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We read with great interest the article by Minocchieri et al., published in this journal and found it very interesting and relevant to the current context.1 However, we have certain observations about the conduct of the study which question its external validity.
The authors used supplemental fractional inspired oxygen (FiO2) of 0.22–0.30 as enrollment criteria for administering surfactant. As per current standard, most of the neonatologist will not agree to give surfactant at such a low FiO2 requirement in the first 4 hours. It might be possible that many enrolled babies could have been easily managed without surfactant and it was an unnecessary intervention for them. This is further supported by the fact that in current study 28% of babies were weaned to room air in the first 4 hours, hence could not be enrolled. Also, the author's suggestion of enrolling babies requiring Fio2 > 25 % seems to be very liberal. Most of the units administer surfactant beyond 30% supplemental oxygen requirement.
The total duration of invasive as well as any mechanical ventilation was higher in the intervention group, suggesting that the harms may outweigh the benefits.
Although the authors showed that the intervention had its intended effect in babies born at >32 weeks’ gestation, in the current era, where universal antenatal steroid coverage is available, these babies hardly need surfactant. In this trial, a significant number of babies > 32 weeks received su...
We read with great interest the article by Minocchieri et al., published in this journal and found it very interesting and relevant to the current context.1 However, we have certain observations about the conduct of the study which question its external validity.
The authors used supplemental fractional inspired oxygen (FiO2) of 0.22–0.30 as enrollment criteria for administering surfactant. As per current standard, most of the neonatologist will not agree to give surfactant at such a low FiO2 requirement in the first 4 hours. It might be possible that many enrolled babies could have been easily managed without surfactant and it was an unnecessary intervention for them. This is further supported by the fact that in current study 28% of babies were weaned to room air in the first 4 hours, hence could not be enrolled. Also, the author's suggestion of enrolling babies requiring Fio2 > 25 % seems to be very liberal. Most of the units administer surfactant beyond 30% supplemental oxygen requirement.
The total duration of invasive as well as any mechanical ventilation was higher in the intervention group, suggesting that the harms may outweigh the benefits.
Although the authors showed that the intervention had its intended effect in babies born at >32 weeks’ gestation, in the current era, where universal antenatal steroid coverage is available, these babies hardly need surfactant. In this trial, a significant number of babies > 32 weeks received surfactant and invasive ventilation, the reason for which is unclear.
Authors used FiO2 alone as a criterion for defining CPAP failure and positive end-expiratory pressure (PEEP) level was not considered. In such cases, many babies who can be managed by increasing PEEP may have got intubated even without adequate recruitment leading to increased intubation rates. This may explain the increased CPAP failure rates in the study population as compared to the historical cohort. On careful analysis of CPAP failure cases, the mean PEEP pressure was 6 cm only, which supports the above hypothesis.
Although, the trial intended to see the effect on intubation and mechanical ventilation, both of which have a direct effect on bronchopulmonary dysplasia (BPD) rates, the better primary outcome would have been the incidence of BPD.
Surprisingly the cesarean delivery rates very high in the study population.
Competing interests: None
Source of funding: None
References:
1. Minocchieri S, Berry CA, Pillow JJ. Nebulised surfactant to reduce severity of respiratory distress: a blinded, parallel, randomised controlled trial. Archives of Disease in Childhood - Fetal and Neonatal Edition. Published Online First: 26 July 2018. doi:10.1136/archdischild-2018-315051
I agree with the authors that the question of end-expiratory pressure at birth needs to focus on CPAP. As the authors highlight, the entirety of the preclinical literature has been performed in mechanically ventilated, intubated and sedated animals, and the role of PEEP on pulmonary blood flow during the actual respiratory transition is yet to be investigated. Neither of these limitations are insurmountable and I am confident the authors can rectify this gap in knowledge.
The rapidly changing cardiorespiratory events immediately following birth and the concerns regarding with too low and too high a PEEP further emphasise the need for a dynamic approach to PEEP levels.
