acteristics of their ventilatory response to hypercapnia, and 3) the ventilatory response to combined hypoxic and hypercapnic stimuli. First, we established that ...
Interaction of hypoxic and hypercapnic breathing pattern in the newborn rat
stimuli
on
MARINA SAETTA AND JACOPO P. MORTOLA Department of Physiology, McGill University, Montreal, Quebec H3G 1 Y6, Canada
SAETTA,MARINA, AND JACOPO P. MORTOLA. Interaction of hypoxic and hypercapnic stimuli on breathing pattern in the newborn rat. J. Appl. Physiol. 62(2): 506-X2,1987.-We aimed to investigate 1) whether newborn rats respond to acute hypoxia with a biphasic pattern as other newborn species, 2) the characteristics of their ventilatory response to hypercapnia, and 3) the ventilatory response to combined hypoxic and hypercapnic stimuli. First, we established that newborn unanesthetized rats (2-4 days old) exposed to 10% O2 respond as other species. Their ventilation (VE), measured by flow plethysmography, immediately increased by 30%, then dropped and remained around normoxic values within 5 min. The drop was due to a decrease in tidal volume, while frequency remained elevated. Hence, alveolar ventilation was about 10% below normoxic value. At the same time O2 consumption, measured manometrically, dropped (-23%), possibly indicating a mechanism to protect vital organs. Ten percent COZ in O2 breathing determined a substantial increase in \jE (+47%), indicating that the respiratory pump is capable of a marked sustained hyperventilation. When CO, was added to the hypoxic mixture, \jE increased by about 85%, significantly more than without the concurrent hypoxic stimulus. Thus, even during the drop in VE of the biphasic response to hypoxia, the respiratory control system can respond with excitation to a further increase in chemical drive. Analysis of the breathing patterns suggests that in the newborn rat 1) in hypoxia the inspiratory drive is decreased but the inspiratory on-switch mechanism is stimulated, 2) hypercapnia increases ventilation mainly through an increase in respiratory drive, and 3) moderate asphyxia induces the most powerful ventilatory response by combining the stimulatory action of hypercapnia and hypoxia. neonatal respiration; control of breathing; respiratory adaptation at birth
oxygen consumption;
MAMMALS, including infants, acute exposure to hypoxia determines a brisk increase in ventilation followed by a gradual drop within minutes (17). In the adult, although some ventilatory adaptation does occur, ventilatory rates remain elevated above control levels for the whole hypoxic exposure (1, 227). Several hypotheses have been put forward to explain the ventilatory response of the newborn to acute hypoxia, including adaptation of peripheral chemoreceptors, changes in respiratory mechanics, and central hypoxic inhibition of respiratory activity (see 17 for review). Adolph and Hoy (l), in the newborn rat, showed that metabolism drops during acute exposure to hypoxia. This has been also observed in other newborn species (7, 15) and could contribute to the fact that the COz drive is not overriding the hypoxic
IN NEWBORN
506
0161-7567/87
$1.50 Copyright
inhibition. It is also possible that newborns have a negative Oz-COz i nteraction, wh .ereby hypoxia would decrease or even totally cancel the stimulatory effec t of co2 (28). Very few studies have examined the ventilatory effects of hypoxia and hypercapnia in the same infants’ population, and the results are not consistent. Apart from the possibility of species differences, it is conceivable that the newborn’s gestational age, the use of tracheostomy or intubation (14, 29), and lack of control of environmental temperature in some studies (6,22) could have introduced confounding variables. The only comprehensive study on intact newborns is by Farber et al. (9), who examined in the same group of newborn and young opossums the ventilatory effects of hypoxia and hypercapnia first as individual stimuli, then combined. However, the regulation of breathing in this marsupial, which is born at an