Effects of inhaled oxygen (up to 40%) on periodic breathing and apnea in preterm infants ZALMAN WEINTRAUB, RUBEN AND HENRIQUE RIGATTO Department
of Pediatrics,
ALVARO,
The University
of Manitoba,
WEINTRAUB, ZALMAN, RUBEN ALVARO, KIM KWIATKOWSKI,DON CATES,AND HENRIQUERIGATTO. Effects of inhaled oxygen (up to 40%) on periodic breathing and apnea in preterm irzfants. J. Appl. Physiol. 72(l): 126-120,1992.-To discover whether increasesin inhaled 0, fraction (FIEF; up Fo40%) decreaseapneavia an increasein minute ventilation (VE) or a
changein respiratory pattern, 15 preterm infants (birth weight 1,300 t 354 g, gestational age 29 t 2 wk, postnatal age 20 t 9 days) breathed 21, 25, 30, 35, and 40% 0, for 10 min in quiet sleep. A nosepieceand a flow-through system were used to measureventilation. Alveolar Pcoz , transcutaneous PO,, and sleepstateswere alsoassessed. All infants had periodic breathing with apneas23 s. With an increase in FI,, breathing becamemore regular and apneasdecreased(P < 0.001). This regularization in breathing was not associatedwith significant changesin TE. However, the variability of VE, tidal volume, and expiratory and inspiratory times decreasedsignificantly. The results indicate that the more regular breathing observed with small increasesin FIEF was not associatedwith significant changesin ventilation. The findings suggestthat the increased oxygenation decreasesapnea and periodicity in preterm infants, not via an increasein ventilation, but through a decrease in breath-to-breath variability of 9~. hyperoxia; newborn infant; respiration; minute ventilation; alveolar gases
PERIODIC BREATHING AND APNEA are common in preterm infants, yet the physiological mechanisms are poorly understood (9, 12, 13, 15). Previous studies have shown that inhalation of 100% 0, abolishes periodic breathing, and this is associated with an increase in minute ventilation (VE; Refs. 2, 5, 12). Conversely, clinical observations have indicated that apnea of prematurity can be treated with a slight increase in inspired 0, fraction (FI,,), usually to -25-30% (7, 13). It is somewhat surprising that, although previous studies have addressed the changes in respiration induced by 100% 0,, only three have examined the effects of a modest increase in 0, (2,512). Because the increase in ventilation in response to 100% 0, in these infants is small, -15%, we thought that a small increase in FI,, might not change respiration via an increase in VE. Therefore we designed this study to test the hypothesis that a stepwise increase in FI,, up to 4O%, would reduce periodic breathing and apnea in preterm infants not by increasing VE but by changing respiratory pattern. 116
KIM
KWIATKOWSKI,
DON
Winnipeg,
R3E OL8, Canada
Manitoba
CATES,
METHODS Subjects. The study population consisted of 15 premature infants, gestational age 29 t 2 (SD) wk, birth weight 1,300 t 354 g, postconceptional age 36 t 6 wk, postnatal age 20 t 9 days, and study weight 1,390 t 385 g. All infants were receiving oral theophylline for apnea; serum levels before the study were within therapeutic levels. The infants were breathing room air and were considered healthy at the time of the study. The study was approved by the Faculty Committee for the Use of Human Subjects in Research at the University of Manitoba. A parental written consent was obtained. d&hods. We measured VE, respiratory frequency (f), tidal volume (VT), inspiratory time (TI), expiratory time (TE), alveolar PCO, (PA& and PO, ( PA~J, electroencephalogram (EEG), electrooculogram (EOG), chest and abdominal movements, diaphragmatic EMG (EMGdi), transcutaneous PO, (Ptco,), 0, saturation (HbO,), and electrocardiogram (ECG). The system used to measure ventilation and alveolar gases has been described previously (6, 12, 14). Briefly, it consisted of a flowmeter and a monel screen. A background flow (2.7 l/min) was used and balanced to an artificial zero. The infant breathed through nostril adaptors and added (expiration) or subtracted (inspiration) flow from the background flow. The flow signal was integrated to give volume. The screen flowmeter was linear up to 6 l/min. The resistance of the system was low (0.1 cmH,O l 1-l min-l). The frequency response of the system varied ~5% from 18 to 120 cycles per minute with volumes of 5-30 ml. A 75-cm-long catheter (PE-20, Clay Adams, New York, NY) was used to sample the inspired and expired gases. A vacuum pump (Duo Seal, catalog no+ 1400, Welch Scientific, 7300) drew gas through the CO, and Beckman 0, analyzers at a rate such that the 95% response time was 0.14 and 0.18 s for each of the analyzers, respectively. Condensation of water vapor in the screen or catheter was absent or minimal because of the high ambient temperature and the background flow of dry gas, making heating unnecessary. EEG, EOG, chest and abdominal displacements, EMGdi, Ptco, HbO,, and ECG were measured as described previously (8). ECGs were used as indexes of infant well-being and not as end point of this study. A representative tracing is shown in Fig. 1, Procedure. Infants were studied on the Ohio neonatal intensive care unit (Ohio Medical Instruments, Madison, l
0161-7567/92 $2.00 Copyright 0 1992 the AmericanPhysiological Society
Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (129.186.138.035) on January 14, 2019.