We appreciate the comments of Zhu and Shi on our crossover trial comparing nHFOV (nasal high frequency oscillatory ventilation) and nCPAP (nasal continuous positive airway pressure) in preterm infants <32 weeks gestational age after extubation from invasive ventilation for respiratory distress syndrome or after less invasive surfactant therapy.1
The aim of our study was to evaluate the efficacy of an oscillatory pressure waveform superposed to CPAP in spontaneously breathing preterm infants suffering from hypercarbia. In our trial, patients received a CPAP of 5 – 8 cmH2O, which represents standard of care in our unit and is in line with the clinical practice within many neonatal centers.2 Individual CPAP levels were the same before (adjusted according to standard of care) and within the study periods.
We agree with Zhu et al that increasing the CPAP level in addition to oscillations may enhance lung recruitment and ventilation. However, the effect of oscillations can hardly be differentiated from elevated CPAP levels in this scenario. Other factors than increased lung recruitment might contribute to increased CO2 clearance (e.g. increased leak flow, increased pharyngeal washout or the infants’ respiratory response). In conclusion, we cannot speculate on the effect of increased CPAP levels when testing nHFOV in our trial, but we would advise against testing differing opening pressures when comparing nHFOV to CPAP respiratory support.
We appreciate the comments of Zhu and Shi on our crossover trial comparing nHFOV (nasal high frequency oscillatory ventilation) and nCPAP (nasal continuous positive airway pressure) in preterm infants <32 weeks gestational age after extubation from invasive ventilation for respiratory distress syndrome or after less invasive surfactant therapy.1
The aim of our study was to evaluate the efficacy of an oscillatory pressure waveform superposed to CPAP in spontaneously breathing preterm infants suffering from hypercarbia. In our trial, patients received a CPAP of 5 – 8 cmH2O, which represents standard of care in our unit and is in line with the clinical practice within many neonatal centers.2 Individual CPAP levels were the same before (adjusted according to standard of care) and within the study periods.
We agree with Zhu et al that increasing the CPAP level in addition to oscillations may enhance lung recruitment and ventilation. However, the effect of oscillations can hardly be differentiated from elevated CPAP levels in this scenario. Other factors than increased lung recruitment might contribute to increased CO2 clearance (e.g. increased leak flow, increased pharyngeal washout or the infants’ respiratory response). In conclusion, we cannot speculate on the effect of increased CPAP levels when testing nHFOV in our trial, but we would advise against testing differing opening pressures when comparing nHFOV to CPAP respiratory support.
We furthermore agree with Zhu et al. that careful consideration has to be given to the individual significance of an intervention free interval in between study periods when planning a cross-over trial.3 However, there is an incongruence across cross-over trials on the use of washout phases and the issue of carry-over effects.4 As detailed in the manuscript, there was no washout phase between both study periods since a wash out in the classical meaning (omission of respiratory support) was not feasible in our trial. Even so, we calculated the carry-over effect for any outcome parameter and found none (table 2).1
We thank Zhu et al for their comments and hope our reply clarified those important aspects to the reader.
References:
1 Klotz D, Schneider H, Schumann S, et al. Non-invasive high-frequency oscillatory ventilation in preterm infants: a randomised controlled cross-over trial. Arch Dis Child Fetal Neonatal Ed 2018;103:F1–F5 . doi: 10.1136/archdischild-2017-313190
2 Beltempo M, Isayama T, Vento M, et al. Respiratory Management of Extremely Preterm Infants: An International Survey. Neonatology 2018;114:28–36 . doi: 10.1159/000487987
3 Wellek S, Blettner M. On the proper use of the crossover design in clinical trials: part 18 of a series on evaluation of scientific publications. Dtsch Arztebl Int 2012; 109:276–281. doi: 10.3238/arztebl.2012.0276
4 Mills EJ, Chan A-W, Wu P, et al. Design, analysis, and presentation of crossover trials. Trials 2009;10:27. doi: 10.1186/1745-6215-10-27
Response to The secret sauce: secrets of high performing neonatal intensive care units
Soghier and Short highlight the importance of local contextual factors in determining the success of improvement initiatives in neonatal units. They draw attention to a number of qualitatively assessed factors, many of which are prefixed by the adjectives “effective”, “active” and, “strong” reflecting the importance of leadership and team culture in effective organisations.
