555 - Exploring the role of sildenafil in brain metabolite concentrations recovery in neonates with hypoxic-ischemic brain injury during the first month of life

Publication Number: 555.4810

Hossein Jomleh, McGill University Faculty of Medicine and Health Sciences, Montréal, PQ, Canada; Maria Jose Castro Gomez, McGill University Faculty of Medicine and Health Sciences, Montreal, PQ, Canada; Emmanouil Rampakakis, McGill University Faculty of Medicine and Health Sciences, Montreal, PQ, Canada; Anie Lapointe, University of Montreal, MOntreal, PQ, Canada; Gabriel Altit, McGill University Faculty of Medicine and Health Sciences, Montreal, PQ, Canada; Guillaume Gilbert, Philips Healthcare, Mississauga, ON, Canada; Robin H. Steinhorn, University of California, San Diego and Rady Children's Hospital, San Diego, CA, United States; Walter E Haefeli, University of Heidelberg/Heidelberg University Hospital/Dept. of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg, Baden-Wurttemberg, Germany; Pia Wintermark, McGill University, Montreal, PQ, Canada

Background: Birth asphyxia and subsequent hypoxic-ischemic encephalopathy (HIE) are major causes of mortality and long-term disabilities. Currently, therapeutic hypothermia (TH) is the only treatment available for these neonates in high-income countries. However, it is often ineffective, especially in low- and middle-income countries, and it does not promote repair. This highlights the urgent need for alternative therapies that can support brain recovery and improve outcomes. One such candidate is enteral sildenafil.

Objective: To assess brain metabolite concentrations using multi-voxel magnetic resonance spectroscopy (MV-MRS) during the first month of life in healthy neonates and neonates with HIE treated with TH +/- sildenafil.

Design/Methods: Prospective neuroimaging study involving healthy neonates and neonates with HIE treated with TH. A subset of neonates with HIE, who developed brain injury despite TH, received a 7-day course of sildenafil (14 doses, administered enterally q12h) starting on Day 2 and ending on Day 9. Brain MRIs were performed on days of life (DOL) 2 (before the sildenafil treatment and during TH), 10 and 30. We compared N-acetyl aspartate (NAA) concentration, NAA/Creatine (Cr), and Lactate (Lac)/NAA ratios in thalamus bilaterally across three groups: neonates without injury (NoBI) (including healthy neonates and HIE neonates without injury treated only with TH), HIE neonates with brain injury treated only with TH (BI+TH), and HIE neonates with brain injury treated with TH and sildenafil (BI+TH/S).

Results: A total of 229 MRI scans were obtained from 12 healthy, 54 NoBI+TH, 37 BI+TH, and 19 BI+TH/S neonates. Table 1 shows the clinical characteristics of enrolled neonates. By DOL10, both brain injury groups (BI+TH and BI+TH/S) showed significant reductions in NAA concentration and NAA/Cr ratio. These reductions persisted in the BI+TH group by DOL30, while the BI+TH/S group’s NAA and NAA/Cr values were no longer significantly different from those in the NoBI group. By DOL30, the BI+TH/S group also had significantly higher NAA/Cr ratios compared to the BI+TH group. Additionally, the Lac/NAA ratio, which was significantly elevated on DOL2 and 10 in both BI groups, was not longer significantly different by DOL 30. Figures 1 and 2 illustrate the differences in NAA concentration and NAA/Cr ratio, respectively, in the thalamus across the three groups.

Conclusion(s): NAA concentration and NAA/Cr ratio were reduced in neonates with HIE despite treatment with TH. Sildenafil appeared to promote recovery of both the concentration and the ratio in this context.

Table 1
Baseline characteristics of neonates enrolled in the study

Figure 1
Changes in mean NAA concentration in the thalamus over the first month of life across the three groups: neonates without injury (NoBI, black), HIE neonates with brain injury treated only with TH (BI+TH, red) and HIE neonates with brain injury treated with both TH and sildenafil (BI+TH/S, blue). (Absence of * indicates a non-significant contrast. Significance levels are as follows: * for 0.01 ≤ p-value < 0.05, ** for 0.001 ≤ p-value < 0.01, and *** for p-value < 0.001)

Figure 2
Changes in mean NAA/Cr values in the thalamus over the first month of life across the three groups: neonates without injury (NoBI, black), HIE neonates with brain injury treated only with TH (BI+TH, red) and HIE neonates with brain injury treated with TH and sildenafil (BI+TH/S, blue). (Absence of * indicates a non-significant contrast. Significance levels are as follows: * for 0.01 ≤ p-value < 0.05, ** for 0.001 ≤ p-value < 0.01, and *** for p-value < 0.001)