INCREASED INHALED
0, AND RESPIRATORY
beats
250
/ min
0
1
VOLUME FLOW L / min
1
co2
%
02
3 ii+--
Cl2SATURATION % CHEST MOVEMENT ABDOMINAL MOVEMENT
10 a3 )c-10
5 cm
RESULTS
seed
IIOcmb
Jw
r
/W
EEG LEFT RlGHT
EYE EYE
EMGdi
100 Nf--
\
IOO A.&.40
JJV
~-+-wup
-m
I
FIG. 1. Representative tracing of a preterm infant breathing periodically and studied at 27 days of age, 1,450 g. EMGdi, diaphragmatic EMG.
WI) in a neutral thermal environment (skin abdominal temperature 36.5 t 0.003”C). After placement of the nosepiece and the various electrodes, and after the infants were fed, they were allowed to initiate sleep while breathing room air. Thereafter, they inhaled 21,25,30,35, and 40% 0, for 10 min each. The order of the various gas trials was randomized only in the initial experiments. Because it did not appear to affect the results, the order used in subsequent studies was from 21 to 40%. Data collection artd unalysis. The last 5 min of each 0, concentration were analyzed for the duration and rate of apnea. The last 3 min were used for calculation of VE, f, and VT; and the last 50 breaths were analyzed for TI, TE, PAC029 and PAO~. EEG and EOG were used to measure sleep states (10). Measurements were made primarily in quiet sleep except for rare occasions when this was techTABLE 1. Respiratory
measurements
21
128.0 217.4
5.5 to.4
0.180 to.014
25
62.5” t8.2
5.0 to.3
29.1*
t7.8
3.6* to.6
5O.P t25.1 24.0* k6.6
30 35 40
DISCUSSION
We found that premature infants with periodic breathing and short apneas responded to a stepwise increase in Frq2 (up to 40%) by regularizing their breathing. The regularlzation of breathing was not associated with a significant change in VE, but it was related to a decrease in breath-to-breath variability in VE. This, in turn, was due to a decreased variability in VT, TI, and TE. These findings suggest that 0, facilitates the appearance of regular breathing independent of an increase in VE. The intrinsic mechanism(s) responsible for this facilitation remains unknown. Regularization of breathing in preterm infants has in preterm
infants
Apnea Length,
029 %
An increase in FI,, was associated with increased PA*, , Pcto,, and HbO, (Table 1). This increase in oxygenation induced a decrease in all types of apneas and a regularization of breathing pattern (Figs. 2-4). Most of the reduction in apnea occurred between 21 and 30% 0,. The mean values of VE, VT, f, TI, TE, and PA,,, did not change significantly with 0, concentrations (Table 1, Fig. 5). Because the mean values of the various respiratory variables did not change when there was obvious change in respiratory pattern, we elected to measure the variances {V = [z (ri - x)“]l(n - l)} of these variables. The variance of VE decreased significantly as inspired FI,, concentration increased (Fig. 6). The decreased variance of irE was, in turn, related to a decrease in the variance of VT, TI, and TE.
at various inspired O2 concentrations
Apnea Rate, no./h
Inspired
117
IN THE NEWBORN
nically inadequate. For the purpose of this study, apneas were defined as pauses of 23 s. They were considered central if flow and respiratory efforts (chest movements and EMGdi) were absent, obstructive if flow was absent but respiratory efforts were present, and mixed if they had components of central and obstructive apneas. The significance of the differences among values obtained in the various FI~~‘s was assessed by repeated analysis of variance measurements and Fisher’s least significant difference test. Values are expressed as means + SE. P s 0.05 was considered significant.
ECG HEART RATE
PATTERN
VE,
VT,
1 kg-’ 9min-’
ml/kg
TI, S
m, S
5.7 to.4
0.54 k-o.03
0.184 to.013
5.2 to.4
0.195
to.011
3.6* to.9 3.6* kO.7
S
PACO, 9
PAO, 9
ptco,
,
HbO,,
Torr
Torr
Torr
%
0.89 to.07
42.7 tl.6
75 t4
55.5 k3.5
90.8 tl.6
0.51 to.03
0.84 to.08
41.5 tl.7
103* t4
59.7 k4.5
92.5 k2.1
5.2 to.3
0.52 kO.02
0.91 kO.09
41.0 tl.6
146* t3
76.3* t5.2
96.6* kO.8
0.197 to.011
5.0 to.4
0.51 to.04
0.84 to.11
41.0 tl.2
190* +_5
79.7* t4.6
98.4* kO.6
0.209 to.016
5.5 Iko.4
0.51 to.03
1.00 kO.14
43.4 kl.6
238” a7
101.7* t8.0
99.8* to.2
l
Values are means t SE. VE, minute ventilation; VT, tidal volume; TI and TE, inspiratory and expiratory time, respectively; Pbo2, and PACT, alveolar PCO~ and PO,, respectively; Ptcoz, transcutaneous PO,; HbO,, 0, saturation. * P 5 0.05 in relation to 21% 0,. Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (129.186.138.035) on January 14, 2019.
