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• Sedation during Therapeutic Hypothermia in Asphyxiated Newborns- Authors’ reply
  Paolo Montaldo, Sudhin Thayyil
  Published on: 2 February 2020
• Sedation during Therapeutic Hypothermia in Asphyxiated Newborns
  Floris Groenendaal, Richard A van Lingen
  Published on: 15 January 2020

• Published on: 2 February 2020

  Sedation during Therapeutic Hypothermia in Asphyxiated Newborns- Authors’ reply

  • Paolo Montaldo, Neonatologist Imperial College London
  • Other Contributors:
    • Sudhin Thayyil, Neonatologist

  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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  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.

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  Conflict of Interest:
  None declared.

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• Published on: 15 January 2020

  Sedation during Therapeutic Hypothermia in Asphyxiated Newborns

  • Floris Groenendaal, Neonatologist University Medical Center Utrecht, Utrecht, Netherlands
  • Other Contributors:
    • Richard A van Lingen, Neonatologist

  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...

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  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

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  Conflict of Interest:
  None declared.

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