CPAP is the standard method of respiratory support in preterm neonates. BCPAP is the most widely used type of CPAP in low- and middle-income countries due to its simplicity of design, ease of use and low cost.[1] Efficacy of BCPAP has been compared against other pressure generating devices in many small RCTs and is the topic of interest amongst neonatologists. Latest systematic review involving 12 eligible studies including 1194 subjects shows a significant reduction of CPAP failure in BCPAP group [RR 0.75 ,95% CI (0.57-0.98)] without any significant impact on mortality, BPD and air leak.[2] However, we want to identify few issues with the review which if addressed, may shift the pooled treatment effect towards ‘null’.
First, authors have used the random-effects meta-analysis (REM) to calculate the pooled effect size. A fixed-effects meta-analysis assumes that all individual studies are trying to estimate a single true effect of the intervention and the pooled estimate is the ‘typical’ intervention effect.[3] However, the REM assumes that different studies are estimating different (but related) treatment effect which have a distribution (assumed to be a normal distribution). The pooled estimate obtained with REM is hence an ‘average’ intervention effect based on the assumption that intervention effects seen in all the individual studies are available for pooling. Therefore, before conducting a REM, publication bias needs to be excluded. If a publication bias exists,...
CPAP is the standard method of respiratory support in preterm neonates. BCPAP is the most widely used type of CPAP in low- and middle-income countries due to its simplicity of design, ease of use and low cost.[1] Efficacy of BCPAP has been compared against other pressure generating devices in many small RCTs and is the topic of interest amongst neonatologists. Latest systematic review involving 12 eligible studies including 1194 subjects shows a significant reduction of CPAP failure in BCPAP group [RR 0.75 ,95% CI (0.57-0.98)] without any significant impact on mortality, BPD and air leak.[2] However, we want to identify few issues with the review which if addressed, may shift the pooled treatment effect towards ‘null’.
First, authors have used the random-effects meta-analysis (REM) to calculate the pooled effect size. A fixed-effects meta-analysis assumes that all individual studies are trying to estimate a single true effect of the intervention and the pooled estimate is the ‘typical’ intervention effect.[3] However, the REM assumes that different studies are estimating different (but related) treatment effect which have a distribution (assumed to be a normal distribution). The pooled estimate obtained with REM is hence an ‘average’ intervention effect based on the assumption that intervention effects seen in all the individual studies are available for pooling. Therefore, before conducting a REM, publication bias needs to be excluded. If a publication bias exists, some studies in the distribution of treatment effects are missing and REM should not be done. This systematic review includes more than 10 studies, the conventionally accepted threshold for assessing the publication bias. Yet, this important step is missed. Given small size of ‘positive’ studies favoring BCPAP, one cannot exclude absence of ‘negative’ unpublished studies.
Second, authors define time-point for the ‘CPAP failure’ at 7 days of use. No consensus exists on what time-point constitutes the ideal cut-off for defining the failure and many studies report 72 h (or other time-points) as the cutoff. We are not sure whether authors were able to obtain the 7-day failure data from all the included studies. In our assessment of the studies, we were able to retrieve the 7-day outcome in only 4 of 12 studies.
Third, it is not clear which risk of bias assessment (ROB) tool has been used by the authors. While the text mentions the use of ROB-2 tool,[4] the risk of bias figures uses the original Cochrane ROB framework.[3]As criteria of the assessment of risk of bias are different in these tools, same domain in a study can be classified to be at high- or low-risk of bias with these two ROB tools. Use of both the tools in a single review may confuse the readers.
Fourth, nasal injury, one of the review outcomes is reported to be twice [RR 2.04(95% CI 1.33-3.14)] more common with BCPAP. The authors have attributed the higher risk of nasal injury to oscillatory effect of BCPAP. But we tend to disagree with this as there is neither sufficient evidence nor biological rationale behind this plausibility. Rather the incidence of nasal injury is highly dependent on the type of nasal interface used.[5] Different CPAP devices use different types of nasal interfaces and individual trials may not have ensured the use of identical interface.
Finally, authors have used meta-regression to investigate the effect of co-variates on the success of CPAP device. However, the choice of co-variates used in the meta-regression (country of origin, type of CPAP used in control arm and risk of bias) seems to be driven by availability bias. Type of nasal interface, starting CPAP pressure, actual measurement and matching of airway pressure in the BCPAP arm of the trial are more important and unaddressed confounding factors.
Contributors SK(supreetkhurana85@gmail.com) and DC contributed to all steps of making this letter.
Funding None.
Competing interest None Declared.
Patient Consent for publication Not required.
References
1. Thukral A, Sankar MJ, Chandrasekaran A, et al. Efficacy and safety of CPAP in low- and middle-income countries. J Perinatol 2016;36(1):S21-S28.
2. Bharadwaj SK, Alonazi A, Banfield L, et al. Bubble versus other continuous positive airway pressure forms: A systematic review and meta-analysis. Arch Dis Child Fetal Neonatal 2020;105:526-531.
3. Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 6.1 [updated September 2020].The Cochrane Collaboration, 2020. Available from training.cochrane.org/handbook/current.(accessed 20 Sep 2020)
4. Sterne JAC, Savovic J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ 2019; 366: l4898.
5. Imbulana DI, Manley BJ, Dawson JA, et al. Nasal injury in preterm infants receiving non-invasive respiratory support: a systematic review. Arch Dis Child Fetal Neonatal Ed 2018 Jan;103(1):F29-F35.
Hollebrandse et al are to be congratulated on achieving such a high follow-up rate at 8 years in a large cohort of preterm infants with intraventricular haemorrhage (IVH). Long-term outcomes related to specific cUS findings are increasingly important as many significant if more subtle neurodevelopmental problems are not detected at earlier follow-up.
