It is estimated that 1.2 million newborn infants die each year from asphyxia-related events . During asphyxia, oxygen and nutrient deprivation (ischemia) result in energy failure leading to death if reperfusion (successful resuscitation) does not occur in time. After a successful resuscitation severely asphyxiated infants frequently develop hypoxic–ischemic encephalopathy (HIE) leading to permanent neurological deficits. 100% oxygen is commonly used for resuscitation of asphyxiated infants. However, recent evidence suggests there is a paradoxical contribution of oxygen to both life and death. Although reperfusion reestablishes O2 delivery, the ischemic tissue responds to reperfusion not only by the restoration of bioenergetics , but also by excessive production of reactive oxygen species (ROS), contributing to reperfusion injury (reviewed in ).
The purpose of resuscitation is to restore tissue oxygen delivery before irreversible damage can occur. Traditionally, the resuscitation of asphyxiated infants has been supplemented with 100% oxygen. However, there is a concern that the use of 100% oxygen for resuscitation of asphyxiated infants carries the potential risk for exacerbation of oxidative injury. This conundrum has triggered experimental and clinical studies to determine whether reoxygenation with room air can substitute for 100% O2 during resuscitation.
Guidelines for the use of room air or 100% O2 in neonatal resuscitation
In 2005 the International Liaison Committee on Resuscitation (ILCOR) recommended that the initial concentrations of O2 for resuscitation of neonates could vary between 21 and 100% . The AHA recommends initiating resuscitation with 100% O2 only when an infant is cyanotic or receives positive-pressure ventilation . The choice of an oxygen concentration for resuscitation requires a full understanding of the risks and benefits for using 100% oxygen or room air in resuscitation.
The outcome measures for resuscitation success
In adult and pediatric patients the rate of return of spontaneous circulation (ROSC) and resuscitation time to ROSC are classical end points to validate the quality of resuscitation . The ROSC is defined as ‘the restoration of a spontaneous perfusing rhythm that results in more than an occasional gasp, fleeting palpated pulse, or arterial waveform’. Signs of the return of spontaneous circulation include rhythmic breathing, coughing or movement. The time at which ROSC is achieved is considered a core data element . In neonatology the term ‘ROSC’ is not widely accepted. The pulse rate, Apgar score, delayed mortality rate and/or incidence of HIE, or both, indices of oxidative stress, time to the first spontaneous breath or cry and recently, the resuscitation time to achieve a targeted SaO2 value have been reported as primary outcome measures to compare resuscitation strategies with the use of 100% O2 or room air [7–9,10•].
The Apgar score is used worldwide; pulse rate, respiratory efforts, skin color, response to suctioning and muscular tone are useful clinical signs to define ROSC. Clearly, when the initial Apgar score is 0–1, cardiopulmonary resuscitation (CPR) is required and timely improvement of the score can validate the efficacy of CPR. It is unclear, however, at what Apgar score a sustained ROSC is achieved. Should the goal of resuscitation be an Apgar score of 4–5, or should we aim for a higher value?
The immediate mortality rate at the resuscitation scene clearly validates the efficacy of resuscitation. However, a late mortality rate may not be directly attributable to the quality of the resuscitation because variables occurring during postresuscitation care influence this outcome. In adult patients the availability of therapeutic hypothermia, interhospital variations in monitoring, respiratory care and treatment greatly influence the delayed survival rate [6,11,12]. It is debatable whether mortality rates recorded in different hospitals following days or weeks after resuscitation accurately represent the quality of resuscitation.
The resuscitation time to the first breath or cry can be viewed as a complementary outcome to the Apgar score. However, the same question is applicable here. Should we initiate or continue hyperoxic ventilation if the Apgar score is 4? If the answer is ‘yes’, then a delayed spontaneous cry or breath should not be surprising, because with a restored circulation chemoreceptors are likely to be suppressed by the hyperoxemia . If the answer is ‘no’, then the changes in inspiratory oxygen content (FiO2) should be driven by the goal-set SaO2. Recent studies in premature neonates have demonstrated that during resuscitation pulse-oximetry reliably monitors circulating oxygen content and a SaO2 goal can be achieved by titrating FiO2 up or down [10•,14•,15].
It is for clinicians to decide what primary outcome directly validates the efficacy of resuscitation. This decision is important for interpretation of the available data and design of future clinical trials and animal studies. If the major goal of resuscitation is to reestablish a sustained spontaneous circulation, then reoxygenation strategies used to achieve this goal may vary, but not the primary end point. Does resuscitation with 100% oxygen or room air result in the faster return of a spontaneous circulation and immediate survival in asphyxiated neonates?
