As authors of the 2015 guidelines we read with interest the “UK neonatal resuscitation survey” [1]. Comparison with 2012 shows a rewarding positive effect of successive guidelines on newborn resuscitation practice.
However, we wanted to address this statement: “…updated guidelines have been criticised for failing to consider data from the Targeted Oxygen in the Resuscitation of Preterm Infants [To2rpido]”. To2rpido [2], published 2017, was unavailable for inclusion in 2015 ILCOR reviews of evidence. [3]. The analysis referred to was post-hoc and unprespecified. Clinicians were not blinded and recruitment was problematic. Enrolling only 5% of eligible infants, To2rpido was terminated after reaching 15% of targeted sample size due to loss of equipoise: ironically, clinicians were concerned about using high oxygen concentrations.
Nonetheless, To2rpido generated such interest that it led to the first neonatal review in ILCOR’s continuous evidence evaluation strategy. [4] Utilising GRADE methodology to rate quality of evidence and strength of recommendations, To2rpido’s impact was downgraded because of high risk of bias. This review [4] continues to recommend “starting with a lower oxygen concentration (21–30%) compared to higher oxygen concentration (60–100%)” whilst highlighting many gaps in our current knowledge.
The use of end-tidal CO2 (ETCO2) detection was not recommended because the guidelines, and Newborn Life Support (NLS) course, focus on airwa...
As authors of the 2015 guidelines we read with interest the “UK neonatal resuscitation survey” [1]. Comparison with 2012 shows a rewarding positive effect of successive guidelines on newborn resuscitation practice.
However, we wanted to address this statement: “…updated guidelines have been criticised for failing to consider data from the Targeted Oxygen in the Resuscitation of Preterm Infants [To2rpido]”. To2rpido [2], published 2017, was unavailable for inclusion in 2015 ILCOR reviews of evidence. [3]. The analysis referred to was post-hoc and unprespecified. Clinicians were not blinded and recruitment was problematic. Enrolling only 5% of eligible infants, To2rpido was terminated after reaching 15% of targeted sample size due to loss of equipoise: ironically, clinicians were concerned about using high oxygen concentrations.
Nonetheless, To2rpido generated such interest that it led to the first neonatal review in ILCOR’s continuous evidence evaluation strategy. [4] Utilising GRADE methodology to rate quality of evidence and strength of recommendations, To2rpido’s impact was downgraded because of high risk of bias. This review [4] continues to recommend “starting with a lower oxygen concentration (21–30%) compared to higher oxygen concentration (60–100%)” whilst highlighting many gaps in our current knowledge.
The use of end-tidal CO2 (ETCO2) detection was not recommended because the guidelines, and Newborn Life Support (NLS) course, focus on airway management without need for intubation. Both explain how, and when, ETCO2 might be used highlighting limitations to its use. The European guidelines, on which UK guidelines are based, state “detection of exhaled carbon dioxide in addition to clinical assessment is recommended as the most reliable method to confirm tracheal placement in neonates with spontaneous circulation”. [5] Given this, considered and careful use of ETCO2 detection best sits within the Advanced Resuscitation of the Newborn Infant (ARNI) course which teaches care, including intubation, beyond Newborn Life Support.
References:
1. Charles E, Hunt K, Murthy V, Harris C, Greenough A. UK neonatal resuscitation survey. Arch Dis Child Fetal Neonatal Ed 2019;104:F324–F325
2. Oei JL, Saugstad OD, Lui K, Wright IM, Smyth JP, Craven P, Wang YA, McMullan R, Coates E, Ward M, Mishra P, De Waal K, Travadi J, See KC, Cheah IG, Lim CT, Choo YM, Kamar AA, Cheah FC, Masoud A, Tarnow-Mordi W. Targeted Oxygen in the Resuscitation of Preterm Infants, a Randomized Clinical Trial. Pediatrics 2017;139:e20161452.
3. Wyllie J, Perlman JM, Kattwinkel J, Wyckoff MH, Aziz K, Guinsburg R, Kim HS, Liley HG, Mildenhall L, Simon WM, Szyld E, Tamura M, Velaphi S; Neonatal Resuscitation Chapter Collaborators. Part 7: Neonatal resuscitation: 2015 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations. Resuscitation 2015;95:e169–201.
4. Welsford M, Nishiyama C, Shortt C, Weiner G, Roehr CC, Isayama T, Dawson JA, Wyckoff MH, Rabi Y; International Liaison Committee on Resuscitation Neonatal Life Support Task Force. Initial Oxygen Use for Preterm Newborn Resuscitation: A Systematic Review With Meta-analysis. Pediatrics 2019;143:e20181828.
