FiO2 delivered. The initial and highest values of FiO2 needed to maintain SpO2 within the ranges are entered by the neonatologist once the resuscitation is completed. The SpO2 monitoring was performed in all infants below 32 weeks and in 60% of infants between 32 and 36 weeks. The patients that did not receive the monitoring were the ones that needed a very brief period of mask ventilation with no time to start the monitoring. A second limitation of the study is that we do not have a standard method of selecting the initial oxygen concentration. The attending neonatologist always chooses the initial oxygen concentration by setting the oxygen blender before the baby is born, independently from the clinical conditions. However, there may be subjectivity and potential bias in taking resuscitation decisions that could have been affected by personal preferences, perceived severity of each case and/or different antenatal and delivery conditions. In order to reduce the inherent bias of the severity of clinical conditions on initial oxygen concentration, we performed univariate analysis in including possible indicators of severity at birth (details in the ‘‘Methods’’ section). Then, we performed a multivariate analysis with these factors. In our multivariate analysis, initial oxygen concentration was shown to be an independent risk factor for MV and intubation in the
4
M. Pierro et al.
J Matern Fetal Neonatal Med, Early Online: 1–6
Table 2. MV in the NICU in preterm resuscitated infants. 32–36 weeks
Downloaded by [New York University] at 03:10 15 March 2016
N ¼ 94
GA, mean ± SD, weeks Apgar 1 min, median (range) Female gender, n (%) C-section, n (%) Prenatal steroids, n (%) Intubation in DR, n (%) Initial oxygen spline 21–50%, mean ± SD Initial oxygen spline 50–100%, mean ± SD
528 weeks
28–31 weeks
N ¼ 369 Adjusted odds ratio (95% CI)
N ¼ 125
N ¼ 105
MV
No MV
Adjusted odds ratio (95% CI)
N ¼ 110
N ¼ 31
MV
No MV
Adjusted odds ratio (95% CI)
MV
No MV
33.8 ± 1.4
34.1 ± 1.4
0.84 (0.688–1.03)
30.2 ± 0.8
30.04 ± 0.7
0.67 (0.43–1.05)
25.1 ± 1.3
25 ± 1.3
0.79 (0.71–0.88)
5 (1–8)
6 (4–9)
0.76 (0.66–0.88)z
4 (0–7)
6 (5–8)
0.64 (0.56–0.79)z
3 (0–5)
5 (2–8)
0.77 (0.68–0.88)z
63 (63.2)
168 (46.6)
0.46 (0.27–0.8)y
39 (36.8)
64 (51.2)
0.86 (0.18–1.2)
13 (40.8)
50 (45)
0.8 (0.49–1.29)
91 (93.7)
291 (80.3)
116 (89.3)
100 (93.6)
28 (83.6)
155 (44.4)
98 (71.1)
84 (80.2)
0.86 (0.36–3.92) 1.18 (0.48–2.85)
91 (87.5)
45 (47.4)
3.1 (1.14–8.37)* 1.15 (0.64–2.05)
24 (75)
70 (65.4)
0.84 (0.36–1.92) 1.04 (0.58–1.85)
41 (42.7)
16 (4.5)
10 (2.3–20.05)z
64 (50)
13 (7)
4.2 (2.03–8.67)z
83 (75.5)
18 (56.3)
5 (2.33–10.67)z
24 ± 5
22 ± 4
1.1 (1.04–1.11)z
30 ± 14
24 ± 6
1.12 (1.08–1.44)*
33 ± 10
31 ± 17
1.01 (0.98–1.04)
60 ± 18
56 ± 16
1 (0.95–1.07)
65 ± 21
58 ± 14
1.01 (0.96–1.06)
69 ± 20
55 ± 10
1.01 (0.96–1.06)
MV, mechanical ventilation. *p50.05. yp50.01. zp50.001. Table 3. Intubation in the DR in preterm resuscitated infants. 32–36 weeks
GA, mean ± SD, weeks Apgar 1 min median (range) Female gender, n (%) C-section, n (%) Prenatal steroids, n (%) Initial oxygen spline 21–50%, mean ± SD Initial oxygen spline 50–100%, mean ± SD
N ¼ 369
Intubation n ¼ 55
Spontaneous breathing n ¼ 408
Adjusted odds ratio (95% CI)
34 ± 1.4
34 ± 1.5
4 (2–8)
6 (4–10)
35 (58)
196 (49)
52 (94)
330 (86)
16 (29)
184 (48)
24 ± 5
23 ± 4
63 ± 20
55 ± 15
MV, mechanical ventilation. *p50.05. yp50.01. zp50.001.