early embryological stage and matures in the hypoxic and hypercapnic environment of the mother’s pouch, seems to be quite different from that of eutherian mammals. For example, the newborn opossum maintains a sustained hyperventilation when exposed to hypoxia, whereas the adult almost does not respond (9). We decided therefore to examine the ventilatory interaction of hypoxic and hypercapnic stimuli in intact unanesthetized full-term newborn rats. First, we have considered the temporal changes after hypoxic challenge. The results indicated that, as in other newborn species, during acute hypoxic exposure ventilation increased only transiently, returning to control values within a few minutes; at this time, O2 consumption was decreased. We then compared in the same group of animals the steady-state ventilatory effects of acute exposure to hypercapnia, moderate asphyxia (hypercapnia and hypoxia), and, finally, moderate asphyxia after a period of hypoxia. METHODS
Experiments have been performed on a total of 39 rats, between 2 and 4 days after birth. Breathing pattern has been measured by flow plethysmography, with a setup similar to that previously described (24, 30). Briefly, the animal was placed prone in a box of about 20 ml with the head emerging through a double layer of paraffin sealing film (Parafilm). Box temperature was continuously monitored and maintained within the thermoneutral range. Airflow in and out the box was measured with a pneumotachograph connected to a differential pressure
0 1987 the American
Physiological
Society
HYPERCAPNIA
AND
HYPOXIA
transducer (Hewlett-Packard model 270); tidal volume was obtained by electronic integration of the flow signal (Hewlett-Packard integrator 8815A). The front part of the plethysmograph was tightly connected to a second chamber which could be flushed with any desired gas mixture. In the first group of 19 animals [age 2.8 t 1.2 (SD) days, body w-t 8.5 t 1.2 g] the acute ventilatory response to 10% O2 in N2 exposure was studied. This was done to establish whether newborn rats respond to acute hypoxia with a biphasic pattern similar to that of other newborn species, as well as the time course of the response. Recordings were obtained with the animal asleep, most likely during rapid-eye-movement sleep, since this phase characterizes virtually the whole sleep time of the newborn rat during the 1st wk after birth (18). Twenty consecutive breaths were analyzed at 30 s and then every minute up to 10 min 30 s since the onset of the hypoxic exposure. The records, obtained at a paper speed of 25 mm/s, were digitized with a graphic tablet (HewlettPackard 9111A) and the data stored on disk by a minicomputer (Hewlett-Packard 9816) for statistical analysis and graphic representation. The variables included tidal volume (VT), breathing frequency (f), minute ventilation (VE), inspiratory and expiratory time (TI and TE), mean inspiratory flow (VT/TI), and inspiratory time over total cycle duration ratio (TI/TT). A second group of 10 rats [age 2.3 t 0.5 (SD) days, body wt 7.5 t 0.8 g] was then exposed to 1) 10% COa in 0, (hypercapnia) for 5 min, 2) a mixture of 10% CO2 and 10% O2 in Nz (moderate asphyxia) for 5 min, and 3) 10% OZ in N, for 5 min followed by 10% O2 and 10% CO2 in N, for 5 additional minutes (hypoxia immediately followed by moderate asphyxia). The three types of exposures were separated by 2 to 4-h intervals during which the pup was returned to the mother and was breathing room air. In all cases measurements were preceded by a period of recording during room air breathing. The animal was exposed to the desired gas concentration for at least 5 min to reach alveolar gas equilibrium. For each condition of gas mixture breathing, and for each of the corresponding preceding air breathing periods, 100 consecutive breaths were analyzed. The variability of minute ventilation among the various air-breathing periods preceding the tests was within 10%. In a third group of 10 newborns the rate of 0, consumption (TO& was measured during air and during 10% 0, (in