Neonatal tolerance to hypoxia: a comparative-physiological approach

Comparative Biochemistry and Physiology Part A 123 (1999) 221 – 234 www.elsevier.com/locate/cbpa

Review

Neonatal tolerance to hypoxia: a comparative-physiological approach D. Singer * Department of Pediatrics, Uni6ersity Clinics, Robert-Koch-Strasse 40, D-37075 Goettingen, Germany Received 27 August 1998; received in revised form 18 March 1999; accepted 30 March 1999

Abstract Newborn mammals exhibit a number of physiological reactions which differ from normal adult physiology and are often regarded as signs of immaturity. However, when looked upon from a comparative point of view, it becomes obvious that some of these ‘physiological peculiarities’ bear striking similarity to adaptation mechanisms known from hypoxia-tolerant animals and may thus contribute to the well-established, yet poorly understood, phenomenon of neonatal hypoxia tolerance. As the mammalian fetus lives at oxygen partial pressures corresponding to 8000 m altitude, the first line of perinatal hypoxia defense consists of long-term adaptations to limited intrauterine oxygen supply: (1) improved O2 transport by fetal acclimatization to high altitude, (2) reduced metabolic rate by hibernation-like deviation from metabolic size allometry, (3) diminished cerebral vulnerability by functional analogies to diving turtle brain, and (4) enhanced metabolic flexibility by optional repartitioning of energy supply from growth to maintenance metabolism. In the case of birth asphyxia, these background mechanisms are complemented by short-term responses to acute oxygen lack: (1) reduction of body temperature as in natural torpor, (2) reduction of heart rate and redistribution of circulation as in diving mammals, (3) reduction of respiration rate typical of ‘hypoxic hypometabolism’, and (4) reduction of blood pH according to the concept of ‘acidotic torpidity’. Although anaerobic metabolism is improved in neonatal mammals by increased glycogen stores, reduced metabolic demands, and sustained wash-out of acid metabolites, neonatal hypoxia tolerance seems to be primarily based on the ability to maintain tissue aerobiosis as long as possible. This is even reflected by isoenzyme patterns which do not consistently favour anaerobic glycolysis and, thus, are reminiscent of the ‘lactate paradox’ found in high altitude adaptation. Altogether, from a biological point of view, the perinatal period appears as a source of adaptive mechanisms that can be refound, in varying combinations, in many survival strategies. From a clinical point of view, the interplay of long- and short-term mechanisms offers a novel approach to estimation of the newborn’s ability to withstand temporary oxygen lack. However, most of these mechanisms are not unambiguous and, above all, not unlimited in their protective effect so that they do not release obstetricians or neonatologists from their obligation to counteract fetal or neonatal hypoxia without delay. © 1999 Elsevier Science Inc. All rights reserved. Keywords: Neonatal hypoxia tolerance; High altitude acclimatization; Metabolic size allometry; Mammalian hibernation; Turtle brain; Energy partitioning; Hypothermia; Diving reflex; Apnea; Acidosis

1. Introduction Transition from intra- to extrauterine life is often accompanied by more or less pronounced hypoxia which bears the risk of cerebral damage but is for the most part remarkably well tolerated by the newborn. Whereas the enhanced hypoxia tolerance of mam* Tel.: +49-551-396262; fax: + 49-551-396252.

malian neonates has long been known from both clinical experience and experimental work, the underlying mechanisms are not yet fully understood [165,226]. However, perinatal hypoxia, in contrast to other transient states of hypoxia in animals, has thus far attracted relatively little interest in comparative physiology. Moreover, most clinical perinatologists are not aware of the striking parallels to be drawn between some of the ‘physiological peculiarities’ of the newborn on the one hand and well-known adaptive mechanisms in hy-

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poxia-tolerant animals on the other. Therefore, few attempts have been made to look at neonatal hypoxia tolerance from a comparative point of view [42,52,53,70,134,137,139,197] although the interdisciplinary approach could help to put neonatal care on a different basis. It is the aim of this paper to bridge the gap between comparative physiology and clinical perinatology by a tentative account of the most obvious ‘biological’ factors involved in the ‘medical’ outcome of the asphyxiated neonate.

2. Attempts to determine neonatal hypoxia tolerance Since the classical observations of the French physiologist Paul Bert [21] on prolonged survival of submerged newborn rats, several attempts have been made to determine neonatal hypoxia tolerance in a variety of mammalian species, progressing from the whole organism to separate tissues and from rather global to increasingly specific methods. Earlier workers emphasized the greater resistance of newborn compared with adult mammals, when subjected to circulatory arrest or exposed to anoxic atmospheres [11,115,175]. Among them, Fazekas et al. [56] found a clear dependence on weight and maturity at birth, with the neonatal survival time in pure nitrogen ranging from 50 min in rats (immature neonates) to 7 min in guinea pigs (mature neonates), in contrast to 3 – 5 min in adult individuals of all species studied. Furthermore, several authors observed a more or less rapid decrease in hypoxia tolerance with increasing postnatal age [4,28,68]. More recent attempts have focused on the brain as the main target organ of perinatal hypoxic injury. Biochemical analysis has revealed a slower decline in tissue ATP in hypoxic neonatal than in adult brain of both mice and rats [48,101]. Physiological studies have found a markedly delayed depolarization and a later increase in extracellular potassium in neonatal as compared to adult rat neurons under hypoxic conditions [76,218]. Similar investigations have been directed to the heart and its ability to tolerate temporary ischemia, mostly in the context of infant heart surgery. It has been shown that during hypoxia, the neonatal myocardium maintains mechanical function better than does adult myocardium of the same species, again associated with a better preservation of electrical activity and a slower decline in tissue ATP [99,107,108]. Moreover, the postischemic recovery of neonatal hearts has proved to be superior to adults [24,237]. With respect to the underlying mechanisms, it must be taken into consideration that the mammalian fetus has to cope with two problems: first, the limited intrauterine oxygen (and substrate) availability, and, second, the additional risk of perinatal asphyxia. Hence, it seems reasonable to subdivide the problem into two

main aspects, namely, long-term adaptations to intrauterine life that form a ‘protective background’ against temporary impairment of oxygen supply, and short-term responses to asphyxia occurring at birth.

3. Long-term adaptations to limited intrauterine oxygen supply

3.1. Fetal acclimatization to high altitude Although it is generally known that the oxygen partial pressure of the mammalian fetus is below the adult values, it is not normally recognized that the 25–40 mm Hg corresponds to a stay at 6000–8000 m altitude, i.e. at the outermost borders of human life—a condition referred to by Barcroft [14] as ‘Everest in utero’. To survive—and to grow—under these conditions, the mammalian fetus must make use of similar mechanisms to those known from acclimatization to high altitude [6,164]. These comprise optimized gas exchange through a large respiratory surface area (lung or placenta, respectively), improved oxygen transport by hematologic adaptations, and metabolic adjustments at the tissue level [62,104,152,185]. Hematologic adaptations in the fetus include polycythemia, increasing oxygen binding capacity, and a leftward-shift of the hemoglobin dissociation curve, enhancing oxygen affinity of the blood [15,79,80,147]. Remarkably, the latter is usually restricted to species that are phylogenetically adapted to mountain and/or fossorial habitats [73,130], and differs from the rightward-shift to be found in humans living in or ascending to high altitudes [9,131]. Apparently, the increased oxygen affinity reduces the amount of polycythemia (and resulting hyperviscosity) in these animals and thereby favours their hemodynamic working capacity in a hypobaric environment. Combined increase in both affinity and capacity provides the neonate with high blood oxygen stores which, like in diving mammals, prolong aerobic latency in the case of interrupted oxygen supply (cf. below). Moreover, the increased capacity may partially reverse the slightly impaired tissue oxygenation resulting from the leftward-shift of the fetal oxygen binding curve. Nevertheless, further adaptations are likely to occur, maintaining tissue respiration even if lowered oxygen tensions cannot be completely compensated for by hematologic adaptations. A perplexing example of such metabolic adjustment is given by the fact that high altitude residents, when subjected to defined exercise, exhibit lower plasma lactate concentrations than do unacclimatized lowlanders under comparable hypoxic conditions. This is in contrast to the higher lactate production to be achieved by physical training and has therefore been called the ‘lactate paradox’ [119,229]. Obviously, intermediate metabolism is somehow rear-

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ranged in these individuals so as to prefer aerobic pathways to lactate formation and, thus, to ensure maximum ATP yield per mole of substrate as long as possible [93]. However, the underlying mechanisms are not fully clear, nor is the question as to whether certain peculiarities of the neonatal metabolism (to be described later) could possibly be based on similar adjustments.

3.2. Perinatal de6iation from metabolic size allometry Another way to favour oxygen supply to tissues consists simply in the reduction of oxygen demand. In the mammalian neonate, metabolic reduction seems to be at least partially achieved by temporary escape from the overall metabolic size relationship, known as Kleiber’s rule [121]. Following this rule, the mass-specific basal metabolic rate of mammals (in watts per kilogram) increases with decreasing body size so as to be higher in the mouse than in the elephant, or higher in the neonate than in the adult, respectively [29,186]. However, immediately after birth, it is still at the maternal level (the fetus behaves ‘like an organ of its mother’), to increase more or less rapidly to the value to be expected from the newborn’s own body mass [230,232]. The perinatal deviation from metabolic size allometry was first described by Bohr [22] and Hasselbalch [81] in guinea pig and chick embryos and explained as an adaptation to limited oxygen and substrate availability through the placenta or egg shell [166,171]. Analogous results were obtained in neonates of various mammalian species including man [44,86]. Remarkably, metabolic rate undergoes the greatest perinatal reduction and the slowest postnatal increase in the smallest and most immature neonates, thus paralleling the degree and dynamics of neonatal hypoxia tolerance described above [197,203,204]. Hence, this mechanism seems to be an important factor of perinatal adaptation in mammalian neonates. Of course, even though metabolic size allometry is an ubiquitous phenomenon which occurs also in poikilothermic animals and is not directly related to homeothermy, its suppression is only feasible in cases where the normal high temperature gradient between ambient and body temperature is temporarily suspended. This is true in the fetus which is submerged in the amniotic liquid at 37°C, as well as in hibernators whose body temperature is temporarily allowed to fall to near-ambient levels, and in whom a similar inactivation of metabolic size relationship has also been described [65,116,202]. Thus, perinatal metabolic reduction cannot be separated from the suppression of homeothermy, as is achieved, by still unknown mechanisms, in the mammalian fetus [169,188].

