Don Cates

Ventilatory response to 100% and 15% O2 during wakefulness and sleep in preterm infants

To examine the ventilatory response to 100% and 15% O2 during wakefulness and sleep, we studied eleven preterm infants birthweight 1770 +/- 102 g; gestational age 32 +/- 1 weeks; postnatal age 31 +/- 5 days) on two occasions each. Wakefulness (W) was present around feeding time and was defined by open eyes for more than 2 min plus presence of purposeful movements. Rapid eye movement (REM) and non-rapid eye movement (N-REM) sleep were defined using electroencephalogram (EEG), electrooculogram (EOG), electrocardiogram (ECG), and body movements. During 100% O2 breathing, immediate (30 s) decreases of 28, 39 and 37% followed by late (5 min) increases in ventilation (Ve) of 42, 49 and 27% were observed during W, REM and N-REM sleep (P greater than 0.05 between states). PaCO2 decreased significantly towards the end of 5 min of breathing 100% O2 in W, REM and N-REM sleep (P greater than 0.05). Average duration of apnea following sudden administration of 100% O2 was 8.5, 11.1 and 8.8 s during W, REM and N-REM sleep (P greater than 0.05 between states). During inhalation of 15% O2, there was a late decrease in ventilation of 19 and 23% during wakefulness and REM sleep, and a sustained increase in Ve of 17% during N-REM sleep (P less than 0.05). PaCO2 at the end of hypoxia (5 min) was significantly decreased in N-REM sleep only (P less than 0.05). We suggest that (i) peripheral chemoreceptor activity is qualitatively intact during W and sleep, as reflected by (a) the immediate changes in Ve during inhalation of high and low O2, and (b) apnea following administration of 100% O2. (ii) The late decrease in ventilation with hypoxia is absent in N-REM sleep.

Effect of Sleep State on Chest Distortion and on the Ventilatory Response to CO2 in Neonates

Summary: The authors studied 10 preterm infants (birth weight, 1840 ± 270 g; gestational age, 31 ± 3 wk) and 10 term infants (birth weight, 3700 ± 320 g; gestational age, 40 ± 1 wk) to evaluate the effect of sleep state on chest distortion and on the ventilatory response to CO2. Sleep state was defined on the basis of body movements, eye movements, and electroencephalogram. Chest distortion was assessed using micromagnetometers applied to the rib cage and abdomen. After a control period breathing 21% O2 in each sleep state, infants were given 3% CO2 to breathe. Respiratory minute volume and frequency, tidal volume, alveolar PCO2 and PO2, CO2 response curves, and chest distortion were measured. It was found that: 1) respiratory minute volume increased and PaCO2 decreased during REM as compared to non-REM sleep in preterm and term infants (P < 0.05); 2) chest distortion was not affected by sleep state, but was more frequent in preterm than in term infants (P < 0.02); 3) the ventilatory response to CO2 was not affected by sleep state (P > 0.4); and 4) CO2 did not affect chest distortion (P > 0.1). These findings indicate: 1) contrary to previous observations, chest distortion is independent of sleep state; and 2) the ventilatory response to CO2 was not affected by sleep state. The authors suggest that the higher prevalence of chest distortion in preterm infants is related to their highly compliant chest wall rather than to differences in sleep state.Speculation: Teleologically, almost anything increases with gestational age. Chest stability, non-REM sleep, ventilatory response to CO2, and prevalence of regular breathing, all increase with maturation. The authors would like to speculate, therefore, that the differences in chest distortion are immaturity rather than sleep state dependent. The authors believe that distortion is present not only because the rib cage muscles are weak or chest wall reflexes inefficient, but also because the bone structure of the rib cage is highly cartilagenous and cannot afford stability.

