704 e-Letters

  • Bubble CPAP for neonates :Is it really better than others!

    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,...

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  • School-age outcomes following intraventricular haemorrhage in infants born extremely preterm – Is it right to blame the IVH?

    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...

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  • Breastfeeding and CMV infection -risks and benefits for the very premature babies

    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.

  • Randomized controlled trials on therapeutic hypothermia for mild neonatal encephalopathy are very fragile

    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...

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  • Its not just about the "lungs"

    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.

  • Sedation during Therapeutic Hypothermia in Asphyxiated Newborns- Authors’ reply

    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),...

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  • Sedation during Therapeutic Hypothermia in Asphyxiated Newborns

    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...

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  • Sepsis and neurodevelopmental outcome in preterm neonates

    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...

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  • The value of C-Reactive Protein in treatment decisions for early onset neonatal sepsis

    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...

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  • Target range 90-95% vs. 91-95%

    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?

    [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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