118
INCREASED
0
21%
25%
INHALED
O2 AND RESPIRATORY
35%
30%
PATTERN
IN THE NEWBORN
40%
INSPIRED OXYGEN FIG. 2. Relationship between apnea (s/min) and inspired 0,. Apnea decreased with increased inspired O2 (P < 0.001). Lack of significance for changes in mixed apneas was probably related to their small number [*:P s 0.05 in relation to 21% 0, (central)].
been observed concomitantly with the administration of agents that increase ventilation, such as 100% 0,, CO,, and methylxanthines (2, 5, 12, 16). On the other hand, agents that depress ventilation, such as hypoxia and morphine, tend to be associated with periodic breathing and apnea. This led to the notion that anything that increases breathing would tend to make it regular (5, 13). Whether such regularization of breathing could be achieved in the absence of an increase in VE was unknown. That preterm infants with clinical apnea improve when FI,, is increased, even to such low levels as 25%, led us to doubt that such a small change in FI,,
cn a
6
I-
W z n
a
21%
co a
15OC
Y
25%
30%
35%
40%
25%
3Q%
35%
40%
-
21%
INSPIRED
OXYGEN
3. Relationship between length and number of apneas and inspired 0,. Both length and number of apneas decreased significantly with increased inspired 0, (*P < 0.001 and P < 0.04, respectively, in relation to 21% 0,). FIG.
35%02
-
FIG. 4. Representative tracing of respiratory flow in 1 preterm infant, age 16 days, 1,600 g. Note regularization of breathing pattern with increased inspired Oz.
would affect ventilation. The present study appears to confirm this, suggesting a significant facilitation and reorganization of breathing pattern in response to a small increase in FI,,. Fenner et al. (7) studied 30 premature infants who exhibited periodic breathing and apneas (mean duration 6.9 s) and in whom the FI,, was gradually increased until periodic breathing and apnea disappeared. They found no change in duration or number of apneas until a given “threshold” concentration was reached. We did not find such threshold, and the regularization of breathing was gradual in our infants, although we did not carefully examine the range between 21 and 30% 0,. The reason for this discrepancy is unclear, but differences in methodology may be relevant. It has been shown previously that periodic breathing and apnea could be induced by lowering the FI,, and that this was related to low arterial PO, (P a,,; Ref. 12). This breathing pattern could be regularized by administration of high 0, (5, 12,15). In both situations, however, the ventilation changed. It decreased with low 0, and increased with high 0,. Rigatto and Brady (12) also found that infants with periodic breathing and apneas could either hypo- or hyperventilate in relationship to regularly breathing infants, depending on the ratio between the ventilation and apneic intervals. If this ratio was ~2, the infants would tend to hypoventilate; if more, they would hyperventilate. Thus infants could either hypo- or hyperventilate, depending on the baseline respiratory pattern (3, 4, 12). In the present study, the apneas were short and the infants’ Ptc,, values were ~45 Torr. The less hypoxic baseline and the small increase in Pa,, might explain the lack of change in iTE in these infants. The results are compatible with the observations of Lee et al. (8), who showed that premature infants, studied until 56 wk of postconceptional age, re-
Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (129.186.138.035) on January 14, 2019.
INCREASED
INHALED
0, AND RESPIRATORY
their breathing patterns without a noticeable * VE and other ventilatory variables. In this longitudinal study, there was also a gradual increase in Pa,, with increased postconceptional age. Finally, the present results agree with conceptual work of Waggener et al. (18), who suggested that the amplitude of the baseline changes in ventilation appears to be crucial to determine the occurrence and duration of apnea in these infants. Although the intrinsic mechanism for a change in breathing pattern with a small increase in PO, is not known, we speculate that such action is mediated via neuromediators in the brain (11). An interesting analogy may be made with the fetal sheep, which is capable of switching from intermittent to continuous breathing if Pa,, is raised in the presence of umbilical cord occlusion but not if Paoz remains unchanged (1). If the increase in Pao, is substantial, to N250 Torr, continuous breathing can be established in the absence of cord occlusion. These observations lead us to hypothesize (1) that the low 0, in the fetus acts as an anesthetic agent, sedating and inhibiting the fetus, as has been suggested previously. Together, these observations suggest that an increase in Paoz greatly facilitates breathing, even if the increase is relatively small. In summary, we measured the change in ventilation
PATTERN
119
IN THE NEWBORN
gularized
change in
21%
25%
INSPIRED
30%
35%
40%
OXYGEN
FIG. 6. Breath-to-breath variance of minute ventilation (VE) plotted against inspired 0, concentration. Variance was measured as v = {[C(xi - $“]I(?2 - 1)}, where zi is individual measurement, x is mean, and n is number of observations. Note progressive decrease in variance with increased inspired 0, (*P < 0.001 in relation to 21% 0,).