NZ) breathing. We used the manometric technique of Warburg (8) as recently adapted for newborn rats and mice and chick embryos (25, 26, 31). This approach represents a simple alternative when the VoB is so small that the difference between the chamber inflow and outflow Po2s cannot be accurately measured. The animal was in a sealed chamber connected to a roller pump that forced air through a CO, absorber. As O2 was consumed, the pressure in the chamber, measured with a sensitive pressure transducer (Statham 12174) falls gradually. Calibration for volume was obtained by injecting a known amount of air and recording the corresponding changes in pressure. Precision of the measurement relies on two important reouirements: first, a perfect seal of the system
ON
NEONATAL
507
RESPIRATION
and second, constant thermoconditions. The first requirement was verified by applying a negative pressure in the chamber and monitoring its stability for a period of time at least equivalent to the recording period. In addition, during the actual recording of Vo2, the chamber was opened to atmosphere for brief periods of time, in order to avoid values of chamber pressure more negative than -5 cmH20. Steady values of temperature within the animal’s appropriate thermoneutral range was usually achieved after l-2 h. This was apparent by a constant base line of the pressure record when no animal was in the chamber. Of course, the consumption of O2 in a sealed system must imply a drop in Po2. This can be minimized by using a relatively large system and shortening the duration of the measurement. Our system had a volume of -900 ml and measurements were carried over four periods each of 10 min duration. In these conditions, by starting the recording with an O2 concentration of 20.9%, at the end of a measurement in a 15-g newborn rat with a %70, of 0.75 ml OJmin STPD (32), one would expect an O2 concentration -20.0%. In practice, gas samples at the end of the experiment revealed a PCO~ slightly higher and a Po2 slightly lower than expected, probably indicating an incomplete gas mixing in the chamber. Although these differences do not appreciably alter vo2 (32), our control measurements of Vo2 were therefore performed in a situation slightly different from standard sea level condition. Values were converted to STPD and expressed per kilogram of body weight. Statistical analysis between groups of data was performed by applying the two-tailed t test for paired or unpaired variables. A significant difference was defined by a P value c 0.05. RESULTS
Breathing pattern and O2consumption in hypoxia. The acute ventilatory response to 10% O2 (in NZ) was characterized by an immediate rise in 18 of 19 animals, in average 30% above the normoxic value (Fig. 1). Ventilation then gradually fell to reach a value not significantly different from control at about 5 min (Table I), with no
w >
90~““““““““““” 0
TIME
1
2
OF
3
4
HYPOXIC
5
6
7
EXPOSURE
8
9
10
11
(mid
1. Ventilatory response to acute exposure to 10% O2 (in Nz) in newborn rats, expressed in percent of control normoxic values. Each point is average of 19 animals: bars, &SD. FIG.
508
HYPERCAPNIA
AND
HYPOXIA
ON
l
1. Breathing pattern before and during hypoxic breathing in newborn rats
TABLE
Minute ventilation, mI/min Tidal volume, ml Breathing rate, breaths/min Inspiratory time, s Expiratory time, s Mean inspiratory flow, ml/s Inspiratory time/total cycle duration, % Values from air breathing
5 min 30 s Hypoxia ______ Absolute value
% Change
10.8t3.8
10.9t3.0
105t21*
0.088-tO.021 126t26
0.076t0.014 150t33
90t26+ 120*18+
0.15t0.04
0.15t0.04
97t14*
0.36t0.09 0.62kO.22
0.29t0.07 0.54t0.13
80&17+ 93t20+
0.30t0.03
0.34t0.04
107t30+
are means t SD for 19 animals. * Not significantly breathing (P > 0.05). t Significantly different (P < 0.05).
different from air
60
50
a +I
X
40
0
CL >
30
I z l-4
20
10
60
IN AIR 2. Rate of O2 consumption per unit of body weight during air breathing vs. corresponding value during 10% O2 (in Nz) breathing. Each symbol refers to a different newborn rat. SoLid line, identity line. FIG.
