Chemoreceptor
Reflexes
in Preterm
Infants:
II. The
Effect
of Gestational
and Postnatal
Age on the
Venti-latory
Response
to Inhaled
Carbon
Dioxide
Henrique Rigatto, M.D., June P. Brady, M.B., B.Chir., and Rafael de Ia Torre Verduzco, M.D.
From the Deparl,nent of Pediatrics, University of Manitoba, Winnipeg Canada, and the Department of Pediatrics and the Cardiovascular Research Institute, University of California, San Francisco
ABSTRACT. We studied nine “healthy” preterm infants (birthweight, 1,000 to 2,000 gm) 58 times during postnatal life to define the effects of gestational and postnatal age on the ventilatory response to carbon dioxide. The infants were given air and 2% and 4% carbon dioxide in air to breathe for five minutes each. We determined respiratory minute and tidal volumes, frequency, heart rate, and alveolar Pco2 and Po2. We measured ventilation with a nosepiece and a screen flowmeter, using a constant flow-through to eliminate valves and reduce dead space. Analyses were made during the fifth minute while the baby breathed the various gas mixtures. The slope of the carbon dioxide response increased 42% from 32 to 37 weeks gestation (P < .05) and 62% from 2 to 27 days of age (P < .025). However, the intercept at .3 liter/mm/kg was the same at different gestational ages, but significantly greater at 2 compared with 27 days of age (P < .05). We suggest that the unresponsiveness with increasing prema-turity is primarily central and that after birth is primarily dependent on the mechanical abnormalities of the lung.
Pediatrics, 55:614, 1975, CARBON DIOXIDE RESPONSE, RE5PIRA-TION, PREMATURE INFANTS, APNEA, GESTATIONAL AND POST-NATAL AGE.
periodically were less mature and had a relative insensitivity to carbon dioxide, manifested by their higher resting arterial Pco2 and shift of the carbon dioxide response curve to the right of that observed in infants breathing regularly.3 There-fore, we decided to reexamine our data to look at the effects of gestational and postnatal age on the
ventilatory response to carbon dioxide.
SUBJECTS
AND METHODS
Subjects
In a previous study we measured the ventila-tory response to inhaled carbon dioxide in 20 preterm infants from 5 to 34 days of age,3 but we did not analyze the effects of gestational or postnatal ages on this response. We have, there-fore, reanalyzed our studies from birth to 30 days
The effects of gestational and postnatal age on the ventilatory response of preterm infants to inhaled carbon dioxide are unknown.’3 They may be important to our understanding of why preterm infants breathe periodically and have prolonged apnea. A decreased sensitivity to carbon dioxide with decreasing gestational age would support the hypothesis that respiratory depression is an underlying mechanism. In a previous study we found that infants breathing
(Received July 22; revision accepted for publication October 14, 1974.)
Supported by Public Health Service grant HD04067, MRC
of Canada grant MA-4980, the Winnipeg Children’s Hospital Research Foundation, Inc., the American Thoracic Society, and the Bay Area Heart Association.
Read in part before the Canadian Society for Clinical Investigation, Montreal, Quebec, January 1974.
- ,...--
-55O---- -;--- :
#{149}
.
500-“A
COmm Hg
A N2
mm HgHEART
RATE
VOLUME ml
AIR
O- L 2%CO 4% CO2
=
:±1
FIG. 1. Representative tracing (baby Mi, second study) breathing air and 2% and 4% carbon dioxide in air. Alveolar nitrogen was used to calculate alveolar Po2.3 Note progressive increase in ventilation with increasing carbon dioxide.
+H+H+fH+H+ffH+1+f1+ffH1+1+H-H+H+-1+fH41+HH+H+H*k+H+H+f+1ftH+f
of life, excluding those in which values for
respi-ratory minute volume were not obtained at three
levels of alveolar carbon dioxide. We also omitted infants with less than four serial studies. This report concerns the data on nine “healthy” preterm infants studied on four to nine occasions each (58 studies). A representative tracing is shown in Figure 1.
Methods
The methods were described3 and will be presented briefly.
The transit time to the carbon dioxide analyzer was 0.16 seconds and the 95% rise time was 0.15 seconds. We calibrated the carbon dioxide
analyzer with gases of known concentration of carbon dioxide in air. Drift of the meter was negligible.
#{176}Theclinical data on these nine infants are listed in the preceding paper (see Table I, 100% oxygen).4 The number of studies were 8, 5, 7, 6, 6, 6, 4, 9, and 7 respectively.
Capillary blood was used to calculate
bicar-bonate levels.3
Procedure
The study was explained to the mother and her written consent was obtained. The infant was kept in an incubator (abdominal skin temperature
= 36.2 ± 0.02 C). We gave the infant air and 2%
and 4% carbon dioxide in air for five minutes each. The infants tolerated the procedure well, but tended to be more restless with 4% carbon dioxide in air.
Analysis
We made almost all measurements during the fifth minute while the baby breathed air and 2% and 4% carbon dioxide in air; for technical reasons, in a few studies the fourth minute was used instead. The maximal ventilatory response was always achieved by three minutes.