and breathing pattern of preterm infants in response to an increase in FI,~ up to 40%. We found that the incidence of apnea d&eases and breathing becomes more regular without an increase in ventilation. The variance in-V~, VT, TI, and TE, however, became greatly reduced with 0,. The findings indicate a facilitating role for 0, on the regularization of breathing pattern in these infants. We thank Paula Baryluk-Raposo and Debbie Bialek for typing and helping in the preparation of the manuscript. This study was supported by grants from the Medical Research Council of Canada (NT-4980) and the Children’s Hospital of Winnipeg Research Foundation. 2. Weintraub was on sabbatical leave from the University of Haifa, Israel, sponsored by the Manitoba Lung Association This work was presented in part at the meeting of the Society for Pediatric Research, Anaheim, CA, May 7-11,199O. Address for reprint requests: H. Rigatto, Neonatal Research, WR125 Women’s Hospital, 735 Notre Dame Ave., Winnipeg, Manitoba R3E OL8, Canada. Received 6 August 1990; accepted in final form 17 August 1991.
50 40
REFERENCES
30
1. BAIER, R. CZYK, AND
J., S. U. HASAN, D. B. CATES, D. HOOPER, B. NOWAH. RIGATTO. Effects of various concentrations of O2 and umbilical cord occlusion on fetal breathing and behavior. J. Appl.
20
Physiol. 2. BRADY,
10 0
8
r
6c 4. 2-
FIG. 5. Minute ventilation and its components, tidal volume and frequency, did not change significantly with increased inspired 02. Values are means + SE.
68: 1597-1604,
1990.
J. P., E. C. COTTON, AND W. H. TOOLEY. Chemoreflexes in the newborn infant: effects of 100% oxygen on heart rate and ventilation. J. Physiol. Land. 172: 332-344, 1964. 3. CHERNICK, V., AND M. E. AVERY. Response to premature infants with periodic breathing to ventilatory stimuli. J. A&. Physiol. 21: 434-440,1966. 4. CHERNICK,
V., F. HELDRICH, AND M. E. AVERY. Periodic breathing of premature infants. J. Pediatr. 64: 330-340, 1964. 5. CROSS, K. W., AND T. E. OPPE. The effect of inhalation of high and low concentrations of oxygen on the respiration of the premature infant. J. Physiol. Land. 117: 38-55, 1952. 6. DAVI, M., K. SANKARAN, M. MACCALLUM, D. CATES, AND H. RIGATTO. Effect of sleep state on chest distortion and on the ventilatory response to COz in neonates. Pediatr. Res. 13: 982-986,1979. FENNER, A., U. SCHALK, H. HOENICKE, A. WENDENBURG, AND T. ROEHLING. Periodic breathing in premature and neonatal babies: incidence, breathing pattern, respiratory gas tensions, response to changes in the composition of ambient air. Pediatr. Res. 7: 174-183, 1973. LEE,
O., R. CACES, K. KWIATKOWSKI, D. CATES, AND H. RIGATTO. A developmental study on types and frequency distribution of
Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (129.186.138.035) on January 14, 2019.
120
INCREASED
INHALED
C& AND RESPIRATORY
short apneas (3 to 15 seconds) in term and preterm infants. Pediatr. Res. 22: 344-349, 1987. 9. MILLER, M. J., V. A. CARLO, J. M. DIFIORE, AND R. J. MARTIN. Airway obstruction during periodic breathing in premature infants. J. Appl. Physiol. 64: 2496-2500, 1988. 10. MORIETTE, G., P, VAN REEMPTS, M. MOORE, D. CATES, AND H. RIGATTO. The effect of rebreathing CO, on ventilation and diaphragmatic electromyography in newborn infants. Respir. Physiol. 62: 387-397,1985. 11. NEUBAUER, J.
of respiration
D., J. E. MELTON, AND N. H. EDELMAN. Modulation during brain hypoxia. J. Appl. Physiol. 68: 441-451,
1990.
12. RIGATTO, H., AND J. P. BRADY. Periodic breathing and apnea in the preterm infants. I. Evidence for hypoventilation possibly due to central respiratory depression. Pediatrics 50: 202-218, 1972. 13. RIGATTO, H. Apnea and periodic breathing. Semin. Perinatol. NY 1: 37%381,1977.
