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Ann Thorac Surg 2000;70:2125-2131
© 2000 The Society of Thoracic Surgeons

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Original article: cardiovascular

Effects of hyperoxia on neonatal myocardial energy status and response to global ischemia

^a Institute of Medical Science, University of Toronto and Division of Cardiovascular Surgery, The Hospital For Sick Children, Toronto, Ontario, Canada

Accepted for publication June 2, 2000.

Address reprint requests to Dr Wittnich, Clinical Sciences Division, University of Toronto, Rm 7256 Medical Sciences Building, 1 King’s College Circle, Toronto, M5S 1A8 ON, Canada
e-mail: c.wittnich{at}utoronto.ca

	Abstract

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Background. This study examines the effect of neonatal exposure to clinically relevant hyperoxia levels on both in vivo myocardial metabolism and the subsequent metabolic response to global ischemia.

Methods. Three-day-old pigs were ventilated to normoxia (80 mm Hg, 2 or 5 hours, n = 11), mild hyperoxia (250 mm Hg, 2 hours, n = 9), or severe hyperoxia (500 mm Hg, 5 hours, n = 14). Ventricular biopsies obtained at the end of the ventilation period, and at early and late ischemia were analyzed for ATP, ADP, AMP, creatine phosphate, glycogen, and lactate.

Results. Hyperoxia did not significantly alter in vivo metabolism. During early ischemia, hearts exposed to severe hyperoxia had better ATP and glycogen preservation (p < 0.003). These hearts exhibited almost complete (92%) creatine phosphate depletion, in contrast to incomplete creatine phosphate use in all other neonatal hearts, even in the face of 30% ATP reductions. However, hearts exposed to severe hyperoxia also had a higher incidence of fibrillation during ischemia, which accelerated ATP and glycogen degradation.

Conclusions. Although severe hyperoxia provided an energy-sparing effect during early ischemia, it also increased the incidence of ventricular fibrillation, which negated this beneficial effect.

	Introduction

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Clinically, infants and children may be exposed to supraphysiologic levels of oxygen (hyperoxia) for varying durations during interventions such as cardiopulmonary bypass or extracorporeal membrane oxygenation. Under these conditions, systemic hyperoxia can reach an arterial partial pressure of oxygen (PaO₂) range of 250 to 500 mm Hg [1, 2] which can last for 4 to 5 hours during cardiac operations [2] or several days during extracorporeal membrane oxygenation [1]. The original rationale for the use of hyperoxia during cardiac operations was to overcome the hypothermia-induced leftward shift of the oxygen–hemoglobin dissociation curve and thus ensure adequate oxygen delivery. Although some degree of hyperoxia may be essential to ensure adequate oxygenation under hypothermic conditions, the rationale for its use under normothermic conditions is less clear. This is particularly relevant as, although the majority of current pediatric cardiopulmonary bypass uses some degree of hypothermia, some cardiopulmonary bypass procedures are done at or near normothermia in both children [3] and adults [4]. In addition, the use of extracorporeal membrane oxygenation as a postsurgical cardiac assist device often exposes the patient to normothermic hyperoxia [5]. This is of particular concern as a review of published research data indicates that hyperoxia exacerbates retrolental fibroplasia leading to blindness in children [6] and also inhibits key enzymes in many metabolic pathways [7] of adult animals, thus causing toxic effects on various tissues. If this metabolic impairment also occurred in children, this could reduce myocardial energy stores and the ability to tolerate a subsequent ischemic stress, and could ultimately affect the outcome of cardiac repair or cardiac assist procedures. Interestingly, a recent publication identified the importance of myocardial energy status on clinical outcome in pediatric patients [8]. Clearly, an analysis of the effects of hyperoxia on the neonatal heart’s energy status is warranted.

The need for study in this area is also emphasized by the publication of a series of studies by Buckberg and colleagues assessing the effects of hyperoxia on the immature heart after a period of acute hypoxia or ischemia [9, 10]. This study identified increased oxidant injury with hyperoxic reoxygenation/reperfusion. Although these studies pointed to hyperoxia-induced oxidant-mediated myocardial dysfunction, the effects of hyperoxia alone could not be isolated from the effects of prior exposure to hypoxia and ischemia/reperfusion or the effects of cardiopulmonary bypass itself (such as complement activation and neurohumoral factors). In addition, the effects on myocardial metabolism and ischemic tolerance were not examined. This article focuses exclusively on the effect of clinically relevant levels of hyperoxia on the previously normoxic neonatal heart’s myocardial metabolic profile and energy levels, and its subsequent metabolic response during ischemia without these other confounding variables.