Whilst contextual factor surveys might have a place in identifying the readiness of teams to undertake active improvement, they do little to assist organisations in improving their own readiness. The features of good healthcare leadership and team culture are not readily measured, and healthcare professionals in the UK have little or no training in the attitudes and skills necessary for leadership in quality improvement.
The Institute for Healthcare Improvement has attempted to describe the features of a high quality healthcare organisation in some detail (1). The British Association of Perinatal Medicine has recently produced Quality Indicators relating to structures and processes relevant to Quality and Patient Safety in the context of current neonatal care in the UK (2), which it is hoped will create a basis for units to develop “quality-readiness”.
There is reason to believe that collaboration across centres might add momentum to quality improvement (3). The UK, which has good access to...
Response to The secret sauce: secrets of high performing neonatal intensive care units
Soghier and Short highlight the importance of local contextual factors in determining the success of improvement initiatives in neonatal units. They draw attention to a number of qualitatively assessed factors, many of which are prefixed by the adjectives “effective”, “active” and, “strong” reflecting the importance of leadership and team culture in effective organisations.
Whilst contextual factor surveys might have a place in identifying the readiness of teams to undertake active improvement, they do little to assist organisations in improving their own readiness. The features of good healthcare leadership and team culture are not readily measured, and healthcare professionals in the UK have little or no training in the attitudes and skills necessary for leadership in quality improvement.
The Institute for Healthcare Improvement has attempted to describe the features of a high quality healthcare organisation in some detail (1). The British Association of Perinatal Medicine has recently produced Quality Indicators relating to structures and processes relevant to Quality and Patient Safety in the context of current neonatal care in the UK (2), which it is hoped will create a basis for units to develop “quality-readiness”.
There is reason to believe that collaboration across centres might add momentum to quality improvement (3). The UK, which has good access to national neonatal data and a mature benchmarking system, is well set up for collaborative neonatal quality improvement. Professional organisations now need to actively promote collaboration by bringing together clinical leaders focused on excellence, encouraging neonatal units to work together, and facilitating a national community of learning. This might be the missing link to producing a step change in the quality of neonatal care.
1. Frankel A, Haraden C, Federico F, Safe LJAF, White EC. A Framework for Safe, Reliable, and Effective Care. Cambridge, MA; 2017.
2. The British Association of Perinatal Medicine. Neonatal Service Quality Indicators. London; 2017. https://www.bapm.org/NSQI
3. ØVretveit J, Bate P, Cleary P, Cretin S, Gustafson D, McInnes K, et al. Quality collaboratives: lessons from research. Qual Saf Health Care [Internet]. 2002;11(4):345–51. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12468695%5Cnhttp://www.pubmedcentral....
Finn et al (1) describe respiratory adaptation in term infants following elective caesarean section and the other intervention of early cord clamping(2). Although the timing of cord clamping was not documented and there is no policy for delayed cord clamping at Cork University Maternity Hospital, the authors state that the neonates were transferred immediately after birth to a Panda Resuscitator and other non-invasive monitoring equipment, thus requiring early cord clamping in all infants studied.
The aim of the study was to define newborn physiological ventilation parameters (respiratory rate (RR), TV, end-tidal carbon dioxide (EtCO2)) over the first minutes of life in healthy-term infants following ECS, in the same way that Dawson and colleagues(3) produced centile charts in 2010 detailing the normalisation of oxygen saturations over time during newborn adaptation after normal vaginal birth. All the babies studied by Dawson et al also experienced a transition of the circulatory system which was interrupted by early cord clamping but, in a study in 2014 by Smit et al(4), in which cord clamping was delayed by at least one minute, they showed that cord clamping had resulted in a lower oxygen saturation during the first few minutes after birth. The median SpO2 of the babies experiencing early cord clamping was 11, 7 and 4% lower at minute 1, 2 and 3 respectively. All these babies already had the advantage of a physiological preparation through the mechanical and hor...