It is reassuring that children with the milder grades of IVH had intellectual outcomes similar to the no-IVH group but of concern is the report of significant motor deficits and cerebral palsy (CP) following grades 1 and 2 IVH. However the outcomes given may not solely be related to IVH but to other pathologies notably cystic periventricular leukomalacia (cPVL) a well-known predictor of motor deficits and CP.[1,2] cPVL was found in 6% and 4% of the children with grades 1 and 2 IVH and 13% and 25% of those with grades 3 and 4 IVH. The authors neither adjust for this pathology, saying that “cPVL may lie along the causal pathway between IVH and adverse outcomes”, nor do they give evidence to support this statement. Indeed the contribution of cPVL to outcomes is not discussed or mentioned in the abstract. We are not aware of evidence that low grade IVH is in a causal pathway to cPVL, and suggested associations between cPVL and higher grades of IVH were based on studies using infrequent ultrasound protocols and without MRI scanning at term equivalent age. [3,4] We are aware of preterm infants who develop late-onset c-PVL no...
Hollebrandse et al are to be congratulated on achieving such a high follow-up rate at 8 years in a large cohort of preterm infants with intraventricular haemorrhage (IVH). Long-term outcomes related to specific cUS findings are increasingly important as many significant if more subtle neurodevelopmental problems are not detected at earlier follow-up.
It is reassuring that children with the milder grades of IVH had intellectual outcomes similar to the no-IVH group but of concern is the report of significant motor deficits and cerebral palsy (CP) following grades 1 and 2 IVH. However the outcomes given may not solely be related to IVH but to other pathologies notably cystic periventricular leukomalacia (cPVL) a well-known predictor of motor deficits and CP.[1,2] cPVL was found in 6% and 4% of the children with grades 1 and 2 IVH and 13% and 25% of those with grades 3 and 4 IVH. The authors neither adjust for this pathology, saying that “cPVL may lie along the causal pathway between IVH and adverse outcomes”, nor do they give evidence to support this statement. Indeed the contribution of cPVL to outcomes is not discussed or mentioned in the abstract. We are not aware of evidence that low grade IVH is in a causal pathway to cPVL, and suggested associations between cPVL and higher grades of IVH were based on studies using infrequent ultrasound protocols and without MRI scanning at term equivalent age. [3,4] We are aware of preterm infants who develop late-onset c-PVL not related to an initial low grade IVH but following (Gram-negative) sepsis or necrotising enterocolitis occurring later in the neonatal period.
Compared to several other studies, a high percentage of infants in this study developed CP (8% with no IVH, and 15, 18, 26 and 75% with grades 1-4 IVH). The higher levels of CP than generally expected for grades 1 and 2 IVH [5,6] may partly be explained by the presence of cPVL. Additionally there may have been non-cystic white matter injury e.g. punctate white matter lesions, cerebellar lesions or strokes that were not detected with the imaging protocol used. The statement "Our study adds to a growing understanding of the negative impact of low grade IVH on motor development" fails to adjust the findings for other lesion(s) known to lead to impaired motor development.
We also find the rates of CP in children with grades 3 and 4 IVH high. These may in part be related to care pathways chosen and the timing of treatment of post-haemorrhagic ventricular dilatation but no information is given about this.[7] One might expect about 50-60% of preterm infants with grade 4 IVH to develop a hemiplegia whilst here it is 75% perhaps influenced by the fact that 25% also had cPVL.
Another unexpected and worrying finding is that the severity of CP was the same in children with lower and higher grades of IVH. This could be due to the inclusion of infants with co-existing c-PVL or other lesions. It is unfortunate that no MRI findings are reported to substantiate the cUS findings particularly in infants with CP following low-grade IVH.
This paper may well be used by neonatologists to give prognoses following IVH in the first week after birth. We are concerned that these data will worry parents unnecessarily, especially those of infants with isolated low-grade IVH. Whilst it is fair to tell parents that other lesions may become apparent or develop we need to distinguish between outcomes due to findings seen at the time of scanning and those related to a potential pathology not yet seen and perhaps developing following unrelated clinical problems.
Yours sincerely
Frances Cowan, Floris Groenendaal and Linda S de Vries
Author affiliations:
Prof Frances M Cowan PhD FRCPCH
Dept. of Paediatrics
Hammersmith Hospital
Imperial College London
W12 0HS, UK
Email f.cowan@imperial.ac.uk
Dr Floris Groenendaal MD PhD and Prof Linda S de Vries MD PhD
Wilhelmina Children’s Hospital,
University Medical Centre Utrecht,
KE 04.123.1, PO Box 85090,
3508 AB Utrecht, Netherlands
References
1. Martinez-Biarge M, Groenendaal F, Kersbergen KJ, Benders MJNL, Foti F, van Haastert IC, Cowan FM, de Vries LS. Neurodevelopmental Outcomes in Preterm Infants with White Matter Injury Using a New MRI Classification. Neonatology. 2019;116(3):227-235
2. van Haastert IC, Groenendaal F, Uiterwaal CS, Termote JU, van der Heide-Jalving M, Eijsermans MJ, Gorter JW, Helders PJ, Jongmans MJ, de Vries LS. Decreasing incidence and severity of cerebral palsy in prematurely born children. J Pediatr. 2011 Jul;159(1):86-91.e1
3. Kusters CDJ, Chen ML, Follett PL Dammann O. "Intraventricular" hemorrhage and cystic periventricular leukomalacia in preterm infants: How are they related? J Child Neurol 2009; 24:1158-1170.
4. Kuban K, Sanocka U, Leviton A, Allred EN, Pagano M, Dammann O, et al. White matter disorders of prematurity: association with intraventricular hemorrhage and ventriculomegaly. J Pediatr 1999; 134:539-546.
5. Payne AH, Hintz SR, Hibbs AM, Walsh MC, Vohr BR, Bann CM, Wilson-Costello DE; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network: Neurodevelopmental outcomes of extremely low-gestational age neonates with low-grade periventricular intraventricular hemorrhage. JAMA Pediatr 2013;167:451–459.
6. Reubsaet P, Brouwer AJ, van Haastert IC, Brouwer MJ, Koopman C, Groenendaal F, de Vries LS. The Impact of Low-Grade Germinal Matrix-Intraventricular Hemorrhage on Neurodevelopmental Outcome of Very Preterm Infants. Neonatology 2017;112(3):203-210.