	Material and methods

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Preparation
Male Yorkshire pigs (3 days old, 1.5 to 2.5 kg) were anesthetized with an intraperitoneal injection of sodium pentobarbital (65 mg/kg), intubated and mechanically ventilated to normoxia with medical air. Arterial blood gases (PaO₂ and PaCO₂) and acid–base status (pH and bicarbonate [HCO₃^-]) were monitored at regular intervals and appropriate ventilatory adjustments ensured that PaO₂ remained at the desired level and PaCO₂ was kept within a normal range (33 to 43 mm Hg).

Experimental protocol
To cover the range of hyperoxia reported clinically, mild hyperoxia was defined as a PaO₂ of 250 mm Hg for 2 hours, whereas severe hyperoxia was defined as a PaO₂ of 500 mm Hg for 5 hours. After stabilization at normoxia, animals were allocated to either the mild hyperoxia (n = 9), severe hyperoxia (n = 14), or normoxia control (PaO₂ = 80 mm Hg, 5 hours n = 5, 2 hours n = 6) study groups. Because the two normoxic control groups (2 and 5 hours) were not significantly different for any measured variable, data from the two groups were combined into a single normoxia control group (n = 11). The desired oxygen levels were achieved by adjusting the fraction of inspired oxygen as required. An overview of the experimental design is seen in Figure 1.

View larger version (25K): [in this window] [in a new window]   Fig 1. Methodology flow figure for the study groups after a short normoxic stabilization period.

All experimental procedures and protocols used in this investigation were reviewed and approved by the University of Toronto Animal Care and Use Committee and are in accordance with the National Institutes of Health "Guide for the Care and Use of Laboratory Animals" (NIH publication no. 85-23, revised 1985) and Canadian Council on Animal Care guidelines.

Myocardial metabolism
Full-thickness, freeze-clamp right ventricular free wall biopsies were immediately immersed in liquid nitrogen, freeze dried, and stored at -86°C for subsequent analysis. Adenine nucleotides (ATP, adenosine diphosphate [ADP], adenosine monophosphate [AMP]) and creatine phosphate (CP) were analyzed by high-performance liquid chromatography, myocardial lactate was determined by spectrophotometric analysis, and glycogen was determined by fluorometry. The total adenine nucleotide content and energy charge were calculated. Because TAN reflects the nondiffusible adenine nucleotides (ATP, ADP, AMP), reduced TAN levels indicate that adenine nucleotide breakdown has shifted to the diffusible adenine nucleoside products (eg, adenosine). In addition, EC is usually buffered to a range of 0.80 to 0.95; therefore, changes in EC would indicate that hyperoxia alters the energy status of the cell. All metabolites are expressed as micromoles per gram dry weight.

Statistical analysis
In the normoxia, mild hyperoxia, and severe hyperoxia groups, myocardial metabolites were obtained in vivo, before ischemia, and at early (15 minutes) and late (ischemic contracture onset) ischemia. Analyses of these metabolic profiles was by univariate repeated measures analysis of variance with Duncan’s multiple range test post hoc. Statistical significance was accepted at p less than 0.05 and trends were identified for 0.05 less than p less than 0.10. All values are expressed as mean ± standard error of the mean, unless indicated otherwise.

	Results

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Ventilation parameters
Baseline values (mean ± standard deviation) for blood gases (PaO₂, 83 ± 11 mm Hg; PaCO₂, 40 ± 4 mm Hg), acid–base status (HCO₃^-, 24 ± 3 mmol/L; pH, 7.40 ± 0.04), and heart rate (162 ± 15 beats/min) were similar among the groups. Once the fractional inspired oxygen was altered to create the hyperoxia study groups, both the mild (PaO₂, 256 ± 22 mm Hg) and severe (PaO₂, 432 ± 38 mm Hg) hyperoxia groups had significantly different (p < 0.0001) PaO₂ from their time-matched normoxic control groups (PaO₂, 82 ± 9 mm Hg). PaCO₂ was maintained within normal limits throughout the study (41 ± 8 mm Hg). Acid–base status (HCO₃^-, 24 ± 0.4 mmol/L; pH, 7.39 ± 0.06) and heart rate (164 ± 24 beats/min) were also stable throughout the ventilatory period and were not statistically different among the groups.

