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
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.
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.
I congratulate the authors for putting the results of this much needed study together and exploring the differences in survival for extremely preterm babies at 22-23 weeks. The outcome for babies born at < 26 weeks hasn't been looked at nationally since the EPICURE 2 study in 2006.
It is interesting to note the regional variation in survival at 22-23 weeks and it warrants further exploring the following issues:
1. Is there a variation nationally in administering antenatal steroids at <24 weeks gestation? The NICE guideline 2015 advocates:
For women between 23+0 and 23+6 weeks of pregnancy who are in suspected or established preterm labour, are having a planned preterm birth or have P-PROM, discuss with the woman (and her family members or carers as appropriate) the use of maternal corticosteroids in the context of her individual circumstances. This is open to interpretation and may not provide consistency in administration of antenatal steroids at 23 to 23+6 weeks. There is no guidance for <23 weeks. It will be useful to explore the practice nationally.
2. The practice for resuscitation at <23 weeks is likely to be variable. The latest national guideline BAPM 2008 advocates If gestational age is certain and less than 23+0 (i.e. at 22 weeks) it would be considered in the best interests of the baby, and standard practice, for resuscitation not to be carried out. The units who were resuscitating babies <23 weeks were deviating from...
I congratulate the authors for putting the results of this much needed study together and exploring the differences in survival for extremely preterm babies at 22-23 weeks. The outcome for babies born at < 26 weeks hasn't been looked at nationally since the EPICURE 2 study in 2006.
It is interesting to note the regional variation in survival at 22-23 weeks and it warrants further exploring the following issues:
1. Is there a variation nationally in administering antenatal steroids at <24 weeks gestation? The NICE guideline 2015 advocates:
For women between 23+0 and 23+6 weeks of pregnancy who are in suspected or established preterm labour, are having a planned preterm birth or have P-PROM, discuss with the woman (and her family members or carers as appropriate) the use of maternal corticosteroids in the context of her individual circumstances. This is open to interpretation and may not provide consistency in administration of antenatal steroids at 23 to 23+6 weeks. There is no guidance for <23 weeks. It will be useful to explore the practice nationally.
2. The practice for resuscitation at <23 weeks is likely to be variable. The latest national guideline BAPM 2008 advocates If gestational age is certain and less than 23+0 (i.e. at 22 weeks) it would be considered in the best interests of the baby, and standard practice, for resuscitation not to be carried out. The units who were resuscitating babies <23 weeks were deviating from the national guidance and it would be useful to explore the reasons to do so.
3. It will be important to monitor the developmental outcomes of babies < 23 weeks gestation. This will be useful to influence decision making in resuscitation and management for this group nationally.
The authors may already be looking to explore these issues as it will be important to put in context the variation in practice for management of extremely preterm babies at 22-23 weeks gestation.
Sirs, we were surprised to read that11 out of 56 units in the
resource rich UK did not administer Rotavirus vaccine to their babies. (1)
Thirty years ago, one of us described a neonatal rotavirus outbreak that
had a considerable morbidity (2). Although these outbreaks continue(3.),
some low resource units like ours (Birth rate 3000/year) are accredited as
Breast Feeding Friendly and have adopted a very enthusiastic breast...
Sirs, we were surprised to read that11 out of 56 units in the
resource rich UK did not administer Rotavirus vaccine to their babies. (1)
Thirty years ago, one of us described a neonatal rotavirus outbreak that
had a considerable morbidity (2). Although these outbreaks continue(3.),
some low resource units like ours (Birth rate 3000/year) are accredited as
Breast Feeding Friendly and have adopted a very enthusiastic breast
feeding friendly initiative. See Compliance with the Baby-Friendly
Hospital Initiative and impact on breastfeeding rates (4) In comparison to
the high resource US units of Summer Sherburne Hawkins's study, our units
have 100% compliance. Probably because our initiative was spearheaded by
the pediatricians in charge (RT). All the students and staff in the
nursery and maternity unit endorsed it. All babies irrespective of birth
weight (700 g upwards) and gestation (27 weeks) get exclusively breast
fed, or expressed raw breast milk from birth onwards. No artificial milks
or fortifiers are used. There are no bounty boxes, advertising, or free
samples endorsing bottle feeding. And no rotavirus immunization. Since
then, there have been no outbreaks of diarrhoeal disease or necrotising
entercolitis in either unit. So, a UK neonatologist faced with the choice
to immunize or not, may have a cost effective and low resource
alternative..
