Waldemar A. Carlo

Continuous positive airway pressure selectively reduces obstructive apnea in preterm infants

Apnea in preterm infants has been classified as obstructive, central (nonobstructive), and mixed, based on the presence or absence of upper airway obstruction. Continuous positive airway pressure (CPAP) is widely used in apneic infants, although its mechanism of action is still unclear. To determine whether CPAP is equally effective in obstructive and nonobstructive apnea, we compared the types of apnea observed in 14 preterm infants during sequential 45-minute periods with and without CPAP. CPAP markedly decreased the incidence of both mixed and obstructive apnea episodes of greater than or equal to 5 seconds (P less than 0.01 and less than 0.03, respectively). In contrast, central apnea episodes of greater than or equal to 5 seconds were entirely unaffected by CPAP. Although minute ventilation was unchanged, transcutaneous PO2 increased by 11 +/- 11 mm Hg during CPAP whether or not apnea was present. We postulate that CPAP reduces apnea in preterm infants by relief of upper airway obstruction, possibly via splinting of the pharyngeal airway.

Decreased ventilation in preterm infants during oral feeding

As respiratory difficulty may accompany nipple feeding in preterm neonates, we studied the effect of oral feeding on ventilation in 23 preterm infants. The infants composed two groups based on their postconceptional age at the time of study: Group A comprised 12 infants 34 to 35.9 weeks of age, and group B, 11 infants 36 to 38 weeks. Ventilation was measured via a nasal mask pneumotachometer, and sucking pressure via a nipple that also permitted milk delivery; transcutaneous PO2 and PCO2 were continuously monitored. The feeding pattern comprised an initial period of continuous sucking of at least 30 seconds, followed by intermittent sucking bursts for the remainder of the feed. When compared with an initial semi-upright control period, minute ventilation (V1) during continuous sucking fell by 52 +/- 6% (P less than 0.001) and 40 +/- 2% (P less than 0.001) in groups A and B, respectively. This was the result of a decrease in respiratory frequency and tidal volume and was associated with a fall in TcPO2 of 13 +/- 4 mm Hg (P less than 0.01) in group A and 10 +/- 2 mm Hg (P less than 0.01) in group B. During intermittent sucking, V1 and TcPO2 recovered partially only in the more mature infants (group B). At the end of the feed, TcPCO2 have risen by 3 +/- 1 mm Hg (P less than 0.001) in group A and by 2 +/- 2 mm Hg (P less than 0.05) in group B. Thus oral feeding results in an impairment of ventilation during continuous sucking and the subsequent recovery during intermittent sucking is dependent on postconceptional age.

Oral breathing in newborn infants.

Newborn infants are considered obligate nasal breathers, hence dependent on a patent nasal airway for ventilation. The conditions under which oral breathing could occur and the contribution of oral ventilation to total ventilation were studied in 30 healthy term infants (aged 1 to 3 days). Nasal and oral airflow were measured using two resistance-matched pneumotachometers, and heart rate, tcPO2, etCO2, and sleep state were continuously recorded. In three of 10 infants studied in undisturbed sleep, spontaneous oronasal breathing was noted during both active and quiet sleep (mean duration 19 +/- 25 minutes), the distribution of tidal volume being 70% +/- 12% nasal and 30% +/- 12% oral. Episodes of oronasal breathing were also observed after crying in six infants (mean duration 21 +/- 19 seconds). In an additional 20 infants, multiple 15-second end-expiratory nasal occlusions were performed; eight (40%) of these infants initiated and sustained oral breathing in response to nasal occlusion. Respiratory rate, tidal volume, heart rate, and tcPO2 did not change when oral breathing occurred in response to nasal occlusion, although minute ventilation decreased from 265 to 199 ml/min/kg (P less than 0.05). These results demonstrate that newborn infants may use the oral airway for ventilation, both spontaneously and in response to complete nasal occlusion.

