34 e-Letters

published between 2020 and 2023

  • 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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