We tested the hypothesis that intracranial pressures and cerebral perfusion pressure in the newborn are more seriously affected by increasing airway pressure during high-frequency oscillatory ventilation (HFOV) than during conventional mechanical ventilation (CMV). Mean airway pressure was acutely elevated in stepwise fashion to 25 cm H2O in six anesthetized, paralyzed newborn lambs. Pressure (mean +/- SE) increased similarly during HFOV and CMV in the jugular vein (7 +/- 1 and 8 +/- 1 cm H2O, respectively), the sagittal sinus (6 +/- 1 and 7 +/- 1 cm H2O), and the cerebrospinal fluid of the lateral ventricle (4 +/- 1 and 6 +/- 1 cm H2O). Decreases in arterial blood pressure (-13 +/- 2 and 10 +/- 2 cm H2O) and cerebral perfusion pressure (-17 +/- 2 and -16 +/- 2 cm H2O) were also similar during HFOV and CMV. Intracranial pressure-volume curves were generated by incrementing cerebrospinal fluid volume in eight lambs. Curves generated during HFOV and CMV were similar, reflecting a similar intracranial compliance during the two ventilatory modes. These data indicate that intracranial compliance and the effects of increasing airway pressure upon intracranial pressures are not significantly different between HFOV and CMV.

During fetal life the lung develops as a liquid-filled structure with low blood flow compared with postnatal life. We studied the effects of liquid expansion of the fetal lung by measuring vascular conductance in perfused lungs in situ and arterial diameters in excised lungs of fetal lambs. Pulmonary vascular conductance invariably rose as the lung was deflated from its initial volume; maximal deflation to residual volume increased conductance 122%. With reexpansion, conductance fell progressively, culminating in cessation of flow at lung volumes of twice the initial volume. These changes persisted after vagotomy and thoracic sympathectomy and therefore were mechanical in character. Lung expansion from residual volume initially expanded 300- to 500-micron arteries but compressed arteries greater than 1,500 micron. Further expansion reduced the caliber of all arteries. Thus increasing lung liquid volume progressively constricts the pulmonary circulation in the fetus. Because the fetal pulmonary vascular resistance-lung volume relationship differs from that of the U-shaped form found in adult lungs, concepts based on the adult pulmonary circulation are not appropriate for liquid-filled fetal lungs.

High frequency ventilation (HFV) systems have the theoretical advantage of producing less barotrauma and lung damage because of the associated smaller oscillations in alveolar pressure compared to conventional ventilators. An index of lung damage is an increase in extravascular lung water but previous studies using HFV have produced conflicting results. Lung wet-to-dry ratio, extravascular lung water and blood mass were measured in 30 rabbits divided into three groups (n = 10); spontaneously breathing (SV), conventional positive pressure ventilation (CV) and high frequency oscillatory ventilation (HFV). HFV maintained normal blood gases and produced a significant reduction in the wet-to-dry weight ratio compared to SV and CV (P less than 0.05). Extravascular lung water and blood mass were significantly reduced in HFV compared to SV (P less than 0.05). It is concluded that the system of HFV used in this study has clinical potential in the treatment of lung injury.

Baroreceptor reflexes can be demonstrated during fetal life, but whether baroreceptors normally regulate fetal arterial pressure is unknown. This problem was addressed directly by measuring arterial pressure and analyzing its variation in eight unanesthetized fetal lambs throughout the last third of gestation, and comparing these data with similar measurements made in seven fetal lambs with denervated arterial baroreceptors. Measurements were made at 5-minute intervals over 24 hours in a total of thirty-three experiments. The coefficient of variation of mean arterial pressure (standard deviation of mean arterial pressure/mean value of mean arterial pressure) expressed as a percentage was used as an index of blood pressure variability. Coefficients averaged 7.0% in intact lambs and 12.1% in barodenervated lambs (P less than 0.001), signifying considerably increased variability of mean arterial pressure after barodenervation. Mean arterial pressure averaged over 24 hours was not different between the two groups prior to 120 days (0.8) of gestation. Between 120 days and term, mean pressure was significantly greater in the denervated fetuses (65 cm H2O) than in the sham-operated controls (60 cm H2O, P less than 0.025). These data demonstrate that a baroreceptor-blood pressure reflex functions during late gestational development in lambs and signify an important role of arterial baroreceptors in regulating fetal arterial pressure. Failure to regulate arterial pressure in the barodenervated fetus could result in significant alterations in placental perfusion and exchange, and in the regional delivery of oxygen and substrates to developing organs in these animals.

