We thank Dr Hewson for his interest in our paper and for raising several intriguing points that challenges current practice about the use of oxygen during the very important first minutes of life of a sick preterm infant. There are several points we would like to clarify in response to his questions.
Firstly, in our study, only 12% (n=96) of preterm infants from the 8 studies reached the recommended SpO2 range (80-85%) and not the lower limit (80%) of this range, as stated by Dr Hewson. The majority of infants were either below (46%) or above (42%) this range at 5 minutes of age.
We agree that neither hyperoxia or hypoxia, even for a few short minutes, is in the best interest of any newborn infant. We concur with Dr Hewson that the current SpO2 recommendations are not evidence-based, especially for sick preterm infants and for either improved short or long-term outcomes. Currently, most clinical practice guidelines recommend the same SpO2 targets for both term and preterm infants (1) and do not take into account, differences in physiological needs. Indeed, Dawson et al showed that even healthy preterm infants needed several minutes more than term infants to achieve SpO2 >90% (2).
We therefore suggest that caution should be exercised before any specific SpO2 target can be recommended (e.g. 90-95% as suggested by Dr Hewson) without a sufficiently large study that is designed to assess both short and long-term outcomes. Clinical practice has swung dram...
We thank Dr Hewson for his interest in our paper and for raising several intriguing points that challenges current practice about the use of oxygen during the very important first minutes of life of a sick preterm infant. There are several points we would like to clarify in response to his questions.
Firstly, in our study, only 12% (n=96) of preterm infants from the 8 studies reached the recommended SpO2 range (80-85%) and not the lower limit (80%) of this range, as stated by Dr Hewson. The majority of infants were either below (46%) or above (42%) this range at 5 minutes of age.
We agree that neither hyperoxia or hypoxia, even for a few short minutes, is in the best interest of any newborn infant. We concur with Dr Hewson that the current SpO2 recommendations are not evidence-based, especially for sick preterm infants and for either improved short or long-term outcomes. Currently, most clinical practice guidelines recommend the same SpO2 targets for both term and preterm infants (1) and do not take into account, differences in physiological needs. Indeed, Dawson et al showed that even healthy preterm infants needed several minutes more than term infants to achieve SpO2 >90% (2).
We therefore suggest that caution should be exercised before any specific SpO2 target can be recommended (e.g. 90-95% as suggested by Dr Hewson) without a sufficiently large study that is designed to assess both short and long-term outcomes. Clinical practice has swung dramatically over the last 10 years, from the use of static levels of pure oxygen without SpO2 monitoring to blending oxygen to meet SpO2 values derived from full-term, healthy infants (3). Much more information is required before we can be confident that any SpO2 or FiO2 recommendations are in the best interest of the infant, especially one that is as physiologically complex as the extremely preterm infant.
In conclusion, we agree with Dr Hewson that the practice of SpO2 targeting and FiO2 titration for preterm infant resuscitation deserves further (and urgent) study. Until such data are available, we advise caution when using oxygen during preterm infant resuscitation and that clinicians should remember to tailor their resuscitation practice to meet the needs of each infant.
1. Wilson A, Vento M, Shah PS et al. A review of international clinical practice guidelines for the use of oxygen in the delivery room resuscitation of preterm infants. Acta Paediatr. 2018;107(1):20-27.
2. Dawson JA, Kamlin CO, Vento M et al. Defining the reference range for oxygen saturation for infants after birth. Pediatrics. 2010;125(6):e1340-7.
3. No authors listed. Co-publishing of the Pediatric and Neonatal Portions of the 2015 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations and the 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Pediatrics. 2015;136 Suppl 2:S83-7.
