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Tessa Martherus1, André Oberthuer2, Janneke Dekker1, Stuart B Hooper3,4, Erin V McGillick3,4, Angela Kribs2, Arjan B te Pas1
1 Department of Paediatrics, Leiden University Medical Center, Leiden, The Netherlands
2 Department of Neonatology, Children’s Hospital University of Cologne, Cologne, Germany
3 The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia
4 Department of Obstetrics and Gynaecology, Monash University, Melbourne, Australia
We thank the author for his interest in our review and for acknowledging that it is timely. In our review we cover the support of spontaneous breathing infants at birth with CPAP and discuss what CPAP pressures should be used. The clinical paper the author is referring to is beyond the scope of this review as the infants were 12-18 hours old and this is a completely different situation dealing with different pulmonary characteristics. In our opinion, mechanical ventilation and PEEP in intubated newborns has very little to contribute to this discussion other than indicating how end-expiratory pressures can improve lung aeration and that at high levels they have a negative impact on pulmonary blood flow and venous return. These points were adequately covered in the references cited and we also note that none of the author's papers report how high PEEP levels impact on pulmonary blood flow....
Tessa Martherus1, André Oberthuer2, Janneke Dekker1, Stuart B Hooper3,4, Erin V McGillick3,4, Angela Kribs2, Arjan B te Pas1
1 Department of Paediatrics, Leiden University Medical Center, Leiden, The Netherlands
2 Department of Neonatology, Children’s Hospital University of Cologne, Cologne, Germany
3 The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia
4 Department of Obstetrics and Gynaecology, Monash University, Melbourne, Australia
We thank the author for his interest in our review and for acknowledging that it is timely. In our review we cover the support of spontaneous breathing infants at birth with CPAP and discuss what CPAP pressures should be used. The clinical paper the author is referring to is beyond the scope of this review as the infants were 12-18 hours old and this is a completely different situation dealing with different pulmonary characteristics. In our opinion, mechanical ventilation and PEEP in intubated newborns has very little to contribute to this discussion other than indicating how end-expiratory pressures can improve lung aeration and that at high levels they have a negative impact on pulmonary blood flow and venous return. These points were adequately covered in the references cited and we also note that none of the author's papers report how high PEEP levels impact on pulmonary blood flow.
To the editor:
We appreciate the work by Klotz et al., published in this journal1, who presented a randomized controlled cross-over trial to determine whether noninvasive high-frequency oscillatory ventilation (nHFOV) decreases CO2 partial pressure(pCO2) in premature infants more effectively than non-invasive continuous positive airway pressure(nCPAP). In this trial, they assigned 26 premature infants of less than 28 weeks’gestational age (GA) to receive either nHFOV or nasal continuous positive airway pressure (nCPAP) immediately after extubation or non-invasive
surfactant treatment. The authors could not etablish an increased
carbon dioxide clearance applying nHFOV compared with
nCPAP in this cohort of preterm infants. The result is in contrast
to previous reports where nHFOV was applied at higher airway
levels compared with nCPAP. Although the author provided brief information about the trial in the paper, we have the following questions about the details of the trial.
1. How was the mean airway pressure (MAP) titrated in the two sequences?
According to the paper, the range of MAPs applied in the two sequences were (5-8cmH2O)and (5-7cmH2O)respectively. The authors emphasized that the MAPs applied to nHFOV and nCPAP are equal, but it is not clear how was the MAP titrated (within the range) in the two sequences. Similar to what is done in invasive high frequency oscillatory ventilation, The MAP applied in nHFOV should be tit...
To the editor:
We appreciate the work by Klotz et al., published in this journal1, who presented a randomized controlled cross-over trial to determine whether noninvasive high-frequency oscillatory ventilation (nHFOV) decreases CO2 partial pressure(pCO2) in premature infants more effectively than non-invasive continuous positive airway pressure(nCPAP). In this trial, they assigned 26 premature infants of less than 28 weeks’gestational age (GA) to receive either nHFOV or nasal continuous positive airway pressure (nCPAP) immediately after extubation or non-invasive
surfactant treatment. The authors could not etablish an increased
carbon dioxide clearance applying nHFOV compared with
nCPAP in this cohort of preterm infants. The result is in contrast
to previous reports where nHFOV was applied at higher airway
levels compared with nCPAP. Although the author provided brief information about the trial in the paper, we have the following questions about the details of the trial.
1. How was the mean airway pressure (MAP) titrated in the two sequences?
According to the paper, the range of MAPs applied in the two sequences were (5-8cmH2O)and (5-7cmH2O)respectively. The authors emphasized that the MAPs applied to nHFOV and nCPAP are equal, but it is not clear how was the MAP titrated (within the range) in the two sequences. Similar to what is done in invasive high frequency oscillatory ventilation, The MAP applied in nHFOV should be titrated according to open lung strategy, performing alveolar recruitment, as published elsewhere2. Open lung strategy is the key to the application of nHFOV, however, it is rarely applied in nCPAP. The most commonly pressure range of CPAP is 3-10cmH2O. In fact, the MAP of higher than 10 cmH2O was often applied in some premature infants with severe respiratory distress syndrome(RDS) or the high risk of developing bronchopulmonary dysplasia(BPD) to perform alveolar recruitment. If MAP used in the nHFOV sequence was not based on open lung strategy but according to nCPAP setting, then the effect of nHFOV and the impact of the oscillations may be greatly dampened due to alveolar collapse. Therefore, providing more details about the adjustments of MAP over time both in the nHFOV and the nCPAP sequence would be extremely helpful to the reader and for future study protocols.
2. How long is the washout period in their trial?
According to the paper, the authors did not describe the length of the washout period. In the design of cross-over trial, the length of washout period should be considered. A recent randomized crossover trial by Ruegger et al.3, the washout period is thirty minutes. If there is no washout period preceded on the assigned therapy in their trial, the statistical results may be affected.
While answers to the above-mentioned questions will enhance our understanding of the promising data presented by Klotz et al. Given the increasing interest in avoiding invasive mechanical ventilation in very preterm infants, it may be time to embark on the first multicenter randomized controlled trial that investigates the effects of nHFOV in very preterm infants.