TABLE I
PHYSIOLOGICAL RESPONsES’ TO INHALATION OF 2% AND 4% CARBON DIOXIDE IN PRETERM INFANTS WITH GE5TATLONAL AGE
Gestational
Insp ired Carbon Dioxide
0.04%
Variables Age (wk) (Air, Control) 2% 4%
Respiratory minute volume (liter/mm/kg)
32 .244 ± .012 .322 ± .020t .418 ± .01St 37 .236 ± .012 .324 ± .022t .470 ± .024t Tidal volume
(mi/kg)
32 6.8 ± .5 7.7 ± .3 9.5 ± 0.7t
37 6.7 ± .6 8.8 ± 1.0 10.9 ± 0.9t Respiratory frequency
(breaths/mm)
32 36 ± 3 42 ± 3 44 ± 2t
37 35 ± 3 37 ± 3 43 ± 3t
Heart rate
(beats/mm)
32 146 ± 6 148 ± 6t 150 ± 6
37 158 ± 7 157 ± 6 161 ± 6t
Actual bicarbonate
(mEg/liter)
32 21 ± 1
37 21 ± 1
Carbon dioxide response
curve Slope
(liter/mm/kg/mm Hg)
32 .024 ± .004
37 .034 ± .004
Intercept
(PC02 mm Hg)
32 39 ± 1
37 41 ± 2
#{176}Values are mean ± standard error.
tP< .05 in relation to control (air).
P <.05 in relation to 37 weeks.
while the infant was breathing air and 2% and 4% carbon dioxide. The intercept was calculated at .3 liter/mm/kg, a value crossing 98% of the slopes.
We analyzed the data as previously described.3 For changes with gestational age we compared values at 32 ± .4 (mean ± SE) with those at
37 ± .3 weeks, according to postnatal age. For changes with postnatal age we compared values at 2 ± .4,5 ± .8, 10 ±
.9, 16
± 2, 19 ± 1, and 27 ± .8 days.RESULTS
Tables I and II show the values obtained in 58 studies. The slope increased 42% from 32 to 37 weeks of gestation (P < .05) and 62% from 2 to 27
days of postnatal life (P < .05) (Fig. 2). However, the intercept at .3 liter/mm/kg was the same at different gestational ages, but significantly great-er at 2 compared with 27 days of age (P < .05).
Neither the intercepts nor the slopes varied at other postnatal ages. The bicarbonate level breathing air did not change with gestational or postnatal age (P > .2). The increase in ventilation was due to a significant increase in tidal volume
(P < .001) with minimal change in frequency
(Fig. 3 and 4). The increase in heart rate with 4% carbon dioxide was unaffected by gestational or postnatal age.
DISCUSSION
We found that the sensitivity of the respiratory system to inhaled carbon dioxide increases with gestational age-the mean slope of the carbon dioxide response curve increasing from 0.024 liter/min/kg/mm Hg at 32 weeks to 0.034 liter! min!kg!mm Hg alveolar Pco2 at 37 weeks
(P < .05). The position of the carbon dioxide response curve determined by the intercept at respiratory minute volume = .3 liter!min!kg did
not change. This position is primarily a function of arterial and spinal fluid bicarbonate levels. The absence of change in position of the curve corre-lated well with the absence of change in arterial-ized bicarbonate levels.
We also found a low respiratory sensitivity to carbon dioxide during the first few days of life-the mean slope of the carbon dioxide response curve being 0.024 at 2 days, compared
VE
L/min/Kg .3O
37 WEEKS 32 WEEKS
.1
,27 DAYS 2 DAYS
10 50 3 40
PACO2 mm Hg
37 WEEKS
32 WEEKS
12
-TIDAL VOLUME
mi/Kg
RESPIRATORY
FREQUENCY
breaths/mm
AIR
2%
CO2
4%
AIR
2%
C02 CO2
4%
C02
.500 A
FIG. 2. The ventilatory sensitivity to inhaled carbon dioxide increases with increasing gestational
age (A) and increasing postnatal age (B).
.500’
VE
L/min/Kg
.300
.100-
8-
4-60
GESTATIONAL
AGE
FIG. 3. The increased ventilatory response to inhaled carbon dioxide with increasing gestational
.500
2
DAYS
27
DAYS
L/min/Kg
VE
.0
‘100
12
TIDAL
VOLUME
8-mi/Kg
4.
RESPIRATORY
1
FREQUENCY
4401:
breaths/mm
I 1 1 I_ I I
AIR
2%
4%
AIR
2%
4%
CO2 CO2 C02
C02
POSTNATAL
AGE
FIG. 4. The increased ventilatory response to inhaled carbon dioxide with increasing postnatal
age is mostly due to an increase in tidal volume with little change in respiratory frequency.
