Effect of Citicoline on Neurological Severity Score and Cerebral Doppler Resistive Index in Neonatal Hypoxic Ischemic Encephalopathy: A Randomized Control Trial

Hypoxic-ischemic encephalopathy (HIE) is a leading cause of neonatal brain injury worldwide. In the developed world, the incidence is estimated at up to 8 per 1,000 live births, while in developing countries, estimates are as high as 26 per 1,000 live births. Approximately 20-30% of infants with HIE die in the neonatal period, and 33-50% of survivors are left with permanent neurodevelopmental abnormalities.1 HIE can be classified into mild (Stage I), moderate (Stage II), and severe (Stage III) based on the Sarnat and Sarnat staging system(Table 1), with stage II and III being associated with the highest morbidity and mortality.

Therapeutic hypothermia remains the standard therapy for HIE. However, its availability, high costs, need for specialized equipment and monitoring limit its use in developing countries like Pakistan, therefore alternative neuroprotective agents are used however there is still no consensus regarding which agent is the most effective. Citicoline (cytidine diphosphate choline) has demonstrated several neuroprotective mechanisms. It helps preserve neuronal membrane integrity by maintaining phospholipids while decreasing phospholipase A2 activity and oxidative damage.2 It also enhances phosphatidylcholine synthesis and promotes glutathione production, thereby decreasing free-radical-mediated neuronal injury. Experimental studies further suggest neuroprotective roles of citicoline as it modulates excitotoxicity by decreasing glutamate levels.3,4 These combined effects may contribute to improved neuronal survival and recovery after hypoxic-ischemic insults. Long term effects have been studied however no study evaluates short term improvement from therapy.

Resistive Index is a parameter assessed on cranial doppler ultrasonography, it is difference between peak systolic and end diastolic pressures in the anterior cerebral arteries, normal value is 0.68-0.72 5it demonstrates cerebral blood flow changes due to hypoxia, lower values have been associated with worse neurological outcome.5 RI has been studied in comparison to MRI and also its changes pre and post therapeutic hypothermia, and has been found to be useful tool6,7. American Academy of Neurology and Practice Committee of the Child Neurology Society recommends RI and end diastolic flow velocity (EDFV) in the anterior cerebral artery to assess cerebral perfusion and early prediction of outcome.8 This study is therefore designed to assess the effect of citicoline on cerebral resistive index and neurological improvement using Sarnat-Sarnat scoring after 3 days of treatment in neonates with hypoxic-ischemic encephalopathy. The findings may contribute to establishing evidence for adjunctive therapeutic strategies aimed at reducing neurological morbidity in affected neonates. Despite its clinical use in some centers, there is limited published evidence regarding the efficacy of citicoline in neonates with HIE.

Inclusion criteria

• All inborn neonates diagnosed with APGAR score (Table 2) less then 8/10 at 5 min of life presenting to the emergency room within the first day of life.
• Outborn babies admitted in the last 24 hours with history or clinical features of perinatal asphyxia.

Exclusion criteria

• Neonates who have received therapeutic hypothermia
• Neonates with congenital, developmental or chromosomal malformations
• Significant antenatal risk factors leading to early-onset sepsis\\DIC or CNS depression unrelated to asphyxia
• Preterm neonates <35 weeks
• No consent could be obtained