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We questioned whether the decrease in O2 consumption (VO2) during hypoxia in newborns is a regulated response or reflects a limitation in O2 availability. Experiments were conducted on previously instrumented conscious newborn dogs. VO2 was measured at a warm ambient temperature (30 degrees C, n = 7) or in the cold (20 degrees C, n = 6), while the animals breathed air or were sequentially exposed to 15 min of fractional inspired O2 (FIO2): 21, 18, 15, 12, 10, 8, and 6%. In normoxia, VO2 averaged 15 +/- 1 (SE) and 25 +/- 1 ml . kg-1 . min-1 in warm and cold conditions, respectively. In the warm condition, hypometabolism (i.e., hypoxic VO2 < normoxic VO2) occurred at FIO2

During acute hypoxia, a hypometabolic response is commonly observed in many newborn and adult mammalian species. We hypothesized that, if hypoxic hypometabolism were entirely a regulated response with no limitation in O2 availability, pharmacological uncoupling of the oxidative phosphorylation should raise O2 consumption (VO2) by similar amounts in hypoxia and normoxia. Metabolic, ventilatory, and cardiovascular measurements were collected from conscious rats in air and in hypoxia, both before and after intravenous injection of the mitochondrial uncoupler 2,4-dinitrophenol (DNP). In hypoxia (10% O2 breathing, 60% arterial O2 saturation), VO2, as measured by an open-flow technique, was less than in normoxia (approximately 80%). Successive DNP injections (6 mg/kg, 4 times) progressively increased VO2 in both normoxia and hypoxia by similar amounts. Body temperature slightly increased in normoxia, whereas it did not change in hypoxia. The DNP-stimulated VO2 during hypoxia could even exceed the control normoxic value. A single DNP injection (17 mg/kg iv) had a similar metabolic effect; it also resulted in hypotension and a drop in systemic vascular resistance. We conclude that pharmacological stimulation of VO2 counteracts the VO2 drop determined by hypoxia and stimulates VO2 not dissimilarly from normoxia. Hypoxic hypometabolism is likely to reflect a regulated process of depression of thermogenesis, with no limitation in cellular O2 availability.

Conscious newborns of 12 species from 4 mammalian orders, ranging in body mass (M) from 1 g (mouse) to 5 kg (deer), were studied during air and during 5% CO2 breathing. The interspecies relationship between oxygen consumption (VO2) and M was the same in air and hypercapnia, in both cases VO2 alpha M 0.90; on average, hypercapnic VO2 was 101% of the air value. In 5% CO2, ventilation (VE) increased in all newborns, mostly because of the increase in tidal volume (178%), whereas breathing rates averaged 98% of the air values. The hyperpnea during CO2 was slightly greater in the larger newborns. Body temperature was not altered by CO2 breathing. We conclude that the average respiratory response of the newborn to moderate hypercapnia is a hyperventilation different from that of the neonatal mammal in acute hypoxia (Mortola et al., Respir. Physiol. 78: 31-43, 1989). In fact, hypercapnic hyperventilation resulted only from the hyperpnea, with no hypometabolic contribution, and the hyperpnea reflected the increase in tidal volume, with no change in rate. It is also concluded that the neonatal hypometabolic response is specific to hypoxia, and not an undifferentiated response to chemoreceptors stimulation.

1. In infants, metabolic rate is highly variable. We investigated whether the strength of the vagal ventilatory inhibitory reflex was modified by the spontaneous changes in metabolic rate. 2. In 20 2-day-old infants, we measured the intensity of the Hering-Breüer expiratory-promoting reflex (inhibition of breathing during maintained lung inflation), the inspired and expired O2 and minute ventilation (VE), from which oxygen consumption (VO2) was calculated. The measurements were performed twice, a few hours apart [6 +/- 1 h SEM)]. 3. On average, VO2 differed by 39 +/- 7% between the two measurements, with no correlation with the time of the day (morning/afternoon) or the time interval from a meal. VE was also significantly higher (19 +/- 6%) when VO2 was higher, because of a larger tidal volume. The Hering-Breüer reflex (quantified as the apnoea time during lung inflation, either the absolute value or normalized by the airway pressure or lung volume) did not differ significantly between the two tests (< 5% difference, P > 0.05), and did not correlate with the changes in VO2 or VE. 4. We conclude that, in the infant, pulmonary vagal inhibition is not sensitive to changes in metabolic drive, presumably because of the low ventilatory chemosensitivity of the newborn.

