No neuroprotective effect of therapeutic hypothermia following lipopolysaccharide-sensitized hypoxia-ischemia: a newborn piglet study

Andersen, Mads; Andersen, Hannah Brogård; Andelius, Ted Carl Kejlberg; Hansen, Lærke Hjøllund; Pinnerup, Regitze; Bjerre, Mette; Ringgaard, Steffen; Schwendimann, Leslie; Gressens, Pierre; Kyng, Kasper Jacobsen; Henriksen, Tine Brink

doi:10.3389/fped.2023.1268237

Cited by 3 publications

(2 citation statements)

References 81 publications

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“…5 Importantly, HT for 24 h did not improve neurological outcomes based on magnetic resonance spectroscopy (MRS) of lactate to N-acetyl aspartate peak area ratio (Lac/NAA), background amplitude-integrated encephalography (aEEG/EEG) activity and immunohistochemistry. 6 Similar findings have been reported by other groups [7][8][9] with evidence of a pathogen-specific response. 10 Melatonin (N-acetyl-5-methoxytryptamine) for NE has shown great promise in preclinical studies.…”

Section: Introductionsupporting

confidence: 87%

“…This therapeutic target was established in previous studies in piglets and is summarised in Figure 8. 34 In this current study of IA-HI, where cooling is not protective, 6,9,35 melatonin monotherapy targeting this therapeutic range is cytoprotective, highlighting its diverse benefits. Aridas and colleagues 13 observed improvement in Lac/NAA, histology and neurobehavioural outcomes with melatonin doses of ∼15 mg/kg/day.…”

Section: Discussionmentioning

confidence: 80%

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Melatonin reduces brain injury following inflammation‐amplified hypoxia–ischemia in a translational newborn piglet study of neonatal encephalopathy

Pang,

Meehan,

Maple

et al. 2024

Journal of Pineal Research

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There is a need to develop therapies for neonatal encephalopathy (NE) in low‐ and middle‐income countries (LMICs) where the burden of disease is greatest and therapeutic hypothermia (HT) is not effective. We aimed to assess the efficacy of melatonin following inflammation‐amplified hypoxia–ischaemia (IA‐HI) in the newborn piglet. The IA‐HI model accounts for the contribution of infection/inflammation in this setting and HT is not cytoprotective. We hypothesised that intravenous melatonin (5% ethanol, at 20 mg/kg over 2 h at 1 h after HI + 10 mg/kg/12 h between 24 and 60 h) is safe and associated with: (i) reduction in magnetic resonance spectroscopy lactate/N‐acetylaspartate (MRS Lac/sNAA); (ii) preservation of phosphorus MRS phosphocreatine/phosphate exchange pool (PCr/Epp); (iii) improved aEEG/EEG recovery and (iv) cytoprotection on immunohistochemistry. Male and female piglets underwent IA‐HI by carotid artery occlusion and reduction in FiO2 to 6% at 4 h into Escherichia coli lipopolysaccharide sensitisation (2 μg/kg bolus + 1 μg/kg/h over 12 h). At 1 h after IA‐HI, piglets were randomised to HI‐saline (n = 12) or melatonin (n = 11). There were no differences in insult severity between groups. Target melatonin levels (15–30 mg/L) were achieved within 3 h and blood ethanol levels were <0.25 g/L. At 60 h, compared to HI‐saline, melatonin was associated with a reduction of 0.197 log10 units (95% CrI [−0.366, −0.028], Pr(sup) 98.8%) in basal‐ganglia and thalamic Lac/NAA, and 0.257 (95% CrI [−0.676, 0.164], Pr(sup) 89.3%) in white matter Lac/NAA. PCr/Epp was higher in melatonin versus HI‐saline (Pr(sup) 97.6%). Melatonin was associated with earlier aEEG/EEG recovery from 19 to 24 h (Pr(sup) 95.4%). Compared to HI‐saline, melatonin was associated with increased NeuN+ cell density (Pr(sup) 99.3%) across five of eight regions and reduction in TUNEL‐positive cell death (Pr(sup) 89.7%). This study supports the translation of melatonin to early‐phase clinical trials. Melatonin is protective following IA‐HI where HT is not effective. These data guide the design of future dose‐escalation studies in the next phase of the translational pipeline.

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Section: Introductionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 80%

Melatonin reduces brain injury following inflammation‐amplified hypoxia–ischemia in a translational newborn piglet study of neonatal encephalopathy

Pang,

Meehan,

Maple

et al. 2024

Journal of Pineal Research

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Uncovering the Role of Inflammation with Asphyxia in the Newborn

Dhillon,

Gressens,

Barks

et al. 2024

Clinics in Perinatology

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Lipopolysaccharide induced systemic inflammation and heart rate variability in a term newborn piglet model

Pedersen,

Renberg,

Christensen

et al. 2024

Pediatr Res

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Background Early biomarkers are needed to improve diagnosis and support antibiotic stewardship in neonatal sepsis. Heart rate variability (HRV) is proposed as such a biomarker. However, there is a lack of studies in term newborns. Infusion of lipopolysaccharide (LPS) from Escherichia coli induces systemic inflammation comparable to sepsis in newborns. We aimed to study the effect of systemic LPS induced inflammation on HRV in term newborn piglets. Methods Baseline HRV was recorded for 1 h. This control period was compared to the hourly HRV for each piglet (n = 9) during 4 h of LPS infusion. For comparison, we used a mixed-effects regression model. Results Systemic inflammation induced by LPS was found to reduce HRV. Compared to baseline, most measures of HRV decreased to lower values compared to baseline at 2 h, 3 h, and 4 h after initiation of LPS infusion. Heart rate (HR) was increased at 2 h, 3 h, and 4 h. When adjusting for HR in the mixed-effects regression model all reductions in HRV were explained by the increase in HR. Conclusions Reduced HRV may be an early biomarker of neonatal sepsis. However, an increase in HR alone could be an already available, more accessible, and interpretable biomarker of sepsis in term neonates. Impact In a term newborn piglet model, systemic inflammation induced by lipopolysaccharide from Escherichia coli reduced heart rate variability measures and increased heart rate. All reductions in heart rate variability were mediated by heart rate. While heart rate variability may be a biomarker of sepsis in term newborns, changes in heart rate alone could be a more readily available biomarker.

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No neuroprotective effect of therapeutic hypothermia following lipopolysaccharide-sensitized hypoxia-ischemia: a newborn piglet study

Cited by 3 publications

References 81 publications

Melatonin reduces brain injury following inflammation‐amplified hypoxia–ischemia in a translational newborn piglet study of neonatal encephalopathy

Melatonin reduces brain injury following inflammation‐amplified hypoxia–ischemia in a translational newborn piglet study of neonatal encephalopathy

Uncovering the Role of Inflammation with Asphyxia in the Newborn

Lipopolysaccharide induced systemic inflammation and heart rate variability in a term newborn piglet model

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