7. Leijser LM, Miller SP, van Wezel-Meijler G, Brouwer AJ, Traubici J, van Haastert IC, Whyte HE, Groenendaal F, Kulkarni AV, Han KS, Woerdeman PA, Church PT, Kelly EN, van Straaten HLM, Ly LG, de Vries LS. Posthemorrhagic ventricular dilatation in preterm infants: When best to intervene? Neurology. 2018;90(8):e698-e706
Footnotes
• Contributors: FMC, FD and LdeV contributed equally to the letter
• Funding: The authors have not declared a specific funding agency in the public, commercial or not-for-profit sectors.
• Competing interests: None declared.
• Provenance and peer review: Not commissioned.
• Patient consent for publication: Not required.
CMV exposure of breast milk fed infants from seropositive mothers is a well known phenomenon. Patel et al. excellent research has shed a very important and troubling consequence of this infection on very low birth premature babies. Yet, some of the information needed for decision making and recommendations is lacking from the published data. From the data we see that 17% (76 of 457 infants) of seropositive mothers decided not to give there babies any breast milk in contrast to 0% ! of seronegative mothers. I think that in order to make a proper decision we need to compare the incidence of Necrotizing Enterocolitis and other complications of prematurity between this group of exclusively formula fed babies and CMV infected babies. Although the numbers may not be sufficient for statistical analysis we might benefit as caregivers from this important information.
Dear Editor,
We read with great interest the systematic review and meta-analysis by Kariholu et al on the evaluation of therapeutic hypothermia as a tool to decrease composite outcome like death, moderate or severe disability at 18 months or more after mild neonatal encephalopathy (NE). [1]. The authors, including 5 randomized controlled trials (RCTs) reporting the considered outcome, found insufficient evidence to recommend routine therapeutic hypothermia for NE [1]. We agree with this statement and we’d like to support it evaluating the fragility index of the RCTs included in this meta-analysis.
The fragility index (FI), an intuitive measure of the robustness of RCTs, was introduced in critical care medicine [2]. The studies with larger FI have more robust findings compared with the studies with poor FI [2]. Recently the FI was applied to different meta-analyses in order to confirm or not the results by including in the analysis the studies with FI greater than zero [3, 4, 5]. We evaluated the FI of the RCTs included in this meta-analysis using a two-by-two contingency table and p-value produced by Fisher exact test [2]. In line with the high risk of bias of the included RCTs, we found no studies with FI more than zero for death or moderate/severe disability (Battin FI=0 p= 0,455, Gluckman FI=0 p=1, Jacobs FI=0 p= 0,729, Thayyil FI=0 p=0.350, Zhou FI=0 p=1) [1].
Since all the included studies are fragile, we strongly support the author’s conclusion that...
Dear Editor,
We read with great interest the systematic review and meta-analysis by Kariholu et al on the evaluation of therapeutic hypothermia as a tool to decrease composite outcome like death, moderate or severe disability at 18 months or more after mild neonatal encephalopathy (NE). [1]. The authors, including 5 randomized controlled trials (RCTs) reporting the considered outcome, found insufficient evidence to recommend routine therapeutic hypothermia for NE [1]. We agree with this statement and we’d like to support it evaluating the fragility index of the RCTs included in this meta-analysis.
The fragility index (FI), an intuitive measure of the robustness of RCTs, was introduced in critical care medicine [2]. The studies with larger FI have more robust findings compared with the studies with poor FI [2]. Recently the FI was applied to different meta-analyses in order to confirm or not the results by including in the analysis the studies with FI greater than zero [3, 4, 5]. We evaluated the FI of the RCTs included in this meta-analysis using a two-by-two contingency table and p-value produced by Fisher exact test [2]. In line with the high risk of bias of the included RCTs, we found no studies with FI more than zero for death or moderate/severe disability (Battin FI=0 p= 0,455, Gluckman FI=0 p=1, Jacobs FI=0 p= 0,729, Thayyil FI=0 p=0.350, Zhou FI=0 p=1) [1].
Since all the included studies are fragile, we strongly support the author’s conclusion that found insufficient evidence supporting the routine use of therapeutic hypothermia in NE. According to our results, we need high quality and stronger RCTs to improve the knowledge on an important topic.
References
1. Kariholu U, Montaldo P, Markati T, et al. Therapeutic hypothermia for mild neonatal encephalopathy: a systematic review and meta-analysis. Archives of Disease in Childhood - Fetal and Neonatal Edition 2020;105:225-228
2. Ridgeon EE, Young PJ, Bellomo R, et al. The Fragility Index in multicenter randomized controlled critical care trials. Crit Care Med 2016;44:1278–1284
3. Vargas M, Servillo G. The End of Corticosteroid in Sepsis: Fragile Results From Fragile Trials. Crit Care Med 2018 46:e1228
4. Vargas M, Servillo G. Liberal versus conservative oxygen therapy in critically ill patients: using the fragility index to determine robust results. Crit Care 2019;23:132
5. Vargas M, Buononanno P, Marra A et al. Fragility Index in Multicenter Randomized Controlled Trials in Critical Care Medicine That Have Shown Reduced Mortality. Crit Care Med. 2020;48:e250-e251
All of these extubation-readyness tests assess respiratory drive / lungs. However, it may be for many preterms that they struggle to maintain their airway despite good drive and lungs that are relatively healthy. This aspect can't be tested and could explain why so many infants who seem able to breath don't do so once the ETT has been taken out.
We thank Floris Gronendal et al. for their views on our sedation survey and highlighting their personal opinion about mandatory sedation during therapeutic hypothermia. They quote two seminal preliminary studies on preterm infants by Anand recruiting 16 and 30 babies each, but not the later definitive Neopain trial on 898 babies, that showed increased adverse outcome (death, intraventricular bleed, periventricular leukomalacia) with morphine, to support their views(1).
Our survey was intended to examine the current practice of pre-emptive opioid sedation during therapeutic hypothermia in ventilated and non-ventilated infants (2). We have only highlighted the variation of sedation practices during therapeutic hypothermia and potentially toxic morphine doses used by some neonatal units in the UK and we have not made any recommendation about using or not routine sedation during therapeutic hypothermia. Such recommendations can only be based on scientific evidence, not on surveys or personal views, and this unfortunately is lacking. Clearly hypothermia in children and adults do require heavy sedation, but we do not feel that these data can be directly extrapolated to newborn infants.