Finn et al (1) describe respiratory adaptation in term infants following elective caesarean section and the other intervention of early cord clamping(2). Although the timing of cord clamping was not documented and there is no policy for delayed cord clamping at Cork University Maternity Hospital, the authors state that the neonates were transferred immediately after birth to a Panda Resuscitator and other non-invasive monitoring equipment, thus requiring early cord clamping in all infants studied.
The aim of the study was to define newborn physiological ventilation parameters (respiratory rate (RR), TV, end-tidal carbon dioxide (EtCO2)) over the first minutes of life in healthy-term infants following ECS, in the same way that Dawson and colleagues(3) produced centile charts in 2010 detailing the normalisation of oxygen saturations over time during newborn adaptation after normal vaginal birth. All the babies studied by Dawson et al also experienced a transition of the circulatory system which was interrupted by early cord clamping but, in a study in 2014 by Smit et al(4), in which cord clamping was delayed by at least one minute, they showed that cord clamping had resulted in a lower oxygen saturation during the first few minutes after birth. The median SpO2 of the babies experiencing early cord clamping was 11, 7 and 4% lower at minute 1, 2 and 3 respectively. All these babies already had the advantage of a physiological preparation through the mechanical and hormonal adjustments that occur during labour and vaginal delivery, so it is quite possible early cord clamping may have an even greater effect on the circulation and respiratory function after elective CS. Animal studies suggest that the effect of early cord clamping is less if respiration and the pulmonary circulation is established. No doubt many of these babies will have already taken their first breath before the cord was clamped, but we do not know how big an effect early clamping had on the overall results. Thus this study only contributes to our understanding of respiratory adaption of the term neonate following elective caesarean section and early cord clamping. ILCOR and NICE both recommend delayed cord clamping at the birth of all uncompromised term neonates. All babies born by elective CS should have delayed clamping if these guidelines are being followed and it is our understanding of the respiratory adaption of these babies which is still needed.
References
1. Finn D, De Meulemeester J, Dann L, et al Respiratory adaptation in term infants following elective caesarean section Archives of Disease in Childhood - Fetal and Neonatal Edition 2018;103:F417-F421.
Moral distress is a good 'umbrella' term but it tends to invite diversionary philosophising when in truth we all know that work in intensive care puts enormous emotional pressures on staff. These can be attended to but as the paper shows, cannot be eradicated. Health care is not a mechanical process. As one of the subjects in this study said "if we removed moral distress we would be like robots" (F443).
In my response to an earlier paper on this theme by the same authors https://adc.bmj.com/content/101/8/701.responses I discussed the benefits and limitations of facilitated discussions. One of the most striking comments from a neonatal intensive care nurse in one such meeting was "if you don't talk about it you don't know it's bad" http://bit.ly/1OyKcfl which perfectly captures our essential ambivalence about looking at troubling experiences in any depth. We are after all practitioners, and the tradition of 'getting on with it' - with occasional intelligent and practical thoughts on process - is the prevailing culture in most health services. Yet after almost 40 years as a psychiatrist in paediatric settings I know that there is a hunger for less systematic, but no less disciplined, attention to the daily experience of health work. This short paper 'stop running and start thinking' (Kraemer 2019...
Moral distress is a good 'umbrella' term but it tends to invite diversionary philosophising when in truth we all know that work in intensive care puts enormous emotional pressures on staff. These can be attended to but as the paper shows, cannot be eradicated. Health care is not a mechanical process. As one of the subjects in this study said "if we removed moral distress we would be like robots" (F443).
