Effect of Doxapram on Cerebral Blood Flow Velocity in Preterm Infants

Abstract

Background: Doxapram is used to treat apnea of prematurity when there is an insufficient response to methylxanthine treatment. As an unwanted side effect, reduced cerebral perfusion has been seen in methylxanthine-treated infants while effects of doxapram on the cerebral perfusion have not been studied yet.

Patients and Methods: Fifteen preterm infants treated with doxapram were included in the study. Birth weight ranged from 380 g to 1150 g (median 740 g), gestational age from 24 to 27 weeks (median 26 weeks). Infants received a doxapram loading dose (2.5 mg/kg) over a 30-minute period, followed by a continuous infusion of 0.5 mg/kg/h. Using Doppler sonography, blood flow velocities and the resistance index were measured in the anterior cerebral artery. Measurements were performed at baseline and 30 and 120 minutes after the start of doxapram.

Results: Maximal systolic blood flow velocity (V_max) decreased significantly after the infants had received the loading dose (V_max baseline: 40.7 cm/s ± 6.9 [mean ± SD]; V_max 30 min: 35 cm/s ± 8.9; p = 0.0017) but returned to near baseline values at 120 min (38.5 ± 9.0, p = 0.22). End-diastolic, time-averaged, and time-averaged maximal velocities did not change significantly at 30 or 120 min.

Conclusions: Doxapram induced a significant decrease in maximal cerebral blood flow velocity. Further studies are needed to assess whether this decrease may be critical to cerebral white matter perfusion in the vulnerable preterm infant.