5. Wyllie J, Bruinenberg J, Roehr CC, Rüdiger M, Trevisanuto D, Urlesberger B. European Resuscitation Council Guidelines for Resuscitation 2015: Section 7. Resuscitation and support of transition of babies at birth. Resuscitation 2015;95:249–63.
Dear Editor,
We read with great interest the network meta-analysis performed by Zeng et al [1]. The authors investigated the comparative efficacy and safety of different corticosteroids in the prevention of bronchopulmonary dysplasia in preterm infants. They included 47 RCTs with 6747 participants. We have several concerns about the study.
First, it looks that the authors are unfamiliar with the procedures of network meta-analysis because there were obvious mistakes. Figure 1 in the study was network plot of different corticosteroids. In Figure 1, the circle size should be proportional to the sample size randomised to each intervention [2]. The line width should be proportional to the study numbers of each direct comparison. However, the circle size was not proportional to the sample size in Figure 1. The line width between dexamethasone (high dose) and placebo also seems inadequate.
Second, various statistical methods or plots have been suggested to assist interpreting the results of network meta-analysis [3]. However, many of them were not performed or presented in this study. For example, since there were direct estimates (i.e., results of pairwise meta-analysis) and indirect estimates (i.e., results of network meta-analysis), the inconsistency between them should be assessed and explored because important inconsistency could threaten the validity of the results. Besides, the authors also didn’t assess small-study effects. Small-study effects could mat...
Dear Editor,
We read with great interest the network meta-analysis performed by Zeng et al [1]. The authors investigated the comparative efficacy and safety of different corticosteroids in the prevention of bronchopulmonary dysplasia in preterm infants. They included 47 RCTs with 6747 participants. We have several concerns about the study.
First, it looks that the authors are unfamiliar with the procedures of network meta-analysis because there were obvious mistakes. Figure 1 in the study was network plot of different corticosteroids. In Figure 1, the circle size should be proportional to the sample size randomised to each intervention [2]. The line width should be proportional to the study numbers of each direct comparison. However, the circle size was not proportional to the sample size in Figure 1. The line width between dexamethasone (high dose) and placebo also seems inadequate.
Second, various statistical methods or plots have been suggested to assist interpreting the results of network meta-analysis [3]. However, many of them were not performed or presented in this study. For example, since there were direct estimates (i.e., results of pairwise meta-analysis) and indirect estimates (i.e., results of network meta-analysis), the inconsistency between them should be assessed and explored because important inconsistency could threaten the validity of the results. Besides, the authors also didn’t assess small-study effects. Small-study effects could materially alter the relative effectiveness and ranking of treatments. The ‘comparison-adjusted’ funnel plot has been suggested to assess the presence of small-study effects. Model that adjusted for small-study effects should be performed if small-study effects was found.
References
1. Zeng L, Tian J, Song F, et al. Corticosteroids for the prevention of bronchopulmonary dysplasia in preterm infants: a networkmeta-analysis. Arch Dis Child Fetal Neonatal Ed. 2018 Nov;103(6):F506-F511.
2. Dias S, Caldwell DM. Network meta-analysis explained. Arch Dis Child Fetal Neonatal Ed. 2019 Jan;104(1):F8-F12.
3. Chaimani A, Higgins JP, Mavridis D, Spyridonos P, Salanti G. Graphical tools for network meta-analysis in STATA. PLoS One. 2013 Oct 3;8(10):e76654.
There seems to be a descrepency regarding the number of babies intubatec in two groups. 56 babies were intubated in high tidal volume group against 14 intubated in the low tidal volume group as per the article. I wondering whether it might have contributed to the high incidence of IVH in the high tidal volume group.
I congratulate Dr Thio and colleagues on their study of PEEP delivery in common neonatal resuscitation devices. This study is timely as clinicians look for more refined strategies to support the preterm lung at birth. Such strategies will require a reliance on equipment in the delivery room.
To allow for interpretation of the findings into the clinical context could the authors comment on the number, and characteristics, of lambs studied, and was this accounted for analysis in Table 1 (for example cluster analysis)? What was the pressure of medical gas supply?
We would like to thank Miller et al for their interest in our recently published review and their responding letter to the editor. The first concern is combining RCTs and cohort studies. We agree that classic Cochrane methods advocate combining only same study designs in a meta-analysis. However, there is also an alternative viewpoint. Appropriate integration of randomized and observational cohort studies may offer opportunities to provide more timely, comprehensive, and generalizable evidence about the medical intervention1. To date, the majority of human milk studies on bronchopulmonary dysplasia (BPD) have been observational cohort studies. Generalizing extensive perspective is motivation for combining randomized and non-randomized evidence in a meta-analysis2. In our review, to detect the possibility of incorporating randomized and observational cohort studies, we assessed the statistic heterogeneity between cohort studies and randomized studies. The test for subgroup differences has been shown in table 3, which demonstrated the statistic heterogeneity (I2 and P values) is generally low. This gave a plausible reason to pool observational and randomized studies in our review. In fact, combining observational and randomized studies has been also performed in a similarly themed review for preventing BPD, when authors compared raw mother’s own milk with pasteurized mother’s own milk3.
