The To2rpido Study: Targeted Oxygenation in the Resuscitation of Premature Infants and their Developmental Outcome

The problem with oxygen: Oxygen (O2) is essential for life but too much (hyperoxia) is toxic and may cause cell inflammation and death. The extremely premature infant is particularly susceptible to O2 toxicity because they do not develop or acquire appropriate defense mechanisms until the 3rd trimester (after 28 weeks gestation). Prolonged or excessive exposure to O2 may, in fact, cause problems like bronchopulmonary dysplasia (BPD) or retinopathy of prematurity (ROP). Children with BPD are in and out of hospitals with chest infections and asthma. They also have lower intelligence and grow more poorly because of repeated episodes of hypoxia (low body O2) from lung damage and steroids. The latter improves lung function but may also impair brain growth. Children with ROP may be severely short-sighted and even blind. Unfortunately, many premature infants, if they survive, still develop BPD and ROP despite considerable advances in prenatal care (e.g. maternal steroids that accelerate lung maturation), postnatal care (e.g. artificial surfactant that aids lung expansion) and an awareness of the profound consequences of O2 toxicity in this population. The use of oxygen during resuscitation: More than 1 million infants around the world do not breathe after birth and require resuscitation. For more than a century, pure or 100% O2 has been given to such infants through breathing masks or tubes. A change in color from blue or white to pink is generally taken to be a positive response to resuscitation. However, recent studies of full-term human newborn infants now advocate caution because there is increasing evidence giving an infant 100% O2 may cause excessive formation of toxic reactive oxygen species (ROS) that injure vital cellular components like membranes and DNA (deoxyribonucleic acid). This may delay the infant’s recovery and even double the risk of death. What about the premature infant? Studies have shown that full-term infants may be resuscitated with room air (RA, 21% O2) with good result. However, premature infants often have some lung immaturity and may need a bit of O2 after birth to prevent hypoxia. How much O2 that is, is not certain. Whether giving a preterm infant lower amounts of O2 during resuscitation may improve outcome is also not known. The aim of the To2rpido study is to see if using RA to start the resuscitation of very premature infants (<31 weeks gestation) reduces oxidative injury and complications such as BPD, ROP, cerebral palsy (CP) and death. Location: This is an international study in Australia (n=3), Malaysia (n=6), Singapore (n=1) and India (n=1). These sites are important to show that the resuscitation techniques used in the To2rpido study may be applied to neonatal intensive care units in both developed and developing nations. How the study will be conducted: We will compare RA to 100% O2 to start the resuscitation of premature infants below 31 weeks gestation in the delivery suite. O2 will be changed depending on the infant’s oxygen saturations (percentage of oxygenated hemoglobin, SaO2) and the infant’s blood will be tested for O2-related stress products. Complications such as death, CP, BPD and ROP will be compared and survivors will be tested at 18-24 months of age for neurological and physical development. Significance: There is still no cure for prematurity, which affects more than 8% of infants worldwide. The number of premature infants has increased by 15% over the last two decades in the USA alone and their care costs more than $30 billion a year. In addition, most of the premature babies are born in non-Western countries and the techniques used in the To2rpido may therefore also have far-reaching consequences for the almost 13 million premature infants born around the world each year.