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Resuscitation of Newborn Infants With 21% or 100% Oxygen: Follow-Up at 18 to 24 Months

Ola D. Saugstad, MD^*, Siddarth Ramji, MD, Simin F. Irani, MD, Safaa El-Meneza, MD, Emil A. Hernandez, MD^¶, Maximo Vento, MD^||, Tiina Talvik, MD^**, Rønnaug Solberg, MD, Terje Rootwelt, MD^* and Odd O. Aalen, PhD

^* Department of Pediatric Research, Rikshospitalet, University of Oslo, Oslo, Norway
Department of Pediatrics, Maulana Azad Medical College, New Delhi, India
Department of Pediatrics, King Edward Memorial Hospital, Mumbai, India
^¶ Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt
^|| Department of Pediatrics, Santo Thomas University Hospital, Manila, The Philippines
^** Department of Pediatrics, Hospital Virgen del Consuelo, Valencia, Spain
Children’s Hospital, Tartu University, Tartu, Estonia
Department of Pediatrics, Vestfold Sentralsykehus, Tønsberg, Norway
^¶¶ Section of Medical Statistics, University of Oslo, Oslo, Norway

	ABSTRACT

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Objective. To follow-up children who had been resuscitated at birth with either 21% or 100% oxygen (O₂).

Methods. A multicenter study with 10 participating centers recruited 609 infants to the Resair 2 study where resuscitation was performed with either 21% or 100% O₂. A follow-up between ages 18 and 24 months was performed. However, during follow-up registration, it was found that 18 infants had been enrolled twice in the original Resair 2 study with different registration numbers, leaving 591 enrolled in the Resair 2 study and 410 enrolled in the 7 centers participating in the follow-up. Of these 410 infants, 79 died (76 in the neonatal and 3 in the postneonatal period). Furthermore, for 8 infants informed consent was not obtained, leaving 323 eligible for follow-up. Of these, 213 infants (66%) were followed-up: 91 (62%) had been resuscitated with 21% O₂, and 122 (69%) with 100% O₂. At a median age of 22 and 20 months (not significant) in the 21% and 100% groups, respectively, a simple questionnaire was filled out and neurologic assessment was performed in addition to measuring anthropometric data.

Results. There were no significant differences in weight, height, or head circumference between the 2 groups. Cerebral palsy developed in 10% and 7%, respectively, in the 2 groups (not significant). In total, 11 cases (12%) in the 21% versus 11 cases (9%) in the 100% O₂ group (odds ratio: 1.39, 95% confidence interval: 0.57–3.36) developed cerebral palsy and/or mental or other delay. Furthermore, it was concluded that 14 (15%) in the 21% group and 12 (10%) in the 100% group were not normal (odds ratio: 1.67, 95% confidence interval: 0.73–3.80).

Conclusions. There were no significant differences in somatic growth or neurologic handicap at an age of 18 to 24 months in infants resuscitated with either 21% or 100% O₂ at birth. Based on these data, resuscitation with ambient air seems to be safe, at least in most cases. More studies are needed to settle this issue.

Key Words: follow-up • newborn • resuscitation • 21% O₂ • 100% O₂

Abbreviations: O₂, oxygen • OR, odds ratio • CI, confidence interval • CP, cerebral palsy • NS, not significant

Resuscitation procedures of the newly born infant have recently been extensively revised.^1–3 However, one important issue that still may need further clarification is the optimal concentration of supplemental oxygen in newborn resuscitation. In fact, 3 clinical studies have recently been performed, indicating that ambient air is as efficient as 100% oxygen (O₂) for resuscitation of newborn infants.^4–6 In one of these studies, significantly higher oxidative stress 1 month after resuscitation was found in infants resuscitated with 100% O₂.⁶ It is surprising and possibly of significance that even a brief exposure to 100% O₂ at birth triggers such long-term effects. These studies also show that the first breath and cry as well as the establishment of a normal regular breathing pattern occur significantly faster in those resuscitated with 21% O₂ compared with 100% O₂.^5,6

One of these studies, the Resair 2 study, was an international multicenter study testing out the efficacy of ambient air (21% O₂) versus 100% O₂ for newborn resuscitation. The early (7-day) neonatal mortality was found to be nearly identical in both groups, although there was tendency toward a lower neonatal mortality in the 21% O₂ group. Infants of the Resair 2 study have been followed-up to the age of 18 to 24 months. We report these follow-up data in this article.