The second concern from Miller et al was how to interpret the out...
We would like to thank Miller et al for their interest in our recently published review and their responding letter to the editor. The first concern is combining RCTs and cohort studies. We agree that classic Cochrane methods advocate combining only same study designs in a meta-analysis. However, there is also an alternative viewpoint. Appropriate integration of randomized and observational cohort studies may offer opportunities to provide more timely, comprehensive, and generalizable evidence about the medical intervention1. To date, the majority of human milk studies on bronchopulmonary dysplasia (BPD) have been observational cohort studies. Generalizing extensive perspective is motivation for combining randomized and non-randomized evidence in a meta-analysis2. In our review, to detect the possibility of incorporating randomized and observational cohort studies, we assessed the statistic heterogeneity between cohort studies and randomized studies. The test for subgroup differences has been shown in table 3, which demonstrated the statistic heterogeneity (I2 and P values) is generally low. This gave a plausible reason to pool observational and randomized studies in our review. In fact, combining observational and randomized studies has been also performed in a similarly themed review for preventing BPD, when authors compared raw mother’s own milk with pasteurized mother’s own milk3.
The second concern from Miller et al was how to interpret the outcome when the evidence from randomized and observational cohort studies were inconsistent. Miller et al stated that “the overall protective effect is driven by the cohort studies alone” in our review. However, this is not the case. In table 3, subgroup of RCT alone in all comparison showed a non-statistically significant trend towards protective effect of human milk on BPD. This meant the overall protective effect was not only driven by the cohort studies, but also attributed to the RCTs. RCTs undisputedly are on a higher level than observational studies. On the other hand, some of our most effective therapies are only supported by ‘lower-level’ observational studies, especially when the evidence from RCT is rare4. As conclusions in our review, we explicitly acknowledge the weakness of the evidence and that more RCTs are needed. A recent review for donor human milk on BPD also highlighted the benefit effect of human milk from observational studies, even though the effect from RCTs was not significant3.
Since neonates often received feeding with partial human milk due to a variety of reasons, paediatrician and parents pay close attention to the possible benefits of partial human milk feeding. One important aim of our review is to provide an overview of different portion/extent of human milk on BPD. In this setting, there are unavoidable overlaps in six categories: exclusive human milk (100% human milk), mainly human milk (50%≤human milk feeding<100%) and any human milk (0<human milk feeding≤100%); exclusive formula (100% formula feeding), mainly formula (50%≤formula feeding<100%) and any formula (0<formula feeding≤100%). A systematic review for human milk on retinopathy of prematurity also adopted the same method using replication of data 5.
We tried to avoid overlap by redefining two categories in our study to: any human milk (0<human milk feeding<50%) and any performed formula (0<human milk feeding<50%). Interestingly, our new meta-analysis only showed benefit from the comparision of exclusive human milk versus exclusive formula group [OR 0.78 (95% confidence interval 0.68 to 0.88)]. There was no statistical effect for other comparisons. Most comparisons included only one or two small studies. Overall, although we could not draw a definitive conclusion for maternal milk on BPD, limited evidence suggests further studies are necessary.
Competing interests None declared.
Reference
1. Cameron C, Fireman B, Hutton B, et al. Network meta-analysis incorporating randomized controlled trials and non-randomized comparative cohort studies for assessing the safety and effectiveness of medical treatments: challenges and opportunities. Systematic reviews 2015; 4: 147.
2. Verde PE, Ohmann C. Combining randomized and non-randomized evidence in clinical research: a review of methods and applications. Research synthesis methods 2015; 6: 45-62.
3. Villamor-Martinez E, Pierro M, Cavallaro G, et al. Donor human milk protects against bronchopulmonary dysplasia: a systematic review and meta-analysis. Nutrients 2018; 10: 238.
4. Verd S, Ginovart G. Human milk is perhaps the single most under-rated strategy to prevent bronchopulmonary dysplasia. Archives of disease in childhood Fetal and neonatal edition 2018 103: F599-f600.
5. Zhou J, Shukla VV, John D, et al. Human milk feeding as a protective factor for retinopathy of prematurity: a meta-analysis. pediatrics 2015; 136: e1576-86.
We thank Ovali et al for their interest in our paper. They emphasise that BPD results from a multifactorial process and has wide variation in severity. We agree that basing the prediction of BPD solely on ventilatory requirement at one week of age would not identify all cases of BPD, as demonstrated by the low sensitivity of 67% demonstrated in our study.[1] The high sensitivity of ventilation at one week of age in predicting the development of BPD (99%), however, means that it could facilitate counselling of parents and act as a screening tool to identify candidates for future trials of therapeutic interventions to prevent BPD.