TABLE
RESPIRATION
min-1 kg-‘, very close to the values previously obtained with different methods (1, 32). In 9 of 10 animals voz decreased during hypoxia (Fig. 2), indicating a group mean drop of about 23% (P c 0.05). Breathing pattern in hypercapnia. Five minutes of exposure to 10% COz in O2 invariably increased VE. The average increase was +47% (Table 2). While VT increased in all animals (in average 45%), the response in f was more variable (in average 2%, not significant). Mean inspiratory flow was markedly increased (53%). Representative volume and flow tracings during air, hypoxic, and hypercapnic breathing are shown in Fig. 3. By comparing the breathing pattern of all the newborns after 5 min of hypercapnic stimulus with that after 5 min of hypoxic stimulus (Fig. 4) major differences are apparent. Hypercapnia increases VT/TI without major changes in f and TI/TT, hence raised VT, whereas hypoxia stimulated f with no or negative effects on VT/TI and decreased VT. Breathing pattern during moderate asphyxia. Breathing a moderate asphyxic mixture (10% O2 and 10% CO2 in NJ stimulated VE in all newborns. After 5 min, TjE was -90% higher than in control conditions and significantly more so than during only hypercapnia (Fig. 5). The rise in VE was determined by a relatively modest increase in f (24%) and by a substantial increase in VT (54%) with respect to normoxic control values. Mean inspiratory flow was therefore much higher than in control conditions (65%), but not significantly higher than during hypercapnia without hypoxia (Table 2). Very similar values of hyperventilation were reached when the asphyxic mixture was administered after 5 min of only hypoxic breathing (Table 2), i.e., at a time during the biphasic response to hypoxia when VE was virtually back to control normoxic values. The individual changes of the main respiratory parameters are shown in the identity plots of Fig. 6. The addition of CO2 after 5 min of hypoxia increased iTE in 9 of 10 animals, to values higher than those achieved during only hypercapnia. Tidal volume increased in all animals, whereas f, which was maintained elevated during hypoxia, decreased in 8 of 10. As the result of these changes, VT/TI increased in all newborns, on average 69% above either normoxic control or hypoxic values, but not significantly higher than during hypercapnia only (Table 2).
additional changes thereafter. During this period, however, breathing rate remained elevated @O-33% above control), whereas tidal volume was below the control values (-10 to -25%). The mean inspiratory flow (VT/ TI) was only slightly affected (-7%). The average control value of vo2 in air was 45.4 ml.
Air (absolute value)
NEONATAL
2. Breathing pattern of newborn rats during air breathing, hypoxia, hypercapnia, and moderate asphyxia
-_____
% Change Air (absolute value)
Minute ventilation, ml/min Tidal volume, ml Breathing rate, breaths/min Inspiratory time, s Expiratory time, s Mean inspiratory flow, ml/s Inspiratory time/total cycle duration, Values are means k SD of 10 newborn from 5 min 10% COz in 02 (P > 0.05).
7.9tl.7 0.076kO.013
108223 0.18t0.03
% rats.
0.44t0.16 0.45t0.08 29.9t3.5 * Significantly
5min In 0,
10%
CO, In Hypoxia
5 min Hypoxia
147225
190t24*
117t30
145t28
154t211-
94tl5
102kl5
124tl7*
93kl3 101-t-18
88+12”r 76tl4*
153t28 96-t-6 different
from
165tl9-t
123~~19 95t9 78tl7 lOOzk21
113*19*
115tl3
5 min
+ 5 min 10% CO, in Hypoxia
+ 5 min Hypoxia
10% CO2 in O2 (P < 0.05).
179t28* 16ltl9-f
108tl2+ 95&11+ 86t9* 169t30-E 106rtlO* t Not
significantly
different
HYPERCAPNIA
AND
HYPOXIA
ON
NEONATAL
509
RESPIRATION
HYPOXIA
0.7 ml Iti
FIG. 3. Newborn rat, 3 days and flow (V) records during and 10% CO2 breathing.
old, ‘7.9 g. Volume air, 10% O2 in NP,
(VT)
HYPERCAPNIA "T 0.7 ml 1
IJJ
260 /
F
120
4 ‘“9OW MEAN
INSP.