The effect of rebreathing CO2 on ventilation and diaphragmatic electromyography in newborn infants

We tested the hypothesis of whether the reduced ventilatory response to CO2 in preterm as compared to term infants is related to primary central unresponsiveness, or to mechanical impairment of the respiratory pump. Eleven preterm (n = 19; gestational age 32 +/- 0.4 wk) and 14 term (n = 24; GA 40 +/- 0.3 wk) infants were studied. Minute integrated diaphragmatic activity EMGDi X f), and mean inspiratory diaphragmatic activity (EMGDi/TI), were used as indices of central output. After 3 min breathing 21% O2 (control), infants rebreathed from a bag containing 5% CO2 in 40% O2 for 2 to 3 minutes. We measured VE, VT, f, VT/TI. Sleep states were monitored. Preterm infants had a decreased ventilatory response to CO2 both in quiet sleep (QS) (0.0379 +/- 0.067 vs 0.505 +/- 0.032 L . (min . kg . kPa PACO2)-1; P less than 0.04) and in active sleep (AS) (0.210 +/- 0.032 vs 0.331 +/- 0.048 L . (min . kg . kPa PACO2)-1; P less than 0.04). The decrease in response primarily was a function of a lack of increase in tidal volume with CO2 in QS and a lack of increase in f in AS. Parallel to these changes there were significant correlations between the increases in EMGDi X f and VE with inhaled CO2 (r = 0.75; P less than 0.001); VT and EMGDi (r = 0.63; P less than 0.01); and between the increases in EMGDi/TI and VT/TI with inhaled CO2 (r = 0.64; P less than 0.001). The results suggest that ventilatory response to CO2 is (1) correlated highly with diaphragmatic indices of central output; (2) less in active than in quiet sleep; (3) less in preterm than in term infants. We conclude that despite their increased chest wall compliance, preterm infant respond less to CO2 because of central unresponsiveness.

A Developmental Study on Types and Frequency Distribution of Short Apneas (3 to 15 Seconds) in Term and Preterm Infants

ABSTRACT: We measured the frequency distribution and the ventilatory correlates of the various types of apneas 3 to 15 s long during sleep in eight term infants (birth weight 3.65 ± 0.16 kg; gestational age 39.5 ± 0.3 wk) and eight preterm infants (birth weight 2.07 ± 0.18 kg; gestational age 34.3 ± 0.4 wk). Each infant was studied on five to seven occasions from birth to 56 wk of postconceptual age using a modified flow-through system. Sixty-six paired epochs of quiet sleep (1163 min) and rapid eye movement sleep (829 min) were analyzed in term infants and 85 paired epochs of quiet sleep (1553 min) and rapid eye movement sleep (1328 min) in preterm infants. Of the 783 apneas recorded in term infants 82% were central, 1.5% obstructive, 0.5% mixed, and 16% were of the breath-holding type; the corresponding figures for the 4086 apneas recorded in preterm infants were 93, 0.5, 1.0, and 5.5%. This distribution was similar in the two sleep states but term infants had a higher percentage of breath-holding apneas than preterm infants (p < 0.01). In preterm infants the rate of central apneas decreased with postnatal age (p < 0.01); in term infants the rate did not change significantly. The duration of apneas showed a modal distribution for central apneas at about 8 s for both groups during the 1st month of life (p < 0.05). The findings suggest: 1) apneas in the newborn and early infancy are primarily central and are more frequent in preterm than in term infants; 2) the higher rate of apnea in healthy preterm infants is accounted for almost entirely by the higher rate of central apneas; 3) a significant decrease in the rate of apnea occurs during the first 4 months after birth; and 4) preterm infants show longer respiratory pauses in both quiet sleep and rapid eye movement sleep when compared to term infants, and a maturation pattern can be discerned by 3 months of age.

Immediate and late ventillatory response to high and low O2 in preterm infants and adult subjects.