Dr John Dearlove, paediatrician, Dr Rosemary Taun, Director of paediatric
services, Port Vila Central Hospital, Port Vila, Vanuatu.
References
1. Jaques S, Bhojnagarwala B, et al Slow uptake of rotavirus
vaccination in UK neonatal units.Arch Dis Child Fetal Neonatal Ed 2014
March 4, 2014 as 10.1136/archdischild-2014-306067
2.Dearlove J C,.Latham P. Et al. Clinical range of neonatal rotavirus
gastroenteritis Br Med J (Clin Res
Ed) 1983;286:1473
3. de Villiers FP , Driessen M. Clinical neonatal rotavirus
infection: association with necrotising enterocolitis.S Afr Med J. 2012
Jun 6;102(7):620-4.
4. Summer Sherburne Hawkins, Ariel Dora Stern et al2, Compliance
with the Baby-Friendly Hospital Initiative and impact on
breastfeeding rates. Arch Dis Child Fetal Neonatal Ed 2014;99:F138-F143
doi:10.1136/archdischild-2013-304842
We congratulate the authors on this study of neonatal transitional circulation performed so quickly after birth. The authors state that the ductal flow ratio reported in their study reflects pulmonary and haemodynamic transition and can be used to monitor neonatal transition in healthy infants. The implication is that their study describes a physiological transition in healthy term infants, but we question that this is the case.
Delivery by elective caesarean section is not a physiological birth but it does permit the neonate an atraumatic birth. We are particularly concerned that the transition may have been disrupted by the timing of cord clamping which was between 30 and 60 seconds. While this is considered delayed cord clamping by some, most guidelines recommend a minimum of 60 seconds have elapsed before the circulation is interrupted by cord clamping. The WHO advises 3 minutes.(1) Not all of the babies in the series had established respiration before clamping and cord clamping before the onset of respiration has a marked effect on cardiac output.(2) It is therefore questionable that the mean and range of results published represents a normal transition in healthy infants.
The normal fetal circulation is well described with the two ventricles pumping in parallel, the right ventricular output being significantly more than the left and the flow across two shunts, right to left in the ductus arteriousus and right to left across the foram...
We congratulate the authors on this study of neonatal transitional circulation performed so quickly after birth. The authors state that the ductal flow ratio reported in their study reflects pulmonary and haemodynamic transition and can be used to monitor neonatal transition in healthy infants. The implication is that their study describes a physiological transition in healthy term infants, but we question that this is the case.
Delivery by elective caesarean section is not a physiological birth but it does permit the neonate an atraumatic birth. We are particularly concerned that the transition may have been disrupted by the timing of cord clamping which was between 30 and 60 seconds. While this is considered delayed cord clamping by some, most guidelines recommend a minimum of 60 seconds have elapsed before the circulation is interrupted by cord clamping. The WHO advises 3 minutes.(1) Not all of the babies in the series had established respiration before clamping and cord clamping before the onset of respiration has a marked effect on cardiac output.(2) It is therefore questionable that the mean and range of results published represents a normal transition in healthy infants.
The normal fetal circulation is well described with the two ventricles pumping in parallel, the right ventricular output being significantly more than the left and the flow across two shunts, right to left in the ductus arteriousus and right to left across the foramen ovale. The normal neonatal circulation is also well described with equal outputs by both ventricles and closed shunts. A closer look at the results suggest some anomalous flow not readily compatible with the end result of the neonatal circulation. For example at ten minutes the mean right ventricular output is 343 mls/kg/min and mean left ventricular output is 212 mls/kg/min and the DA flow is 8mls/kg/min left to right. (ratio R to L =0.9). Where does the right ventricle get the 343 output as only 212 - 8 are reaching the systemic circulation and returning to the right atrium. Also if the pulmonary blood flow is 343+8 = 351, the excess of 141 must be spilling left to right across the foramen ovale. Reverse flow in the foramen ovale is described but has not been quantified. We question that these flows are evidence that this heart is now close to transitioning to a parallel ventricular pattern with equal outputs. Reverse flow across the foramen ovale of 141 is contributing to over 40% of the right ventricular output. This blood has just been through the pulmonary circulation and is oxygenated but is now returning to the right ventricle to be pumped through the pulmonary circulaton once more. Such flow is completely inefficient. Can the authors explain this anomaly in physiogical terms or could this finding in fact be a demonstration that the early clamping at under 60 seconds sometimes before the onset of respiration has indeed disrupted the transitional circulation ?