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3.3. Adapti6e benefits from brain immaturity Although the deviation from metabolic size allometry provides a more general background for perinatal metabolic reduction, this does not preclude that, particularly in the case of the brain, immaturity itself plays an additional role in reducing metabolic needs. In fact, neonatal hypoxia tolerance has long been known to be associated with a very low cerebral metabolic rate [48,87,101,219] and this has usually been ascribed to the state of immaturity [140,165]. However, only recently has more information become available on what immaturity really means. In this respect, it is worth mentioning that the marked delay in extracellular potassium increase and hypoxic depolarization, as has been observed in neonatal as compared to adult brain tissue [76,218], has analogously been described for the turtle in comparison with the rat brain [47,192], as a correlate of the turtle’s striking ability to remain completely submerged for up to several months. Obviously, the enhanced hypoxia tolerance in neonatal versus adult mammals somehow parallels the superiority of reptilian over mammalian species to withstand temporary hypoxia [101,146]. As the high metabolic rate and the subsequent vulnerability of homeothermic beings is thought to be due to an elevated membrane leakiness and a correspondingly increased pump rate [51,103], the higher resistance of poikilothermic vertebrates seems to be closely related to their lower membrane permeability [50,210]. In fact, a lower channel density was also found in brain tissue of neonatal as compared to adult mammals [111,236], suggesting that in both cases, similar energy-saving membrane properties are involved. Another important factor in natural tolerance to hypoxia is an attenuated cerebral excitotoxicity. Even though an increased release of inhibitory neurotransmitters, as has been found in the turtle [161,162], seems not to be operative in (and, probably, not appropriate to) the developing mammalian brain, the liberation of excitatory amino acids is greatly retarded as a consequence of the lower energy requirements and the correspondingly delayed anoxic depolarization of neonatal neurons [75,167]. This underlines the assumption that functional similarities between lower vertebrate and immature mammalian tissues may explain part of their increased tolerance to hypoxia.

3.4. Adapti6e benefits from growth metabolism In addition to the aforementioned mechanisms, some hypoxia-tolerant organisms seem to be able to further reduce their energy needs in response to impaired supply without building up an oxygen deficit [177]. This was described in diving turtles and seals [105,187] and repeatedly observed in the mammalian fetus and

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neonate, as well [7,43,54,110,157,193]. Although the exact mechanisms are still obscure, it has been supposed that growth itself, as a non-essential part of metabolism, might play a key role in this ability. In fact, total energy turn-over can be subdivided into two major parts, referred to as maintenance metabolism (basal metabolic rate, thermoregulation, and physical work) and production metabolism (growth and reproduction). As was originally postulated by Rubner [180], these seem to be hierarchically arranged so that in the case of limited supply, production can be temporarily suspended for the benefit of maintenance. The idea of ‘partition’ or ‘allocation’ of energy turn-over was taken up by Wieser [231] who added experimental evidence of this being a relatively widespread adaptive mechanism among lower and higher vertebrates [122,126]. Obviously, the fetal condition of high growth rate offers a favourable background for metabolic adaptation to limited oxygen availability, and the clinical finding of ‘intrauterine growth retardation’ might be regarded not only as a symptom of, but also as an adaptive reaction to, low oxygen and substrate supply. This hypothesis is reinforced by the fact that chronic hypoxia, e.g. in children native to high altitudes [238,239] or in patients suffering from cyanotic heart defects [20,133], is regularly associated with growth retardation, and that, conversely, reduction of maintenance metabolism, e.g. by optimized thermal protection, has proved to promote growth both in experimental animals and in human preterm neonates [39,69]. However, it is not yet clear to what extent this mechanism is able to reduce energy needs. Estimations assume up to 40% of the fetal oxygen consumption rate to be growth-dependent and, thus, temporarily dispensible without affecting pure survival [54,193]. In preterm neonates, metabolic cost of growth (defined as the energy expended for synthetic processes, except the energy content of the synthesized matter itself) still amounts to 10 – 15% of the overall energy expenditure [71,174].

4. Acute adaptations to perinatal asphyxia Whereas the above mechanisms are already present in the fetus and form a ‘protective background’ against temporary oxygen lack, a number of additional responses are only elicited when perinatal asphyxia really sets in. Since most of them differ from physiological reactions to be expected in adults under comparable conditions, they are usually considered as ‘physiological peculiarities of the neonate’. However, a comparative analysis reveals striking parallels to adaptive mechanisms found in hypoxia-tolerant animals.

4.1. Reduction of body temperature In view of their small size and the disproportionately low metabolic rate, neonates are especially prone to hypothermia which, in clinical perinatology, is widely feared for its adverse effects. However, these are merely due to cold defense reactions which, starting from peripheral vasoconstriction and metabolic increase, lead to acidosis and impaired lung perfusion and may thus, by themselves, initiate a ‘vicious cycle’ of hypoxia [176,200]. Whenever thermoregulation is suppressed, be it by internal set point deviation (natural torpor) or by external influence of drugs (narcosis), a fall in body temperature results in a reduction of metabolic rate and, thereby, exerts a protective effect against hypoxia [198,199,214]. Accordingly, ‘deliberate cooling’ is not only a widespread mechanism in natural adaptation strategies [233,234], but has also essentially contributed to the progress in infant heart surgery [120,172]. Newborn mammals, despite the above clinical reservations, have long been known to survive lower body temperatures than do adult individuals of the same species [3,168]. Their enhanced tolerance to cooling may not only be due to similar mechanisms at the cellular level [91], but also reflect a contributory role of hypothermia in neonatal hypoxia tolerance. In fact, even the earliest workers noted that a reduction in ambient temperature was one of the most effective ways to further prolong the survival time of asphyxiated mammalian neonates [21,28,56]. This is based on the fact that in species born in a very immature state, prenatal inactivation of thermoregulation still persists after birth [83,197], or, in more developed neonates, hypoxia itself acts as a suppressor of non-shivering thermogenesis [49,85,149,153]. In these cases, the perinatal change in thermal environment leads to ‘near-induced’ cooling which, by reducing instead of increasing metabolic rate, favours hypoxic survival. Hence, though earlier attempts to use hypothermia in the neonatological field [148,150] failed due to the underestimated thermoregulatory capabilities [30,31] and the subsequently impaired outcome [195,196] of human term and moderately preterm babies, this does not preclude a beneficial or, at least, ambivalent role of hypothermia in asphyxiated and/or highly immature neonates, as has been repeatedly suggested by individual case reports [41,82]. Moreover, recent evidence seems to indicate that pharmacologically induced systemic hypothermia or even topical head cooling might also be able to reduce postasphyctic reperfusion injury in the neonatal brain [216,222].

4.2. Reduction of heart rate (di6ing reflex) In contrast to the increase in heart rate normally occurring in hypoxic adult mammals, any impairment of oxygen supply is promptly followed by bradycardia

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in the mammalian fetus and neonate. This is accompanied by transient shunting of blood flow from peripheral tissues to central organs [109,154,158,213] and thus corresponds to a physiological response pattern to be found in aquatic mammals and birds, known as the ‘diving reflex’ [5,35,90,123]. Due to this redistributory reaction, originally described by Scholander [187] as the ‘master switch of life’, the most vulnerable central organs of diving mammals continue to work aerobically while the more resistant peripheral tissues are temporarily left anaerobic. As a consequence, a sudden washout of lactate from peripheral tissues after emergence and re-opening of the peripheral circulation is typically observed [159]. This is different from amphibians and reptiles which during their prolonged periods of submergence mainly rely on depressed metabolism and anaerobic glycolysis and, therefore, exhibit a slow but continuous increase in blood lactate throughout the period of submergence [138]. The circulatory centralization involved in the diving reflex results from a release of catecholamines which, in the neonate, is already triggered by physiological ‘birth stress’ and further reinforced by intercurrent hypoxia [129]. Its importance as an ‘emergency reaction’ to perinatal asphyxia has been demonstrated in the lamb fetus where, based on the combination of peripheral vasoconstriction and local vasodilation, aerobic metabolism of both heart [59,60] and brain [113,114] tissue is kept fairly constant, while overall oxygen consumption is markedly reduced. The hemodynamic response is supported by an increased blood hemoglobin content which, apart from being an adaptation to high altitude (cf. above), is also found in aquatic mammals and birds and prolongs the time span from the onset of hypoxia or ischemia to the exhaustion of oxygen stores [191,205]. Moreover, it is accompanied by a reduction in heart rate and cardiac output which not only reflects, but also itself contributes to the minimization of energy consumption within the centralized circulation [27]. Thus, even though in human obstetrics, fetal bradycardias, known as the cardiotocographic ‘decelerations’, are taken as a sign of more or less pronounced perinatal stress, they appear, from a more biological viewpoint, to be part of a protective reaction, contributing to the retardation of final asystole typical of neonatal hearts [2,40].