Dear Editors,
I read with interest the review article of Martherus and co-workers entitled ‘Supporting breathing of preterm infants at birth: a narrative review’. Despite the ongoing focus on the respiratory transition at birth, clinical strategies that improve outcome are lacking. As such the authors should be congratulated on this timely review. As they emphasise, there is still a dearth of human data, and much of the literature regarding pressure strategies at birth remains in the domain of preclinical studies. The authors thus appropriately focused on the preclinical literature with regards to CPAP and PEEP levels, acknowledging that end-expiratory pressure remains the foundation of respiratory support. Table 1 and the accompanying text unfortunately do not fully achieve the authors stated aims of providing a summary of ‘the currently available literature’ concerning the ‘effect of different CPAP strategies in the very preterm lung at birth.’ Whilst this section provides a nice summary of six worthy studies arising predominantly from the authors’ own lab it cannot be considered inclusive or complete.
The authors suggest that PEEP titration maybe useful during the respiratory transition. In 2014 we were the first to report the use of a high PEEP titration strategy at birth in preterm lambs, providing an escalating and then de-escalating PEEP (dynamic) strategy with transient PEEP levels up to 20 cmH2O. We demonstrated improved oxygenation and lung mechanic...
Dear Editors,
I read with interest the review article of Martherus and co-workers entitled ‘Supporting breathing of preterm infants at birth: a narrative review’. Despite the ongoing focus on the respiratory transition at birth, clinical strategies that improve outcome are lacking. As such the authors should be congratulated on this timely review. As they emphasise, there is still a dearth of human data, and much of the literature regarding pressure strategies at birth remains in the domain of preclinical studies. The authors thus appropriately focused on the preclinical literature with regards to CPAP and PEEP levels, acknowledging that end-expiratory pressure remains the foundation of respiratory support. Table 1 and the accompanying text unfortunately do not fully achieve the authors stated aims of providing a summary of ‘the currently available literature’ concerning the ‘effect of different CPAP strategies in the very preterm lung at birth.’ Whilst this section provides a nice summary of six worthy studies arising predominantly from the authors’ own lab it cannot be considered inclusive or complete.
The authors suggest that PEEP titration maybe useful during the respiratory transition. In 2014 we were the first to report the use of a high PEEP titration strategy at birth in preterm lambs, providing an escalating and then de-escalating PEEP (dynamic) strategy with transient PEEP levels up to 20 cmH2O. We demonstrated improved oxygenation and lung mechanics compared to mechanical ventilation using a PEEP of 6 cmH2O following a 30s Sustained Inflation (Tingay et al Ped Res 2014;75:288-94), later showing that this difference remained true irrespective of whether antenatal steroids or surfactant therapy was also used (Tingay et al Ped Res 2016;79:916-21). At the advice of one of the authors (SH) we then included an additional group managed with tidal inflations and a static PEEP of 8 cmH2O, as well as the sustained inflation and dynamic PEEP strategies, in our preterm lamb studies (Tingay et al Am J Respir Cell Mol Biol 2016;54:263-72). This study, demonstrated that both early and later (60 min life) aeration were more evenly distributed using a dynamic escalating/de-escalating PEEP strategy (maximum PEEP 20 cmH2O) than either static PEEP or an initial sustained inflation in preterm lambs without antenatal steroid or postnatal surfactant therapy. We replicated these differences between dynamic PEEP and static PEEP 8 cmH2O in a larger study of preterm lambs with antenatal steroid exposure (Tingay et al Am J Physiol Lung Cell Mol Physiol 2017;312:L32-L41).
An important finding of all these studies was that overexpansion was not noted with dynamic, transient PEEP during the respiratory transition and our strategy resulted in lower rate of airleak in lambs, unlike the study of Probyn (Ref 33).
More recently, we showed that transient PEEP exposure to 10 cmH2O, using a PEEP titration from 5 to 10 cmH2O, in 20 preterm infants <18 hours old resulted in improved lung volumes, without overexpansion, and that this volume could be maintained after PEEP was reduced in 65% of infants (Bhatia et al J Ped 2017;187:80-88), whilst acknowledging this study was performed in aerated lungs, it provides further support for the use of dynamic PEEP in the Delivery Room.
Of course whilst these studies only add to the body of literature regarding PEEP during the respiratory transition they must be considered within the context of the already large body of literature regarding PEEP level in the already aerated preterm lung. This includes, but is not limited to, the work of the Jobe group (for example Naik et al AJRCCM 2001;164:494-8), and Monkman et al (Crit Care Med 2004;32:2471-5).
The preclinical, and physiological clinical, literature regarding PEEP and CPAP in early preterm life is substantial. The variables influencing the interplay between volume state and applied pressure during the respiratory transition suggest that a dynamic approach to PEEP will be needed.
Answer to “SEDATION FOR NEONATAL INTUBATION IN THE DELIVERY ROOM”
Dear Editor
We were honoured to read the kind comment from Dr Subhash C Shaw (1) concerning our article « Nasal midazolam vs ketamine for neonatal intubation in the delivery room: a randomised trial” by Milési et al published in Arch Dis Child Fetal Neonatal Ed 2018; 103: F221-F226.1 » (2).
Dr Shaw rose several important questions:
He questions the possibility to keep a good respiratory drive with an anaesthetic procedure in delivery room. At the time of this study (2012) we were not using the INSURE procedure. For two years we are using the “Less Invasive Ventilation (LISA)” with a sedation protocol. Our protocol is proposing either intra-venous (IV) KETAMINE (0.5 mg/kg) or intra-nasal (IN) (0.2 mg/kg) MIDAZOLAM if an IV line is unavailable. Keeping a good respiratory drive is a key issue with this new technique. Therefore the anaesthetic issue is a very challenging one. Several authors show that it was possible to insure a good sedation level while keeping a good respiratory drive (3-5). In our experience with LISA and IN MIDAZOLAM (personal data) the success rate defined by the absence of intubation within the first 72 hours occurred in 7/10 of the cases, which was similar to the one described in the literature with or without any sedation (3-6).
There are still some controversies regarding MIDAZOLAM safety. This drug is widely used in Europe (7). The myoclonic movements are...
Answer to “SEDATION FOR NEONATAL INTUBATION IN THE DELIVERY ROOM”
Dear Editor
We were honoured to read the kind comment from Dr Subhash C Shaw (1) concerning our article « Nasal midazolam vs ketamine for neonatal intubation in the delivery room: a randomised trial” by Milési et al published in Arch Dis Child Fetal Neonatal Ed 2018; 103: F221-F226.1 » (2).