	METHODS

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The Resair 2 study included 609 infants in need of resuscitation. The study was not blinded and the infants were pseudo-randomized because those born on equal days were resuscitated with ambient air and those on odd dates with 100% O₂. The entry criterion for enrollment in the study was: apnea or gasping with heart rate <80 beats per minute at birth necessitating resuscitation. Exclusion criteria were: birth weight <1000 g, lethal anomalies, hydrops, cyanotic congenital heart defects, and stillbirths. A stillbirth was diagnosed when a heart rate was never established.⁵ A total of 144 were born between 27 and 37 weeks (70 in the 21% and 74 in the 100% O₂ group).

When registering the follow-up forms, it was discovered that some patients had been reported twice with different identification numbers. We went back to the Resair 2 forms and discovered that 18 patients had been registered twice also in the original Resair 2 study. Of these 18 patients, 8 had been resuscitated with 21% and 10 with 100% O₂, changing the exact number of enrolled infants in the Resair 2 study from 609 to 591. A total of 280 (47%) had been resuscitated with 21% O₂ and 311 (53%) with 100% O₂, exactly the same distribution that was reported,⁵ also in accordance with the number of odd (51%) versus equal (49%) days in the enrollment period.

The basic data of Resair 2 such as birth weight, gestational age, gender distribution, Apgar scores, heart rates, or neonatal mortality were not changed because of the correction from 609 to 591 enrolled patients. Neonatal mortality was 15% in the room air group and 21% in the oxygen group, giving an uncorrected odds ratio (OR) of 0.68 (95% confidence interval [CI]: 0.44–1.06), very similar to 15% and 21% (OR: 0.67, 95% CI: 0.43–1.04) reported in the original Resair 2 study.⁵

Of the 10 centers contributing to the Resair 2 study, only 7 participated in the follow-up study. In the primary study, these 7 centers had contributed with 410 (69%) of the total cohort of 591 enrolled patients. Of these 410 children, 76 had died during the neonatal period, 30 of 186 (16%) in 21% O₂ group and 46 of 224 (21%) in the 100% O₂ group. A total of 75% died of a cause that could be directly linked to perinatal depression such as asphyxia, bleeding, or meconium aspiration. Deaths not directly related to perinatal depression were infections, prematurity, congenital malformations, and unspecific birth trauma. Furthermore, 3 more died in the postneonatal period, between 3 and 5 months of age, of meningitis, sudden infant death syndrome, and spinal muscle atrophy type 1.

Parental informed consent for participating in the follow-up study had not been obtained in 8 of the remaining infants, leaving 323 infants eligible for follow-up. Of these, 147 (46%) had been resuscitated with 21% O₂ and 176 (54%) with 100% O₂, also in accordance with the distribution of the original Resair 2 study.⁵ A total of 213 (66%) follow-up forms were received. Of those reported for follow-up, 91 (43%) had been resuscitated with 21% and 122 (57%) with 100% O₂, giving a follow-up percentage of 62% in the 21% group and 69% in the 100% O₂ group. Figure 1 shows a flowchart of the patients, and Table 1 shows the contribution from each participating hospital.

View larger version (26K): [in this window] [in a new window]   Fig 1. Flowchart of Resair 2 follow-up patients.

The follow-up questionnaire was simple and basic and intended to detect obvious neurologic delays. The age when developmental milestones were reached was noted. A normal neat pincer grip was defined if the child was able to use its thumb and index finger to pick up a small piece of white paper on another large, white paper. Language skill was checked by counting the number of words in the child’s vocabulary and whether or not she/he could speak in 2-word sentences. The mother assessed hearing by checking if the child turned its head toward a bell. Walking was considered normal if it was steady and unsupported. Cerebral palsy (CP) was diagnosed if the examiner found the child spastic with increased deep tendon reflexes. Mental skills using a standardized test were not tested formally, but the examiner was asked to conclude if there was any obvious mental retardation judged clinically. Any disease such as septicemia/meningitis, inborn error of metabolism, head trauma, severe malnutrition, or other causes of developmental delay were noted. The examiner performed a general neurologic examination observing posture, tone, spontaneous movements, as well as testing tendon reflexes. Based on the examiner’s judgment, he/she was asked to conclude whether or not the child had developed normally.

Statistics
Statistical analyses were performed with SPSS 11 for windows (SPSS, Inc, Chicago, IL). OR with 95% CI was used. Median and 95% CIs, or 5th and 95th percentiles are given, and nonparametric tests (2-tailed Mann-Whitney U test) were used when the distribution of the variable was not normal. Parametric tests (2-tailed t test) were used when the variables were approximately normally distributed.

