Umbilical cord occlusion stimulates breathing independent of blood gases and pH

The role of umbilical cord occlusion in the initiation of breathing at birth was investigated by use of 16 unanesthetized fetal sheep near full term. Artificial ventilation with high-frequency oscillation was used to control fetal arterial blood gas tensions. At baseline, PCO2 was maintained at control fetal values and PO2 was elevated to between 25 and 50 Torr. In the first study on six intact and four vagotomized fetuses, arterial PCO2 and PO2 were maintained constant during two 30-min periods of umbilical cord occlusion. Nevertheless, the mean fetal breathing rate increased significantly when the umbilical cord was occluded. In the second study on six intact fetuses, hypercapnia (68 Torr) was imposed by adding CO2 to the ventilation gas. When the umbilical cord was occluded, there was a significantly greater stimulation of breathing (rate, incidence, and amplitude) in response to hypercapnia than in response to hypercapnia alone. During cord occlusion, plasma prostaglandin E2 concentration decreased significantly. Results indicate that cord occlusion stimulates breathing possibly by causing the removal of a placentally produced respiratory inhibitor such as prostaglandin E2 from the circulation.     

Pulmonary vagal innervation is required to establish adequate alveolar ventilation in the newborn lamb

To investigate the effects of bilateralintrathoracic vagotomy on the establishment of continuous breathing andeffective gas exchange at birth, we studied 8 chronically instrumented, unanesthetized, sham-operated and 14 vagotomized newborn lambs after aspontaneous, unassisted vaginal delivery. Fetal lambs wereinstrumented in utero to record sleep states, diaphragmatic electromyogram, blood pressure, arterial pH, and blood-gas tensions. Six of eight sham-operated lambs established effective gas exchange within 10 min of birth, whereas 12 of 14 vagotomized animals developed respiratory acidosis and hypoxemia (P = 0.008). Breathing frequency in vagotomized newborns was significantlylower during the entire postnatal period compared with sham-operatednewborns. Vagotomized subjects also remained hypothermic during theentire postnatal period (P < 0.05).Bronchoalveolar lavage indicated an increased minimum surface tension,whereas lung histology showed perivascular edema and partialatelectasis in the vagotomized group. We conclude that stimulation ofbreathing and effective gas exchange are critically dependent on intactvagal nerves during the transition from fetal to neonatallife.

     

Mechanism of stimulation of pulmonary prostacyclin synthesis at birth

In order to investigate the mechanism behind ventilation-induced pulmonary prostacyclin production at birth, chloralose anesthetized, exteriorized, fetal lambs were ventilated with a gas mixture that did not change blood gases (fetal gas) and unventilated fetal lungs were perfused with blood containing increased O2 and decreased CO2. Ventilation with fetal gas (3%O2, 5%CO2) increased net pulmonary prostacyclin (as 6-keto-PGF1 alpha) production from -5.1 +/- 4.4 to +12.6 +/- 7.6 ng/kg X min. When ventilation was stopped, net pulmonary prostacyclin production returned to nondetectable levels. Ventilation with gas mixtures which increased pulmonary venous PO2 and decreased PCO2 also stimulated pulmonary prostacyclin production, but did not have greater effects than did ventilation with fetal gas. In order to determine if increasing PO2 or decreasing PCO2 could stimulate pulmonary prostacyclin production independently from ventilation, unventilated fetal lamb lungs were perfused with blood that had PO2 and PCO2 similar to fetal blood, blood with elevated O2, and blood that had PO2 and PCO2 values similar to arterial blood of newborn animals. Neither increased O2 nor decreased CO2 in the blood perfusing the lungs stimulated pulmonary prostacyclin synthesis. We conclude that the mechanism responsible for the stimulation of pulmonary prostacyclin production with the onset of ventilation at birth is tissue stress during establishment of gaseous ventilation and rhythmic ventilation.     

Gas-blood PCO2 gradients during avian gas exchange.

