Presented at the Neonatal Society 2006 Widdowson Meeting.
Wood T, Hobbs C, Tucker A, Aquilina K, Thoresen M
Child Health, Clinical Sciences at South Bristol, University of Bristol, UK
Background: Beyond its anti-epileptic action via inhibitory GABAA receptors, phenobarbital may also protect the brain via antioxidant, anti-lipid peroxidation and membrane stabilising properties (1). In addition, its wide clinical use makes it an attractive adjunct to hypothermia in treating hypoxic-ischaemic brain injury in the neonate. Aim: To test the combined neuroprotective effect of phenobarbital and hypothermia (HT) after unilateral hypoxia-ischaemia, compared to the protection offered by phenobarbital or HT alone.
Aim: To test the combined neuroprotective effect of phenobarbital and hypothermia (HT) after unilateral hypoxia-ischaemia, compared to the protection offered by phenobarbital or HT alone.
Design/Methods: All procedures were undertaken in accordance with UK ethical guidelines. Ninety-six 7-days old (P7) Wistar rat pups underwent ligation of the left common carotid artery under halothane anaesthesia (1.5% in 2:1 nitrous oxide to oxygen), followed by hypoxia (8% oxygen) for 90min at normothermia (36ºC). Pups were then randomised between 4 post insult treatment groups; (i) no treatment, (ii) 3 hours of HT (32ºC), (iii) phenobarbital (40mg/kg), or (iv) the combination of phenobarbital and 3 hours of HT. The functional effects of HI and subsequent treatment was assessed at P12, P14 and P21, using two behavioural tests – grip traction (ability to support body weight by forepaws), as an indicator of strength; and negative geotaxis (time to rotate to head up position on a slope), as an indicator of postural reflexes and motor function.
Results: At normothermia, 40mg/kg phenobarbital orally was well absorbed with a plasma level of 78μmol/L by 30 min and peak levels of 150μmol/L after 2 hours. Animals treated with phenobarbital, with or without hypothermia, performed significantly better in the grip traction task (p = 0.0105 and p < 0.0001 respectively; Figure 1A) and the negative geotaxis task (p < 0.0001; Figure 1B) than untreated animals or those treated with hypothermia alone.
Discussion: In this model of neonatal HI, a single oral dose of phenobarbital, administered shortly after hypoxia-ischaemia, offered impressive preservation of motor function up to two weeks after the insult. In this model we have shown that neuromotor testing at these timepoints correlates well with pathological changes seen in the brain. If long-term studies confirm the beneficial effect of Phenobarbital combined with hypothermia it might be a useful treatment strategy after perinatal asphyxia.
Acknowledgements: This work is supported by the Laerdal Foundation for Acute Medicine (Norway) and SPARKS (UK).
References
1. Vannucci RC and Perlman JM. Pediatrics 1997;100(6):1004-14.