Respiratory sensations during heavy exercise in subjects without respiratory chemosensitivity.

Breathlessness arises from increased medullary respiratory center activity projecting to the forebrain (respiratory corollary discharge hypothesis). Subjects with congenital central hypoventilation syndrome (CCHS) lack the normal hyperpnea and breathlessness during hypercapnia. The corollary discharge hypothesis predicts that if CCHS subjects have normal hyperpnea during exercise, they will experience normal breathlessness during exercise. To test this, we studied four CCHS subjects and six matched controls during an exhausting constant-load cycling test requiring substantial anaerobiosis. CCHS subjects rated significantly less breathlessness at the end of the test than controls, but ventilation (index of respiratory corollary discharge) was also somewhat lower in CCHS (not significant). In both groups, breathlessness increased disproportionately more than ventilation towards the end of exercise. These data failed to disprove the corollary discharge hypothesis of breathlessness, but do suggest that the relationship between ventilation and breathlessness is non-linear and/or that projections of chemoreceptor afferents to the forebrain (presumed lacking in CCHS) is one source of breathlessness in normals.

Acoustic method to quantitatively assess the position and patency of infant endotracheal tubes: preliminary results in rabbits.

In this preliminary laboratory study, an acoustical method was evaluated to quantitatively assess the position and patency of an infant-size endotracheal tube (ETT) by in vivo and in vitro measurements. The method consists of emitting an audible sound pulse into the ETT and the airways, and deriving position and patency information from the timing and characteristics of the returning echoes. The method's capacity to measure ETT changes of position in the tracheae of five anesthetized New Zealand white rabbits (weight, 4.3-4.9 kg; age, 1.5-3 years) was found to be accurate to 0.7 +/- 3.6 mm (mean +/- 95% CI) over a distance of 5 cm. The method was also shown to reliably differentiate between tracheal, bronchial, and esophageal intubations by means of an acoustically inferred diameter of the passageway just beyond the ETT tip. To assess the accuracy of estimating lumen obstruction, in vitro acoustical measurements were performed in different size ETTs (2.5, 3.0, 3.5, and 4.0 mm inner diameter), with obstructions ranging from 5-100% reduction in cross-sectional area. The system identified the sizes of these obstructions to within +/-7%. This technology has the potential for continuous, computer-based monitoring of breathing-tube function through instantaneous detection of ETT malposition or obstruction before it leads to a serious medical condition.

Vocal cord dysfunction associated with exercise in adolescent girls.

Vocal cord dysfunction (VCD) has been reported in adolescents only rarely. Two patients are described whose initial diagnosis was exercise-induced bronchospasm (EIB). However, evaluation revealed inspiratory stridor and flattening of the inspiratory limb of the flow-volume curve. Flexible fiberoptic rhinolaryngoscopy revealed adduction of vocal cords during inspiration. Patients were treated with speech therapy and have remained free of symptoms. VCD should be considered in adolescents who are unresponsive to treatment for EIB.

RET proto-oncogene is important for the development of respiratory CO2 sensitivity.

Brain stem muscarinic cholinergic pathways are important in respiratory carbon dioxide (CO2) chemosensitivity. Defects in the muscarinic system have been reported in children with congenital/developmental disorders of respiratory control such as sudden infant death syndrome (SIDS) and congenital central hypoventilation syndrome (CCHS). This early onset of disease suggests a possible genetic basis. The muscarinic system is part of the autonomic nervous system which develops from the neural crest. Ret proto-oncogene is important for this development. Thus, a potential role for ret in the development of respiratory CO2 chemosensitivity was considered. Using plethysmography, we assessed the ventilatory response to inhaled CO2 in the unanesthetized offsprings of ret +/- mice. Fractional increases in minute ventilation during hypercapnia relative to isocapnia were 5.1 +/- 3.2, 3.0 +/- 1.6 and 1.4 +/- 0.8 for the ret +/+, ret +/- and ret +/- mice, respectively. The ret knockout mice have a depressed ventilatory response to inhaled CO2. Therefore, the ret gene is an important factor in the pathway of neuronal development which allow respiratory CO2 chemosensitivity.

Cardiac function and behavioral reactivity during infancy.

Longitudinal cardiac data from the end of the fetal period to 21 months of age were examined for change and stability over age and relations to the temperamental characteristics of high and low reactivity at 4 months of age and fear to the unfamiliar in the second year. Heart period and power in the cardiac spectra changed dramatically over the first 2 years, and individual differences were not preserved until 9-14 months of age. Sleep heart period at 2 weeks of age and low frequency power at 2 months of age were better predictors of the temperamental categories than later measures of the same variables, suggesting that cardiac function early in life may be an especially sensitive index of temperamental qualities.

