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OBJECTIVE: To evaluate the effects of early treatment with CPAP on nutritional intake and in-hospital growth rates of extremely preterm (EPT) infants. STUDY DESIGN: EPT infants (24–0/7 to 27–6/7 weeks of gestation) enrolled in the Surfactant Positive Airway Pressure and Pulse Oximetry Trial (SUPPORT) were included. EPT infants who died before 36 weeks’ postmenstrual age (PMA) were excluded. The growth rates from birth to 36 weeks’ PMA and follow-up outcomes at 18–22 months’ corrected age of EPT infants randomized at birth to either early CPAP (intervention group) or early intubation for surfactant administration (control group) were analyzed. RESULTS: 810 of 1316 infants enrolled in SUPPORT (414 in intervention group, 396 in control group) had growth data analyzed. Median gestational age was 26 weeks and mean birthweight was 839 grams. Baseline characteristics, total nutritional intake, and in-hospital comorbidities were not significantly different between groups. In a regression model, growth rates between birth and 36 weeks’ PMA as well as growth rates during multiple intervals from birth to day 7, day 7 to14, day 14 to 21, day 21 to 28, day 28 to 32 weeks’ PMA, and 32 weeks’ PMA to 36 weeks’ PMA did not differ between treatment groups. Independent of treatment group, higher growth rates from day 21 to day 28 were associated with a lower risk of Bayley III cognitive score

To characterize the changes in respiratory mechanics and ventilatory timing that accompany apnea in premature infants, we evaluated 36 apneas in 13 premature infants (birth weight, 1,200 +/- 350 g, postconceptional age at study 34 +/- 3 wk). Apnea was defined as a ventilatory pause > or = 10s accompanied by a decrease in heart rate of 20 beats/min. Nasal airflow was recorded with a pneumotachometer, and esophageal, pharyngeal, and nasal mask pressures were continuously measured. Inspiratory time (TI), expiratory time (TE), tidal volume (VT), and VT/TI were determined over five breaths before and after apnea. In addition, total pulmonary resistance (RT) and supraglottic resistance (Rs) were measured over the same epochs in inspiration and expiration. Before apnea, TE and RT increased (P < 0.05 and < 0.01, respectively); however, Rs did not change. Immediately after apnea, prolongation of TI occurred and both RT and Rs were increased (P < 0.01), consistent with continued upper airway instability. However, within two breaths after resolution of the apnea, RT and Rs returned to normal, reflecting rapid recovery of upper airway and total pulmonary resistance. The ventilatory changes that precede and follow apnea closely resemble those occurring during periodic breathing.

The effects of hypercapnia produced by CO2 rebreathing on total pulmonary, supraglottic, and lower airway (larynx and lungs) resistance were determined in eight premature infants [gestational age at birth 32 +/- 3 (SE) wk, weight at study 1,950 +/- 150 g]. Nasal airflow was measured with a mask pneumotachograph, and pressures in the esophagus and oropharynx were measured with a fluid-filled or 5-Fr Millar pressure catheter. Trials of hyperoxic (40% inspired O2 fraction) CO2 rebreathing were performed during quiet sleep. Total pulmonary resistance decreased progressively as end-tidal PCO2 (PETCO2) increased from 63 +/- 23 to 23 +/- 15 cmH2O.l-1.s in inspiration and from 115 +/- 82 to 42 +/- 27 cmH2O.l-1.s in expiration between room air (PETCO2 37 Torr) and PETCO2 of 55 Torr (P less than 0.05). Lower airway resistance (larynx and lungs) also decreased from 52 +/- 22 to 18 +/- 14 cmH2O.l-1.s in inspiration and from 88 +/- 45 to 30 +/- 22 cmH2O.l-1.s in expiration between PETCO2 of 37 and 55 Torr, respectively (P less than 0.05). Resistance of the supraglottic airway also decreased during inspiration from 7.2 +/- 2.5 to 3.6 +/- 2.5 cmH2O.l-1.s and in expiration from 7.6 +/- 3.3 to 5.3 +/- 4.7 cmH2O.l-1.s at PETCO2 of 37 and 55 Torr (P less than 0.05). The decrease in resistance that occurs within the airway in response to inhaled CO2 may permit greater airflow at any level of respiratory drive, thereby improving the infant's response to CO2.