It is a deleterious proposition to declare benefits to moral distress. In their recent response, Epstein and Hurst (2017) eloquently articulated many reasons for this. A better approach may be to invoke the work of Hans Selye (1974) and the parallels drawn by Rambur, Vallett, Cohen, and Tarule (2010) in advocating for the potential benefits of moral stress; not moral distress. The authors of the present article effectively revealed clinicians' general misunderstanding and misapplication of the concept of moral distress. Indeed, the authors acknowledged this explicitly: "This study demonstrates the importance of asking what clinical providers mean by 'moral distress' and/or what researchers mean when investigating this phenomenon" (p. F4). The authors' conclusions about frequency of moral distress and "inevitability" of moral distress are based on clinician self-report; not on a generally accepted definition of moral distress. Likewise, the authors do not use a validated, reliable tool to quantify moral distress (such as the Moral Distress Thermometer, Wocial & Weaver, 2013). Much qualitative research has been done that has clarified the concept of moral distress; it is not simply whatever the clinician says it is. As ethicist Denise Dudzinski (2016) stated, "clinicians benefit by distinguishing between distress and moral distress" and "without mapping the ethical dimensions of distress, clinicians are left...
It is a deleterious proposition to declare benefits to moral distress. In their recent response, Epstein and Hurst (2017) eloquently articulated many reasons for this. A better approach may be to invoke the work of Hans Selye (1974) and the parallels drawn by Rambur, Vallett, Cohen, and Tarule (2010) in advocating for the potential benefits of moral stress; not moral distress. The authors of the present article effectively revealed clinicians' general misunderstanding and misapplication of the concept of moral distress. Indeed, the authors acknowledged this explicitly: "This study demonstrates the importance of asking what clinical providers mean by 'moral distress' and/or what researchers mean when investigating this phenomenon" (p. F4). The authors' conclusions about frequency of moral distress and "inevitability" of moral distress are based on clinician self-report; not on a generally accepted definition of moral distress. Likewise, the authors do not use a validated, reliable tool to quantify moral distress (such as the Moral Distress Thermometer, Wocial & Weaver, 2013). Much qualitative research has been done that has clarified the concept of moral distress; it is not simply whatever the clinician says it is. As ethicist Denise Dudzinski (2016) stated, "clinicians benefit by distinguishing between distress and moral distress" and "without mapping the ethical dimensions of distress, clinicians are left with gnawing, nebulous distress without adequate ways to root out and rectify its causes" (p. 324). So before moral distress is declared as beneficial and inevitable, a clear definition of the concept must be set forth and adhered to.
Dudzinski, D. M. (2016). Navigating moral distress using the moral distress map. Journal of Medical Ethics, 42(5), 321-324. doi:10.1136/medethics-2015-103156
Epstein, E. G. & Hurst, A. R. (2017). Looking at the Positive Side of Moral Distress: Why It's a Problem. Journal of Clinical Ethics, 28(1), 37-41.
Rambur, B., Vallett, C., Cohen, J. A., & Tarule, J. (2010). The moral cascade: Distress, eustress, and the virtuous organization. Journal of Organizational Moral Psychology, 1(1), 41-54.
Selye, H. (1974). Stress without distress. Philadelphia, PA: Lippincott, Williams, and Wilkins.
Wocial, L. D., & Weaver, M. T. (2013). Development and psychometric testing of a new tool for detecting moral distress: the Moral Distress Thermometer. Journal of Advanced Nursing, 69(1), 167-174. doi:10.1111/j.1365-2648.2012.06036.x
We agree that conceptual clarity is of great value. Furthermore we acknowledge that some ‘distress’ experienced by our clinicians was not of a moral nature – such as the distress that results from tragic circumstances. We believe that in practice, distress and moral distress overlap. It can be difficult for clinicians to isolate the precise aetiology of their distress. We have furthermore acknowledged that these factors mean that the frequency of ‘moral distress’ may be overestimated in this study. However we are unclear why the ‘distress’ experienced by our clinicians is better labelled as ‘moral stress’. We maintain that conceptual clarity must be of clinical significance and be meaningful to those experiencing it. The clinicians participating were not uncomfortable with the idea that good things could arise from ‘distressing’ situations. It seems a disservice to the healthcare professionals in our study experiencing it to relabel it as ‘stress’ rather than ‘distress’ for the purpose of a less unsettling conclusion. We assume that Mr Hickox remains sceptical that moral distress, as strictly defined (that is, where a clinician feels anguish due to being constrained from acting in accordance with his/her moral judgement), may have some positive attributes. We will outline why we believe that in addition to decreasing moral distress and it’s negative consequences, we – and...