Slow weight gain is associated with increased periodic breathing in healthy infants.

To investigate the hypothesis that weight gain can influence periodic breathing in healthy infants, we prospectively studied, by nocturnal pneumogram technique, respiration and heart rate in 99 full-term infants during the first month of life. Eighty-eight infants had a repeat study at about 2 months of age. Pneumograms were analyzed visually for percent periodic breathing (%PB), and by computer for mean respiratory rate and mean heart rate. We found a median %PB of 0.9 initially and of 0.3 at about 2 months of age. The 95th percentile was 13.5 at 2 weeks and 7.3 at 2 months, higher than previously reported. Between the two ages tested, %PB was inversely correlated with weight gain (P < 0.001, < 0.03, respectively). Infants with greater weight gain had a greater fall in %PB (P < 0.03). We conclude that in the first 2 months of life, slow weight gain is associated with increased periodic breathing.

Effect of mental activity on breathing in congenital central hypoventilation syndrome.

Congenital central hypoventilation syndrome (CCHS) is associated with hypoventilation during sleep, but breathing can be adequate during wakefulness. It has been assumed that in awake CCHS patients breathing is activated by the forebrain, even voluntarily (i.e. Ondine's Curse). We tested whether or not an abnormal breathing pattern can be provoked by intense mental concentration in CCHS patients as this would be expected to disturb any voluntary control over breathing if present. Breathing (inductance plethysmography), end-tidal PCO2) (PETCO2), arterial oxygen saturation (SaO2) and EEG were measured in 5 children with CCHS (aged 8-17 years) and 5 controls during 5 min periods while resting; reading; performing mental arithmetic and playing a hand-held "Nintendo" game. There were no significant differences between controls and CCHS (unpaired t-tests, P > 0.05) in mean breath duration, tidal volume, ventilation, SaO2 or PETCO2 during REST or the conditions of mental stimulation. Both groups increased ventilation during mental stimulation. Respiratory variability was not greater in CCHS in any condition. These data provide indirect evidence that CCHS patients do not require voluntary activation of every breath (they do not have Ondine's Curse) and suggest that mental concentration might stimulate the respiratory complex as part of a generalised CNS arousal.

Follicular bronchitis in the pediatric population.

Five patients in a pediatric population were identified with idiopathic follicular bronchitis (IFB) by open lung biopsy and their case records were reviewed. All were tachypneic and had a chronic cough by 6 weeks of age. The physical examination was characterized by diffuse fine crackles in four patients and by coarse rhonchi in one. The chest radiographs in all demonstrated a diffuse interstitial pattern. None had a collagen vascular or an autoimmune disease demonstrable. Response to corticosteroid therapy was minimal. Associated or coincidental esophageal reflux was treated surgically in two. No viral or bacterial agents were isolated in the sputum or the biopsy specimens. Patients have been followed up for 2 to 15 years; the conditions of all patients improved at about 2 to 4 years of age. The older patients have residual mild obstructive lung disease. To our knowledge, this is the first reported series of IFB in the pediatric population.

Respiratory sensations in subjects who lack a ventilatory response to CO2.

An urge to breath is perceived during breath hold and hypercapnia (termed 'air hunger') and during heavy exercise (often termed 'shortness of breath'). To better understand the neural mechanisms responsible for these sensations we studied five patients (8-17 years old) with congenital central hypoventilation syndrome (CCHS) who lack ventilatory response to CO2. CCHS patients reported no respiratory discomfort during CO2 inhalation or during maximal breath hold which was of much longer duration than age-matched controls. However, all 3 CCHS patients who exercised heavily reported some sensations akin to shortness of breath (they increased breathing nearly as much as controls). Our results are consistent with two possibilities. First, the air hunger of hypercapnia and breath hold is caused by projection to the forebrain of respiratory chemoreceptor afferents which bypass the respiratory centers, while exercise shortness of breath is caused by direct projections of limb afferents or locomotory center activity. Second, air hunger and shortness of breath share the same origin--projection of increased brain stem respiratory center motor activity (corollary discharge) to the forebrain.

Ventilatory responses to exercise in humans lacking ventilatory chemosensitivity.