Stimulation of chemo-, irritant, and pulmonary C-fiber receptors reflexly constricts airway smooth muscle and alters ventilation in mature animals. These reflex responses of airway smooth muscle have, however, not been clearly characterized during early development. In this study we compared the maturation of reflex pathways regulating airway smooth muscle tone and ventilation in anesthetized, paralyzed, and artificially ventilated 2- to 3- and 10-wk-old piglets. Tracheal smooth muscle tension was measured from an open tracheal segment by use of a force transducer, and phrenic nerve activity was measured from a proximal cut end of the phrenic nerve. Inhalation of 7% CO2 caused a transient increase in tracheal tension in both age groups, whereas hypoxia caused no airway smooth muscle response in either group. The phrenic responses to 7% CO2 and 12% O2 were comparable in both age groups. Lung deflation and capsaicin (20 micrograms/kg iv) administration did not alter tracheal tension in the younger piglets but caused tracheal tension to increase by 87 +/- 28 and 31 +/- 10%, respectively, in the older animals (both P less than 0.05). In contrast, phrenic response to both stimuli was comparable between ages: deflation increased phrenic activity while capsaicin induced neural apnea. Laryngeal stimulation did not increase tracheal tension but induced neural apnea in both age groups. These data demonstrate that between 2 and 10 wk of life, piglets exhibit developmental changes in the reflex responses of airway smooth muscle situated in the larger airways in response to irritant and C-fiber but not chemoreceptor stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Non-invasive techniques for monitoring ventilation in infants are widely used in short-term laboratory-studies but have not been evaluated in routine clinical settings. To determine whether respiratory inductance plethysmography (RIP) can provide reproducible measurements of tidal volume (VT) in premature infants over an extended period of time, we monitored respiration in eight healthy preterm infants over 4.9 +/- 1.0 hours (mean +/- SD). The algebraic sum (Sum) of rib cage (RC) and abdominal (AB) motion signals (obtained by RIP) was calculated and presented over the entire recording period as percent of an initial 5 minute calibration period. VT was simultaneously measured with a nasal mask pneumotachometer with infants in prone and supine positions during active and quiet sleep. Infants were studied in the morning (AM) and again in the afternoon (PM). Between these studies they were returned to the nursery wearing the RIP in a continuous record mode. For all patients there was a significant linear relationship between VT (in mL measured by pneumotachometer) and Sum (in % of calibration value, RIP). Neither the slope of the relationship (0.074 +/- 0.03 in AM vs. 0.071 +/- 0.02 in PM), nor its variability as measured by standard error of the estimate (SEE) (2.3 +/- 0.5 in AM vs. 2.5 +/- 0.8 in PM) changed significantly from AM to PM. The relationship between VT and Sum, as well as the variability of that relationship, was not altered by position, asynchrony of RC and AB, respiratory rate, or percent RC contribution to Sum. We conclude that RIP produces consistent measurements of respiratory effort over 5 hours in healthy preterm infants without need for recalibration and is not affected by routine care.

We tested the hypothesis that healthy preterm infants have attenuated ventilatory responses to hypercapnia, associated with a decreased rib cage contribution to ventilation, in the supine versus prone position.We elicited hypercapnic ventilatory responses from 19 healthy preterm infants (postconceptional age 35 +/- 1 weeks) who were being prepared for hospital discharge. The O2 saturation was continuously monitored. Before and during CO2 rebreathing, ventilation was measured with a nasal mask pneumotachygraph and was derived from chest wall motion as determined by respiratory inductance plethysmograph. This measuring method allowed us to compare both ventilation and the percentage rib cage contribution to ventilation between supine and prone positions. Statistical analysis employed analysis of variance with repeated measures.The supine position was associated with a higher respiratory rate (p0.02) and lower O2 saturation (p0.007) than the prone position. The increase in ventilation in response to hypercapnia was lower in the supine than in the prone position. This was statistically significant for the respiratory inductance plethysmograph (p0.008) but not the pneumotachygraph (p = 0.077), and was associated with a smaller rib cage contribution to ventilation in the supine than in the prone position (p0.0001).Respiratory control may be vulnerable when healthy preterm infants are placed supine. Widespread avoidance of the prone position may not be appropriate for such patients.