In vivo myocardial energy status
Exposure to hyperoxia produced subtle enhancement in many in vivo myocardial energy stores, although an ischemic stress was generally required to generate statistical significance between the study groups. For instance, relative to normoxia (19.0 ± 1.3 µmol/g), ATP content was 6% higher in mild hyperoxia and 14% higher in severe hyperoxia (Fig 2A), indicating a potential dose effect; however, this did not achieve statistical significance (p = 0.14). In vivo CP levels (Fig 2B) were also 19% and 14% higher with exposure to mild and severe hyperoxia, respectively. Of the other myocardial metabolites analyzed (Table 1), only the in vivo ADP content yielded statistical significance with significantly higher ADP in mild hyperoxia than in normoxia (p = 0.01). In addition, both the mild (16%) and severe (14%) hyperoxia groups exhibited a statistical trend (p = 0.09) to higher TAN levels compared to normoxia. Interestingly, myocardial glycogen (Fig 3) and lactate (Table 1) were not statistically different between the study groups. Thus, exposure to hyperoxia generally produced subtle enhancement of in vivo myocardial energy status.

View larger version (26K): [in this window] [in a new window]   Fig 2. The effects of hyperoxia on myocardial energy substrate levels including (A) ATP content and (B) creatine phosphate (CP) content. Groups shown are normoxia (open), mild hyperoxia (hatch), and severe hyperoxia (cross-hatch). Values are mean ± standard error of the mean in micromoles per gram dry weight. Statistical differences are as indicated: *p < 0.004 versus in vivo; p < 0.02 versus normoxia; p < 0.009 versus mild hyperoxia; p < 0.01 versus early ischemia.

View larger version (56K): [in this window] [in a new window]   Fig 3. The effects of hyperoxia on myocardial glycogen content. Groups shown are mild hyperoxia (hatch) and severe hyperoxia (cross-hatch). Values are mean ± standard error of the mean in micromoles per gram dry weight. Statistical differences are as indicated: *p < 0.05 versus in vivo.

During early ischemia, severely hyperoxic hearts only had a 16% ATP reduction from in vivo (p = 0.08) compared with much more extensive 27% to 30% reductions in normoxic (p = 0.003) and mildly hyperoxic (p = 0.0007) hearts (Fig 2A). Although all groups had further significant ATP depletion by late ischemia, hearts exposed to mild and severe hyperoxia had a statistical trend (p = 0.06) to higher ATP levels compared to normoxic hearts. In addition, although CP was significantly reduced (p < 0.0001) in all groups during early ischemia, the severe hyperoxia group had 83% depletion (p = 0.009 versus mild hyperoxia) compared with 60% and 63% reductions in the normoxia and mild hyperoxia groups, respectively (Fig 2B). Interestingly, by late ischemia, the normoxia and mild hyperoxia groups had incomplete 69% and 65% CP depletion, whereas the severe hyperoxia group had almost complete 92% CP depletion (p = 0.0009 versus mild hyperoxia). Also, although the severe hyperoxic group had unaltered myocardial glycogen during early ischemia, the mild hyperoxic group had a significant (41%, p = 0.04) glycogen depletion (Fig 3). However, by late ischemia, both the mild (53%, p = 0.01) and severe (64%, p < 0.0001) hyperoxia groups had quantitatively similar significant glycogen depletion.

The content of all other measured and calculated myocardial metabolites at the end of the ventilation period (in vivo) and both early and late during ischemia are shown in Table 1. The indicators of the overall status of the cell, TAN and EC, both yield interesting profiles during ischemia. During early ischemia, TAN content decreased 12% in normoxic hearts (p = 0.14; not significant) and 20% in mild hyperoxia (p = 0.006), but was unaltered in the severe hyperoxia group. Thus, despite similar ADP and AMP content at early ischemia, the severe hyperoxia group had higher TAN content than normoxia (p = 0.009). By late ischemia, the mild hyperoxic hearts had higher ADP than normoxia (p < 0.0001), whereas both the mild (p = 0.004) and severe (p = 0.002) hyperoxia groups had preservation of TAN relative to normoxia. In addition, although all groups had 8% to 10% reductions in myocardial EC during early ischemia, this only achieved statistical significance in the normoxia group (p = 0.04). By late ischemia, although EC was significantly reduced in all study groups, the normoxia group reached the lowest EC level.