4.3. Reduction of respiration rate In this context, it is still a matter of debate whether the periodic breathing and apnea often observed in preterm and/or otherwise compromised neonates should be regarded as a sign of immaturity of the respiratory control (and, thus, as a potential cause of hypoxia) or rather as the reflection of temporary metabolic depression (and, thus, as part of a protective response to hypoxia). On the one hand, instability of

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respiratory rhythm is only ‘affordable’ during intrauterine life when breathing movements can already be observed although they are still not of vital importance for the fetus [32]. In the case of preterm birth, the same condition may itself produce or at least reinforce hypoxia and, thus, appears as a symptom of immaturity of the respiratory network [145,181]. This is further supported by the observation that species normally born in a very immature state are equipped with a ‘disproportionately’ stable respiratory drive [240], even under hypoxic conditions [13]. On the other hand, cessation of ventilation seems to be more or less a physiological phenomenon which, by suspending the ‘non-essential’ work of breathing, reflects a self-protective response in the mammalian fetus [127,128]. In fact, apart from being an essential component of the ‘diving reflex’, temporary apnea or intermittent ventilation is regularly found in various states of reduced metabolism among vertebrates [151,190]. This is also true for small mammals which due to their low body weight have a high specific metabolic rate and, therefore, are especially endangered by scarcity of food or oxygen. Some of them are capable, apparently by similar mechanisms as are described here, of a short-term reduction of their metabolic and respiratory rate [61,63], so that the hypoxic switching-down of breathing rate in neonates may form a physiological part of this more complex response rather than an isolated pathological event [23,155].

4.4. Reduction of blood pH In clinical practice, umbilical artery pH is routinely used as a monitor of perinatal asphyxia [25,106]. However, apart from indicating lack of oxygen, temporary accumulation and consecutive wash-out of acid metabolites is an inevitable consequence of the circulatory redistribution involved in the ‘diving reflex’ [53,187] and may itself contribute to the ‘metabolic arrest’ to be observed in unperfused tissues of diving mammals [78,95]. Moreover, in many natural strategies, respiratory acidosis, through its inhibitory effects on overall enzymatic activity [142], on central thermoregulatory mechanisms [235], and on brown fat responsiveness to noradrenergic stimulation [49,143], plays an auxiliary role in metabolic reduction. Thus, it may be supposed that, beyond its well-known vasodilatatory effect on cerebral circulation (as part of the fetal ‘emergency reaction’) [8,77], hypercarbia may help to suppress inappropriate cold defense reactions and to minimize metabolic rate in cerebral hypoxia [194,217,223]. Altogether, this agrees with recent evidence that a low cord blood pH alone does not necessarily imply neurological damage unless a critical duration of asphyxia has been exceeded [18,57,135,182]. Though from a clinical point of view, perinatal acidosis

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is taken as a symptom of hypoxic-ischemic insult and as a predictor of unfavourable outcome, it may, from a biological point of view, act as a mediator of additional metabolic reduction and, thus, reflect another adaptive response of the asphyxiated neonate.

5. Transition from aerobic to anaerobic metabolism From the foregoing, it becomes clear that neonatal hypoxia tolerance is not merely due to increased anaerobic capacity, but rather to mechanisms maintaining tissue aerobiosis as long as possible, despite limited oxygen availability. This is mainly achieved by strict reduction in metabolic rate which not only avoids an overall discrepancy between oxygen demand and oxygen supply, but also favours oxygen diffusion from capillaries to mitochondria at low oxygen tensions. Following the formulae given by Krogh [125] and Warburg [227], the ‘critical depth’, i.e. the maximal distance oxygen can reach by diffusion, is inversely related to the square root of oxygen consumption rate [165,228]. This means that any reduction in oxygen consumption rate leads to a marked improvement in tissue oxygenation [26,72,215], and thus explains the long-lasting maintenance of — at least partial — aerobiosis, as was experimentally observed in the hypoxic neonatal brain [163]. If, however, oxygen supply threatens to fall below demand, a redistribution of circulation occurs for the benefit of central organs, accompanied by a decrease in whole body oxygen consumption. This partly reflects the transitory switching-over of peripheral tissues to anaerobic metabolism which, in its turn, results in a wash-out of acid metabolites after ‘emergence’. However, as has already been observed in diving marine mammals and has also been found in mammalian neonates, neither the amount of lactate accumulated nor the compensatory posthypoxic increase in metabolic rate (to ‘repay the oxygen debt’) is as high as would be expected in the case of unchanged metabolic needs. This is indicative of a hypoxic hypometabolism which, as has been recently confirmed by an elegant study on newborn dogs [64,178], cannot be simply regarded as a passive consequence of limited oxygen availability, but rather reflects a regulatory reduction in oxygen demand. Although the underlying mechanisms are not yet fully understood, part of this ‘oxyconformistic’ response seems to be explainable by the hypoxic suppression of thermogenesis and the subsequent fall in body temperature. Further metabolic reduction may result from the repartitioning of energy turn-over, from the building-up of metabolic acidosis in temporarily unperfused tissues, and, perhaps, from an acute lowering in membrane permeability (‘channel arrest’), like that occurring in hypoxic turtle hepatocytes [33,98].

Of course, the marked delay of anaerobiosis in central organs does not imply that this would be of minor adaptive importance. On the contrary, the crucial role of anaerobic glycolysis for the hypoxic survival of newborn mammals has been supported by experimental results indicating that iodacetate pretreatment abolishes part of their enhanced hypoxia tolerance [88,89,183], just as has been observed in diving turtles [19]. Glycolysis is greatly facilitated in mammalian neonates by a number of favourable conditions which partly coincide with those delaying onset of anaerobic metabolism, namely, decreased metabolic rate, increased energy stores, and improved end-product removal. Among them, metabolic reduction which is further reinforced by slowed heart rate and by the state of electrical silence readily adopted by the hypoxic neonatal brain [220,226], minimizes the mismatch between metabolic needs and anaerobic capacity and, thus, retards the rapid fall in turn-over rate otherwise typical of hypoxic mammalian tissues [141,201]. Moreover, it slows the breakdown of glycogen stores which have long been known to be elevated in term neonates [45,156,189,206]. This is especially true for the neonatal heart where the regular postnatal decrease in these stores may contribute to the gradual loss of extra hypoxia tolerance with increasing age [99], a phenomenon that could be partly reversed by external glucose substitution [66,67]. A similar dependence on carbohydrate supply was observed by Vannucci and co-workers for the anoxic neonatal brain [221,224] although, for adult stroke patients, glucose infusions had been rejected [160,170], due to the risk of severe tissue acidosis [102,173]. The difference may at least partly be based on the continuing wash-out of acid metabolites which is guaranteed, in newborn mammals, by the unusually well maintained cardiac function. Apart from these favourable conditions, there seems to be, in the neonate, no consistent enzymatic pattern differing from adults that would result in an increased anaerobic capacity [112,179]. On the contrary, it has been found that during late intrauterine development the LDH isoenzyme pattern in central organs (except the brain) starts shifting from the LDH 5 (muscle) to the LDH 1 (heart) subtype which means that the capacity to reduce pyruvate to lactate is being partly replaced by the capacity to oxidize lactate to pyruvate [16,96,144,211]. Thus, the neonatal heart, contrary to what was expected earlier [100,209], does not exceed the adult heart in its dependence on anaerobic glycolysis, but rather contributes to the clearance of lactate from the circulation [58–60]. Most remarkably, this is reminiscent of the enzymatic adaptation which, in mountain residents, has been postulated as a potential mechanism of minimized lactate production despite hypoxic conditions (the ‘lactate paradox’) [94,97], suggesting that in fact, in neonatal tissues, enzymatic patterns are to be found similar to those in high-altitude acclimatization.

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6. Synthesis: comprehensive view of neonatal hypoxia tolerance Whereas the term ‘neonatal adaptation’ is usually used for the transition processes from intra- to extrauterine life such as onset of lung ventilation and switching from fetal to adult circulation [208], the mammalian neonate obviously is also adapted to the associated risk of hypoxia. Parallels between physiological responses of mammalian neonates and adaptation mechanisms in hypoxia-tolerant mammals suggest that this specific strategy is partially composed of mechanisms known from high-altitude acclimatization, breath-hold diving, and hibernation, completed by some additional advantages resulting from immaturity and growth. Thus, neonatal hypoxia tolerance appears to be an example of how a specific strategy may emerge as a novel combination of mechanisms already known from other conditions. Conversely, the striking uniformity of physiological mechanisms to be found in different survival strategies among mammals may at least partly be due to the fact that these are common to all mammals during fetal and early neonatal life. The above analysis has revealed some general features of neonatal adaptation to hypoxia which can finally be summarized in ten points: (1) First, the newborn’s ability to withstand hypoxia seems to be a resistance rather than a tolerance in its strict sense. This means that the neonate tends to avoid a mismatch between oxygen demand and oxygen supply rather than to rely on anaerobiosis, even though for this ultimate situation, precautions are also taken. (2) The individual mechanisms of the strategy are arranged in gradual order, progressing from long-term adaptations to limited intrauterine oxygen availability to short-term adaptations to additional perinatal asphyxia. Within this sequence, the chronic adjustments seem to a certain degree to be a precondition for the effectiveness of the acute responses. Thus, for instance, when the oxygen binding capacity is not sufficiently increased by intrauterine ‘acclimatization to high altitude’, the protective effect of the ‘diving reflex’ in perinatal asphyxia is also impaired. Similarly, when the repartitioning of energy turn-over has already been exhausted due to long-lasting placental dysfunction, metabolic demands cannot be further reduced in acute impairment of oxygen supply. This agrees perfectly with clinical and experimental observations that the anemic or intrauterine growth-retarded fetus has an increased risk of suffering perinatal hypoxic/ischemic injury [17,117]. Whenever short-term responses such as bradycardia are elicited in utero, they indicate that the long-term mechanisms are overstressed and that the fetus is severely compromised. (3) From this, it follows that perinatal adaptation is not solely based on biochemical properties of one spe-