Reference 1. World Health Organization (WHO), US Agency for International Development (US AID), Maternal and Child Health Integrated Program (MCHIP). (2013). Delayed cord clamping of the umbilical cord to reduce infant anaemia. Updated 2013. Available from: http://www.mchip.net/node/1562 (Accessed June 12, 2014). 2. Bhatt S, Alison BJ,Wallace EM, Crossley KJ, Gill AW, Kluckow M, et al. Delaying cord clamping until ventilation onset improves cardiovascular function at birth in preterm lambs. J Physiol 2013 591(Pt 8): 2113-26.
We read Hsieh et al's paper with much interest. In an experimental study of ethanol introduction in an empty isolette, they conclude that neonates in isolettes are at risk of of inadvertent exposure to ethanol from hands cleaned with ethanol-based hand sanitiser.
We would like to share with the readers of Arch Dis Child Fetal Neonatal, the results of a similar study conducted in 2011. Measurements of isopropanol/ethanol exposure were conducted for 9 neonates nursed in incubators1. We found very variable exposure profiles with peak isopropanol/ethanol value of 1982, respectively 906 ppm. A wide range of possible exposure situations were also investigated using a one-box dispersion model2. Both our clinical and experimental papers offered different approaches to reduce the potential isopropanol/ethanol exposure for neonates nursed in isolettes.
We were delighted to read that the results from Hsieh et al. were concordant with our findings. We believe that this new publication gives further evidence and emphasis on the, unfortunately often underestimated, issue of neonatal exposure to gaseous pollutants.
1 Paccaud et al. Hand-disinfectant alcoholic vapors in incubators. JNPM 4(1):15-19, 2011
2 Vernez et al. Solvent vapours in incubators: a source of exposure among neonates? Gefahrstoffe -Reinhaltung der Luft 71 (5):209-214, 2011
We thank you very much for your question and we would appreciate having the opportunity to share the full results of the regression analyses for our 3 outcomes: neurodevelopmental impairment, significant neurodevelopmental impairment and significant neurodevelopmental impairment or death. The omission of this information was due solely to the manuscript restrictions on words and tables. We agree with you that this information is useful. As we are not able to provide tables in an e-letter, we would be happy to share this information via e-mail with any interested reader.
Sincerely,
Anne Synnes, MDCM, MHSC, FRCPC
Neonatologist, BC Women’s Hospital and Health Centre,
Clinical Professor, Department of Pediatrics, University of British Columbia
Director, Canadian Neonatal Follow-Up Network
Vancouver, Canada
We are delighted that our work received the attention of the neonatal community. The protocol in the study was exactly as stated in our paper, oral feeds were offered at least once in 72 hours, more often if cues were evident. As cue-based feeding depends on individual infants’ physiological wellbeing and readiness to feed a traditional feeding guideline based on volume and time would be contradictory. The cue based feeding might have some effect on earlier achievement of the full oral feeding.(1) Usual total feeding volume in our unit is between 120 ml/kg/day to 180 ml/kg/day and this depends on several factors: co-morbidity (e.g. patent ductus arteriosus, chronic lung disease), type of milk (maternal breast milk, donor breast milk, different type of formulas), weight gain. The total enteral intake would not be feasible to protocolize. The volume taken orally (volume per feed and hike of feeds) was determined by the effort and energy of each individual baby as opposed to following any particular schedule (as mentioned earlier cue-based or infant-led feeding). As our cohort consisted of infants on full enteral feeding, there was no specific definition of feeding intolerance and indeed we did not identify any problems with feeding intolerance in the trial.
