Maturation of respiratory unanesthetized newborn
control rabbits
in
I. WYSZOGRODSKI, B. T. THACH, AND J. MILIC-EMIL1 Department of Physiology, McGill University, Montreal, Quebec H3G 1 Y6, Canada catheter was inserted into the trachea and secured by suture. The neck incision was closed and the animal was lightly restrained, laid on its side, and placed inside a 3-liter glass jar which served as a pressure plethysmograph. All recordings were made at least 30 min after the effects of the ether anesthesia had worn off (9, 24). Copper mesh sponges were placed inside the jar to ensure isothermal gas compression (15). The temperature inside the jar was maintained at 34-35”C, the neutral temperature for newborn rabbits (9, 24). The warmth, slight restraint, and natural position had a quieting effect on the animals who appeared to be in no discomfort from the surgical wound or the airway occlusions when not anesthetized. Tracheal and plethysmograph pressures were measured with two HewlettPackard 270 differential transducers and recorded on a Beckman recorder. The bottle was connected to the atmosphere by a slow leak (t,,, = 30 s). On random breaths, the tracheal catheter- was occluded at end expiration for one respiratory cycle. Ten to fifteen occlusions were. performed on each animal during spontaneous room air breathing. All the data were collected when the animal appeared to be completely relaxed in that there was absence of limb movements and muscular twitching. Furthermore, both tidal volume and respiratory frequency were regular. This suggests that the animals were in quiet sleep during the recording time. However, in view of the fact that neither the electroencephalogram nor the electrooculogram were recorded there is no direct proof of the sleep state of the animal. In this connection, it should be noted that periods of active muscular twitching and irregular respiratory patterns were present in all rabbits but these data were not analyzed. Data Analysis All analysis refers to the occluded breaths and the immediately preceding unloaded breathing cycles. From the plethysmographic records we obtained the control (unloaded) tidal volume (VT), inspiratory (TI), expiratory (TE), total (Ttot) breathing cycle durations, as described elsewhere (24). Instantaneous ventilation (VE) and respiratory frequency (f) were computed from the above variables. For the occluded breaths, the duration of the respiratory phases was obtained from the tracheal pressure records, as previously described (24). During occlusion, the change in thoracic gas volume due to decompression was obtained from the plethysmographic records. The volumet,ric data were analyzed both by the conventional equation
WYSZOGRODSKI, I., B. T. THACH, AND J. MILIC-EMILI. Maturation of respiratory control in unanesthetized newborn rabbits. J, Appl. Physiol.: Respirat. Environ. Exercise Physiol. 44(2): 304-310, 1978. -The maturation of control of breathing was studied in unanesthetized rabbit pups breathing room air in a body plethysmograph during the first 8 postnatal days. Measurements include pulmonary ventilation (VE), tidal volume (VT), inspiratory (TI) and total breathing cycle (Ttot) durations, TI/Ttot, mean inspiratory flow (VT/TO, and tracheal pressure developed by the inspiratory muscles 0.1 and 0.2 s after the onset of inspirations with airways occluded at functional residual capacity (P,,Vl and P,,.,). All of the above variables increased progressively from the 1st to the 8th day, which remained constant. except for P,., , Poe2, and TIlTtot The constancy of TI/Ttot implies that the increase in VE with age was due entirely to increased VT/TI. The constancy of P,., and PUaz implies that the increase in VT/TI with age was due to decreased “effective” impedance of the respiratory system. The latter probably mainly reflects increased compliance and decreased flow resistance with growth. The results also show that during the first 8 days of life there is a progressive shift to the right in the VT vs. TI relationship.
control of rate and depth of breathing; tracheal occlusion pressure; breathing pattern in newborn rabbits; HeringBreuer inflation reflex
IN RECENT YEARS there has been growing interest in the study of regulation of breathing in newborn animals (5, 8, 9, 21, 24), but no systematic description of the postnatal maturation of the control of breathing has been reported, except for the work of Marlot (14) on kittens. His observations were made at weekly intervals following birth and pertain chiefly to the anesthetized and decerebrate states. The present study examines the maturation of respiration in unanesthetized rabbit pups breathing room air during the first 8 postnatal days. We report in detail changes in breathing pattern with age. In addition, the tracheal pressure generated by the inspiratory muscles with occluded airway at functional residual capacity (II, 25) was determined. MATERIALS
AND
l
METHODS
The general methodology has been described previously (9, 24). Thirty-five New Zealand rabbit pups were studied between 0.5 and 8 days of age. Three, ten, five, three, eight, and six rabbits were studied at 0.5, 1, 2, 3, 5, and 8 days, respectively. The rabbits were anesthetized transiently with diethyl ether and a polyethylene 304
Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (137.154.019.149) on January 12, 2019.
RESPIRATORY
CONTROL
IN
NEWBORN
305
RAl3BITS
VE =VTXf and by a recently
introduced VIZ = (VTITI)
function
(1) (3, 16)
x (TIlTtot)
(2)
The purpose of an .alyzing ventilation by EQ. 2 is that it divides it into two components, one (VT/TI) representing an index of “inspiratory drive” (or central inspiratory activity) which is increasingly being used in studies of control of breathing (1, 3, 9, 16), and the other (TI/ Ttot) representing a dimensionless number which reflects the fraction of time during which the inspiratory muscles are active (on duty), and hence can conveniently be termed the inspiratory “duty cycle?’ Clearly, Eq. 2 is focused on inspiratory events. This seems appropriate within the context of the present experiments because, in animals breathing room air at rest, it is highly likely that ventilation is sustained entirely by activity of the inspiratory muscles. In this connection it should be noted that all of our animals exhibited an end-expiratory pause, a result consistent with absence of phasic activity of expiratory muscles. Since recent evidence indicates that in newborn rabbits the inspiratory volume-time profile is not always linear, and hence changes in TI may per se affect VT/TI (9>, we have also measured V,., and Vom2, i.e., the volumes inspired 0.1 and 0.2 s, respectively, after the onset of inspiration. These two variables are volumetric indices of central inspiratory activity which are independent of TI (9). In addition, measurements of tracheal pressure generated by the inspiratory muscles 0.1 (P,.,) and 0.2 (PO-J s after th e onset of inspiration and peak pressure (P,& obtained with occluded airways at functional residual capacity were made. PO,l, Pom2,Voml, Voa2, and VT/TI are respiratory output parameters related to inspiratory neural drive, as they represent mechanical transforms of the rate of rise of central inspiratory activity (1, 4; 9). P,, 1, P, 2, and Pmax are indices of respiratory center output which are independent of the flow resistance and compliance of the respiratory system, whereas this is not the case for V, 1, V, 2, and VT/ TI (3. 9). Tests of significance were perfdrmed using the Student t-test. RESULTS
Figure 1 illustrates ventilatory variables point represents the tained for all rabbits the bars indicate the
the relationship between various and postnatal age. Each data average of the mean values obat any given postnatal age, while corresponding standard errur of l
l The term “duty cycle” is used in other disciplines (e.g., electrical engineering) to denote the fraction of a periodic cycle that is energetically active. 2 Strictly speaking, electrical activity of the inspiratory muscles precedes by a few milliseconds the onset of mechanical (volumetric> inspiration and continues during part of expiration. Thus, the volumetric TIlTtot ratio represents the fraction of time during which the inspiratory muscles are actively causing inspiration, i.e., they are contracting myometrically. In this connection it should be noted that normally the volumetric TI corresponds closely to the neural TI, measured in terms of time elapsed from the onset to the peak of the integrated diaphragmatic electromyogram (17).