We agree that conceptual clarity is of great value. Furthermore we acknowledge that some ‘distress’ experienced by our clinicians was not of a moral nature – such as the distress that results from tragic circumstances. We believe that in practice, distress and moral distress overlap. It can be difficult for clinicians to isolate the precise aetiology of their distress. We have furthermore acknowledged that these factors mean that the frequency of ‘moral distress’ may be overestimated in this study. However we are unclear why the ‘distress’ experienced by our clinicians is better labelled as ‘moral stress’. We maintain that conceptual clarity must be of clinical significance and be meaningful to those experiencing it. The clinicians participating were not uncomfortable with the idea that good things could arise from ‘distressing’ situations. It seems a disservice to the healthcare professionals in our study experiencing it to relabel it as ‘stress’ rather than ‘distress’ for the purpose of a less unsettling conclusion. We assume that Mr Hickox remains sceptical that moral distress, as strictly defined (that is, where a clinician feels anguish due to being constrained from acting in accordance with his/her moral judgement), may have some positive attributes. We will outline why we believe that in addition to decreasing moral distress and it’s negative consequences, we – and many of our research participants – also think moral distress may not always be avoidable nor negative.
Disproportionate or aggressive medical treatments considered not in a patient’s best interests are commonly cited as key causes of moral distress(Prentice, Janvier et al. 2016). This may occur when there is disagreement between the treating team and the family, due to differently held beliefs and values. Though principles of harm draw some guidance around the role of parents in decision-making, many of these cases still fall within the broad ‘zone of parental discretion’(Gillam 2016, McDougall, Gillam et al. 2016). If we accept that parents have a significant role in decision-making and are ethically permitted to choose options for their child that are not (in our opinion) ideal, then a degree of moral distress is ‘inevitable’. This inevitability stems from differences in subjective beliefs and values and does not necessarily reflect an organisational failing as Epstein suggests(Epstein and Hurst 2017). The experience of moral distress in these situations – in accordance with standard definitions– can be traumatic and we do not mean to downplay this in any way. Yet as Dudinski notes “[m]oral intuitions should not be ignored, nor are they definitive. They must bear the weight of ethical scrutiny”(Dudzinski 2016). If we do not accept that moral distress can lead to constructive discussions, patient advocacy and a mechanism for progressive thought then we are left with moral distress acting as a vehicle for blame(Dudzinski 2016), often inferring that the clinical lead either is failing to listen to the concerns of others or lacks the moral courage to change the current management plan(Prentice 2017). Both of these may be unfair assumptions amidst the complex end-of-life considerations and decision-making dynamics. More worrisome is that the net effect may be to place undue pressure on the family to acquiesce to a particular treatment plan to resolve the net moral distress of the treating team – what we have elsewhere referred to as ‘moral transference’(Prentice, Gillam et al. 2017). The moral distress experienced by families is too often neglected in such conversations.
Moral distress is a burden, but it can also be something from which we can grow and learn, and our patients can benefit from. Should we not therefore be willing to accept some of its positive attributes along with all the bad? Is it fair for our patients’ families to bear the burden if we cannot?
Dudzinski, D. M. (2016). "Navigating moral distress using the moral distress map." Journal of Medical Ethics 42(5): 321-324.
Epstein, E. and A. Hurst (2017). "Looking at the Positive Side of Moral Distress: Why It's a Problem." Journal of Clinical Ethics 28(1): 37-41.
Gillam, L. (2016). "The zone of parental discretion: An ethical tool for dealing with disagreement between parents and doctors about medical treatment for a child." Clinical Ethics 11(1): 1-8.
McDougall, R., L. Gillam and H. Gold (2016). The zone of parental discretion. When Doctors and Parents Disagree. R. McDougall, C. Delany and L. Gillam, The Federation Press: 17.