PATTERN
IN THE NEWBORN
H., AND J. P. BRADY. A new nosepiece for measuring in preterm infants. J. Appl. Physiol. 32: 423-424, 1972. 15. RIGATTO, H., J. P. BRADY, AND B. CHIR. Periodic breathing and apnea in preterm infants: Hypoxia as a primary event. Pediatrics
14. RIGATTO,
ventilation
50: 219-228,1972. 16. SHANNON, D, C., F. GOTAY, I. M. STEIN, TODRES, AND F. M. B. MOYLAN. Prevention
M. C. ROGERS, I, D. of apnea and bradycardia in low-birth weight infants. Pediatrics 55: 589-594, 1975. 17. SMITH, W. D. A. Developments in America in nitrous oxide anesthesia between world wars. Br. J. Anaesth. 44: 215-221, 1972. 18. WAGGENER, T. B., STARK, A. R., COHLAN, B. A., AND I. D. FRANTZ III. Apnea duration is related to ventilatory oscillation characteristics in newborn infants. J. Appl. Physiol. 7: 536-544, 1984. 19. WILSON, J. L., S. B. LONG, AND P. J. HOWARD. Respiration of premature infants: response to variations of oxygen and to increased carbon dioxide in inspired air. Am. J. Dis. Child. 63: lOtSO1085,1942.
Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (129.186.138.035) on January 14, 2019.
of Pediatrics,
ALVARO,
The University
of Manitoba,
WEINTRAUB, ZALMAN, RUBEN ALVARO, KIM KWIATKOWSKI,DON CATES,AND HENRIQUERIGATTO. Effects of inhaled oxygen (up to 40%) on periodic breathing and apnea in preterm irzfants. J. Appl. Physiol. 72(l): 126-120,1992.-To discover whether increasesin inhaled 0, fraction (FIEF; up Fo40%) decreaseapneavia an increasein minute ventilation (VE) or a
changein respiratory pattern, 15 preterm infants (birth weight 1,300 t 354 g, gestational age 29 t 2 wk, postnatal age 20 t 9 days) breathed 21, 25, 30, 35, and 40% 0, for 10 min in quiet sleep. A nosepieceand a flow-through system were used to measureventilation. Alveolar Pcoz , transcutaneous PO,, and sleepstateswere alsoassessed. All infants had periodic breathing with apneas23 s. With an increase in FI,, breathing becamemore regular and apneasdecreased(P < 0.001). This regularization in breathing was not associatedwith significant changesin TE. However, the variability of VE, tidal volume, and expiratory and inspiratory times decreasedsignificantly. The results indicate that the more regular breathing observed with small increasesin FIEF was not associatedwith significant changesin ventilation. The findings suggestthat the increased oxygenation decreasesapnea and periodicity in preterm infants, not via an increasein ventilation, but through a decrease in breath-to-breath variability of 9~. hyperoxia; newborn infant; respiration; minute ventilation; alveolar gases
PERIODIC BREATHING AND APNEA are common in preterm infants, yet the physiological mechanisms are poorly understood (9, 12, 13, 15). Previous studies have shown that inhalation of 100% 0, abolishes periodic breathing, and this is associated with an increase in minute ventilation (VE; Refs. 2, 5, 12). Conversely, clinical observations have indicated that apnea of prematurity can be treated with a slight increase in inspired 0, fraction (FI,,), usually to -25-30% (7, 13). It is somewhat surprising that, although previous studies have addressed the changes in respiration induced by 100% 0,, only three have examined the effects of a modest increase in 0, (2,512). Because the increase in ventilation in response to 100% 0, in these infants is small, -15%, we thought that a small increase in FI,, might not change respiration via an increase in VE. Therefore we designed this study to test the hypothesis that a stepwise increase in FI,, up to 4O%, would reduce periodic breathing and apnea in preterm infants not by increasing VE but by changing respiratory pattern. 116
KIM
KWIATKOWSKI,
DON
Winnipeg,
R3E OL8, Canada
Manitoba
CATES,
METHODS Subjects. The study population consisted of 15 premature infants, gestational age 29 t 2 (SD) wk, birth weight 1,300 t 354 g, postconceptional age 36 t 6 wk, postnatal age 20 t 9 days, and study weight 1,390 t 385 g. All infants were receiving oral theophylline for apnea; serum levels before the study were within therapeutic levels. The infants were breathing room air and were considered healthy at the time of the study. The study was approved by the Faculty Committee for the Use of Human Subjects in Research at the University of Manitoba. A parental written consent was obtained. d&hods. We measured VE, respiratory frequency (f), tidal volume (VT), inspiratory time (TI), expiratory time (TE), alveolar PCO, (PA& and PO, ( PA~J, electroencephalogram (EEG), electrooculogram (EOG), chest and abdominal movements, diaphragmatic EMG (EMGdi), transcutaneous PO, (Ptco,), 0, saturation (HbO,), and electrocardiogram (ECG). The system used to measure ventilation and alveolar gases has been described previously (6, 12, 14). Briefly, it consisted of a flowmeter and a monel screen. A background flow (2.7 l/min) was used and balanced to an artificial zero. The infant breathed through nostril adaptors and added (expiration) or subtracted (inspiration) flow from the background flow. The flow signal was integrated to give volume. The screen flowmeter was linear up to 6 l/min. The resistance of the system was low (0.1 cmH,O l 1-l min-l). The frequency response of the system varied ~5% from 18 to 120 cycles per minute with volumes of 5-30 ml. A 75-cm-long catheter (PE-20, Clay Adams, New York, NY) was used to sample the inspired and expired gases. A vacuum pump (Duo Seal, catalog no+ 1400, Welch Scientific, 7300) drew gas through the CO, and Beckman 0, analyzers at a rate such that the 95% response time was 0.14 and 0.18 s for each of the analyzers, respectively. Condensation of water vapor in the screen or catheter was absent or minimal because of the high ambient temperature and the background flow of dry gas, making heating unnecessary. EEG, EOG, chest and abdominal displacements, EMGdi, Ptco, HbO,, and ECG were measured as described previously (8). ECGs were used as indexes of infant well-being and not as end point of this study. A representative tracing is shown in Fig. 1, Procedure. Infants were studied on the Ohio neonatal intensive care unit (Ohio Medical Instruments, Madison, l
0161-7567/92 $2.00 Copyright 0 1992 the AmericanPhysiological Society
Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (129.186.138.035) on January 14, 2019.