140
10%
HYPOXIA FIG.
against Values symbol
160
160
200
220
240
260
FLOW
4. Ventilatory parameters during hypoxia (10% 02 in N2) corresponding vafues during hypercapnia (10% CO, in 02). are expressed as percent of control normoxic condition. Each refers to a different newborn rat. Solid lines, identity lines.
On the basis of the average measurements in breathing pattern (Tables 1 and Z), a schematic summary of the spirograms during air breathing, hypoxia, hypercapnia, and moderate asphyxia is presented in Fig. 7.
CO2
IN
OXYGEN
FIG. 5. Minute ventilation during hypercapnia (10% CO2 in 02) against corresponding values during moderate asphyxia (10% CO2 and 10% O2 in Nz). Values are expressed as percent of control normoxic values. Each symbol refers to a different newborn rat. SoLid line, identity line. DISCuSSION
Responseto hypoxia. The biphasic ventilatory response to acute hypoxia of newborn rats is similar to that of other newborn species (17, 33). After a few minutes of exposure, VE is little or no different from the normoxic value. The prevalence of the positive response in f versus
510
HYPERCAPNIA
AND
HYPOXIA
ON
VENTILATION
200
l
l
150
l
100
.
.
.
a*
MEAN
INSP.
FLOW
L
IO
t
HYPOXIA
6. Ventilatory parameters during hypoxia (10% O2 in NJ against corresponding values during moderate asphyxia (10% CO2 and 10% O2 in N,) immediately following 5 min of hypoxia. Values are condition. Each symbol expressed as percent of control normoxic rat. Solid lines, identity lines. to a different newborn FIG.
W > 3 6 >
TIME 7. Schematic during air breathing, in O,), and moderate from values of Tables FIG.
summary hypoxia asphyxia 1 and 2.
of average spirograms in newborn rats (10% O2 in Nz), hypercapnia (10% CO2 (10% CO, and 10% O2 in Nz), derived Dashed line, control spirogram.
the small or negative response in VT appears to be common to other species studied in the unanesthetized condition (2, 4, 16, 19). Although in the puppy the response depends on sleep stage (16), in the kitten this pattern seems to be independent of the state of arousal and clearly related to postnatal development (2). In the adult, several factors suggest that hypoxia acts both peripherally, through the stimulation of the chemoreceptors with a positive effect on the ventilatory drive ( VT/TI), and centrally by stimulating respiratory frequency and depressing tidal volume (23). The changes in breathing pattern of the newborn during acute hypoxia resemble those observed in unanesthetized adult cats after carotid body denervation (13,23). This may suggest, therefore, that in the intact newborn the central effect of hypoxia prevails over the hyperventilatory effects of peripheral chemoreceptor stimulation. Since the newborn’s peripheral chemoreceptors appear to be able to maintain an increased activity during hypoxia even when VE drops (reviewed by Walker, 33), one would speculate that their input is either gated centrally or not sufficientlv nowerful to maintain the increase in respiratory
NEONATAL
RESPIRATION
output. In the adult chemodenervated animal the central depressant effect of hypoxia on VT (23) was found to occur despite the shortening in TI and the increase in the generation of the central inspiratory activity (13). Hence, in the adult, the central hypoxic depression of VT is explained by a decrease in the volume threshold for inspiratory inhibition (leftward shift of the VT-TI curve). On the other hand, in the newborn rat, the drop in VT occurred with no changes in TI and possibly a drop in VT/TI (Table 1). Similar results were obtained in kittens (2). Thus we can speculate that, in the newborn, hypoxia decreases both the rate of generation of the central inspiratory activity and the inspiratory off-switch threshold. In conclusion, if we take the changes in breathing pattern as reflecting changes in respiratory activity (5), hypoxia in the newborn, as in the adult, appears to activate the respiratory neuronal network by lowering the inspiratory off-switch threshold and facilitating the inspiratory on-switch. In consequence, expiratory time (TE) decreases. Quite opposite from the adult, though, the inspiratory output in the hypoxic newborn is slightly decreased, and this is presumably due to a drop in the central contribution of the input from the peripheral chemoreceptors. In resting newborn mice the metabolic rate was found to be substrate limited, since it increased when the animals were breathing pure 0, (26). One would therefore expect metabolism to be very sensitive to a decrease in alveolar PO,. In our rats, assuming a dead space equal to one-third of VT, the changes in breathing pattern during hypoxia indicated a 5-10% drop in alveolar ventilation, yielding an O2 alveolar flow -45% of the normoxic breathing value. At the same time voz dropped of -23%. It would seem therefore that, whereas the inability to defend alveolar Po2 represents an obvious handicap for the newborn, the drop in metabolism represents a protective mechanism oriented to preserve arterial PO,. The