Clinical trials and systematic reviews
There have been several randomized clinical trials comparing the efficacy of resuscitation with room air or 100% O2 in depressed term and preterm infants [7–9,10•,15,16]. In two studies accounting for more than 80% of reported infants (reviewed in ), the 1-minute Apgar score was significantly lower in the 100% O2 group compared with room air-resuscitated infants; P = 0.01  and 0.004 . At 5 min the Apgar scores were similar in both groups. These results suggest that resuscitation with room air improves the 5-min Apgar score as efficiently as the resuscitation with 100% O2, although the initial severity of asphyxia was significantly less in the group resuscitated with room air. In the ‘Resair 2’ trial 25.7% of infants resuscitated with room air (for 90 s) required a switch to 100% O2 secondary to a poor response . The same proportion of infants resuscitated with 100% O2 also exhibited a poor response by 90 s. Unfortunately, no subgroup analysis of these cohorts (the severity of asphyxia at birth) has been reported. The results of two trials by Vento et al.[9,16] suggest that, in infants with initial Apgar scores 3 or 4, resuscitation with room air is as effective as resuscitation with 100% O2. Although these studies have limitations [17,18], the clinical significance of these [7–9,16] reports is enormous. These studies suggest that it may be inappropriate to recommend 100% oxygen for resuscitation of all depressed neonates . Indeed, the trial with the largest number of enrolled patients demonstrated that the majority (74.3%) of infants born with initial Apgar scores between 1 and 7 would exhibit an adequate response to resuscitation initiated with room air . However, prior to revision of the current neonatal resuscitation guideline it has to be established that resuscitation initiated with room air is not inferior to resuscitation with 100% O2 in achieving a sustained ROSC in asphyxiated term infants at greatest risk of mortality (initial Apgar score 0–1).
Wang et al.[10•] demonstrated that the median Apgar score at 5 min was significantly higher in premature neonates resuscitated with 100% O2 versus room air. In this trial the initiation of resuscitation with room air failed to achieve a targeted SaO2 value of 80–85% by 5 min of life. If the combination of a targeted SaO2 value and Apgar score at 5 min of life reliably reflects the quality of circulation and oxygenation during CPR, then these data question the use of room air as an initial gas for resuscitation of premature infants. In a recent study by Dawson et al.resuscitation of infants <30 weeks gestation with air or 100% oxygen. Arch Dis Child Fetal Neonatal Ed 2008. [Epub ahead of print]
Animal models and resuscitation with 100% O2 and room air
Almost all studies published to date investigated resuscitation with room air or 100% oxygen using a model of hypoxia-induced asphyxia in immature mammals. This model reproducibly induces a systemic metabolic acidosis consistent with that seen in depressed human neonates. However, it does not reproducibly result in collapse of cerebral circulation relevant to severe asphyxia in humans. For instance, global hypoxia in piglets is associated with a significantly increased (not decreased) cerebral blood flow (CBF) at the end of asphyxic insult . To avoid this limitation, Solas et al.[21–23] combined a global hypoxic or hypoxic–hypercarbic exposure with a brief occlusion of both carotid arteries. This modification induced a profound (<10% compared with a baseline) decrease in the CBF, placing the brain at high risk for ischemic injury (the most critical event in severely asphyxiated neonates). In this modified piglet model, reoxygenation with 100% O2 resulted in significantly faster normalization of mean arterial blood pressure and more complete restoration of the microcirculation in the cerebral cortex compared with reoxygenation with 21% O2[21,23]. Using a neonatal mouse model of hypoxic–ischemic brain injury induced by permanent ligation of right carotid artery and hypoxic exposure, Presti et al. also reported that restoration of cerebral blood flow occurred significantly faster if reoxygenation was initiated with 100% O2 compared with room air. It remains unclear, however, whether this increased rate of CBF restoration driven by 100% O2 attenuates or exacerbates the extent of ischemic brain injury. In a model of hypoxia–ischemia in normocapnic newborn piglets Solas et al.[21–23] observed significantly higher levels of excitatory amino acids in the striatum, a lower mean arterial pressure, and a significantly greater degree of hypoperfusion in the cerebral cortex after reoxygenation with 21% oxygen compared with 100% oxygen. This suggests a less favorable outcome in the group receiving room air . These data indicate that, in animal models of hypoxia–ischemia, reoxygenation with room air significantly delays restoration of systemic and cerebral circulations – the ultimate goal of resuscitation. However, there are limitations in the design of these studies: the degree of asphyxia was not severe enough to cause circulatory collapse, an event associated with Apgar score 0–1, and the reoxygenation time (30 min) was chosen arbitrarily without defining the physiological response targeted by hyperoxic or normoxic reoxygenation. Therefore, these studies cannot clarify whether, in the subject with an arrested circulation, the initiation of resuscitation with room air will result in the same rate of ROSC as achieved with 100% O2. In mature pigs, hyperbaric hyperoxic ventilation during resuscitation significantly improved the rate of sustained ROSC and immediate survival after prolonged (15 and 25 min) cardiopulmonary arrest [25,26••]. Similarly, when neonatal mice with a ligated right carotid artery were subjected to prolonged hypoxia associated with circulatory collapse defined by the cessation of blood flows in brain and peripheral tissues, the rate of ROSC and immediate survival were significantly (χ2P = 0.023) greater if reoxygenation was initiated with 100% O2 than with room air (Fig. 1a–c, unpublished observation). These data suggest that, in animals with an arrested circulation, resuscitation with the use of a gas with a maximal O2 content is superior to the use of gas with lower O2 concentration. It is possible that concentrations other then 100% O2 would also result in a success rate similar to that achieved with 100% O2. However, before this research is undertaken, animal studies appropriately designed to test the efficacy of resuscitation should determine whether 100% O2 is indeed superior to room air in enhancing immediate survival.
