Discussion
seizures, seizure, traumatic brain injury, neurologic disability, stroke, HIE, acute ischemic stroke
ADVERSE EVENTS, STROKE, BRAIN HYPOXIA, ADVERSE EFFECTS, SECONDARY
HIE is still one of the major causes of mortality and neurologic disability in neonates [In this study, citicoline was tried as a neuroprotector drug in neonates with moderate to severe HIE in whom therapeutic cooling was not applicable due to several reasons and citicoline was found to have good neuroprotecting results in the treatment group compared to the control group. To our knowledge, this is the first clinical trial to use citicoline as a neuroprotector in neonates with HIE.In this trial, we reported a significant reduction in post-discharge seizures in citicoline-treated group compared to the control group. Moreover, the duration of seizures was significantly shorter in citicoline treated neonates compared to the control group. Similar results were documented in a small pilot study performed by Khushdil et al. [One of the important effects of citicoline intake is the decreased glutamate release after accumulation after brain hypoxia, with a subsequent reduction of seizure activity of the brain that is aided by a decrease in the number of glutamatergic synapses and extracellular glutamate concentration [Cranial ultrasound scanning and MRI brain in our study showed better results in the citicoline treated group compared to the control group after 4 weeks of treatment. Moreover, there was a significant improvement of neurodevelopmental outcomes at 9 and 12 m of age in the treatment group compared to the control group.Several mechanisms can be responsible for the neuroprotective effects of citicoline in neonates with HIE. Citicoline is vital in the production of phospholipids which are necessary for the formation and regeneration of neuronal cytoplasmic and mitochondrial membranes following damage [Part of the citicoline protective and restorative effects on the central nervous system (CNS) is by increasing Na + /K + ATPase activity, decreasing lipid peroxidation, improving neuroplasticity, and increasing the synthesis of neurotransmitters such as acetylcholine (Ach), and dopamine [Moreover, one of the explanations of functional improvement after citicoline use in post stroke patients is the ability of citicoline to do mobilization of endothelial progenitor cells from the bone marrow of stroke patients, these cells secrete growth factors. These growth factors when tried experimentally as treatment have been shown to improve cognitive recovery in conditions such as traumatic brain injury and experimental stroke [Another randomized, placebo-controlled, double-blind clinical study had also showed benefits with short-term use of citicoline for 6 weeks in acute ischemic stroke with significant recovery at 12 weeks when compared to placebo with no differences with placebo in adverse events [This study showed that there was a statistically significant reduction in the duration of NICU stay, inotrope use, and MV in the treatment group compared to the control group. Due to its broad spectrum of activity on neural tissue, citicoline is considered a promising neuroprotector drug. Furthermore, citicoline is reported to be a safe drug with no serious adverse effects [The main limitations of this study are being a two-center study with a limited number of patients and short follow-up period. Thus, larger multicenter studies with higher number of patients including the trial of different doses of citicoline and longer follow up are needed to prove the potential efficacy of citicoline in neonatal HIE. Moreover, we preferred 4 weeks for scanning by MRI rather than 2 weeks secondary to some technical difficulties like transportation of mechanically ventilated children as some patients enrolled in the study were mechanically ventilated and others were too unwell and unstable to be scanned within the first weeks after birth.