Early randomized intervention with high-frequency jet ventilation in respiratory distress syndrome

To determine whether early use of high-frequency jet ventilation reduces neonatal mortality or pulmonary morbidity rates, we randomly selected 42 infants with clinical and radiographic evidence of severe respiratory distress syndrome to receive either high-frequency jet ventilation or conventional ventilation. Separate sequential analyses (two-sided, alpha = 0.05, power = 0.95 to detect 85:15 advantage) were performed for mortality rates, air leaks, bronchopulmonary dysplasia, intraventricular hemorrhage, and assignment crossover, and a combined analysis was performed, with death overriding other outcome variables. Enrollment was completed when the combined analysis reached the sequential design boundary indicating no treatment difference. Mortality rates (19% among infants receiving high-frequency jet ventilation vs 24% among infants receiving conventional ventilation), the incidence of air leaks (48% vs 52%), bronchopulmonary dysplasia (39% vs 41%), and intraventricular hemorrhage (33% vs 43%), and assignment crossovers (14% vs 24%) did not differs significantly between the treatment groups. We conclude that early use of high-frequency jet ventilation does not prevent or substantially reduce mortality or morbidity rates associated with assisted ventilation.

Randomized trial of high-frequency jet ventilation versus conventional ventilation in respiratory distress syndrome*

To compare high-frequency jet ventilation (HFJV) with pressure-limited time-cycled conventional ventilation (CV), we randomized 41 infants with clinical and radiographic evidence of respiratory distress syndrome during the first day of life to receive either HFJV or CV. Standardized ventilatory protocols were used for 48 hours, after which CV was administered to both groups. Despite comparable oxygenation (arterial/alveolar oxygen tension ratio), mean airway pressure was lower in the HFJV group (9 +/- 2 vs 13 +/- 2 cm H2O, P less than 0.001), and thus the arterial/alveolar oxygen tension ratio corrected for mean airway pressure was improved in the HFJV group (P less than 0.05). PaCO2 was lower during HFJV (37 +/- 3 vs 42 +/- 3 mm Hg, P less than 0.05) despite a comparable peak inspiratory pressure. The incidence of air leaks, progression of intraventricular hemorrhage, and mortality during the 48-hour period did not differ between the two groups. Bronchoscopies in eight infants given HFJV and five given CV revealed no microscopic evidence of necrotizing tracheobronchitis, but one infant given HFJV had evidence of necrotizing tracheitis at autopsy. We conclude that for 48 hours during the acute stage of respiratory distress syndrome, HFJV can maintain adequate gas exchange at lower mean airway pressure than during CV, without an increase in the incidence of side effects.

Effect of maturation on oral breathing in sleeping premature infants

To evaluate the influence of postnatal maturation on oral breathing, we measured nasal and oral ventilation during sleep and the ventilatory response to nasal occlusion in 11 preterm infants. Studies were repeated at 31-32, 33-34, and 35-36 weeks postconceptional age. Premature infants had rare episodes of spontaneous oronasal breathing during sleep. The frequency of oral breathing in response to nasal occlusion increased with advancing postconceptional age, from 8% +/- 8% at 31-32 weeks to 26% +/- 18% at 33-34 weeks and 28% +/- 33% at 35-36 weeks. Oral breathing in preterm infants, unlike that in term infants, was characterized by intermittent airway obstruction leading to a significant decrease in respiratory rate, tidal volume, minute ventilation, and tcpo2 (P less than 0.005). When inspiratory (Rl) and expiratory (RE) resistances during nasal and oral breathing were compared, Rl increased from 41 +/- 30 to 234 +/- 228 (P less than 0.004) and RE from 62 +/- 16 to 145 +/- 43 cm H2O X L-1 X sec (P less than 0.004). The ability of preterm infants to use the oral route of breathing thus increases with advancing postnatal maturation, but its effectiveness may remain limited by high oral airway resistance.

Principles of Neonatal Assisted Ventilation

Based on the current knowledge of pulmonary mechanics and the results of clinical studies, we have reviewed principles that govern gas exchange during assisted ventilation in infants with RDS. Guidelines for changes in ventilator settings have been presented with respect to their specific effects on CO2 elimination and O2 uptake. In addition, their possible mechanisms of action and potential side effects have been addressed. General strategies have been presented, but they must be employed with caution. All infants will not exhibit the expected response to changes in ventilator setting, and thus their ventilatory management, as well as their general medical care, will need to be individualized.