	RESULTS

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The age of examination, mother and father’s age, and the duration of their education were not significantly different between the 2 groups (Table 2). Nine infants were examined between the ages of 12 to 18 months, 3 in the 21% and 6 in the 100% O₂ group.

Hearing tested grossly by the child’s turning of the head toward a bell was abnormal in 3 children in the 21% group and 2 children in the 100% O₂ group (NS).

CP and Neurologic Delay
A total of 17 children developed cerebral palsy and 1 a hemiparesis. Nine (10%) of these belonged to the 21% O₂ group (7 spastic di/hemiplegia, 1 spastic quadriplegia, and 1 mixed CP), and 9 (7%) to the 100% O₂ group (6 spastic diplegia, 2 mixed CP, and 1 with a hemiparesis following a capsula interna insult), P = .51, OR 1.38 (95% CI: 0.52–3.62). Two children had had nonfebrile seizures, one in each group. Other delays such as mental retardation or gross motor delay were found in 5 other infants in the 21% O₂ group (6%) and 4 infants in the 100% O₂ group (3%) NS. It was concluded that in the 21% O₂ group, an abnormal development was present in a total of 14 cases (15%) versus 12 cases (10%) in the 100% O₂ group, P = .22, OR 1.67 (95% CI: 0.73–3.80).

	DISCUSSION

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In this study, newborn infants who at birth had been resuscitated with either ambient air or 100% O₂ were followed up to the age of 18 to 24 months. No significant differences were found regarding postneonatal mortality. The percentage of children of those eligible to be enrolled in the follow-up study was 66% (62% of 21% O₂ and 69% of 100% O₂ group). It would had been an advantage with a higher follow-up rate; on the other hand, there are no indications that those lost for follow-up were different compared with those who were followed up in respect to birth weight, gestational age, gender, or severity of birth depression.

In surviving children, there were no differences between the 2 groups in somatic growth or psychomotor development. Furthermore, no significant differences were found regarding CP or other delays.

Although the testing in this follow-up study was relatively simple without formal testing of mental skills, we still feel it is prudent to conclude that no differences regarding psychomotor development between the 2 groups were found. However, in future studies there is a need for a formal follow-up to school age using standardized tests.

These data therefore indicate it is safe to resuscitate newborn infants with ambient air using the present protocol with a back up with 100% O₂ after 90 seconds in case of so-called resuscitation failure.⁵ In fact, it was a strong tendency to a lowered neonatal mortality in those resuscitated with 21% compared with 100% O₂.⁵ Despite this, as we have underlined previously,⁵ we cannot exclude the possibility that some subgroups of infants could benefit from resuscitation with oxygen supplementation. This has to be tested out in larger studies stratified for birth weight and gestational age as well as for the severity of perinatal depression. Such studies need to include a formal follow-up part. Because the Resair 2 study basically included term infants with relatively few preterm infants, and none with birth weight <1000 g, the effect on resuscitation of preterm infants should be explored specifically in future studies.

It has previously been shown by Lundstrom et al⁷ that premature infants given 80% O₂ at birth for a brief period of time had a 20% reduction of cerebral blood flow 2 hours later compared with infants given 21% O₂. Whether this affects brain metabolism or development is not known, although it is not likely to do so. On the other hand, Solaas et al^8,9 in newborn piglets with hypoxemia combined with unilateral carotic ligation, found a more rapid restoration of brain metabolism and cerebral cortical microcirculation, when pure O₂ was used for resuscitation compared with 21% O₂. This difference was not present in striatum and seems to almost completely disappear in the presence of mild hypercapnia.

Recently, Vento et al^6,10 detected elevated oxidative stress (assessed by oxidized to reduced glutathione ratio in erythrocytes and oxidation products of mitochondria DNA in urine [8-OH deoxyguanosine]) in infants resuscitated with 100% O₂ even 1 month after birth. Infants resuscitated with 21% O₂ had normalized oxidative stress at this time. Because oxidative stress might influence growth and development of the newborn brain,^11,12 it is tempting to suggest that oxygen exposure at birth, even for a brief period of time, might trigger long-term effects. It is therefore of interest that Cnattingius et al¹³ in a study from Sweden analyzed risk factors for childhood acute lymphatic leukemia and found that a brief exposure to 100% O₂ of only a few minutes at birth significantly increases the risk (more than two-fold). Therefore, it seems that pure oxygen given around birth might have long-term effects on the growing child probably by augmenting oxidative stress for weeks. Furthermore, in a recent study in newborn piglets in which asphyxia was induced by pneumothorax, Temesvari et al¹⁴ have demonstrated that animals resuscitated with 21% O₂ had a significantly better neurologic score than those given 100% O₂.