the mean. In Fig. lA, ventilation (mllmin) is plotted on the ordinate against postnatal age in days. It is seen that as the newborn rabbit matures ventilation increases. However, when VE is corrected for body weight (Fig. lB> no significant changes are seen to occur with age. Figure 1C shows that VT increases progressively with postnatal age. This increase is maintained after correction of VT for body weight (Fig. 1D). Figure 1E indicates that the frequency of breathing decreases with age, having a mean value of about 75 breaths/min 0.5 days after birth and 45 breathslmin after 8 days. Figure 13’ shows that the prolongation of total respiratory cycle durati .on with age was associated with an increase in both TT and TE. The latter is represented by the vertical difference between the Tr and Ttot curves in Fig. ZF. That the changes in TI and TE with postnatal age are proportional is shown in Fig. 2A which demonstrates that TIlTtot, the inspiratory duty cycle, remains unchanged with age. A constant TIlTtot ratio implies that the ratio of TE to TI must also remain constant as seen in the fol lowing equation Tr/Ttot
= TI/(TI
+
TE)
= l/(1
+ %/TQ
(3)
According to Eq. 2, the fact that the TIlTtot ratio did not change with age implies that the change in ventilation observed in the postnatal period results entirely from an increase in mean inspiratory flow (Fig. 2B). When VT/TI is corrected for body weight (Fig. ZC) no significant changes are observed with age. As shown in Fig. 3, Voml and V, 2, corrected for body weight, also did not change significantly with postnatal age, indicating that in the present experiments the postnatal changes in VT/TI reflected proportional changes in rate of filling W 0.1 and V,,,) of the lungs. Thus, in this instance Voml, V 0.21 and VT/TI represent equivalent indices of the output of the respiratory centers. In all rabbits the tracheal occlusion pressure represented the net pressure developed by the inspiratory muscles because the occlusions were made at the relaxed volume of the respiratory system. Indeed, in all rabbits the tracheal pressure during the occluded expiration returned to zero (atmospheric) pressure (9). Furthermore, all rabbit pups exhibited an end-expiratory pause during both occluded and unoccluded breathing, a result consistent with a return of lung volume during the expiration to the relaxed volume of the respiratory system. Figure 4A shows the relationship of postnatal age with P,,., and Po,Z as well as with the peak inspira. tory pressure developed during tracheal occlusion (P,,,). It can be seen that the rate of rise of i.nspiratory pressure, expressed as P,,., and Po.2, did not change with age. Furthermore, analysis of the results revealed that the ratio of P, . JP, 2 did not change significantly with age, indicating that in newborn rabbits age does ‘ not affect the shape of the occlusion pressure wave (3). P max on the other hand, increased progressively with age. Since the rate of rise of pressure did not change with age, the rise in Pm,, was due entirely to prolongation of the occluded inspiratory duration. Because during the occluded inspirations there were relatively large changes in lung volume due to decompression which caused a shortening of TI due to phasic lung volume
Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (137.154.019.149) on January 12, 2019.
306
WYSZOGRODSKI,
THACH,
AND
MILIC-EMILI
80
0
I
I
I
I
1
2
4
6
8
10
,POSTNATAl
AGE
0
[days)
4
2
1. Relationship of various respiratory variables and postnatal age. Each point represents (in this and subsequent figures) the mean k 1 SE of mean values obtained for each rabbit. A; ventilation; B; ventilation corrected for body weight; C: tidal volume; D: tidal FIG.
19.
A
0 0
t
1 2 POSTNATAL
FIG.
corrected
I
1 4
I
T
1 6 AGE
25
I 0
10
O0
tdaysl
2. Relationship of inspiratory duty for body weight (C) with postnatal
(TI/Ttot)
AGE
10
0
(drryal
I
I
II
1 4
I 6
I 8
r
(A),
4
POSTNATAL
no4 i
8
I 2
2
6 AOE
8
10
(day@)
volume corrected for body weight; E: respiratory frequency; F: inspiratory time (TI) and total breath duration (Ttot). Note that the vertical difference between Ttot and TI represents the duration of expiration (TE),
POSTNATAL
cycle age.
8
6
POSTNATAL
mean
AGE
inspiratory
C
0 l0
0
(days1
t
1
t
,
I 2
1 4
I 6
I 8
POSTNATAL
flow
rate
(VTITI)
(B),
and
AGE
mean
10
tdaysl
inspiratory
flow
rate
feedback (II), we have computed the values of Pmax with postnatal age. However, when P, ,/VO 2 is corrected that would obtain in the absence of any change in lung for body weight (Fig. 4C), there are nb significant volume during the occluded inspiration, namely lpomaX. changes, except between day 1 and 3. Similar results p&X was obtained by multiplying the unloaded VT by were obtained in terms of POJV, 1. the tceffectivef’ elastance of the total respiratory system, Figure 5A shows the relationship between the group as described elsewhere (11). Analysis of this data indimean control tidal volume (closed circles) and occluded cates that the P,,,/p”,,, ratio did not change signifiVT (open circles) plotted against the reciprocal value of cantly with age, averaging 0.61 and 0.65, respectively, inspiratory duration ( ~/TI),~ Note that the occluded VT in the youngest and oldest group of rabbits studied. was rather large due to the dead space of the equipment. In Fig. 4B, the “effective” impedance of the respiraIt can be seen that with increasing age, the VT versus tory system, which is obtained by dividing P, 2 by V, 2 To validate the linearity of plots such as are shown in Fig. 5A, (the volume of the unoccluded breath at 0.2 ‘s) (9), is we 3 subjected rabbit pups to different inspiratory elastic loads, as related to postnatal age. Except for a transient increase described elsewhere (11). A linear relation between VT and l/T1 was between day 0.5 and 1, this variable tends to decrease obtained, in line with previous findings on newborn rabbits (9). Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (137.154.019.149) on January 12, 2019.
RESPIRATORY
CONTROL
IN
NEWI3ORN
307
RAl3lBITS
the mean inspiratory flow, while the slope of the solid lines joining the filled and open circles indicates the corresponding mean expiratory flow rates (ZO), all corrected for body weight. Up to 8 days of age, the mean inspiratory flow corrected for body weight does not change systematically with age. The duration of inspiration, on the other hand, tends to increase progressively with age, resulting in an increased VT/BW (Fig. 1D). Similarly, the slopes of the expiratory limbs in this schematic diagram are essentially the same at all ages.