Summary: The differences in the immediate (30 sec or l min) and late (5 min) ventilatory response to high and low O2 have not been quantitated in preterm infants and adult subjects using the same methods. It was thought that these differences might explain the paradoxical ventilatory response to CO2 at various O2 concentrations in preterm infants (12). Thus, 9 preterm infants and 10 adult subjects were given 21% O2 to breathe and then 100 or 15% O2 for 5 min each. Adults also breathed 15% O2 before 100% O2 or 12% O2 in order to make their resting arterial PO2 more comparable to those of infants breathing 21% O2. The ventilatory response to 100% O2 was the same in preterm infants and adult subjects, but the late response to 15% O2 remained paradoxical, ventilation decreasing at 5 min by 18% in infants and increasing by 19% in adults. The authors conclude: 1) the traditional concept of the ventilatory response to 100% O2 being different in infants and adult subjects is false; 2) the notion that the response to low O2 is paradoxical in infants is correct; and 3) the data do not explain why the response to CO2 under various background concentrations of O2 in infants is the reverse of that in adult subjects, but the depressed ventilatory response to hypoxia in infants may justify, at least in part, their flatter response to CO2 during low O2 breathing.Speculation: The findings suggest that the response of preterm infants to high and low O2 per se is not the cause of the paradoxical response to CO2 under various background concentrations of O2. If it were, it would be expected that the response to low and high O2 would differ in infants and adults. This was true for hypoxia only, the response to hyperoxia being the same in infants and adults. The speculation, therefore, is that differences in cerebral blood flow caused by CO2 and O2 interaction may be responsible for the paradoxical response to CO2.

Airway closure during mixed apneas in preterm infants: is respiratory effort necessary?

Airway closure during mixed apneas in preterm infants may be due to lack of tone in the upper airway followed by collapse and obstruction or diaphragmatic action inducing obstruction. We examine whether respiratory efforts are necessary for airway closure using a new method of detecting airway obstruction, based on the disappearance of an amplified cardiac pulse observed on the respiratory flow tracing. We analyzed 198 episodes of mixed apnea of various lengths (> or = 3 seconds) observed in 33 preterm infants (birth weight, 1.4 +/- 0.1 kg [mean +/- SEM]; study weight, 1.7 +/- 0.1 kg; gestational age, 29 +/- 1 weeks; post-natal age, 33 +/- 4 days). The great majority of these episodes (88%) had a central, followed by an obstructive, component. Infants were studied by using a nosepiece and a flow-through system. Respiratory efforts (abdominal and chest movements) were recorded. Of the apneas, 20 were or = 20 seconds. Of the 198 mixed apneas, 151 (76%) occurred in the absence of any respiratory effort; 43 (22%) showed a simultaneous cessation of the cardiac oscillation and respiratory effort; and 4 (2%) showed diaphragmatic activity appearing after cessation of the cardiac oscillation (airway occlusion). Respiratory efforts never preceded the cessation of the cardiac oscillation. The findings suggest that diaphragmatic action is not needed to occlude the airway in mixed apneas. The simultaneous cessation of cardiac oscillations (airway occlusion) and onset of respiratory efforts may indicate that such effort contributes to closure or is induced by the same stimulus that closes the airway. We speculate that the mechanism for airway closure in mixed apneas is most likely a lack of upper airway tone, which normally occurs with the cessation of a central drive to breathe.

A Randomized Controlled Trial of Theophylline Versus CO2 Inhalation for Treating Apnea of Prematurity

OBJECTIVE To determine whether inhalation of 0.8% CO(2) in preterm infants decreases the duration and rate of apnea as effectively as or better than theophylline with fewer adverse side effects. STUDY DESIGN A prospective, randomized, control study of 42 preterm infants of gestational age 27 to 32 weeks assigned to receive inhaled CO(2) (n = 21) or theophylline (n = 21). The study group had a mean (+/- standard error of the mean) birth weight of 1437 +/- 57 g, gestational age of 29.4 +/- 0.3 weeks, and postnatal age of 43 +/- 4 days. After a control period, 0.8% CO(2) or theophylline was given for 2 hours, followed by a recovery period. RESULTS In the CO(2) group, apneic time and rate decreased significantly, from 9.4 +/- 1.6 seconds/minute and 94 +/- 15 apneic episodes/hour to 3.0 +/- 0.5 seconds/minute and 34 +/- 5 apneic episodes/hour. In the theophylline group, apneic time and rate decreased significantly, from 8 +/- 1 seconds/minute and 80 +/- 8 apneic episodes/hour to 2.5 +/- 0.4 seconds/minute and 28 +/- 3 apneic episodes/hour. Cerebral blood flow velocity (CBFV) decreased only during theophylline administration. CONCLUSIONS Our findings suggest that inhaled low (0.8%) CO(2) concentrations in preterm infants is at least as effective as theophylline in decreasing the duration and number of apneic episodes, has fewer side effects, and causes no changes in CBFV. We speculate that CO(2) may be a better treatment for apnea of prematurity than methylxanthines.