Preclinical studies on sedation during therapeutic hypothermia are conflicting. Thoresen et al. showed no reduction in neuropathology scores in a piglet model for hypoxic injury without general anaesthesia that were cooled for 24 hours compared with those that were not cooled(3),...
We thank Floris Gronendal et al. for their views on our sedation survey and highlighting their personal opinion about mandatory sedation during therapeutic hypothermia. They quote two seminal preliminary studies on preterm infants by Anand recruiting 16 and 30 babies each, but not the later definitive Neopain trial on 898 babies, that showed increased adverse outcome (death, intraventricular bleed, periventricular leukomalacia) with morphine, to support their views(1).
Our survey was intended to examine the current practice of pre-emptive opioid sedation during therapeutic hypothermia in ventilated and non-ventilated infants (2). We have only highlighted the variation of sedation practices during therapeutic hypothermia and potentially toxic morphine doses used by some neonatal units in the UK and we have not made any recommendation about using or not routine sedation during therapeutic hypothermia. Such recommendations can only be based on scientific evidence, not on surveys or personal views, and this unfortunately is lacking. Clearly hypothermia in children and adults do require heavy sedation, but we do not feel that these data can be directly extrapolated to newborn infants.
Preclinical studies on sedation during therapeutic hypothermia are conflicting. Thoresen et al. showed no reduction in neuropathology scores in a piglet model for hypoxic injury without general anaesthesia that were cooled for 24 hours compared with those that were not cooled(3), and speculated that this was due to lack of sedation. On the other hand, Gunn et al. demonstrated significant improvement in neuropathology scores in fetal lambs cooled for 72 hours without sedation compared with those that were not(4).
Secondary analysis from the National Institute of Child Health and Human Development (NICHD) (5)and Magnetic Resonance Biomarkers in Neonatal Encephalopathy (MARBLE) (6)studies examined the effect of sedation in term infants during therapeutic hypothermia. Routine sedation was not associated with neuroprotection, but increased the hospital stay.
There are many difficulties in quantifying pain in neonates undergoing therapeutic hypothermia. Often shivering is equated to stress, which may only indicate depletion of brown fat(7). Clinicians tend to use sedation to stop shivering, although the evidence to support this practice is unclear(8). We are only suggesting that the jury is still out on pre-emptive opioid sedation during therapeutic hypothermia, and at present, it is unclear whether this practice beneficial or harmful. This issue can be answered only by developing better markers for quantifying stress in infants with encephalopathy and rigorously evaluating the safety and efficacy of opioid therapy during therapeutic hypothermia in clinical trials.
References
1. Anand KJ, Hall RW, Desai N, et al. Effects of morphine analgesia in ventilated preterm neonates: primary outcomes from the NEOPAIN randomised trial. Lancet (London, England) 2004; 363(9422): 1673-82.
2. Montaldo P, Vakharia A, Ivain P, et al. Pre-emptive opioid sedation during therapeutic hypothermia. Archives of disease in childhood Fetal and neonatal edition 2020; 105(1): 108-9.
3. Thoresen M, Satas S, Loberg EM, et al. Twenty-four hours of mild hypothermia in unsedated newborn pigs starting after a severe global hypoxic-ischemic insult is not neuroprotective. Pediatric research 2001; 50(3): 405-11.
4. Gunn AJ, Gunn TR, de Haan HH, Williams CE, Gluckman PD. Dramatic neuronal rescue with prolonged selective head cooling after ischemia in fetal lambs. The Journal of clinical investigation 1997; 99(2): 248-56.
5. Natarajan G, Shankaran S, Laptook AR, et al. Association between sedation-analgesia and neurodevelopment outcomes in neonatal hypoxic-ischemic encephalopathy. Journal of perinatology : official journal of the California Perinatal Association 2018; 38(8): 1060-7.
6. Liow N, Montaldo P, Lally PJ, et al. Preemptive Morphine During Therapeutic Hypothermia After Neonatal Encephalopathy: A Secondary Analysis. Therapeutic hypothermia and temperature management 2019.
7. Hu HH, Wu TW, Yin L, et al. MRI detection of brown adipose tissue with low fat content in newborns with hypothermia. Magnetic resonance imaging 2014; 32(2): 107-17.
8. Pitoni S, Sinclair HL, Andrews PJ. Aspects of thermoregulation physiology. Current opinion in critical care 2011; 17(2): 115-21.
Sir,
In their paper Montaldo et al. suggest that routine use of morphine in infants with perinatal asphyxia and therapeutic hypothermia (TH) is not useful and potentially harmful (Arch Dis Child Fetal Neonatal Ed. 2020:108-09). They rightfully suggest that morphine may accumulate during TH. However, in a recent study using multicentre data we have proposed novel dosing schedules for morphine and midazolam during TH thereby avoiding the risk of drug accumulation1.
Montaldo et al. state that “… it is unclear if morphine suppresses the nociceptive cortical activity in babies…” referring to a study of oral morphine for acute procedural pain in preterm infants.
Only since the late 1980s opioids are used during neonatal surgery following two classical papers by Anand showing that pre-emptive opioid analgesia following cardiac surgery in human infants dramatically decreased mortality and morbidity rates by suppressing pain and stress2 3.
As written by Montaldo et al. the right of universal pain relief is undisputed, also in human infants, and it is generally accepted through many animal experiments that TH is stressful. Furthermore, sedation and analgesia during TH after cardiac arrest in adults is well tolerated and effective4.
Therefore we are very reluctant to remove the mandatory use of sedatives including morphine from our international Dutch and Flemish guideline of TH, and we would like to stimulate others to use analgesia, while avoiding the...
Sir,
In their paper Montaldo et al. suggest that routine use of morphine in infants with perinatal asphyxia and therapeutic hypothermia (TH) is not useful and potentially harmful (Arch Dis Child Fetal Neonatal Ed. 2020:108-09). They rightfully suggest that morphine may accumulate during TH. However, in a recent study using multicentre data we have proposed novel dosing schedules for morphine and midazolam during TH thereby avoiding the risk of drug accumulation1.
Montaldo et al. state that “… it is unclear if morphine suppresses the nociceptive cortical activity in babies…” referring to a study of oral morphine for acute procedural pain in preterm infants.