INCREASED INHALED
0, AND RESPIRATORY
beats
250
/ min
0
1
VOLUME FLOW L / min
1
co2
%
02
3 ii+--
Cl2SATURATION % CHEST MOVEMENT ABDOMINAL MOVEMENT
10 a3 )c-10
5 cm
RESULTS
seed
IIOcmb
Jw
r
/W
EEG LEFT RlGHT
EYE EYE
EMGdi
100 Nf--
\
IOO A.&.40
JJV
~-+-wup
-m
I
FIG. 1. Representative tracing of a preterm infant breathing periodically and studied at 27 days of age, 1,450 g. EMGdi, diaphragmatic EMG.
WI) in a neutral thermal environment (skin abdominal temperature 36.5 t 0.003”C). After placement of the nosepiece and the various electrodes, and after the infants were fed, they were allowed to initiate sleep while breathing room air. Thereafter, they inhaled 21,25,30,35, and 40% 0, for 10 min each. The order of the various gas trials was randomized only in the initial experiments. Because it did not appear to affect the results, the order used in subsequent studies was from 21 to 40%. Data collection artd unalysis. The last 5 min of each 0, concentration were analyzed for the duration and rate of apnea. The last 3 min were used for calculation of VE, f, and VT; and the last 50 breaths were analyzed for TI, TE, PAC029 and PAO~. EEG and EOG were used to measure sleep states (10). Measurements were made primarily in quiet sleep except for rare occasions when this was techTABLE 1. Respiratory
measurements
21
128.0 217.4
5.5 to.4
0.180 to.014
25
62.5” t8.2
5.0 to.3
29.1*
t7.8
3.6* to.6
5O.P t25.1 24.0* k6.6
30 35 40
DISCUSSION
We found that premature infants with periodic breathing and short apneas responded to a stepwise increase in Frq2 (up to 40%) by regularizing their breathing. The regularlzation of breathing was not associated with a significant change in VE, but it was related to a decrease in breath-to-breath variability in VE. This, in turn, was due to a decreased variability in VT, TI, and TE. These findings suggest that 0, facilitates the appearance of regular breathing independent of an increase in VE. The intrinsic mechanism(s) responsible for this facilitation remains unknown. Regularization of breathing in preterm infants has in preterm
infants
Apnea Length,
029 %
An increase in FI,, was associated with increased PA*, , Pcto,, and HbO, (Table 1). This increase in oxygenation induced a decrease in all types of apneas and a regularization of breathing pattern (Figs. 2-4). Most of the reduction in apnea occurred between 21 and 30% 0,. The mean values of VE, VT, f, TI, TE, and PA,,, did not change significantly with 0, concentrations (Table 1, Fig. 5). Because the mean values of the various respiratory variables did not change when there was obvious change in respiratory pattern, we elected to measure the variances {V = [z (ri - x)“]l(n - l)} of these variables. The variance of VE decreased significantly as inspired FI,, concentration increased (Fig. 6). The decreased variance of irE was, in turn, related to a decrease in the variance of VT, TI, and TE.
at various inspired O2 concentrations
Apnea Rate, no./h
Inspired
117
IN THE NEWBORN
nically inadequate. For the purpose of this study, apneas were defined as pauses of 23 s. They were considered central if flow and respiratory efforts (chest movements and EMGdi) were absent, obstructive if flow was absent but respiratory efforts were present, and mixed if they had components of central and obstructive apneas. The significance of the differences among values obtained in the various FI~~‘s was assessed by repeated analysis of variance measurements and Fisher’s least significant difference test. Values are expressed as means + SE. P s 0.05 was considered significant.