[1] Hunt K, Dassios T, Ali K, et al. Prediction of bronchopulmonary dysplasia development. Arch Dis Child Fetal Neonatal Ed 2018 [Epub ahead of print].
I wish to comment about the outcomes you have selected for your study on gastroschisis and in particular caution against the use of 'primary closure' as an outcome at all. There are a number of reasons for this. Firstly, implicit in the use of primary closure as an outcome is a belief that it is either a good or bad thing. The literature would not support that either delayed closure or primary closure is superior, therefore it is impossible to know how to interpret a higher (or lower) rate of primary closure following either Caesarian section or vaginal delivery. Is a higher rate of primary closure good or bad? Secondly, the increasing use by paediatric surgeons of the preformed silo to manage return of the visceral contents to the abdominal cavity means that the closure technique may be prescribed rather than one that is dependent on other factors (such as mode of delivery). Its relevance therefore as an outcome is highly questionable.
I note also that you encountered 'differences in definition of outcomes, choice of outcome measures and variation in reporting methods'. Such difficulties can be a real challenge in the context of a meta-analysis and preclude accurate evidence synthesis. One proposed way to address this challenge is the development and use of a Core Outcome Set. A Core Outcome Set is a set of outcomes that has been derived through consensus methodology across stakeholder groups as being the most important outcomes to measure in re...
I wish to comment about the outcomes you have selected for your study on gastroschisis and in particular caution against the use of 'primary closure' as an outcome at all. There are a number of reasons for this. Firstly, implicit in the use of primary closure as an outcome is a belief that it is either a good or bad thing. The literature would not support that either delayed closure or primary closure is superior, therefore it is impossible to know how to interpret a higher (or lower) rate of primary closure following either Caesarian section or vaginal delivery. Is a higher rate of primary closure good or bad? Secondly, the increasing use by paediatric surgeons of the preformed silo to manage return of the visceral contents to the abdominal cavity means that the closure technique may be prescribed rather than one that is dependent on other factors (such as mode of delivery). Its relevance therefore as an outcome is highly questionable.
I note also that you encountered 'differences in definition of outcomes, choice of outcome measures and variation in reporting methods'. Such difficulties can be a real challenge in the context of a meta-analysis and preclude accurate evidence synthesis. One proposed way to address this challenge is the development and use of a Core Outcome Set. A Core Outcome Set is a set of outcomes that has been derived through consensus methodology across stakeholder groups as being the most important outcomes to measure in research related to a condition. The concept being that if all studies of a condition use a core outcome set then it is much easier to perform meta-analysis reliably. Other benefits include being more certain that the most important outcomes (as defined by a range of stakeholder groups) are being measured and reported.
We have recently developed a core outcome set for gastroschisis (Allin et al Arch Dis Child Fetal Neonatal Ed 2018 doi: 10.1136/archdischild-2017-314560) and would like to bring this to your and other researchers' attention. We believe it may help with some of the difficulties you have encountered in evidence synthesis and will provide a framework for other researchers when selecting which outcomes to measure in future studies of infants with gastroschisis.
We would like to thank Dr. Hutchon for his considered letter and for highlighting a number of important points. We very much acknowledge his experience in the area of cord management at the time of delivery and his ongoing endeavours to advocate for appropriate cord management at the time of delivery(1). He correctly notes that there is no current formal policy for cord management at delivery for term newborn infants in our institution, which undoubtedly results in variability in practice. In a recently completed prospective study evaluating cardiac output in healthy term infants, we have noted that approximately one third of infants had early cord clamping and two thirds some form of placental transfusion, either as delayed or milking. Whilst we cannot be certain or draw any definitive inferences, it is likely that this same variability exits in our cohort of patients. The point related to ‘immediate transfer’ to the resuscitaire may be somewhat misleading. This relates to once the cord is clamped, and not that the cord was immediately clamped in each case(2). We acknowledge that this terminology may be confusing, and therefore cannot concur that our results relate to early cord clamping alone. It is also important to highlight that all our newborns were spontaneously breathing at delivery and did not require any assistance with adaptation.
He makes a very valid comparison with oxygen saturation values in term infants highlighti...
