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Pre-emptive morphine sedation during hypothermic neuroprotection for neonatal encephalopathy is associated with adverse outcomes: an uncontrolled cohort study

Presented at the Neonatal Society 2018 Autumn Meeting.

Liow N1, Lally PJ, Teiserskas J, Montaldo P, Oliveira V, Mendoza J, Kumar V, Atreja G, Kariholu U, Slater R, Shankaran S, Thayyil S

1 Imperial College London, UK
2 Oxford University, UK
3 Wayne State University, USA

Background: Therapeutic hypothermia is an established treatment for moderate to severe neonatal encephalopathy (NE). Despite none of the major cooling trials mandating opioid sedation, it is now common practice among cooling centres in the UK. We examined the association of routine pre-emptive opioid sedation during therapeutic hypothermia with brain injury and adverse neurodevelopmental outcomes after moderate or severe NE.

Methods: In this secondary analysis, we included all babies with moderate or severe NE recruited to the MARBLE (Magnetic Resonance Biomarkers in Neonatal Encephalopathy) study (1). The North London Research Ethics Committee and the 8 clinical sites in the UK and USA approved the study (11/H0717/6). All babies had 3-Tesla magnetic resonance (MR) imaging and thalamic proton spectroscopy within 2 weeks after birth, and neurodevelopmental outcome assessment (Bayley III) at 2 years of age. The primary outcome was death or moderate or severe disability at 2 years.

Results: Of the 186 babies with moderate and severe NE, baseline characteristics of the 142 (76%) who received routine morphine sedation were comparable to the 30 (16%) who did not (Table). Babies receiving morphine were significantly more hypotensive (49% vs. 23%, p=0.03) and had significantly longer hospital stays (12 days vs. 9 days, p=0.009) compared to those who did not. Basal ganglia/thalamic, cortical and white matter injury and MR spectroscopy Lactate/N-acetyl aspartate metabolite peak area ratios were similar in both groups.

Adverse outcomes (death or moderate or severe disability) were seen in 21% (17/127) of the morphine group, and 0% in the nonmorphine group (p=0.04) (un-adjusted for the severity of NE). In a sub-group of 34 babies scanned on a single 3T Phillips MR scanner, no relationship was observed between the morphine dose and white matter fractional anisotropy, adjusted for the severity of NE.

Pre-emptive morphine sedation during hypothermic neuroprotection for neonatal encephalopathy is associated with adverse outcomes: an uncontrolled cohort study

Conclusion: In this uncontrolled multi-centre prospective cohort study, pre-emptive morphine sedation did not provide any neuroprotective benefit, and was associated with prolonged hospital stays. Carefully designed clinical trials are required to establish optimal sedation and supportive care during therapeutic hypothermia.

Corresponding author: Natasha.liow@nhs.net

References
1. Lally et al. Magnetic resonance spectroscopy assessment of brain injury after moderate hypothermia in neonatal encephalopathy: a prospective multi-centre study. Lancet Neurology (in press)

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