Dr Shaw rose several important questions:
He questions the possibility to keep a good respiratory drive with an anaesthetic procedure in delivery room. At the time of this study (2012) we were not using the INSURE procedure. For two years we are using the “Less Invasive Ventilation (LISA)” with a sedation protocol. Our protocol is proposing either intra-venous (IV) KETAMINE (0.5 mg/kg) or intra-nasal (IN) (0.2 mg/kg) MIDAZOLAM if an IV line is unavailable. Keeping a good respiratory drive is a key issue with this new technique. Therefore the anaesthetic issue is a very challenging one. Several authors show that it was possible to insure a good sedation level while keeping a good respiratory drive (3-5). In our experience with LISA and IN MIDAZOLAM (personal data) the success rate defined by the absence of intubation within the first 72 hours occurred in 7/10 of the cases, which was similar to the one described in the literature with or without any sedation (3-6).
There are still some controversies regarding MIDAZOLAM safety. This drug is widely used in Europe (7). The myoclonic movements are a well-known transient side effect of this drug. It could occur in 1 to 3% of cases. We didn’t notice this problem during the present study but we faced it only once on a 27-week-old boy. The myoclonic movements resolved spontaneously (8).
The studies suggesting that midazolam may increase the NICU length of stay were published in 1994 and 1999 (9). The ventilation and sedation practices have changed a lot. In our study the length of stay was not different among the two groups.
As a conclusion, we share Dr Subhah’s concerns. We are thinking that we need more data in order to assess the efficiency and security of IN MIDAZOLAM. Nevertheless as an alternative to IV anaesthetic drugs, it seems to be an elegant and easy way to insure some comfort for those neonates in this very uncomfortable situation even when a respiratory drive is required.
1 Subhash C Shaw, Arjun Kurup , Kannan Venkatnarayan sedation for neonatal intubation in the delivery room. Arch Dis Child Fetal Neonatal Ed. 2018 26 May
2 Milési C, Baleine J, Mura T et al. Nasal midazolam vs ketamine for neonatal intubation in the delivery room: a randomised trial. Arch Dis Child Fetal Neonatal Ed. 2018;103:F221-F226.
3 Dekker J, Lopriore E, Rijken M et al Sedation during Minimal Invasive Surfactant Therapy in Preterm Infants. Neonatology. 2016;109:308‑13.
4 Descamps CS, Chevallier M, Ego A et al. Propofol for sedation during less invasive surfactant administration in preterm infants. Arch Dis Child Fetal Neonatal Ed. 2017;102:F465
5 Bourgoin L, Caeymaex L, Decobert F et al. Administering atropine and ketamine before less invasive surfactant administration resulted in low pain scores in a prospective study of premature neonates. Acta Paediatr. 2018;107:1184-1190
6 Aldana-Aguirre JC, Pinto M, Featherstone RM, Kumar M. Less invasive surfactant administration versus intubation for surfactant delivery in preterm infants with respiratory distress syndrome: a systematic review and meta-analysis. Arch Dis Child Fetal Neonatal Ed. 2017 ;102:F17-F23.
7 Durrmeyer X, Daoud P, Decobert F, et al. Premedication for neonatal endotracheal intubation: results from the epidemiology of procedural pain in neonates study. Pediatr Crit Care Med 2013;14:e169–75.
8 Baleine J, Milési C, Mesnage R, et al. Intubation in the delivery room: experience with
nasal midazolam. Early Hum Dev 2014;90:39–43.
9 Ng E, Taddio A, Ohlsson A, et al. Intravenous midazolam infusion for sedation of infants in the neonatal intensive care unit. Cochrane Database Syst Rev 2017;1:CD002052.
We thank the letter authors for commending most of our protocol decisions. A multicenter trial is always associated with a number of compromises, e.g. between standardization and freedom of therapy, between insufficient and overzealous data collection, and between too few and too many exploratory statistical tests.
For detecting BPD, we used criteria that included all cases with requirement of supplemental oxygen or mechanical support at a postmenstrual age of 36 weeks. This definition was the same as moderate or severe BPD in the more recently formulated consensus definition, and has been used in many other previous trials, testing ventilation modes, high-frequency ventilation, steroid use, permissive hypercapnia, and many others. This made our results comparable to previously published data.
We thank the letter authors for commending most of our protocol decisions. A multicenter trial is always associated with a number of compromises, e.g. between standardization and freedom of therapy, between insufficient and overzealous data collection, and between too few and too many exploratory statistical tests.
For detecting BPD, we used criteria that included all cases with requirement of supplemental oxygen or mechanical support at a postmenstrual age of 36 weeks. This definition was the same as moderate or severe BPD in the more recently formulated consensus definition, and has been used in many other previous trials, testing ventilation modes, high-frequency ventilation, steroid use, permissive hypercapnia, and many others. This made our results comparable to previously published data.
Few authors have previously chosen to limit their BPD definition to the severe cases only. The letter's authors are correct that when analyzing the severe BPD cases separately, there were significantly more cases in the high PCO2 target group in comparison to the control group, which may indicate harm associated with the high target group, especially as BPD is also associated with other adverse outcomes. However, the numbers were small and a possibility of just seeing random noise remains. Specifically, the cited difference of more cases of severe BPD in the high target group was in part compensated by fewer infants in the high PCO2 target group having moderate BPD. If the high PCO2 target was consistently harmful, there should have been both, more infants with severe BPD and more infants with moderate BPD, in the high target group. This situation, with opposite differences regarding the moderately and severely affected infants, increases suspicions that the significant difference regarding severe BPD may be just random noise, and strongly cautions against over-interpreting this piece of data. The risk of random noise being incidentally found statistically significant increases with the number of exploratory analyses performed.
Following the suggestion in the letter, we have also recalculated the logistic regression analysis with 'severe BPD' replacing 'moderate or severe BPD'. The results were similar to the ones published: a significant association of 'severe BPD' with PDI<70 (p=0.13) or MDI<70 (p=0.12) was not found. Logistic regression analyses were not used to estimate the magnitude of risks, but rather, to identify important risk factors. For this purpose, logistic regression analyses are well-suited.