We would like to thank Dr. Hutchon for his considered letter and for highlighting a number of important points. We very much acknowledge his experience in the area of cord management at the time of delivery and his ongoing endeavours to advocate for appropriate cord management at the time of delivery(1). He correctly notes that there is no current formal policy for cord management at delivery for term newborn infants in our institution, which undoubtedly results in variability in practice. In a recently completed prospective study evaluating cardiac output in healthy term infants, we have noted that approximately one third of infants had early cord clamping and two thirds some form of placental transfusion, either as delayed or milking. Whilst we cannot be certain or draw any definitive inferences, it is likely that this same variability exits in our cohort of patients. The point related to ‘immediate transfer’ to the resuscitaire may be somewhat misleading. This relates to once the cord is clamped, and not that the cord was immediately clamped in each case(2). We acknowledge that this terminology may be confusing, and therefore cannot concur that our results relate to early cord clamping alone. It is also important to highlight that all our newborns were spontaneously breathing at delivery and did not require any assistance with adaptation.
He makes a very valid comparison with oxygen saturation values in term infants highlighting the differences in oxygen saturation values between the Australian (3)and Leiden studies(4), attributing this difference to the impact of delayed cord clamping. It is interesting to note that there was a higher degree of bradycardia less than 80bpm in the Leiden cohort who received delayed cord clamping(4). A recent single centre study performed in Melbourne by Blank et al provides even greater clarity on respiratory adaptation(5). They evaluated similar respiratory variables to our measurements in a cohort of term infants, delivered both vaginally and by caesarean section. They did not identify any difference in respiratory variables between spontaneously breathing term infants based on mode of delivery. This is interesting when one considers that their hospital policy mandates caesarean delivered babies have immediate clamping and vaginally delivered have delayed clamping performed. This would suggest that in healthy term infants who do not require any respiratory support at birth, the timing of cord clamping results in no obvious difference in immediate respiratory variables over the first 10 mins of life. However this does not imply that delayed cord clamping has no immediate benefits on babies who may need support during this period of adaptation, and future work in this area is certainly warranted.
Eugene Dempsey and Daragh Finn
References
1. Hutchon D, Bettles N. Motherside care of the term neonate at birth. Matern Health Neonatol Perinatol. 2016;2:5.
2. Finn D, De Meulemeester J, Dann L, Herlihy I, Livingstone V, Boylan GB, et al. Respiratory adaptation in term infants following elective caesarean section. Arch Dis Child Fetal Neonatal Ed. 2018;103(5):F417-F21.
3. Dawson JA, Kamlin CO, Vento M, Wong C, Cole TJ, Donath SM, et al. Defining the reference range for oxygen saturation for infants after birth. Pediatrics. 2010;125(6):e1340-7.
4. Smit M, Dawson JA, Ganzeboom A, Hooper SB, van Roosmalen J, te Pas AB. Pulse oximetry in newborns with delayed cord clamping and immediate skin-to-skin contact. Arch Dis Child Fetal Neonatal Ed. 2014;99(4):F309-14.
5. Blank DA, Gaertner VD, Kamlin COF, Nyland K, Eckard NO, Dawson JA, et al. Respiratory changes in term infants immediately after birth. Resuscitation. 2018;130:105-10.
To the editor;
We have read the study of Hunt et al. describing the prediction of bronchopulmonary dysplasia (BPD) development at 1 week of age. (1). As it is very well known, BPD is a multifactorial disease with different clinical forms such as mild, moderate and severe. Early prediction of the disease is a clinically significant issue, such that early preventive measures may be taken, especially in cases with high risk. In our opinion, basing the prediction of BPD only on the ventilation requirement at 1 week of age is not appropriate. Respiratory distress syndrome and mechanical ventilation are important factors in the development of BPD but mechanical ventilation need is not sufficent enough for prediction in a disease with many risk factors. We had developed a simple clinical scoring system for the prediction of BPD, which takes into account the birthweight, gestational age, gender, hemodynamically signifiicant patent ductus arteriosus (HsPDA), respiratory distress syndrome, hypotension and intraventricular hemorrhage, at 72 hours of postnatal age (2). A score of less than 4 was considered as low, 4-6 as low intermediate, 7-9 as high intermediate and a score of above 9 was considered as high risk, in order to optimize the predictive values of lowest and highest categories. Among these parameters, HsPDA was the most significant one. The receiver operator curves (ROC) was 0.930, the negative predictive value of a score less than 4 were 95,9 whereas a positive pre...
