Donald B. Cates

Hypoxic airway constriction in infants of very low birth weight recovering from moderate to severe bronchopulmonary dysplasia

We hypothesized that infants recovering from severe bronchopulmonary dysplasia have airway constriction that is, at least in part, related to borderline hypoxia. If this hypothesis were correct, pulmonary resistance should decrease with the administration of oxygen. To test this hypothesis, we studied 10 infants recovering from severe bronchopulmonary dysplasia (study weight 2490 +/- 275 gm; birth weight 1010 +/- 89 gm; postnatal age 73 +/- 7 days; postconceptional age 38.5 +/- 1.6 weeks) and 10 matched control infants (study weight 2430 +/- 179 gm; birth weight 2320 +/- 195 gm; postnatal age 25 +/- 4 days; postconceptional age 37.5 +/- 0.8 weeks). Resistance and compliance were measured by means of a mask with a flowmeter and an esophageal balloon (with the PEDS computer program). Measurements in both groups were made in quiet sleep, without sedation, during the inhalation of room air and during the fifth minute of oxygen inhalation. We found that (1) total pulmonary resistance, significantly higher in infants with bronchopulmonary dysplasia than in control infants, decreased from 206.1 +/- 47 cm H2O.L-1.sec-1 during inhalation of room air to 106.5 +/- 20.9 during inhalation of 100% oxygen (p less than 0.05) and (2) pulmonary dynamic compliance, lower in infants with bronchopulmonary dysplasia than in control infants, increased significantly with the administration of 100% oxygen. The results suggest that infants with bronchopulmonary dysplasia have airway constriction and that this is alleviated by inhalation of oxygen.

Clinical and physiological responses to prolonged nasogastric administration of doxapram for apnea of prematurity

We hypothesized that enteral doxapram would effectively treat apnea of prematurity without the appearance of major side effects. Of 16 infants, 10 (BW 1,520 +/- 102 g) received doxapram alone and 6 (BW 1,020 +/- 35 g) received doxapram plus theophylline. Apneas decreased from 16.7 +/- 1.9 to 2.1 +/- 0.6 in infants receiving doxapram alone, and from 38.2 +/- 4.4 to 7.9 +/- 2.2 apneas/24 h in those receiving doxapram plus theophylline. This was associated with an increase in alveolar ventilation, a shift of the ventilatory response to CO2 to the left, and no change in the immediate ventilatory response to 100% oxygen. Side effects included premature teeth buds corresponding to the lower central incisors, prevalence of occult blood in stool and necrotizing enterocolitis. The findings suggest that doxapram effectively controls apnea when given enterally, but should be used cautiously because of potentially harmful side effects.

Effect of Feeding on the Chemical Control of Breathing in the Newborn Infant

Summary: To examine the influence of feeding on the chemical control of breathing in neonates, we studied the ventilatory response to 3% CO2 in air in nine bottle fed (BOT) and eight breast fed (BR) term infants during feeding while the infants were alert. Control responses were obtained either before or after feeding. VE, respiratory frequency, tidal volume, inspiratory time, expiratory time, and sum of inspiratory and expiratory time, VT/Ti, Ti/Ttot, PACO2 and slope (S) of CO2 response (liter/min/kg/mmHg) were determined. During 3% CO2 while resting BR had a lower VE, VT, VT/ Ti than BOT and S in BR was 40% of BOT (P < 0.05). During feeding and CO2 when compared to resting and CO2 there was no difference in either BR or BOT in VT/Ti but Ti/Ttot decreased in both groups. During feeding, S in BOT was reduced from 0.049 ± 0.012 (mean ± S.E.) to 0.013 ± 0.002 (74% reduction) and in BR from 0.020 ± 0.002 to 0.009 ± 0.002 (55%). Thus, behavioral activity (either BR or BOT) markedly depresses the ventilatory response to chemical stimuli (CO2). This modification is primarily related to changes in “effective” respiratory timing (Ti/Ttot) rather than mean inspiratory flow (VT/Ti).Speculation: This is the first demonstration in the newborn infant that behavioral activity (feeding) can override the usual ventilatory control mechanisms. The precise mechanism is unknown and requires further study.