The letter's authors further point out, that permissive hypercapnia is increasingly used as a ventilation strategy. We hope, that this is not the case, since our trial certainly does not provide a scientific basis for such a management change. While there is some evidence that mild hypercapnia may be associated with minor benefits, higher PCO2 targets, as the letter authors point out correctly, have not been shown to improve outcome. This holds also true for our trial, where all trends pointed in the opposite direction, and a significant increase of NEC was found (see Thome UH et al., Lancet Respir Med 3: 534-43, 2015). We have also carefully tested multiple subgroups in search for conditions in which the high PCO2 target may be associated with significant outcome differences in one direction or the other. We did not find a singlesubgroup that showed benefits associated with the high PCO2 target. The most striking result in this search was found in the subgroup of infants with the most severe lung disease. These infants had a significantly worse outcome when randomized to the high PCO2 target, a finding that had been included in our initial publication (see also Thome UH et al., Lancet Respir Med 3: 534-43, 2015).
Since significant differences were only found in subgroups or when using non-predefined outcomes, harmful effects of high PCO2 targets, as used in our trial, cannot be proven, although we sympathize with the view that some results may suggest this interpretation.
Prof. Dr. med. Ulrich H. Thome
Facharzt für Kinder- und Jugendmedizin / Neonatologie / Pädiatrische Intensivmedizin Leiter der Selbständigen Abteilung Neonatologie Universitätsklinik für Kinder- und Jugendmedizin Zentrum für Frauen- und Kindermedizin Liebigstraße 20a, Haus 6
Dear Editor,
We read with great interest the article “Nasal midazolam vs ketamine for neonatal intubation in the delivery room: a randomised trial” by Milési et al published in Arch Dis Child Fetal Neonatal Ed 2018; 103: F221-F226.1 We complement the authors for this well conducted randomized trial on a very important subject of sedation while neonatal intubation. Having gone through the article, we would like to add the following.
The intubations done were all non-emergent, with the mean gestational age being 27.6 (24-34) and 28.3 (24-36) weeks in both the groups respectively. It will be interesting to know what percentage of infants underwent Intubation, Surfactant administration, Extubation (INSURE)2 and placed back on nasal CPAP. As good respiratory drive is an essential prerequisite for nasal CPAP, there are concerns for sedation while attempting INSURE.
The other concern is about the safety of both the drugs used in neonatal particularly in preterm population. There are reports of paradoxical stimulation of central nervous system including myoclonic movements associated with administration of midazolam.3 There is also evidence to suggest midazolam administration leading to increased NICU stay and adverse neurological events.4 The oscillometric blood pressure measurement recorded intermittently as in this study might not capture continuous invasive blood pressure changes.
Finally, as the article very succinctly explained that the dosage of keta...
Dear Editor,
We read with great interest the article “Nasal midazolam vs ketamine for neonatal intubation in the delivery room: a randomised trial” by Milési et al published in Arch Dis Child Fetal Neonatal Ed 2018; 103: F221-F226.1 We complement the authors for this well conducted randomized trial on a very important subject of sedation while neonatal intubation. Having gone through the article, we would like to add the following.
The intubations done were all non-emergent, with the mean gestational age being 27.6 (24-34) and 28.3 (24-36) weeks in both the groups respectively. It will be interesting to know what percentage of infants underwent Intubation, Surfactant administration, Extubation (INSURE)2 and placed back on nasal CPAP. As good respiratory drive is an essential prerequisite for nasal CPAP, there are concerns for sedation while attempting INSURE.
The other concern is about the safety of both the drugs used in neonatal particularly in preterm population. There are reports of paradoxical stimulation of central nervous system including myoclonic movements associated with administration of midazolam.3 There is also evidence to suggest midazolam administration leading to increased NICU stay and adverse neurological events.4 The oscillometric blood pressure measurement recorded intermittently as in this study might not capture continuous invasive blood pressure changes.
Finally, as the article very succinctly explained that the dosage of ketamine used was in all probability inadequate to cause sedation, we feel that a larger trial should be conducted to establish the best pre-intubation medication in the delivery room, keeping both efficacy and safety in mind.
1. Milési C, Baleine J, Mura T, et al. Nasal midazolam vs ketamine for neonatal intubation in the delivery room: a randomised trial. Archives of Disease in Childhood - Fetal and Neonatal Edition 2018; 103: F221-F226.
2. Carlo Dani, Iuri Corsini, Giovanna Bertini, Giulia Fontanelli, Simone Pratesi & Firmino F. Rubaltelli (2010) The INSURE method in preterm infants of less than 30 weeks' gestation, The Journal of Maternal-Fetal & Neonatal Medicine, 23:9, 1024-1029, DOI: 10.3109/14767050903572174
3. Gupta MK, Mondkar JA, Hegde D. Paradoxical reaction to midazolam in preterm neonates: a case series. Indian J Crit Care Med 2018; 22: 300-2
4. Ng E, Taddio A, Ohlsson A. Intravenous midazolam infusion for sedation of infants in the neonatal intensive care unit. Cochrane Database of Systematic Reviews 2017, Issue 1. Art. No.: CD002052. DOI: 10.1002/14651858.CD002052.pub3.
Dilini I Imbulana and coworkers have published a good systematic review of nasal injuries in preterm infants receiving non-invasive respiratory support1. They included the early work by Robertson et al.2 but not the criticism from us3 or from the company selling the device4. At that time (1996), we had experiences of treatment of about 750 newborns with early versions of Infant Flow, including extremely preterm infants. We had not a single case of significant nasal injury. Imbulana et al. rightly write that it is important to chose correct size of nasal prongs (not too small). It is also crucial to avoid a hard pressure of the CPAP device on the nose. Moderate air leaks are acceptable. Several of the lesions published by Robertson and others are probable caused by attempts to avoid air leaks by a too tight connection between the CPAP device and the nose.
Neonatal nurses from various hospitals and countries should meet face-to-face or via Skype to discuss and compare how they adapt CPAP devices to preterm newborns.
Infant Flow was invented by the anaesthetists Drs Gunnar Moa and Kjell Nilsson at our hospital. We were the first paediatrician and neonatologist to use Infant Flow but we haven’t received any fees or other benefit for that.
References
1. Imbulana DI, Manley BJ, Dawson JA, Davis PG, Owen LS. Nasal injury in preterm infants receiving non-invasive respiratory support: a systematic review. Archives of Disease in Childhood - Fetal and Neonatal...
Dilini I Imbulana and coworkers have published a good systematic review of nasal injuries in preterm infants receiving non-invasive respiratory support1. They included the early work by Robertson et al.2 but not the criticism from us3 or from the company selling the device4. At that time (1996), we had experiences of treatment of about 750 newborns with early versions of Infant Flow, including extremely preterm infants. We had not a single case of significant nasal injury. Imbulana et al. rightly write that it is important to chose correct size of nasal prongs (not too small). It is also crucial to avoid a hard pressure of the CPAP device on the nose. Moderate air leaks are acceptable. Several of the lesions published by Robertson and others are probable caused by attempts to avoid air leaks by a too tight connection between the CPAP device and the nose.
