Respiratory sensitivity before and after birth.

A description is first given of respiratory activity in the fetus and its control. Evidence suggests that when the fetus makes respiratory movements, it is in a state comparable to REM sleep in the newborn and adult and that in the alternating periods of apnoea, it is in quiet sleep. It does not appear that the respiratory movements are normally regulated by chemical or reflex, e.g. Hering Breuer, inputs though they are enhanced by CO2 and depressed by hypoxia. In the apnoeic periods, breathing movements are virtually impossible to elicit by chemical or reflex means. Evidence from examination of peripheral inputs indicates that: the carotid body chemoreceptors are inhibited at receptor level, stimulation of the aortic chemoreceptors affects the circulation only and although pulmonary stretch receptors are active and are excited by inflation of the fetal lung, such inflation does not affect discharge in medullary respiratory units or phrenic nerve. Since there is no real evidence of immaturity of the respiratory system in late gestation and since chemical and most reflex inputs appear to provide an adequate stimulus, it is most probable that the periods of apnoea are caused by an inhibitory process, possibly of supra-pontine origin which acts close to medullary respiratory units and effectively inhibits the operation of the automatic component. This inhibitory process may operate periodically; or continuously and be periodically overridden in REM sleep. After birth, breathing is normally continuous and sensitive to lung inflation, CO2 and after a variable delay, to hypoxia. This may be due to the lifting of the inhibitory process allowing activation of the automatic component. However, there is evidence that even in normal, full term infants, full maturation of the automatic component is not complete until about three months of age and in the meanwhile, breathing tends to be imperfectly regulated and subject to damped oscillations when disturbed.

Chemoreceptors and their reflexes with special reference to the fetus and newborn.

Such evidence as there is indicates that hypoxia excites peripheral chemoreceptors in the adult by causing a fall in the rate of oxidative phosphorylation and that this process is potentiated by a rise in PCO2 which most probably acts by altering intracellular pH. What is unclear is whether this occurs in Type I cells or in sensory fibres and whether either should be regarded as the primary receptor. There is also uncertainty about the role of noradrenaline and dopamine, which are stored and presumably secreted in the chemoreceptor complex: are they, respectively, excitatory and inhibitory transmitters or do they modulate an underlying chemoreceptive process? In the fetus, the carotid body chemoreceptors are largely insensitive despite an adequate chemical stimulus; they are activated at or shortly after birth by an unknown process and thereafter, in the newborn period, they appear to be involved in sensing chemical changes in arterial plasma and assisting in respiratory stability but there is some evidence that they only become fully effective some days or even weeks after birth. There is now compelling evidence that important if not unique central chemoreceptors, sensitive to changes in pH of brain extracellular fluid are located superficially in the ventro-lateral part of the medulla in the adult but in the fetus it appears that these receptors or their afferent discharge are in some way inhibited such that respiratory activity when it occurs is driven largely by supra-pontine influences, the so-called 'automatic' component of respiratory control being largely if not entirely suppressed. At birth, this component is clearly activated since breathing is continuous and sensitive to chemical stimulation. It is probable that in a proportion of newborn, activation of this component is either imperfect or delayed which would lead to respiratory instability or even failure and this would be more likely to occur in quiet sleep than in rapid-eye-movement sleep or with the newborn awake. A more complete understanding of the changes in sensitivity of the central and peripheral chemoreceptors and their reflexes at birth is required before the reasons for inadequate respiratory control in the newborn period can be appreciated.

Measurements of the partial pressure of oxygen in the carotid body of fetal sheep and newborn lambs.

The partial pressure of oxygen in chemoreceptors tissue of the carotid body was measured in parallel with arterial oxygen tension in eleven sheep fetuses exteriorized from 9 ewes anaesthetized with pentobarbitone, in 6 of these fetuses in the transitional period following occlusion of the umbilical cord and the start of artificial pulmonary ventilation and in 6 naturally born lambs, 10-36 h old. In the fetal carotid body, O2 gradients were very small and, in the majority of tests, the arterial-to-tissue O2 difference was small or negligible. During the transitional period, this difference increased as arterial PO2 rose and in the newborn lamb, this difference was as large as that reported in the adult carotid body. These results indicate that in the fetal carotid body, the levels of blood flow and metabolism are likely to be homogeneous and that the ratio of O2 supply and O2 consumption is high, that in the transitional period and in the newborn, either O2 supply falls or O2 consumption increases or both, and that these changes are both O2-dependent and persist although arterial PO2 in the newborn is reduced to or close to fetal levels. The possible mechanisms are discussed.

The role of sympathetic nerves in the activation of the carotid body chemoreceptors at birth in the sheep.

