Evaluating resuscitation practices on the basis of evidence: The findings at first glance may seem illogical☆☆☆
Article Outline
Abbreviations: E2 2000 , Evidence Evaluation Conference, ILCOR , International Liaison Committee for Resuscitation
See related article, p 240 .
Perinatal asphyxia accounts for a large proportion of infant mortality and is responsible for many of the lifelong disabilities its survivors have. Therefore, defining the optimum technique for neonatal resuscitation becomes tremendously important in the list of challenges for improving health care delivery. The American Academy of Pediatrics, the American Heart Association, and the International Liaison Committee for Resuscitation (ILCOR) have addressed this challenge by organizing a periodical 5-year review of the current status of the science regarding resuscitation, after which clinical recommendations are structured around the science. The early recommendations were based primarily on logic and experience, because very few studies had been conducted.1 But considerable progress has been made through the subsequent iterations of the reviews. The needs of the neonate have been recognized as quite different from those of the adult or even the older child. Several of the previously recommended actions such as the use of bicarbonate, vagolytics, and myocardial and respiratory stimulants have been removed or de-emphasized, as described in the report from the most recent Evidence Evaluation Conference (E22000)2.
Probably the two most controversial neonatal issues discussed in E22000 were that neonates who had been asphyxiated should perhaps have their heads packed in ice and that consideration should be given to resuscitating infants with room air (21%) rather than 100% oxygen. Each of these strategies are intended to reduce hypoxic–ischemic cellular injury—the first through inhibition of hypoxia-induced neuronal cell death and the second through minimizing the burst of oxygen-free radicals known to be released during the process of reoxygenation. The hypothermia recommendation offended many clinicians who had been taught since the 1950s that keeping a baby warm was the key to improving neonatal survival. And the avoidance of supplemental oxygen suggestion seemed to fly in the face of the knowledge that asphyxia and its sequelae were the result of oxygen deprivation, that the efficiency of cellular energy production, as measured by generation of adenosine triphosphate, was highly dependent on the presence of oxygen, and that pulmonary hypertension—a common complication of perinatal asphyxia—is often relieved by prompt and consistent administration of supplemental oxygen. Although there were some animal studies suggesting benefits from each of these new actions, the wisdom of the E22000 evaluators was that both required more evidence from human trials before being recommended for widespread implementation.
In this issue of The Journal we are fortunate to have the results of one human study examining the 21% versus 100% oxygen question.3 This is the second report of a controlled trial from this group of investigators, although it is not clear whether the subjects from their first report4 are included in the current one. In the current article by Vento et al, 106 newly born infants with varying degrees of asphyxia were randomized to be resuscitated with either 21% or 100% oxygen. Although 151 infants were initially enrolled in the study, 45 of these were subsequently removed for failing to meet criteria or for methodologic reasons, so that only 106 were included in the final analysis. Blood samples were collected at birth from the umbilical cord, at the onset of spontaneous respirations, and again 10 minutes later, when recovery was considered complete. The investigators also examined cord blood samples from 22 nonasphyxiated control neonates, but for practical and ethical reasons were unable to collect the latter two samples from the controls. There was no difference in mortality, whether the infants were resuscitated with room air or with 100% oxygen, but the infants resuscitated with oxygen initiated spontaneous respirations a minute or two later. The blood analyses showed that all groups, including the controls, had evidence of oxidative stress at birth, but those resuscitated with oxygen developed significantly higher values after resuscitation than infants resuscitated with room air.
Another group of investigators led by Saugstad in Norway has reported similar findings from two separate clinical trials.5, 6 The previous trials and the current trial have found no difference in mortality, whether newly born infants were resuscitated with room air or with 100% oxygen, and there was evidence that exposure to the supplemental oxygen resulted in generation of excessive reactive oxygen species that may prove injurious to neural and other tissues. There is considerable evidence from animal models that exposure to hyperoxia during and after the hypoxic period can generate excessive neurotoxic compounds7, 8 and that resuscitation with room air may result in better neurologic outcome.9 Markers of increased oxidative stress have been found in human neonates as long as 28 days after resuscitation with 100% oxygen.4
But before we decide to move from one extreme (100% oxygen) to the other (21%, or perhaps even hypoxemia10), we need to examine the existing evidence carefully. First, is it clear that the infants examined in the current and previous trials were really severely asphyxiated? The vast majority of neonates can be resuscitated quite effectively by simply ventilating the lungs adequately.11 It is primarily infants who have had long intrapartum hypoxia and ischemia, those who require resuscitation at extremely low gestations, and those who require advanced stages of cardiopulmonary resuscitation that are more likely to die or have sequelae. All of the subjects in the current study were born at term and had rapidly improving Apgar scores. Oxygen saturations of >90% were achieved within 2 minutes of birth and only 2 of the 106 babies required supplemental oxygen after the resuscitation. The observation that onset of spontaneous respirations was delayed slightly in the supplemental oxygen group is not surprising in that chemoreceptors were likely suppressed by the continuing hyperoxemia after resuscitation.