The optimal resuscitation procedure should probably be tailored to every infant according to its oxygen saturation so that oxygen supplementation is individualized according to each infant’s need. This requires fast acting and reliable pulse oximeters and a more thorough knowledge of the normal saturation values the first seconds and minutes of life according to the gestational age.¹⁵ Because pulse oximeters are expensive it is, however, not realistic even if technical problems are solved, that they will be used routinely globally in all infants suffering from depression at birth.

The present follow-up study obviously has several weaknesses. The Resair 2 study was not designed for a follow-up. The number followed up might be too small to pick up any differences. For instance, to detect a 5% difference in abnormal development (15% vs 10%) would require a sample size of 680 in each group with a power of 0.8 and a significance level of 0.05. The mortality in the Resair 2 study was high compared with figures in industrialized countries. How this might affect the long-term outcome is not known but it is perhaps reasonable to suggest that the rate of sequelae also would be lower in industrialized countries.

	CONCLUSIONS

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This follow-up study indicates that newborn infants with birth weight >1000 g, who at birth had been resuscitated with either 21% or 100% O₂, have similar outcomes at follow-up between 18 and 24 months regarding both somatic growth and psychomotor development. Because neonatal mortality shows a tendency toward lower levels in infants resuscitated with 21% compared with those resuscitated with 100% O₂, it seems that resuscitation with ambient air is safe and efficient, at least in most cases needing newborn resuscitation. However, it can not be concluded from this study that subgroups of newborn infants would not need oxygen supplementation at birth. Whether or not 100% O₂ for newborn resuscitation is detrimental should be tested out in new and even larger studies with long-term follow-up.

	ACKNOWLEDGMENTS

 
The Laerdal Foundation for Acute Medicine and the Norwegian Council for Research supported this study.

	FOOTNOTES

 
Received for publication May 16, 2002; Accepted Jan 6, 2003.

Reprint requests to (O.D.S.) Department of Pediatric Research, Rikshospitalet, 0027 Oslo, Norway. E-mail: o.d.saugstad{at}klinmed.uio.no

	REFERENCES

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 

1. World Health Organization. Basic Newborn Resuscitation. Geneva, Switzerland: World Health Organization; 1998
2. Kattwinkel J, Niermeyer S, Nadkarni V, et al. ILCOR advisory statement: resuscitation of the newly born infant: an advisory statement from the pediatric working group of the International Liaison Committee on Resuscitation. Circulation.1999; 99 :1927 –1938[Free Full Text]
3. Niermeyer, S, Kattwinkel J, Van Reempts P, et al. International Guidelines for Neonatal Resuscitation: an excerpt from the Guidelines 2000 for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care: International Consensus on Science. Contributors and Reviewers for the Neonatal Resuscitation Guidelines. Pediatrics.2000; 106(3) . Available at: http://www.pediatrics.org/cgi/content/full/106/3/e29
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6. 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; 107 :642 –647[Abstract/Free Full Text]
7. Lundstrom K, Pryds O, Greisen G. Oxygen at birth and prolonged cerebral vasoconstriction in preterm infants. Arch Dis Child.1995; 73 :F81 –F86
8. Solaas A-B, Kutzsche S, Vinje M, Saugstad OD. Cerebral hypoxemia-ischemia and reoxygenation with 21% or 100% oxygen in newborn piglets: effects on extracellular levels of excitatory amino acids and microcirculation. Pediatr Crit Care Med.2001; 2 :340 –345[CrossRef][Medline]
9. Solaas A-B, Kalous P, Davis J, Saugstad OD. The effects of recombinant superoxide dismutase (rh-SOD) and reoxygenation with 21% or 100% O₂ in asphyxiated newborn piglets. Pediatr Res.2001; 49 :307A
10. Vento M, Asensi M, Sastre J, Garcia-Sala F, Vina J. Six years of experience with the use of room air for the resuscitation of asphyxiated newly born term infants. Biol Neonate.2001; 79 :261 –267[CrossRef][ISI][Medline]
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