Neonatal nurses from various hospitals and countries should meet face-to-face or via Skype to discuss and compare how they adapt CPAP devices to preterm newborns.
Infant Flow was invented by the anaesthetists Drs Gunnar Moa and Kjell Nilsson at our hospital. We were the first paediatrician and neonatologist to use Infant Flow but we haven’t received any fees or other benefit for that.
References
1. Imbulana DI, Manley BJ, Dawson JA, Davis PG, Owen LS. Nasal injury in preterm infants receiving non-invasive respiratory support: a systematic review. Archives of Disease in Childhood - Fetal and Neonatal Edition 2018;103(1):F29-F35.
2. Robertson NJ, McCarthy LS, Hamilton PA, et al. Nasal deformities resulting from flow driver continuous positive airway pressure. Arch Dis Child Fetal Neonatal Ed 1996;75:F209–12.
3. Smedsaas-Löfvenberg A, Faxelius G, Axelsson I, Lagercrantz H. Nasal deformities at a UK hospital. Archives of Disease in Childhood - Fetal and Neonatal Edition 1998;78:F156.
4. Foster SJ. Nasal deformities arising from flow driver continuous positive airway pressure. Archives of Disease in Childhood - Fetal and Neonatal Edition 1998;78:F156.
We read with interest the follow up study by Thome and colleagues assessing neurodevelopmental outcomes of the extremely low birth weight (ELBW) infants from the Permissive Hypercapnia in Extremely Low Birthweight Infants (PHELBI) trial1.
This study makes an important contribution to the evidence-base on the strategy of permissive hypercapnia for ELBW infants. It is a well-powered, multicentre trial and we commend the authors for the ambitious decision to include only intubated ELBW infants and also the use of a clinician-guided treatment protocol. While the methodology allows some systematic bias, there is strong external validity with a patient population representative of ‘real-life’ clinical practice.
We question the choice to combine the subgroups with moderate and severe bronchopulmonary dysplasia (BPD) for statistical analysis. In Table 2, we note the non-significant p-value for the combined outcome of moderate/severe BPD of 0.30 and no reported p-values for the individual subgroups moderate BPD and severe BPD. Using the raw data provided in Table 2, we calculate a p-value for severe BPD as significant at 0.01, suggesting an increase.
There is considerable clinical difference between patients with moderate BPD (requiring FiO2 <30% at 36 weeks or discharge) and those with severe BPD (requiring FiO2 ≥30% and/or positive pressure ventilation)2. Other than increased risk of mortality and respiratory disease, severity of BPD correlates with incr...
We read with interest the follow up study by Thome and colleagues assessing neurodevelopmental outcomes of the extremely low birth weight (ELBW) infants from the Permissive Hypercapnia in Extremely Low Birthweight Infants (PHELBI) trial1.
This study makes an important contribution to the evidence-base on the strategy of permissive hypercapnia for ELBW infants. It is a well-powered, multicentre trial and we commend the authors for the ambitious decision to include only intubated ELBW infants and also the use of a clinician-guided treatment protocol. While the methodology allows some systematic bias, there is strong external validity with a patient population representative of ‘real-life’ clinical practice.
We question the choice to combine the subgroups with moderate and severe bronchopulmonary dysplasia (BPD) for statistical analysis. In Table 2, we note the non-significant p-value for the combined outcome of moderate/severe BPD of 0.30 and no reported p-values for the individual subgroups moderate BPD and severe BPD. Using the raw data provided in Table 2, we calculate a p-value for severe BPD as significant at 0.01, suggesting an increase.
There is considerable clinical difference between patients with moderate BPD (requiring FiO2 <30% at 36 weeks or discharge) and those with severe BPD (requiring FiO2 ≥30% and/or positive pressure ventilation)2. Other than increased risk of mortality and respiratory disease, severity of BPD correlates with increased risk and severity of neurodevelopmental impairment (NDI)3. Analysis of all three subgroups of BPD severity might alter the findings and influence the conclusions drawn.
Conflicting results were yielded from the regression analyses, which may reflect the choice to cluster moderate and severe BPD together. The authors identified moderate/severe BPD as a risk factor for milder NDI, but did not find a significant association with severe NDI. Further, we question the choice to quantify risk using logistic regression to generate odds ratios, as opposed to other statistical models to calculate relative risk. This strategy has been shown to overestimate the measure of association in RCTs and lead to misinterpretation of results4.
Permissive hypercapnia is increasingly used as a ventilation strategy. The limited evidence to date does not, however, suggest that this improves outcomes for ELBW infants and there have been trends toward worse neurodevelopmental outcomes. While it is commendable to publish a ‘no difference’ result, we would be interested to know if the data were analysed stratifying for all three subgroups whether the findings might suggest permissive hypercapnia in EBLW confers higher risk of severe BPD and thereby poorer long-term outcomes.
Dr Eden C Andrew MBBS
Dr James Holberton MBBS, FRACP
Dr Gillian Opie MBBS, FRACP
Dr Andrew Watkins MBBS, FRACP
1. Thome UH, Genzel-Boroviczeny O, Bohnhorst B et al. Neurodevelopmental outcomes of extremely low birthweight infants randomised to different PCO2 targets: the PHELBI follow-up study. Arch Dis Child Fetal Neonatal Ed. 2017;102(5):F376-82
2. Ehrenkranz RA, Walsh MC, Vohr BR et al. Validation of the National Institutes of Health Consensus Definition of Bronchopulmonary Dysplasia. Pediatrics. 2005;116:1353-60.
3. Walsh MC, Morris BH, Wrage LA et al. Extremely Low Birthweight Neonates with Protracted Ventilation: Mortality and 18-Month Neurodevelopmental Outcomes. J Ped. 2005;146(6):798-804.
4. Knol MJ, Duijnhoven RG, Grobbee DE et al. Potential Misinterpretation of Treatment Effects Due to Use of Odds Ratios and Logistic Regression in Randomized Controlled Trials. PLoS One. 2011;6(6):e21248.