Only since the late 1980s opioids are used during neonatal surgery following two classical papers by Anand showing that pre-emptive opioid analgesia following cardiac surgery in human infants dramatically decreased mortality and morbidity rates by suppressing pain and stress2 3.
As written by Montaldo et al. the right of universal pain relief is undisputed, also in human infants, and it is generally accepted through many animal experiments that TH is stressful. Furthermore, sedation and analgesia during TH after cardiac arrest in adults is well tolerated and effective4.
Therefore we are very reluctant to remove the mandatory use of sedatives including morphine from our international Dutch and Flemish guideline of TH, and we would like to stimulate others to use analgesia, while avoiding the risk of drug accumulation by using novel dosing recommendations.
References
1. Favie LMA, Groenendaal F, van den Broek MPH, et al. Pharmacokinetics of morphine in encephalopathic neonates treated with therapeutic hypothermia. PLoS One 2019;14(2):e0211910.
2. Anand KJ, Sippell WG, Aynsley-Green A. Randomised trial of fentanyl anaesthesia in preterm babies undergoing surgery: effects on the stress response. Lancet 1987;1(8527):243-8.
3. Anand KJ, Hickey PR. Halothane-morphine compared with high-dose sufentanil for anesthesia and postoperative analgesia in neonatal cardiac surgery. N Engl J Med 1992;326(1):1-9.
4. May TL, Seder DB, Fraser GL, et al. Moderate-dose sedation and analgesia during targeted temperature management after cardiac arrest. Neurocrit Care 2015;22(1):105-11.
Floris Groenendaal and Richard van Lingen, 7 January 2020
In their follow-up analysis of the PREMILOC trial, Baud et al.[1] found significantly better neurodevelopmental outcomes at 22 months postmenstrual age in those extreme preterm neonates of 24 and 25 weeks of gestation who had been treated with early hydrocortisone during the first ten days after birth. Improvements in global neurological assessments were most pronounced for moderate to severe neurodevelopmental impairment, with a prevalence of 2.1% in the hydrocortisone and 18.4% in the placebo group. In this context it has to be remembered that early hydrocortisone treatment had been associated with a significant increase in the late-onset sepsis rate before discharge for those most immature neonates of 24 and 25 weeks of gestation.[2]
In their meta-analysis including seventeen observational studies, Alshaikh et al.[3] described “an increased risk of one or more long-term neurodevelopmental impairments … including cerebral palsy” in very-low-birth-weight infants who had suffered from culture-proven sepsis during the neonatal period. A follow-up analysis of extreme preterm neonates below 32 weeks of gestation found a significantly higher frequency of cerebral palsy at five years of age in those who had developed early- and/or late-onset sepsis.[4] Correspondingly, a positive association of Coagulase-negative staphylococcus sepsis and the risk of cognitive delay at a corrected age between 30 and 42 months has been reported in preterm neonates below 29 weeks of gestati...
In their follow-up analysis of the PREMILOC trial, Baud et al.[1] found significantly better neurodevelopmental outcomes at 22 months postmenstrual age in those extreme preterm neonates of 24 and 25 weeks of gestation who had been treated with early hydrocortisone during the first ten days after birth. Improvements in global neurological assessments were most pronounced for moderate to severe neurodevelopmental impairment, with a prevalence of 2.1% in the hydrocortisone and 18.4% in the placebo group. In this context it has to be remembered that early hydrocortisone treatment had been associated with a significant increase in the late-onset sepsis rate before discharge for those most immature neonates of 24 and 25 weeks of gestation.[2]
In their meta-analysis including seventeen observational studies, Alshaikh et al.[3] described “an increased risk of one or more long-term neurodevelopmental impairments … including cerebral palsy” in very-low-birth-weight infants who had suffered from culture-proven sepsis during the neonatal period. A follow-up analysis of extreme preterm neonates below 32 weeks of gestation found a significantly higher frequency of cerebral palsy at five years of age in those who had developed early- and/or late-onset sepsis.[4] Correspondingly, a positive association of Coagulase-negative staphylococcus sepsis and the risk of cognitive delay at a corrected age between 30 and 42 months has been reported in preterm neonates below 29 weeks of gestation.[5]
Undoubtedly, neurological development is a multi-factorial process with a multitude of influencing factors. The above described clear association between neonatal sepsis and neurological sequelae from previous studies is not only contrary to the results by Baud et al.[1], but further emphasizes the significance of their findings from the PREMILOC trial. As the authors had not discussed this relevant issue in their publications,[1] we would like to point that out.
REFERENCES
1. Baud O, Trousson C, Biran V, et al. Two-year neurodevelopmental outcomes of extremely preterm infants treated with early hydrocortisone: treatment effect according to gestational age at birth. Arch Dis Child Fetal Neonatal Ed 2019;104(1):F30–5. doi: 10.1136/archdischild-2017-313756.
2. Baud O, Maury L, Lebail F, et al. Effect of early low-dose hydrocortisone on survival without bronchopulmonary dysplasia in extremely preterm infants (PREMILOC): a double-blind, placebo-controlled, multicentre, randomised trial. Lancet 2016;387(10030):1827–36. doi: 10.1016/S0140-6736(16)00202-6.
3. Alshaikh B, Yusuf K, Sauve R. Neurodevelopmental outcomes of very low birth weight infants with neonatal sepsis: systematic review and meta-analysis. J Perinatol 2013;33:558–64. doi: 10.1038/jp.2012.167.
4. Mitha A, Foix-L'Hélias L, Arnaud C, et al. Neonatal infection and 5-year neurodevelopmental outcome of very preterm infants. Pediatrics 2013;132:e372–80. doi: 10.1542/peds.2012-3979.
5. Alshaikh B, Yee W, Lodha A, et al. Coagulase-negative staphylococcus sepsis in preterm infants and long-term neurodevelopmental outcome. J Perinatol 2014;34:125–9. doi: 10.1038/jp.2013.155.