The avian respiratory system is a crosscurrent gas exchange system. One of the aspects of this type of gas exchange system is that end-expired PCO2 is greater than arterial PCO2, the highest possible value being equal to mixed venous PCO2. We made steady-state measurements of arterial, mixed venous, and end-expired PCO2 in anesthetized, spontaneously breathing chickens during inhalation of room air or 4-8% CO2. We found end-expired PCO2 to be higher than both arterial and mixed venous PCO2, the sign of the differences being such as to oppose passive diffusion. The observation that end-expired PCO2 was higher than arterial PCO2 can be explained on the basis of crosscurrent gas exchange. However, the observation that end-expired PCO2 exceeded mixed venous PCO2 must be accounted for by some other mechanism. The positive end-expired to mixed venous PCO2 gradients can be explained if it is postulated that the charged membrane mechanism suggested by Gurtner et al. (Respiration Physiol. 7: 173-187, 1969) is present in the avian lung.     

Placental gas exchange in the guinea-pig: fetal blood gas tensions following the reduction of maternal oxygen capacity with carbon monoxide

The effect of CO hypoxia on the placental exchange of respiratory gases was studied in anaesthetized pregnant guinea-pigs near term. Fetal PO2 and PCO2 were measured by mass spectrometry from a blood gas catheter in the right atrium. Administration of 5 ml CO over 65 s reduced maternal oxygen capacity by 26%. There was a rapid fall in fetal arterial PO2 and a more gradual rise in fetal PCO2. It was shown in separate experiments that the carboxyhaemoglobin content of fetal blood did not alter greatly in the first few min. after CO administration, which is the interval within which fetal PO2 was seen to fall. The alteration in fetal gas tensions can therefore be ascribed to the increased oxygen affinity and reduced oxygen capacity occasioned by the presence of carboxyhaemoglobin in the maternal blood. The alteration in placental oxygen transfer was calculated from the experimental findings, using a mathematical model of placental gas exchange in the guinea-pig. The total reduction in the oxygen transfer was 32% of the initial value. It was calculated that the reduction in maternal oxygen capacity was responsible for about two-thirds of this decrease, the remainder being due to the increased oxygen affinity of maternal blood.     

Rate of rise of intrapulmonary CO2 drives breathing frequency in garter snakes.

Garter snakes increase ventilation in response to elevated venous PCO2 without a concomitant rise in arterial PCO2 (Furilla et al. Respir. Physiol. 83: 47-60, 1991). Elevating venous PCO2 will increase the PCO2 gradient between pulmonary arterial blood and intrapulmonary gas during inspiration, leading to a greater rate of rise of intrapulmonary CO2 after inspiration. Because the lung contains CO2-sensitive receptors, I assessed the effect of the rate of rise of intrapulmonary CO2 on ventilation in unidirectionally ventilated snakes. CO2 concentration was altered using a digital gas mixer connected to a personal computer. Breathing frequency was highly correlated with the rate of rise intrapulmonary CO2 but only slightly affected by peak intrapulmonary CO2. On the other hand, tidal volume was more closely related to peak intrapulmonary CO2 than to the rate of rise of CO2. Bilateral pulmonary or cervical vagotomy nearly eliminated the ventilatory response associated with altered CO2 rise times but had little influence on the tidal volume response to the rate of rise of CO2. The mechanism whereby breathing frequency is controlled by the rate of rise of intrapulmonary CO2 is likely to originate with intrapulmonary chemoreceptors and may be important in the control of breathing during exercise.     

Gas exchange abnormalities after pneumonectomy in conditioned foxhounds

Loss of a major portion of lung tissue has been associated with impaired exercise capacity, but the underlying mechanisms are not well defined. We studied the alterations in gas exchange during exercise before and after left pneumonectomy in three conditioned foxhounds. After pneumonectomy, minute ventilation and O2 consumption at comparable submaximal work loads were unchanged but arterial PCO2 at any work load was higher, implying that ventilatory response to CO2 was impaired. Arterial hypoxemia and an elevated alveolar-arterial O2 tension difference (AaDO2) developed during heavy exercise. Using the multiple inert gas elimination technique, we determined the distributions of ventilation-perfusion (VA/Q) ratios postpneumonectomy. Significant increase in VA/Q inequality developed during exercise while the foxhounds were breathing room air, accounting for an average of 42% of the total increase in AaDO2 while diffusion limitation accounted for 58%. While the animals were breathing hypoxic gas mixture, diffusion limitation accounted for an average of 88% of the total increase AaDO2. Cardiac output and O2 delivery were reduced at a given O2 consumption after pneumonectomy. After pneumonectomy, the animals reached O2 consumptions close to the maximum expected for normal dogs. Compensation for the impairment in O2 delivery post-pneumonectomy occurred mainly by an increase in hemoglobin concentration. Training probably played an important role in returning exercise capacity toward prepneumonectomy levels. We conclude that significant abnormalities in gas exchange develop during exercise after loss of 42% of lung tissue, but the animals demonstrate a remarkable ability to compensate for these changes.     