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cific organ, but rather appears as a complex strategy of the whole organism. More specifically, it is not restricted to the brain (as the target organ for perinatal hypoxic/ischemic injury), but involves other organs, such as the heart. In fact, the maintenance of a residual circulation with the subsequent preservation of glucose supply and the continuous wash-out of acid end-products appears as an essential precondition for the improved anaerobic survival of neonatal brain. (4) A common feature of both long- and short-term mechanisms is metabolic reduction. This is primarily due to the deviation from metabolic size allometry and to the immaturity of brain tissue, completed by the suspension of ‘non-essential’ parts of metabolism and by the lowering of body temperature, and eventually further reinforced by hypercapnia/acidosis. Reduced metabolic rate is adaptive to limited oxygen availability in utero and improves diffusion of oxygen into tissues despite low capillary partial pressure. Moreover, it reduces the mismatch between the high metabolic demands of mammalian tissues and the low capacity of anaerobic pathways and thus favours anaerobic metabolism, as well. (5) Closely related to metabolic reduction is the switching-off of thermoregulation. This condition, which during intrauterine life is the counterpart of suppressed metabolic size allometry, persists even after birth in extremely immature neonates, resulting in a poikilothermic thermal behaviour. In more mature neonates, hypoxia itself acts as a suppressor of nonshivering thermogenesis so that in the case of exposure to cold, metabolic increase is largely avoided, thus allowing ‘near-induced’ hypothermia. (6) Redistribution of blood flow and energy supply seems to be a further important mechanism of perinatal adaptation, both at the whole body and at the cellular level. Whereas the diving reflex preserves aerobic metabolism in central organs, the ‘renunciation’ of non-essential parts of metabolism limits the oxygen deficit built up by peripheral tissues, while cut off from the circulation. Moreover, even within central organs, the reduction of working in favour of maintenance metabolism helps to bridge a period of insufficient oxygen supply. (7) A common feature of the short-term reactions to perinatal asphyxia is the abandonment of counterregulatory responses and the endogenous ‘slowing-down’ of life processes which deviates from homeostatic organization of normal adult physiology. Thus, instead of thermoregulatory metabolic increase, reflectory tachycardia, and augmentation of breathing, a reduction of all these functions (fall of body temperature, bradycardia, and apnea) is found in neonatal asphyxia, corresponding to the start of breath-hold diving or to the onset of mammalian hibernation [12,199].

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(8) Anaerobiosis is greatly postponed by the aforementioned mechanisms. If, however, it sets in, it is favoured by low metabolic rate, high substrate stores, and wash-out of lactate from tissues. These favourable preconditions are completed by enzymatic adaptations which however, at least in certain tissues, tend to minimize rather than to enhance lactate production, similar to the ‘lactate paradox’ known from high-altitude acclimatization. (9) Immaturity itself is not an unambiguous factor in this interplay. On the one hand, as far as it is accountable for reduced membrane leakiness, suppressed thermoregulation and correspondingly low metabolic needs, it can exert a protective effect per se. However, as far as it is associated with insufficient glycogen stores [136], incomplete tissue vascularization [46], and reduced capacity of free radical detoxification [184], it may be the cause of rather than a protection from hypoxic or posthypoxic injury. (10) Similar reservations apply to the acute defense reactions which are not unlimited in their protective effect and which, in the case of inappropriate onset or self-perpetuation, may themselves be detrimental. This is especially true for hypothermia and apnea which, when elicited in otherwise well neonates, may produce rather than prevent hypoxia. In addition, acute renal failure [118,207], necrotizing enterocolitis [36,124], and coagulation disorders [37,38] occurring in asphyxiated neonates are examples of how severe ‘peripheral’ effects may result from the circulatory redistribution ‘for the benefit of central organs’. Moreover, in premature neonates, most of the factors involved in the hypoxia response are strongly correlated with an increased risk of intraventricular hemorrhage [84,132,212,225]. It must be kept in mind that the neonate, unlike a diving animal, does not have the opportunity of terminating a hypoxic episode at its own choice. Incidentally, more recent studies on marine mammals have shown that voluntary diving differs from forced diving in that peripheral vasoconstriction is attenuated in favour of a better perfusion of swimming musculature [92]. Apparently, the full redistributory reaction is confined to emergency situations when, for instance, the diving animal gets lost under the ice [34], suggesting that partial anaerobiosis is not a regular option even in these very well-adapted beings. The last point makes clear that for the obstetrician or neonatologist involved, early interruption of hypoxic stress remains the primary objective whenever any of the above ‘symptoms’ occurs. Nevertheless, the comparative analysis helps to understand the conditions and limits of hypoxia tolerance in the neonate, as well as the intriguing ambiguity of common ‘prognostic’ factors such as perinatal acidosis. Moreover, it allows some interesting conclusions with respect to human preterm neonates. Thus, for instance, it is obvious that

the onset of thermoregulation and the slow, but unavoidable increase in metabolic rate triggered by preterm birth must result in a decreasing overall tolerance to hypoxia. Furthermore, the growth retardation typical of preterm neonates appears as a necessary consequence of the temporary repartitioning of energy towards maintenance metabolism. And lastly, even the anemia of prematurity [10,74] may be explained, among others, by the sudden ‘declimatization to sea-level’ [1,55] with correspondingly lower concentrations of erythropoietin circulating in the blood. Although there is now increasing insight into the neurohumoral mediators governing the hemodynamic, respiratory and thermoregulatory responses to birth and/or hypoxia (prostaglandins, arginine vasopressin and, above all, adenosine), their potential clinical use awaits further research [128,188,234]. Hence, reducing environmental stress by ‘minimal handling’ and optimized thermal protection thus far remain the most important measures to protect preterm neonates from adverse metabolic stimulation. Perhaps, in view of the striking ‘oxyconformistic’ ability of fetal and neonatal tissues to reduce their oxygen consumption without building-up an oxygen deficit, the role of oxygen itself as a regulator of perinatal metabolism should be given more attention. At any rate, the comparative approach indicates that physiological mechanisms which from the human adult perspective appear ‘immature’ or ‘pathological’, may still have their own adaptive value, and thus suggests a less ‘anthropocentric’ view of perinatal responses to hypoxia.

References [1] Abbrecht PH, Littell JK. Plasma erythropoietin in men and mice during acclimatization to different altitudes. J Appl Physiol 1972;32:54 – 8. [2] Adamsons K, Myers RE. Late decelerations and brain tolerance of the fetal monkey to intrapartum asphyxia. Am J Obstet Gynecol 1977;128:893 – 900. [3] Adolph EF. Tolerance to cold and anoxia in infant rats. Am J Physiol 1948;155:366 – 77. [4] Adolph EF. Regulations during survival without oxygen in infant mammals. Respir Physiol 1969;7:356 – 68. [5] Andersen HT. Physiological adaptations in diving vertebrates. Physiol Rev 1966;46:212 – 43. [6] Anselmino KJ, Hoffmann F. Die Ursachen des Icterus neonatorum. Arch Gyna¨kol 1931;147:69 – 71. [7] Asakura H, Ball KT, Power GG. Interdependence of arterial pO2 and O2 consumption in the fetal sheep. J Dev Physiol 1990;13:205 – 13. [8] Ashwal S, Dale PS, Longo LD. Regional cerebral blood flow: studies in the fetal lamb during hypoxia, hypercapnia, acidosis, and hypotension. Pediatr Res 1984;18:1309 – 16. [9] Aste-Salazar H, Hurtado A. The affinity of hemoglobin for oxygen at sea level and at high altitudes. Am J Physiol 1944;142:733 – 43. [10] Attias D. Pathophysiology and treatment of the anemia of prematurity. J Pediatr Hematol Oncol 1995;17:13 – 8.

D. Singer / Comparati6e Biochemistry and Physiology, Part A 123 (1999) 221–234 [11] Avery RC, Johlin JM. Relative susceptibility of adult and young mice to asphyxiation. Proc Soc Exp Biol Med 1931/ 32;29:1184 – 6. [12] Babkin PS. Neirofiziologicheskie i klinicheskie aspektly intranatal’noi gibernatsii ploda. Zh Nevropatol Psikhiatr 1984;84:1627 – 30 (Neurophysiologic and clinical aspects of intranatal fetal hibernation). [13] Ballanyi K, Kuwana SI, Vo¨lker A, Morawietz G, Richter DW. Developmental changes in the hypoxia tolerance of the in vitro respiratory network of rats. Neurosci Lett 1992;148:141 – 4. [14] Barcroft J. Researches in prenatal life. Oxford: Blackwell, 1946. [15] Barcroft J, Elliott RHE, Flexner LB, Hall FG, Herkel W, McCarthy EF, et al. Conditions of foetal respiration in the goat. J Physiol 1935;83:192–214. [16] Barrie SE, Harris P. Myocardial enzyme activities in guinea pigs during development. Am J Physiol 1977;233:H707– 10. [17] Bauer R, Zwiener U, Buchenau W, Hoyer D, Witte H, Lampe V, et al. Restricted cardiovascular and cerebral performance of intra-uterine growth retarded newborn piglets during severe hypoxia. Biomed Biochim Acta 1989;48:697–705. [18] Beeby PJ, Elliott EJ, Henderson-Smart DJ, Rieger ID. Predictive value of umbilical artery pH in preterm infants. Arch Dis Child 1994;71:F93 –6. [19] Belkin DA. Anaerobiosis in diving turtles. Physiologist 1962;5:105. [20] Bernstein D, Teitel D, Sidi D, Heymann MA, Rudolph AM. Redistribution of regional blood flow and oxygen delivery in experimental cyanotic heart disease in newborn lambs. Pediatr Res 1987;22:389 – 93. [21] Bert P. Lec¸ons sur la physiologie compare´e de la respiration. Paris: Baillie`re, 1870. [22] Bohr C. Der respiratorische Stoffwechsel des Sa¨ugethierembryos. Skand Arch Physiol 1900;10:413–24. [23] Bonora M, Boule M, Gautier H. Ventilatory strategy in hypoxic or hypercapnic newborns. Biol Neonate 1994;65:198 – 204. [24] Bove EL, Stammers AH. Recovery of left ventricular function after hypothermic global ischemia: age-related differences in the isolated working rabbit heart. J Thorac Cardiovasc Surg 1986;91:115 – 22. [25] Bretscher J, Saling E. pH values in the human fetus during labor. Am J Obstet Gynecol 1967;97:906–11. [26] Bretschneider HJ. Sauerstoffbedarf und -versorgung des Herzmuskels. Verh Dtsch Ges Kreislaufforsch 1961;27:32–59. [27] Bretschneider HJ, Hu¨bner G, Knoll D, Lohr D, Nordbeck H, Spieckermann PG. Myocardial resistance and tolerance to ischemia: physiological and biochemical basis. J Cardiovasc Surg 1975;16:241 – 60. [28] Britton SW, Kline RF. Age, sex, carbohydrate, adrenal cortex and other factors in anoxia. Am J Physiol 1945/46;145:190– 202. [29] Bru¨ck K. Heat production and temperature regulation. In: Stave U, editor. Perinatal physiology, 2nd ed. New York: Plenum, 1978:455 –98. [30] Bru¨ck K. Neonatal thermal regulation. In: Polin RA, Fox WW, editors. Fetal and neonatal physiology, vol. 1. Philadelphia: Saunders, 1992:488–515. [31] Bru¨ck K, Parmelee AH, Bru¨ck M. Neutral temperature range and range of ‘thermal comfort’ in premature infants. Biol Neonate 1962;4:32 –51. [32] Bryan AC, Bowes G, Maloney JE. Control of breathing in the fetus and the newborn. In: Fishman AP, Cherniack NS, Widdicombe JG, editors. Handbook of physiology, Section 3, The respiratory system, Vol. II, Control of breathing, Part 2. Bethesda: American Physiological Society, 1986: 621–47. [33] Buck LT, Hochachka PW. Anoxic suppression of Na(+)-K(+)ATPase and constant membrane potential in hepatocytes: support for channel arrest. Am J Physiol 1993;265:R1020– 5.