l/Tr function is progressively more steep and shifted to the left, the latter indicating that with increasing age the duration of inspiration at VT = 0 (i.e,, TIO) increases progressively. The data in Fig. 54 allow the conventional VT vs, TI relationship to be computed (Fig. 5B). It can be seen that with maturation, the VT vs. TI function is shifted progressively to the right. When tidal volumes are plotted against inspiratory durations expressed as a fraction of Tr” (ll), similar relationships were obtained for all ages studied (Fig. SC). Also shown in Fig. 5 are plots of tidal volume, corrected for body weight, as a function of ~/TI, TI, and TI/TIO. The results of the present study are summarized schematically in Fig. 6 where tidal volume, corrected for body weight, is plotted against time. Filled circles represent the VT, corrected for body weight, at each age, plotted against the corresponding TI. The open circles represent the total breathing cycle duration at each age. The slope of the broken lines joining the onset of inspiration with the filled circles represents l0
DISCUSSION
The present study indicates that in the newborn rabbit, ventilation increases, during the first 8 postnatal days. As previously observed, this is associated with a rise in tidal volume and a fall in respiratory frequency (2, 5, 7, 8, 21, 23). Th e increase in VT is due both to increased Tr and VT/TI, In a previous study we have observed that in some rabbits aged one day the inspiratory volume-time profile is curvilinear and hence they exhibit a Tr-dependent mean inspiratory flow (9), In the animals of the present study, however, the postnatal increase in VT/TI could not be attributed to the prolongation in Tz because V, 1, V, 2, and VT/TI increased proportionately with age.- This‘ either indicates that in the animals of the present study the inspiratory volumetime profile was relatively linear or, more likely, that when different groups of animals are studied as a function of age, the TI dependence of mean inspiratory flow is lost within the scatter of the data, When corrected for body weight, VT/TI as well as V, I and V,., did not show significant changes with postnatal age. Since TdTtot also did not change, it follows from eq. 2 that all of the increase in VE with age was due to increased VTITI. Obviously, since neither VT/TI, corrected for body weight, nor TI/Ttot changed with age, VE corrected for body weight was also independent of age. Rate of rise of tracheal occlusion pressure (PO., and
I
I 01 0
I
vo.2 4 1
I
I
I
1
2 4 POSTNATAL
6 AGE
8
10
Idays)
Relationship of volume inspired 0.1 (V,.,) and 0.2 (V,.,> s after the onset of inspiration, both corrected for body weight, with postnatal age. FIG.
3.
1
24 t
24
0
2 FIG.
4
6
8
10
4. A : PO+l, POm2, Pmax, and Pk,,
0
2
4
6
8
POSTNATAL AM ldaysl versus age. B : PO,z/VO~z versus
10
0
2
age. C: P,.,/(V,+,/BW)
4
6
versus
age.
8
10
Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (137.154.019.149) on January 12, 2019.
308
WYSZOGRODSKI,
0
1
2
l/T1
3
4
0
*4
-8
~sec-~)
THACH,
AND
MILIC-EMILI
4 TI”
4
1.6
TI
( sea
‘020%---
0
1
2
l/T1
3
4
5
0
-4
.8 1-2 Tr (sea
WC-~)
FIG. 5. Relationship between tidal volume (in ml above FRC) and the reciprocal of inspiratory duration (A); inspiratory duration (B); and inspiratory duration expressed as a fraction of Tr”, the inspiratory duration when VT = 0 (C). D, E, and F: similar
PO *) also did not change significantly with postnatal age, while P,,, increased on the average from 10.8 cmH,O on day 0.5 to 25.3 cmH,O on day 8, the latter resulting entirely from prolongation of TI on occlusion. It should be noted that during the occluded inspirations there were substantial changes in lung volume due to decompression (Fig. 5) and as a result P, 1, PO 2, and P max were underestimated. In the case of Pi,, underestimation was caused by shortening of TI due to phasic (vagal) lun g volume-related feedback (11). This error was substantial (up to 39%) but could be corrected. In the case of P, 1 and PO2, the error was probably smaller than for P,,, because * vagal feedback does not affect the initial rate of rise of tracheal occlusion pressure (25, 26). We estimated it as follows. According to Pengelly et al. (18), at constant inspiratory muscle activity and constant lung volume, the relation between tracheal pressure (P) and rate of change in lung .volume (v) is given by P = P0 - kV
(4)
where P0 is the pressure at V = 0 and k is a constant. In our case, the value of k could be estimated by dividing P, 2 by the difference between control V, namely V,.,; and occluded v, namely occluded V, 2, the latter representing the change in lung volume’ 0.2 s after the onset of the occluded inspiration. PO0 ,2 can
14
2-O
0
l2
4 w
lQ
relationships for VT corrected for body weight. Each point represents the average of mean values for each rabbit. Filled circles: control breaths; open circles: occluded breaths. Numbers on curves indicate postnatal age in days.
then be computed by multiplying k by V, 2* Between day 0.5 and 2, the average P, ,/p”, 2 ratio ‘ranged between 0.73 and 0.75 while from day 3 to 8 it varied between 0.81 and 0.83. Similar results were obtained for PO ,/p”, 1, where the average values ranged between 0.7 and 0.73 in days 0.5-2, and between 0.75 and 0.79 in days 3-8. On the basis of the above computation it can be concluded that our values of P,-, and Pow2were probably underestimated by 17-30% and, more important, that the error was nearly constant over the age span studied. It should be noted, however, that the above analysis was based on the assumption that, within the range of lung volumes considered, P depended solely on V but not on V. This assumption appears to be justified at least with respect to our PIj,, estimates, in view of the small values of both occluded and unoccluded V, I. The apparent constancy of P, I and P, 2 in the postnatal period does not mean necessarily that the inspiratory neural drive did not change between day 0.5 and 8. Indeed, with growth there may be substantial changes in the geometry and intrinsic properties of the respiratory muscles, as well as in functional residual capacity, all factors which can affect the transform function of neural drive into inspiratory pressure (3, 12, 18, 25, 26), In this connection it should be noted that the values of P, .1 and P,., that we have obtained in
Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (137.154.019.149) on January 12, 2019.
RESPIRATORY
CONTROL
IN
NEWBORN
309
RABBITS
the present study are similar to those that are found in our laboratory in anesthetized adult cats and rabbits, as well as in awake man. Considering, the pliability of the rib cage of newborns, and hence a tendency to exhibit paradoxical movement of the rib cage during airway occlusion (IZ), the finding of similar values of PO 1 and PO2 in newborns and adults is of considerable interest because, as a result of paradoxing of the rib cage, the airway occlusion pressure would be expected to be less in the newborns. The decrease in P, .JV,,., with age probably reflects mainly increasing compliance and decreasing flow resistance of the respiratory system in the growing animals However, age-dependent changes in geometry and intrinsic properties of inspiratory muscles, as well as other factors (e.g., paradoxical motion of the rib cage), may h&e contributed to the drop in P,,.,/V, .2 with maturation (3, 12, 18, 25). With increasing age, both Tr and TE increased progressively in a constant proportion, as shown by the constancy of Tr/Ttot (Fig. 2A). Our animals, however, were tracheostomized, and hence the modulation of the breathing pattern from pharyngeal and laryngeal receptors (6) was bypassed. Whether in intact rabbits TI/ Ttot remains also unchanged in the postnatal period remains as yet to be determined. Analysis of the data of Taeusch et al. (23) for intact newborn infants indicates that Tr/Ttot stays virtually constant during the
l 016-
I.0
TIME
FIG. 6. Schematic cycle with postnatal and TI; open circles: lines: mean inspiratory tively, both corrected age in days. Note that pause.