Dear Editor
We read with interest the letter by Sur et al in response to our article (1). It was very reassuring to note that our findings were replicated in their study confirming the potential scale of antibiotic reduction while identifying all ‘blood culture positive’ sepsis. We did not collect data on CRP in our study. The evidence does not support a single CRP measurement as a reliable tool to help decisions to initiate treatment in the context of early onset neonatal sepsis (EOS), particularly in asymptomatic infants[2]. Consistent normal values over first 48 hours are associated with absence of EOS; but abnormal values in an asymptomatic infant are unreliable to predict culture proven sepsis [2-5]. CRP concentrations increase in neonates in response to a number of non-infective inflammatory conditions such as asphyxia, meconium aspiration, tissue trauma and pneumothorax. Serial CRP trend is irrelevant in treatment initiation decisions, and in low incidence conditions such as EOS, its value in predicting true culture positive EOS is below that is expected of a good and reliable test (Likelihood ratio 3.0)[4,6). The American Academy of Paediatrics states that diagnosis of EOS cannot be made using CRP in the absence of positive blood or CSF culture [2]. For asymptomatic low / moderate risk infants (currently treated with presumptive antibiotics), a period of observation / serial physical examination may be used instead of invasive tests to identify at an early...
Dear Editor
We read with interest the letter by Sur et al in response to our article (1). It was very reassuring to note that our findings were replicated in their study confirming the potential scale of antibiotic reduction while identifying all ‘blood culture positive’ sepsis. We did not collect data on CRP in our study. The evidence does not support a single CRP measurement as a reliable tool to help decisions to initiate treatment in the context of early onset neonatal sepsis (EOS), particularly in asymptomatic infants[2]. Consistent normal values over first 48 hours are associated with absence of EOS; but abnormal values in an asymptomatic infant are unreliable to predict culture proven sepsis [2-5]. CRP concentrations increase in neonates in response to a number of non-infective inflammatory conditions such as asphyxia, meconium aspiration, tissue trauma and pneumothorax. Serial CRP trend is irrelevant in treatment initiation decisions, and in low incidence conditions such as EOS, its value in predicting true culture positive EOS is below that is expected of a good and reliable test (Likelihood ratio 3.0)[4,6). The American Academy of Paediatrics states that diagnosis of EOS cannot be made using CRP in the absence of positive blood or CSF culture [2]. For asymptomatic low / moderate risk infants (currently treated with presumptive antibiotics), a period of observation / serial physical examination may be used instead of invasive tests to identify at an early stage the very few who develop sepsis(7, 8).
References:
1. Goel N, Shrestha S, Smith R, et al. Screening for early onset neonatal sepsis: NICE guidance-based practice versus projected application of the Kaiser Permanente sepsis risk calculator in the UK population. Arch Dis Child Fetal Neonatal Ed. 2019 Online First Jul 11. DOI: 10.1136/archdischild-2018-316777.
2. Puopolo KM, Benitz WE, Zaoutis TE. AAP Committee on Fetus and Newborn, AAP Committee on Infectious Diseases. Management of Neonates Born at ≥35 0/7 Weeks’ Gestation with Suspected or Proven Early-Onset Bacterial Sepsis. Pediatrics. 2018;142(6):e20182894
3. Mukhopadhyay S, Puopolo KM. Risk assessment in neonatal early onset sepsis. Semin Perinatol. 2012 Dec; 36(6):408-15.
4. Benitz W.E., Han M.Y., Madan A., et al: Serial serum C-reactive protein levels in the diagnosis of neonatal infection. Pediatrics 1998; 102: E41.
5. Benitz WE. Adjunct laboratory tests in the diagnosis of early-onset neonatal sepsis. Clin Perinatol. 2010;37: 421–438.
6. Neonatal infection (early onset): antibiotics for prevention and treatment. Clinical guideline [CG149]. Published August 2012.https://www.nice.org.uk/guidance/cg149/evidence/full-guideline-pdf-18817....
7. Kuzniewicz MW, Puopolo KM, Fischer A, Walsh EM, Li S, Newman TB, et al. A Quantitative, Risk-Based Approach to the Management of Neonatal Early-Onset Sepsis. JAMA Pediatr.2017 Apr 1;171(4):365-371.
8. Berardi A, Tzialla C, Travan L et al. Secondary prevention of early-onset sepsis: a less invasive Italian approach for managing neonates at risk. Ital J Pediatr. 2018; 44: 73
We were impressed by the conduct and results of Reynolds et al.’s randomised controlled cross-over trial comparing Vapotherm’s IntellO2 device with manual control of inspired oxygen, showing improvement in the proportion of time spent within the target oxygen saturation range (automated arm mean 80% of time in 90-95% range vs. manual 49%). The findings are consistent with a meta-analysis referenced within their paper [1].
The Neonatal Oxygenation Prospective Meta-analysis (NeOProM) shows that targeting oxygen saturations of 91–95% with an oximeter with a correctly configured algorithm, carries a 38% survival advantage [2]. The co-ordinator of the NeOProM collaboration has stated that the “Infants born extremely preterm … should have their oxygen saturation levels targeted between 91% and 95%” [3].
The difference between the saturation targeting approach adopted by Reynolds et al., and NeOProM may appear small but, on account of the sigmoidal shape of the haemoglobin–oxygen dissociation curve, significant hypoxic shifts will occur with small changes in oxygen saturation.
Given the rigor of the NeOProM findings, would Reynolds et al. agree that targeting oxygen saturations of 91-95% is an important first step, whilst we wait for products which will allow improved titration of oxygen delivery?
References:
[1] Mitra S, Singh B, El-Naggar W, McMillan DD. Automated versus manual control of inspired oxygen to target oxygen saturation in prete...
We were impressed by the conduct and results of Reynolds et al.’s randomised controlled cross-over trial comparing Vapotherm’s IntellO2 device with manual control of inspired oxygen, showing improvement in the proportion of time spent within the target oxygen saturation range (automated arm mean 80% of time in 90-95% range vs. manual 49%). The findings are consistent with a meta-analysis referenced within their paper [1].
The Neonatal Oxygenation Prospective Meta-analysis (NeOProM) shows that targeting oxygen saturations of 91–95% with an oximeter with a correctly configured algorithm, carries a 38% survival advantage [2]. The co-ordinator of the NeOProM collaboration has stated that the “Infants born extremely preterm … should have their oxygen saturation levels targeted between 91% and 95%” [3].