Developmental changes in respiratory, febrile, and cardiovascular responses to PGE(2) in newborn lambs

PGE(2) has centrally mediated respiratory, febrile, and cardiovascular effects that markedly differ between fetal and adult life. We hypothesized that the transition from fetal to adult responses to PGE(2) occurs in the newborn period. Thus effects of an intracarotid infusion of PGE(2) (3 microg/min for 60 min) were determined in unanesthetized newborn lambs at 5, 10, and 15 days after birth. At 5 days, PGE(2) reduced central CO(2) sensitivity, reduced lung ventilation due to a decrease in breathing frequency, and induced hypercapnia. By 15 days, these effects of PGE(2) had waned significantly. In contrast, phasic (expiratory) thyroarytenoid muscle electromyogram activity, number of short apneas, and incidence of Biot periodic breathing were similarly increased at all three ages. PGE(2) induced a sustained fever at 10 and 15 days. Heart rate and mean arterial blood pressure were unchanged in contrast to marked increases observed by others in adults. Results showed that the transition from fetal to adult respiratory and febrile responses to PGE(2) occurs in early postnatal life, whereas adult cardiovascular responses develop later in life in sheep.     

Effects of various concentrations of O2 and umbilical cord occlusion on fetal breathing and behavior

To test the hypothesis that continuous fetal breathing could be induced by hyperoxemia alone or by hyperoxemia and umbilical cord occlusion, even in the absence of a rise in arterial PCO2 (PaCO2), we studied 18 chronically instrumented fetal sheep on 34 occasions using our window model (18). After a resting cycle (1 low-voltage followed by 1 high-voltage electrocortical activity epoch), the fetal lung was distended via an endotracheal tube using mean airway pressure of approximately cmH2O. Inspired N2, 17% O2, and 100% O2 were given to the fetus during one cycle each. While 100% O2 was given, the umbilical cord was occluded (balloon cuff).(ABSTRACT TRUNCATED AT 250 WORDS)     

Initiation of pulmonary gas exchange by fetal sheep in utero

The role of umbilical cord occlusion in the initiation of breathing at birth was investigated using unanesthetized fetal sheep that were provided with access to a tracheal supply of hyperoxic air. Near-term fetuses were studied in utero to eliminate extraneous sensory stimuli. Gasping movements began 1.4 +/- 0.1 min after cord occlusion. Breathing was irregular for several minutes before continuous breathing (greater than or equal to 40 min-1) began 6 +/- 1 min after cord occlusion (n = 10). Arterial PO2 rose significantly from 18 +/- 2 mmHg before occlusion and was 115 +/- 15 mmHg immediately before cord release at 15 or 30 min. Breathing continued even during high-voltage electrocortical activity. Cord release caused the breathing rate to decrease from 77 +/- 13 min-1 during the last 5 min of cord occlusion to 5 +/- 3 min-1 10 min after cord release (P less than 0.002; n = 7). Results indicate the change from placental to lung gas exchange can occur in the absence of sensory and thermal changes normally present at birth and that the transition is reversible.     

Effects of high-frequency and conventional ventilation on the premature lamb lung

Twelve sets of twin lambs were delivered prematurely by cesarean section at 133-136 days gestational age and ventilated for 3 h with either high-frequency oscillation (HFO) or conventional mechanical ventilation (CMV). Blood gases and pH values were monitored at 30-min intervals, and ventilator settings were adjusted to maintain CO2 partial pressure (PCO2) values within the normal range. There were no differences in the sequential blood gas or pH values between the HFO or CMV lambs. Mean airway pressures (MAP) between 8.0 and 20.4 cmH2O were required, indicating lung disease of variable severity in the lambs. The bidirectional protein leak from the vascular space to the airways and alveoli and vice versa was measured with radiolabeled albumins given by intravascular injection and with fetal lung fluid at birth. The albumin leaks in both directions increased as MAP required to normalize PCO2 increased, but the degree of leak was independent of type of ventilation. Pathological findings of epithelial necrosis and hyaline membranes occurred to a similar extent in lung sections from both groups of lambs. In the HFO animals less phosphatidylcholine in the alveolar wash and more of a tracer dose of radiolabeled natural surfactant that had been given at birth became tissue associated. These results indicate a decrease in the initial secretion of surfactant and/or a stimulation of reuptake in the HFO animals. HFO did not protect the immature lung from the development of large protein leaks or the pathological changes of the respiratory distress syndrome.     