The first oral feed in our trial was 9.3 ± 6.5 days after randomization in High Flow (HF) group and 10.9 ± 4.8 days in nasal Continuous Positive Airway Pressure (CPAP) group, that is 33.3 ± 0.9 weeks of postmenstru...
We are delighted that our work received the attention of the neonatal community. The protocol in the study was exactly as stated in our paper, oral feeds were offered at least once in 72 hours, more often if cues were evident. As cue-based feeding depends on individual infants’ physiological wellbeing and readiness to feed a traditional feeding guideline based on volume and time would be contradictory. The cue based feeding might have some effect on earlier achievement of the full oral feeding.(1) Usual total feeding volume in our unit is between 120 ml/kg/day to 180 ml/kg/day and this depends on several factors: co-morbidity (e.g. patent ductus arteriosus, chronic lung disease), type of milk (maternal breast milk, donor breast milk, different type of formulas), weight gain. The total enteral intake would not be feasible to protocolize. The volume taken orally (volume per feed and hike of feeds) was determined by the effort and energy of each individual baby as opposed to following any particular schedule (as mentioned earlier cue-based or infant-led feeding). As our cohort consisted of infants on full enteral feeding, there was no specific definition of feeding intolerance and indeed we did not identify any problems with feeding intolerance in the trial.
The first oral feed in our trial was 9.3 ± 6.5 days after randomization in High Flow (HF) group and 10.9 ± 4.8 days in nasal Continuous Positive Airway Pressure (CPAP) group, that is 33.3 ± 0.9 weeks of postmenstrual age and 33.6 ± 0.7 weeks respectively. This would be in keeping with premature newborn physiology, when efficient coordination of suck, swallow and breathing occurring between 32 and 36 weeks of gestation.(2, 3) In fact this result compares favorably to previous reports. Hwang et al. in their cohort of infants born below 32 weeks of gestation reported first oral feed at 33.9 ± 1.7 weeks of postmenstrual age. Their group included all infants born below 32 weeks who achieved full oral feeding before discharge.(4) The infants included in our cohort were more premature (born below 30 weeks of gestation). We also excluded the ‘healthiest’ infants who were off respiratory support (63 in total, which would be over 40% of eligible infants). On the other hand we excluded also the ‘sickest’ infants with high respiratory support (19 infants) and infants who were not established on full enteral feeds at 32 weeks of gestation (5 infants). Shetty et al. in their cohort of infants similar in profile to our population reported first oral feed at median of 35 weeks of postmenstrual age (range 33 to 44 weeks) in CPAP group and 34.4 (range 33 to 37.86) in HF/CPAP group.(3) A physiological study undertaken by Amaizu et al. showed ability of infants born between 26 and 29 weeks of gestation to tolerate 1 to 2 oral feeds in 24 hours at 34.0 ± 1.0 weeks of postmenstrual age, this ability improved with gestational age at birth (34.4 ± 1.2 weeks at 26 to 27 weeks of gestation versus 33.6 ± 0.6 weeks at 28 to 29 weeks of gestation). It is worth noting that these were stable infants without chronic lung disease.(5) We would therefore believe that our results fully reflect the physiology of oral feeding in preterm newborns and would be fully justifiable for clinical practice.
We are using non-nutritive sucking in our unit as a standard practice.
We would like to thank you for the correction of our terminology used in reference to the important work of Shetty et al., however we believe that their work was a retrospective cohort study (retrospectively comparing two cohorts of infants managed differently in different time epochs).(3)
We firmly believe that our conclusion was justified that there was no difference in the duration to reach full oral feeds between stable preterm infants managed on HF Nasal Cannula and those managed on nasal CPAP, and that oral feeding was feasible and safe regardless of the method used for non-invasive respiratory support.(6)
1. Watson J, McGuire W. Responsive versus scheduled feeding for preterm infants. Cochrane database of systematic reviews (Online). 2016(8):CD005255. Epub 2016/09/01.