The difference between the saturation targeting approach adopted by Reynolds et al., and NeOProM may appear small but, on account of the sigmoidal shape of the haemoglobin–oxygen dissociation curve, significant hypoxic shifts will occur with small changes in oxygen saturation.
Given the rigor of the NeOProM findings, would Reynolds et al. agree that targeting oxygen saturations of 91-95% is an important first step, whilst we wait for products which will allow improved titration of oxygen delivery?
References:
[1] Mitra S, Singh B, El-Naggar W, McMillan DD. Automated versus manual control of inspired oxygen to target oxygen saturation in preterm infants: a systematic review and meta-analysis. Journal of Perinatology. 2018; 38, 351–360 doi:10.1038/s41372-017-0037-z
[2] Askie LM, Darlow BA, Finer N, et al. Association Between Oxygen Saturation Targeting and Death or Disability in Extremely Preterm Infants in the Neonatal Oxygenation Prospective Meta-Analysis Collaboration [published correction appears in JAMA. 2018 Jul 17;320(3):308]. JAMA. 2018;319(21):2190–2201. doi:10.1001/jama.2018.5725
[3] Askie LM., Meta-analysis of Oxygenation Saturation Targeting Trials Do Infant Subgroups Matter? Clin Perinatol 2019 doi.org/10.1016/j.clp.2019.05.003
CPAP is the standard method of respiratory support in preterm neonates. BCPAP is the most widely used type of CPAP in low- and middle-income countries due to its simplicity of design, ease of use and low cost.[1] Efficacy of BCPAP has been compared against other pressure generating devices in many small RCTs and is the topic of interest amongst neonatologists. Latest systematic review involving 12 eligible studies including 1194 subjects shows a significant reduction of CPAP failure in BCPAP group [RR 0.75 ,95% CI (0.57-0.98)] without any significant impact on mortality, BPD and air leak.[2] However, we want to identify few issues with the review which if addressed, may shift the pooled treatment effect towards ‘null’.
Show MoreFirst, authors have used the random-effects meta-analysis (REM) to calculate the pooled effect size. A fixed-effects meta-analysis assumes that all individual studies are trying to estimate a single true effect of the intervention and the pooled estimate is the ‘typical’ intervention effect.[3] However, the REM assumes that different studies are estimating different (but related) treatment effect which have a distribution (assumed to be a normal distribution). The pooled estimate obtained with REM is hence an ‘average’ intervention effect based on the assumption that intervention effects seen in all the individual studies are available for pooling. Therefore, before conducting a REM, publication bias needs to be excluded. If a publication bias exists,...
Hollebrandse et al are to be congratulated on achieving such a high follow-up rate at 8 years in a large cohort of preterm infants with intraventricular haemorrhage (IVH). Long-term outcomes related to specific cUS findings are increasingly important as many significant if more subtle neurodevelopmental problems are not detected at earlier follow-up.
It is reassuring that children with the milder grades of IVH had intellectual outcomes similar to the no-IVH group but of concern is the report of significant motor deficits and cerebral palsy (CP) following grades 1 and 2 IVH. However the outcomes given may not solely be related to IVH but to other pathologies notably cystic periventricular leukomalacia (cPVL) a well-known predictor of motor deficits and CP.[1,2] cPVL was found in 6% and 4% of the children with grades 1 and 2 IVH and 13% and 25% of those with grades 3 and 4 IVH. The authors neither adjust for this pathology, saying that “cPVL may lie along the causal pathway between IVH and adverse outcomes”, nor do they give evidence to support this statement. Indeed the contribution of cPVL to outcomes is not discussed or mentioned in the abstract. We are not aware of evidence that low grade IVH is in a causal pathway to cPVL, and suggested associations between cPVL and higher grades of IVH were based on studies using infrequent ultrasound protocols and without MRI scanning at term equivalent age. [3,4] We are aware of preterm infants who develop late-onset c-PVL no...
Show MoreCMV exposure of breast milk fed infants from seropositive mothers is a well known phenomenon. Patel et al. excellent research has shed a very important and troubling consequence of this infection on very low birth premature babies. Yet, some of the information needed for decision making and recommendations is lacking from the published data. From the data we see that 17% (76 of 457 infants) of seropositive mothers decided not to give there babies any breast milk in contrast to 0% ! of seronegative mothers. I think that in order to make a proper decision we need to compare the incidence of Necrotizing Enterocolitis and other complications of prematurity between this group of exclusively formula fed babies and CMV infected babies. Although the numbers may not be sufficient for statistical analysis we might benefit as caregivers from this important information.
Dear Editor,
Show MoreWe read with great interest the systematic review and meta-analysis by Kariholu et al on the evaluation of therapeutic hypothermia as a tool to decrease composite outcome like death, moderate or severe disability at 18 months or more after mild neonatal encephalopathy (NE). [1]. The authors, including 5 randomized controlled trials (RCTs) reporting the considered outcome, found insufficient evidence to recommend routine therapeutic hypothermia for NE [1]. We agree with this statement and we’d like to support it evaluating the fragility index of the RCTs included in this meta-analysis.
The fragility index (FI), an intuitive measure of the robustness of RCTs, was introduced in critical care medicine [2]. The studies with larger FI have more robust findings compared with the studies with poor FI [2]. Recently the FI was applied to different meta-analyses in order to confirm or not the results by including in the analysis the studies with FI greater than zero [3, 4, 5]. We evaluated the FI of the RCTs included in this meta-analysis using a two-by-two contingency table and p-value produced by Fisher exact test [2]. In line with the high risk of bias of the included RCTs, we found no studies with FI more than zero for death or moderate/severe disability (Battin FI=0 p= 0,455, Gluckman FI=0 p=1, Jacobs FI=0 p= 0,729, Thayyil FI=0 p=0.350, Zhou FI=0 p=1) [1].
Since all the included studies are fragile, we strongly support the author’s conclusion that...
All of these extubation-readyness tests assess respiratory drive / lungs. However, it may be for many preterms that they struggle to maintain their airway despite good drive and lungs that are relatively healthy. This aspect can't be tested and could explain why so many infants who seem able to breath don't do so once the ETT has been taken out.