ECG HEART RATE
PATTERN
VE,
VT,
1 kg-’ 9min-’
ml/kg
TI, S
m, S
5.7 to.4
0.54 k-o.03
0.184 to.013
5.2 to.4
0.195
to.011
3.6* to.9 3.6* kO.7
S
PACO, 9
PAO, 9
ptco,
,
HbO,,
Torr
Torr
Torr
%
0.89 to.07
42.7 tl.6
75 t4
55.5 k3.5
90.8 tl.6
0.51 to.03
0.84 to.08
41.5 tl.7
103* t4
59.7 k4.5
92.5 k2.1
5.2 to.3
0.52 kO.02
0.91 kO.09
41.0 tl.6
146* t3
76.3* t5.2
96.6* kO.8
0.197 to.011
5.0 to.4
0.51 to.04
0.84 to.11
41.0 tl.2
190* +_5
79.7* t4.6
98.4* kO.6
0.209 to.016
5.5 Iko.4
0.51 to.03
1.00 kO.14
43.4 kl.6
238” a7
101.7* t8.0
99.8* to.2
l
Values are means t SE. VE, minute ventilation; VT, tidal volume; TI and TE, inspiratory and expiratory time, respectively; Pbo2, and PACT, alveolar PCO~ and PO,, respectively; Ptcoz, transcutaneous PO,; HbO,, 0, saturation. * P 5 0.05 in relation to 21% 0,. Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (129.186.138.035) on January 14, 2019.
118
INCREASED
0
21%
25%
INHALED
O2 AND RESPIRATORY
35%
30%
PATTERN
IN THE NEWBORN
40%
INSPIRED OXYGEN FIG. 2. Relationship between apnea (s/min) and inspired 0,. Apnea decreased with increased inspired O2 (P < 0.001). Lack of significance for changes in mixed apneas was probably related to their small number [*:P s 0.05 in relation to 21% 0, (central)].
been observed concomitantly with the administration of agents that increase ventilation, such as 100% 0,, CO,, and methylxanthines (2, 5, 12, 16). On the other hand, agents that depress ventilation, such as hypoxia and morphine, tend to be associated with periodic breathing and apnea. This led to the notion that anything that increases breathing would tend to make it regular (5, 13). Whether such regularization of breathing could be achieved in the absence of an increase in VE was unknown. That preterm infants with clinical apnea improve when FI,, is increased, even to such low levels as 25%, led us to doubt that such a small change in FI,,
cn a
6
I-
W z n
a
21%
co a
15OC
Y
25%
30%
35%
40%
25%
3Q%
35%
40%
-
21%
INSPIRED
OXYGEN
3. Relationship between length and number of apneas and inspired 0,. Both length and number of apneas decreased significantly with increased inspired 0, (*P < 0.001 and P < 0.04, respectively, in relation to 21% 0,). FIG.
35%02
-
FIG. 4. Representative tracing of respiratory flow in 1 preterm infant, age 16 days, 1,600 g. Note regularization of breathing pattern with increased inspired Oz.
would affect ventilation. The present study appears to confirm this, suggesting a significant facilitation and reorganization of breathing pattern in response to a small increase in FI,,. Fenner et al. (7) studied 30 premature infants who exhibited periodic breathing and apneas (mean duration 6.9 s) and in whom the FI,, was gradually increased until periodic breathing and apnea disappeared. They found no change in duration or number of apneas until a given “threshold” concentration was reached. We did not find such threshold, and the regularization of breathing was gradual in our infants, although we did not carefully examine the range between 21 and 30% 0,. The reason for this discrepancy is unclear, but differences in methodology may be relevant. It has been shown previously that periodic breathing and apnea could be induced by lowering the FI,, and that this was related to low arterial PO, (P a,,; Ref. 12). This breathing pattern could be regularized by administration of high 0, (5, 12,15). In both situations, however, the ventilation changed. It decreased with low 0, and increased with high 0,. Rigatto and Brady (12) also found that infants with periodic breathing and apneas could either hypo- or hyperventilate in relationship to regularly breathing infants, depending on the ratio between the ventilation and apneic intervals. If this ratio was ~2, the infants would tend to hypoventilate; if more, they would hyperventilate. Thus infants could either hypo- or hyperventilate, depending on the baseline respiratory pattern (3, 4, 12). In the present study, the apneas were short and the infants’ Ptc,, values were ~45 Torr. The less hypoxic baseline and the small increase in Pa,, might explain the lack of change in iTE in these infants. The results are compatible with the observations of Lee et al. (8), who showed that premature infants, studied until 56 wk of postconceptional age, re-
Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (129.186.138.035) on January 14, 2019.