Reflex and chemical responses of tracheal submucosal glands in piglets

In adult animals, airway fluid secretion is enhanced reflexly via central nervous system pathways, and locally by mediators such as substance P. To evaluate the role of maturation on these regulatory mechanisms, we compared the effects of reflex stimulation and intravenous substance P administration on airway secretion in anesthetized, paralyzed and artificially ventilated piglets, 9 to 22 days of age, and older piglets all aged 10 weeks. Airway secretion was monitored by counting the hillocks appearing in the upper trachea in an exposed field of tracheal epithelium (1.2 cm2) coated with powdered tantalum. In younger animals, mechanical stimulation of the larynx had no discernible effect on tracheal submucosal gland secretion. Neither excitation of airway irritant receptors nor stimulation of pulmonary C-fiber receptors by capsaicin caused a significant increase of fluid secretion from tracheal submucosal glands. In addition, stimulation of peripheral chemoreceptors by ventilating animals with 12% O2 in N2, and 6% O2 in N2, failed to induce a substantial change in airway secretion, when compared with number of hillocks in the control period. Furthermore, administration of sodium cyanide had little or no effect on baseline secretion. In contrast, to the weak reflex responses in younger piglets electrical stimulation of the vagus nerve caused the number of hillocks to increase on average by 16.3 +/- 2.3 (P less than 0.01). In addition, local application of a pledget soaked in solution of methacholine caused the number of hillocks to increase by 32.1 +/- 5.2 (P less than 0.01). Intravenous administration of substance P also induced an augmentation in fluid secretion. Increase in concentration of substance P (10(-8), 10(-7), 10(-6), and 10(-5) M, 1 ml) was associated with a concomitant elevation in the number of activated submucosal glands (5.3 +/- 2.6, 10.0 +/- 4.4, 27.1 +/- 4.5, 41 +/- 5). In older piglets, stimulation of laryngeal mucosa, airway irritant receptors, as well as stimulation of pulmonary C-fiber receptors induced a significant increase in tracheal secretion, although stimulation of peripheral chemoreceptors had no effect on airway secretion. These data suggest that reflex responses of submucosal glands are weak during early postnatal development, however, tracheal submucosal glands do respond to exogenously administered cholinergic substances and tachykinin peptides.

Relationship of pulse oximetry to arterial oxygen tension in infants

Pulse oximetry is a useful technique for noninvasive oxygen monitoring in sick infants. We simultaneously measured oxygen saturation by pulse oximetry and on arterial blood samples by co-oximetry as well as PaO2 and the relative content of fetal (F) and adult hemoglobin in order to evaluate the reliability of pulse oximetry. Comparisons were made in triplicate in ten infants with acute cardiorespiratory disease less than 7 days of age and in 11 infants with chronic lung disease greater than 28 days of age. Oxygen saturation pulse oximetry and arterial saturation were well correlated over a wide range of saturation values. In infants with chronic lung disease, PO2 derived from pulse oximetry was within 10 torr of measured PaO2 in 73% of comparisons. In contrast, calculated PaO2 was within 10 torr of measured PaO2 in only 50% of comparisons in patients with acute disorders. The chronic infants all had less than 10% hemoglobin F, but in the acute infants, hemoglobin F ranged from 26% to 83%. Nonetheless, correction of oxygen dissociation curves for type of hemoglobin in these acute infants failed to improve the correlation between calculated and measured PaO2. We conclude that pulse oximetry saturations and their derived PaO2 values correlated well with measured arterial saturation and PaO2 obtained from arterial blood samples in neonates with chronic lung disease and prolonged oxygen dependence. In infants with acute cardiorespiratory problems, pulse oximetry unreliably reflects PaO2, but may be useful in detecting clinical deterioration.

Biphasic Response of Respiratory Frequency to Hypercapnea in Preterm Infants

ABSTRACT: The time course of the transient ventilatory response to a sudden change in Inspired gas from room air to 4% CO2 in air was examined in 11 healthy preterm neonates. Changes in minute ventilation (V1), tidal volume (VT), and respiratory frequency (f) were determined over 4 to 5 min of CO2 inhalation during both quiet (QS) and active sleep (AS) in each infant. In both states there was a brisk increase of mean V1 in response to 4% CO2, while mean VT increased more slowly and mean f only increased transiently at 1 to 2 min. Exponential curve fitting to the change in Vi and VT for each infant accounted for 64 ± 20% of the variance in Vi during QS as compared to 30 ± 18% during AS (p<0.003). In only six infants did exponential curves fitted to the changes in V1 and VT during QS reach 90% of their steady state values within 4 to 5 min of CO2 exposure. Their time to reach 90% of steady state was always shorter for V1 than VT (p<0.01). Frequency showed a biphasic response with a transient rise at 1 to 2 min (p<0.05) and return to control levels at steady state. These data indicate that not all preterm infants reach a new level of steady state ventilation within 4 to 5 min of 4% CO2 inhalation. Furthermore, many infants exhibit a biphasic response of f over time which causes V1 to reach steady state prior to VT.