To the editor;
We have read the study of Hunt et al. describing the prediction of bronchopulmonary dysplasia (BPD) development at 1 week of age. (1). As it is very well known, BPD is a multifactorial disease with different clinical forms such as mild, moderate and severe. Early prediction of the disease is a clinically significant issue, such that early preventive measures may be taken, especially in cases with high risk. In our opinion, basing the prediction of BPD only on the ventilation requirement at 1 week of age is not appropriate. Respiratory distress syndrome and mechanical ventilation are important factors in the development of BPD but mechanical ventilation need is not sufficent enough for prediction in a disease with many risk factors. We had developed a simple clinical scoring system for the prediction of BPD, which takes into account the birthweight, gestational age, gender, hemodynamically signifiicant patent ductus arteriosus (HsPDA), respiratory distress syndrome, hypotension and intraventricular hemorrhage, at 72 hours of postnatal age (2). A score of less than 4 was considered as low, 4-6 as low intermediate, 7-9 as high intermediate and a score of above 9 was considered as high risk, in order to optimize the predictive values of lowest and highest categories. Among these parameters, HsPDA was the most significant one. The receiver operator curves (ROC) was 0.930, the negative predictive value of a score less than 4 were 95,9 whereas a positive predictive values of a score more than 9 was 100. The validation of the results have yielded similar data. Other scoring systems may be found in the literature. Therefore we believe that the findings of Hunt et al should be interpreted with caution and more studies should be performed on the subject.
1) Hunt KA, Dassios T, Ali K, et al. Arch Dis Child Fetal neonatal Ed. Epub ahead of print, 2018; 18 October, doi: 10.1136/archdischild-2018-315343
2) Gürsoy T, Hayran M, Derin H, Ovali, F. A clinical scoring system to predict the development of bronchopulmonary dysplasia. Am J Perinatol 2015; 32(7): 659-66
We read with great interest the article by Minocchieri et al., published in this journal and found it very interesting and relevant to the current context.1 However, we have certain observations about the conduct of the study which question its external validity.
The authors used supplemental fractional inspired oxygen (FiO2) of 0.22–0.30 as enrollment criteria for administering surfactant. As per current standard, most of the neonatologist will not agree to give surfactant at such a low FiO2 requirement in the first 4 hours. It might be possible that many enrolled babies could have been easily managed without surfactant and it was an unnecessary intervention for them. This is further supported by the fact that in current study 28% of babies were weaned to room air in the first 4 hours, hence could not be enrolled. Also, the author's suggestion of enrolling babies requiring Fio2 > 25 % seems to be very liberal. Most of the units administer surfactant beyond 30% supplemental oxygen requirement.
The total duration of invasive as well as any mechanical ventilation was higher in the intervention group, suggesting that the harms may outweigh the benefits.
Although the authors showed that the intervention had its intended effect in babies born at >32 weeks’ gestation, in the current era, where universal antenatal steroid coverage is available, these babies hardly need surfactant. In this trial, a significant number of babies > 32 weeks received su...
We read with great interest the article by Minocchieri et al., published in this journal and found it very interesting and relevant to the current context.1 However, we have certain observations about the conduct of the study which question its external validity.
The authors used supplemental fractional inspired oxygen (FiO2) of 0.22–0.30 as enrollment criteria for administering surfactant. As per current standard, most of the neonatologist will not agree to give surfactant at such a low FiO2 requirement in the first 4 hours. It might be possible that many enrolled babies could have been easily managed without surfactant and it was an unnecessary intervention for them. This is further supported by the fact that in current study 28% of babies were weaned to room air in the first 4 hours, hence could not be enrolled. Also, the author's suggestion of enrolling babies requiring Fio2 > 25 % seems to be very liberal. Most of the units administer surfactant beyond 30% supplemental oxygen requirement.
The total duration of invasive as well as any mechanical ventilation was higher in the intervention group, suggesting that the harms may outweigh the benefits.
Although the authors showed that the intervention had its intended effect in babies born at >32 weeks’ gestation, in the current era, where universal antenatal steroid coverage is available, these babies hardly need surfactant. In this trial, a significant number of babies > 32 weeks received surfactant and invasive ventilation, the reason for which is unclear.
Authors used FiO2 alone as a criterion for defining CPAP failure and positive end-expiratory pressure (PEEP) level was not considered. In such cases, many babies who can be managed by increasing PEEP may have got intubated even without adequate recruitment leading to increased intubation rates. This may explain the increased CPAP failure rates in the study population as compared to the historical cohort. On careful analysis of CPAP failure cases, the mean PEEP pressure was 6 cm only, which supports the above hypothesis.
Although, the trial intended to see the effect on intubation and mechanical ventilation, both of which have a direct effect on bronchopulmonary dysplasia (BPD) rates, the better primary outcome would have been the incidence of BPD.
Surprisingly the cesarean delivery rates very high in the study population.
Competing interests: None
Source of funding: None
References:
1. Minocchieri S, Berry CA, Pillow JJ. Nebulised surfactant to reduce severity of respiratory distress: a blinded, parallel, randomised controlled trial. Archives of Disease in Childhood - Fetal and Neonatal Edition. Published Online First: 26 July 2018. doi:10.1136/archdischild-2018-315051
As authors of the 2015 guidelines we read with interest the “UK neonatal resuscitation survey” [1]. Comparison with 2012 shows a rewarding positive effect of successive guidelines on newborn resuscitation practice.
