EBNEO commentary: Dexmedetomidine versus morphine for neonates with encephalopathy undergoing therapeutic hypothermia.

Abstract

Cosnahan A, Angert R, Jano E, Wachtel E. Dexmedetomidine versus intermittent morphine for sedation of neonates with encephalopathy undergoing therapeutic hypothermia. Journal of Perinatology 2021; 41(9):2284-2291. PMID 33649447 The use of sedation during TH is important to provide compassionate care and prevent stress and shivering. While non-pharmacologic approaches should be utilised first-line, some neonates require sedation to limit stress and provide comfort. A neonatal piglet study of HIE suggested that TH is not neuroprotective in the absence of sedation.1 However, animal studies have demonstrated that sedatives, analgesics and/or anaesthetics may have long-term deleterious effects on the developing brain through inhibition of NMDA glutamate receptors or enhancement of GABA-mediated depolarisation triggering widespread apoptotic neurodegeneration.2, 3 Healthcare providers must balance managing stress and pain with the risks that accompany sedation in neonates. Morphine and fentanyl, both opioid agonists, have historically been used during TH to provide sedation. However, these agents have significant side effects including respiratory depression, delayed gastrointestinal motility and hypotension. Additionally, the global hypoxic–ischemic insult that occurs during HIE leads to a high incidence of acute kidney injury and acute liver injury,4 which may slow metabolism and clearance of medications such as morphine and fentanyl. These pharmacokinetic alterations, along with PK alterations related to TH itself, can lead to accumulation of the medication, further increasing the risk of adverse effects.4, 5 In a secondary analysis of 169 neonates enrolled in one study, neonates receiving morphine were more likely to be hypotensive (49% vs. 25%, p = 0.02) and had a longer hospital stay (12 days vs. 9 days, p = 0.009) compared with those who did not receive morphine.6 Dexmedetomidine is an α2-adrenergic agonist that provides analgesia, anxiolysis and sedation. The activation of central α2-receptors prevents shivering during TH, inhibits inflammatory cytokines and may result in endogenous neuroprotection.5 Dexmedetomidine does not appear to have significant impact on the respiratory drive or gastrointestinal motility. The most common use-limiting adverse effect is bradycardia. Pharmacokinetic alterations have been demonstrated in animals, but there are limited data in neonates, with a single study reporting comparable or lower clearance, larger volume of distribution and longer elimination half-life in patients with HIE undergoing TH compared with those without HIE.7 In a single-centre retrospective cohort study of 19 neonates with HIE undergoing TH, dexmedetomidine was administered at an average rate of 0.3 mcg/kg/h (range 0.2–0.5 mcg/kg/h). Two patients received dexmedetomidine monotherapy, and 17 received fentanyl initially. Thirteen of those 17 patients had fentanyl discontinued within 4 h of starting dexmedetomidine. The authors concluded that dexmedetomidine was effective for sedation in neonates with HIE undergoing TH.8 The study presented here adds to the growing body of literature that dexmedetomidine may be effective and safe for sedation and analgesia during TH. It is important to note the small sample size and lack of significant differences between groups for many of the respiratory and gastrointestinal outcomes assessed. Despite the limitations of this study, the potential benefits of dexmedetomidine should be considered when selecting a sedative in neonates undergoing TH. Future research should focus on gathering additional pharmacokinetic data for dexmedetomidine in HIE/TH and the evaluation of longer-term neurologic outcomes in neonates undergoing TH. https://ebneo.org/ebneo-commentary-dexmedetomidine-vs-morphine This review did not have a funding source. The authors have no conflicts of interest to report.