Reflex heart rate (HR) responses to hypotension were studied in chronically instrumented fetal and newborn lambs. Studies spanned 106–141 days of gestation and 1–22 days after birth. Brief hypotensive stimuli (10 s) were produced by inflation of a cuff implanted around the inferior vena cava; HR and mean arterial pressure (MAP) were recorded from a carotid arterial catheter. Autonomic nervous control of HR was examined using selective sympathetic beta-adrenergic blockade (propranolol 1 mg/kg), cholinergic blockade (atropine 0.2–0.3 mg/kg), and total autonomic blockade (propranolol plus atropine). In newborn lambs (n = 4) HR increased progressively as MAP was reduced in the range 5–50%. Tachycardia during mild hypotension (< 15% MAP fall) was due to sympathetic activation as it was abolished by propranolol. During severe hypotension ( > 30% MAP fall) tachycardia was reduced by selective beta-adrenergic blockade and by cholinergic blockade, and totally abolished by total autonomic blockade; thus withdrawal of vagal tone plus augmentation of sympathetic activity contribute to the increase of HR in response to large MAP falls in the newborn. Fetal lambs (n = 4) responded with tachycardia in mild hypotension (< 15% MAP fall) but this was reversed when hypotension was severe (> 30% MAP fall). The primary tachycardia was due to sympathetic activation and was indistinguishable from the newborn response. Reversal of the tachycardia in severe hypotension was due to increased vagal activity which counteracted the sympathetic acceleration. This pattern of simultaneous activation of the opposing autonomic pathways prevents tachycardia and appears to be a characteristic fetal response to severe hypotensive and hypoxemic stress.

Respiratory responses to hypercapnia were studied in seven chronic in utero fetal lambs between 105 and 138 days' gestation (16 expts). Fetal arterial CO2 tension was raised (mean increase 9.9 Torr) by altering maternal inspired gas concentrations. Diaphragmatic electromyogram (EMG) was recorded as the index of respiratory activity. Electrocortical and electroocular activity (3 fetuses) were monitored in an attempt to define sleep state. Average respiratory rate increased (90%) and fetal apnea decreased (60%) during hypercapnia. Mean respiratory rate during "on" periods (greater than 6 EMG bursts/min) increased significantly during hypercapnia throughout the gestational epoch studied. Mean duration of the inspiratory time (TI) showed no significant change. Variability in both rate and TI decreased in response to CO2 at all gestations. Integrated EMG activity per burst divided by TI increased significantly at all gestations; however, no gestational increase in responsiveness to CO2 was seen. Sleep states were not able to be consistently identified, and a quantifiable electrocortical response to CO2 was not observed. These results indicate a relatively early functional maturation of fetal respiratory responses to CO2.

Respiratory activity (diaphragmatic electromyogram) was recorded in six unanesthetized in utero fetal lambs, between 0.7 of gestation and term. Respiratory patterns generated by the fetus showed developmental changes that included 1) an emergence of a periodic modulation of respiratory rate producing alternating active and quite phases (mean cycle length of 37 min between 130 and 140 days' gestation; 2) an increase in percentage apnea (expiratory time greater than 10 s) from 20% at 110 days to 60% at 140 days; and 3) a linear decrease in the 2-h average respiratory rate, while mean rate during active phases showed no consistent gestational decline. Electrocortical and electroocular activity was monitored in three of six fetuses; however, discrete sleep state patterns could not be consistently identified. The results demonstrate a gestational change in the respiratory patterns of the developing fetus and suggest an orderly maturation of the mechanisms controlling respiratory neuronal output.