However, we wanted to address this statement: “…updated guidelines have been criticised for failing to consider data from the Targeted Oxygen in the Resuscitation of Preterm Infants [To2rpido]”. To2rpido [2], published 2017, was unavailable for inclusion in 2015 ILCOR reviews of evidence. [3]. The analysis referred to was post-hoc and unprespecified. Clinicians were not blinded and recruitment was problematic. Enrolling only 5% of eligible infants, To2rpido was terminated after reaching 15% of targeted sample size due to loss of equipoise: ironically, clinicians were concerned about using high oxygen concentrations.
Nonetheless, To2rpido generated such interest that it led to the first neonatal review in ILCOR’s continuous evidence evaluation strategy. [4] Utilising GRADE methodology to rate quality of evidence and strength of recommendations, To2rpido’s impact was downgraded because of high risk of bias. This review [4] continues to recommend “starting with a lower oxygen concentration (21–30%) compared to higher oxygen concentration (60–100%)” whilst highlighting many gaps in our current knowledge.
The use of end-tidal CO2 (ETCO2) detection was not recommended because the guidelines, and Newborn Life Support (NLS) course, focus on airwa...
Show MoreDear Editor,
Show MoreWe read with great interest the network meta-analysis performed by Zeng et al [1]. The authors investigated the comparative efficacy and safety of different corticosteroids in the prevention of bronchopulmonary dysplasia in preterm infants. They included 47 RCTs with 6747 participants. We have several concerns about the study.
First, it looks that the authors are unfamiliar with the procedures of network meta-analysis because there were obvious mistakes. Figure 1 in the study was network plot of different corticosteroids. In Figure 1, the circle size should be proportional to the sample size randomised to each intervention [2]. The line width should be proportional to the study numbers of each direct comparison. However, the circle size was not proportional to the sample size in Figure 1. The line width between dexamethasone (high dose) and placebo also seems inadequate.
Second, various statistical methods or plots have been suggested to assist interpreting the results of network meta-analysis [3]. However, many of them were not performed or presented in this study. For example, since there were direct estimates (i.e., results of pairwise meta-analysis) and indirect estimates (i.e., results of network meta-analysis), the inconsistency between them should be assessed and explored because important inconsistency could threaten the validity of the results. Besides, the authors also didn’t assess small-study effects. Small-study effects could mat...
There seems to be a descrepency regarding the number of babies intubatec in two groups. 56 babies were intubated in high tidal volume group against 14 intubated in the low tidal volume group as per the article. I wondering whether it might have contributed to the high incidence of IVH in the high tidal volume group.
I congratulate Dr Thio and colleagues on their study of PEEP delivery in common neonatal resuscitation devices. This study is timely as clinicians look for more refined strategies to support the preterm lung at birth. Such strategies will require a reliance on equipment in the delivery room.
To allow for interpretation of the findings into the clinical context could the authors comment on the number, and characteristics, of lambs studied, and was this accounted for analysis in Table 1 (for example cluster analysis)? What was the pressure of medical gas supply?
In Reply
We would like to thank Miller et al for their interest in our recently published review and their responding letter to the editor. The first concern is combining RCTs and cohort studies. We agree that classic Cochrane methods advocate combining only same study designs in a meta-analysis. However, there is also an alternative viewpoint. Appropriate integration of randomized and observational cohort studies may offer opportunities to provide more timely, comprehensive, and generalizable evidence about the medical intervention1. To date, the majority of human milk studies on bronchopulmonary dysplasia (BPD) have been observational cohort studies. Generalizing extensive perspective is motivation for combining randomized and non-randomized evidence in a meta-analysis2. In our review, to detect the possibility of incorporating randomized and observational cohort studies, we assessed the statistic heterogeneity between cohort studies and randomized studies. The test for subgroup differences has been shown in table 3, which demonstrated the statistic heterogeneity (I2 and P values) is generally low. This gave a plausible reason to pool observational and randomized studies in our review. In fact, combining observational and randomized studies has been also performed in a similarly themed review for preventing BPD, when authors compared raw mother’s own milk with pasteurized mother’s own milk3.
The second concern from Miller et al was how to interpret the out...
Show MoreWe thank Ovali et al for their interest in our paper. They emphasise that BPD results from a multifactorial process and has wide variation in severity. We agree that basing the prediction of BPD solely on ventilatory requirement at one week of age would not identify all cases of BPD, as demonstrated by the low sensitivity of 67% demonstrated in our study.[1] The high sensitivity of ventilation at one week of age in predicting the development of BPD (99%), however, means that it could facilitate counselling of parents and act as a screening tool to identify candidates for future trials of therapeutic interventions to prevent BPD.
[1] Hunt K, Dassios T, Ali K, et al. Prediction of bronchopulmonary dysplasia development. Arch Dis Child Fetal Neonatal Ed 2018 [Epub ahead of print].