Key words

Doxapram - cerebral blood flow velocity - apnea of prematurity

References

• 1 Barrington K J, Finer N N, Peters K L, Barton J. Physiological effects of doxapram in idiopathic apnea of prematurity.  J Pediatr. 1986;  108 125-129
• 2 Barrington K J, Finer N N, Torok-Both G, Jamali F, Coutts R T. Dose-response relationship of doxapram in the therapy for refractory idiopathic apnea of prematurity.  Pediatrics. 1987;  80 22-27
• 3 Blanchard P W, Aranda J V. Pharmacotherapy of respiratory control disorders. Beckerman RC, Brouillette RT, Hunt CE Respiratory Control Disorders in Infants and Children. Baltimore; Williams & Wilkin 1992: 352-370
• 4 De Villiers G S, Walele A, Van der Merwe P L, Kalis N N. Second-degree atrioventricular heart block after doxapram administration.  J Pediatr. 1998;  133 149-150
• 5 Dani C, Bertini G, Reali M F, Tronchin M, Wiechmann L, Martelli E, Rubaltelli F F. Brain hemodynamic changes in preterm infants after maintenance dose caffeine and aminophylline treatment.  Biol Neonate. 2000;  78 27-32
• 6 Du Plessis A J, Volpe J J. Perinatal brain injury in the preterm and term newborn.  Curr Opin Neurol. 2002;  15 151-157
• 7 Govan J J, Ohlsson A, Ryan M L, Myhr T, Fong K. Aminophylline and Doppler time-averaged mean velocity in the middle cerebral artery in preterm neonates.  J Paediatr Child Health. 1995;  31 461-464
• 8 Hack M, Wilson-Costello D, Friedman H, Taylor G H, Schluchter M, Fanaroff A A. Neurodevelopment and predictors of outcomes of children with birth weights less than 1000 g.  Arch Pediatr Adolesc Med. 2000;  154 725-731
• 9 Henderson-Smart D J, Steer P A. Doxapram treatment for apnea in preterm infants.  Cochrane Database Syst Rev. 2001;  4 CD000074
• 10 Henderson-Smart D J, Steer P. Doxapram versus methylxanthine for apnea in preterm infants.  Cochrane Database Syst Rev. 2000;  4 CD000075
• 11 Hoecker C, Nelle M, Poeschl J, Beedgen B, Linderkamp O. Caffeine impairs cerebral and intestinal blood flow velocity in preterm infants.  Pediatrics. 2002;  109 784-787
• 12 Jacobs S E, O'Brian K, Inwood S, Kelly E N, Whyte H E. Outcome of infants 23 - 26 weeks gestation pre- and post-surfactant.  Acta Paediatr. 2000;  89 959-965
• 13 Maillard C, Boutroy M J, Fresson J, Barbe F, Hascoet J M. QT interval lengthening in premature infants treated with doxapram.  Clin Pharmacol Ther. 2001;  70 540-545
• 14 Martin R J, Fanaroff A A. Neonatal apnea, bradycardia, or desaturation: does it matter?.  J Pediatr. 1998;  132 758-759
• 15 McDonnell M, Ives N K, Hope P L. Intravenous aminophylline and cerebral blood flow in preterm infants.  Arch Dis Child. 1992;  67 416-418
• 16 Mosca F, Bray M, Lattanzio M, Fumagalli M, Tosetto C. Comparative evaluation of the effects of indomethacin and ibuprofen on cerebral perfusion and oxygenation in preterm infants with patent ductus arteriosus.  J Pediatr. 1997;  131 549-554
• 17 Nelle M, Hoecker C, Linderkamp O. Effects of bolus tube feeding on cerebral blood flow velocity in neonates.  Arch Dis Child Fetal Neonatal Ed. 1997;  76 54-56
• 18 Poets C F, Darraj S, Bohnhorst B. Effect of doxapram on episodes of apnoea, bradycardia and hypoxaemia in preterm infants.  Biol Neonate. 1999;  76 207-213
• 19 Pryds O, Schneider S. Aminophylline reduces cerebral blood flow in stable, preterm infants without affecting the visual evoked potential.  Eur J Pediatr. 1991;  150 366-369
• 20 Roll C, Hüning B, Kaunicke M, Krug J, Horsch S. Umbilical artery catheter blood sampling decreases cerebral blood volume and oxygenation in very low birthweight infants.  Acta Paediatr. 2000;  89 862-866
• 21 Roll C, Knief J, Horsch S, Hanssler L. Effect of surfactant administration on cerebral haemodynamics and oxygenation in premature infants - a near infrared spectroscopy study.  Neuropediatrics. 2000;  31 16-23
• 22 Roll C, Horsch S, Knief J, Husing J, Hanssler L. Comparison of effects of endotracheal suction and surfactant administration on hemodynamics and oxygenation of premature infants - a near infrared spectroscopy study.  Z Geburtshilfe Neonatol. 2001;  205 104-109
• 23 Rosenkrantz T S, Oh W. Aminophylline reduces cerebral blood flow velocity in low-birth-weight infants.  Am J Dis Child. 1984;  138 489-491
• 24 Schmidt B. Methylxanthine therapy in premature infants: sound practice, disaster, or fruitless byway?.  J Pediatr. 1999;  135 526-528
• 25 Sreenan C, Etches P C, Demianczuk N, Robertson C M. Isolated mental developmental delay in very low birth weight infants: association with prolonged doxapram therapy for apnea.  J Pediatr. 2001;  139 832-837
• 26 Tay-Uyboco J, Kwiatkowski K, Cates D B, Seifert B, Hasan S U, Rigatto H. Clinical and physiological responses to prolonged nasogastric administration of doxapram for apnea of prematurity.  Biol Neonate. 1991;  69 190-200
• 27 Uehara H, Yoshioka H, Nagai H, Ochiai R, Naito T, Hasegawa K. et al . Doxapram accentuates white matter injury in neonatal rats following bilateral carotid artery occlusion.  Neurosci Lett. 2000;  281 191-194
• 28 Wood N S, Marlow N, Costeloe K, Gibson A J, Wilkinson A R. Neurologic and developmental disability after extremely preterm birth.  N Engl J Med. 2000;  343 378-384