Reflex control of inspiratory duration in newborn infants

We applied graded resistive and elastic loads and total airway occlusions to single inspirations in six full-term healthy infants on days 2-3 of life to investigate the effect on neural and mechanical inspiratory duration (TI). The infants breathed through a face mask and pneumotachograph, and flow, volume, airway pressure, and diaphragm electromyogram (EMG) were recorded. Loads were applied to the inspiratory outlet of a two-way respiratory valve using a manifold system. Application of all loads resulted in inspired volumes decreased from control (P less than 0.001), and changes were progressive with increasing loads. TI measured from the pattern of the diaphragm EMG (TIEMG) was prolonged from control by application of all elastic and resistive loads and by total airway occlusions, resulting in a single curvilinear relationship between inspired volume and TIEMG that was independent of inspired volume trajectory. In contrast, when TI was measured from the pattern of airflow, the effect of loading on the mechanical time constant of the respiratory system resulted in different inspired volume-TI relationships for elastic and resistive loads. Mechanical and neural inspired volume and duration of the following unloaded inspiration were unchanged from control values. These findings indicate that neural inspiratory timing in infants depends on magnitude of phasic volume change during inspiration. They are consistent with the hypothesis that termination of inspiration is accomplished by an "off-switch" mechanism and that inspired volume determines the level of vagally mediated inspiratory inhibition to trigger this mechanism.     

On the relation between expiratory duration and subsequent inspiratory duration

To characterize respiratory interphase relationships in dogs, inspiratory duration (TI) or expiratory duration (TE) was systematically altered by electrical activation of vagal afferents, and the effect on subsequent TE or TI values was measured from the phrenic discharge. A linear TI-subsequent TE relationship was found. Following a vagally mediated prolongation of TE, 1) TI was prolonged, and the TE-subsequent TI relationship was curvilinear, 2) the threshold for inspiratory termination by phasic vagal inputs was increased, 3) the amplitude of the time course of the phrenic discharge was reduced so that the peak discharge reached the same level at inspiratory termination independent of TI, 4) the effect on TI prolongation persisted for several breaths whereas the effect was minimal on subsequent TE values, and 5) for tonic inputs the direct shortening of TI was nearly offset by the indirect lengthening of TI. These studies suggest the existence of slow central mechanisms that provide adaptation to elevated levels of vagal input in the control of TI. These mechanisms may also be responsible for the interphase timing relationships.     

Breath-by-breath interactions between inspiratory and expiratory duration in occlusive sleep apnea

We examined interactions between inspiratory duration (TI), expiratory duration (TE), and inspiratory (esophageal) pressure (Pes) generation in seven subjects with confirmed occlusive sleep apnea. Breath-by-breath values of TI, TE, and Pes were identified by digital computer during 21 260-s epochs of repetitive occlusive apnea during non-rapid-eye-movement sleep. The control theory of interacting nonlinear oscillators was used to categorize the interaction between TI and TE for each epoch as either 1) synchronization, the strongest possible interaction between biological oscillators; 2) relative entrainment, a moderate interaction between oscillators; or 3) relative coordination, a weak interaction. The latter two interactions were characterized by systemic oscillations in the moving cross-correlation between TI and TE. The relationship between TI and Pes was analyzed in a similar fashion. Significant oscillations were present in all three parameters (P less than 0.0001 for each). We observed significant negative correlations between TI and TE and between TI and Pes (P less than 0.001 for each) when all breaths for all epochs were pooled. In no epoch was there a significant positive correlation between TI and TE or Pes. All three interactions were observed between TI and TE: five epochs of synchronization, nine of relative entrainment, and seven of relative coordination. In contrast, 19 of 21 epochs exhibited synchronization between TI and Pes, with 2 epochs of relative entrainment. The relative frequency of TI vs. Pes synchronization was significantly greater than TI vs. TE synchronization (P less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)     

Urinary excretion of dimethylarginines in premature infants

Urinary excretion of NG,N'G-dimethylarginine (NG,N'G-Me2Arg) and NG,NG-dimethylarginine (NG,NG-Me2Arg) was measured in premature infants. The NG,N'G-Me2Arg/NG,NG-Me2Arg ratio was much higher in newborn infants than in older children or adults. Linear regression analysis showed a significant negative correlation between the degree of maturity and the excretion of NG,N'G-Me2Arg. A significant direct linear relationship also was found between the excretion of NG,N'G-Me2Arg and the rate of whole body nitrogen flux and of protein synthesis and catabolism. No correlation was found between the excretion of the dimethylarginines and 3-methylhistidine, but the dimethylarginine/3-methylhistidine ratio declined with advancing conceptual age. A direct linear relationship was found between excretion of NG,N'G-Me2Arg and NG,NG-Me2Arg and whole body nonskeletal muscle protein breakdown. No correlation was found between nonskeletal muscle protein catabolism and 3-methylhistidine excretion. We estimate that approximately 0.34 mumole of dimethylarginine are excreted per gram of nonskeletal muscle protein catabolized. Dietary intake did not affect the excretion of either NG,N'G-Me2Arg or NG,NG-Me2Arg. The data suggest that measurement of urinary dimethylarginines might be useful in the nutritional assessment of premature infants.     