229

[34] Butler PJ. Respiratory and cardiovascular control during diving in birds and mammals. J Exp Biol 1982;100:195 – 221. [35] Butler PJ, Jones DR. Physiology of diving of birds and mammals. Physiol Rev 1997;77:837 – 99. [36] Caplan MS, Hedlund E, Adler L, Hsueh W. Role of asphyxia and feeding in a neonatal rat model of necrotizing enterocolitis. Pediatr Pathol 1994;14:1017 – 28. [37] Chadd MA, Elwood PC, Gray OP, Muxworthy SM. Coagulation defects in hypoxic full-term newborn infants. Br Med J 1971;4:516 – 8. [38] Chessells JM, Wigglesworth JS. Coagulation studies in severe birth asphyxia. Arch Dis Child 1971;46:253 – 6. [39] Chevillard L, Portet R, Cadot M. Growth rate of rats born and reared at 5 and 30°C. Fed Proc 1963;22:699 – 703. [40] Cohn HE, Piasecki GJ, Jackson BT. The effect of fetal heart rate on cardiovascular function during hypoxemia. Am J Obstet Gynecol 1980;138:1190 – 9. [41] Currie AE. How cold can you get? A case of severe neonatal hypothermia. J R Soc Med 1994;87:293 – 4. [42] Davis JA, Tizard JPM. Practical problems of neonatal paediatrics considered in relation to animal physiology. Br Med Bull 1961;17:168 – 73. [43] Dawes GS. Oxygen consumption and hypoxia in the newborn animal. In: Wolstenholme GEW, O’Connor M, editors. Somatic stability in the newly born. Ciba Foundation Symposium. London: Churchill, 1961:170 – 82. [44] Dawes GS, Mott JC. The increase in oxygen consumption of the lamb after birth. J Physiol 1959;146:295 – 315. [45] Dawes GS, Mott JC, Shelley HJ. The importance of cardiac glycogen for the maintenance of life in foetal lambs and newborn animals during anoxia. J Physiol 1959;146:516 – 38. [46] Diemer K. Capillarisation and oxygen supply of the brain. In: Lu¨bbers DW, Luft UC, Thews G, Witzleb E, editors. Oxygen transport in blood and tissue. Stuttgart: Thieme, 1968:118–23. [47] Doll CJ, Hochachka PW, Reiner PB. Effects of anoxia and metabolic arrest on turtle and rat cortical neurons. Am J Physiol 1991;260:R747– 55. [48] Duffy TE, Kohle SJ, Vannucci RC. Carbohydrate and energy metabolism in perinatal rat brain: relation to survival in anoxia. J Neurochem 1975;24:271 – 6. [49] Eales FA, Small J. Effects of acute hypoxia on heat production capacity in newborn lambs. Res Vet Sci 1985;39:212 –5. [50] Edwards RA, Lutz PL, Baden DG. Relationship between energy expenditure and ion channel density in the turtle and rat brain. Am J Physiol 1989;257:R1354– 8. [51] Else PL, Hulbert AJ. Evolution of mammalian endothermic metabolism: ‘leaky’ membranes as a source of heat. Am J Physiol 1987;253:R1 – 7. [52] Elsner R, Gooden B. Diving and asphyxia: a comparative study of animals and man. Monogr Physiol Soc 1983;40:1 –168. [53] Elsner R, Franklin DL, van Citters RL, Kenney DW. Cardiovascular defense against asphyxia: studies of circulatory responses to diving in aquatic and land animals clarify some reactions to asphyxia. Science 1966;153:941 – 9. [54] Fahey JT, Lister G. Response to low cardiac output: developmental differences in metabolism during oxygen deficit and recovery in lambs. Pediatr Res 1989;26:180 – 7. [55] Faura J, Ramos J, Reynafarje C, English E, Finne P, Finch CA. Effect of altitude on erythropoiesis. Blood 1969;33:668–76. [56] Fazekas JF, Alexander FAD, Himwich HE. Tolerance of the newborn to anoxia. Am J Physiol 1941;134:281 – 7. [57] Fee SC, Malee K, Deddish R, Minogue JP, Socol ML. Severe acidosis and subsequent neurological status. Am J Obstet Gynecol 1990;162:802 – 6. [58] Fisher DJ, Heymann MA, Rudolph AM. Myocardial oxygen and carbohydrate consumption in fetal lambs in utero and in adult sheep. Am J Physiol 1980;238:H399– 405.

230

D. Singer / Comparati6e Biochemistry and Physiology, Part A 123 (1999) 221–234

[59] Fisher DJ, Heymann MA, Rudolph AM. Fetal myocardial oxygen and carbohydrate consumption during acutely induced hypoxemia. Am J Physiol 1982;242:H657–61. [60] Fisher DJ, Heymann MA, Rudolph AM. Fetal myocardial oxygen and carbohydrate metabolism in sustained hypoxemia in utero. Am J Physiol 1982;243:H959–63. [61] Frappell P, Lanthier C, Baudinette RV, Mortola JP. Metabolism and ventilation in acute hypoxia: a comparative analysis in small mammalian species. Am J Physiol 1992;262:1040– 6. [62] Frisancho AR. Functional adaptation to high altitude hypoxia: changes occurring during growth and development are of major importance in man’s adapting to high altitudes. Science 1975;187:313 – 9. [63] Gautier H. Interactions among metabolic rate, hypoxia, and control of breathing. J Appl Physiol 1996;81:521–7. [64] Gautier H. Invited editorial on ‘oxygen transport in conscious newborn dogs during hypoxic hypometabolism’. J Appl Physiol 1998;84:761 – 2. [65] Geiser F. Reduction of metabolism during hibernation and daily torpor in mammals and birds: temperature effect or physiological inhibition? J Comp Physiol 1988;158B:25– 37. [66] Gelli MG, Enho¨rning G, Hultman E, Bergstro¨m J. Glucose infusion in the pregnant rabbit and its effect on glycogen content and activity of foetal heart under anoxia. Acta Paediatr Scand 1968;57:209 –14. [67] Gennser G. Influence of hypoxia and glucose on contractility of papillary muscles from adult and neonatal rabbits. Biol Neonate 1972;21:90–106. [68] Glass HG, Snyder FF, Webster E. The rate of decline in resistance to anoxia of rabbits, dogs and guinea pigs from the onset of viability to adult life. Am J Physiol 1944;140:609 – 15. [69] Glass L, Silverman WA, Sinclair JC. Effect of the thermal environment on cold resistance and growth of small infants after the first week of life. Pediatrics 1968;41:1033–64. [70] Gooden BA. The evolution of asphyxial defense. Integr Physiol Behav Sci 1993;28:317–30. [71] Gudinchet F, Schutz Y, Micheli JL, Stettler E, Je´quier E. Metabolic cost of growth in very low-birth-weight infants. Pediatr Res 1982;16:1025–30. [72] Gutierrez G, Warley AR, Dantzker DR. Oxygen delivery and utilization in hypothermic dogs. J Appl Physiol 1986;60:751 – 7. [73] Hall FG, Dill DB, Barron ESG. Comparative physiology in high altitudes. J Cell Comp Physiol 1936;8:301–13. [74] Halpe´rin DS, Fe´lix M, Wacker P, Lacourt G, Babel JF, Wyss M. The anemia of prematurity: causes and therapeutic consequences. In: Bauer C, Koch KM, Scigalla P, Wieczorek L, editors. Erythropoietin: molecular physiology and clinical applications. New York: Marcel Dekker, 1993:365–77. [75] Hanley FL. Organ development and maturation. In: Jonas RA, Elliott MJ, editors. Cardiopulmonary bypass in neonates, infants and young children. Oxford: Butterworth Heinemann, 1994:5 – 26. [76] Hansen AJ. Extracellular potassium concentration in juvenile and adult rat brain cortex during anoxia. Acta Physiol Scand 1977;99:412 – 20. [77] Hansen NB, Brubakk AM, Bratlid D, Oh W, Stonestreet BS. The effects of variations in PaCO2 on brain blood flow and cardiac output in the newborn piglet. Pediatr Res 1984;18:1132 – 6. [78] Harken AH. Hydrogen ion concentration and oxygen uptake in an isolated canine hindlimb. J Appl Physiol 1976;40:1– 5. [79] Haselhorst G, Stromberger K. U8 ber den Gasgehalt des Nabelschnurblutes vor und nach der Geburt des Kindes und u¨ber den Gasaustausch in der Plazenta, I. Mitteilung. Z Geburtsh Gyna¨kol 1930;98:49–78.