first week of life. According to their data, this ratio averages 0.47 in the first 15-33 h of life and 0.50 between 4-6 days. With maturation there was a progressive shift to the right in the VT vs. TI and VT/BW vs. TI relationships (Fig. 5, B and E). No substantial age dependence was observed when VT and VT/BW were plotted against TX/ TI” (Fig. 5, C and F). The prolongation of TIO with age may reflect a change in the bulbopontine setting of duration of inspiration (1, 11) and/or decreased tone of pulmonary stretch receptors activity (19). However, tonic vagal activity has been seen to be negligible in both newborn (24) and adult rabbits (26) and in adult cats (10, 11). In a recent study, Knill and Bryan (12) have shown that in newborn infants airway occlusion may cause a reduction in duration of inspiration as compared to control (unloaded) inspiratory duration. They have attributed this to an intercostal-phrenic inhibitory reflex (20) which may act to shorten inspiratory duration during airway occlusion. In the present study airway occlusion always resulted in a prolongation of inspiratory duration. This is consistent with the observation of Schwieler (21) who noted that both kittens and newborn rabbits acquire the intercostal load-compensatory mechanism only after lo-15 days of age. Thus, the phasic lung volume-related shortening of TI observed in the present study can probably be attributed entirely to the Hering-Breuer inflation reflex. In fact, in newborn rabbits phasic lung volume-related modulation of TI is abolished by bilateral cervical vagotomy (21). Our results suggest that during the first eight postnatal days the strength of the phasic lung volume-related influence on TI increases. Indeed, for any given VT and VTIBW the difference between Tr” and TX increased with maturation (Fig. 5). Although, as described in METHODS, it is likely that our data pertain to quiet sleep, we have no direct evidence that this was indeed the case. In view of this uncertainty, it should be noted that in the immediate postnatal period there is a decrease in the ratio of active (REM) to quiet (non-REM) sleep as the animal matures (22). This may have influenced some of the age-related changes described in the present study.
5
tsec)
summary of changes in the average respiratory age. Filled circles: relation between VT/BW total breath cycle duration. Broken and soLid and mean expiratory flow rates, respecfor body weight. Numbers indicate postnatal in actual spirograms there was an expiratory
The authors thank Mr. W. Lee-Foon for his technical assistance, Mr. K. Holeczek for art and photography, and Dr. R. A. Epstein for suggesting the term “duty cycle” for TIlTtot. This study was supported by the Canadian Heart Foundation, the Medical Research Council of Canada, and the Hospital for Sick Children Foundation, Toronto, Canada. I. Wyszogrodski is a recipient of a Canadian Heart Foundation Medical Scientist award. Received
for publication
4 April
1977.
REFERENCES 1. CLARK, F. J., AND C. VON EULER. On the regulation of depth and rate of breathing. J. Physiol., London 222: 267-295, 1972. 2. CROSS,K. W. The respiratory rate and volume of the newborn infant. J. PhysioZ., London 109: 459-474, 1949. 3. DERENNE, J-P., J. COUTURE, S. ISCOE, W. A. WHITELAW, AND J. MILK-EMILI. Occlusion pressures in men rebreathing CO, under methoxyflurane anesthesia. J. AppZ. PhysioZ. 40: 805814, 1976. 4. ELDRIDGE, F. L. Relationship between respiratory nerve and
muscle activity and muscle force output. J. Appl. Physiol. 39: 567-574, 1975. 5. FARBER, J. P. Development of pulmonary reflexes and pattern of breathing in the Virginia opossum. Respiration Physiol. 14: 278-286, 1972. 6. GAUTIER, H., J. E. REMMERS, AND D. BARTLETT, JR. Control of the duration of expiration. Respiration Physiol. 18: 205-221, 1972. 7. GLEISS, J., AND F. HOLDERBERG. Studies about respiratory regu-
Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (137.154.019.149) on January 12, 2019.
310 lation of the newborn. BioZ. Neonat. 5: 350-378, 1963. 8. GODFREY, S. Respiratory and cardiovascular changes during asphyxia and resuscitation of fetal and newborn rabbits. Quart. J. Exp. Physiol. 53: 97-118, 1968. 9. GOLDBERG, M. S., AND J. MILDEMILI. Effect of pentobarbital sodium on respiratory control in newborn rabbits. J. AppZ. Physiol.: Respirut . Environ. Exercise Physiol. 42: 845-851, 1977. 10, GRUNSTEIN, M. M., I. WYSZOGRODSKI, AND J. MILIC-EMILI. Regulation of frequency and depth of breathing during expiratory threshold loading in cats. J. Appl, PhysioZ, 38: 869-874, 1975. 11. GRUNSTEIN, M, M., M. YOUNES, AND J. MXLIC-EMILI. Control of tidal volume and respiratory frequency in anesthetized cats. J. AppZ. Physiol. 35: 463-467, 1973. 12. KNILL, R., AND A, C, BRYAN. An intercostal-phrenic inhibitory reflex in human newborn infants. J. Appl. Physiol. 40: 352-356, 1976. 13. LYNNE-DAVIES, P., J. COUTURE, L. D. PENGELLY, D. WEST, P. R. BROMAGE, AND J. MILIC-EMILX. Partitioning of immediate ventilatory stability to added elastic loads in cats. J. Appl. Physiol, 30: 814-819, 1971. 14. MARLOT, D. Recherches SW Ze confrble Nerveux de la Respiration Chex Ze Chaton (doctoral thesis), Amiens, France: Facu& de Mkdecine, 1976. 15. MEAD, J. Control of respiratory frequency. J. Appl. PhysioE. 15: 325-336, 1960. 16. MILIC-EMILI, J , , AND M. M. GRUNSTEIN. Drive and timing components of ventilation. Chest 70, Suppl.: 131-133, 1976. 17. MISEROCCHI, G., AND J. MILDEMILL. Effect of mechanical factors on the relation between rate and depth of breathing in
WYSZOGRODSKI,
THACH,
AND
MILIC-EMIL1
cats. J. AppZ. Physiol. 41: 277-284, 1976. 18. PENGELLY, L. D., A. M. ALDERSON, AND J. MJLIC-EMILI. Mechanics of the diaphragm, J. AppZ. Physiol. 30: 797-805, 1971. 19. PHILLIPSON, E. A. Vagal control of breathing pattern independent of lung inflation in conscious dogs. J. AppZ. Physiol. 37: 183-189, 1974. 20. REMMERS, J. E. Inhibition of inspiratory activity by intercostal muscle afferents. Respiration Physiol. 10: 358-383, 1970. 21. SCHWIELER, G. H. Respiratory regulation during postnatal development in cats and rabbits and some of its morphological substrate. Acta Physiol. Stand. Suppl. 304: 1-123, 1968. 22, STERMAN, M. B., AND T. HOPPENBROUWERS. The development of sleep-waking and rest-activity patterns from fetus to adult in man, In: Brain Development and Behavior, edited by M. B. Sterman, D, J. McGinty, and A. M. Adinolfi. New York: Academic, 1971, p. 203-227. 23. TAEUSCH, H. W., JR., S. CARSON, I. D. FRANTZ, AND J. MILICEMILI. Respiratory regulation after elastic loading and CO, rebreathing in normal term infants. J. Pediat, 88: 102-111, 1976. 24. THACH, B. T., I. WYSZOGRODSKI, AND J. MILK-EMILI. Effect of ether on control of rate and depth of breathing in newborn rabbits. J, AppZ. Physiol, 40: 281-286, 1976. 25. WHITELAW, W. A., J.-P. DERENNE, AND J. MILIC-EMILI. Occlusion pressure as a measure of respiratory center output in conscious man. Respiration Physiol. 23: 181-199, 1975. 26. YOUNES, M., S. ISCOE, AND J. MILK-EMILI. A method for the assessment of phasic vagal influence on tidal volume. J. Appl. Physiol. 38: 335-343, 1975.
Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (137.154.019.149) on January 12, 2019.
control rabbits
in
I. WYSZOGRODSKI, B. T. THACH, AND J. MILIC-EMIL1 Department of Physiology, McGill University, Montreal, Quebec H3G 1 Y6, Canada catheter was inserted into the trachea and secured by suture. The neck incision was closed and the animal was lightly restrained, laid on its side, and placed inside a 3-liter glass jar which served as a pressure plethysmograph. All recordings were made at least 30 min after the effects of the ether anesthesia had worn off (9, 24). Copper mesh sponges were placed inside the jar to ensure isothermal gas compression (15). The temperature inside the jar was maintained at 34-35”C, the neutral temperature for newborn rabbits (9, 24). The warmth, slight restraint, and natural position had a quieting effect on the animals who appeared to be in no discomfort from the surgical wound or the airway occlusions when not anesthetized. Tracheal and plethysmograph pressures were measured with two HewlettPackard 270 differential transducers and recorded on a Beckman recorder. The bottle was connected to the atmosphere by a slow leak (t,,, = 30 s). On random breaths, the tracheal catheter- was occluded at end expiration for one respiratory cycle. Ten to fifteen occlusions were. performed on each animal during spontaneous room air breathing. All the data were collected when the animal appeared to be completely relaxed in that there was absence of limb movements and muscular twitching. Furthermore, both tidal volume and respiratory frequency were regular. This suggests that the animals were in quiet sleep during the recording time. However, in view of the fact that neither the electroencephalogram nor the electrooculogram were recorded there is no direct proof of the sleep state of the animal. In this connection, it should be noted that periods of active muscular twitching and irregular respiratory patterns were present in all rabbits but these data were not analyzed. Data Analysis All analysis refers to the occluded breaths and the immediately preceding unloaded breathing cycles. From the plethysmographic records we obtained the control (unloaded) tidal volume (VT), inspiratory (TI), expiratory (TE), total (Ttot) breathing cycle durations, as described elsewhere (24). Instantaneous ventilation (VE) and respiratory frequency (f) were computed from the above variables. For the occluded breaths, the duration of the respiratory phases was obtained from the tracheal pressure records, as previously described (24). During occlusion, the change in thoracic gas volume due to decompression was obtained from the plethysmographic records. The volumet,ric data were analyzed both by the conventional equation
WYSZOGRODSKI, I., B. T. THACH, AND J. MILIC-EMILI. Maturation of respiratory control in unanesthetized newborn rabbits. J, Appl. Physiol.: Respirat. Environ. Exercise Physiol. 44(2): 304-310, 1978. -The maturation of control of breathing was studied in unanesthetized rabbit pups breathing room air in a body plethysmograph during the first 8 postnatal days. Measurements include pulmonary ventilation (VE), tidal volume (VT), inspiratory (TI) and total breathing cycle (Ttot) durations, TI/Ttot, mean inspiratory flow (VT/TO, and tracheal pressure developed by the inspiratory muscles 0.1 and 0.2 s after the onset of inspirations with airways occluded at functional residual capacity (P,,Vl and P,,.,). All of the above variables increased progressively from the 1st to the 8th day, which remained constant. except for P,., , Poe2, and TIlTtot The constancy of TI/Ttot implies that the increase in VE with age was due entirely to increased VT/TI. The constancy of P,., and PUaz implies that the increase in VT/TI with age was due to decreased “effective” impedance of the respiratory system. The latter probably mainly reflects increased compliance and decreased flow resistance with growth. The results also show that during the first 8 days of life there is a progressive shift to the right in the VT vs. TI relationship.
control of rate and depth of breathing; tracheal occlusion pressure; breathing pattern in newborn rabbits; HeringBreuer inflation reflex
IN RECENT YEARS there has been growing interest in the study of regulation of breathing in newborn animals (5, 8, 9, 21, 24), but no systematic description of the postnatal maturation of the control of breathing has been reported, except for the work of Marlot (14) on kittens. His observations were made at weekly intervals following birth and pertain chiefly to the anesthetized and decerebrate states. The present study examines the maturation of respiration in unanesthetized rabbit pups breathing room air during the first 8 postnatal days. We report in detail changes in breathing pattern with age. In addition, the tracheal pressure generated by the inspiratory muscles with occluded airway at functional residual capacity (II, 25) was determined. MATERIALS
AND
l
METHODS
The general methodology has been described previously (9, 24). Thirty-five New Zealand rabbit pups were studied between 0.5 and 8 days of age. Three, ten, five, three, eight, and six rabbits were studied at 0.5, 1, 2, 3, 5, and 8 days, respectively. The rabbits were anesthetized transiently with diethyl ether and a polyethylene 304
Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (137.154.019.149) on January 12, 2019.
RESPIRATORY
CONTROL
IN
NEWBORN
305
RAl3BITS
VE =VTXf and by a recently
introduced VIZ = (VTITI)
function
(1) (3, 16)
x (TIlTtot)
(2)
The purpose of an .alyzing ventilation by EQ. 2 is that it divides it into two components, one (VT/TI) representing an index of “inspiratory drive” (or central inspiratory activity) which is increasingly being used in studies of control of breathing (1, 3, 9, 16), and the other (TI/ Ttot) representing a dimensionless number which reflects the fraction of time during which the inspiratory muscles are active (on duty), and hence can conveniently be termed the inspiratory “duty cycle?’ Clearly, Eq. 2 is focused on inspiratory events. This seems appropriate within the context of the present experiments because, in animals breathing room air at rest, it is highly likely that ventilation is sustained entirely by activity of the inspiratory muscles. In this connection it should be noted that all of our animals exhibited an end-expiratory pause, a result consistent with absence of phasic activity of expiratory muscles. Since recent evidence indicates that in newborn rabbits the inspiratory volume-time profile is not always linear, and hence changes in TI may per se affect VT/TI (9>, we have also measured V,., and Vom2, i.e., the volumes inspired 0.1 and 0.2 s, respectively, after the onset of inspiration. These two variables are volumetric indices of central inspiratory activity which are independent of TI (9). In addition, measurements of tracheal pressure generated by the inspiratory muscles 0.1 (P,.,) and 0.2 (PO-J s after th e onset of inspiration and peak pressure (P,& obtained with occluded airways at functional residual capacity were made. PO,l, Pom2,Voml, Voa2, and VT/TI are respiratory output parameters related to inspiratory neural drive, as they represent mechanical transforms of the rate of rise of central inspiratory activity (1, 4; 9). P,, 1, P, 2, and Pmax are indices of respiratory center output which are independent of the flow resistance and compliance of the respiratory system, whereas this is not the case for V, 1, V, 2, and VT/ TI (3. 9). Tests of significance were perfdrmed using the Student t-test. RESULTS
Figure 1 illustrates ventilatory variables point represents the tained for all rabbits the bars indicate the
the relationship between various and postnatal age. Each data average of the mean values obat any given postnatal age, while corresponding standard errur of l
l The term “duty cycle” is used in other disciplines (e.g., electrical engineering) to denote the fraction of a periodic cycle that is energetically active. 2 Strictly speaking, electrical activity of the inspiratory muscles precedes by a few milliseconds the onset of mechanical (volumetric> inspiration and continues during part of expiration. Thus, the volumetric TIlTtot ratio represents the fraction of time during which the inspiratory muscles are actively causing inspiration, i.e., they are contracting myometrically. In this connection it should be noted that normally the volumetric TI corresponds closely to the neural TI, measured in terms of time elapsed from the onset to the peak of the integrated diaphragmatic electromyogram (17).
