Martha J. Miller

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.

Persistence of the biphasic ventilatory response to hypoxia in preterm infants

OBJECTIVE To characterize postnatal maturation of the biphasic ventilatory response to hypoxia in order to determine whether it persists beyond the first weeks of life in preterm infants, and the contributions of respiratory frequency and tidal volume to this response. METHODS Stable preterm infants were studied at two postnatal ages, 2 to 3 weeks (n = 12) and 4 to 8 weeks (n = 12), before hospital discharge at 35 weeks (range, 33 to 38 weeks) of postconceptional age. Infants were exposed to 5 minutes of 15% (or 13%) inspired oxygen; ventilation, oxygen saturation, end-tidal partial pressure of carbon dioxide, and heart rate were simultaneously recorded. RESULTS Minute ventilation exhibited a characteristic biphasic response to hypoxia at both postnatal ages, regardless of the development of periodic breathing. At both ages there was a transient increase in tidal volume, which peaked at 1 minute, accompanied by a sustained decrease in respiratory frequency as a result of significant prolongation of expiratory time. CONCLUSION The characteristic biphasic ventilatory response to hypoxia persists into the second month of postnatal life in preterm infants. We speculate that this finding is consistent with the prolonged vulnerability of such infants to neonatal apnea.

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.

Characteristics of hypoxemic episodes in very low birth weight infants on ventilatory support

OBJECTIVE To characterize hypoxemic episodes in very low birth weight infants with mechanically ventilated lungs and to describe their natural history and the effect of body position. STUDY DESIGN Tidal volume, respiratory rate, oxygen saturation, heart rate, and body movement were continuously recorded in 10 very low birth weight infants who exhibited episodes of hypoxemia during mechanical ventilation (birth weight, 810 +/- 133 gm; postconceptional age at study, 30 +/- 1.6 weeks). Frequency of hypoxemic episodes was compared in both prone and supine positions. RESULTS Seventy-eight percent of hypoxemic episodes began in association with body movement as well as heart rate acceleration. Thereafter the spontaneous and delivered minute ventilation both decreased during the first 15 seconds of hypoxemia. The former decrease was due to a significant decrease in frequency of spontaneous respiration, whereas the latter was associated with a significant decrease in delivered tidal volume. Minute ventilation returned to normal before recovery of oxygenation. A change in body position from supine to prone significantly decreased the frequency of hypoxemic episodes. CONCLUSION Hypoxemic episodes in infants who are on ventilatory support are characterized by (1) movement and cardioacceleration at initiation; (2) a decrease in both spontaneous and delivered minute ventilation, and (3) a lower incidence in the prone position. We speculate that spontaneous movement during sleep can trigger cardiopulmonary reflex responses that initiate and propagate these episodes.

Genioglossus Response to Airway Occlusion in Apneic Versus Nonapneic Infants

ABSTRACT. The ability to maintain pharyngeal patency is compromised in infants who have apneic episodes associated with airway obstruction. Since the genioglossus (GG) muscle is thought to be important in maintaining pharyngeal patency, we measured the GG EMG with sublingual surface electrodes during unobstructed breathing and in response to end-expiratory airway occlusion. Studies were performed in nine premature infants with mixed and obstructive apnea and in eight nonapneic control infants. Phasic GG EMG was usually absent during normal tidal breathing in both groups of infants, however, GG activity typically appeared during airway occlusion. The response of the GG muscle during airway occlusion differed between control and apneic infants. During the first three occluded inspiratory efforts, control infants had 42 ± 5, 74 ± 5, and 80 ± 5% (mean ± SEM) of their occlusions associated with a GG EMG response, respectively. In contrast, apneic infants had significantly fewer (13 ± 4, 38 ± 9, and 52 ± 9%) occlusions associated with a GG EMG response. There was a delay in onset of the GG EMG when compared to the onset of the diaphragm EMG and initial negative esophageal pressure swing, but this delay decreased with each subsequent appearance of the GG EMG in both infant groups. Infants with mixed and obstructive apnea thus have decreased activation of their GG in response to occlusion which may reflect their inability to recruit dilating muscles of the upper airway during spontaneous airway obstruction.

A Comparison of Swallowing During Apnea and Periodic Breathing in Premature Infants

ABSTRACT: Periodic breathing and apnea are two forms of ventilatory instability which are commonly observed in premature infants. This study was undertaken to characterize the pattern of swallowing during apnea and compare this pattern to that present during periodic breathing. We assessed the frequency and distribution of swallows during the respiratory pauses of apnea and periodic breathing in 22 premature infants birth weight 1.2 ± 0.2 kg, postconceptional age 34 ± 2 wk. Twelve infants had apnea and 10 exhibited periodic breathing. During sleep the pharyngeal phase of swallowing was detected by a catheter in the pharynx and esophageal peristalsis by an esophageal pressure catheter. Nasal airflow was monitored by a pneumotachometer. During apnea, the frequency of swallows was significantly greater than during the respiratory pauses of periodic breathing (15.9 ± 8.2 versus 0.72 ± 0.73 swallows/min, respectively, p < 0.0001) and also much higher than the rate of spontaneous swallows during sleep in either group (0.66 ± 0.66 and 0.58 ± 1.08 swallows/min, respectively). We conclude that an increased rate of swallowing is characteristic of apnea in premature infants, and distinguishes apnea from the respiratory pauses of periodic breathing.