[80] Haselhorst G, Stromberger K. U8 ber den Gasgehalt des Nabelschnurblutes vor und nach der Geburt des Kindes und u¨ber den Gasaustausch in der Plazenta, II. Mitteilung. Z Geburtsh Gyna¨kol 1931;100:48 – 70. [81] Hasselbalch AK. U8 ber den respiratorischen Stoffwechsel des Hu¨hnerembryos. Skand Arch Physiol 1900;10:353 – 402. [82] Hazan J, Maag U, Chessex P. Association between hypothermia and mortality rate of premature infants — revisited. Am J Obstet Gynecol 1991;164:111 – 2. [83] Hensel H, Bru¨ck K, Raths P. Homeothermic organisms. In: Precht H, Christophersen J, Hensel H, Larcher W, editors. Temperature and life. Berlin: Springer, 1973:503 – 761. [84] Herting E, Gefeller O, Speer CP, Harms K, Halliday HL, Curstedt T, et al. Intracerebral haemorrhages in surfactant treated neonates with severe respiratory distress syndrome: age at diagnosis, severity and risk factors. Eur J Pediatr 1994;153:842 – 9. [85] Hill J. The oxygen consumption of new-born and adult mammals: its dependence on the oxygen tension in the inspired air and on the environmental temperature. J Physiol 1959;149:346– 73. [86] Hill JR, Rahimtulla KA. Heat balance and the metabolic rate of new-born babies in relation to environmental temperature; and the effect of age and of weight on basal metabolic rate. J Physiol 1965;180:239 – 65. [87] Himwich HE, Fazekas JF. Comparative studies of the metabolism of the brain of infant and adult dogs. Am J Physiol 1941;132:454 – 9. [88] Himwich HE, Fazekas JF, Alexander FAD. Effects of cyanide and iodoacetate on survival period of infant rats. Proc Soc Exp Biol Med 1941;46:553 – 4. [89] Himwich HE, Bernstein AO, Herrlich H, Chesler A, Fazekas JF. Mechanisms for the maintenance of life in the newborn during anoxia. Am J Physiol 1941/42;135:387– 91. [90] Hochachka PW. Diving marine mammals. In: Living without oxygen: closed and open systems in hypoxia tolerance. Cambridge, MA: Harvard University Press, 1980:145 – 69. [91] Hochachka PW. Defense strategies against hypoxia and hypothermia. Science 1986;231:234 – 41. [92] Hochachka PW. Balancing conflicting metabolic demands of exercise and diving. Fed Proc 1986;45:2948 – 52. [93] Hochachka PW. The lactate paradox: analysis of underlying mechanisms. Ann Sports Med 1988;4:184 – 8. [94] Hochachka PW. Adaptability of metabolic efficiencies under chronic hypoxia in man. In: Hochachka PW, Lutz PL, Sick T, Rosenthal M, van den Thillart G, editors. Surviving hypoxia: mechanisms of control and adaptation. Boca Raton, FL: CRC Press, 1993:127 – 35. [95] Hochachka PW, Guppy M. Metabolic arrest and the control of biological time. Cambridge, MA: Harvard University Press, 1987. [96] Hochachka PW, Somero GN. Mammalian developmental adaptations. In: Biochemical adaptation. Princeton: Princeton University Press, 1984:250 – 78. [97] Hochachka PW, Stanley C, McKenzie DC, Villena A, Monge C. Enzyme mechanisms for pyruvate-to-lactate flux attenuation: a study of sherpas, quechuas, and hummingbirds. Int J Sports Med 1992;13(Suppl 1):S119 – 22. [98] Hochachka PW, Buck LT, Doll CJ, Land SC. Unifying theory of hypoxia tolerance: molecular/metabolic defense and rescue mechanisms for surviving oxygen lack. Proc Nat Acad Sci USA 1996;93:9493 – 8. [99] Hoerter J. Changes in the sensitivity to hypoxia and glucose deprivation in the isolated perfused rabbit heart during perinatal development. Pflu¨g Arch 1976;363:1 – 6. [100] Hoerter JA, Opie LH. Perinatal changes in glycolytic function in response to hypoxia in the incubated or perfused rat heart. Biol Neonate 1978;33:144 – 61.

D. Singer / Comparati6e Biochemistry and Physiology, Part A 123 (1999) 221–234 [101] Holowach-Thurston J, McDougal DB. Effect of ischemia on metabolism of the brain of the newborn mouse. Am J Physiol 1969;216:348 – 52. [102] Hossmann KA. Experimentelle Grundlagen der Ischa¨mietoleranz des Hirns. Z Kardiol 1987;76(Suppl 4):47–66. [103] Hulbert AJ, Else PL. Comparison of the ‘mammal machine’ and the ‘reptile machine’: energy use and thyroid activity. Am J Physiol 1981;241:R350–6. [104] Hurtado, A. Animals in high altitudes: Resident man. In: Dill DB, editor. Handbook of physiology, Section 4, Adaptation to the environment. Washington, DC: American Physiological Society, 1964, 843 –60. [105] Jackson DC. Metabolic depression and oxygen depletion in the diving turtle. J Appl Physiol 1968;24:503–9. [106] James LS, Weisbrot IM, Prince CE, Holaday DA, Apgar V. The acid-base status of human infants in relation to birth asphyxia and the onset of respiration. J Pediatr 1958;52:379 – 94. [107] Jarmakani JM, Nakazawa M, Nagatomo T, Langer GA. Effect of hypoxia on mechanical function in the neonatal mammalian heart. Am J Physiol 1978;235:H469–74. [108] Jarmakani JM, Nagatomo T, Nakazawa M, Langer GA. Effect of hypoxia on myocardial high-energy phosphates in the neonatal mammalian heart. Am J Physiol 1978;235:H475–81. [109] Jensen A, Berger R. Fetal circulatory responses to oxygen lack. J Dev Physiol 1991;16:181–207. [110] Jensen A, Hohmann M, Kunzel W. Dynamic changes in organ blood flow and oxygen consumption during acute asphyxia in fetal sheep. J Dev Physiol 1987;9:543–59. [111] Jiang C, Xia Y, Haddad GG. Role of ATP-sensitive K + channels during anoxia: major differences between rat (newborn and adult) and turtle neurons. J Physiol 1992;448:599 – 612. [112] Jones CT, Rolph TP. Metabolism during fetal life: a functional assessment of metabolic development. Physiol Rev 1985;65:357 – 430. [113] Jones MD, Sheldon RE, Peeters LL, Meschia G, Battaglia FC, Makowski EL. Fetal cerebral oxygen consumption at different levels of oxygenation. J Appl Physiol 1977;43:1080–4. [114] Jones MD, Sheldon RE, Peeters LL, Makowski EL, Meschia G. Regulation of cerebral blood flow in the ovine fetus. Am J Physiol 1978;235:H162–6. [115] Kabat H. The greater resistance of very young animals to arrest of the brain circulation. Am J Physiol 1940;130:588–99. [116] Kaiser C. The physiology of natural hibernation. New York: Pergamon, 1961:93–103. [117] Kariniemi V. Fetal anemia and heart rate patterns. J Perinat Med 1982;10:167 – 73. [118] Karlowicz MG, Adelman RD. Non-oliguric and oliguric acute renal failure in asphyxiated term neonates. Pediatr Nephrol 1995;9:718 – 22. [119] Kayser B. Lactate during exercise at high altitude. Eur J Appl Physiol 1996;74:195–205. [120] Kirklin JW, Barratt-Boyes BG. Hypothermia, circulatory arrest, and cardiopulmonary bypass. In: Cardiac surgery. New York: Wiley, 1986:29–82. [121] Kleiber M. The fire of life: an introduction to animal energetics. New York: Wiley, 1961. [122] Koch F, Wieser W. Partitioning of energy in fish: can reduction of swimming activity compensate for the cost of production? J Exp Biol 1983;107:141–6. [123] Kooyman GL, Castellini MA, Davis RW. Physiology of diving in marine mammals. Annu Rev Physiol 1981;43:343–56. [124] Kosloske AM. A unifying hypothesis for pathogenesis and prevention of necrotizing enterocolitis. J Pediatr 1990;117:S68 – 74.

