11/11/2004
Use and misuse of oxygen in the newborn period

Ola Didrik Saugstad, MD, PhD
Professor of Pediatrics, University of Oslo, Norway

Oxygen is one of the most used drugs in medicine, and especially so in the newborn period. In many cases oxygen supplementation is needed and is lifegiving, but we also are aware of its toxic effects. In spite of this we still do not know exactly the correct way to administer this drug. For instance, the correct dose and duration of therapy, neither for term and premature babies in need of resuscitation at birth nor for preterm infants requiring oxygen supplementation beyond the delivery room, is not fully known.

Oxygen
Oxygen was probably discovered and described already in 1604 by the Polish alchemist Sendivogius who heated nitre and released what he called aerial nitre. Sendivogius described this substance as the Elixir of life without which no mortal can live. This was approximately 170 years before Scheele and Priestly who up to now have been honored as the discoverers of oxygen.

After the experiments of Scheele, Priestly and most especially Lavoisier, oxygen quickly came into use in adult medicine. When oxygen was introduced in newborn medicine almost 100 years ago no critical questions seemed to be raised. Even as recently as a decade ago the American Heart Association stated that a brief exposure of 100% oxygen around birth does not represent any risk. But today we are slowly understanding that this might not be so.

Both clinical and experimental studies the recent decade or so have brought this field forward and more clinical studies are now planned. While awaiting the results and conclusions of these studies we in the meanwhile still may draw some conclusions regarding the use of oxygen in the newborn period.

Resuscitation
Several animal studies and five clinical studies have demonstrated that hypoxic newborn subjects may be resuscitated with ambient air. If this is the case it represents a step forward since it simplifies the resuscitation procedure and also reduces the costs. Becoming independent of the oxygen tank resuscitation can be carried out wherever a birth finds place merely by using a mask coupled to a self-inflating bag. Many places in the world newborn resuscitation was previously not even initiated if oxygen was not
available because it has been considered absolutely needed for this procedure.

The WHO took a brave and important step forward when they in 1998 stated that room air can be used for basic resuscitation of the newborn. It also represented a leap forward when the American Heart Association/American Academy of Pediatrics in their guidelines of 2000 underlined that resuscitation should be carried out with ambient air if oxygen is not
available.

Animal data accumulated recently are now strongly indicating that room air is not only equal to pure oxygen it gives less injury in several organs as the lung, myocardium and brain.

The following is known from studies in newborn hypoxic piglets:

• Resuscitation with pure oxygen increases the concentration of reactive oxygen species both in the lungs and the brain, by contrast to resuscitation with room air that does give such elevations.
• Brain injury is augmented when assessed by increase in glycerol and
  metalloproteinases in the brain, and by histologic changes. Some of the same biochemical changes are also found in the lung and heart.
• Short term neurologic recovery is poorer as well in those animals resuscitated with oxygen compared with ambient air.

That the lungs are affected by inhaling pure oxygen might be possible to understand, however that also the heart and brain are affected is more astonishing and perhaps more concerning.

In the human infants needing resuscitation at birth it has been shown that pure oxygen triggers an increased oxidative stress at least four weeks after birth. A recent meta-analysis including 1737 infants resuscitated either with 21% or 100% oxygen has given the dramatic finding that neonatal mortality is reduced 40% in the 21% group (OR 0.59 (95% CI 0.40-0.87). Further, short term recovery is also faster in these infants since heart rate at 90 seconds and Apgar score at 5 min are significantly higher. Time to first breath is significantly earlier, in median 0.5 min in room air resuscitated infants.

Another concerning finding has been that newborn babies exposed to pure oxygen only for 3-10 minutes after birth have a significant increased risk of developing childhood leukemia.

Oxygenation in the neonatal period beyond the delivery room
Five studies have so far systematically investigated the effect of high or low oxygen saturation in extremely low birth weight infants. The design of these studies are different, some follow the children immediately after birth and the following weeks and one study randomised infants to standard or high saturations at post conceptional age of 32 weeks. Still, in spite of the disparities and weaknesses of these studies all of them equivocally
indicate that a lower saturation gives less ROP stage 3-4 and less pulmonary problems.
Time in oxygen and on artificial ventilation is longer in the high saturation babies than in the low saturation babies. Some of these studies even indicate that growth is slower in those nursed in a high saturation milieu. From these studies it seems that saturation should be kept at 92%. It also seems clear from these and other studies that fluctuations in SaO2 should be avoided. The saturation peaks in relation to suctioning or bagging therefore should be avoided. Careful teaching of the staff - doctors and not least important nurses - is needed in order to achieve this.

What about the children who have a high saturation in spite of breathing room air? It is today common that even among the most immature infants supplementary oxygen is not needed and SaO2 > 95% often is seen. This may be the backside of the coin due to introduction to extremely potent and efficient therapies such as antenatal corticosteroids and postnatal surfactant therapy. In one recent investigation such infants were studied
separately with respect to development of severe ROP. These children progressed to threshold ROP to lesser extent than babies purposely nursed in a high saturation (McGrecog ML, et al. Pediatrics 2002;110:540-544 Free Full Text).
Such healthy babies for some reason seems to be less vulnerable at least to develop severe ROP.

Conclusions and recommendations
Pure oxygen should be avoided for routine and basic newborn resuscitation. Any extra oxygen given should be titrated according to the SaO2. Optimal resuscitation therefore would require saturation measurements.

Regarding ELBWI SaO2 should not exceed 92% and strict controls to avoid peaks is imperative. Whether SaO2 values should be different the first 1-2 weeks of life compared with the following weeks is not known.

Top