Eighteen very-low-birth-weight (VLBW) infants who met study criteria were observed during routinely scheduled feedings, twice in one day, once with a nasogastric (NG) tube and once without, in random order. Breathing and sucking measurements were compared with and without NG tube placement. During the prefeed period, minute ventilation and tidal volume were significantly lower with an NG tube than without the tube. During the continuous sucking (CS) period after commencement of oral feeding, minute ventilation, tidal volume, pulse rate, and oxygen saturation were also lower with the tube. During both CS and subsequent intermittent sucking periods, infants sucked less forcefully and took less formula with the tube. Based on these findings, if VLBW infants have an NG tube in place, clinicians are urged to monitor for breathing compromise, oxygen desaturation, and bradycardia during oral feeding.

Upper airway muscles and the diaphragm may have different quantitative responses to chemoreceptor stimulation. To compare the respiratory muscle responses to changes in CO2, 10 ventilator-dependent preterm infants (gestational age 28 +/- 1 wk, postnatal age 40 +/- 6 days, weight 1.4 +/- 0.1 kg) were passively hyperventilated to apnea and subsequently hypoventilated. Electromyograms from the genioglossus, alae nasi, posterior cricoarytenoid, and diaphragm were recorded from surface electrodes. Apneic CO2 thresholds of all upper airway muscles (genioglossus 46.8 +/- 4.3 Torr, alae nasi 42.4 +/- 3.6 Torr, posterior cricoarytenoid 41.6 +/- 3.2 Torr) were higher than those of the diaphragm (38.8 +/- 2.6 Torr, all P less than 0.05). Above their CO2 threshold levels, responses of all upper airway muscles appeared proportional to those of the diaphragm. We conclude that nonproportional responses of the respiratory muscles to hypercapnia may be the result of differences in their CO2 threshold. These differences in CO2 threshold may cause imbalance in respiratory muscle activation with changes in chemical drive, leading to upper airway instability and obstructive apnea.

The effects of continuous positive airway pressure (CPAP) on supraglottic and total pulmonary resistance were determined in 10 healthy premature infants (postconceptional age 34 +/- 2 wk, weight at study 1,628 +/- 250 g). Nasal airflow was measured with a mask pneumotachograph, and pressures in the esophagus and oropharynx were measured with a 5-Fr Millar or fluid-filled catheter. Nasal CPAP between 0 and 5 cmH2O correlated well with oropharyngeal pressure (r = 0.94). Total supraglottic resistance, total pulmonary resistance, and supraglottic resistance in inspiration and expiration were measured on increasing CPAP. Total supraglottic resistance decreased from 46 +/- 29 to 17 +/- 16 cmH2O.l-1.s (P less than 0.005) between 0 and 5 cmH2O CPAP, and a delay in return of resistance to control values was seen as CPAP was reciprocally decreased to 0. CPAP produced a decrease in supraglottic resistance in both inspiration and expiration, from 41 +/- 26 to 14 +/- 9 and from 33 +/- 17 to 10 +/- 6 cmH2O.l-1.s, respectively (P less than 0.01). Total pulmonary resistance also decreased from 161 +/- 40 to 95 +/- 24 cmH2O.l-1.s (P less than 0.01) between 0 and 5 cmH2O CPAP. The decrease in total supraglottic resistance in these infants accounted for 60% of the change in total pulmonary resistance, which occurred on CPAP of 5 cmH2O. We speculate that CPAP may decrease supraglottic resistance directly through mechanical splinting of the airway. This effect of CPAP may be the primary mechanism by which this form of therapy reduces apnea with an obstructive component in premature infants.