adult rat experiences an immediate drop in Vo2 with hypoxia, which, however, in contrast to the newborn (25), is not maintained when the hypoxic stimulus persists for several days (27). The larger drop in alveolar ventilation than in 30, may suggest that the former is the cause of the metabolic changes and not vice versa, although a time course of these events is required for a clarification of this aspect. Nevertheless, it is conceivable that a drop in cell metabolism at the level of both inspiratory and expiratory neurons may contribute to decrease, respectively, the central inspiratory activity and the inhibition on the inspiratory neurons, this latter yielding therefore a facilitation of the inspiratory on-switch mechanism. Response to hypercapnia. Quite differently from the response to hypoxia, newborn rats respond to hypercapnia with a sustained hyperventilation. The hypercapnic hyperventilation was achieved through an increase in VT with minimal changes in frequency or in the timing components of the respiratory cycle, as we have previously observed (30). Hence, the increase in ventilation was determined by an increase in central inspiratory
HYPERCAPNIA
AND
HYPOXIA
activity (VT/TI) and, possibly, in the inspiratory offswitch threshold. This indicates that newborn rats, despite their very high resting ventilatory rate with respect to larger mammalian species (24), can still increase the inspiratory activity well above the basal values. Therefore, the neonatal respiratory pump is capable of maintaining a sustained respiratory input. In contrast to what is observed in adult unanesthetized rats during hypercapnia (20, 21), the increase in VT of the newborn rat occurred with very small changes in TI, indicating a very steep VT-TI relationship. In part, t-his result could be due to the increase in inspiratory offswitch threshold determined by the higher level of CO2 (3); on the other hand, hypercapnia stimulates the pulmonary stretch receptors (ll), which would decrease the slope of the VT-TI curve. If one considers the curve as an index of the Hering-Breuer volume threshold (5), these results may therefore indicate that the duration of the inspiratory time depends less on vagal, volume-related activity in the newborn than in the adult rat. This is in keeping with reports of a smaller activity of pulmonary stretch receptors and less powerful reflexes mediated by these receptors in newborns than in adults (10, 12) Interaction of hypoxia and hypercapnia. Breathing a moderate asphyxic mixture determined a sustained hyperventilation, more marked than breathing the same CO, concentration in hyperoxia. Analysis of the breathing pattern reveals that this difference is not due to major changes in VT, TI, or VT/TI but to a shortening of TE (Fig. 7). The positive ventilatory interaction between hypercapnia and hypoxia in the newborn rat can be therefore interpreted as the combined effect of two stimulatory actions on the respiratory rhythm generator, the increased central inspiratory activity due to hypercapnia, and the facilitation of the inspiratory on-switch due to hypoxia. Similar ventilatory responses to moderate asphyxia were observed whether the asphyxic mixture was delivered after air breathing or after 5 min of hypoxia, i.e., during the dropping phase of the biphasic ventilatory response. This would seem to exclude the possibility, at least in the newborn rat, that an increase in the mechanical impedance of the respiratory system is the major cause of the drop in ventilation during hypoxia, contrary to what was previously suggested (19). If we assume that during moderate asphyxia the volume of the dead space is similar to that during air breathing, about one-third of tidal volume, the observed changes in breathing pattern indicate a doubling in alveolar ventilation during moderate asphyxia! This change would yield very similar alveolar 0, flows between asphyxic and normoxic breathing, suggesting that during moderate asphyxia the arterial Pop should be close to the normal range. This should be even more so if during asphyxia the metabolic rate were below normal, as suggested by some measurements in the newborn opossum (9) In conclusion, analysis of the breathing pattern during steadv-state hvnoxic or hvnercannic breathing in the
ON
NEONATAL
511
RESPIRATION
newborn rat indicated that the alveolar ventilation is respectively decreased and increased. The former is associated to a drop in Vo2, which must minimize the changes in arterial Po2. Moderate asphyxia appears to determine the most powerful ventilatory response, by combining the stimulatory effects of hypercapnia on the inspiratory activity and of hypoxia on the inspiratory on-switch mechanism. We thank Dr. T. Trippenbach for the very valuable discussions in the preparation of the manuscript. M. Saetta was a research fellow from the Meakins Christie Laboratories. This study was supported by Medical Research Council of Canada. Received
26 March
1986; accepted
in final
form
19 August
1986.
