Oxygen Toxicity in the Resuscitation in Extremely Premature Infants (OXTOX)

• Neonatal mortality [ Time Frame: 28 days of life ] [ Designated as safety issue: No ]
• Oxidative stress [ Time Frame: at day 1, 2 and 7 ] [ Designated as safety issue: No ]
• Bronchopulmonary dysplasia [ Time Frame: 36 weeks postconceptional age ] [ Designated as safety issue: No ]
• Retinopathy of prematurity [ Time Frame: 40 weeks postconceptional ] [ Designated as safety issue: No ]
• Neurodevelopment [ Time Frame: 24 months postnatal ] [ Designated as safety issue: No ]

• Neonatal mortality [ Time Frame: 28 days of life ]
• Oxidative stress [ Time Frame: at day 1, 2 and 7 ]
• Bronchopulmonary dysplasia [ Time Frame: 36 weeks postconceptional age ]
• Retinopathy of prematurity [ Time Frame: 40 weeks postconceptional ]
• Neurodevelopment [ Time Frame: 24 months postnatal ]

The investigators hypothesize that using low oxygen concentrations during resuscitation of extremely premature infants will avoid oxidative stress derived damage and improve outcome.

This is a prospective randomized trial enrolling premature infants of less than 28 weeks gestation. Patients are randomly assigned to become resuscitation with an initial oxygen inspiratory fraction (FiO2) of 30% or 90%. Main objective is to reach a target saturation of 85% at 15 min of life.

Immediately after birth pre-and-postductal pulse oximeters are set and oxygen saturation (SpO2) continuously monitored and registered as long as the patient requires oxygen supplementation. FiO2 is stepwise adjusted (increased or decreased 10%) every 90 sec according to heart rate, SpO2 and responsiveness.

Blood samples are drawn from umbilical cord and at day 1, 2 and 7 from peripheral vein to determine oxidative stress markers (GSH, GSSG), angiogenic factors (VEGF, VEGF receptors, Angiopoietin), pro-inflammatory markers (IL8, TNF alfa) and pro-apoptotic markers (Fas Ligand; Cytochrome C).

Urine is collected every day during the first week of life to determine oxidative stress markers (8-oxo-dG; O-tyrosine; F2 isoprostanes; Isofurans).

Babies are followed in the NICU and clinical condition recorded. Serial examinations for ROP and Auditory evoked potentials will be performed. Neurodevelopmental outcome is evaluated at 2 years of postnatal life. Main outcome: Achievement of a target saturation of 85% at 15 min of life. Secondary outcomes: acute complications during delivery; chronic complications (BPD, ROP, IPVH); mortality in the neonatal period.

• Birth Asphyxia
• Premature Birth

• Procedure: Resuscitation
  Use of inspiratory fraction of oxygen needed to achieve oxygen saturation in the preset limits 85-88%
• Procedure: Resuscitation
  Oxygen inspiratory fraction needed to keep oxygen saturation in the preset limits of 90-93%

• Experimental: LOX
  Low saturation group of premature infants that will be kept within preset limits of 85-89%
  Intervention: Procedure: Resuscitation
• Active Comparator: HOX
  HOX group of premature infants will be kept within preset saturation limits of 90-93%
  Intervention: Procedure: Resuscitation

• Vento M, Asensi M, Sastre J, Garcia-Sala F, Pallardo FV, Vina J. Resuscitation with room air instead of 100% oxygen prevents oxidative stress in moderately asphyxiated term neonates. Pediatrics. 2001 Apr;107(4):642-7.
• Vento M, Asensi M, Sastre J, Lloret A, Garcia-Sala F, Minana JB, Vina J. Hyperoxemia caused by resuscitation with pure oxygen may alter intracellular redox status by increasing oxidized glutathione in asphyxiated newly born infants. Semin Perinatol. 2002 Dec;26(6):406-10.
• Vento M, Asensi M, Sastre J, Lloret A, Garcia-Sala F, Vina J. Oxidative stress in asphyxiated term infants resuscitated with 100% oxygen. J Pediatr. 2003 Mar;142(3):240-6. Erratum in: J Pediatr. 2003 Jun;142(6):616.
• Saugstad OD, Ramji S, Irani SF, El-Meneza S, Hernandez EA, Vento M, Talvik T, Solberg R, Rootwelt T, Aalen OO. Resuscitation of newborn infants with 21% or 100% oxygen: follow-up at 18 to 24 months. Pediatrics. 2003 Aug;112(2):296-300.
• Saugstad OD, Ramji S, Vento M. Resuscitation of depressed newborn infants with ambient air or pure oxygen: a meta-analysis. Biol Neonate. 2005;87(1):27-34. Epub 2004 Sep 20. Review.
• Vento M, Sastre J, Asensi MA, Vina J. Room-air resuscitation causes less damage to heart and kidney than 100% oxygen. Am J Respir Crit Care Med. 2005 Dec 1;172(11):1393-8. Epub 2005 Sep 1.
• Saugstad OD, Ramji S, Vento M. Oxygen for newborn resuscitation: how much is enough? Pediatrics. 2006 Aug;118(2):789-92. No abstract available.
• Bookatz GB, Mayer CA, Wilson CG, Vento M, Gelfand SL, Haxhiu MA, Martin RJ. Effect of Supplemental Oxygen on Reinitiation of Breathing after Neonatal Resuscitation in Rat Pups. Pediatr Res. 2007 Apr 5; [Epub ahead of print]
• Escrig R, Arruza L, Izquierdo I, Villar G, Sáenz P, Gimeno A, Moro M, Vento M. Achievement of targeted saturation values in extremely low gestational age neonates resuscitated with low or high oxygen concentrations: a prospective, randomized trial. Pediatrics. 2008 May;121(5):875-81.

Inclusion Criteria:

• Prematurity of less than 28 weeks gestation

Exclusion Criteria:

• Severe malformations
• Chromosomopathies
• Informed consent not signed