Kim Kwiatkowski

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.

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.

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.

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.

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 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.

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.

Morphology of Sighs and Their Role in the Control of Breathing in Preterm Infants, Term Infants and Adults

Background: Although there is evidence that sighs are important to restore lung volume, the factors responsible for inducing a sigh and the effects of sighs on the stability of the respiratory system remain unclear. Objective: To compare newborn with adult sigh morphology in order to better understand the physiological mechanisms that induce sighs and the role sighs play on the control of breathing in infants. Design/Methods: We measured respiratory variables during control, the pre-sigh, the sigh, and the post-sigh period during quiet and REM sleep in 10 preterm infants, 10 term infants and 10 adults using a flow-through system. Results: No significant differences were observed in any of the respiratory variables between the pre-sigh and the control breaths in any of the subjects in any of the two sleep states, suggesting that indices of respiratory drive are not predictive of an impending sigh. Sighs were relatively larger in infants than in adults and had a characteristic biphasic inspiratory flow observed almost exclusively in infants. While post-sigh ventilation was usually increased in adults, it was usually decreased in infants due to the presence of apneas. Conclusions: The established indexes of respiratory drive are not predictive of an impeding sigh. When compared with control breaths, sighs are much larger in preterm and term infants than in adults. These big augmented breaths in infants are often followed by apnea and hypoventilation likely secondary to the increased activity of the peripheral chemoreceptors present in neonates.