The end-product lactate also exhibited group-specific accumulation during ischemia (Table 1). Interestingly, all groups had similar, significant, fivefold lactate accumulation at early ischemia (p < 0.0001) and further lactate accumulation by late ischemia. However, group-specific differences became evident at late ischemia. Specifically, compared to the normoxic group, the final lactate content was 17% higher in the mild hyperoxic group (p = 0.06) and 47% higher in the severe hyperoxia group (p < 0.0001). Because this lactate level in the severe hyperoxia group was also significantly higher that the mild hyperoxia group (p = 0.0025), this suggests that the oxygen dose determined the final lactate content.

Ventricular fibrillation
Within each study group, in vivo metabolite levels before VF were not significantly different between hearts that fibrillated and those that did not. However, as an observation, the incidence of fibrillation with the initiation of ischemia appears to have a threshold response to the oxygen level. Specifically, the severe hyperoxic group had a 50% prevalence of VF, compared to 27% in normoxic hearts and 11% the mild hyperoxic group. When the effect of VF on myocardial metabolite status during early ischemia was assessed (Fig 4A–C), VF in normoxic hearts did not alter their ATP content at early ischemia (VF, 13.7 ± 1.7; non-VF, 13.8 ± 1.2 µmol/g). In contrast, the protective effects seen with exposure to severe hyperoxia in nonfibrillating hearts was eliminated. Specifically, when VF occurred in hearts exposed to severe hyperoxia, the ATP (Fig 4A) and glycogen (Fig 4C) depletion profiles closely resembled those of normoxic hearts, whereas EC was reduced from 0.85 ± 0.01 µmol/g to 0.75 ± 0.04 µmol/g. In addition, although VF induced further CP depletion in all study groups, the extent of CP depletion was more profound in severely hyperoxic hearts (95%) than normoxic hearts (88%). These VF-induced changes in the metabolic profile during ischemia seen in hearts previously exposed to severe hyperoxia were associated with a significant 36% shortening (p = 0.0003) in the time to peak ischemic contracture, indicating increased susceptibility to ischemic injury. Thus, there was an increased rate of metabolic deterioration and a deleterious effect on ischemic tolerance when VF occurred after exposure to severe hyperoxia.

View larger version (15K): [in this window] [in a new window]   Fig 4. The effects of fibrillation on substrate levels during early ischemia in severely hyperoxic hearts. (A) ATP content, (B) creatine phosphate (CP) content, (C) glycogen content. Groups shown are severe hyperoxia, nonfibrillating (•) and severe hyperoxia, fibrillating (). Values are mean ± standard error of the mean in micromoles per gram dry weight. Statistical differences are as indicated: *p < 0.006 versus in vivo; #p < 0.03 versus nonfibrillating.

	Comment

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In vivo myocardial energy status
In this study, in vivo exposure to mild and severe hyperoxia yielded, if anything, a subtle ATP elevation compared to normoxia. This was not a simple shift in the adenine nucleotide pool as the levels of the lower adenine nucleotides, ADP and AMP, were similar to or above those of normoxic hearts. In fact, this subtle enhancement was also reflected in slightly higher TAN levels in both hyperoxic groups. Thus, not only were hyperoxic hearts able to fulfil their immediate energy requirements, but there was actually a subtle "sparing" of the overall adenine nucleotide content.

The neonatal heart relies extensively on glycolysis to maintain its energy levels [15]. Adults exposed to 100% oxygen have rapid inhibition of enzymes required for glycolysis [16] and glycogenolysis [7]. Should this hyperoxic effect also occur in the neonatal heart, it could impair the neonate’s ability to metabolize glucose and glycogen to maintain its energy status. The lack of significant differences in the absolute in vivo myocardial glycogen content does not preclude the possibility of equal hyperoxia-induced reductions in both glycogen synthesis and degradation as the absolute cellular glycogen content is determined by a balance between these two processes.

Clearly, the current study does not suggest that exposure to hyperoxia produced detrimental effects on in vivo neonatal myocardial energy status. The effects of hyperoxia on myocardial energy levels appear to be, if anything, energy sparing. Whether this reflects an inability to use these energy stores is unclear. To further evaluate this issue, hearts were exposed to global ischemia as an additional metabolic stress.

