A respiratory sensory reflex in response to CO, inhibits breathing in preterm infants RUBEN E. ALVARO, ZALMAN WEINTRAUB, KIM KWIATKOWSKI, DONALD B. CATES, AND HENRIQUE RIGATTO Departments of Pediatrics, Physiology, and Reproductive Medicine, University Winnipeg, Manitoba R3E OL8, Canada ALVARO, RUBEN E., ZALMAN WEINTRAUB, KIM KWIAT, KOWSKI, DONALD B. CATES, AND HENRIQUE RIGATTO. A respiratory sensory reflex in response to CO, inhibits breathing inpreterm infants. J. Appl. Physiol. 73(4): 15584563, 1992.-Traditionally, the increase in ventilation occurring after -4 s of CO, inhalation in preterm infants has been attributed to an action at the peripheral chemoreceptors. However, on a few occasions, we have observed a short apnea (2-3 s) in response to 35% CO, in these infants. To test the hypothesis that this apnea reflects a respiratory sensory reflex to CO,, we gave nine preterm infants [birth wt 1.5 t 0.1 (SE) kg, gestational age 31 t 1 wk] 78% CO, while they breathed 21% 0,. To study the doseresponse relationship, we also gave 2, 4, 6, and 8% CO, to another group of seven preterm infants (birth wt 1.5 * 0.1 kg, gestational age 31 2 1 wk). In the first group of infants, minute ventilation during 21% 0, breathing (0.232 t 0.022 1 min-’ kg-‘) decreased after CO, administration (0.140 t 0.025, P < 0.01) and increased with CO, removal (0.380 t 0.054, P < 0.05). This decrease in ventilation was related to an apnea (12 t 2.6 s) occurring 7.7 t 0.8 s after the beginning of CO, inhalation. There was no significant change in tidal volume. In the second group of infants, minute ventilation increased during administration of 2, 4, and 6% CO, but decreased during 8% CO, because of the presence of an apnea. These findings suggest that inhalation of a high concentration of CO, (>6%) inhibits breathing through a respiratory sensory reflex, as described in adult cats (H. A. Boushey and P. S. Richardson. J. Physiol. Lond. 228: 181-191, 1973). This inhibitory reflex to CO, may mask the peripheral chemoreceptor response to CO, in these infants, because it coincides with the maximal response of these receptors. l
apnea; carbon dioxide breathing response
response;
newborn
infant;
l
upper airway;
the increase in ventilation occurring after -4 s of CO, inhalation in preterm infants has been attributed to an action at the peripheral chemoreceptors (1, 12, 13, 23). However, on a few occasions, we have observed a short apnea (Z-3 s) in response to 35% CO, at the time when ventilation should have increased as a result of the action of CO, at the peripheral chemoreceptors. We thought this inhibition of breathing might represent a respiratory sensory reflex, as described previously (2, 3, 7). We decided, therefore, to give 7-8% CO, to a group of preterm infants for a short period of time while they breathed room air, to test the hypothesis that CO, inhibits breathing in these infants, probably through a respiratory sensory reflex. To further investigate the
TRADITIONALLY,
1558
0161-7567/92
$2.00 Copyright
of Manitoba,
dose-response relationship at lower CO, concentrations, we gave 2,4,6, and 8% CO, to another group of preterm infants. METHODS
Subjects. The study population consisted of two groups of “healthy” preterm infants. Group 1 [n = 9, birth wt 1,456 t 62 (SE) g, gestational age 31 t 0.5 wk, postnatal age 21 t 2 days, study wt 1,670 t 110 g] received only 7-8% CO,. Group 2 (n = 7, birth wt 1,549 t 117 g, gestational age 31 t 0.5 wk, postnatal age 22 t 6 days, study wt 1,808 t 198 g) received 2,4,6, and 8% CO,. The study was approved by the Faculty Committee for the Use of Human Subjects in Research, and a written consent was obtained from at least one parent of each infant. Methods. The system used to measure ventilation and alveolar gases has been described previously (27, 28). Briefly, it consisted of a flowmeter and a monel screen. We used a constant background flow (3 l/min) to eliminate valves and reduce dead space. The infant breathed through the nostril adapters and added to (expiration) or subtracted (inspiration) from the background flow. This background flow was balanced to an artificial zero. The flow signal was integrated to give volume. The screen flowmeter had a linear deflection up to 6 l/min. The resistance of the system was low (0.1 cmH,O 1-l min). The frequency response of the system was linear, varying '-*
2 0
RESULTS
In group 1, TjE decreased from 0.232 t 0.022 1. min-l kg-’ during control to 0.140 t 0.025 during CO, inhalation (P < 0.01). This decrease was related primarily to the presence of an apnea. VT did not change significantly during CO, inhalation (see Figs. 3 and 4). The apnea occurred on average at 7.7 t 0.8 s after the beginning of CO, inhalation and had a mean duration of 12 t 2.6 s (Fig. 2). There was no significant change in any of the ventilatory variables measured on the breaths l
”
control
3'2' before
1 8t
apnea
+co
2
FIG. 4. Breath-by-breath changes in ventilatory variables with inhalation of CO,. There is no change in VE preceding apnea. Values are means + SE. Control and post, values of various breaths during control and after CO,, respectively. Pace,, arterial Pco,. *P -< 0.05 in relation to control.