Pulmonary gas exchange and acid-base state at 5,260 m in high-altitude Bolivians and acclimatized lowlanders.

Pulmonary gas exchange and acid-base state were compared in nine Danish lowlanders (L) acclimatized to 5,260 m for 9 wk and seven native Bolivian residents (N) of La Paz (altitude 3,600-4,100 m) brought acutely to this altitude. We evaluated normalcy of arterial pH and assessed pulmonary gas exchange and acid-base balance at rest and during peak exercise when breathing room air and 55% O2. Despite 9 wk at 5,260 m and considerable renal bicarbonate excretion (arterial plasma HCO3- concentration = 15.1 meq/l), resting arterial pH in L was 7.48 +/- 0.007 (significantly greater than 7.40). On the other hand, arterial pH in N was only 7.43 +/- 0.004 (despite arterial O2 saturation of 77%) after ascent from 3,600-4,100 to 5,260 m in 2 h. Maximal power output was similar in the two groups breathing air, whereas on 55% O2 only L showed a significant increase. During exercise in air, arterial PCO2 was 8 Torr lower in L than in N (P < 0.001), yet PO2 was the same such that, at maximal O2 uptake, alveolar-arterial PO2 difference was lower in N (5.3 +/- 1.3 Torr) than in L (10.5 +/- 0.8 Torr), P = 0.004. Calculated O2 diffusing capacity was 40% higher in N than in L and, if referenced to maximal hyperoxic work, capacity was 73% greater in N. Buffering of lactic acid was greater in N, with 20% less increase in base deficit per millimole per liter rise in lactate. These data show in L persistent alkalosis even after 9 wk at 5,260 m. In N, the data show 1) insignificant reduction in exercise capacity when breathing air at 5,260 m compared with breathing 55% O2; 2) very little ventilatory response to acute hypoxemia (judged by arterial pH and arterial PCO2 responses to hyperoxia); 3) during exercise, greater pulmonary diffusing capacity than in L, allowing maintenance of arterial PO2 despite lower ventilation; and 4) better buffering of lactic acid. These results support and extend similar observations concerning adaptation in lung function in these and other high-altitude native groups previously performed at much lower altitudes.     

Pulmonary function of the green sea turtle, Chelonia mydas

Lung volumes, oxygen uptake (VO2), end-tidal PO2, and PCO2, diffusing capacity of the lungs for CO (DLCO), pulmonary blood flow (QL) and respiratory frequency were measured in the green sea turtle (Chelonia mydas) (49-127 kg body wt). Mean lung volume (VL) determined from helium dilution was 57 ml/kg and physiological dead space volume (VD) was about 3.6 ml/kg. QL, determined from acetylene uptake during rebreathing, increased in proportion to VO2 with temperature. Therefore, constant O2 content difference was maintained between pulmonary arterial and venous blood. DLCO, measured using a rebreathing technique, was 0.04 ml X kg-1 X min-1 X Torr-1 at 25 degrees C. Several cardiopulmonary characteristics in C. mydas are advantageous to diving: large tidal volume relative to functional residual capacity promotes fast exchange of the alveolar gas when the turtle surfaces for breathing: and the concomitant rise of pulmonary blood flow and O2 uptake with temperature assures efficient O2 transport regardless of wide temperature variations encountered during migrations.     