Myocardial tolerance and metabolic response to ischemia
In normoxic tissue, ischemia results in rapid (within 60 seconds) inhibition of aerobic metabolism [13]. Under these conditions, the heart attempts to maintain ATP supply by anaerobic metabolism of glucose and glycogen, as well as high-energy phosphoryl transfer from CP, ADP, and AMP [13]. Even a slight prolongation of aerobic metabolism during early ischemia could maintain ATP levels for longer and spare these other energy stores. This concept is supported by a report, in adult animals, in which prior exposure to hyperbaric hyperoxia provided up to 5 minutes of additional protection against cerebral ischemic injury, which these investigators speculated was due to a delay in ischemia-induced ATP depletion [17].

In the current study, exposure to severe hyperoxia was associated with minimally reduced myocardial ATP and glycogen content during early ischemia, in contrast to the significant reductions in both normoxic and mildly hyperoxic hearts. This delay in ATP and glycogen depletion could be due to prolonged aerobic metabolism or reduced ATP utilization in the severely hyperoxic neonatal heart. Because lactate is the end product of anaerobic glycolysis, prolonged aerobic metabolism would result in reduced lactate formation. However, the normoxic and hyperoxic groups both had similar lactate elevations by 15 minutes of ischemia, suggesting that aerobic metabolism was likely not prolonged. During this early ischemic period, the severe hyperoxia group also had more extensive CP depletion indicating that ATP decline may have been more extensively buffered by high-energy phosphoryl transfer from CP.

Interestingly, previous studies found that the activity of creatine kinase, which transfers a high-energy phosphate from CP to ADP, was limited in neonates compared to adults [18], thus reducing the ability to mobilize CP in response to metabolic stress. Under ischemic conditions, this limited CP mobilization would force the neonatal heart to rely on other pathways to maintain ATP levels. A greater reliance on glycolysis would ultimately result in earlier glycogen depletion [19]. The normoxic and mildly hyperoxic hearts in the current study exhibited this profile during early ischemia. Specifically, these two groups had only partially reduced CP stores and significantly depleted myocardial glycogen. In contrast, adult hearts subjected to metabolic stress immediately mobilize endogenous CP stores to maintain ATP [20] and only resort to glycogen utilization during prolonged stress [19, 20]. The severely hyperoxic neonatal hearts in our study exhibited this mature adultlike profile in which there was rapid, near-complete CP depletion, followed by a significant reduction in glycogen content. This delayed glycogen utilization and concomitant greater late lactate accumulation in severely hyperoxic hearts also indicates that hyperoxia did not adversely affect the ultimate glycolytic potential in these hearts. Although the direct action of hyperoxia on creatine kinase has yet to be confirmed, the more adultlike CP depletion profile during early ischemia provided evidence for hyperoxia-induced changes in this high-energy phosphoryl transfer pathway.

Recovery of function after an ischemic stress has been shown to be inversely related to 5' nucleotidase activity, which regulates the degradation of AMP to adenosine, and thus determines the adenine nucleotide content [21]. A reduction in this enzyme’s activity could spare adenine nucleotides (TAN). Because reductions in both ATP and TAN have been associated with postischemic myocardial dysfunction [22], preservation of TAN levels is unquestionably desirable. A previous study in the neonatal dog retina showed that prolonged exposure to normobaric hyperoxia reduced 5' nucleotidase activity [23]. In addition to preservation of ATP during early ischemia, the severe hyperoxia group in the current study also had preserved TAN levels. These findings suggest that 5' nucleotidase in the neonatal myocardium may also be sensitive to high oxygen. Hearts exposed to severe hyperoxia had 14% higher in vivo ATP levels and 11% lower ATP depletion during early ischemia, which was accompanied by a 15% prolongation of the time to peak ischemic contracture, indicating that the beneficial metabolic profile is associated with increased ischemic tolerance. However, exposure to severe hyperoxia also induced a much higher incidence of ventricular fibrillation that was associated with significant additional metabolic stress.