Carotid body chemoreceptor afferent discharge was recorded in the sinus nerve of sheep fetuses within a few days of term, exteriorized from ewes given pentobarbitone anaesthesia, and in six newborn lambs, 7-21 h old. Chemoreceptor discharge, defined as such since it was irregular, had no relation to the heart beat and was excited by hypoxia, hypercapnia, H+ and NaCN, was recorded in only 8 out of 20 fetuses. It was abundant in both the newborn lambs and also in fetus carotid bodies studied in vitro. Although electrical stimulation of the sympathetic fibres to the carotid body excited the fetal chemoreceptors and caused a fall in carotid body blood flow, the fetal chemoreceptors still responded to natural stimuli and drugs in both fetus and lamb after the sympathetic pathway had been cut. Further, there appeared to be clear dissociation of chemoreceptor and sympathetic activation shortly after birth. These results confirm and extend earlier studies and they suggest that, although the sympathetic pathway may contribute to chemoreceptor activation at birth, other, possibly more important, factors must be involved. These are discussed.

Fluctuations of Pa, CO2 with the same period as respiration in the cat.

1. A CO2 sensor using mass spectrometry is described. It responds linearly to O2 and CO2 with a time constant of 0.5 sec: it is not affected by pressure or flow in the physiological range: its temperature coefficient is 4 mm Hg PCO2 per degree C at 37 degrees C. 2. When this sensor and its through flow cuvette were placed in a common carotid artery-to-jugular vein loop in anaesthetized cats breathing spontaneously or being ventilated artificially, fluctuations of Pa, CO2 which had the same period as respiration were readily observed. 3. The amplitude of these fluctuations varied inversely with respiratory frequency being less than 1.5 mmHg Pa, CO2 in the range of normal respiratory frequencies in the cat, 25--35 min-1. The amplitude also varied with the mixed venous-to-end tidal CO2 difference which was altered either by giving the cat CO2 to inhale or infusing CO2 intravenously. 4. We have concluded that these fluctuations of Pa, CO2 are unlikely to provide a significant drive to ventilation at normal respiratory frequencies but they may provide a signal that gas exchange in the lung is less than optimal.

Changes in partial pressure of carbon dioxide with time in carotid arterial blood in cats.

1. A rapidly responding CO2 sensor and cuvette were placed in the carotid artery of anaesthetized cats and changes of PCO2 in post-pulmonary capillary blood were recorded when flow through the cuvette was suddenly stopped. 2. Under control conditions when the cats breathed spontaneously or were ventilated artificially, stop-flow caused Pa, CO2 to decay by 2--5 mmHg reaching a new equilibrium in 10--15 sec. The amount by which CO2 decayed was reduced by the inhalation of high O2. The decay was enhanced by hypoxia, the inhalation or infusion of CO2. It was reversed by the administration of acetazolamide: now with stop-flow, Pa, CO2 rose by 8--15 mmHg. 3. the mechanism of this decay is uncertain. We propose that it is due to the transfer of CO2 from plasma to red cells in post-capillary blood in response to the reduction of [H+]i as H+ binds to Hb following the oxylabile release of CO2 from Hb.

A structure in the wall of the internal carotid artery in the rat.

A structure has been found consistently in the wall of the internal carotid artery of the rat as it passes through the carotid canal. It consists of modified smooth muscle cells arranged longitudinally which exhibit abundant pinocytosis and are located close to endothelial cells, with which they make contact. These cells do not appear to be innervated. The closeness of this structure to the arterial lumen, into which it may actually protrude, suggests that it may be sensitive to vaso-active substances in arterial blood. If so, it is well place to affect cerebral blood flow.

The cholinergic pathway to cerebral blood vessels. I. Morphological studies.

The application of cobalt chloride to the peripheral cut end of the greater superficial petrosal nerve (g.s.p.n.) in rats revealed that only a few fibers in the plexus of nerves on the adventitial surface of the internal carotid artery were in axonal continuity with the g.s.p.n. A similarly small contribution of cholinergic fibers to cerebral blood vessels from this nerve was suggested by the observation that section of the g.s.p.n. resulted in an insignificant reduction in the density of the AChE-staining plexus in the internal carotid and cerebral arteries and in the incidence of at most 2% degenerate terminals of those observed on the middle cerebral artery. Alternative explanations of the results are discussed: that the AChE-staining fibers are postganglionic, that the time course for degeneration is unusually slow and that non-cholinergic fibers stain non-specifically for AChE. It is concluded that a cholinergic dilator pathway is most probably carried by the g.s.p.n. but that it is not unique.

The cholinergic pathway to cerebral blood vessels. II. Physiological studies.