We agree that neurodevelopmental outcome may be an important outcome to measure following any neonatal surgery and would certainly welcome any study that reported this outcome in infants with gastroschisis. However following a rigorous consensus process as we have described, neurodevelopmental outcome was not selected as part of the core outcome set. We emphasise that the outcomes within the core outcome set are not the only outcomes that should be measured in future research but are the minimum recommended. Additional outcomes such as neurodevelopmental outcomes may of course be reported.
Response to comment from Drs Golumbek and Guidici
Drs Golumbek and Guidici are quite correct that characteristics of infants with gastroschisis, such as complexity of the condition at birth, may affect their prognosis. We are quite clear that this core outcome set should be used for observational studies which follow-up a cohort of infants based on these characteristics, as well as trials or observational studies which follow-up infants who have been managed using different surgical approaches. We agree that some of these outcomes are not specific to gastroschisis, but our aim was not to produce a core outcome set that had only gastroschisis specific outcomes within it, but one that contained the most important outcomes for infants with gastroschisis – some of which may apply equally to other infants. Growth at birth is not...
We agree that neurodevelopmental outcome may be an important outcome to measure following any neonatal surgery and would certainly welcome any study that reported this outcome in infants with gastroschisis. However following a rigorous consensus process as we have described, neurodevelopmental outcome was not selected as part of the core outcome set. We emphasise that the outcomes within the core outcome set are not the only outcomes that should be measured in future research but are the minimum recommended. Additional outcomes such as neurodevelopmental outcomes may of course be reported.
Response to comment from Drs Golumbek and Guidici
Drs Golumbek and Guidici are quite correct that characteristics of infants with gastroschisis, such as complexity of the condition at birth, may affect their prognosis. We are quite clear that this core outcome set should be used for observational studies which follow-up a cohort of infants based on these characteristics, as well as trials or observational studies which follow-up infants who have been managed using different surgical approaches. We agree that some of these outcomes are not specific to gastroschisis, but our aim was not to produce a core outcome set that had only gastroschisis specific outcomes within it, but one that contained the most important outcomes for infants with gastroschisis – some of which may apply equally to other infants. Growth at birth is not an outcome of postnatal treatment, therefore IUGR in this instance is not relevant, postnatal growth is clearly important whether or not an infants is small for gestational age at birth. We emphasise that the outcomes within the core outcome set are not the only outcomes that should be measured in future research but are the minimum recommended.
Dear Nick Brown
Editor in chief, Arch Dis Child Fetal Neonatal
We read with interest the study titled “Development of a gastroschisis core outcome set” by Benjamin Saul Raywood Allin et al1, and we have several questions and comments.
The aim of the authors is to design a core outcome set to be used in research in order to reduce outcome reporting heterogeneity and to help improve the clinical relevance of the research. The authors state that “Many gastroschisis studies investigate outcomes that are not relevant to patients or clinical practice”. However, they don´t clarify how they arrived to this hypothesis.
This study has developed a gastroschisis core outcome set consisting of eight outcomes that are important to parents, people born with gastroschisis and clinicians.
The eight outcomes are death, sepsis, growth, number of operations, time on parenteral nutrition, liver disease, number of severe gastrointestinal complications and quality of life. Regarding growth, it should be noticed that children born with gastroschisis are frequently intrauterine growth restricted, and therefore, this issue should be clarified - it is not always an outcome; gastrointestinal complications are also (up to 25% of gastroschisis population in some reports) a frequent component of the malformation itself, so this should be clarified when speaking of “complications”.
In high income countries, adverse outcomes are related to the presence of complex gast...
Dear Nick Brown
Editor in chief, Arch Dis Child Fetal Neonatal
We read with interest the study titled “Development of a gastroschisis core outcome set” by Benjamin Saul Raywood Allin et al1, and we have several questions and comments.
The aim of the authors is to design a core outcome set to be used in research in order to reduce outcome reporting heterogeneity and to help improve the clinical relevance of the research. The authors state that “Many gastroschisis studies investigate outcomes that are not relevant to patients or clinical practice”. However, they don´t clarify how they arrived to this hypothesis.
This study has developed a gastroschisis core outcome set consisting of eight outcomes that are important to parents, people born with gastroschisis and clinicians.
The eight outcomes are death, sepsis, growth, number of operations, time on parenteral nutrition, liver disease, number of severe gastrointestinal complications and quality of life. Regarding growth, it should be noticed that children born with gastroschisis are frequently intrauterine growth restricted, and therefore, this issue should be clarified - it is not always an outcome; gastrointestinal complications are also (up to 25% of gastroschisis population in some reports) a frequent component of the malformation itself, so this should be clarified when speaking of “complications”.
In high income countries, adverse outcomes are related to the presence of complex gastroschisis, which is not mentioned in this publication, and there are also several features associated with neonatal mortality (i.e., liver contained in the defect) that should be mentioned. We don’t believe that length of stay is a gastroschisis-specific variable associated with adverse outcomes; it is known that longer stays predict adverse outcomes in infants undergoing NICU admission.
The type of surgical approach is still being debated (as the authors stated) 2, 3, but the long-term outcomes are probably not related to this but, rather, to the type and size of the defect, the presence of complex gastroschisis, and the access to early intervention programs.
Twenty two parents completed all three phases of the Delphi process, most of them (64%) with children under five years of age at the time of the study. Recent publications alert about the association between gastroschisis and poorer verbal intelligence, an increased risk for poor performance on several aspects of attention, response inhibition and fine motor skills at school age 4, 5; therefore, it seems very important to have a larger sample of parents of school-aged children before considering that some aspects of their outcomes are not relevant.
We consider that high-quality observational studies and randomised controlled trials are required to assess the outcomes of gastroschisis patients, but those should definitively include more gastroschisis-specific variables, neurodevelopmental outcomes, and social behavior.
Respectfully,
Lidia B. Giúdici, MD
Pediatrician- Neonatologist
High Risk Newborn Follow Up Program Pedro de Elizalde Children's Hospital, Buenos Aires-Argentina
Postgraduate Neurodevelopment Specialization Director- Buenos Aires Medical College
Member of SEGUISIBEN- SIBEN (Iberoamerican Society of Neonatology)
Sergio G. Golombek, MD, MPH, FAAP
Professor of Pediatrics and Clinical Public Health
New York Medical College
Attending Neonatologist
Regional Neonatal Center-Maria Fareri Children's Hospital
Westchester Medical Center-Valhalla, NY 10595
President, SIBEN (Iberoamerican Society of Neonatology)
Ph # (914) 493-8488<tel:(914)%20493-8488>
FAX +1-914- 493-1005 Tel +1-914-493-8488
References
1- Allin BSR, Hall NJ, Ross AR, et al. Arch Dis Child Fetal Neonatal Ed Epub ahead of print: doi:10.1136/ archdischild-2017-314560
2- Charlesworth P, Ibiyinka A, Hammerton Ch et al. Preformed silos versus traditional abdominal wall closure in gastroschisis: 163 infants at a single institution. Eur J Pediatr Surg 2014; 24: 88-93.