Second, as evidenced by data from the controls and as the authors and others have demonstrated by previous studies, a certain degree of oxidative stress is a normal phenomenon of transition from the relatively hypoxemic intrauterine environment to the hyperoxemic state after air breathing. Determining the optimum degree and rate of this change under different scenarios becomes difficult.
Third, perhaps neither of the extremes examined in this and previous studies has evaluated the optimum strategy. It would seem that restoration of adequate cellular energy production while minimizing the generation of reactive oxygen species should be the goal. We know from basic biochemistry that 18 to 19 times more adenosine triphosphate is generated from glucose during aerobic than during anaerobic metabolism; rapid reversal of the anaerobic state without overoxygenating would seem to be a reasonable target. This reversal may be achieved more quickly with supplemental oxygen. However, once ventilation and cardiac output have been restored, there should be no need for excess oxygen, and the evidence would indicate that such an excess is likely deleterious, particularly in the infant born significantly preterm. Therefore perhaps we should be aiming to restore normoxia quickly and to achieve normal levels of blood oxygen throughout and beyond the resuscitation process. More aggressive use of the pulse oximeter in the delivery setting may facilitate achieving this goal.
Despite the recommendations made in 2000 by ILCOR that 100% oxygen continue to be used, it appears as if many have already changed their practices to some degree. Preliminary results from a recent international survey of a sample of academic centers disclosed that approximately 50% of the neonatologists responding from 13 countries reported that they already have begun to modify the percentage of oxygen used during neonatal resuscitation in their institutions.12
It has been suggested that as many as 7000 asphyxiated neonates would need to be randomized to room air versus 100% oxygen to achieve adequate statistical power to determine with confidence which of these oxygen concentrations is most appropriate for resuscitation of newborns.13 Such a trial may not be unreasonable through a collaborative, multicenter, and possibly international effort. But maybe we are testing the wrong hypothesis. Any future massive randomized trial may need a third arm—one where achievement of normoxemia throughout the resuscitation process would be the goal. In the meantime, perhaps during the upcoming Evidence Evaluation 2005 Conference, the reviewers will decide that there is already sufficient evidence on both sides of the issue that achievement of normoxemia during neonatal resuscitation should be our goal.
References
- Standards for cardiopulmonary resuscitation (CPR) and emergency cardiac care (ECC). JAMA. 1974;227(suppl):833–868
- International guidelines for neonatal resuscitation: an excerpt from the Guidelines 2000 for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care: International Consensus on Science. Pediatrics. 2000;106:E29
- . Oxidative stress in asphyxiated term infants resuscitated with 100% oxygen. J Pediatr. 2003;142:240–246
- . Resuscitation with room air instead of 100% oxygen prevents oxidative stress in moderately asphyxiated term neonates. Pediatrics. 2001;107:642–647
- . Resuscitation of asphyxic newborn infants with room air or 100% oxygen. Pediatr Res. 1993;34:809–812
- . Resuscitation of asphyxiated newborn infants with room air or oxygen: an international controlled trial: The Resair 2 study. Pediatrics. 1998;102:e1
- . Hypoxanthine, xanthine, and uric acid in newborn pigs during hypoxemia followed by resuscitation with room air or 100% oxygen. Crit Care Med. 1993;21:1058–1065
- . Hypoxemia and reoxygenation with 21% or 100% oxygen in newborn pigs: changes in blood pressure, base deficit, and hypoxanthine and brain morphology. Pediatr Res. 1992;32:107–113
- . Cardiopulmonary-cerebral resuscitation with 100% oxygen exacerbates neurological dysfunction following nine minutes of normothermic cardiac arrest in dogs. Resuscitation. 1994;27:159–170
- . Early cerebral metabolic and electrophysiological recovery during controlled hypoxemic resuscitation in piglets. J Appl Physiol. 1998;84:1208–1216
- . Cardiopulmonary resuscitation in the delivery room: associated clinical events. Arch Pediatr Adolesc Med. 1995;149:20–25
- Personal communication from Colm P. F. O'Donnell. Melbourne: Royal Women's Hospital , Australia; December 30, 2002;
- . Room air or oxygen for asphyxiated babies?. Lancet. 1998;352:341–342
☆ Reprint requests: John Kattwinkel, MD, Charles Fuller Professor of Neonatology, University of Virginia, Department of Pediatrics, Box 800386, Charlottesville, VA 22908.
☆☆ J Pediatr 2003;142:221-2.
PII: S0022-3476(03)00048-9
doi:10.1067/mpd.2003.147
© 2003 Published by Elsevier Inc.
Refers to article:
- Oxidative stress in asphyxiated term infants resuscitated with 100% oxygen
