23 - Glucose, lactate, and ketones - energy metabolism during therapeutic hypothermia in neonates with hypoxic-ischemic encephalopathy – the GLactiK pilot study

Publication Number: 1020.23

Ulrike Mietzsch, University of Washington School of Medicine/ Seattle Children's Hospital, Seattle, WA, United States; Nina Natarajan, University of Washington School of Medicine, Seattle, WA, United States; Mihai Puia-Dumitrescu, University of Washington School of Medicine, Seattle, WA, United States; Janessa Law, University of Washington School of Medicine, Seattle, WA, United States; Reece Alstat, Seattle Children's Hospital, Seattle, WA, United States; Olivia C. Brandon, University of Washington School of Medicine, Seattle, WA, United States; Thomas Wood, University of Washington, Seattle, WA, United States

Background: In infants with hypoxic-ischemic encephalopathy (HIE), failure of aerobic metabolism impairs ATP production. Energy substrates such as glucose, lactate, and beta-hydroxybutyrate (BHB) may also not be reliably accessible, exacerbating energy failure. Exogenous BHB has shown promise as a neuroprotectant in animal models of HIE. However, it is fundamental to first understand the natural trajectory of energy metabolites and influence of HIE severity prior to initiating human studies of BHB for neuroprotection.

Objective: To investigate the temporal changes of circulating energy metabolites (glucose, lactate and BHB) in neonates with moderate or severe HIE during therapeutic hypothermia (TH) and their relation to overall illness.

Design/Methods: In this exploratory single center pilot study, serial glucose, lactate, and BHB levels were measured from residual clinical blood specimens during TH. Clinical and demographic data were collected and analyzed descriptively by severity of HIE. Metabolite variables were plotted over time by HIE severity and assessed within epochs of time (0-12h, 12-24h, 24-48h, 48-72h). An organ score (OS) was used to assess overall severity of illness (Figure 2). Metabolites were compared using mixed-effects models with random effect of infants adjusting for HIE severity and vasoactive medication exposure.

Results: 36 patients with HIE (moderate n=25, severe n=11) were included between January and September 2025. Patient characteristics are shown in Table 1. Neonates with severe HIE had persistently higher lactate (p=0.038) and a non-significant late rise in glucose (p=0.22) compared to those with moderate HIE (Figure 1). When assessing overall severity of illness, infants with an OS of 5-6 had a persistently elevated lactate compared to those with an OS of 0 or 1-4 in all epochs (p < 0.05 for all) and displayed a significant increase in glucose over time compared to those with an OS of 0 (OS*Time interaction p=0.034). While BHB levels were initially similar across all three OS groups, BHB rose significantly after 24 h in those with an OS of 0 compared to those with an OS of 1-4 or 5-6 (interaction p< 0.001 for both), which was not influenced by any individual organ system but rather overall severity of illness.

Conclusion(s): Our data show a relationship between illness severity and temporal energy metabolite profiles. BHB decreases over time in infants with multi-organ involvement likely reflecting impaired production and/or reduced utilization. This data will assist in designing a much-needed human trial of BHB supplementation for neuroprotection.

Table 1
Patient Characteristics. Descriptive analyses were performed using Fisher's exact test and Mann-Whitney U test; a p-value of 0.05 was considered statistically significant. EEG=electroencephalogram; MRI=magnetic resonance imaging; IQR=interquartile range; AST=aspartate amino transferase; INR=international normalized ratio

Figure 1
Locally estimated scatterplot smoothing (LOESS) of blood glucose (A), lactate (B), and beta-hydroxybutyrate (BHB, C) trajectory in the first 24h after birth, stratified by severity of HIE. Infants with severe HIE had persistently higher lactate (p=0.038) and a late rise in glucose relative to those with moderate HIE, though the latter was not significant (48-72h, p=0.22). No clear difference in the pattern of BHB over time was seen by severity of HIE.

Figure 2
Boxplots of median blood glucose (A), lactate (B), and beta-hydroxybutyrate (BHB, C) within four epochs (0-12h, 12-24h, 24-48h, 48-72h) by degree of peripheral organ involvement. Compared to those with no organ impairment, those with an organ score of 5-6 displayed a significant increase in glucose over time (interaction p=0.034, A). Lactate was persistently higher in infants with an organ score of 5-6 compared to those with an organ score of 0 or 1-4 in all epochs (p < 0.05 for all, B). Compared to those with an organ score of 1-4 or 5-6, those with an organ score of 0 had BHB levels that increase over time (interaction p<0.001 for both), being significantly higher in the 24-48h and 48-72h epochs (C). To assess end-organ injury, 1 point was given for each of the 6 categories (maximum 6 points): a) Pulmonary-need for mechanical ventilation outside the delivery room, b)Hypotension- requiring vasoactive medications, c) Renal-creatinine >1.5 mg/dL, d) Liver - aspartate aminotransferase (AST) >100 U/L, e) Disseminated intravascular coagulopathy (DIC) - International normalized ratio (INR)>2.0 and/or thrombocytopenia < 100K, f) Dysglycemia - blood glucose < 50 g/dL (2.78 mM) or > 200mg/dL (11.1 mM).