We tested the hypothesis that the sinoaortic afferents may contribute to normoxic thermogenesis and to the magnitude of the hypometabolic response to hypoxia. Adult rats were either sinoaortic denervated (SAX; n = 20) or sham operated (Sham; n = 20). A few days after the operation, gaseous metabolism [O2 uptake (VO2) and CO2 production (VCO2)] was measured with an open-flow system at ambient temperatures (Tamb) of 20, 25, 30, and 35 degrees C as the animal was resting awake. At thermoneutrality (Tamb 30 degrees C) or higher Tamb there was no difference in VO2 or VCO2. Below thermoneutrality, metabolic rate was significantly lower in SAX than in Sham animals (-14 and -16% at 20 and 25 degrees C, respectively). Colonic temperature and arterial PO2 were also slightly less, whereas arterial PCO2 and pH, mean arterial pressure, and heart rate did not differ significantly between the two groups. Exposure to acute hypoxia (10% inspired O2, 20-30 min) at Tamb 20 and 25 degrees C significantly reduced VO2 in both groups to a similar value; hence, at either Tamb, the metabolic drop during hypoxia in Sham animals was larger than that in SAX animals. Hypercapnia (5% CO2 breathing) did not change VO2 in either group. We conclude that in the rat at Tamb slightly below thermoneutrality, the sinoaortic afferents 1) provide a small but significant contribution to normoxic thermogenesis and 2) are not required for the manifestation of the drop in metabolism during hypoxia.

Hyperventilation and decreased metabolic rate are commonly observed in newborns during acute hypoxia; whether these responses are also present during sustained hypoxia is not known. We asked whether infants at high altitude had higher ventilation and lower metabolism than lowlanders. Ventilation (VE), oxygen consumption (VO2), and carbon dioxide production (VCO2) were measured in newborn (< 1 day old) full-term infants in La Paz (altitude 3,800 m; inspired oxygen pressure [PIO2], 92 mm Hg) and in Santa Cruz (altitude, 400 m; PIO2, 141 mm Hg), Bolivia. Each group consisted of 30 infants selected to have similar body weight. The mothers, Amerindians and mestizos, were born in the corresponding cities or at equivalent altitudes. Despite the lower inspired oxygen concentration in La Paz (0.107 ml STPD O2/ml BTPS air) than in Santa Cruz (0.164), neither VE nor VO2 or VCO2 differed between the two groups. The breathing pattern was deeper and slower at high altitude. From the values of VE and VO2 it was calculated that high-altitude infants extracted more O2 (+62%) from the inspired air than did the lowlanders. When given pure O2 to breathe, both groups of infants similarly increased VE and gaseous metabolism; even during hyperoxia, however, the ventilatory O2 extraction was higher (+50%) in the highlanders. We conclude that, contrary to what is observed in acute hypoxia, infants at high altitude maintain metabolic rate with no major alterations in VE. The ability to use a greater fraction of the inspired O2 at high altitude probably results from functional and structural alterations stimulated by fetal hypoxia.

Whole body metabolic rate was measured by open-flow respirometry in 2-day-old rats at ambient temperatures (Ta) between 40 and 15 degrees C, changed at a rate of 0.5 degrees C/min, during normoxia or hypoxia (10% inspired O2). In normoxia, the thermoneutral range was found to be very narrow, at around 33 degrees C, suggesting a limited effectiveness in the mechanisms controlling heat dissipation. At lower or higher Ta, metabolism was at first increased; this increase could be maintained for at least 30 min at 30 and 35 degrees C, i.e., slightly below or above thermoneutrality, but it was not maintained at lower Ta. The metabolic response to Ta was not sufficient to maintain body temperature (Tb). In hypoxia, at all Ta, oxygen consumption (VO2) was consistently less than in normoxia and was linearly related to Ta (Q10 approximately 1.4). The rat's specific heat was 4 J.g-1.degrees C-1, and the time constant of passive heat exchange was 2.2 +/- 0.5 min; from these values it was calculated that the normoxic VO2 of the 2-day-old rat could be per se sufficient to maintain Tb of 35-36 degrees C at Ta of 33 degrees C, while at lower Ta the metabolic response could not be adequate to maintain Tb. In hypoxia, Tb was directly dependent on Ta.(ABSTRACT TRUNCATED AT 250 WORDS)