the mean. In Fig. lA, ventilation (mllmin) is plotted on the ordinate against postnatal age in days. It is seen that as the newborn rabbit matures ventilation increases. However, when VE is corrected for body weight (Fig. lB> no significant changes are seen to occur with age. Figure 1C shows that VT increases progressively with postnatal age. This increase is maintained after correction of VT for body weight (Fig. 1D). Figure 1E indicates that the frequency of breathing decreases with age, having a mean value of about 75 breaths/min 0.5 days after birth and 45 breathslmin after 8 days. Figure 13’ shows that the prolongation of total respiratory cycle durati .on with age was associated with an increase in both TT and TE. The latter is represented by the vertical difference between the Tr and Ttot curves in Fig. ZF. That the changes in TI and TE with postnatal age are proportional is shown in Fig. 2A which demonstrates that TIlTtot, the inspiratory duty cycle, remains unchanged with age. A constant TIlTtot ratio implies that the ratio of TE to TI must also remain constant as seen in the fol lowing equation Tr/Ttot
= TI/(TI
+
TE)
= l/(1
+ %/TQ
(3)
According to Eq. 2, the fact that the TIlTtot ratio did not change with age implies that the change in ventilation observed in the postnatal period results entirely from an increase in mean inspiratory flow (Fig. 2B). When VT/TI is corrected for body weight (Fig. ZC) no significant changes are observed with age. As shown in Fig. 3, Voml and V, 2, corrected for body weight, also did not change significantly with postnatal age, indicating that in the present experiments the postnatal changes in VT/TI reflected proportional changes in rate of filling W 0.1 and V,,,) of the lungs. Thus, in this instance Voml, V 0.21 and VT/TI represent equivalent indices of the output of the respiratory centers. In all rabbits the tracheal occlusion pressure represented the net pressure developed by the inspiratory muscles because the occlusions were made at the relaxed volume of the respiratory system. Indeed, in all rabbits the tracheal pressure during the occluded expiration returned to zero (atmospheric) pressure (9). Furthermore, all rabbit pups exhibited an end-expiratory pause during both occluded and unoccluded breathing, a result consistent with a return of lung volume during the expiration to the relaxed volume of the respiratory system. Figure 4A shows the relationship of postnatal age with P,,., and Po,Z as well as with the peak inspira. tory pressure developed during tracheal occlusion (P,,,). It can be seen that the rate of rise of i.nspiratory pressure, expressed as P,,., and Po.2, did not change with age. Furthermore, analysis of the results revealed that the ratio of P, . JP, 2 did not change significantly with age, indicating that in newborn rabbits age does ‘ not affect the shape of the occlusion pressure wave (3). P max on the other hand, increased progressively with age. Since the rate of rise of pressure did not change with age, the rise in Pm,, was due entirely to prolongation of the occluded inspiratory duration. Because during the occluded inspirations there were relatively large changes in lung volume due to decompression which caused a shortening of TI due to phasic lung volume
Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (137.154.019.149) on January 12, 2019.
306
WYSZOGRODSKI,
THACH,
AND
MILIC-EMILI
80
0
I
I
I
I
1
2
4
6
8
10
,POSTNATAl
AGE
0
[days)
4
2
1. Relationship of various respiratory variables and postnatal age. Each point represents (in this and subsequent figures) the mean k 1 SE of mean values obtained for each rabbit. A; ventilation; B; ventilation corrected for body weight; C: tidal volume; D: tidal FIG.
19.
A
0 0
t
1 2 POSTNATAL
FIG.
corrected
I
1 4
I
T
1 6 AGE
25
I 0
10
O0
tdaysl
2. Relationship of inspiratory duty for body weight (C) with postnatal
(TI/Ttot)
AGE
10
0
(drryal
I
I
II
1 4
I 6
I 8
r
(A),
4
POSTNATAL
no4 i
8
I 2
2
6 AOE
8
10
(day@)
volume corrected for body weight; E: respiratory frequency; F: inspiratory time (TI) and total breath duration (Ttot). Note that the vertical difference between Ttot and TI represents the duration of expiration (TE),
POSTNATAL
cycle age.
8
6
POSTNATAL
mean
AGE
inspiratory
C
0 l0
0
(days1
t
1
t
,
I 2
1 4
I 6
I 8
POSTNATAL
flow
rate
(VTITI)
(B),
and
AGE
mean
10
tdaysl
inspiratory
flow
rate
feedback (II), we have computed the values of Pmax with postnatal age. However, when P, ,/VO 2 is corrected that would obtain in the absence of any change in lung for body weight (Fig. 4C), there are nb significant volume during the occluded inspiration, namely lpomaX. changes, except between day 1 and 3. Similar results p&X was obtained by multiplying the unloaded VT by were obtained in terms of POJV, 1. the tceffectivef’ elastance of the total respiratory system, Figure 5A shows the relationship between the group as described elsewhere (11). Analysis of this data indimean control tidal volume (closed circles) and occluded cates that the P,,,/p”,,, ratio did not change signifiVT (open circles) plotted against the reciprocal value of cantly with age, averaging 0.61 and 0.65, respectively, inspiratory duration ( ~/TI),~ Note that the occluded VT in the youngest and oldest group of rabbits studied. was rather large due to the dead space of the equipment. In Fig. 4B, the “effective” impedance of the respiraIt can be seen that with increasing age, the VT versus tory system, which is obtained by dividing P, 2 by V, 2 To validate the linearity of plots such as are shown in Fig. 5A, (the volume of the unoccluded breath at 0.2 ‘s) (9), is we 3 subjected rabbit pups to different inspiratory elastic loads, as related to postnatal age. Except for a transient increase described elsewhere (11). A linear relation between VT and l/T1 was between day 0.5 and 1, this variable tends to decrease obtained, in line with previous findings on newborn rabbits (9). Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (137.154.019.149) on January 12, 2019.
RESPIRATORY
CONTROL
IN
NEWI3ORN
307
RAl3lBITS
the mean inspiratory flow, while the slope of the solid lines joining the filled and open circles indicates the corresponding mean expiratory flow rates (ZO), all corrected for body weight. Up to 8 days of age, the mean inspiratory flow corrected for body weight does not change systematically with age. The duration of inspiration, on the other hand, tends to increase progressively with age, resulting in an increased VT/BW (Fig. 1D). Similarly, the slopes of the expiratory limbs in this schematic diagram are essentially the same at all ages.