Autonomic nervous control of heart rate (HR) during hypoxia was studied longitudinally using 9 chronically catheterized fetal lambs (109 day to term) and 10 newborn lambs (2--28 days old). Changes in heart rate (deltaHR) during hypoxia were age-dependent. Before 120 days of gestation deltaHR was insignificant, but between 120 days to term bradycardia occurred. The newborn response was marked tachycardia. Autonomic influences on HR were quantified using atropine and propranolol blockade. In fetal lambs, antagonistic increases in parasympathetic and sympathetic outflows were evident during hypoxia. In hypoxic lambs 120 days to term, net bradycardia reflected predominant parasympathetic cardio-deceleration; before 120 days of gestation both the parasympathetic and sympathetic outflows increased, but no net deltaHR occurred. In hypoxic newborn lambs, sympathetic and parasympathetic changes contributed synergistically to the net tachycardia. Thus the pattern of autonomic control of HR during hypoxia differs in fetal and newborn lambs. Changes in sympathetic and parasympathetic influences are antagonistic in the fetus, but synergistic in the newborn.

The development of submucosal glands in the respiratory tract was studied by light and scanning electron microscopy in the rat, fetal dog and fetal sheep. From the results obtained the present concepts about the formation of these glands in man were questioned and an alternative hypothesis proposed. With scanning electron microscopy the development of the submucosal gland was seen to begin with an aggregation of low electron-responsive cells. Within such an aggregate, a pit, several microns in diameter, was formed. This pit was usually surrounded by medium electron-responsive cells possessing primary cilia in the rat, and by low electron-responsive cells in the fetal dog. In the rat medium electron-responsive cells appeared in other areas of the aggregate, preceded by apical elevations on the low electron-responsive cells. Further development in the rat led to a disappearance of the low electron-responsive cells, differentiation of ciliated and brush cells, and enlargement of the gland orifice. With light microscopy it was observed that the initial gland buds in both the rat and fetal sheep contained lumina several microns in size. These have not been reported by previous investigators. The bud extended into the underlying tissue and developed many simple tubules. The lumina of these tubules were consistently larger than the channel close to the epithelial surface. The cells of these tubules were also the first to differentiate into mucous and serous cells. The development of glands in the rat, in contrast to the sheep, began after birth. In the sheep, unlike the rat, the lumina of the developing glands were often filled with acidic mucosubstances, even though the cells of these glands did not stain for such material. Hence it is suggested that this material is derived from the mucin-containing cells of the surface epithelium and is carried into the interior of the developing gland by the fluid present in the respiratory tract during intrauterine life.

The fine structure of the epithelium in the larynx and trachea has been described in detail in a variety of mammals with transmission (Rhodin & Dalhamn, 1956; Rhodin, 1959; Watson & Brinkman, 1964; Rhodin, 1966; Frasca et al. 1968; Hansell & Moretti, 1969; Hama & Nagata, 1970; Jeffery & Reid, 1975) or combined transmission and scanning electron microscopy (Dahlgren, Dalen & Dalhamn, 1972; Andrews, 1974; Castleman, Dungworth & Tyler, 1974; Alexander, et al. 1975). However, much less is known about the changes that occur in the morphology of this epithelium between birth and maturity. It is therefore the purpose of this paper to describe, with scanning electron microscopy complemented by light microscopy, the changes that occur in the appearance of the epithelium of the larynx and trachea of the rat from birth onwards.

The relationship between lung liquid flow and fetal lung development has been studied at the cellular level using ultrastructural techniques. Continuous in utero tracheal ligation and drainage (over a period of 21-28 days) both result in malformations of the developing fetal lamb lung. Ligated lungs are larger, and drained lungs are smaller, than normal lungs at a similar gestational age. These changes are not merely due to altered lung liquid volume, but actual tissue growth thas been affected. Future alveolar wall thinning is enhanced in ligated lungs and inhibited in drained lungs, whilst the presence of differentiated alveolar type II cells (probably related to surfactant production) is decreased in ligated lungs and markedly enhanced in drained lungs. These results indicate the importance of fetal lung liquid in the regulation of pulmonary development in the fetus.