Hyperoxia has previously been found to increase metabolic rate (oxygen consumption [VO2] and CO2 production [VCO2]) in newborn mammals. We asked whether the same occurs in the newborn infant. Breathing pattern was measured in 25 full-term infants, 1 to 2 days of age, from the spirometric record obtained with a pneumotachograph attached to a face mask. Concentrations of O2 and CO2 were continuously measured at the mouth; VO2 and VCO2 were computed as the product of VE and the difference between inspired and expired concentration of the respective gases, 5 min of air (FIO2 = 0.21) and 5 min of O2 (FIO2 = 1). A bias flow through the mask and pneumotachograph delivered the inspired gas and eliminated the effects of the instrumental dead space. In neither case did measurements at 1 min significantly differ from those taken at 5 min. In hyperoxia VE increased in 22 of the 25 infants, in average +18% (p less than 0.001, paired two-tailed t test). Because of a rise in tidal volume (+35%, p less than 0.001) and a decrease in breathing rate (-11%, p less than 0.005) alveolar ventilation (VA) increased by about 58% (p less than 0.001). VO2 and VCO2 increased by 25% and 17%, respectively (p less than 0.001). The rise in VO2 was too large to be explained by the greater respiratory work of the hyperventilation, whereas that of VCO2 was not large enough to fully explain the increase in VA. We conclude that in newborn humans, as in other newborn species, the normoxic metabolic rate seems to be limited by the availability of O2.(ABSTRACT TRUNCATED AT 250 WORDS)

Aerobic metabolism (oxygen consumption, VO2, and carbon dioxide production, VCO2) has been measured in newborn rats at 2 days of age during normoxia, 30 min of hyperoxia (100% O2) and an additional 30 min of recovery in normoxia at ambient temperatures of 35 degrees C (thermoneutrality) or 30 degrees C. In normoxia, at 30 degrees C VO2 was higher than at 35 degrees C. With hyperoxia, VO2 increased in all cases, but more so at 30 degrees C (+20%) than at 35 degrees C (+9%). Upon return to normoxia, metabolism readily returned to the prehyperoxic value. The results support the concept that the normoxic metabolic rate of the newborn can be limited by the availability of oxygen. At temperatures below thermoneutrality the higher metabolic needs aggravate the limitation in oxygen availability, and the positive effects of hyperoxia on VO2 are therefore more apparent.

We asked whether the lack of sustained hyperventilation during acute hypoxia, often reported to occur in the infant, is a common characteristic among newborn mammalian species, and to which extent inter-species differences may be accounted for by differences in metabolic responses. Ventilation (VE) and breathing pattern have been measured by flow-plethysmography or by the barometric method in normoxia and after 10 min of 10% O2 breathing in newborn mammals of 17 species over a 3 g to 20 kg range in body size. In 14 of these species oxygen consumption (VO2) has also been measured by a manometric technique or by calculation from the changes in chamber O2 pressure. VE and VO2 changed in proportion, among species, both in normoxia and hypoxia. In hypoxia, VE was higher, similar, or even lower than in normoxia, with some relation to the degree of maturity of the species at birth. In general, the small or absent VE responses to hypoxia resulted from small or no increase in tidal volume, while breathing frequency stayed elevated. The few departures from this pattern could be explained by interspecies differences in hypoxic sensitivity, since additional experiments in kittens and puppies indicated that, with more severe hypoxia, the pattern changed from rapid and shallow to deep and slow. In all cases, irrespective of the magnitude of the VE response, the VE/VO2 (and the mean inspiratory flow/VO2) increased during hypoxia, because the drop in VE, when present, was accompanied by an even larger drop in VO2. In fact, VO2 in hypoxia decreased in most species, although to variable degrees. Body temperature either did not change or decreased slightly, possibly indicating a trend toward a decrease of the set point of thermoregulation during hypoxia. In conclusion, the analysis gave further support to the concept that, during acute hypoxia, changes in metabolic rate play a paramount role in the ventilatory response of the newborn mammal.