The effect of stimulating the greater superficial petrosal nerve (g.s.p.n.) upon retroglenoid venous blood flow has been tested in anaesthetized, paralysed and artificially ventilated rats. In 11 out of 15 tests, blood flow increased by an average of 25% with a time to peak response of 28 s. This response was abolished with the injection of atropine 0.1 mg kg-1 injected intra-arterially. With both petrosal nerves intact, the administration of 6-7% CO2 in air or 15% O2 in N2 caused average increases in blood flow of 105% and 45% respectively. These responses were not affected by bilateral section of the g.s.p.n. Similar experiments were carried out in 5 anaesthetized, spontaneously breathing rabbits in which, in addition to PaCO2 and PaO2, PO2, PCO2 and blood flow in the caudate nucleus were measured continuously using chronically implanted mass spectrometer catheters and heated thermistors. Caudate nucleus blood flow increased in response to hypoxia and hypercapnia and this response was not significantly affected by section of one or both g.s.p.n., sinus or vagus nerves. With section of sinus and vagus nerves, blood flow changed passively with arterial pressure.

Carbon dioxide and venous return and their interaction as stimuli to ventilation in the cat.

1. Respiratory responses were measured in forty-seven cats, made decerebrate or anaesthetized with pentobarbitone or chloralose-urethane, to changes in the level of CO(2) infused into the inferior vena cava via an external oxygenator circuit or to changes in the volume of venous return or to the inhalation of CO(2).2. No consistent difference was found between the respiratory response to the increase in the level of CO(2) infused or CO(2) inhaled provided that the volume of venous return during both sets of tests was held constant at normal levels.3. If the volume of venous return was increased and the level of CO(2) infused maintained at levels such that V(CO2) did not increase, ventilation increased with a fall in P(a, CO2), a response lying approximately on the isometabolic curve.4. If the volume of venous return and the level of CO(2) infusion were raised together, a spectrum of intermediate respiratory responses was obtained which reproduced all those seen in earlier papers, in muscular exercise or other hypermetabolic states.5. None of the steady-state respiratory responses was significantly affected by bilateral vagotomy or section of the sinus nerves, though sinus nerve section slowed the responses to infused or inhaled CO(2) and they were then less precisely controlled.6. Additional experiments indicated that where CO(2) was infused or inhaled, the effective stimulus to respiration was an increase in mean P(a, CO2) in proportion to the CO(2) added and that the respiratory response to CO(2) was enhanced by reduced blood volume. How the changes in venous return were sensed and affected respiration, remains unclear.7. These results may explain why previous workers have obtained exaggerated respiratory responses to the infusion of CO(2) and why respiration increases rapidly at the start of exercise and is then maintained at high levels without discernible change in the chemical stimulus in arterial blood.

The pH of brain extracellular fluid in the cat.

1. The blood supply to the medulla was determined by the injection of indian ink via the vertebral arteries. Virtually the whole medulla was supplied by penetrating vessels from the ventral surface. The highest density of small arterioles and venules was found close to the roots of XII and on the ventrolateral surface.2. The pH of extracellular fluid (pH(e.c.f.)) was measured with pH microelectrodes of tip size 1-3 mum in cortex and medulla in seventeen cats, anaesthetized with pentobarbitone or a chloralose-urethane mixture. Parallel measurements were made of the pH of c.s.f. and plasma, the DC potential between plasma and brain and ventilation or phrenic nerve discharge.3. In the majority of tests under steady conditions, the pH of e.c.f. was found to be lower than that of c.s.f. by between 0.03 and 0.08 units. No systematic pH gradients could be found to a depth of 5 mm beneath the surface of either medulla or cortex.4. When plasma P(CO2) was altered, pH(e.c.f.) changed with a latent period and speed of response related to the density of blood vessels. In vascular areas of the medulla and in the cortex, the latent period of 4 sec and the change of pH(e.c.f.) coincided with changes in ventilation. Changes in pH(c.s.f.) over the same areas were invariably slower.5. CO(2) buffering capacities were in the order plasma > e.c.f. > c.s.f. Typical values were respectively, -2.2, -2.1 and -1.6.6. The pH of e.c.f. was unaffected by the intravenous injection of H+ and only slowly by the injection of HCO(3)-. Only up to a depth of 1 mm beneath the surface was pH(e.c.f.) affected by superfusion of mock c.s.f. in the range 6.8-8.0 units. This response had a latent period of 2-3 min and was complete in 15 min.7. The pH of e.c.f. fell with hypoxia after a latent period of > 1 min and if all vasosensory nerves had been cut, pH(e.c.f.) was markedly affected by changes of blood pressure.8. These results indicate that even under steady conditions, the pH of e.c.f. and c.s.f. is not identical, that pH(e.c.f.) is more obviously affected by changes in P(a, CO2) than pH(c.s.f.) and that putative H+ sensors which drive respiratory neurones are likely to be similarly affected.