Prentice, T. (2017). Accepting the Good with the Bad when Living with Moral Distress. AAP Section on Bioethics, American Academy of Pediatrics.
Prentice, T., A. Janvier, L. Gillam and P. G. Davis (2016). "Moral distress within neonatal and paediatric intensive care units: a systematic review." Archives of Disease in Childhood 101(8): 701-708.
Prentice, T. M., L. Gillam, P. G. Davis and A. Janvier (2017). "The use and misuse of moral distress in neonatology." Seminars in Fetal and Neonatal Medicine.
Answer to “SEDATION FOR NEONATAL INTUBATION IN THE DELIVERY ROOM”
Dear Editor
We were honoured to read the kind comment from Dr Subhash C Shaw (1) concerning our article « Nasal midazolam vs ketamine for neonatal intubation in the delivery room: a randomised trial” by Milési et al published in Arch Dis Child Fetal Neonatal Ed 2018; 103: F221-F226.1 » (2).
Dr Shaw rose several important questions:
He questions the possibility to keep a good respiratory drive with an anaesthetic procedure in delivery room. At the time of this study (2012) we were not using the INSURE procedure. For two years we are using the “Less Invasive Ventilation (LISA)” with a sedation protocol. Our protocol is proposing either intra-venous (IV) KETAMINE (0.5 mg/kg) or intra-nasal (IN) (0.2 mg/kg) MIDAZOLAM if an IV line is unavailable. Keeping a good respiratory drive is a key issue with this new technique. Therefore the anaesthetic issue is a very challenging one. Several authors show that it was possible to insure a good sedation level while keeping a good respiratory drive (3-5). In our experience with LISA and IN MIDAZOLAM (personal data) the success rate defined by the absence of intubation within the first 72 hours occurred in 7/10 of the cases, which was similar to the one described in the literature with or without any sedation (3-6).
There are still some controversies regarding MIDAZOLAM safety. This drug is widely used in Europe (7). The myoclonic movements are...
Answer to “SEDATION FOR NEONATAL INTUBATION IN THE DELIVERY ROOM”
Dear Editor
We were honoured to read the kind comment from Dr Subhash C Shaw (1) concerning our article « Nasal midazolam vs ketamine for neonatal intubation in the delivery room: a randomised trial” by Milési et al published in Arch Dis Child Fetal Neonatal Ed 2018; 103: F221-F226.1 » (2).
Dr Shaw rose several important questions:
He questions the possibility to keep a good respiratory drive with an anaesthetic procedure in delivery room. At the time of this study (2012) we were not using the INSURE procedure. For two years we are using the “Less Invasive Ventilation (LISA)” with a sedation protocol. Our protocol is proposing either intra-venous (IV) KETAMINE (0.5 mg/kg) or intra-nasal (IN) (0.2 mg/kg) MIDAZOLAM if an IV line is unavailable. Keeping a good respiratory drive is a key issue with this new technique. Therefore the anaesthetic issue is a very challenging one. Several authors show that it was possible to insure a good sedation level while keeping a good respiratory drive (3-5). In our experience with LISA and IN MIDAZOLAM (personal data) the success rate defined by the absence of intubation within the first 72 hours occurred in 7/10 of the cases, which was similar to the one described in the literature with or without any sedation (3-6).
There are still some controversies regarding MIDAZOLAM safety. This drug is widely used in Europe (7). The myoclonic movements are a well-known transient side effect of this drug. It could occur in 1 to 3% of cases. We didn’t notice this problem during the present study but we faced it only once on a 27-week-old boy. The myoclonic movements resolved spontaneously (8).
The studies suggesting that midazolam may increase the NICU length of stay were published in 1994 and 1999 (9). The ventilation and sedation practices have changed a lot. In our study the length of stay was not different among the two groups.
As a conclusion, we share Dr Subhah’s concerns. We are thinking that we need more data in order to assess the efficiency and security of IN MIDAZOLAM. Nevertheless as an alternative to IV anaesthetic drugs, it seems to be an elegant and easy way to insure some comfort for those neonates in this very uncomfortable situation even when a respiratory drive is required.