Birth upregulates nitric oxide synthase activity in the porcine lung

Developmental changes in the lung occur at birth, allowing for the transition from placental to air breathing. Here we have measured nitric oxide synthase (NOS) activity in the porcine lung pre and post partum. NOS activity, which was predominantly calcium dependent, was low in full term fetal tissue compared to that present in lungs from the newborn (5 minutes post partum), 1, 3, 6 and 14 day old animals. No increase in activity was seen when fetal pigs were allowed to breathe for 5 minutes. Specific activity remained low in fetal tissue following partial purification. By contrast, levels of NOS III protein in tissue extracts and in pulmonary arterial endothelial cells, demonstrated by immunohistochemistry, were similar in tissue from the fetal and newborn animals. Thus NOS activity is significantly lower in fetal when compared to postnatal lung tissue despite comparable amounts of NOS III protein being expressed, and birth is followed by an abrupt increase in enzyme activity in animals born at term which correlates with an increase in protein expression.     

Effects of vagal denervation on cardiorespiratory and behavioral responses in the newborn lamb.

Recently, Wong et al. (Wong KA, Bano A, Rigaux A, Wang B, Bharadwaj B, Schurch S, Green F, Remmers JE, and Hasan SU, J Appl Physiol 85: 849-859, 1998) demonstrated that fetal lambs that have undergone vagal denervation prenatally do not establish adequate alveolar ventilation shortly after birth. In their study, however, vagal denervation was performed prenatally and the deleterious effects of vagal denervation on breathing patterns and gas exchange could have resulted from the prenatal actions of the neurotomy. To quantify the relative roles of pre- vs. postnatal vagal denervation on control of breathing, we studied 14 newborn lambs; 6 were sham operated, and 8 were vagally denervated below the origin of the recurrent laryngeal nerve. Postoperatively, all denervated animals became hypoxemic and seven of eight succumbed to respiratory failure. In vagally denervated lambs, expiratory time increased, whereas respiratory rate, minute ventilation, and lung compliance decreased compared with the sham-operated animals. In the early postoperative period, the frequency of augmented breaths was lower but gradually increased over time in the denervated vs. sham-operated group. The dynamic functional residual capacity was significantly higher than the passive functional residual capacity among the sham-operated group compared with the denervated group. No significant differences were observed in the prevalence of various sleep states and in the amount of total phospholipids or large- and small-aggregate surfactants between the two groups. We provide new evidence indicating that intrauterine actions of denervation are not required to explain the effects of vagal denervation on postnatal survival. Our data suggest that vagal input is critical in the maintenance of normal breathing patterns, end-expiratory lung volume, and gas exchange during the early neonatal period.     

Fetal oxygen consumption and PO2 during hypercapnia in pregnant sheep

In 12 experiments on 9 chronically-cathetized pregnant sheep (116-143 days of gestation), fetal oxygen consumption, umbilical blood flow and blood gas values were measured before, during and after a 30-min period of hypercapnia, induced by having the ewes breathe 5% CO2 and 18% O2 in N2. During the large amplitude breathing stimulated by hypercapnia, O2 consumption increased by 21%, solely via a rise in O2 extraction. During apnoeic periods and low amplitude breathing in the hypercapnia period, oxygen consumption was not different from the control value, but fetal arterial and umbilical venous PO2 was significantly raised, by 3 and 6 mm Hg respectively. These changes were probably due to a Bohr shift in the maternal oxygen dissociation curve. During large amplitude breathing, PO2 fell to control levels, probably due in part to the increase in O2 extraction. It is concluded that vigorous breathing movements in the fetal sheep, such as those stimulated by hypercapnia, result to an increase in fetal O2 demands. Further, the work of such breathing is large, and probably equivalent to that performed in adults during vigorous hyperventilation against an inspiratory resistance.     

Method for measuring respiration in sleep: capnography for determining ventilation]

Ventilation serves the exchange of gases between the organism and the environment. Oxygen uptake and CO2 elimination are controlled by feedback loops, that keep fluctuations in arterial CO2 pressure (PaCO2) within narrow limits Disorders in the central regulation of breathing, or impairment of the respiratory apparatus, may result in a mismatch between metabolic CO2 production and ventilatory CO2, elimination and thus in fluctuations in the PaCO2: inappropriately increased ventilation (hyperventilation) causes hypocapnia, and reduced ventilation (hypoventilation) causes hypercapnia. In order to detect such disorders during sleep, PCO2 measurement is of great importance, but direct and continuous measurement of the PaCO2 is invasive and thus unsuitable in the clinical setting. An alternative is capnography, the continuous measurement of PCO2 in inhaled and exhaled air on the basis of ultrared light absorption. This paper reviews the method, its features and limitations, and the possibilities of improving capnography to better detect sleep-related breathing disorders. In addition, data obtained from 57 patients with predominantly normal lung function, but suspected sleep disordered breathing are presented. Simultaneous measurements of capnography PETCO2) and capillary PaCO2 revealed a PETCO2 difference of +0.63 +/- 3.3 (SD) Torr. PaCO2 (38.8 +/- 4.1 Torr) and PETCO2 (38.1 +/- 4.3 Torr) were not significantly different with a correlation coefficient of r = 0.68 (p < 0.001). Thus 46% of the variation in PETCO2 was explained by changes in PaCO2. Currently the literature contains few further data on capnography during sleep. It is concluded that, provided the limitations of the method are respected and comparison with the PETCO2 is made, capnography may be a useful, noninvasive and continuous measuring method for assessing ventilation during sleep in patients with suspected sleep related breathing disorders.     