528 weeks
28–31 weeks
N ¼ 94
N ¼ 125
N ¼ 105
N ¼ 110
N ¼ 31
Intubation n ¼ 64
Spontaneous breathing n ¼ 166
Adjusted odds ratio (95% CI)
Intubation n ¼ 100
Spontaneous breathing n ¼ 41
Adjusted odds ratio (95% CI)
0.84 (0.64–1.11) 0.5 (0.4–0.61)z 0.83 (0.41–1.63) 2.23 (0.69–7.24) 0.42 (0.19–0.92)* 1.05 (1.01–1.09)*
30.13 ± 0.8
30.18 ± 0.7
1.02 (0.57–1.87) 0.43 (0.13–0.59)z 1.08 (0.42–2.77) 0.52 (0.08–3.34) 0.45 (0.14–1.19) 1.05 (1.01–1.06)*
24.5 ± 1.3
26 ± 0.9
3 (0–5)
6 (2–7)
20 (48.8)
43 (42)
35 (80.1)
87 (86.2)
30 (65.6)
64 (64.4)
34 ± 21
27 ± 11
0.67 (0.58–0.77)y 0.47 (0.38–0.57)z 1.08 (0.6–1.99) 1.64 (0.58–4.62) 1.07 (0.52–2.19) 1 (0.97–1.04)
4 (1–7)
6 (5–8)
23 (35.9)
80 (47.2)
59 (93.4)
157 (92.3)
50 (75.7)
133 (80.2)
31 ± 16
25 ± 7
1.03 (0.95–1.07)
67 ± 24
58 ± 10
1.03 (0.95–1.08)
66 ± 22
53 8
1 (0.94–1.07)
Oxygen and neonatal resusciation
Downloaded by [New York University] at 03:10 15 March 2016
DOI: 10.3109/14767058.2015.1100161
DR. However, given the retrospective character of the data, we describe measures of association and not causality. We found that mean maximum oxygen concentration rarely reached 50% even in infants below 28 weeks (mean 45%±25). As previously shown by different authors [21–23], initiating resuscitation with 100% oxygen frequently exposes preterm infants to excessively high SpO2. There is evidence that even brief exposures to high oxygen at birth can cause oxidative stress and inflammation, and increase the need for MV and risk of bronchopulmonary dysplasia [24]. Surveys of neonatal resuscitation practices with regards to oxygen administration in very low birth weight infants showed wide variability according to different centers and countries, but also amongst neonatologists at the same center [25–27]. Further studies are needed to determine the optimal initial concentration comparing room air and other oxygen concentrations, considering 100% is likely too high for preterm infants as well as term infants. In the AAP guidelines and in several studies, infants below 32 weeks are usually grouped together. We divided infants below 28 weeks and between 28 and 31 weeks of gestation, according to the established knowledge regarding lung development. Between the 16th and 26th weeks of fetal development, the canalicular stage takes place and the exchanging portion of the lung is formed and vascularized. However, the terminal sac and production of surfactant starts around 26 weeks during the saccular stage that encompasses the period from 26 weeks until term [28]. We found that, in infants below 28 weeks, initial oxygen concentration was not related in any way to the respiratory outcomes or complications of prematurity. On the contrary, in infants with gestational age between 28 and 31 weeks, each additional unit of oxygen up to 50% was associated with an increased rate of MV and intubation in the DR similar to late preterm infants. Based on these data, we suggest the need for the establishment of subcategories of infants below 32 weeks of gestational age for the purpose of providing recommendations for neonatal resuscitation. The finding that oxygen concentration up to 50% seemed to be associated with poor short-term outcomes in infants between 32 and 36 weeks of gestational age, in which no recommendations regarding initial oxygen concentration are currently available [2], seems noteworthy. Almost 50% of these infants could complete the entire resuscitation in room air, and the maximum oxygen concentration required was 30%±13.5. Studies on late preterm infants are urgently needed in order find optimal initial oxygen concentration in DR.
Conclusions Cautionary notes about our data include that, as for all retrospective studies, our findings cannot prove causality. Our observations further stress that randomized studies are urgently needed to arrive at definitive recommendations for the optimal initial oxygen concentration during neonatal resuscitation. In infants between 32 and 36 weeks of gestational age, in which no recommendations regarding initial oxygen concentration are currently available, our data suggest that lower initial oxygen concentrations may
5
contribute to improve short-term respiratory outcomes. In infants below 32 weeks of gestational age, it may be necessary to establish subcategories of infants for the purpose of providing recommendations for neonatal resuscitation.
Acknowledgements We thank Dr. Fabio Candotti, MD (National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA), Dr. Bernard The´baud, MD, PhD (Professor of Pediatrics, Department of Pediatrics, Children’s Hospital of Eastern Ontario) and Dr. Stefano Ghirardello, MD (Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan) for the scientific revision of our manuscript. We thank Dr. Ashraf Kharrat, MD (Children Hospital of Eastern Ontario) the English revision of the manuscript.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.