I wish to comment about the outcomes you have selected for your study on gastroschisis and in particular caution against the use of 'primary closure' as an outcome at all. There are a number of reasons for this. Firstly, implicit in the use of primary closure as an outcome is a belief that it is either a good or bad thing. The literature would not support that either delayed closure or primary closure is superior, therefore it is impossible to know how to interpret a higher (or lower) rate of primary closure following either Caesarian section or vaginal delivery. Is a higher rate of primary closure good or bad? Secondly, the increasing use by paediatric surgeons of the preformed silo to manage return of the visceral contents to the abdominal cavity means that the closure technique may be prescribed rather than one that is dependent on other factors (such as mode of delivery). Its relevance therefore as an outcome is highly questionable.
I note also that you encountered 'differences in definition of outcomes, choice of outcome measures and variation in reporting methods'. Such difficulties can be a real challenge in the context of a meta-analysis and preclude accurate evidence synthesis. One proposed way to address this challenge is the development and use of a Core Outcome Set. A Core Outcome Set is a set of outcomes that has been derived through consensus methodology across stakeholder groups as being the most important outcomes to measure in re...
Show MoreWe would like to thank Dr. Hutchon for his considered letter and for highlighting a number of important points. We very much acknowledge his experience in the area of cord management at the time of delivery and his ongoing endeavours to advocate for appropriate cord management at the time of delivery(1). He correctly notes that there is no current formal policy for cord management at delivery for term newborn infants in our institution, which undoubtedly results in variability in practice. In a recently completed prospective study evaluating cardiac output in healthy term infants, we have noted that approximately one third of infants had early cord clamping and two thirds some form of placental transfusion, either as delayed or milking. Whilst we cannot be certain or draw any definitive inferences, it is likely that this same variability exits in our cohort of patients. The point related to ‘immediate transfer’ to the resuscitaire may be somewhat misleading. This relates to once the cord is clamped, and not that the cord was immediately clamped in each case(2). We acknowledge that this terminology may be confusing, and therefore cannot concur that our results relate to early cord clamping alone. It is also important to highlight that all our newborns were spontaneously breathing at delivery and did not require any assistance with adaptation.
He makes a very valid comparison with oxygen saturation values in term infants highlighti...
Show MoreTo the editor;
Show MoreWe have read the study of Hunt et al. describing the prediction of bronchopulmonary dysplasia (BPD) development at 1 week of age. (1). As it is very well known, BPD is a multifactorial disease with different clinical forms such as mild, moderate and severe. Early prediction of the disease is a clinically significant issue, such that early preventive measures may be taken, especially in cases with high risk. In our opinion, basing the prediction of BPD only on the ventilation requirement at 1 week of age is not appropriate. Respiratory distress syndrome and mechanical ventilation are important factors in the development of BPD but mechanical ventilation need is not sufficent enough for prediction in a disease with many risk factors. We had developed a simple clinical scoring system for the prediction of BPD, which takes into account the birthweight, gestational age, gender, hemodynamically signifiicant patent ductus arteriosus (HsPDA), respiratory distress syndrome, hypotension and intraventricular hemorrhage, at 72 hours of postnatal age (2). A score of less than 4 was considered as low, 4-6 as low intermediate, 7-9 as high intermediate and a score of above 9 was considered as high risk, in order to optimize the predictive values of lowest and highest categories. Among these parameters, HsPDA was the most significant one. The receiver operator curves (ROC) was 0.930, the negative predictive value of a score less than 4 were 95,9 whereas a positive pre...
We read with great interest the article by Minocchieri et al., published in this journal and found it very interesting and relevant to the current context.1 However, we have certain observations about the conduct of the study which question its external validity.
Show MoreThe authors used supplemental fractional inspired oxygen (FiO2) of 0.22–0.30 as enrollment criteria for administering surfactant. As per current standard, most of the neonatologist will not agree to give surfactant at such a low FiO2 requirement in the first 4 hours. It might be possible that many enrolled babies could have been easily managed without surfactant and it was an unnecessary intervention for them. This is further supported by the fact that in current study 28% of babies were weaned to room air in the first 4 hours, hence could not be enrolled. Also, the author's suggestion of enrolling babies requiring Fio2 > 25 % seems to be very liberal. Most of the units administer surfactant beyond 30% supplemental oxygen requirement.
The total duration of invasive as well as any mechanical ventilation was higher in the intervention group, suggesting that the harms may outweigh the benefits.
Although the authors showed that the intervention had its intended effect in babies born at >32 weeks’ gestation, in the current era, where universal antenatal steroid coverage is available, these babies hardly need surfactant. In this trial, a significant number of babies > 32 weeks received su...
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