1 Subhash C Shaw, Arjun Kurup , Kannan Venkatnarayan sedation for neonatal intubation in the delivery room. Arch Dis Child Fetal Neonatal Ed. 2018 26 May
2 Milési C, Baleine J, Mura T et al. Nasal midazolam vs ketamine for neonatal intubation in the delivery room: a randomised trial. Arch Dis Child Fetal Neonatal Ed. 2018;103:F221-F226.
3 Dekker J, Lopriore E, Rijken M et al Sedation during Minimal Invasive Surfactant Therapy in Preterm Infants. Neonatology. 2016;109:308‑13.
4 Descamps CS, Chevallier M, Ego A et al. Propofol for sedation during less invasive surfactant administration in preterm infants. Arch Dis Child Fetal Neonatal Ed. 2017;102:F465
5 Bourgoin L, Caeymaex L, Decobert F et al. Administering atropine and ketamine before less invasive surfactant administration resulted in low pain scores in a prospective study of premature neonates. Acta Paediatr. 2018;107:1184-1190
6 Aldana-Aguirre JC, Pinto M, Featherstone RM, Kumar M. Less invasive surfactant administration versus intubation for surfactant delivery in preterm infants with respiratory distress syndrome: a systematic review and meta-analysis. Arch Dis Child Fetal Neonatal Ed. 2017 ;102:F17-F23.
7 Durrmeyer X, Daoud P, Decobert F, et al. Premedication for neonatal endotracheal intubation: results from the epidemiology of procedural pain in neonates study. Pediatr Crit Care Med 2013;14:e169–75.
8 Baleine J, Milési C, Mesnage R, et al. Intubation in the delivery room: experience with
nasal midazolam. Early Hum Dev 2014;90:39–43.
9 Ng E, Taddio A, Ohlsson A, et al. Intravenous midazolam infusion for sedation of infants in the neonatal intensive care unit. Cochrane Database Syst Rev 2017;1:CD002052.
Dear Editor,
We read with great interest the article “Nasal midazolam vs ketamine for neonatal intubation in the delivery room: a randomised trial” by Milési et al published in Arch Dis Child Fetal Neonatal Ed 2018; 103: F221-F226.1 We complement the authors for this well conducted randomized trial on a very important subject of sedation while neonatal intubation. Having gone through the article, we would like to add the following.
The intubations done were all non-emergent, with the mean gestational age being 27.6 (24-34) and 28.3 (24-36) weeks in both the groups respectively. It will be interesting to know what percentage of infants underwent Intubation, Surfactant administration, Extubation (INSURE)2 and placed back on nasal CPAP. As good respiratory drive is an essential prerequisite for nasal CPAP, there are concerns for sedation while attempting INSURE.
The other concern is about the safety of both the drugs used in neonatal particularly in preterm population. There are reports of paradoxical stimulation of central nervous system including myoclonic movements associated with administration of midazolam.3 There is also evidence to suggest midazolam administration leading to increased NICU stay and adverse neurological events.4 The oscillometric blood pressure measurement recorded intermittently as in this study might not capture continuous invasive blood pressure changes.
Finally, as the article very succinctly explained that the dosage of keta...
Dear Editor,
We read with great interest the article “Nasal midazolam vs ketamine for neonatal intubation in the delivery room: a randomised trial” by Milési et al published in Arch Dis Child Fetal Neonatal Ed 2018; 103: F221-F226.1 We complement the authors for this well conducted randomized trial on a very important subject of sedation while neonatal intubation. Having gone through the article, we would like to add the following.
The intubations done were all non-emergent, with the mean gestational age being 27.6 (24-34) and 28.3 (24-36) weeks in both the groups respectively. It will be interesting to know what percentage of infants underwent Intubation, Surfactant administration, Extubation (INSURE)2 and placed back on nasal CPAP. As good respiratory drive is an essential prerequisite for nasal CPAP, there are concerns for sedation while attempting INSURE.