Pregnant rats were exposed to a cold environment (4 degrees C for almost the whole pregnancy) and the effects on the newborn rats' ventilation, metabolic rate and morphological lung appearance were examined. In cold-exposed rats oxygen consumption (VO2) increased during pregnancy and was 23% more than in control rats 1 day after delivery. All pups were born at term in litters of similar size. At 2-4 days after birth, in the pups born from cold-exposed mothers ("cold" pups), body weight (BW) and lung weight (LW) were reduced, with respect to control newborns, in a similar proportion. In "cold" pups the mean chord of subpleural alveoli was larger and lung volume smaller than in control pups. Both specific minute ventilation (VE/kg), measured by flow plethysmography, and specific oxygen consumption (VO2/kg), measured manometrically, were similar between the two groups. However, tidal volume/BW was smaller and breathing frequency higher in "cold" pups, a breathing pattern which appears necessary to fulfil normal metabolic requirements despite lung immaturity. These results suggest that cold exposure during pregnancy represents a maternal stress which results in somatic and pulmonary underdevelopment of the neonate.

Newborns respond to acute hypoxia with a brief increase in ventilation (VE) followed by a decline toward the normoxic value. We asked to what extent this biphasic pattern is determined by changes in metabolic rate. In newborn awake kittens within the first week after birth we measured VE by the barometric method, oxygen consumption (VO2) and CO2 production (VCO2) by manometric techniques during air breathing and after 10 min of 10% O2 breathing. In hypoxia, VO2 and VCO2 dropped (about 45% and 35%, respectively) with a slight decrease in body temperature. VE was as in normoxia and, from the changes in breathing pattern, a drop in alveolar ventilation was calculated. Since the drop in VCO2 exceeded that in calculated alveolar ventilation (VA), a decrease in PACO2 (estimated at about 5 mm Hg) was expected. This decrement was confirmed by measurements of transcutaneous PCO2, which dropped an average of 3.3 mm Hg in the hypoxic kittens, even when VE was below the normoxic value. Hence, despite the decline in VE and VA during the biphasic response, the newborn continued to hyperventilate with respect to CO2 production, lowering PCO2. The strategy of dropping VO2 instead of maintaining the energetic requirements by increasing VE was not determined by mechanical constraints, since all kittens hyperventilated when exposed to CO2, either in air or hypoxia. Several implications of the tight coupling between ventilation and metabolism are discussed, including a possible role in the genesis of periodic breathing in hypoxia.

Newborn mammals of medium or large sized species have ventilatory rates, expressed per kg body weight, larger than adults of corresponding size, while newborns of the smallest species do not. We hypothesized that the oxygen consumption of the smallest newborns is limited by the supply of oxygen and reasoned that if this were the case, an increase in Po2 of the inspired air should decrease their ventilation/oxygen consumption (VE/Vo2) ratio. We exposed 1-2 days old newborn mice for 5 min to 21% O2 in N2 or 100% O2, then measured their breathing pattern, by flow plethysmography, and Vo2 with an isovolume closed system. During hyperoxia the VE/Vo2 ratio dropped in average 36%, since VE decreased in 14 out of 18 animals and Vo2 increased in all the animals tested. The drop in VE was due to a prolongation of the expiratory time, with no changes in inspiratory time or tidal volume. During expiration, interruptions of the expiratory flow and tendency to maintain the lung inflated, a characteristic of neonatal respiration, were more pronounced with 100% O2 than 21% O2 breathing. We conclude that the resting metabolic rate of newborn mice is limited by the supply of oxygen; when Po2 is raised, metabolism increases and ventilatory rate decreases in favor of a breathing pattern aimed to preserve lung volume elevated.