We have attempted in this review to give an account of an afferent vagal input from the lower respiratory tract that has still to be explored fully, and to present experimental evidence that this fine fibre afferent system plays a significant role in the neural control of respiratory function in both normal and pathological circumstances.

Afferent vagal C fibre innervation of the lungs and airways and its functional significance

Inhibition of Hypoxia-inducible Factor (HIF) Hydroxylases by Citric Acid Cycle Intermediates POSSIBLE LINKS BETWEEN CELL METABOLISM AND STABILIZATION OF HIF

(1973). Sensory Irritation by Airborne Chemicals. CRC Critical Reviews in Toxicology: Vol. 2, No. 3, pp. 299-363.

Sensory Irritation by Airborne Chemicals

Objective To compare the hospital course and clinical outcome of preterm infants with respiratory distress syndrome treated with surfactant and managed with high-frequency oscillatory ventilation (HFOV) or conventional mechanical ventilation (CV) as their primary mode of ventilator support. Design A prospective randomized clinical trial. Setting Three community-based level III neonatal intensive care units. Subjects A total of 125 neonates who were 35 weeks or less estimated gestation requiring intubation and assisted ventilation for respiratory distress syndrome with arterial to alveolar oxygen ratio less than .50. Interventions Patients were randomized to continue CV (61 patients) or be changed to HFOV (64 patients) after exogenous surfactant administration (100 mg/kg). HFOV was used in a strategy to promote lung recruitment and maintain lung volume. Protocol respiratory care guidelines were followed; otherwise routine care was provided by each neonatal intensive care unit. Measurements and main results No differences were noted in demographic features between the two study groups. The study population birth weight was 1.51 +/- .47 kg (mean +/- SD), gestational age was 30.9 +/- 2.5 weeks, and study entry age was 2 to 3 hours. Patients randomized to HFOV demonstrated the following significant findings compared with CV-treated patients: vasopressor support was less intensive; surfactant redosing was not as frequent; oxygenation improved more rapidly and remained higher during the first 7 days; fewer infants required prolonged supplemental oxygen or ventilator support; treatment failure was reduced; more patients survived without chronic lung disease at 30 days; need for continuous supplemental oxygen at discharge was less; frequency of necrotizing enterocolitis illness was lower; there were fewer abnormal hearing tests; and hospital costs were decreased. No differences were seen between the two study groups in the frequency or severity of patent ductus arteriosus, air leak, retinopathy of prematurity, or intraventricular hemorrhage. Length of hospital stay and survival to discharge were similar for HFOV- and CV-treated infants. Conclusions When used early with a lung recruitment strategy, HFOV after surfactant replacement resulted in clinical outcomes consistent with a reduction in both acute and chronic lung injury. Benefit was evident for preterm infants both less than or equal to 1 kg and more than 1 kg. In addition, early HFOV treatment may have had a more global effect on patient health throughout the hospitalization, resulting in reduced morbidity and decreased health care cost.

The Provo multicenter early high-frequency oscillatory ventilation trial: improved pulmonary and clinical outcome in respiratory distress syndrome.

We have identified the tracheal and laryngeal afferent nerves regulating cough in anaesthetized guinea-pigs. Cough was evoked by electrical or mechanical stimulation of the tracheal or laryngeal mucosa, or by citric acid applied topically to the trachea or larynx. By contrast, neither capsaicin nor bradykinin challenges to the trachea or larynx evoked cough. Bradykinin and histamine administered intravenously also failed to evoke cough. Electrophysiological studies revealed that the majority of capsaicin-sensitive afferent neurones (both Adelta- and C-fibres) innervating the rostral trachea and larynx have their cell bodies in the jugular ganglia and project to the airways via the superior laryngeal nerves. Capsaicin-insensitive afferent neurones with cell bodies in the nodose ganglia projected to the rostral trachea and larynx via the recurrent laryngeal nerves. Severing the recurrent nerves abolished coughing evoked from the trachea and larynx whereas severing the superior laryngeal nerves was without effect on coughing. The data indicate that the tracheal and laryngeal afferent neurones regulating cough are polymodal Adelta-fibres that arise from the nodose ganglia. These afferent neurones are activated by punctate mechanical stimulation and acid but are unresponsive to capsaicin, bradykinin, smooth muscle contraction, longitudinal or transverse stretching of the airways, or distension. Comparing these physiological properties with those of intrapulmonary mechanoreceptors indicates that the afferent neurones mediating cough are quite distinct from the well-defined rapidly and slowly adapting stretch receptors innervating the airways and lungs. We propose that these airway afferent neurones represent a distinct subtype and that their primary function is regulation of the cough reflex.

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/jphysiol.2003.057885

Identification of the tracheal and laryngeal afferent neurones mediating cough in anaesthetized guinea-pigs.

The influence of the degree of coupling between the breathing and cycling rhythms (K) on oxygen uptake 
$$\dot V_{O_2 } $$

 was examined in 30 volunteers. They cycled on an ergometer with a load equal to 50% of their work capacity 170 in two experimental runs with spontaneous breathing rhythm, and in a further two runs with acoustically triggered breathing. K was continuously ascertained. 
$$\dot V_{O_2 } $$

 and other respiratory parameters were measured by an automatic “breath-by-breath analysis” system. In 16 subjects, 
$$\dot V_{O_2 } $$

 -differences between runs were correlated with the differences in K. In the majority of these subjects (12), 
$$\dot V_{O_2 } $$

 decreased significantly with increasing K. In 14 subjects, 
$$\dot V_{O_2 } $$

 -and K-variations within individual runs were analyzed. Phases with higher K were regularly accompanied by a decrease in 
$$\dot V_{O_2 } $$

 . It is concluded that coupling the breathing and cycling rhythms reduces 
$$\dot V_{O_2 } $$

 for a given moderate work load, although the magnitude of the 
$$\dot V_{O_2 } $$

 -reduction varies considerably between individuals.