The other concern is about the safety of both the drugs used in neonatal particularly in preterm population. There are reports of paradoxical stimulation of central nervous system including myoclonic movements associated with administration of midazolam.3 There is also evidence to suggest midazolam administration leading to increased NICU stay and adverse neurological events.4 The oscillometric blood pressure measurement recorded intermittently as in this study might not capture continuous invasive blood pressure changes.
Finally, as the article very succinctly explained that the dosage of ketamine used was in all probability inadequate to cause sedation, we feel that a larger trial should be conducted to establish the best pre-intubation medication in the delivery room, keeping both efficacy and safety in mind.
1. Milési C, Baleine J, Mura T, et al. Nasal midazolam vs ketamine for neonatal intubation in the delivery room: a randomised trial. Archives of Disease in Childhood - Fetal and Neonatal Edition 2018; 103: F221-F226.
2. Carlo Dani, Iuri Corsini, Giovanna Bertini, Giulia Fontanelli, Simone Pratesi & Firmino F. Rubaltelli (2010) The INSURE method in preterm infants of less than 30 weeks' gestation, The Journal of Maternal-Fetal & Neonatal Medicine, 23:9, 1024-1029, DOI: 10.3109/14767050903572174
3. Gupta MK, Mondkar JA, Hegde D. Paradoxical reaction to midazolam in preterm neonates: a case series. Indian J Crit Care Med 2018; 22: 300-2
4. Ng E, Taddio A, Ohlsson A. Intravenous midazolam infusion for sedation of infants in the neonatal intensive care unit. Cochrane Database of Systematic Reviews 2017, Issue 1. Art. No.: CD002052. DOI: 10.1002/14651858.CD002052.pub3.
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 thank Dr Hewson for his interest in our paper and for raising several intriguing points that challenges current practice about the use of oxygen during the very important first minutes of life of a sick preterm infant. There are several points we would like to clarify in response to his questions.
Firstly, in our study, only 12% (n=96) of preterm infants from the 8 studies reached the recommended SpO2 range (80-85%) and not the lower limit (80%) of this range, as stated by Dr Hewson. The majority of infants were either below (46%) or above (42%) this range at 5 minutes of age.
We agree that neither hyperoxia or hypoxia, even for a few short minutes, is in the best interest of any newborn infant. We concur with Dr Hewson that the current SpO2 recommendations are not evidence-based, especially for sick preterm infants and for either improved short or long-term outcomes. Currently, most clinical practice guidelines recommend the same SpO2 targets for both term and preterm infants (1) and do not take into account, differences in physiological needs. Indeed, Dawson et al showed that even healthy preterm infants needed several minutes more than term infants to achieve SpO2 >90% (2).
We therefore suggest that caution should be exercised before any specific SpO2 target can be recommended (e.g. 90-95% as suggested by Dr Hewson) without a sufficiently large study that is designed to assess both short and long-term outcomes. Clinical practice has swung dram...
Show MoreIt is a deleterious proposition to declare benefits to moral distress. In their recent response, Epstein and Hurst (2017) eloquently articulated many reasons for this. A better approach may be to invoke the work of Hans Selye (1974) and the parallels drawn by Rambur, Vallett, Cohen, and Tarule (2010) in advocating for the potential benefits of moral stress; not moral distress. The authors of the present article effectively revealed clinicians' general misunderstanding and misapplication of the concept of moral distress. Indeed, the authors acknowledged this explicitly: "This study demonstrates the importance of asking what clinical providers mean by 'moral distress' and/or what researchers mean when investigating this phenomenon" (p. F4). The authors' conclusions about frequency of moral distress and "inevitability" of moral distress are based on clinician self-report; not on a generally accepted definition of moral distress. Likewise, the authors do not use a validated, reliable tool to quantify moral distress (such as the Moral Distress Thermometer, Wocial & Weaver, 2013). Much qualitative research has been done that has clarified the concept of moral distress; it is not simply whatever the clinician says it is. As ethicist Denise Dudzinski (2016) stated, "clinicians benefit by distinguishing between distress and moral distress" and "without mapping the ethical dimensions of distress, clinicians are left...