Chemical control of respiratory frequency and tidal volume during sleep in preterm infants.

During a given sleep state, respiration changes from periodic to regular and vice-versa. Because such spontaneous changes occur without changes in electro-encephalogram (EEG), electro-oculogram (EOG), electro-cardiogram (ECG) or body movements, we hypothesized that they are induced by chemical stimuli such as CO2. To test this hypothesis we examined 12 preterm infants in whom spontaneous changes in respiratory pattern were allowed to occur within the same sleep state, and infants in whom such changes were induced by inhalation of 0.3% to 1.2% CO2. Using a nosepiece and a screen flowmeter we measured the respiratory pattern, VE, f, VT, TI, TE, Ttot, VT/TI, TI/Ttot and PACO2. In REM sleep, spontaneous changes from periodic to regular were associated with increase in VE from 0.466 (mean) to 0.530 L/min (P less than 0.5) and CO2 induced changes accompanied by an increase in VE from 0.416 to 0.571 L/min (P less than 0.05). Similarly in N-REM sleep, VE increased from 0.385 to 0.445 L/min (P less than 0.05) during CO2 induced changes, and from 0.420 to 0.454 L/min (P less than 0.05) during CO2 induced changes, and from 0.420 to 0.454 L/min (P less than 0.05) during CO2 induced changes. Increased VE produced both spontaneously or by CO2 administration was associated with decreased VT, decreased Ttot, decreased VT/TI and slight increase in PACO2. We suggest that changes in respiratory pattern occurring within the same sleep state are chemically mediated.

The morphology of periodic breathing in infants and adults

To test the hypothesis that the crescendo-decrescendo type of pattern of periodic breathing is more common in infants than in adulthood, we examined the morphologies of periodic breathing in four groups of subjects: group 1 (n=10, gestational age 30+/-1 week), group 2 (n=10, GA 31+/-1 week), group 3 (n=10, GA 38+/-1 week), and group 4 (n=10, age 50+/-4 years). Respiratory pattern and ventilation were measured using a flow-through system. The breathing morphologies were defined according to the respiratory flow. We found (1) a predominant crescendo-decrescendo pattern in preterm infants (groups 1 and 2, >50%) and this changed to a predominant decrescendo breathing in adults (group 4, 50%); (2) total breathing cycle and its phases did not change significantly among the neonatal groups, but they almost doubled in adult subjects; however, the number of breaths per breathing interval remained the same (crescendo-decrescendo) or less (flat and decrescendo) in adults as compared to preterm infants; (3) the duty cycle (breathing interval/cycle duration) remained consistent with age; and (4) at the beginning of each breathing interval, alveolar P(CO2) was highest and alveolar P(O2) and O2 saturation lowest. The findings suggest a change in the strategy of the respiratory control system during periodic breathing between the infant and the adult, perhaps dictated by mechanical and chemoreceptor limitations early in age, with a switch from a crescendo-decrescendo to a predominantly decrescendo pattern.

Respiratory pacemaker cells responsive to CO2 in the upper medulla: Dose response and effects of mediators

We previously reported on the presence of respiratory pacemaker cells that are highly sensitive to CO2, in a region of the medulla oblongata in the fetal rat, 2 mm rostral to the obex. We now report on the CO2 dose responses of these cells, as well as their responsiveness to certain chemical agents known to affect breathing in the fetus. Twenty‐day‐old fetal Sprague Dawley rats were block‐dissected, and the cells of target areas were dissociated as previously described. Neuronal cells were plated on a medullary background and placed in the incubator with 10% CO2 for 2–3 weeks. Cells were then studied using patch‐clamp techniques.