Sighs and Their Relationship to Apnea in the Newborn Infant

To test the hypothesis that sighs are mechanistically important in triggering apnea, we studied 10 preterm infants, group 1: body weight 1.8 +/- 0.1 kg, gestational age 33 +/- 1 weeks, postnatal age 21 +/- 4 days, and 10 term infants, group 2: body weight 3.9 +/- 0.15 kg, gestational age 40 +/- 0.4 weeks, postnatal age 1.4 +/- 0.2 days. Instantaneous ventilatory changes associated with a sigh were studied in another 10 preterm infants, group 3: body weight 1.6 +/- 0.11 kg, gestational age 32 +/- 0.4 weeks, postnatal age 25 +/- 4 days. Ventilation was measured using a nosepiece and a flow-through system. Sleep states were recorded. Sighs were more frequent in preterm than in term infants (0.4 +/- 0.04 vs. 0.18 +/- 0.03 sighs/min; p = 0.03) and in rapid eye movement than in quiet sleep (0.5 +/- 0.05 vs. 0.3 +/- 0.05 sighs/min; p = 0.05). Of 722 apneas, 235 (33%) were associated with a sigh; of these, 113 (48%) preceded and 122 (52%) followed a sigh. Sighs induced with airway occlusion (groups 1 and 2) were more frequent after occlusion on 21 than on 35% O2, particularly when O2 saturation was low and negative airway pressure high. Instantaneous ventilation measured over 10 breaths preceding a sigh did not show any trend indicating the possible appearance of a sigh. Tidal volume increased from 7.5 +/- 0.7 before the sigh to 18.9 +/- 0.7 ml/kg (p < 0.01) during a sigh, with a significant increase in inspiratory drive. Ventilation increased from 0.327 +/- 0.041 to 0.660 +/- 0.073 l/min/kg.(ABSTRACT TRUNCATED AT 250 WORDS)

Small preterm infants (≤1500 g) have only a sustained decrease in ventilation in response to hypoxia

ABSTRACT: The classic “biphasic” ventilatory response to 15% O2 was previously observed in preterm infants who were Large compared with those in the intensive care nursery today. We hypothesized that in the smaller infant (≤1500 g) the response might be closer to that of the fetus, with no initial increase in ventilation. Thus, we studied 14 healthy preterm infants ≤ 1500 g [birth weight 1220 ± 63 g (mean ± SEM); gestationl age 29 ± 0.4 wlq postnatal age 17 ± 3 d] during rapid eye movement and quiet sleep. Ventilation was measured using a nosepiece and a flowthrough system. Sleep states were defined using EEC, electro-oculogram, and body movements. After a control period in 21% O2 (3 min), infants breathed 15% O2, for 5 min. In rapid eye movement sleep, minute ventilation decreased from 0.186 ± 0.020 (control) to 0.178 ± 0.021 (30 s) to 0.171 ± 0.017 (1 min;p = 0.03), to 0.145 ± 0.016 (3 min; p = 0.002), and to 0.129 ± 0.011 1 ± min−1 kg−1 (5 min; p = 0.004). In quiet sleep, it decreased from 0.173 ± 0.019 (control) to 0.164 ± 0.019 (30 s), to 0.166 ± 0.019 (1 ± min−1 to 0.148 ± 0.013 (3 min; p = 0.03) and to 0.146 ± 0.012 1 ± min−1 ± kg−1 (5 min; p =0.04). These changes in ventilation were primarily related to a decrease in frequency in rapid eye movement [38 ± 2 (control) versus 28 ± 3 (5 min); p 0.01 and in quiet sleep [36 ± 5 (control) versus 27 ± 3 (5 min); p = 0.02]. Changes in tidal volume were negligible. These findings suggest that the classic biphas response to hypoxia is not observed in very small preterm infants. These infants show only a sustained decrease in ventilation with low O2. We speculate that the response reflects a more pronounced inhibitory mechanism induced by hypoxia at this gestational age, representing an intermediate profile between that observed in the fetus and that present in larger neonates.

The biphasic ventilatory response to hypoxia in preterm infants is not due to a decrease in metabolism

The mechanism underlying the biphasic ventilatory response to hypoxia in neonates is poorly understood. Because alveolar PCO2 (PACO2) decreases and remains low during hypoxia, it has been argued that a decrease in metabolism may occur. We hypothesized that if the late decrease in ventilation during hypoxia is due to a decrease in CO2 production, an increase in PACO2 should abolish it. We studied 27 preterm infants [birth weight, 1,700 ± 41 g (mean ± SEM); study weight, 1,760 ± 36 g; gestational age 32 ± 0.2 weeks; postnatal age, 17 ± 1 days]. A flow‐through system and Beckman analyzers were used to measure ventilation and alveolar gases. Metabolism was expressed as changes in oxygen consumption. Infants were studied randomly during hypoxia alone (15% O2 + N2, n = 55) and during hypoxia plus CO2, (0.5% CO2, n = 30; 2% CO2, n = 10). Each experiment consisted of 2 minutes of control measurements (21% O2), 5 minutes of measurements during hypoxia alone or hypoxia plus CO2, followed by 2 minutes of recovery (21% O2). We found a biphasic response to hypoxia with or without CO2 supplementation, the percent change in ventilation from initial peak hyperventilation to late hypoventilation at 5 minutes being ‐16 ± 2 on 15% O2; ‐9 ± 3 on 15% O2; + 0.5% CO2 and ‐15 ± 9 on 15% O2; + 2% CO2; (P < 0.05).The decrease in ventilation was primarily due to a significant decrease in frequency; tidal volume increased. Oxygen consumption decreased similarly with the various inspired gas mixtures during hypoxia. These findings indicate that the decrease in ventilation during hypoxia is unlikely to be solely due to a decrease in metabolism since the late decrease in ventilation following initial hyperventilation still occurred despite the elimination of a fall in PACO2. We speculate that the mechanism underlying the late decrease in ventilation is likely of central origin, probably mediated through the release of inhibitory neurotransmitters. Pediatr Pulmonol. 1996; 22:287–294.