The resuscitation-induced oxidative stress and FiO2
It is expected that a successful resuscitation will initiate oxidative reperfusion injury in tissues with maladaptive metabolic changes induced by ischemia. It is also expected that any delay in the delivery of O2 will exacerbate cellular energy deficits, reducing chances for functional recovery. Successful normoxic or hypoxic resuscitation may potentially reduce production of reactive oxygen species by limiting O2 flooding into ischemic tissue. Numerous animal studies have tested this hypothesis. However, were these studies really designed to test the effect of resuscitation with 100% oxygen? In the vast majority of reports, hyperoxic ventilation was used for a prolonged period of time in anesthetized animals with an already restored circulation, often resulting in extreme hyperoxemia [20–22,27–31]. For instance, in the study by Haase et al. piglets (following hypoxic exposure) were ‘resuscitated’ with either 21 or 50 or 100% O2 for 1 h, resulting in excessive hyperoxic exposure (PaO2 more than 300 mmHg). The authors reported a significantly greater oxidation of glutathione in the intestinal tissue in piglets ventilated with 100% O2 compared with other groups. The morphological evidence for intestinal damage was found only in animals ‘resuscitated’ for 4 h with 50 and 100% O2. This report may have some translational value for postresuscitation critical care, but its relevance to resuscitation is uncertain. All animal research to date has the same limitation, the absence of a physiological end point to justify the use of 100% O2. For instance, why should hyperoxic reoxygenation last 15 or 30 min and not 3 min? Presti et al. have shown that it took only 2 min of hyperoxic reoxygenation to reestablish cerebral blood flow in hypoxic–ischemic mice. In anesthetized piglets asphyxiated by a full respiratory arrest for 10 min, reoxygenation with 100% O2 reestablished cortical CBF to the baseline level within 4 min , yet hyperoxic ventilation was continued in both studies for 30  and 60 min resulting in a PaO2 = 348 ± 57 mmHg . If the goal of CPR is to reestablish spontaneous circulation, then studies published to date provide no evidence that resuscitation with the use of 100% O2 (not postresuscitation care) exacerbates oxidative tissue injury and results in a significantly more extended ischemic brain (or other tissue) damage. However, it is absolutely clear from the animal data that all efforts should be made to avoid uncontrolled use of O2 following a successful resuscitation.
There are clinical reports by Vento et al.[9,16,33] suggesting that, compared with resuscitation with room air, the use of 100% O2 is associated with significantly increased levels of circulating markers of oxidative stress persisting for several weeks following asphyxia. These data are intriguing, since the temporal peak for hypoxic–ischemic brain injury occurs within hours to days after the insult followed by a smoldering neuroapoptosis coinciding with brain tissue repair over several weeks . Therefore, elevated markers of oxidative stress detected at 28 days after an index event may be associated both with the injurious effect of oxygen (as suggested by authors) and with active cerebral healing as reactive oxygen species mediate neovascularization and tissue growth [35,36]. These reports by Vento et al.[9,16,33] showing clinical evidence for exacerbation of oxidative stress following hyperoxic resuscitation highlighted the need for the revision of the use of 100% oxygen in resuscitation of all depressed infants and additional animal studies properly designed to compare the effect of normoxic and hyperoxic resuscitation on postischemic oxidative damage and long-term neurological outcome.
A successful resuscitation induces oxidative stress. The results from clinical trials suggest that the infants born with a preserved circulation can be successfully reoxygenated with room air. No clinical or experimental evidence exists to support the belief that the use of room air for resuscitation of asphyxiated infants born with a collapsed circulation results in the same rate of ROSC or resuscitation time to ROSC as resuscitation with 100% oxygen. Animal studies strongly indicate that hyperoxic exposure extended into a postresuscitation management of asphyxia is detrimental. There is no compelling evidence that the use of 100% oxygen for resuscitation limited to the ROSC exacerbates postischemic oxidative damage. Thus, on the basis of current data, reoxygenation with room air should be recommended for depressed infants born with a preserved spontaneous circulation (heart rate >60 beats per minute). The use of 100% oxygen should be reserved for resuscitation of asphyxiated infants born with an arrested or markedly depressed (heart rate <60 beats per minute) circulation.
This work was supported by NINDS grant #NS 056146. Authors are thankful to Dr Richard Polin for his editorial assistance.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 273).
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