REFERENCES 1. ADOLPH, E. F., AND P. A. HOY. Ventilation of lungs in infant and adult rats and its responses to hypoxia. J. Appl. Physiol. 15: 10751086, 1960. 2. BONORA, M., D. MARLOT, H. GAUTIER, AND B. DURON. Effects of hypoxia on ventilation during postnatal development in conscious kittens. J. Appl. Physiol. 56: 1464-1471, 1984. 3. BRADLEY, G. W., C. VON EULER, I. MARTTILA, AND B. RODS. Steady state effects of CO, and temperature on the relationship between lung volume and inspiratory duration (Hering-Breuer threshold curve). Acta Physiol. Stand. 92: 351-363, 1974. P. FOULON, AND R. BEGIN. Diphasic 4. BUREAU, M. A., R. ZINMAN, ventilatory response to hypoxia in newborn lambs. J. Appl. Physiol. 56: 84-90, 1984. 5. CLARK, F. J., AND C. VON EULER. On the regulation of depth and rate of breathing. J. Physiol. Lond. 222: 267-295, 1972. 6. CROSS, K. W., J. M. D. HOOPER, AND J. M. LORD. Anoxic depression of the medulla in the new-born infant. J. Physiol. Lond. 125: 628-640, 1954. 7. CROSS, K. W., J. P. M. TIZARD, AND D. A. H. TRYTHALL, The metabolism of newborn infants breathing 15% oxygen (Abstract). J. Physiol. Lond. 129: 69P-7OP, 1959. 8. DIXON, M. Munometric Methods (2nd ed.). New York: Macmillan, 1943. 9. FARBER, J. P., H. N. HULTGREN, AND S. M. TENNEY. Development of the chemical control of breathing in the Virginia Opossum. Respir. Physiol. 14: 267-277, 1972. 10. FISHER, J. T., AND G. SANT’AMBROGIO. Airway and lung receptors and their reflex effects in the newborn. Pediatr. Pulmonol. 1: 112126,1985. 11. FISHER, J. T., F. B. SANT’AMBROGIO, AND G. SANT’AMBROGIO. Stimulation of tracheal slowly adapting stretch receptors by hypercapnia and hypoxia. Respir. Physiol. 53: 325-339, 1983. 12. GAULTIER, C., AND J. P. MORTOLA. Hering-Breuer inflation reflex in young and adult mammals. Can. J. Physiol. Pharmacol. 59: 1017-1021,198l. 13. GAUTIER, H., AND M. BONORA. Possible alteration in brain monoamine metabolism during hypoxia-induced tachypnea in cats. J. Appl. Physiol. 49: 769-777, 1980. 14. GUTHRIE, R. D., W. A. LAFRAMBOISE, T. A. STANDAERT, G. VAN BELLE, AND D. E WOODRUM. Ventilatory interaction between oxygen and carbon dioxide in the preterm primate. Pediatr. Res. 19: 528-533, 1985. 15. HADDAD, G. G., M. R. GANDHI, AND R. B. MELLINS. O2 consumption during hypoxia in sleeping puppies (Abstract). Am. Reu. Respir. Dis. 123: 183, 1981. 16. HADDAD, G. G., M. R. GANDHI, AND R. B. MELLINS. Maturation of ventilatory response to hypoxia in puppies during sleep. J. Appl. Physiol. 52: 309-314, 1982. 17. HADDAD, G. G., AND R. B. MELLINS. Hypoxia and respiratory control in early life. Annu. Reu. Physiol. 46: 629-643, 1984. 18. JOUVET MOUNIER, D., L. ASTIC, AND D. LACOTE. Ontogenesis of the states of sleep in rat, cat, and guinea pig during the first postnatal month. Deu. PsychobioZ. 2: 216-239, 1970. 19. LAFRAMBOISE, W. A., R. D. GUTHRIE, T. A. STANDAERT, AND D. WOODRUM. Pulmonary mechanics during ventilatory response to
512
HYPERCAPNIA hypoxemia
in the
newborn
monkey.