231

[125] Krogh A. The number and distribution of capillaries in muscles with calculations of the oxygen pressure head necessary for supplying the tissue. J Physiol 1918/19;52:409– 15. [126] Krumschnabel G, Wieser W. Energy allocation and material flux in fish hepatocytes under stress. In: Gnaiger E, Gellerich FN, Wyss M, editors. What is controlling life? Innsbruck: Innsbruck University Press, 1994:238 – 9. [127] Lagercrantz H. What does the preterm infant breathe for? Controversies on apnea of prematurity. Acta Paediatr 1992;81:733 – 6. [128] Lagercrantz H. Improved understanding of respiratory control — implications for the treatment of apnoea. Eur J Pediatr 1995;154(Suppl 3):S10 – 2. [129] Lagercrantz H, Slotkin TA. The ‘stress’ of being born. Sci Am 1986;254(4):92– 102. [130] Lechner AJ. Respiratory adaptations in burrowing pocket gophers from sea level and high altitude. J Appl Physiol 1976;41:168 – 73. [131] Lenfant C, Ways P, Aucutt C, Cruz J. Effect of chronic hypoxic hypoxia on the O2-Hb dissociation curve and respiratory gas transport in man. Respir Physiol 1969;7:7 – 29. [132] Levene MI, Fawer CL, Lamont RF. Risk factors in the development of intraventricular haemorrhage in the preterm neonate. Arch Dis Child 1982;57:410 – 7. [133] Linde LM, Dunn OJ, Schireson R, Rasof B. Growth in children with congenital heart disease. J Pediatr 1967;70:413–9. [134] Lister G. Metabolic responses to hypoxia. Crit Care Med 1993;21(Suppl. 9):S340 – 1. [135] Low JA. The role of blood gas and acid-base assessment in the diagnosis of intrapartum fetal asphyxia. Am J Obstet Gynecol 1988;159:1235– 40. [136] Lubchenco LO, Bard H. Incidence of hypoglycemia in newborn infants classified by birth weight and gestational age. Pediatrics 1971;47:831 – 8. [137] Lutz PL. Mechanisms for anoxic survival in the vertebrate brain. Annu Rev Physiol 1992;54:601 – 18. [138] Lutz PL, Hochachka PW. Hypoxia defense mechanisms: a comparison between diving reptiles and mammals. In: Hochachka PW, Lutz PL, Sick T, Rosenthal M, van den Thillart G, editors. Surviving hypoxia: mechanisms of control and adaptation. Boca Raton, FL: CRC Press, 1993:459–69. [139] Lutz PL, Nilsson GE. The brain without oxygen: causes of failure and mechanisms for survival. Austin: Landes, 1994:89– 103. [140] Lutz PL, Nilsson GE, Pere´z-Pinzo´n MA. Anoxia tolerant animals from a neurobiological perspective. Comp Biochem Physiol 1996;113B:3 – 13. [141] Ma¨enpa¨a¨ PH, Ra¨iha¨ NCR. Effects of anoxia on energy-rich phosphates, glycogen, lactate and pyruvate in the brain, heart and liver of the developing rat. Ann Med Exp Fenn 1968;46:306 – 17. [142] Malan A. Enzyme regulation, metabolic rate and acid-base state in hibernation. In: Gilles R, editor. Animals and environmental fitness, vol. 1. Oxford: Pergamon, 1980:487 – 501. [143] Malan A. pH as a control factor of cell function in hibernation: the case of brown adipose tissue thermogenesis. In: Malan A, Canguilhem B, editors. Living in the cold. London: Libbey, 1989:333 – 41. [144] Markert CL, Ursprung H. The ontogeny of isozyme patterns of lactate dehydrogenase in the mouse. Dev Biol 1962;5:363–81. [145] Martin RJ, Miller MJ, Carlo WA. Pathogenesis of apnea in preterm infants. J Pediatr 1986;109:733 – 41. [146] McDougal DB, Holowach J, Howe MC, Jones EM, Thomas CA. The effects of anoxia upon energy sources and selected metabolic intermediates in the brains of fish, frog and turtle. J Neurochem 1968;15:577 – 88.

232

D. Singer / Comparati6e Biochemistry and Physiology, Part A 123 (1999) 221–234

[147] Metcalfe J, Moll W, Bartels H. Gas exchange across the placenta. Fed Proc 1964;23:774–80. [148] Miller JA. New approaches to preventing brain damage during asphyxia. Am J Obstet Gynecol 1971;110:1125–33. [149] Miller JA, Miller FS. Interactions between hypothermia and hypoxia-hypercapnia in neonates. Fed Proc 1966;25:1338 – 41. [150] Miller JA, Miller FS, Westin B. Hypothermia in the treatment of asphyxia neonatorum. Biol Neonate 1964;6:148–63. [151] Milsom WK. Intermittent breathing in vertebrates. Annu Rev Physiol 1991;53:87 –105. [152] Monge C, Le´on-Velarde F. Physiological adaptation to high altitude: oxygen transport in mammals and birds. Physiol Rev 1991;71:1135 – 72. [153] Moore RE. Oxygen consumption and body temperature in new-born kittens subjected to hypoxia and reoxygenation. J Physiol 1959;149:500–18. [154] Morin FC, Weiss KI. Response of the fetal circulation to stress. In: Polin RA, Fox WW, editors. Fetal and neonatal physiology, vol. 1. Philadelphia: Saunders, 1992:620–9. [155] Mortola JP, Rezzonico R, Lanthier C. Ventilation and oxygen consumption during acute hypoxia in newborn mammals: a comparative analysis. Respir Physiol 1989;78:31–43. [156] Mott JC. The ability of young mammals to withstand total oxygen lack. Br Med Bull 1961;17:144–8. [157] Mott JC. Oxygen consumption of the newborn. Fed Proc 1963;22:814 – 7. [158] Mott JC. Control of the foetal circulation. J Exp Biol 1982;100:129 – 46. [159] Murphy B, Zapol WM, Hochachka PW. Metabolic activities of heart, lung, and brain during diving and recovery in the Weddell seal. J Appl Physiol 1980;48:596–605. [160] Myers RE, Yamaguchi S. Nervous system effects of cardiac arrest in monkeys: preservation of vision. Arch Neurol 1977;34:65 – 74. [161] Nilsson GE. Neurotransmitters and anoxia resistance: comparative physiological and evolutionary perspectives. In: Hochachka PW, Lutz PL, Sick T, Rosenthal M, van den Thillart G, editors. Surviving hypoxia: mechanisms of control and adaptation. Boca Raton, FL: CRC Press, 1993:401 – 13. [162] Nilsson GE, Lutz PL, Jackson TL. Neurotransmitters and anoxic survival of the brain: a comparison between anoxia-tolerant and anoxia-intolerant vertebrates. Physiol Zool 1991;64:638 – 52. [163] Nioka S, Chance B, Smith DS, Mayevsky A, Reilly MP, Alter C, et al. Cerebral energy metabolism and oxygen state during hypoxia in neonate and adult dogs. Pediatr Res 1990;28:54 – 62. [164] Opitz E. U8 ber die intrauterine Sauerstoffversorgung der Frucht. Zentralbl Gyna¨kol 1949;71:113–28. [165] Opitz E, Schneider M. U8 ber die Sauerstoffversorgung des Gehirns und den Mechanismus von Mangelwirkungen. Erg Physiol Biol Chem Exp Pharmakol 1950;46:126–260. [166] Paganelli CV, Rahn H. Adult and embryonic metabolism in birds and the role of shell conductance. In: Seymour RS, editor. Respiration and metabolism of embryonic vertebrates. Dordrecht: Dr W Junk Publishers, 1984:193–204. [167] Pere´z-Pinzo´n MA, Nilsson GE, Lutz PL. Relationship between ion gradients and neurotransmitter release in the newborn rat striatum during anoxia. Brain Res 1993;602:228–33. [168] Popovic P, Popovic V. Survival of newborn ground squirrels after supercooling or freezing. Am J Physiol 1963;204:949 – 52. [169] Power GG. Fetal thermoregulation: animal and human. In: Polin RA, Fox WW, editors. Fetal and neonatal physiology, vol. 1. Philadelphia: Saunders, 1992:477–83. [170] Pulsinelli WA, Waldman S, Rawlinson D, Plum F. Moderate hyperglycemia augments ischemic brain damage: a neuropathologic study in the rat. Neurology 1982;32:1239–46.

[171] Rahn H. Comparison of embryonic development in birds and mammals: birth weight, time, and cost. In: Taylor CR, Johansen K, Bolis L, editors. A companion to animal physiology. Cambridge: Cambridge University Press, 1982:124 – 37. [172] Rebeyka I. Hypothermia. In: Jonas RA, Elliott MJ, editors. Cardiopulmonary bypass in neonates, infants and young children. Oxford: Butterworth Heinemann, 1994:54 – 66. [173] Rehncrona S, Rose´n I, Siesjo¨ BK. Excessive cellular acidosis: an important mechanism of neuronal damage in the brain? Acta Physiol Scand 1980;110:435 – 7. [174] Reichman BL, Chessex P, Putet G, Verellen GJE, Smith JM, Heim T, et al. Partition of energy metabolism and energy cost of growth in the very low-birth-weight infant. Pediatrics 1982;69:446 – 51. [175] Reiss M, Haurowitz F. U8 ber das Verhalten junger und alter Tiere bei Erstickung. Klin Wschr 1929;8:743 – 4. [176] Ritzerfeld S, Singer D, Speer CP, Schiffmann H, Harms K. Notfalltransporte von Neu- und Fru¨hgeborenen: Vorausschauende Versorgung schu¨tzt vor Komplikationen. Notarzt 1997;13:1 – 7. [177] Robin ED. Of men and mitochondria: coping with hypoxic dysoxia. Am Rev Respir Dis 1980;122:517 – 31. [178] Rohlicek CV, Saiki C, Matsuoka T, Mortola JP. Oxygen transport in conscious newborn dogs during hypoxic hypometabolism. J Appl Physiol 1998;84:763 – 8. [179] Rolph TP, Jones CT, Parry D. Ultrastructural and enzymatic development of fetal guinea pig heart. Am J Physiol 1982;243:H87 – 93. [180] Rubner M. U8 ber Kompensation und Summation von funktionellen Leistungen des Ko¨rpers. Sitzungsber Ko¨nigl Preuss Akad Wiss, 1910:316 – 24. [181] Ruggins NR. Pathophysiology of apnoea in preterm infants. Arch Dis Child 1991;66:70 – 3. [182] Ruth VJ, Raivio KO. Perinatal brain damage: predictive value of metabolic acidosis and the Apgar score. Br Med J 1988;297:24 – 7. [183] Samson FE, Dahl NA. Cerebral energy requirement of neonatal rats. Am J Physiol 1957;188:277 – 80. [184] Saugstad OD. Oxygen toxicity in the neonatal period. Acta Paediatr Scand 1990;79:881 – 92. [185] Schmidt-Nielsen K. Animal physiology: adaptation and environment, 3rd ed. Cambridge: Cambridge University Press, 1983. [186] Schmidt-Nielsen K. Scaling: why is animal size so important? Cambridge: Cambridge University Press, 1984. [187] Scholander PF. The master switch of life. Sci Am 1963;209:92– 106. [188] Schro¨der HJ, Power GG. Basic aspects of fetal thermal homeostasis. In: Zeisberger E, Scho¨nbaum E, Lomax P, editors. Thermal balance in health and disease: recent basic research and clinical progress. Basel: Birkha¨user, 1994:235 – 49. [189] Shelley HJ. Glycogen reserves and their changes at birth and in anoxia. Br Med Bull 1961;17:137 – 43. [190] Shelton G, Boutilier RG. Apnoea in amphibians and reptiles. J Exp Biol 1982;100:245 – 73. [191] Shin’oka T, Shum-Tim D, Jonas RA, Lidov HG, Laussen PC, Miura T, et al. Higher hematocrit improves cerebral outcome after deep hypothermic circulatory arrest. J Thorac Cardiovasc Surg 1996;112:1610– 20. [192] Sick TJ, Rosenthal M, LaManna JC, Lutz PL. Brain potassium homeostasis, anoxia, and metabolic inhibition in turtles and rats. Am J Physiol 1982;243:R281– 8. [193] Sidi D, Kuipers JRG, Teitel D, Heymann MA, Rudolph AM. Developmental changes in oxygenation and circulatory responses to hypoxemia in lambs. Am J Physiol 1983;245:H674– 82.