In my response to an earlier paper on this theme by the same authors https://adc.bmj.com/content/101/8/701.responses I discussed the benefits and limitations of facilitated discussions. One of the most striking comments from a neonatal intensive care nurse in one such meeting was "if you don't talk about it you don't know it's bad" http://bit.ly/1OyKcfl which perfectly captures our essential ambivalence about looking at troubling experiences in any depth. We are after all practitioners, and the tradition of 'getting on with it' - with occasional intelligent and practical thoughts on process - is the prevailing culture in most health services. Yet after almost 40 years as a psychiatrist in paediatric settings I know that there is a hunger for less systematic, but no less disciplined, attention to the daily experience of health work. This short paper 'stop running and start thinking' (Kraemer 2019 https://onlinelibrary.wiley.com/doi/abs/10.1111/camh.12282 ) summarises a parallel but subjugated tradition of respecting the curiosity and courage of front line workers which I hope can gain greater prominence in future.
Huang et al recently summarised the role of human milk (HM) in bronchopulmonary dysplasia via a systematic review and meta-analysis of the available evidence. 1 With renewed interest in exclusive HM diets and various HM products now available, it is important for health professionals to have access to quality reviews of the evidence. We would like to make some observations on the Huang article, informed by our recent review. 2
There were two main differences in inclusion criteria between Huang’s review and ours: Huang et al included infants born <37 weeks’ gestation whereas ours was limited to very low birth weight infants. Huang et al also searched Chinese data-bases for studies in English and Chinese, in addition to conventional databases, partially addressing a limitation of our review which was restricted to studies published in English.
In their main results, Huang et al have combined RCTs and cohort studies with forest plots showing an overall protective effect of HM. However, in Table 3, in which data are presented by study design, no effect of HM from RCTs is evident. Thus, the overall protective effect is driven by the cohort studies alone. Cochrane methods recommend that different study designs should not be combined in a meta-analysis3 as they can be expected to differ systematically. By not reporting analyses of the different study designs, Huang et al overstate the benefits of HM.
In our recent meta-analysis 2 of human milk and morbidity...
Huang et al recently summarised the role of human milk (HM) in bronchopulmonary dysplasia via a systematic review and meta-analysis of the available evidence. 1 With renewed interest in exclusive HM diets and various HM products now available, it is important for health professionals to have access to quality reviews of the evidence. We would like to make some observations on the Huang article, informed by our recent review. 2
There were two main differences in inclusion criteria between Huang’s review and ours: Huang et al included infants born <37 weeks’ gestation whereas ours was limited to very low birth weight infants. Huang et al also searched Chinese data-bases for studies in English and Chinese, in addition to conventional databases, partially addressing a limitation of our review which was restricted to studies published in English.
In their main results, Huang et al have combined RCTs and cohort studies with forest plots showing an overall protective effect of HM. However, in Table 3, in which data are presented by study design, no effect of HM from RCTs is evident. Thus, the overall protective effect is driven by the cohort studies alone. Cochrane methods recommend that different study designs should not be combined in a meta-analysis3 as they can be expected to differ systematically. By not reporting analyses of the different study designs, Huang et al overstate the benefits of HM.
In our recent meta-analysis 2 of human milk and morbidity in very low birth weight infants, we used four comparisons: exclusive HM vs exclusive preterm formula (EPTF); any HM vs EPTF, high vs low dose of HM and pasteurised vs unpasteurised HM finding inconclusive evidence for an effect in all comparisons. The only significant finding was in the high vs low dose HM comparison for 18 cohort studies (RR 0.84 95% CI 0.73, 0.96), but with very low certainty. Findings from RCTs for this comparison were not significant and, taking evidence from both types of studies, we concluded a lack of evidence and that further studies may change the effect size seen.
Lastly, we are worried by the replication of data in each of the forest plots. The same five studies have been included (with the same number of events) in all six forest plots. It may be more appropriate to determine, where possible, the subgroup of the population studied that met each comparison criteria (i.e.: exclusive HM; exclusive formula; mainly HM; mainly formula; any HM) and enter the appropriate number of events and totals without repetition – or alternatively to enter each study into the one comparison that best suits their study protocol. It would be interesting to see how these changes to methods impact on the results.