3- Weil BR, Leysa CM, Rescorla FJ. The jury is still out: changes in gastroschisis management over the last decade are associated with both benefits and shortcomings. J Pediatr Surg 2012; 47: 119-124.
4- Giúdici L, Bokser V, Maricic M A, Golombek SG, Ferrario C., Babies born with gastroschisis and followed up to the age of six years faced long-term morbidity and impairments. Acta Paediatr. 2016; 105(6): 275-280.
5- Lap et al. Functional outcome at school age of children born with gastroschisis. Early Human Development 106–107 (2017) 47–52
Tessa Martherus1, André Oberthuer2, Janneke Dekker1, Stuart B Hooper3,4, Erin V McGillick3,4, Angela Kribs2, Arjan B te Pas1
1 Department of Paediatrics, Leiden University Medical Center, Leiden, The Netherlands
2 Department of Neonatology, Children’s Hospital University of Cologne, Cologne, Germany
3 The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia
4 Department of Obstetrics and Gynaecology, Monash University, Melbourne, Australia
We thank the author for his interest in our review and for acknowledging that it is timely. In our review we cover the support of spontaneous breathing infants at birth with CPAP and discuss what CPAP pressures should be used. The clinical paper the author is referring to is beyond the scope of this review as the infants were 12-18 hours old and this is a completely different situation dealing with different pulmonary characteristics. In our opinion, mechanical ventilation and PEEP in intubated newborns has very little to contribute to this discussion other than indicating how end-expiratory pressures can improve lung aeration and that at high levels they have a negative impact on pulmonary blood flow and venous return. These points were adequately covered in the references cited and we also note that none of the author's papers report how high PEEP levels impact on pulmonary blood flow....
Show MoreTo the editor:
Show MoreWe appreciate the work by Klotz et al., published in this journal1, who presented a randomized controlled cross-over trial to determine whether noninvasive high-frequency oscillatory ventilation (nHFOV) decreases CO2 partial pressure(pCO2) in premature infants more effectively than non-invasive continuous positive airway pressure(nCPAP). In this trial, they assigned 26 premature infants of less than 28 weeks’gestational age (GA) to receive either nHFOV or nasal continuous positive airway pressure (nCPAP) immediately after extubation or non-invasive
surfactant treatment. The authors could not etablish an increased
carbon dioxide clearance applying nHFOV compared with
nCPAP in this cohort of preterm infants. The result is in contrast
to previous reports where nHFOV was applied at higher airway
levels compared with nCPAP. Although the author provided brief information about the trial in the paper, we have the following questions about the details of the trial.
1. How was the mean airway pressure (MAP) titrated in the two sequences?
According to the paper, the range of MAPs applied in the two sequences were (5-8cmH2O)and (5-7cmH2O)respectively. The authors emphasized that the MAPs applied to nHFOV and nCPAP are equal, but it is not clear how was the MAP titrated (within the range) in the two sequences. Similar to what is done in invasive high frequency oscillatory ventilation, The MAP applied in nHFOV should be tit...
Dear Editors,
I read with interest the review article of Martherus and co-workers entitled ‘Supporting breathing of preterm infants at birth: a narrative review’. Despite the ongoing focus on the respiratory transition at birth, clinical strategies that improve outcome are lacking. As such the authors should be congratulated on this timely review. As they emphasise, there is still a dearth of human data, and much of the literature regarding pressure strategies at birth remains in the domain of preclinical studies. The authors thus appropriately focused on the preclinical literature with regards to CPAP and PEEP levels, acknowledging that end-expiratory pressure remains the foundation of respiratory support. Table 1 and the accompanying text unfortunately do not fully achieve the authors stated aims of providing a summary of ‘the currently available literature’ concerning the ‘effect of different CPAP strategies in the very preterm lung at birth.’ Whilst this section provides a nice summary of six worthy studies arising predominantly from the authors’ own lab it cannot be considered inclusive or complete.
The authors suggest that PEEP titration maybe useful during the respiratory transition. In 2014 we were the first to report the use of a high PEEP titration strategy at birth in preterm lambs, providing an escalating and then de-escalating PEEP (dynamic) strategy with transient PEEP levels up to 20 cmH2O. We demonstrated improved oxygenation and lung mechanic...
Show MoreAnswer to “SEDATION FOR NEONATAL INTUBATION IN THE DELIVERY ROOM”
Dear Editor
Show MoreWe were honoured to read the kind comment from Dr Subhash C Shaw (1) concerning our article « Nasal midazolam vs ketamine for neonatal intubation in the delivery room: a randomised trial” by Milési et al published in Arch Dis Child Fetal Neonatal Ed 2018; 103: F221-F226.1 » (2).
Dr Shaw rose several important questions:
He questions the possibility to keep a good respiratory drive with an anaesthetic procedure in delivery room. At the time of this study (2012) we were not using the INSURE procedure. For two years we are using the “Less Invasive Ventilation (LISA)” with a sedation protocol. Our protocol is proposing either intra-venous (IV) KETAMINE (0.5 mg/kg) or intra-nasal (IN) (0.2 mg/kg) MIDAZOLAM if an IV line is unavailable. Keeping a good respiratory drive is a key issue with this new technique. Therefore the anaesthetic issue is a very challenging one. Several authors show that it was possible to insure a good sedation level while keeping a good respiratory drive (3-5). In our experience with LISA and IN MIDAZOLAM (personal data) the success rate defined by the absence of intubation within the first 72 hours occurred in 7/10 of the cases, which was similar to the one described in the literature with or without any sedation (3-6).
There are still some controversies regarding MIDAZOLAM safety. This drug is widely used in Europe (7). The myoclonic movements are...
We thank the letter authors for commending most of our protocol decisions. A multicenter trial is always associated with a number of compromises, e.g. between standardization and freedom of therapy, between insufficient and overzealous data collection, and between too few and too many exploratory statistical tests.