A study of breathing pattern and ventilation in newborn infants and adult subjects

Experimentally modified breathing pattern in human subjects, by varying the inspired gas mixture or administering different neuromodulators, has been studied extensively in the past, yet unmodified breathing has not. Moreover, most data refer to infants during sleep and adults during wakefulness. We studied the baseline breathing pattern of preterm infants [n= 10; GA 30 (27–34) wk (median, range)]; term infants [n= 10; GA 40 (39–41) wk)], and adult subjects [n= 10; age 31 (17–48) y)] during quiet sleep. A flow‐through system was used to measure ventilation. We found: (i) instantaneous ventilation was 0.273 ± 0.006, 0.200 ± 0.003, and 0.135 ± 0.002 Lmin‐1.kg‐1 in preterm, term infants, and adult subjects; the coefficients of variation were 39%, 25%, and 14% (p <0.01). The greater coefficient of variation in neonates compared to adults related to increased variability in Vt (39% and 25% in preterm and term infants vs 14% in adults; p < 0.01) and f (39% and 22% vs 9%; p < 0.01). The major determinant of frequency in preterm infants was Te (81% variability), Ti varying less (25% variability); (ii) VT/Ti decreased and Ti/Ttot increased with age; (iii) the higher breath‐to‐breath variability in preterm infants was associated with larger changes in alveolar PCO2 and a larger variability in O2 saturation than later in life.

Small preterm infants (less than or equal to 1500 g) have only a sustained decrease in ventilation in response to hypoxia.

ABSTRACT: The classic “biphasic” ventilatory response to 15% O2 was previously observed in preterm infants who were Large compared with those in the intensive care nursery today. We hypothesized that in the smaller infant (≤1500 g) the response might be closer to that of the fetus, with no initial increase in ventilation. Thus, we studied 14 healthy preterm infants ≤ 1500 g [birth weight 1220 ± 63 g (mean ± SEM); gestationl age 29 ± 0.4 wlq postnatal age 17 ± 3 d] during rapid eye movement and quiet sleep. Ventilation was measured using a nosepiece and a flowthrough system. Sleep states were defined using EEC, electro-oculogram, and body movements. After a control period in 21% O2 (3 min), infants breathed 15% O2, for 5 min. In rapid eye movement sleep, minute ventilation decreased from 0.186 ± 0.020 (control) to 0.178 ± 0.021 (30 s) to 0.171 ± 0.017 (1 min;p = 0.03), to 0.145 ± 0.016 (3 min; p = 0.002), and to 0.129 ± 0.011 1 ± min−1 kg−1 (5 min; p = 0.004). In quiet sleep, it decreased from 0.173 ± 0.019 (control) to 0.164 ± 0.019 (30 s), to 0.166 ± 0.019 (1 ± min−1 to 0.148 ± 0.013 (3 min; p = 0.03) and to 0.146 ± 0.012 1 ± min−1 ± kg−1 (5 min; p =0.04). These changes in ventilation were primarily related to a decrease in frequency in rapid eye movement [38 ± 2 (control) versus 28 ± 3 (5 min); p 0.01 and in quiet sleep [36 ± 5 (control) versus 27 ± 3 (5 min); p = 0.02]. Changes in tidal volume were negligible. These findings suggest that the classic biphas response to hypoxia is not observed in very small preterm infants. These infants show only a sustained decrease in ventilation with low O2. We speculate that the response reflects a more pronounced inhibitory mechanism induced by hypoxia at this gestational age, representing an intermediate profile between that observed in the fetus and that present in larger neonates.

Cranial blood volume changes during mechanical ventilation and spontaneous breathing in newborn infants

We derived a noninvasive method to compare changes in cranial blood volume during mechanical ventilation with changes occurring during spontaneous breathing in newborn infants. In ten infants receiving mechanical ventilation, cranial blood volume increased during inspiration by a mean of 8.3%. We found a consistent relationship between clinical estimation of lung compliance and the amount of cranial volume expansion. During spontaneous breathing in ten infants cranial blood volume decreased during inspiration by a mean of 5.8%. The findings indicate the need for careful monitoring during periods of rapid changes in lung compliance.

Diaphragmatic Activity and Ventilation in Preterm Infants

To determine the effects of inhaled CO2 and abdominal loading on diaphragmatic electromyography (EMGdi) and ventilation during sleep, we studied 10 preterm infants (birth weight