l/Tr function is progressively more steep and shifted to the left, the latter indicating that with increasing age the duration of inspiration at VT = 0 (i.e,, TIO) increases progressively. The data in Fig. 54 allow the conventional VT vs, TI relationship to be computed (Fig. 5B). It can be seen that with maturation, the VT vs. TI function is shifted progressively to the right. When tidal volumes are plotted against inspiratory durations expressed as a fraction of Tr” (ll), similar relationships were obtained for all ages studied (Fig. SC). Also shown in Fig. 5 are plots of tidal volume, corrected for body weight, as a function of ~/TI, TI, and TI/TIO. The results of the present study are summarized schematically in Fig. 6 where tidal volume, corrected for body weight, is plotted against time. Filled circles represent the VT, corrected for body weight, at each age, plotted against the corresponding TI. The open circles represent the total breathing cycle duration at each age. The slope of the broken lines joining the onset of inspiration with the filled circles represents l0
DISCUSSION
The present study indicates that in the newborn rabbit, ventilation increases, during the first 8 postnatal days. As previously observed, this is associated with a rise in tidal volume and a fall in respiratory frequency (2, 5, 7, 8, 21, 23). Th e increase in VT is due both to increased Tr and VT/TI, In a previous study we have observed that in some rabbits aged one day the inspiratory volume-time profile is curvilinear and hence they exhibit a Tr-dependent mean inspiratory flow (9), In the animals of the present study, however, the postnatal increase in VT/TI could not be attributed to the prolongation in Tz because V, 1, V, 2, and VT/TI increased proportionately with age.- This‘ either indicates that in the animals of the present study the inspiratory volumetime profile was relatively linear or, more likely, that when different groups of animals are studied as a function of age, the TI dependence of mean inspiratory flow is lost within the scatter of the data, When corrected for body weight, VT/TI as well as V, I and V,., did not show significant changes with postnatal age. Since TdTtot also did not change, it follows from eq. 2 that all of the increase in VE with age was due to increased VTITI. Obviously, since neither VT/TI, corrected for body weight, nor TI/Ttot changed with age, VE corrected for body weight was also independent of age. Rate of rise of tracheal occlusion pressure (PO., and
I
I 01 0
I
vo.2 4 1
I
I
I
1
2 4 POSTNATAL
6 AGE
8
10
Idays)
Relationship of volume inspired 0.1 (V,.,) and 0.2 (V,.,> s after the onset of inspiration, both corrected for body weight, with postnatal age. FIG.
3.
1
24 t
24
0
2 FIG.
4
6
8
10
4. A : PO+l, POm2, Pmax, and Pk,,
0
2
4
6
8
POSTNATAL AM ldaysl versus age. B : PO,z/VO~z versus
10
0
2
age. C: P,.,/(V,+,/BW)
4
6
versus
age.
8
10
Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (137.154.019.149) on January 12, 2019.
308
WYSZOGRODSKI,
0
1
2
l/T1
3
4
0
*4
-8
~sec-~)
THACH,
AND
MILIC-EMILI
4 TI”
4
1.6
TI
( sea
‘020%---
0
1
2
l/T1
3
4
5
0
-4
.8 1-2 Tr (sea
WC-~)
FIG. 5. Relationship between tidal volume (in ml above FRC) and the reciprocal of inspiratory duration (A); inspiratory duration (B); and inspiratory duration expressed as a fraction of Tr”, the inspiratory duration when VT = 0 (C). D, E, and F: similar
PO *) also did not change significantly with postnatal age, while P,,, increased on the average from 10.8 cmH,O on day 0.5 to 25.3 cmH,O on day 8, the latter resulting entirely from prolongation of TI on occlusion. It should be noted that during the occluded inspirations there were substantial changes in lung volume due to decompression (Fig. 5) and as a result P, 1, PO 2, and P max were underestimated. In the case of Pi,, underestimation was caused by shortening of TI due to phasic (vagal) lun g volume-related feedback (11). This error was substantial (up to 39%) but could be corrected. In the case of P, 1 and PO2, the error was probably smaller than for P,,, because * vagal feedback does not affect the initial rate of rise of tracheal occlusion pressure (25, 26). We estimated it as follows. According to Pengelly et al. (18), at constant inspiratory muscle activity and constant lung volume, the relation between tracheal pressure (P) and rate of change in lung .volume (v) is given by P = P0 - kV
(4)
where P0 is the pressure at V = 0 and k is a constant. In our case, the value of k could be estimated by dividing P, 2 by the difference between control V, namely V,.,; and occluded v, namely occluded V, 2, the latter representing the change in lung volume’ 0.2 s after the onset of the occluded inspiration. PO0 ,2 can
14
2-O
0
l2
4 w
lQ
relationships for VT corrected for body weight. Each point represents the average of mean values for each rabbit. Filled circles: control breaths; open circles: occluded breaths. Numbers on curves indicate postnatal age in days.
then be computed by multiplying k by V, 2* Between day 0.5 and 2, the average P, ,/p”, 2 ratio ‘ranged between 0.73 and 0.75 while from day 3 to 8 it varied between 0.81 and 0.83. Similar results were obtained for PO ,/p”, 1, where the average values ranged between 0.7 and 0.73 in days 0.5-2, and between 0.75 and 0.79 in days 3-8. On the basis of the above computation it can be concluded that our values of P,-, and Pow2were probably underestimated by 17-30% and, more important, that the error was nearly constant over the age span studied. It should be noted, however, that the above analysis was based on the assumption that, within the range of lung volumes considered, P depended solely on V but not on V. This assumption appears to be justified at least with respect to our PIj,, estimates, in view of the small values of both occluded and unoccluded V, I. The apparent constancy of P, I and P, 2 in the postnatal period does not mean necessarily that the inspiratory neural drive did not change between day 0.5 and 8. Indeed, with growth there may be substantial changes in the geometry and intrinsic properties of the respiratory muscles, as well as in functional residual capacity, all factors which can affect the transform function of neural drive into inspiratory pressure (3, 12, 18, 25, 26), In this connection it should be noted that the values of P, .1 and P,., that we have obtained in
Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (137.154.019.149) on January 12, 2019.
RESPIRATORY
CONTROL
IN
NEWBORN
309
RABBITS
the present study are similar to those that are found in our laboratory in anesthetized adult cats and rabbits, as well as in awake man. Considering, the pliability of the rib cage of newborns, and hence a tendency to exhibit paradoxical movement of the rib cage during airway occlusion (IZ), the finding of similar values of PO 1 and PO2 in newborns and adults is of considerable interest because, as a result of paradoxing of the rib cage, the airway occlusion pressure would be expected to be less in the newborns. The decrease in P, .JV,,., with age probably reflects mainly increasing compliance and decreasing flow resistance of the respiratory system in the growing animals However, age-dependent changes in geometry and intrinsic properties of inspiratory muscles, as well as other factors (e.g., paradoxical motion of the rib cage), may h&e contributed to the drop in P,,.,/V, .2 with maturation (3, 12, 18, 25). With increasing age, both Tr and TE increased progressively in a constant proportion, as shown by the constancy of Tr/Ttot (Fig. 2A). Our animals, however, were tracheostomized, and hence the modulation of the breathing pattern from pharyngeal and laryngeal receptors (6) was bypassed. Whether in intact rabbits TI/ Ttot remains also unchanged in the postnatal period remains as yet to be determined. Analysis of the data of Taeusch et al. (23) for intact newborn infants indicates that Tr/Ttot stays virtually constant during the
l 016-
I.0
TIME
FIG. 6. Schematic cycle with postnatal and TI; open circles: lines: mean inspiratory tively, both corrected age in days. Note that pause.