For detecting BPD, we used criteria that included all cases with requirement of supplemental oxygen or mechanical support at a postmenstrual age of 36 weeks. This definition was the same as moderate or severe BPD in the more recently formulated consensus definition, and has been used in many other previous trials, testing ventilation modes, high-frequency ventilation, steroid use, permissive hypercapnia, and many others. This made our results comparable to previously published data.
...Show MoreDear Editor,
Show MoreWe read with great interest the article “Nasal midazolam vs ketamine for neonatal intubation in the delivery room: a randomised trial” by Milési et al published in Arch Dis Child Fetal Neonatal Ed 2018; 103: F221-F226.1 We complement the authors for this well conducted randomized trial on a very important subject of sedation while neonatal intubation. Having gone through the article, we would like to add the following.
The intubations done were all non-emergent, with the mean gestational age being 27.6 (24-34) and 28.3 (24-36) weeks in both the groups respectively. It will be interesting to know what percentage of infants underwent Intubation, Surfactant administration, Extubation (INSURE)2 and placed back on nasal CPAP. As good respiratory drive is an essential prerequisite for nasal CPAP, there are concerns for sedation while attempting INSURE.
The other concern is about the safety of both the drugs used in neonatal particularly in preterm population. There are reports of paradoxical stimulation of central nervous system including myoclonic movements associated with administration of midazolam.3 There is also evidence to suggest midazolam administration leading to increased NICU stay and adverse neurological events.4 The oscillometric blood pressure measurement recorded intermittently as in this study might not capture continuous invasive blood pressure changes.
Finally, as the article very succinctly explained that the dosage of keta...
Dilini I Imbulana and coworkers have published a good systematic review of nasal injuries in preterm infants receiving non-invasive respiratory support1. They included the early work by Robertson et al.2 but not the criticism from us3 or from the company selling the device4. At that time (1996), we had experiences of treatment of about 750 newborns with early versions of Infant Flow, including extremely preterm infants. We had not a single case of significant nasal injury. Imbulana et al. rightly write that it is important to chose correct size of nasal prongs (not too small). It is also crucial to avoid a hard pressure of the CPAP device on the nose. Moderate air leaks are acceptable. Several of the lesions published by Robertson and others are probable caused by attempts to avoid air leaks by a too tight connection between the CPAP device and the nose.
Show MoreNeonatal nurses from various hospitals and countries should meet face-to-face or via Skype to discuss and compare how they adapt CPAP devices to preterm newborns.
Infant Flow was invented by the anaesthetists Drs Gunnar Moa and Kjell Nilsson at our hospital. We were the first paediatrician and neonatologist to use Infant Flow but we haven’t received any fees or other benefit for that.
References
1. Imbulana DI, Manley BJ, Dawson JA, Davis PG, Owen LS. Nasal injury in preterm infants receiving non-invasive respiratory support: a systematic review. Archives of Disease in Childhood - Fetal and Neonatal...
We read with interest the follow up study by Thome and colleagues assessing neurodevelopmental outcomes of the extremely low birth weight (ELBW) infants from the Permissive Hypercapnia in Extremely Low Birthweight Infants (PHELBI) trial1.
This study makes an important contribution to the evidence-base on the strategy of permissive hypercapnia for ELBW infants. It is a well-powered, multicentre trial and we commend the authors for the ambitious decision to include only intubated ELBW infants and also the use of a clinician-guided treatment protocol. While the methodology allows some systematic bias, there is strong external validity with a patient population representative of ‘real-life’ clinical practice.
We question the choice to combine the subgroups with moderate and severe bronchopulmonary dysplasia (BPD) for statistical analysis. In Table 2, we note the non-significant p-value for the combined outcome of moderate/severe BPD of 0.30 and no reported p-values for the individual subgroups moderate BPD and severe BPD. Using the raw data provided in Table 2, we calculate a p-value for severe BPD as significant at 0.01, suggesting an increase.
There is considerable clinical difference between patients with moderate BPD (requiring FiO2 <30% at 36 weeks or discharge) and those with severe BPD (requiring FiO2 ≥30% and/or positive pressure ventilation)2. Other than increased risk of mortality and respiratory disease, severity of BPD correlates with incr...
Show MoreResponse to comment from Dr Mark W Davies:
We agree that neurodevelopmental outcome may be an important outcome to measure following any neonatal surgery and would certainly welcome any study that reported this outcome in infants with gastroschisis. However following a rigorous consensus process as we have described, neurodevelopmental outcome was not selected as part of the core outcome set. We emphasise that the outcomes within the core outcome set are not the only outcomes that should be measured in future research but are the minimum recommended. Additional outcomes such as neurodevelopmental outcomes may of course be reported.
Response to comment from Drs Golumbek and Guidici
Drs Golumbek and Guidici are quite correct that characteristics of infants with gastroschisis, such as complexity of the condition at birth, may affect their prognosis. We are quite clear that this core outcome set should be used for observational studies which follow-up a cohort of infants based on these characteristics, as well as trials or observational studies which follow-up infants who have been managed using different surgical approaches. We agree that some of these outcomes are not specific to gastroschisis, but our aim was not to produce a core outcome set that had only gastroschisis specific outcomes within it, but one that contained the most important outcomes for infants with gastroschisis – some of which may apply equally to other infants. Growth at birth is not...
Show MoreDear Nick Brown
Editor in chief, Arch Dis Child Fetal Neonatal
We read with interest the study titled “Development of a gastroschisis core outcome set” by Benjamin Saul Raywood Allin et al1, and we have several questions and comments.
Show MoreThe aim of the authors is to design a core outcome set to be used in research in order to reduce outcome reporting heterogeneity and to help improve the clinical relevance of the research. The authors state that “Many gastroschisis studies investigate outcomes that are not relevant to patients or clinical practice”. However, they don´t clarify how they arrived to this hypothesis.
This study has developed a gastroschisis core outcome set consisting of eight outcomes that are important to parents, people born with gastroschisis and clinicians.
The eight outcomes are death, sepsis, growth, number of operations, time on parenteral nutrition, liver disease, number of severe gastrointestinal complications and quality of life. Regarding growth, it should be noticed that children born with gastroschisis are frequently intrauterine growth restricted, and therefore, this issue should be clarified - it is not always an outcome; gastrointestinal complications are also (up to 25% of gastroschisis population in some reports) a frequent component of the malformation itself, so this should be clarified when speaking of “complications”.
In high income countries, adverse outcomes are related to the presence of complex gast...
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