2. Foster JP, Psaila K, Patterson T. Non-nutritive sucking for increasing physiologic stability and nutrition in preterm infants. Cochrane database of systematic reviews (Online). 2016;10:CD001071. Epub 2016/11/02.
3. Shetty S, Hunt K, Douthwaite A, Athanasiou M, Hickey A, Greenough A. High-flow nasal cannula oxygen and nasal continuous positive airway pressure and full oral feeding in infants with bronchopulmonary dysplasia. Archives of disease in childhood Fetal and neonatal edition. 2016;101(5):F408-11. Epub 2016/02/18.
4. Hwang YS, Ma MC, Tseng YM, Tsai WH. Associations among perinatal factors and age of achievement of full oral feeding in very preterm infants. Pediatrics and neonatology. 2013;54(5):309-14. Epub 2013/05/11.
5. Amaizu N, Shulman R, Schanler R, Lau C. Maturation of oral feeding skills in preterm infants. Acta paediatrica. 2008;97(1):61-7. Epub 2007/12/07.
6. Glackin SJ, O'Sullivan A, George S, Semberova J, Miletin J. High flow nasal cannula versus NCPAP, duration to full oral feeds in preterm infants: a randomised controlled trial. Archives of disease in childhood Fetal and neonatal edition. 2017;102(4):F329-F32. Epub 2016/12/25.
We thank dr. Kumar and dr. Yadav for their interest in our study. We hope that by stating ‘delayed cord clamping may not be advisable in second-born MC twins after vaginal birth’, we expressed that gynecologists could consider to deviate from the international guidelines in some cases. It is possible that not all babies will benefit from placental transfusion in a similar way. However, we certainly agree with dr. Kumar and dr. Yadav that the optimal timing of umbilical cord clamping in twins warrants further investigation.
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 MoreWe 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 MoreDilini 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...
I congratulate the authors for putting the results of this much needed study together and exploring the differences in survival for extremely preterm babies at 22-23 weeks. The outcome for babies born at < 26 weeks hasn't been looked at nationally since the EPICURE 2 study in 2006.
Show MoreIt is interesting to note the regional variation in survival at 22-23 weeks and it warrants further exploring the following issues:
1. Is there a variation nationally in administering antenatal steroids at <24 weeks gestation? The NICE guideline 2015 advocates:
For women between 23+0 and 23+6 weeks of pregnancy who are in suspected or established preterm labour, are having a planned preterm birth or have P-PROM, discuss with the woman (and her family members or carers as appropriate) the use of maternal corticosteroids in the context of her individual circumstances. This is open to interpretation and may not provide consistency in administration of antenatal steroids at 23 to 23+6 weeks. There is no guidance for <23 weeks. It will be useful to explore the practice nationally.
2. The practice for resuscitation at <23 weeks is likely to be variable. The latest national guideline BAPM 2008 advocates If gestational age is certain and less than 23+0 (i.e. at 22 weeks) it would be considered in the best interests of the baby, and standard practice, for resuscitation not to be carried out. The units who were resuscitating babies <23 weeks were deviating from...
Sirs, we were surprised to read that11 out of 56 units in the resource rich UK did not administer Rotavirus vaccine to their babies. (1) Thirty years ago, one of us described a neonatal rotavirus outbreak that had a considerable morbidity (2). Although these outbreaks continue(3.), some low resource units like ours (Birth rate 3000/year) are accredited as Breast Feeding Friendly and have adopted a very enthusiastic breast...
Dear Sir,
We congratulate the authors on this study of neonatal transitional circulation performed so quickly after birth. The authors state that the ductal flow ratio reported in their study reflects pulmonary and haemodynamic transition and can be used to monitor neonatal transition in healthy infants. The implication is that their study describes a physiological transition in healthy term infants, but we question that this is the case.
Delivery by elective caesarean section is not a physiological birth but it does permit the neonate an atraumatic birth. We are particularly concerned that the transition may have been disrupted by the timing of cord clamping which was between 30 and 60 seconds. While this is considered delayed cord clamping by some, most guidelines recommend a minimum of 60 seconds have elapsed before the circulation is interrupted by cord clamping. The WHO advises 3 minutes.(1) Not all of the babies in the series had established respiration before clamping and cord clamping before the onset of respiration has a marked effect on cardiac output.(2) It is therefore questionable that the mean and range of results published represents a normal transition in healthy infants.