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CO, RESPONSE
IN PRETERM
1. Physiological measurements in response to inhalation
TABLE
VE, 1. min-’
l
f,
kg-’
VT,
breaths/min
ml/kg
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INFANTS
of 7-8% CO, in preterm infants (group 1) VTITI, ml kg-’ s-’ l
P&o, 7 Torr
TI/TT
l
Control
0.232kO.022
34.9t3.9
0.199+0.035 0.258kO.051 0.140&0.025*
32.1k4.8 29.623.3 34.2k4.1 33.4k4.5 18.5+3.3*
0.420+0.086 0.380t0.054*
45.8t9.1 46.6k8.0
6.9k0.6
ll.lkO.7
0.365+0.024
38.2k1.4
10.2k1.3 11.8kO.9 12.721.4 11.8k1.2 11.5kO.8
0.32 1 kO.036 0.314t0.040 0.373kO.043 0.365kO.050 0.318+0.024*
46.5t2.6* 54.3*2.4* 56.4+2.5* 57.3+2.4* 48.32 1.5’
16.0+1.4* 16.9+1.4*
0.411~0.051 0.416kO.025
46.5+2.8* 40.9k2.1
CO, added
1st breath 2nd breath 3rd breath Breath preapnea Mean
0.217kO.031
0.296kO.056
6.3t0.7 7.4kO.6 8.420.8 8.Okl.l 7.4kO.4 Post-CO,
breath Mean 1st
Values are means + SE. ATE, minute ventilation; alveolar PC02. * P < 0.05 relative to control.
f, respiratory frequency; VT, tidal volume; VT/TI, inspiratory
0.214 t 0.019 (4% CO,; P = 0.03), and from 0.182 t 0.008 to 0.229 t 0.018 (6% CO,; P = 0.04) (Fig. 6). DISCUSSION
We found that inhalation of 8% CO, for a few seconds induced an immediate inhibition of breathing. This inhibition was characterized primarily by the presence of a short apnea of - 12 s. VE decreased in association with apnea and immediately increased with CO, removal; this latter increase was mainly due to an increase in VT. This response is best explained by a respiratory sensory reflex, most likely located in the 1ipper airway (2, 3, 7, 9).
FLOW
drive; TI/TT,
duty
cycle;
Pboz,
The response occurs -8 s after the beginning of CO, administration and, as such, may at times mask the immediate increase in 7jE due to peripheral chemoreceptor stimulation occurring at -4 s. It is somewhat surprising that this reflex to CO, has not been described in these infants previously, considering that so many investigators have measured the ventilatory response to CO,. The most likely explanation is that, with the inhaled CO, traditionally used with either the steady-state or rebreathing method, the infant senses the increase in CO, in a gradual manner. In the present experiments, this higher inspired CO, was given as a square wave, and therefore its effect on the airways may
~.min-' :: -3. co,
FLOW
10.3k1.3” 8.5+0.7*
56 *O-
L.m&-’
co 2%
q
4 8
q
6% CO,
&
w
Iv \
0 P
FIG. different
5. Representative tracing of respiratory flow and alveolar PCO~ (Pbo ) in 1 preterm infant after inhalation concentrations of COz. Significant apnea occurred only with 8% Cd,.
of
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CO, RESPONSE
1562
IN PRETERM
INFANTS
nea) suggest that a neural reflex mechanism is probably 02%
m4%
BS%
IS%
CO2
involved. Perkett and Vaughan (26) showed that a laryngeal reflex can be elicited in some preterm infants by instillation
of water
into the hypopharynx,
which
results
in apnea. Because most of the stimuli applied to the larynx are apneogenic, one can speculate that CO, in these infants
stimulates
receptors
that
inhibit
breathing.
These reflex responses seem to be stronger in younger animals (16), although their relevance to spontaneous apnea in preterm infants remains speculative. Other pos-
sibilities, such as the action of CO, being mediated via slowly adapting lower airway receptors (15) or via the CO2 ON
CONTROL
CO2
OFF
decreased only during inhalation of 8% CO, because of presence of an apnea. *p < 0.001in relation to other concentrations of co,. FIG.
6. iiE
have been magnified. VE
Because the immediate
i ncrease in
mediated at the peripheral chemoreceptor level in
response to CO, is rarely seen in newborn infants, it is possible that this reflex may be masking some of the chemoreceptor responses even when given in concentrations