1. In healthy humans during aerobic exercise ventilation increases and mean arterial PCO2 usually remains constant over a wide range of CO2 production. 2. Congenital central hypoventilation syndrome (CCHS) is associated with ineffective chemoreceptor regulation of breathing and severe hypoventilation during sleep (requiring mechanical ventilation) reflecting abnormalities in the brainstem respiratory complex or its chemoreceptor input. Such patients can have adequate spontaneous ventilation during resting wakefulness and participate in normal activities. 3. If children with CCHS have normal ventilatory responses to exercise then chemoreceptors are not necessary for this ventilatory response or the resultant control of Pa,CO2 during exercise. We studied five children with CCHS (aged 8-17 years) with abnormally low ventilatory responses to steady-state increased end-tidal PCO2 (< 9 ml min-1 kg-1 mmHg-1) and five age-matched controls. 4. Depth and rate of breathing, end-tidal PCO2, end-tidal PO2, CO2 production, O2 utilization and heart rate were monitored during the following conditions: whilst subjects stood at rest; following the onset of treadmill exercise (4 m.p.h.); during steady-state exercise (4 m.p.h.); during an incremental maximal exercise test; and during recovery from exercise. 5. There were no significant differences in the ventilatory responses between CCHS subjects and controls during the onset of treadmill exercise, in the dynamic response in achieving the steady-state exercise, during steady-state exercise, in the recovery from steady-state exercise, or during incremental exercise (up to the point of presumed blood lactate accumulation, as indicated by gas exchange criteria). There was a very small mean increase in PCO2 in both groups during steady-state exercise (controls 1.4 mmHg; CCHS 2.2 mmHg). 6. The only differences which emerged between groups were (i) slightly more variability in PCO2 in the CCHS group during steady-state exercise, and (ii) the CCHS subjects did not hyperventilate, as the controls did, at exercise levels above the point of presumed blood lactate accumulation. 7. Breath-by-breath coefficient of variation of ventilation was significantly reduced in both groups during steady-state exercise compared to rest. There were no differences between groups in either state. 8. We conclude that chemoreceptors are not necessary for an appropriate ventilatory response to aerobic exercise. Hence, other stimuli, such as afferent information from the exercising limbs or signals related to activation of the motor cortex, can increase alveolar ventilation in close proportion to CO2 production. 9. The lack of hyperventilatory response to blood lactate accumulation during heavy exercise provides good evidence that these CCHS patients have ineffective peripheral chemoreception.

Prospective identification of the risk of SIDS.

In the general population, there are a number of epidemiologic and physiologic factors that have been identified as increasing the risk for SIDS. To date, optimum combinations of these factors do not sufficiently discriminate the high-risk infant in order to serve as a basis for prospective screening. In the subsequently born sibling, the risk is only slightly increased, and, again, there are no factors that discriminate the infant at risk of death. Among infants who have sustained an ALTE, there are several identifiable causes or physiologic factors associated with high risk for a repeated event. This article has reviewed the association between risk factors and death in each of these three categories of patients.

Phase delay of pulmonary acoustic transmission from trachea to chest wall.

The frequency-dependent propagation time, or phase delay tau (f), of sonic noise transmission from the trachea to the chest wall was estimated over the 100-600 Hz frequency range using a phase estimation technique from measurements performed on eight healthy subjects. Since tau (f) can be greater than one period of the input signal at frequencies greater than 100 Hz, the unambiguous phase estimate at 100 Hz was used as a starting-point to determine the phase angle H(f) and tau (f) at higher frequencies under the constraint that the spectra did not exhibit large point-to-point discontinuities. The resulting tau (f) range of 0.9-4.1 ms is consistent with sound propagation to the chest wall through both airways and surrounding parenchyma. The frequency and spatial dependence of tau (f) indicates that with increasing frequency more sonic energy travels further into the branching airway structure before coupling into the parenchyma. These results suggest that information concerning distinct regional lung structures may be obtained by probing the system acoustically over selected frequency bands.

Cellular interstitial pneumonitis in infants. A clinicopathologic study.

Five infants had interstitial pneumonitis with constant histologic findings, which was different from that previously described in children. All the infants presented with tachypnea at birth and persistent disease, both clinically and radiographically, despite treatment. Open-lung biopsy in each case showed a diffuse interstitial thickening due to pale oval and spindle-shaped histiocytes without scarring. This neonatal cellular interstitial pneumonitis differs both clinically and histologically from the usual interstitial pneumonitis, lymphocytic interstitial pneumonitis and desquamative interstitial pneumonitis observed in adults and children. The etiology of this cellular interstitial pneumonitis in neonates is unknown.