Ventricular fibrillation
Arrhythmias are a common occurrence with myocardial ischemia [24] and are considered a marker of ischemic injury [13]. This is particularly relevant in infants who have a high incidence of arrhythmias during reperfusion after cardiopulmonary bypass [25]. Several potential explanations for this increased incidence in newborns have been proposed, including the proximity of surgical incisions to conductive tissue in these small hearts. Interestingly, neonatal cardiac operation inevitably involves hyperoxia, even before myocardial ischemic [2]. The possible role of hyperoxia in this increased incidence of arrhythmias has never been considered. The finding of an increased incidence of fibrillation with the initiation of ischemia in severely hyperoxic hearts may be relevant to this clinical issue. Interestingly, in a report on adult dogs undergoing regional ischemia (left anterior descending coronary artery occlusion), ventilation with severe hyperoxia also yielded a 37% incidence of fibrillation compared to only 20% with ventilation at mild hyperoxia [26]. These investigators concluded that the oxygen level influenced the incidence of ventricular fibrillation in the adult myocardium. A similar but more profound effect was noted in the current neonatal pig study in which the initiation of ischemia was associated with an 11% incidence of fibrillation with mild hyperoxia, compared with a 50% incidence in the severe hyperoxia group. Clearly, excessive arterial oxygen levels influence the incidence of fibrillation; however, the precise mechanism has yet to be determined.

Although ventricular fibrillation exacerbates ischemic injury in adult hearts, fibrillation reportedly does not alter ischemic injury in neonatal hearts, as determined by the time to ischemic contracture [27]. For instance, in the current study, ventricular fibrillation did not alter the time to ischemic contracture in normoxic neonatal hearts. In contrast, ventricular fibrillation in severely hyperoxic hearts did result in the loss of ATP and glycogen preservation during early ischemia, and a significant reduction in the time to the development of ischemic injury. Thus, compared to normoxic neonatal hearts, severely hyperoxic neonatal hearts had an increased incidence of fibrillation and exhibited increased sensitivity to ischemia. When determining what oxygen level should be used in the neonate, the potential energy-sparing effect afforded by severe hyperoxia must be weighed against the increased incidence of fibrillation seen in the current study, which resulted in the elimination of any beneficial metabolic effects.

In conclusion, in 1785, Lavoisier accurately referred to oxygen as a "double-edged sword," as it appears to have both beneficial and detrimental effects. In our study, severe hyperoxia produced protective energy-sparing metabolic effects during early ischemia, but increased the incidence of fibrillation, which was associated with compromised myocardial energy status and reduced ischemic tolerance. This study suggests that hyperoxia should be used with caution in neonates, particularly in those prone to myocardial arrhythmias.

	Acknowledgments

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We acknowledge Dr Howard Green and Margaret Burnett, from the University of Waterloo, for their biochemical expertise and W. Jack Wallen and Michael P. Belanger, from the University of Toronto, for their technical assistance. Grant funding for this research was provided by the Heart and Stroke Foundation of Ontario (Grant no. T4181) and personal funding for Shona Torrance was provided by a Research Fellowship from the Ontario Ministry of Health.