Show MoreWe agree that conceptual clarity is of great value. Furthermore we acknowledge that some ‘distress’ experienced by our clinicians was not of a moral nature – such as the distress that results from tragic circumstances. We believe that in practice, distress and moral distress overlap. It can be difficult for clinicians to isolate the precise aetiology of their distress. We have furthermore acknowledged that these factors mean that the frequency of ‘moral distress’ may be overestimated in this study. However we are unclear why the ‘distress’ experienced by our clinicians is better labelled as ‘moral stress’. We maintain that conceptual clarity must be of clinical significance and be meaningful to those experiencing it. The clinicians participating were not uncomfortable with the idea that good things could arise from ‘distressing’ situations. It seems a disservice to the healthcare professionals in our study experiencing it to relabel it as ‘stress’ rather than ‘distress’ for the purpose of a less unsettling conclusion. We assume that Mr Hickox remains sceptical that moral distress, as strictly defined (that is, where a clinician feels anguish due to being constrained from acting in accordance with his/her moral judgement), may have some positive attributes. We will outline why we believe that in addition to decreasing moral distress and it’s negative consequences, we – and...
Show MoreAnswer to “SEDATION FOR NEONATAL INTUBATION IN THE DELIVERY ROOM”
Dear Editor
Show MoreWe were honoured to read the kind comment from Dr Subhash C Shaw (1) concerning our article « Nasal midazolam vs ketamine for neonatal intubation in the delivery room: a randomised trial” by Milési et al published in Arch Dis Child Fetal Neonatal Ed 2018; 103: F221-F226.1 » (2).
Dr Shaw rose several important questions:
He questions the possibility to keep a good respiratory drive with an anaesthetic procedure in delivery room. At the time of this study (2012) we were not using the INSURE procedure. For two years we are using the “Less Invasive Ventilation (LISA)” with a sedation protocol. Our protocol is proposing either intra-venous (IV) KETAMINE (0.5 mg/kg) or intra-nasal (IN) (0.2 mg/kg) MIDAZOLAM if an IV line is unavailable. Keeping a good respiratory drive is a key issue with this new technique. Therefore the anaesthetic issue is a very challenging one. Several authors show that it was possible to insure a good sedation level while keeping a good respiratory drive (3-5). In our experience with LISA and IN MIDAZOLAM (personal data) the success rate defined by the absence of intubation within the first 72 hours occurred in 7/10 of the cases, which was similar to the one described in the literature with or without any sedation (3-6).
There are still some controversies regarding MIDAZOLAM safety. This drug is widely used in Europe (7). The myoclonic movements are...
Dear Editor,
Show MoreWe read with great interest the article “Nasal midazolam vs ketamine for neonatal intubation in the delivery room: a randomised trial” by Milési et al published in Arch Dis Child Fetal Neonatal Ed 2018; 103: F221-F226.1 We complement the authors for this well conducted randomized trial on a very important subject of sedation while neonatal intubation. Having gone through the article, we would like to add the following.
The intubations done were all non-emergent, with the mean gestational age being 27.6 (24-34) and 28.3 (24-36) weeks in both the groups respectively. It will be interesting to know what percentage of infants underwent Intubation, Surfactant administration, Extubation (INSURE)2 and placed back on nasal CPAP. As good respiratory drive is an essential prerequisite for nasal CPAP, there are concerns for sedation while attempting INSURE.
The other concern is about the safety of both the drugs used in neonatal particularly in preterm population. There are reports of paradoxical stimulation of central nervous system including myoclonic movements associated with administration of midazolam.3 There is also evidence to suggest midazolam administration leading to increased NICU stay and adverse neurological events.4 The oscillometric blood pressure measurement recorded intermittently as in this study might not capture continuous invasive blood pressure changes.
Finally, as the article very succinctly explained that the dosage of keta...
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...
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