References:
1. Huang J, Zhang L, Tang J, et al. Arch Dis Child Fetal Neonatal Ed Epub ahead of print: Human milk as a protective factor for bronchopulmonary dysplasia: a systematic review and meta-analysis [June 2018]. doi:10.1136/ archdischild-2017-314205
2. Miller J, Tonkin E, Damarell R et al. A Systematic Review and Meta-Analysis of Human Milk Feeding and Morbidity in Very Low Birth Weight Infants. Nutrients 2018, 10, 707; doi:10.3390/nu10060707
3. Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.handbook.cochrane.org.
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.
We read with great interest the article by Minocchieri et al., published in this journal and found it very interesting and relevant to the current context.1 However, we have certain observations about the conduct of the study which question its external validity.
Show MoreThe authors used supplemental fractional inspired oxygen (FiO2) of 0.22–0.30 as enrollment criteria for administering surfactant. As per current standard, most of the neonatologist will not agree to give surfactant at such a low FiO2 requirement in the first 4 hours. It might be possible that many enrolled babies could have been easily managed without surfactant and it was an unnecessary intervention for them. This is further supported by the fact that in current study 28% of babies were weaned to room air in the first 4 hours, hence could not be enrolled. Also, the author's suggestion of enrolling babies requiring Fio2 > 25 % seems to be very liberal. Most of the units administer surfactant beyond 30% supplemental oxygen requirement.
The total duration of invasive as well as any mechanical ventilation was higher in the intervention group, suggesting that the harms may outweigh the benefits.
Although the authors showed that the intervention had its intended effect in babies born at >32 weeks’ gestation, in the current era, where universal antenatal steroid coverage is available, these babies hardly need surfactant. In this trial, a significant number of babies > 32 weeks received su...
I agree with the authors that the question of end-expiratory pressure at birth needs to focus on CPAP. As the authors highlight, the entirety of the preclinical literature has been performed in mechanically ventilated, intubated and sedated animals, and the role of PEEP on pulmonary blood flow during the actual respiratory transition is yet to be investigated. Neither of these limitations are insurmountable and I am confident the authors can rectify this gap in knowledge.
The rapidly changing cardiorespiratory events immediately following birth and the concerns regarding with too low and too high a PEEP further emphasise the need for a dynamic approach to PEEP levels.
Dear Editor
We appreciate the comments of Zhu and Shi on our crossover trial comparing nHFOV (nasal high frequency oscillatory ventilation) and nCPAP (nasal continuous positive airway pressure) in preterm infants <32 weeks gestational age after extubation from invasive ventilation for respiratory distress syndrome or after less invasive surfactant therapy.1
The aim of our study was to evaluate the efficacy of an oscillatory pressure waveform superposed to CPAP in spontaneously breathing preterm infants suffering from hypercarbia. In our trial, patients received a CPAP of 5 – 8 cmH2O, which represents standard of care in our unit and is in line with the clinical practice within many neonatal centers.2 Individual CPAP levels were the same before (adjusted according to standard of care) and within the study periods.
...Show MoreWe agree with Zhu et al that increasing the CPAP level in addition to oscillations may enhance lung recruitment and ventilation. However, the effect of oscillations can hardly be differentiated from elevated CPAP levels in this scenario. Other factors than increased lung recruitment might contribute to increased CO2 clearance (e.g. increased leak flow, increased pharyngeal washout or the infants’ respiratory response). In conclusion, we cannot speculate on the effect of increased CPAP levels when testing nHFOV in our trial, but we would advise against testing differing opening pressures when comparing nHFOV to CPAP respiratory support.
Response to The secret sauce: secrets of high performing neonatal intensive care units
Soghier and Short highlight the importance of local contextual factors in determining the success of improvement initiatives in neonatal units. They draw attention to a number of qualitatively assessed factors, many of which are prefixed by the adjectives “effective”, “active” and, “strong” reflecting the importance of leadership and team culture in effective organisations.
Whilst contextual factor surveys might have a place in identifying the readiness of teams to undertake active improvement, they do little to assist organisations in improving their own readiness. The features of good healthcare leadership and team culture are not readily measured, and healthcare professionals in the UK have little or no training in the attitudes and skills necessary for leadership in quality improvement.