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.

Increased respiratory drive as an inhibitor of oral feeding of preterm infants

This study was designed to determine whether increased respiratory drive induced by inhalation of carbon dioxide would alter the reflex and voluntary components of feeding. For 10 preterm infants (mean +/- SD: postconceptional age at study, 34 +/- 2 weeks; weight, 2.1 +/- 0.2 kg), four trials of nutritive feeding were offered: two while the infants were inhaling a gas mixture containing 40% oxygen and two while the infants were breathing 40% oxygen and 7% carbon dioxide. Nasal airflow was monitored with a pneumotachygraph. Pressure-sensitive catheters in the esophagus and in the feeding nipple were used to detect swallowing and sucking. Sucking frequency and pattern, rate of swallowing, end-tidal carbon dioxide, and minute ventilation were recorded for 30-second epochs during feeding. When the inhaled gas mixture was switched from 40% oxygen to 40% oxygen and 7% carbon dioxide, sucking frequency decreased from 53 +/- 10 to 48 +/- 12 and from 54 +/- 12 to 40 +/- 19 sucks/min, respectively (p < 0.005). Frequency of swallowing also fell during the two feeding epochs on 7% carbon dioxide, from 45 +/- 15 to 40 +/- 15 and from 43 +/- 14 to 31 +/- 16 swallows/min (p < 0.003). Thus acute hypercapnea was accompanied by a decrease in rate of both sucking and swallowing during nutritive feeding. Increased ventilatory drive may directly inhibit nutritive feeding behavior in premature infants.

Infant animal model of pulmonary mycotoxicosis induced by Stachybotrys chartarum

In recent years cases of often fatal pulmonary hemorrhage in infants have been associated with water damaged homes and the toxigenic fungusStachybotrys chartarum. The fungal spores contain mycotoxins which could be injurious to the rapidly developing lung. In order to understand the developmental pathophysiology of this disease we developed an infant rat model of stachybotrytoxicosis describing the effects of fungal spores on survival, growth, histopathology of the lung and respiration. Conidia ofS. chartarum were instilled intratracheally (1.0–8.0 × 105/gm wt.) in 4-dold Sprague-Dawley rat pups. Two control groups received either sterile PBS or a suspension of spores extensively extracted with ethanol to remove toxins. Lethal dose response was determined (LD50 = 2.7 × 105 spores/gm wt.). All dead pups had extensively hemorrhagic lungs. Growth of surviving animals was impaired in a dose-dependent manner. Changes of pulmonary function parameters in rats treated with 1.1 × 105 spores/g were consistent with an increased respiratory resistance. Histology of lungs revealed fresh hemorrhage, sparse hemosiderin-laden macrophages, and evidence of inflammation including thickened alveolar septa infiltrated by lymphocytes and mononuclear cells and intra-alveolar macrophages. Significant increases (p = 0.001) in numbers of macrophages (2-fold), lymphocytes (5-fold) and neutrophils (7-fold) were found in BAL fluid. Hemoglobin was elevated 2-fold (p = 0.004). Proinflammatory mediator IL-1β increased more than 6-fold and TNF-α30-fold (p = 0.001). Extracted spores had a minimal effect on all examined parameters in BAL fluid indicating that mycotoxins are primarily responsible for the hemorrhagic and inflammatory response.

Recurrent hypoxic exposure and reflex responses during development in the piglet.

The effects of recurrent hypoxia on cardiorespiratory reflexes were characterized in anesthetized piglets at 2-10 d (n=15), 2-3 weeks (n=11) and 8-10 weeks (n=8). Responses of phrenic and hypoglossal electroneurograms (ENG(phr) and ENG (hyp)) to hypoxia (8% 0(2), bal N(2), 5 min), hypercapnia (7% CO(2) bal O(2), 5 min) and intravenous capsaicin were tested before and after recurrent exposure to 11 episodes of hypoxia (8% O(2) bal N(2), 5 min). In piglets 2-10 d, ENG(phr) response to hypoxia declined in proportion to the number of hypoxic exposures; however, ENG (hyp) response to hypoxia was unchanged. In piglets at 2-10 d, intracisternal injection of bicuculline (GABA(A) receptor antagonist) reversed effects of recurrent hypoxia on ENG(phr) hypoxic response, eliminated apnea during hypoxia, as well as the delay in appearance of ENG(phr) after hypoxia. The ENG(phr) response to 7% CO(2) inhalation also decreased after recurrent hypoxia; however, the ENG(phr) response to C-fiber stimulation by capsaicin was unaltered. Piglets at 2-3 and 8-10 weeks were resistant to the depressive effects of recurrent hypoxia on respiratory reflex responses. We conclude that the response of the anesthetized newborn piglet to recurrent hypoxia is dominated by increasing inhibition of phrenic neuroelectrical output during successive hypoxic exposures. Central GABAergic inhibition may contribute significantly to the cumulative effects of repeated hypoxia in the newborn piglet experimental model.