INCREASED
INHALED
0, AND RESPIRATORY
their breathing patterns without a noticeable * VE and other ventilatory variables. In this longitudinal study, there was also a gradual increase in Pa,, with increased postconceptional age. Finally, the present results agree with conceptual work of Waggener et al. (18), who suggested that the amplitude of the baseline changes in ventilation appears to be crucial to determine the occurrence and duration of apnea in these infants. Although the intrinsic mechanism for a change in breathing pattern with a small increase in PO, is not known, we speculate that such action is mediated via neuromediators in the brain (11). An interesting analogy may be made with the fetal sheep, which is capable of switching from intermittent to continuous breathing if Pa,, is raised in the presence of umbilical cord occlusion but not if Paoz remains unchanged (1). If the increase in Pao, is substantial, to N250 Torr, continuous breathing can be established in the absence of cord occlusion. These observations lead us to hypothesize (1) that the low 0, in the fetus acts as an anesthetic agent, sedating and inhibiting the fetus, as has been suggested previously. Together, these observations suggest that an increase in Paoz greatly facilitates breathing, even if the increase is relatively small. In summary, we measured the change in ventilation
PATTERN
119
IN THE NEWBORN
gularized
change in
21%
25%
INSPIRED
30%
35%
40%
OXYGEN
FIG. 6. Breath-to-breath variance of minute ventilation (VE) plotted against inspired 0, concentration. Variance was measured as v = {[C(xi - $“]I(?2 - 1)}, where zi is individual measurement, x is mean, and n is number of observations. Note progressive decrease in variance with increased inspired 0, (*P < 0.001 in relation to 21% 0,).
and breathing pattern of preterm infants in response to an increase in FI,~ up to 40%. We found that the incidence of apnea d&eases and breathing becomes more regular without an increase in ventilation. The variance in-V~, VT, TI, and TE, however, became greatly reduced with 0,. The findings indicate a facilitating role for 0, on the regularization of breathing pattern in these infants. We thank Paula Baryluk-Raposo and Debbie Bialek for typing and helping in the preparation of the manuscript. This study was supported by grants from the Medical Research Council of Canada (NT-4980) and the Children’s Hospital of Winnipeg Research Foundation. 2. Weintraub was on sabbatical leave from the University of Haifa, Israel, sponsored by the Manitoba Lung Association This work was presented in part at the meeting of the Society for Pediatric Research, Anaheim, CA, May 7-11,199O. Address for reprint requests: H. Rigatto, Neonatal Research, WR125 Women’s Hospital, 735 Notre Dame Ave., Winnipeg, Manitoba R3E OL8, Canada. Received 6 August 1990; accepted in final form 17 August 1991.
50 40
REFERENCES
30
1. BAIER, R. CZYK, AND
J., S. U. HASAN, D. B. CATES, D. HOOPER, B. NOWAH. RIGATTO. Effects of various concentrations of O2 and umbilical cord occlusion on fetal breathing and behavior. J. Appl.
20
Physiol. 2. BRADY,
10 0
8
r
6c 4. 2-
FIG. 5. Minute ventilation and its components, tidal volume and frequency, did not change significantly with increased inspired 02. Values are means + SE.
68: 1597-1604,
1990.
J. P., E. C. COTTON, AND W. H. TOOLEY. Chemoreflexes in the newborn infant: effects of 100% oxygen on heart rate and ventilation. J. Physiol. Land. 172: 332-344, 1964. 3. CHERNICK, V., AND M. E. AVERY. Response to premature infants with periodic breathing to ventilatory stimuli. J. A&. Physiol. 21: 434-440,1966. 4. CHERNICK,
V., F. HELDRICH, AND M. E. AVERY. Periodic breathing of premature infants. J. Pediatr. 64: 330-340, 1964. 5. CROSS, K. W., AND T. E. OPPE. The effect of inhalation of high and low concentrations of oxygen on the respiration of the premature infant. J. Physiol. Land. 117: 38-55, 1952. 6. DAVI, M., K. SANKARAN, M. MACCALLUM, D. CATES, AND H. RIGATTO. Effect of sleep state on chest distortion and on the ventilatory response to COz in neonates. Pediatr. Res. 13: 982-986,1979. FENNER, A., U. SCHALK, H. HOENICKE, A. WENDENBURG, AND T. ROEHLING. Periodic breathing in premature and neonatal babies: incidence, breathing pattern, respiratory gas tensions, response to changes in the composition of ambient air. Pediatr. Res. 7: 174-183, 1973. LEE,
O., R. CACES, K. KWIATKOWSKI, D. CATES, AND H. RIGATTO. A developmental study on types and frequency distribution of
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INCREASED
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C& AND RESPIRATORY
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D., J. E. MELTON, AND N. H. EDELMAN. Modulation during brain hypoxia. J. Appl. Physiol. 68: 441-451,
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H., AND J. P. BRADY. A new nosepiece for measuring in preterm infants. J. Appl. Physiol. 32: 423-424, 1972. 15. RIGATTO, H., J. P. BRADY, AND B. CHIR. Periodic breathing and apnea in preterm infants: Hypoxia as a primary event. Pediatrics
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