The Institute for Healthcare Improvement has attempted to describe the features of a high quality healthcare organisation in some detail (1). The British Association of Perinatal Medicine has recently produced Quality Indicators relating to structures and processes relevant to Quality and Patient Safety in the context of current neonatal care in the UK (2), which it is hoped will create a basis for units to develop “quality-readiness”.
There is reason to believe that collaboration across centres might add momentum to quality improvement (3). The UK, which has good access to...
Show MoreFinn et al (1) describe respiratory adaptation in term infants following elective caesarean section and the other intervention of early cord clamping(2). Although the timing of cord clamping was not documented and there is no policy for delayed cord clamping at Cork University Maternity Hospital, the authors state that the neonates were transferred immediately after birth to a Panda Resuscitator and other non-invasive monitoring equipment, thus requiring early cord clamping in all infants studied.
The aim of the study was to define newborn physiological ventilation parameters (respiratory rate (RR), TV, end-tidal carbon dioxide (EtCO2)) over the first minutes of life in healthy-term infants following ECS, in the same way that Dawson and colleagues(3) produced centile charts in 2010 detailing the normalisation of oxygen saturations over time during newborn adaptation after normal vaginal birth. All the babies studied by Dawson et al also experienced a transition of the circulatory system which was interrupted by early cord clamping but, in a study in 2014 by Smit et al(4), in which cord clamping was delayed by at least one minute, they showed that cord clamping had resulted in a lower oxygen saturation during the first few minutes after birth. The median SpO2 of the babies experiencing early cord clamping was 11, 7 and 4% lower at minute 1, 2 and 3 respectively. All these babies already had the advantage of a physiological preparation through the mechanical and hor...
Show MoreMoral distress is a good 'umbrella' term but it tends to invite diversionary philosophising when in truth we all know that work in intensive care puts enormous emotional pressures on staff. These can be attended to but as the paper shows, cannot be eradicated. Health care is not a mechanical process. As one of the subjects in this study said "if we removed moral distress we would be like robots" (F443).
In my response to an earlier paper on this theme by the same authors https://adc.bmj.com/content/101/8/701.responses I discussed the benefits and limitations of facilitated discussions. One of the most striking comments from a neonatal intensive care nurse in one such meeting was "if you don't talk about it you don't know it's bad" http://bit.ly/1OyKcfl which perfectly captures our essential ambivalence about looking at troubling experiences in any depth. We are after all practitioners, and the tradition of 'getting on with it' - with occasional intelligent and practical thoughts on process - is the prevailing culture in most health services. Yet after almost 40 years as a psychiatrist in paediatric settings I know that there is a hunger for less systematic, but no less disciplined, attention to the daily experience of health work. This short paper 'stop running and start thinking' (Kraemer 2019...
Show MoreHuang et al recently summarised the role of human milk (HM) in bronchopulmonary dysplasia via a systematic review and meta-analysis of the available evidence. 1 With renewed interest in exclusive HM diets and various HM products now available, it is important for health professionals to have access to quality reviews of the evidence. We would like to make some observations on the Huang article, informed by our recent review. 2
Show MoreThere were two main differences in inclusion criteria between Huang’s review and ours: Huang et al included infants born <37 weeks’ gestation whereas ours was limited to very low birth weight infants. Huang et al also searched Chinese data-bases for studies in English and Chinese, in addition to conventional databases, partially addressing a limitation of our review which was restricted to studies published in English.
In their main results, Huang et al have combined RCTs and cohort studies with forest plots showing an overall protective effect of HM. However, in Table 3, in which data are presented by study design, no effect of HM from RCTs is evident. Thus, the overall protective effect is driven by the cohort studies alone. Cochrane methods recommend that different study designs should not be combined in a meta-analysis3 as they can be expected to differ systematically. By not reporting analyses of the different study designs, Huang et al overstate the benefits of HM.
In our recent meta-analysis 2 of human milk and morbidity...
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...
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