Background Lung disease in very low borth weight (VLBW) infants is known to affect weight gain. We consider whether the results of a pulmonary function test (PFT) in the first weeks of life are associated with infants9 weight at 36 weeks post-menstrual age (Wt36). Methods We studied conventionally ventilated infants Results 55 infants with mean GA of 25.4 wks (range 23-38) and BW of 737g (range 500-1105) had a PFT performed on a mean age of 15 days (range 7-21). Mean Cdyn was 0.39 cc/cmH2O (range 0.20-0.66), and Rexp 226 cm H20/L/sec (range 53-348). One infant died before reaching 36 weeks adjusted age and was excluded from further analysis. Mean Wt36 was 1847g (range 1267-2350). In univariate analysis, Cdyn was significantly (p≤0.001) associated with Wt36. When weight at the time of PFT was added to this model, the effect size on Cdyn dropped by 29%, but Cdyn remained significant (p=0.027). In contrast, Rexp, duration of parenteral nutrition, days until enteral feedings of 100kcal/kg were achieved, days on the ventilator, and ventilation status at 36 weeks were not significantly associated with Wt36 in univariate models. In a multivariate linear regression model (R2=0.55), Cdyn remained significant (coefficient 583 g/cc/cmH20, p=0.035) after controlling for weight at the time of PFT, GA, and duration of parenteral nutrition. GA and weight at the time of the PFT were significant in this model, but duration of parenteral nutrition was not. Conclusion In VLBW infants, Cdyn is associated with Wt36. These results highlight the effect of lung disease on growth in VLBW infants, and may reflect work of breathing or overall severity of illness. Furthermore, they emphasize the relationship between early pulmonary status and outcome.

To characterize changes in pulmonary resistance, timing, and respiratory drive during periodic breathing, we studied 10 healthy preterm infants (body wt 1,340 +/- 240 g, postconceptional age 35 +/- 2 wk). Periodic breathing in these infants was defined by characteristic cycles of ventilation with intervening respiratory pauses greater than or equal to 2 s. Nasal airflow was recorded with a pneumotachometer, and esophageal or pharyngeal pressure was recorded with a fluid-filled catheter. Pulmonary resistance at half-maximal tidal volume, inspiratory time (TI), expiratory time (TE), and mean inspiratory flow (VT/TI) were derived from computer analysis of five cycles of periodic breathing per infant. In 80% of infants periodic breathing was accompanied by completely obstructed breaths at the onset of ventilatory cycles; the site of airway obstruction occurred within the pharynx. The first one-third of the ventilatory phase of each cycle was accompanied by the highest airway resistance of the entire cycle (168 +/- 98 cmH2O.l-1.s). In all infants TI was greatest at the onset of the ventilatory cycle, VT/TI was maximal at the midpoint of the cycle, and TE was longest in the latter two-thirds of each cycle. A characteristic increase and subsequent decrease of 4.5 +/- 1.9 ml in end-expiratory volume also occurred within each cycle. These results demonstrate that partial or complete airway obstruction occurs during periodic breathing. Both apnea and periodic breathing share the element of upper airway instability common to premature infants.

Despite widespread tcPCO2 monitoring the relationship between tcPCO2 and PaCO2 remains unclear. It has been assumed that after standard temperature correction, a constant metabolic factor can explain the elevation of tcPCO2 over PaCO2. Our data demonstrate a progressive increase in the difference between temperature corrected tcPCO2 and PaCO2 as PaCO2 increases. Thus a constant metabolic factor cannot account for the elevation of temperature corrected tcPCO2 over PaCO2. We speculate that as PaCO2 rises, CO2 production exceeds removal resulting in a progressive gradient between temperature corrected tcPCO2 and PaCO2.