Decrease in plasma prostaglandin E2 is not essential for the establishment of continuous breathing at birth in sheep

Depression of prostanoid concentrations by indomethacin induces continuous breathing in fetal sheep, but it is not known whether this is associated with changes in fetal behaviour. Furthermore, the relationship between changes in prostaglandin E2 (PGE2) concentration after delivery and the appearance of continuous breathing has not been examined. We hypothesized that the decrease in fetal PGE2 by infusion of indomethacin would induce continuous breathing and a change in behaviour such that the fetus should come to resemble a newborn lamb; and coinciding with the establishment of continuous breathing at birth, PGE2 concentrations would decrease to a critical level below that present in the fetus. We found that continuous breathing in fetal sheep induced by infusion of indomethacin was related to a decrease in PGE2 from 436 +/- 114 to 189 +/- 73 pg/ml (P less than 0.005) but that this was not associated with fetal wakefulness. In addition, measurements of carotid arterial PGE2 concentrations showed that the beginning of continuous breathing after birth occurred at a plasma concentration of PGE2 of 1245 +/- 260 pg/ml, a value about three times higher than the 422 +/- 53 pg/ml measured in the fetus during breathing activity. Together these findings suggest that PGE2 is not primarily involved in the establishment of continuous breathing at birth.     

Fetal breathing movements and lung maturation in the congenitally abnormal human fetus

Fetal breathing movements have been studied in conjunction with features of anatomical and biochemical development of the lung at birth in fetuses with congenital abnormalities affecting the respiratory system. Total absence of fetal breathing movements or abnormal fetal breathing movements were associated with lung hypoplasia and failure of normal surfactant release into saline extracts of lung fluid. Surfactant synthesis was demonstrated regardless of the presence or absence of fetal breathing movements. The study supports the hypothesis that normal fetal breathing movements are important for fetal lung development and suggests that surfactant synthesis and its release are independent. The latter process may be dependent upon fetal breathing movements while the former is not.     

Within-breath PCO2 levels in the airways and at the pulmonary stretch receptor sites

The discharge frequency of pulmonary stretch receptors (PSRs) shows an inverse responsiveness to the CO2 partial pressure (PCO2), which is limited to an extremely hypocapnic range. During inspiration extremely hypocapnic PCO2 levels are obtained in a large part of the respiratory tract due to the diffusion limited gas mixing. The question remains whether PSRs in combination with these low levels of PCO2 are involved in the regulation of breathing. As a necessary first step to be able to answer this question, this paper is devoted to the calculation of the within-breath PCO2 transients in the respiratory tract and the corresponding PCO2 oscillations in the superficial airway tissue. For PSRs located in the smooth muscles of large bronchi, the calculations predict a time delay of a few seconds to adapt their discharge frequency to a change in PCO2 in the airway lumen. The result is in good agreement with the observed time delay reported in the literature. For the PSRs located in the acini the calculated time constant of their discharge response to PCO2 variations in the lumen is much smaller than 250 ms. This implies a within-breath response to the oscillating luminal PCO2. Further, the calculations show that a CO2 diffusion front is established within the acini during early inspiration. This diffusion front penetrates further and further into the acini with increasing work load due to the concomitant increase in inspiratory flow. As a consequence, the discharge frequency vs. volume response curve of PSRs, especially those located in distal airways, may be modified by a flow-induced PCO2-related contribution.(ABSTRACT TRUNCATED AT 250 WORDS)