AND
J. AppZ.
Physiol.
HYPOXIA 55:
1008-
1014,1983. 20. LAI, Y.-L., to acute
Y. TSUYA, AND J. HILDEBRANDT. CO2 exposure in the rat. J. AppZ.
Ventilatory response Physiol. 45: 611-618,
1978. 21. MARTIN-BODY, 22.
R. L., AND J. patterns in the awake and Respir. Physiol. 61: 105-113, MILLER, H. C. Effect of high oxygen on the respiration of
ON
concentration of carbon dioxide and full term infants. Pediatrics 14: 104-
113,1954.
like ventilatory
24.
29.
adaptation
J. P., C. A. MORGAN, AND V. VIRGONA. Respiratory to chronic hypoxia in newborn rats. J. AppZ. Physiol.
61:1329-1336,1986. 26. MORTOLA, ventilatory
J. P., AND S. M. TENNEY. Effects of hyperoxia on and metabolic rates of newborn mice. Respir. Physiol.
to chronic
Rat as a model for human hypoxia. J. AppZ. Physiol. 44:
AND S. M. TENNEY. Hypoxia and carbon dioxide as separate and interactive depressants of ventilation. Respir. Physiol. 28: 347-358, 1976. PURVES, M. J. The respiratory response of the new-born lamb to inhaled CO2 with and without accompanying hypoxia. J. PhysioZ.
Lond.185:78-94,1966. 30. SAETTA, M., AND J. P. MORTOLA. 31.
56:1533-1540,1984. 25. MORTOLA,
adaptation
763-769,1978. 28. Ou, L. C., M. J. MILLER,
23. MILLER,
M. J., AND S. M. TENNEY. Hypoxia-induced tachypnea in carotid-deafferented cats. Respir. Physiol. 23: 31-39, 1975. MORTOLA, J. P. Breathing pattern in newborns. J. Appl. Physiol.
RESPIRATION
63:267-274,1986. 27. OLSON, E. G., JR., AND J. A. DEMPSEY.
D. SINCLAIR. Analysis of respiratory in the halothane anaesthetized rat.
1985.
NEONATAL
32.
Breathing pattern and CO2 response in newborn rats before and during anesthesia. J. AppZ. Physiol. 58: 1988-1996, 1985. STOCK, M. K., M. A. ASSON-BATRES, AND J. METCALFE. Stimulatory and persistent effect of acute hyperoxia on respiratory gas exchange of the chick embryo. Respir. Physiol. 62: 217-230, 1985. TAYLOR, P. M. Oxygen consumption in new-born rats. J. Physiol.
Lond.154:153-168,1960. 33. WALKER, D. W. Peripheral and newborn.
Anna
and central chemoreceptors Rev. Physiol. 46: 687-703,1984.
in the fetus