Despite widespread use of transcutaneous PCO2 (TcPCO2) monitoring, the precise relationship between TcPCO2 and PaCO2 remains unclear. It has been widely assumed that theoretical correction of TcPCO2 (combining temperature correction with a constant metabolic factor of 4 mm Hg) accounts for the elevation of TcPCO2 over PaCO2. To test this assumption, TcPCO2 was measured with a 44 degrees C electrode and compared to PaCO2 in 60 normotensive infants with cardiorespiratory disease during the first four +/- six days of life (mean +/- SD) (range one to 36 days). During hypocapnea, from PaCO2. In contrast, during normocapnea, theoretically corrected TcPCO2 exceeded PaCO2 by 5 +/- 4 mm Hg (P less than .001), and similarly during hypercapnea, theoretically corrected TcPCO2 exceeded PaCO2 by 9 +/- 6 mm Hg (P less than .001). These data suggest that, as PaCO2 increases, there may be an imbalance between tissue CO2 production and removal, resulting in a progressively increasing gradient between TcPCO2 and PaCO2. Clarification of the relationship between TcPCO2 and PaCO2 should enhance the interpretation of TcPCO2 measurements in infants.

Despite widespread tcPCO2 monitoring the relationship between tcPCO2 and PaCO2 remains unclear. It has been assumed that after standard temperature correction, a constant metabolic factor can explain the elevation of tcPCO2 over PaCO2. Our data demonstrate a progressive increase in the difference between temperature corrected tcPCO2 and PaCO2 as PaCO2 increases. Thus a constant metabolic factor cannot account for the elevation of temperature corrected tcPCO2 over PaCO2. We speculate that as PaCO2 rises, CO2 production exceeds removal resulting in a progressive gradient between temperature corrected tcPCO2 and PaCO2.

Because neonatal apnea is frequently associated with airway obstruction, we compared relative changes in activity between various upper airway muscles and the diaphragm during hypercapnic stimulation. The technique of hyperoxic CO2 rebreathing was employed in 17 healthy, sleeping preterm infants studied at a postnatal age of 32 +/- 12 days. Surface diaphragm (DIA) electromyograms (EMGs) were recorded in all infants, and noninvasive measurements of posterior cricoarytenoid (PCA), genioglossus (GG), and alae nasi (AN) EMGs were analyzed in 11, 9, and 8 infants, respectively. During the control period, consistent phasic EMGs were recorded from the DIA in all infants and from the PCA in 8 infants, but from the GG and AN each in only one infant. During CO2 rebreathing, minute ventilation and end-tidal CO2 increased linearly as CO2 rose from 31 +/- 5 to 51 +/- 5 Torr. DIA and PCA EMGs also had proportional and comparable increases throughout rebreathing. In contrast, both GG and AN responses differed from the DIA and PCA (P less than 0.001) and exhibited minimal or absent responses at low levels of hypercapnia. Consistent GG and AN EMGs appeared at comparable levels of end-tidal CO2 (47 +/- 5 and 45 +/- 5 Torr, respectively) and subsequently increased linearly in most infants. We conclude that during CO2 rebreathing the initially delayed and subsequently linear responses of the GG and AN EMGs indicate a high CO2 threshold for these muscles.

The transient ventilatory responses to hypercapnia were studied in nine healthy preterm infants. We administered 4% CO2 in air for at least 7 min during quiet sleep and measured frequency (f), inspiratory time (TI), expiratory time (TE), tidal volume (VT), and minute ventilation (VI). Frequency increased over the first 2 min of CO2 inhalation (P less than 0.05) and then decreased to control values (P less than 0.05). This response was secondary to changes in TE, which decreased over the first 2 min (P less than 0.05) and then returned to control values, whereas TI did not change. The late increase in TE was associated with an increased percent of breaths exhibiting retardation of expiratory flow (braking) (P less than 0.05). These breaths had longer TE than the breaths without braking (P less than 0.05). Exponential curves made to fit the increases in VI and VT revealed that only 67% of the infants reached 90% of steady state for both VI and VT over the 7-min study period. The time to 90% of steady state was always shorter for VI than VT (P less than 0.05) due to the transient changes in f. The results indicate that the transient changes of f in response to hypercapnia are secondary to changes in TE, which appear unique to human infants. We speculate that the expiratory braking that develops during the course of CO2 inhalation increases lung volume, resulting in prolongation of TE via mechanoreceptor-mediated reflexes.