References 1. Lee AC, Cousens S, Wall SN, et al. Neonatal resuscitation and immediate newborn assessment and stimulation for the prevention of neonatal deaths: a systematic review, meta-analysis and Delphi estimation of mortality effect. BMC Public Health 2011;11:S3–12. 2. International Guidelines for Neonatal Resuscitation: an excerpt from the guidelines 2000 for cardiopulmonary resuscitation and emergency cardiovascular care: International Consensus on Science. Pediatrics 2000;67:293–303. 3. International Liaison Committee on Resuscitation. 2005 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations. Part 7: Neonatal resuscitation. Resuscitation 2005;67:293–303. 4. Wyllie J, Perlman JM, Kattwinkel J, et al. Part 11: Neonatal resuscitation: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations. Resuscitation 2010;81:e260–87. 5. Ramji S, Ahuja S, Thirupuram S, et al. Resuscitation of asphyxic newborn infants with room air or 100% oxygen. Pediatr Res 1993; 34:809–12. 6. Saugstad OD, Rootwelt T, Aalen O. Resuscitation of asphyxiated newborn infants with room air or oxygen: an international controlled trial: the Resair 2 study. Pediatrics 1998;102:e1. 7. Tan A, Schulze A, O’Donnell CP, Davis PG. Air versus oxygen for resuscitation of infants at birth. Cochrane Database Syst Rev 2005; 2:CD002273. 8. Saugstad OD, Ramji SS, Vento M. Resuscitation of depressed newborn infants with ambient air or pure oxygen: a meta-analysis. Biol Neonate 2005;87:27–34. 9. Davis PG, Tan A, O’Donnell CP, Schulze A. Resuscitation of newborn infants with 100% oxygen or air: a systematic review and meta-analysis. Lancet 2004;364:1329–33. 10. Rabi Y, Rabi D, Yee W. Room air resuscitation of the depressed newborn: a systematic review and meta-analysis. Resuscitation 2007;72:353–63. 11. Saugstad OD. Resuscitation of newborn infants with 21% or 100% oxygen: an updated systematic review and meta-analysis. Neonatology 2008;94:176–82. 12. Jobe A, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med 2001;163:1723–9. 13. Papile L, Burstein J, Burstein R, et al. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J Pediatr 1978;92:529–34. 14. The Committee for the ClassiEcation of Retinopathy of Prematurity. An international classiEcation of retinopathy of prematurity. Arch Ophthalmol 1984;102:1130–4.
6
M. Pierro et al.
Downloaded by [New York University] at 03:10 15 March 2016
15. Bell MJ, Ternberg JL, Feigin RD, et al. Neonatal necrotizing enterocolitis: therapeutic decision based upon clinical staging. Ann Surg 1978;187:1–7. 16. de Vries LS, Eken P, Dubowitz LM. The spectrum of leukomalacia using cranial ultrasound. Behav Brain Res 1992;49:1–6. 17. Dawson JA, Kamlin CO, Vento M, et al. Defining the reference range for oxygen saturation for infants after birth. Pediatrics 2010; 125:e1340–7. 18. Task Force on Prolonged Apnea: prolonged apnea. Pediatrics 1978; 61:651. 19. Gitto E, Reiter RJ, Karbownik M, et al. Respiratory distress syndrome in the newborn: role of oxidative stress. Intensive Care Med 2001;27: 1116–23. 20. Vento M, Asensi M, Sastre J, et al. Resuscitation with room air instead of 100% oxygen prevents oxidative stress in moderately asphyxiated term neonates. Pediatrics 2001;107:642–7. 21. Wang CL, Anderson C, Leone TA, et al. Resuscitation of preterm neonates by using room air or 100% oxygen. Pediatrics 2008;121: 1083–9. 22. Rabi Y, Singhal N, Nettel-Aguirre A. Room-air versus oxygen administration for resuscitation of preterm infants: the ROAR study. Pediatrics 2011;128:e374–38.
J Matern Fetal Neonatal Med, Early Online: 1–6
23. Dawson JA, Kamlin CO, Wong C, et al. Oxygen saturation and heart rate during delivery room resuscitation of infants530 weeks’ gestation with air or 100% oxygen. Arch Dis Child Fetal Neonatal Ed 2009;94:F87–91. 24. Vento M, Moro M, Escrig R, et al. Preterm resuscitation with low oxygen causes less oxidative stress, inflammation, and chronic lung disease. Pediatrics 2009;124:e439–49. 25. Trevisanuto D, Doglioni N, Ferrarese P, et al. Neonatal resuscitation of extremely low birthweight infants: a survey of practice in Italy. Arch Dis Child Fetal Neonatal Ed 2006;91: F123–4. 26. El-Naggar W, McNamara PJ Delivery room resuscitation of preterm infants in Canada: current practice and views of neonatologists at level III centers. J Perinatol 2012;32: 491–7. 27. Leone TA, Rich W, Finer NN. A survey of delivery room resuscitation practices in the United States. Pediatrics 2006;117: e164–75. 28. Schoenwolf GC, Larsen WJ. Development of the respiratory system and body cavities, in Larsen’s human embryology. 4th ed. New York, Edinburgh: Churchill Livingstone; 2009.