We thank Floris Gronendal et al. for their views on our sedation survey and highlighting their personal opinion about mandatory sedation during therapeutic hypothermia. They quote two seminal preliminary studies on preterm infants by Anand recruiting 16 and 30 babies each, but not the later definitive Neopain trial on 898 babies, that showed increased adverse outcome (death, intraventricular bleed, periventricular leukomalacia) with morphine, to support their views(1).
Our survey was intended to examine the current practice of pre-emptive opioid sedation during therapeutic hypothermia in ventilated and non-ventilated infants (2). We have only highlighted the variation of sedation practices during therapeutic hypothermia and potentially toxic morphine doses used by some neonatal units in the UK and we have not made any recommendation about using or not routine sedation during therapeutic hypothermia. Such recommendations can only be based on scientific evidence, not on surveys or personal views, and this unfortunately is lacking. Clearly hypothermia in children and adults do require heavy sedation, but we do not feel that these data can be directly extrapolated to newborn infants.
Preclinical studies on sedation during therapeutic hypothermia are conflicting. Thoresen et al. showed no reduction in neuropathology scores in a piglet model for hypoxic injury without general anaesthesia that were cooled for 24 hours compared with those that were not cooled(3),...
Show MoreSir,
Show MoreIn their paper Montaldo et al. suggest that routine use of morphine in infants with perinatal asphyxia and therapeutic hypothermia (TH) is not useful and potentially harmful (Arch Dis Child Fetal Neonatal Ed. 2020:108-09). They rightfully suggest that morphine may accumulate during TH. However, in a recent study using multicentre data we have proposed novel dosing schedules for morphine and midazolam during TH thereby avoiding the risk of drug accumulation1.
Montaldo et al. state that “… it is unclear if morphine suppresses the nociceptive cortical activity in babies…” referring to a study of oral morphine for acute procedural pain in preterm infants.
Only since the late 1980s opioids are used during neonatal surgery following two classical papers by Anand showing that pre-emptive opioid analgesia following cardiac surgery in human infants dramatically decreased mortality and morbidity rates by suppressing pain and stress2 3.
As written by Montaldo et al. the right of universal pain relief is undisputed, also in human infants, and it is generally accepted through many animal experiments that TH is stressful. Furthermore, sedation and analgesia during TH after cardiac arrest in adults is well tolerated and effective4.
Therefore we are very reluctant to remove the mandatory use of sedatives including morphine from our international Dutch and Flemish guideline of TH, and we would like to stimulate others to use analgesia, while avoiding the...
In their follow-up analysis of the PREMILOC trial, Baud et al.[1] found significantly better neurodevelopmental outcomes at 22 months postmenstrual age in those extreme preterm neonates of 24 and 25 weeks of gestation who had been treated with early hydrocortisone during the first ten days after birth. Improvements in global neurological assessments were most pronounced for moderate to severe neurodevelopmental impairment, with a prevalence of 2.1% in the hydrocortisone and 18.4% in the placebo group. In this context it has to be remembered that early hydrocortisone treatment had been associated with a significant increase in the late-onset sepsis rate before discharge for those most immature neonates of 24 and 25 weeks of gestation.[2]
Show MoreIn their meta-analysis including seventeen observational studies, Alshaikh et al.[3] described “an increased risk of one or more long-term neurodevelopmental impairments … including cerebral palsy” in very-low-birth-weight infants who had suffered from culture-proven sepsis during the neonatal period. A follow-up analysis of extreme preterm neonates below 32 weeks of gestation found a significantly higher frequency of cerebral palsy at five years of age in those who had developed early- and/or late-onset sepsis.[4] Correspondingly, a positive association of Coagulase-negative staphylococcus sepsis and the risk of cognitive delay at a corrected age between 30 and 42 months has been reported in preterm neonates below 29 weeks of gestati...
Dear Editor
Show MoreWe read with interest the letter by Sur et al in response to our article (1). It was very reassuring to note that our findings were replicated in their study confirming the potential scale of antibiotic reduction while identifying all ‘blood culture positive’ sepsis. We did not collect data on CRP in our study. The evidence does not support a single CRP measurement as a reliable tool to help decisions to initiate treatment in the context of early onset neonatal sepsis (EOS), particularly in asymptomatic infants[2]. Consistent normal values over first 48 hours are associated with absence of EOS; but abnormal values in an asymptomatic infant are unreliable to predict culture proven sepsis [2-5]. CRP concentrations increase in neonates in response to a number of non-infective inflammatory conditions such as asphyxia, meconium aspiration, tissue trauma and pneumothorax. Serial CRP trend is irrelevant in treatment initiation decisions, and in low incidence conditions such as EOS, its value in predicting true culture positive EOS is below that is expected of a good and reliable test (Likelihood ratio 3.0)[4,6). The American Academy of Paediatrics states that diagnosis of EOS cannot be made using CRP in the absence of positive blood or CSF culture [2]. For asymptomatic low / moderate risk infants (currently treated with presumptive antibiotics), a period of observation / serial physical examination may be used instead of invasive tests to identify at an early...
We were impressed by the conduct and results of Reynolds et al.’s randomised controlled cross-over trial comparing Vapotherm’s IntellO2 device with manual control of inspired oxygen, showing improvement in the proportion of time spent within the target oxygen saturation range (automated arm mean 80% of time in 90-95% range vs. manual 49%). The findings are consistent with a meta-analysis referenced within their paper [1].
The Neonatal Oxygenation Prospective Meta-analysis (NeOProM) shows that targeting oxygen saturations of 91–95% with an oximeter with a correctly configured algorithm, carries a 38% survival advantage [2]. The co-ordinator of the NeOProM collaboration has stated that the “Infants born extremely preterm … should have their oxygen saturation levels targeted between 91% and 95%” [3].
The difference between the saturation targeting approach adopted by Reynolds et al., and NeOProM may appear small but, on account of the sigmoidal shape of the haemoglobin–oxygen dissociation curve, significant hypoxic shifts will occur with small changes in oxygen saturation.
Given the rigor of the NeOProM findings, would Reynolds et al. agree that targeting oxygen saturations of 91-95% is an important first step, whilst we wait for products which will allow improved titration of oxygen delivery?
References:
Show More[1] Mitra S, Singh B, El-Naggar W, McMillan DD. Automated versus manual control of inspired oxygen to target oxygen saturation in prete...
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