Effect of allopurinol on postasphyxial free radical formation, cerebral hemodynamics, and electrical brain activity.
OBJECTIVE
Free radical-induced postasphyxial reperfusion injury has been recognized as an important cause of brain tissue damage. We investigated the effect of high-dose allopurinol (ALLO; 40 mg/kg), a xanthine-oxidase inhibitor and free radical scavenger, on free radical status in severely asphyxiated newborns and on postasphyxial cerebral perfusion and electrical brain activity.


METHODS
Free radical status was assessed by serial plasma determination of nonprotein-bound iron (microM), antioxidative capacity, and malondialdehyde (MDA; microM). Cerebral perfusion was investigated by monitoring changes in cerebral blood volume (delta CBV; mL/100 g brain tissue) with near infrared spectroscopy; electrocortical brain activity (ECBA) was assessed in microvolts by cerebral function monitor. Eleven infants received 40 mg/kg ALLO intravenously, and 11 infants served as controls (CONT). Plasma nonprotein-bound iron, antioxidative capacity, and MDA were measured before 4 hours, between 16 and 20 hours, and at the second and third days of age. Changes in CBV and ECBA were monitored between 4 and 8, 16 and 20, 58 and 62, and 104 and 110 hours of age.


RESULTS
Six CONT and two ALLO infants died after neurologic deterioration. No toxic side effects of ALLO were detected. Nonprotein-bound iron (mean +/- SEM) in the CONT group showed an initial rise (18.7 +/- 4.6 microM to 21.3 +/- 3.4 microM) but dropped to 7.4 +/- 3.5 microM at day 3; in the ALLO group it dropped from 15.5 +/- 4.6 microM to 0 microM at day 3. Uric acid was significantly lower in ALLO-treated infants from 16 hours of life on. MDA remained stable in the ALLO group, but increased in the CONT group at 8 to 16 hours versus < 4 hours (mean +/- SEM; 0.83 +/- 0.31 microM vs 0.50 +/- 0.14 microM). During 4 to 8 hours, delta CBV-CONT showed a larger drop than delta CBV-ALLO from baseline. During the subsequent registrations CBV remained stable in both groups. ECBA-CONT decreased, but ECBA-ALLO remained stable during 4 to 8 hours of age. Neonates who died had the largest drops in CBV and ECBA.


CONCLUSIONS
This study suggests a beneficial effect of ALLO treatment on free radical formation, CBV, and electrical brain activity, without toxic side effects.
Van Bel
F
F
Department of Pediatrics, Leiden University Hospital, The Netherlands.
Shadid
M
M
Moison
R M
RM
Dorrepaal
C A
CA
Fontijn
J
J
Monteiro
L
L
Van De Bor
M
M
Berger
H M
HM
D000493:Allopurinol / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D000963:Antimetabolites / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D001238:Asphyxia Neonatorum / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D001921:Brain / Q000098:blood supply / Q000187:drug effects* / Q000503:physiopathology; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D004569:Electroencephalography / Q000187:drug effects; D004594:Electrophysiology; D005609:Free Radicals / Q000378:metabolism*; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007231:Infant, Newborn; D015227:Lipid Peroxidation / Q000187:drug effects
D000963:Antimetabolites; D005609:Free Radicals; D000493:Allopurinol