	References

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1. Rosenberg E.M., Cook L.N. Electromechanical dissociation in newborns treated with extracorporeal membrane oxygenation: an extreme form of cardiac stun syndrome. Crit Care Med 1991;19:780-784.[Medline]
2. Aoshima M., Yokota M., Shiraishi Y., et al. Prolonged aortic cross clamping in early infancy and method of myocardial preservation. J Cardiovasc Surg 1988;29:591-595.[Medline]
3. Pooley R.W., Hayes C.J., Edie R.N., Gersony W.M., Bowman F.O., Malm J.R. Open-heart experience in infants using normothermia and deep hypothermia. Ann Thorac Surg 1976;22:415-423.[Abstract]
4. Kuntschen F.R., Galletti P.M., Hahn C., Arnulf J.J., Isetta C., Dor V. Alterations of insulin and glucose metabolism during cardiopulmonary bypass under normothermia. J Thorac Cardiovasc Surg 1985;89:97-106.[Abstract]
5. Dickson M.E., Hirthler M.A., Simoni J., Bradley C.A., Goldthorn J.F. Stunned myocardium during extracorporeal membrane oxygenation. Am J Surg 1990;160:644-651.[Medline]
6. Gunn T.R., Easdown J., Outerbridge E.W., Aranda J.V. Risk factors in Retrolental Fibroplasia. Pediatrics 1980;65:1096-1100.[Abstract/Free Full Text]
7. Balentine J.D. Pathology of oxygen toxicity. New York: Academic Press, 1982.
8. Najm H.K., Wallen W.J., Belanger M.P., et al. Does the degree of cyanosis affect myocardial adenosine triphosphate levels and function in children undergoing surgical procedures for congenital heart disease?. J Thorac Cardiovasc Surg 2000;119:515-524.[Abstract/Free Full Text]
9. Ihnken K., Morita K., Buckberg G.D. Studies of hypoxemic/reoxygenation injury with aortic clamping: XI. Cardiac advantages of normoxemic versus hyperoxemic management during cardiopulmonary bypass. J Thorac Cardiovasc Surg 1995;110:1255-1264.
10. Morita K., Ihnken K., Buckberg G.D., Sherman M.P., Young H.H. Studies of hypoxemic/reoxygenation injury: IX. Without aortic clamping. Importance of avoiding perioperative hyperoxemia in the setting of previous cyanosis. J Thorac Cardiovasc Surg 1995;110:1235-1244.
11. Torrance S.M., Belanger M.P., Wallen W.J., Wittnich C. Neonatal pig hearts’ metabolic and functional response to the development of ischemic contracture—Is recovery possible?. Pediatr Res 2000;48:191-199.[Medline]
12. Hearse D.J. Oxygen deprivation and early myocardial contractile failure: a reassessment of the possible role of adenosine triphosphate. Am J Cardiol 1979;44:1115-1121.[Medline]
13. Katz A.M. The ischemic heart. In: Katz A.M., ed. Physiology of the heart. New York: Raven Press, 1992:609-637.
14. Arieli R., Ben-Haim S.A., Hayam G., Edonte Y. Heart energetic efficiency in O₂-exposed rats studied in isolated working heart. J Appl Physiol 1992;73:2289-2296.[Abstract/Free Full Text]
15. Barrie S.E., Harris P. Myocardial enzyme activities in guinea pigs during development. Am J Physiol 1977;233:H707-H710.
16. Horn R.S., Haugaard E.S., Haugarrd N. The mechanisms of the inhibition of glycolysis by oxygen in rat heart homogenates. Biochim Biophys Acta 1965;99:549-552.[Medline]
17. Slonim N.B., Hamilton L.H. Respiratory physiology. St. Louis: CV Mosby, 1987:226-228.
18. Ingwall J.S., Kramer M.F., Woodman D., Friedman W.F. Maturation of energy metabolism in the lamb: changes in myosin ATPase and creatine kinase activities. Pediatr Res 1981;15:1128-1133.[Medline]
19. Wittnich C., Peniston C., Ianuzzo D., Abel J.G., Salerno T.A. Relative vulnerability of neonatal and adult hearts to ischemic injury. Circulation 1987;76(suppl 5):156-160.
20. McGilvery R.W., Goldstein G.W. Biochemistry. A functional approach. Philadelphia: WB Saunders, 1983:370-380.
21. Grosso M.A., Banerjee A., St. Cyr J.A., et al. Cardiac 5'-nucleotidase activity increases with age, and inversely relates to recovery from ischemia. J Thorac Cardiovasc Surg 1992;103:206-209.[Abstract]
22. Asimakis G.K., Zwischenberger J.B., Inners-McBride K., Sordahl L.A., Conti V. Postischemic recovery of mitochondrial adenine nucleotides in the heart. Circulation 1992;85:2212-2220.[Abstract/Free Full Text]
23. Lutty G.A., Merges C., McLeod D.S. 5' Nucleotidase and adenosine during retinal vasculogenesis and oxygen-induced retinopathy. Invest Ophthalmol Vis Sci 2000;41:218-229.[Abstract/Free Full Text]
24. Kléber A.G. Consequences of acute ischemia for the electrical and mechanical function of the ventricular myocardium. A brief review. Experientia 1990;46:1162-1167.[Medline]
25. LeBlanc J.G. Cardiac rhythm disturbances and pacemakers. In: LeBlanc J.G., Williams W.G., eds. The operative and postoperative management of congenital heart defects. Mount Kisco: Futura, 1993:329-349.
26. Pifarré R., Wilson S.M., Hufnagel C.A. The influence of oxygen and helium upon ventricular fibrillation. J Thorac Cardiovasc Surg 1968;55:535-537.[Medline]
27. Vicenti W., Bukhanov K., Semelhago L., Salerno T.A., Wittnich C. Increased susceptibility of fibrillating hearts to irreversible ischemia: a comparison of adult versus neonatal hearts. Am Coll Surg Surg Forum 1987;XXXVIII:199-202.

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