D. Singer / Comparati6e Biochemistry and Physiology, Part A 123 (1999) 221–234 [194] Siesjo¨ BK. Cerebral metabolic rate in hypercarbia—a controversy. Anesthesiology 1980;52:461–5. [195] Silverman WA, Fertig JW, Berger AP. The influence of the thermal environment upon the survival of newly born premature infants. Pediatrics 1958;22:876–86. [196] Sinclair JC. Effect of the thermal environment on neonatal mortality and morbidity: state of the evidence. In: Okken A, Koch J, editors. Thermoregulation of sick and low birth weight neonates. Berlin: Springer, 1995:127–41. [197] Singer D. Thermometry and calorimetry in the neonate: recent advances in monitoring and research. Thermochim Acta 1998;309:39 – 47. [198] Singer D, Bretschneider HJ. Metabolic reduction in hypothermia: pathophysiological problems and natural examples — Part 1. Thorac Cardiovasc Surgeon 1990;38:205–11. [199] Singer D, Bretschneider HJ. Metabolic reduction in hypothermia: pathophysiological problems and natural examples — Part 2. Thorac Cardiovasc Surgeon 1990;38:212–9. [200] Singer D, Schiffmann H. Thermoregulatorische Besonderheiten des pa¨diatrischen Patienten. In: Weyland W, Braun U, Kettler D, editors. Perioperative Hypothermie: Probleme, Pra¨vention und Therapie. Ebelsbach: Aktiv Druck, 1997:110–22. [201] Singer D, Bach F, Bretschneider HJ, Kuhn HJ. Microcalorimetric monitoring of ischemic tissue metabolism: influence of incubation conditions and experimental animal species. Thermochim Acta 1991;187:55–69. [202] Singer D, Bach F, Bretschneider HJ, Kuhn HJ. Metabolic size allometry and the limits to beneficial metabolic reduction: hypothesis of a uniform specific minimal metabolic rate. In: Hochachka PW, Lutz PL, Sick T, Rosenthal M, van den Thillart G, editors. Surviving hypoxia: mechanisms of control and adaptation. Boca Raton, FL: CRC Press, 1993:447 – 58. [203] Singer D, Hehenkamp E, Zeller U, Schmidt H, Kuhn HJ, Schro¨ter W. Postnatal development of metabolic rate in preterm human and small marsupial neonates: different patterns in pathological and physiological prematurity. Eur J Pediatr 1995;154:251. [204] Singer D, Zeller U, Hehenkamp E, Schmidt H, Kuhn HJ. Suppression and activation of metabolic size allometry in marsupial and preterm human neonates: a comparative calorimetric investigation. Physiol Zool 1995;68:126. [205] Snyder GK. Respiratory adaptations in diving mammals. Respir Physiol 1983;54:269–94. [206] Stafford A, Weatherall JAC. The survival of young rats in nitrogen. J Physiol 1960;153:457–72. [207] Stapleton FB, Jones DP, Green RS. Acute renal failure in neonates: incidence, etiology and outcome. Pediatr Nephrol 1987;1:314 – 20. [208] Stave U. Maturation, adaptation, and tolerance. In: Stave U, editor. Perinatal physiology. New York: Plenum, 1978:27 – 36. [209] Su JY, Friedman WF. Comparison of the responses of fetal and adult cardiac muscle to hypoxia. Am J Physiol 1973;224:1249– 53. [210] Suarez RK, Doll CJ, Buie AE, West TG, Funk GD, Hochachka PW. Turtles and rats: a biochemical comparison of anoxia-tolerant and anoxia-sensitive brains. Am J Physiol 1989;257:R1083– 8. [211] Subhash MN, Shankar SK, Rama BS. Lactate dehydrogenase isoenzyme patterns in human foetal tissues during development. Indian J Physiol Pharmacol 1986;30:271–9. [212] Szymonowicz W, Yu VYH, Wilson FE. Antecedents of periventricular haemorrhage in infants weighing 1250 g or less at birth. Arch Dis Child 1984;59:13–7. [213] Talner NS, Lister G, Fahey JT. Effects of asphyxia on the myocardium of the fetus and newborn. In: Polin RA, Fox WW, editors. Fetal and neonatal physiology, vol. 1. Philadelphia: Saunders, 1992:759–69.

233

[214] Thauer R, Brendel W. Hypothermie. Prog Surg 1962;2:73–271. [215] Thews G. Die Sauerstoffdiffusion im Gehirn. Ein Beitrag zur Frage der Sauerstoffversorgung der Organe. Pflu¨g Arch 1960;271:197 – 226. [216] Thoresen M, Wyatt J. Keeping a cool head, post-hypoxic hypothermia — an old idea revisited. Acta Paediatr 1997;86:1029 – 33. [217] Trafton J, Tombaugh G, Yang S, Sapolsky R. Salutary and deleterious effects of acidity on an indirect measure of metabolic rate and ATP concentrations in CNS cultures. Brain Res 1996;731:122 – 31. [218] Trippenbach T, Richter DW, Acker H. Hypoxia and ion activities within the brain stem of newborn rabbits. J Appl Physiol 1990;68:2494 – 503. [219] Tyler DB, van Harreveld A. The respiration of the developing brain. Am J Physiol 1942;136:600 – 3. [220] Vannucci RC, Duffy TE. Cerebral metabolism in newborn dogs during reversible asphyxia. Ann Neurol 1977;1:528 – 34. [221] Vannucci RC, Mujsce DJ. The effect of glucose on perinatal hypoxic-ischemic brain damage. Biol Neonate 1992;62:215–24. [222] Vannucci RC, Perlman JM. Interventions for perinatal hypoxic-ischemic encephalopathy. Pediatrics 1997;100:1004–14. [223] Vannucci RC, Towfighi J, Heitjan DF, Brucklacher RM. Carbon dioxide protects the perinatal brain from hypoxic-ischemic damage: an experimental study in the immature rat. Pediatrics 1995;95:868 – 74. [224] Vannucci RC, Brucklacher RM, Vannucci SJ. The effect of hyperglycemia on cerebral metabolism during hypoxia-ischemia in the immature rat. J Cereb Blood Flow Metab 1996;16:1026– 33. [225] Volpe JJ. Intraventricular hemorrhage and brain injury in the premature infant: neuropathology and pathogenesis. Clin Perinatol 1989;16:361 – 86. [226] Volpe JJ. Hypoxic-ischemic encephalopathy: biochemical and physiological aspects. In: Neurology of the newborn, 3rd ed. Philadelphia: Saunders, 1995:211 – 59. [227] Warburg O. Versuche an u¨berlebendem Carcinomgewebe (Methoden). Biochem Z 1923;142:317 – 33. [228] Weibel ER. Delivering oxygen to cells. In: The pathway for oxygen: structure and function in the mammalian respiratory system. Cambridge, MA: Harvard University Press, 1984:175– 210. [229] West JB. Lactate during exercise at extreme altitudes. Fed Proc 1986;45:2953 – 7. [230] Wieser W. A distinction must be made between the ontogeny and the phylogeny of metabolism in order to understand the mass exponent of energy metabolism. Respir Physiol 1984;55:1 – 9. [231] Wieser W. Energy allocation by addition and by compensation: an old principle revisited. In: Wieser W, Gnaiger E, editors. Energy transformations in cells and organisms. Stuttgart: Thieme, 1989:98 – 105. [232] Wilkie DR. Metabolism and body size. In: Pedley TJ, editor. Scale effects in animal locomotion. London: Academic Press, 1977:23 – 36. [233] Wood SC. Interactions between hypoxia and hypothermia. Annu Rev Physiol 1991;53:71 – 85. [234] Wood SC, Gonzales R. Hypothermia in hypoxic animals: mechanisms, mediators, and functional significance. Comp Biochem Physiol 1996;113B:37 – 43. [235] Wu¨nnenberg W, Kuhnen G, Laschefski-Sievers F. CNS regulation of body temperature in hibernators and non-hibernators. In: Heller HC, Musacchia XJ, Wang LCH, editors. Living in the cold: physiological and biochemical adaptations. New York: Elsevier, 1986:185 – 92. [236] Xia Y, Haddad GG. Postnatal development of voltage-sensitive Na + channels in rat brain. J Comp Neurol 1994;345:279–87.

234

D. Singer / Comparati6e Biochemistry and Physiology, Part A 123 (1999) 221–234

[237] Yano Y, Braimbridge MV, Hearse DJ. Protection of the pediatric myocardium: differential susceptibility to ischemic injury of the neonatal rat heart. J Thorac Cardiovasc Surg 1987;94:887 – 96. [238] Yip R. Altitude and birth weight. J Pediatr 1987;111:869 – 76.

.

[239] Yip R, Binkin NJ, Trowbridge FL. Altitude and childhood growth. J Pediatr 1988;113:486 – 9. [240] Zou DJ. Respiratory rhythm in the isolated central nervous system of newborn opossum. J Exp Biol 1994;197:201– 13.