Reflex control of expiratory duration in newborn infants

We investigated the effect on expiratory duration (TE) of application of graded resistive and elastic loads and total airway occlusions to single expirations in 9 full-term healthy infants studied on the 2nd or 3rd day of life. The infants breathed through a face mask and pneumotachograph, and flow, volume, airway pressure, and diaphragm electromyogram (EMG) were recorded. Loads were applied to the expiratory outlet of a two-way respiratory valve using a manifold system. Application of all loads resulted in expired volumes (VE) decreased from control (P less than 0.05), and changes were progressive with increasing loads. As VE became smaller, end-expiratory volume (EEV) became greater. TE, measured either from the pattern of airflow or airway pressure, or from diaphragm EMG activity, progressively increased with increasing loads and was greatest with total occlusions (P less than 0.05, compared with control). Resistive loading resulted in a greater accumulated VE history than elastic loading to the same EEV. For equivalent changes in EEV, TE was more prolonged with resistive than with elastic loading. Expiratory loading did not change the inspiratory duration determined from the diaphragm EMG activity of the breath immediately following each loaded expiration. These findings in infants are consistent with an integrative neural mechanism that modulates TE in response to the accumulated VE history, including both EEV and rate of lung deflation.     

Assessment of airway resistance in preterm infants during incremental inspiratory flow-resistive loading

Extrathoracic airway (ETA) stability was tested by inspiratory flow-resistive loading in 10 preterm infants to determine whether ETA collapsibility was directly related to the size of the added load. A fall in intraluminal pressure was produced by applying two inspiratory flow-resistive loads of lower (L1) and higher (L2) magnitudes. An increase in intrinsic resistance was used as an index of upper airway collapsibility. Total pulmonary resistance did not change from baseline with L1 (73 +/- 26 to 71 +/- 25 cmH2O.l-1.s) but increased significantly with L2 (72 +/- 21 to 99 +/- 34 cmH2O.l-1.s, P less than 0.02) secondary to a rise in inspiratory resistance (55 +/- 21 to 109 +/- 55 cmH2O.l-1.s, P less than 0.05). Expiratory resistance did not change significantly with either load. Proximal airway pressure was more negative with L2 than with L1 in every infant (mean -4.5 +/- 0.6 vs. -3.6 +/- 0.9 cmH2O, P less than 0.05). This study shows that the ETA of preterm infants is pressure passive at high but not at low collapsing pressures, and possible explanations include limited "active" compensation by upper airway dilator muscles and an overwhelming of the "passive" defense offered by the intrinsic rigidity of the ETA to large changes in transmural pressure.     

Diaphragmatic work of breathing in premature human infants

Present methods of assessing the work of breathing in human infants do not account for the added load when intercostal muscle activity is lost and rib cage distortion occurs. We have developed a technique for assessing diaphragmatic work in this circumstance utilizing measurements of transdiaphragmatic pressure and abdominal volume displacement. Eleven preterm infants without evidence of lung disease were studied. During periods of minimal rib cage distortion, inspiratory diaphragmatic work averaged 5.9 g X cm X ml-1, increasing to an average of 12.4 g X cm X ml-1 with periods of paradoxical rib cage motion (P less than 0.01). Inspiratory work was strongly correlated with the electrical activity of the diaphragm as measured from its moving time average (P less than 0.05). Assuming a mechanical efficiency of 4% in these infants, the caloric cost of diaphragmatic work may reach 10% of their basal metabolic rate in periods with rib cage distortion. When lung disease is superimposed, the increased metabolic demands of the diaphragm may predispose preterm infants to fatigue and may contribute to a failure to grow.     

Maturation of feedback control of thyrotropin in premature infants

Serum thyrotropin (TSH), free T4 and free T3 concentrations were measured longitudinally in 26 preterm infants for 14 weeks after birth, using highly sensitive immunoradiometric assays. Serum TSH values on days 4-5 were positively correlated with gestational age and birth weight. In the premature infants of 25 weeks mean gestation, the mean TSH concentrations increased from a very low value of 0.84 microU/ml at 5 days to a peak value of 6.1 microU/ml by 5 weeks of age, then slightly decreased and remained stable. Serum free T4 and free T3 concentrations increased in parallel and free T3 level reached the range of term infants by 6 weeks. Serum free T4/TSH and free T3/TSH ratios began to increase at the 6th week of age. The results suggest that: (i) the thyroid hormone feedback control of pituitary TSH release in the extremely premature infants begins to mature after 6 weeks of postnatal age, (ii) the maturation pattern of the hypothalamic-pituitary-thyroid system in premature infants is similar to that of the intrauterine fetus.     

Airway obstruction during periodic breathing in premature infants

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.