The normal fetal circulation is well described with the two ventricles pumping in parallel, the right ventricular output being significantly more than the left and the flow across two shunts, right to left in the ductus arteriousus and right to left across the foram...
Show MoreSir,
We read Hsieh et al's paper with much interest. In an experimental study of ethanol introduction in an empty isolette, they conclude that neonates in isolettes are at risk of of inadvertent exposure to ethanol from hands cleaned with ethanol-based hand sanitiser.
We would like to share with the readers of Arch Dis Child Fetal Neonatal, the results of a similar study conducted in 2011. Measurements of isopropanol/ethanol exposure were conducted for 9 neonates nursed in incubators1. We found very variable exposure profiles with peak isopropanol/ethanol value of 1982, respectively 906 ppm. A wide range of possible exposure situations were also investigated using a one-box dispersion model2. Both our clinical and experimental papers offered different approaches to reduce the potential isopropanol/ethanol exposure for neonates nursed in isolettes.
We were delighted to read that the results from Hsieh et al. were concordant with our findings. We believe that this new publication gives further evidence and emphasis on the, unfortunately often underestimated, issue of neonatal exposure to gaseous pollutants.
1 Paccaud et al. Hand-disinfectant alcoholic vapors in incubators. JNPM 4(1):15-19, 2011
2 Vernez et al. Solvent vapours in incubators: a source of exposure among neonates? Gefahrstoffe -Reinhaltung der Luft 71 (5):209-214, 2011
Dear Dr. Degraeuwe,
We thank you very much for your question and we would appreciate having the opportunity to share the full results of the regression analyses for our 3 outcomes: neurodevelopmental impairment, significant neurodevelopmental impairment and significant neurodevelopmental impairment or death. The omission of this information was due solely to the manuscript restrictions on words and tables. We agree with you that this information is useful. As we are not able to provide tables in an e-letter, we would be happy to share this information via e-mail with any interested reader.
Sincerely,
Anne Synnes, MDCM, MHSC, FRCPC
Neonatologist, BC Women’s Hospital and Health Centre,
Clinical Professor, Department of Pediatrics, University of British Columbia
Director, Canadian Neonatal Follow-Up Network
Vancouver, Canada
We are delighted that our work received the attention of the neonatal community. The protocol in the study was exactly as stated in our paper, oral feeds were offered at least once in 72 hours, more often if cues were evident. As cue-based feeding depends on individual infants’ physiological wellbeing and readiness to feed a traditional feeding guideline based on volume and time would be contradictory. The cue based feeding might have some effect on earlier achievement of the full oral feeding.(1) Usual total feeding volume in our unit is between 120 ml/kg/day to 180 ml/kg/day and this depends on several factors: co-morbidity (e.g. patent ductus arteriosus, chronic lung disease), type of milk (maternal breast milk, donor breast milk, different type of formulas), weight gain. The total enteral intake would not be feasible to protocolize. The volume taken orally (volume per feed and hike of feeds) was determined by the effort and energy of each individual baby as opposed to following any particular schedule (as mentioned earlier cue-based or infant-led feeding). As our cohort consisted of infants on full enteral feeding, there was no specific definition of feeding intolerance and indeed we did not identify any problems with feeding intolerance in the trial.
Show MoreThe first oral feed in our trial was 9.3 ± 6.5 days after randomization in High Flow (HF) group and 10.9 ± 4.8 days in nasal Continuous Positive Airway Pressure (CPAP) group, that is 33.3 ± 0.9 weeks of postmenstru...
We thank dr. Kumar and dr. Yadav for their interest in our study. We hope that by stating ‘delayed cord clamping may not be advisable in second-born MC twins after vaginal birth’, we expressed that gynecologists could consider to deviate from the international guidelines in some cases. It is possible that not all babies will benefit from placental transfusion in a similar way. However, we certainly agree with dr. Kumar and dr. Yadav that the optimal timing of umbilical cord clamping in twins warrants further investigation.
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