TABLE II
PHYSIOLOGICAL RESPON5ES TO INHALATION OF 2% AND 4% CuisoN DIOxIDE IN PRETERM INFANTS WITH POSTNATAL ACE
Inspired Carbon Dioxide
Postnatal -
-Age 0.04%
Variables (Days) (Air, Control) 2% 4%
Respiratory minute
volume
(liter/mm/kg)
2 .179 ± .019 .240 ± .042 .328 ± .043t 5 .222 ± .019 .298 ± .033t .391 ± .029t 10 .231 ± .013 .316 ± .023t .426 ± .028t 14 .271 ± .015 .342 ± .026t .429 ± .026t 19 .284 ± .026 .352 ± .031t .477 ± .029t
27 .289 ± .020 .354 ± .028t .424 ± .027t
Tidal volume (mi/kg)
2 4.7 ± .5 6.2 ± .8t 8.4 ± .6t
5 5.8 ± .5 8.1 ± .51- 10.0 ± .7t
10 6.6 ± .6 9.0 ± .6t 10.9 ± 1.Ot
14 6.5 ± .5 8.0 ± .5t 9.3 ± .5t
19 6.6 ± .7 8.6 ± .7t 10.1 ± .8t
TABLE II (CownNuD)
2 38±3 39±3 39±3
S 38±3 37±3 39±3
Respiratory
frequency 10 35 ± 3 35 ± 3 39 ± 2
(breaths/mm) 14 42 ± 5 43 ± 3 46 ± 3
19 43±6 41±5 47±4
27 46±4 48±4 59±3t
Heart rate (beats/mm)
2 141±5 142±4 146±4t
5 143±3 146±3t 146±3
10 142±5 144±4 145±4
-14 154 ± 5 158 ± St 156 ± 4
19 154±5 152±5 153±5
27 162±3 160±4 160±4
Actual bicarbonate (mEq/liter)
2 21±1
-5 20±1 -
-10 20 ± 1
14 . 18 ± 1
-19 20±1 -
-27 20±1 -
-Carbon dioxide response curve
Slope
(liter/mmn/kg/mmHg)
2 .024 ± .007
5 .026 ± .004
10 .028 ± .005
14 .025 ± .004
19 .028 ± .005
27 .039 ± .007
2 47±4t
Intercept
I
5 41±3(PC02 mm Hg) 10 42 ± 1
14 38±2
19 37±3
27 38±2
#{176}Valuesare mean ± standard error. tP <.05 in relation to control (air).
P < .05 in relation to 27 days.
27 days of postnatal age (P < .05). As there was
no significant difference in bicarbonate, the flatter response seen soon after birth might
explain the increased intercept at .3 liter!min!kg.
(Fig. 2). Neither the slope nor intercept varied at
other ages. Therefore, the major finding during postnatal life was a decreased carbon dioxide response curve at 2 days of age.
The decreased response at low gestational age may be due to an inherent lack of response of the “respiratory centers,” to the effect of vagal modu-lation of breathing,5 or to both. However, it is difficult to determine the individual contribution of these factors and we could not do it with our
methods.6 Thus, it is only possible to conclude that the respiratory system is depressed both at 32
weeks of gestational age and soon after birth. It is
tempting to postulate that the depression with gestational age is primarily central, and with
postnatal
age is primarily vagal-dependent. Therespiratory depression with gestational age may be related to an ontogenetically primitive sleep
associated with rapid eye movements7 and
“wet lung” at this age. It is likely that these changes associated with excessive interstitial fluid in the lungs will have major effects on the vagal modulation of breathing. We attempted to avoid these effects in our analysis of gestational age by using studies from 5 to 20 days of postnatal age at mean gestational ages of 32 and 37 weeks. Thus, it is possible that the differences in the carbon dioxide responsiveness with gestational age are
primarily central and those with postnatal age are
primarily vagal-dependent.
When we compared all our data in preterm infants with the adult, we also found that the carbon dioxide response curve was shifted to the left without major change in slope.’2 This shift to the left has been explained by lower levels of bicarbonate ion early in life.’ ‘‘“ Earlier findings
of less’2 or more’ sensitive response to inhaled carbon dioxide may in part be due to the effects of
gestational and postnatal age.
The increase in ventilation with inhaled carbon dioxide has been attributed to an increase in tidal
volume with little change in respiratory
frequen-cy.”2 However, most of the studies have been qualitative rather than quantitative. Figures 3 and 4 show that the increase in tidal volume alone
can account for almost all the increase in
respira-tory minute volume, the change in frequency usually being minimal.
The increase in heart rate with inhaled carbon dioxide has been demonstrated before in man.’4 We showed that preterm infants also increase their heart rate with carbon dioxide, although
statistical significance was not always obtained.
SPECULATION
The depression of the respiratory system with increasing prematurity may be an important factor underlying periodic breathing and apnea
(>
20 seconds) in preterm infants.CONCLUSION
In 58 studies in nine preterm infants we meas-ured the ventilatory response to inhaled carbon dioxide at different gestational and postnatal ages. We found a lack of sensitivity to carbon dioxide at low gestational ages and in early postnatal life. We suggest that the unresponsiveness with
increasing prematurity is primarily central and that after birth is primarily dependent on the mechanical abnormalities of the lung.
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ACKNOWLEDGMENT