first week of life. According to their data, this ratio averages 0.47 in the first 15-33 h of life and 0.50 between 4-6 days. With maturation there was a progressive shift to the right in the VT vs. TI and VT/BW vs. TI relationships (Fig. 5, B and E). No substantial age dependence was observed when VT and VT/BW were plotted against TX/ TI” (Fig. 5, C and F). The prolongation of TIO with age may reflect a change in the bulbopontine setting of duration of inspiration (1, 11) and/or decreased tone of pulmonary stretch receptors activity (19). However, tonic vagal activity has been seen to be negligible in both newborn (24) and adult rabbits (26) and in adult cats (10, 11). In a recent study, Knill and Bryan (12) have shown that in newborn infants airway occlusion may cause a reduction in duration of inspiration as compared to control (unloaded) inspiratory duration. They have attributed this to an intercostal-phrenic inhibitory reflex (20) which may act to shorten inspiratory duration during airway occlusion. In the present study airway occlusion always resulted in a prolongation of inspiratory duration. This is consistent with the observation of Schwieler (21) who noted that both kittens and newborn rabbits acquire the intercostal load-compensatory mechanism only after lo-15 days of age. Thus, the phasic lung volume-related shortening of TI observed in the present study can probably be attributed entirely to the Hering-Breuer inflation reflex. In fact, in newborn rabbits phasic lung volume-related modulation of TI is abolished by bilateral cervical vagotomy (21). Our results suggest that during the first eight postnatal days the strength of the phasic lung volume-related influence on TI increases. Indeed, for any given VT and VTIBW the difference between Tr” and TX increased with maturation (Fig. 5). Although, as described in METHODS, it is likely that our data pertain to quiet sleep, we have no direct evidence that this was indeed the case. In view of this uncertainty, it should be noted that in the immediate postnatal period there is a decrease in the ratio of active (REM) to quiet (non-REM) sleep as the animal matures (22). This may have influenced some of the age-related changes described in the present study.
5
tsec)
summary of changes in the average respiratory age. Filled circles: relation between VT/BW total breath cycle duration. Broken and soLid and mean expiratory flow rates, respecfor body weight. Numbers indicate postnatal in actual spirograms there was an expiratory
The authors thank Mr. W. Lee-Foon for his technical assistance, Mr. K. Holeczek for art and photography, and Dr. R. A. Epstein for suggesting the term “duty cycle” for TIlTtot. This study was supported by the Canadian Heart Foundation, the Medical Research Council of Canada, and the Hospital for Sick Children Foundation, Toronto, Canada. I. Wyszogrodski is a recipient of a Canadian Heart Foundation Medical Scientist award. Received
for publication
4 April
1977.
REFERENCES 1. CLARK, F. J., AND C. VON EULER. On the regulation of depth and rate of breathing. J. Physiol., London 222: 267-295, 1972. 2. CROSS,K. W. The respiratory rate and volume of the newborn infant. J. PhysioZ., London 109: 459-474, 1949. 3. DERENNE, J-P., J. COUTURE, S. ISCOE, W. A. WHITELAW, AND J. MILK-EMILI. Occlusion pressures in men rebreathing CO, under methoxyflurane anesthesia. J. AppZ. PhysioZ. 40: 805814, 1976. 4. ELDRIDGE, F. L. Relationship between respiratory nerve and
muscle activity and muscle force output. J. Appl. Physiol. 39: 567-574, 1975. 5. FARBER, J. P. Development of pulmonary reflexes and pattern of breathing in the Virginia opossum. Respiration Physiol. 14: 278-286, 1972. 6. GAUTIER, H., J. E. REMMERS, AND D. BARTLETT, JR. Control of the duration of expiration. Respiration Physiol. 18: 205-221, 1972. 7. GLEISS, J., AND F. HOLDERBERG. Studies about respiratory regu-
Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (137.154.019.149) on January 12, 2019.
310 lation of the newborn. BioZ. Neonat. 5: 350-378, 1963. 8. GODFREY, S. Respiratory and cardiovascular changes during asphyxia and resuscitation of fetal and newborn rabbits. Quart. J. Exp. Physiol. 53: 97-118, 1968. 9. GOLDBERG, M. S., AND J. MILDEMILI. Effect of pentobarbital sodium on respiratory control in newborn rabbits. J. AppZ. Physiol.: Respirut . Environ. Exercise Physiol. 42: 845-851, 1977. 10, GRUNSTEIN, M. M., I. WYSZOGRODSKI, AND J. MILIC-EMILI. Regulation of frequency and depth of breathing during expiratory threshold loading in cats. J. Appl, PhysioZ, 38: 869-874, 1975. 11. GRUNSTEIN, M, M., M. YOUNES, AND J. MXLIC-EMILI. Control of tidal volume and respiratory frequency in anesthetized cats. J. AppZ. Physiol. 35: 463-467, 1973. 12. KNILL, R., AND A, C, BRYAN. An intercostal-phrenic inhibitory reflex in human newborn infants. J. Appl. Physiol. 40: 352-356, 1976. 13. LYNNE-DAVIES, P., J. COUTURE, L. D. PENGELLY, D. WEST, P. R. BROMAGE, AND J. MILIC-EMILX. Partitioning of immediate ventilatory stability to added elastic loads in cats. J. Appl. Physiol, 30: 814-819, 1971. 14. MARLOT, D. Recherches SW Ze confrble Nerveux de la Respiration Chex Ze Chaton (doctoral thesis), Amiens, France: Facu& de Mkdecine, 1976. 15. MEAD, J. Control of respiratory frequency. J. Appl. PhysioE. 15: 325-336, 1960. 16. MILIC-EMILI, J , , AND M. M. GRUNSTEIN. Drive and timing components of ventilation. Chest 70, Suppl.: 131-133, 1976. 17. MISEROCCHI, G., AND J. MILDEMILL. Effect of mechanical factors on the relation between rate and depth of breathing in
WYSZOGRODSKI,
THACH,
AND
MILIC-EMIL1
cats. J. AppZ. Physiol. 41: 277-284, 1976. 18. PENGELLY, L. D., A. M. ALDERSON, AND J. MJLIC-EMILI. Mechanics of the diaphragm, J. AppZ. Physiol. 30: 797-805, 1971. 19. PHILLIPSON, E. A. Vagal control of breathing pattern independent of lung inflation in conscious dogs. J. AppZ. Physiol. 37: 183-189, 1974. 20. REMMERS, J. E. Inhibition of inspiratory activity by intercostal muscle afferents. Respiration Physiol. 10: 358-383, 1970. 21. SCHWIELER, G. H. Respiratory regulation during postnatal development in cats and rabbits and some of its morphological substrate. Acta Physiol. Stand. Suppl. 304: 1-123, 1968. 22, STERMAN, M. B., AND T. HOPPENBROUWERS. The development of sleep-waking and rest-activity patterns from fetus to adult in man, In: Brain Development and Behavior, edited by M. B. Sterman, D, J. McGinty, and A. M. Adinolfi. New York: Academic, 1971, p. 203-227. 23. TAEUSCH, H. W., JR., S. CARSON, I. D. FRANTZ, AND J. MILICEMILI. Respiratory regulation after elastic loading and CO, rebreathing in normal term infants. J. Pediat, 88: 102-111, 1976. 24. THACH, B. T., I. WYSZOGRODSKI, AND J. MILK-EMILI. Effect of ether on control of rate and depth of breathing in newborn rabbits. J, AppZ. Physiol, 40: 281-286, 1976. 25. WHITELAW, W. A., J.-P. DERENNE, AND J. MILIC-EMILI. Occlusion pressure as a measure of respiratory center output in conscious man. Respiration Physiol. 23: 181-199, 1975. 26. YOUNES, M., S. ISCOE, AND J. MILK-EMILI. A method for the assessment of phasic vagal influence on tidal volume. J. Appl. Physiol. 38: 335-343, 1975.
Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (137.154.019.149) on January 12, 2019.