Effect of coupling the breathing- and cycling rhythms on oxygen uptake during bicycle ergometry

Decreased arterial partial oxygen pressure (PaO2) below a certain level presents a strong stimulus for increasing cerebral blood flow Although several field studies examined the time course of global cerebral blood flow (gCBF) changes during hypoxia at high altitude, little was known about the regional differences in the flow pattern Positron emission tomography (PET) with [(15)O]H2O was used on eight healthy volunteers to assess regional cerebral blood flow (rCBF) during short-term exposure to hypoxia corresponding to simulated altitudes of 3,000 and 4,500 m Scans at the simulated altitudes were preceded and followed by baseline scans at the altitude of Zurich (450 m, baseline-1 and baseline-2) Each altitude stage lasted 20 minutes From baseline to 4,500 m, gCBF increased from 344 +/- 59 to 416 +/- 90 mL x minute(-1) x 100 g(-1) (mean +/- SD), whereas no significant change was noted at 3,000 m During baseline-2 the flow values returned to those of baseline-1 Statistical parametric mapping identified the hypothalamus as the only region with excessively increased blood flow at 4,500 m (+328% +/- 219% relative to baseline-1) The corresponding value for the thalamus, the structure with the second largest increase, was 192% +/- 163% Compared with the rest of the brain, an excessive increase of blood flow during acute exposure to hypoxia is found in the hypothalamus The functional implications are at present unclear Further studies of this finding should elucidate its meaning and especially focus on a potential association with the symptoms of acute mountain sickness

https://journals.sagepub.com/doi/pdf/10.1097/00004647-199808000-00011

Changes of cerebral blood flow during short-term exposure to normobaric hypoxia.

The relationship between pedalling- and breathing rhythm was studied in 34 medical students (“non-cyclists”) and 10 racing cyclists on an electromagnetic bicycle-ergometer, the effective work load of which (50 W, 100 W, 150 W, 200 W) was independent of the pedalling rate. The criteria used were integer p/b ratios (pedalling rate being a multiple of breathing frequency) and phase coupling (the breathing phases starting preferentially at a certain angle of the pedalling cycle).

Relation between pedalling- and breathing rhythm.

In order to investigate whether vascular endothelial growth factor (VEGF) and inflammatory pathways are activated during acute hypobaric hypoxia in subjects who are susceptible to high-altitude pulmonary oedema (HAPE-S), seven HAPE-S and five control subjects were exposed to simulated altitude corresponding to 4000 m in a hypobaric chamber for 1 day. Peripheral venous blood was taken at 450 m (Zurich level) and at 4000 m, and levels of erythropoietin (EPO), VEGF, interleukin-6 (IL-6) and the acute-phase proteins complement C3 (C3), alpha1-antitrypsin (alpha1AT), transferrin (Tf) and C-reactive protein (CRP) were measured. Peripheral arterial oxygen saturation (SaO2) was recorded. Chest radiography was performed before and immediately after the experiment. EPO increased during altitude exposure, correlating with SaO2, in both groups (r = -0.86, P < 0.001). Venous serum VEGF did not show any elevation despite a marked decrease in SaO2 in the HAPE-S subjects [mean (SD) HAPE-S: 69.6 (9.1)%; controls: 78.7 (5.2)%]. C3 and alpha1AT levels increased in HAPE-S during hypobaric hypoxia [from 0.94 (0.11) g/l to 1.07 (0.13) g/l, and from 1.16 (0.08) g/l to 1.49 (0.27) g/l, respectively; P < 0.05], but remained within the clinical reference ranges. No significant elevations of IL-6, Tf or CRP were observed in either group. The post-exposure chest radiography revealed no signs of oedema. We conclude that VEGF is not up-regulated in HAPE-S and thus does not seem to increase critically pulmonary vascular permeability during the 1st day at high altitude. Furthermore, our data provide evidence against a clinically relevant inflammation in the initial phase of exposure to hypoxia in HAPE-S, although C3 and alpha1AT are mildly induced.

Effects of hypobaric hypoxia on vascular endothelial growth factor and the acute phase response in subjects who are susceptible to high-altitude pulmonary oedema.

In order to anlayse the respiratory, cardiovascular, and ECG responses to acute hypoxic hypoxia, three experimental series were carried out in a randomized manner on 11 healthy, unacclimatized volunteers at rest during standardized stepwise exposure to 6000 m (PAO2 35.2±2.9 mmHg/4.7±0.4 kPa) in a low-pressure chamber a) without (control), b) with propranolol, and c) with atropine combined with propranolol. The results, show that hypoxic hyperventilation and alveolar gases are not affected by activation of the sympatho-adrenal axis or by parasympathetic withdrawal. Sympathetic activity, however, increases heart rate, stroke volume (pulse pressure), estimated cardiac output and systolic blood pressure, whereas decreased parasympathetic activity increases heart rate and estimated cardiac output, but lowers stroke volume. The fall in peripheral resistance, observed during progressive hypoxia in all three groups, is thought to be due to hypoxia-induced depression of the vasomotor center. At altitude catecholamine secretion and vagal withdrawal synergistically account in the ECG for the R-R shortening, the relative Q-T lengthening, the elevation of the P wave and the ST-T flattening. Probable direct hypoxic effects on the heart are the increase in P-Q duration and the minor but still significant depression of the T wave. It is concluded that at altitude increased sympatho-adrenal and decreased parasympathetic activity is without effect on hypoxic hyperventilation, but accounts for most of the cardiovascular and ECG changes. Diminution of sympathetic activity and imminent vagotonia arising after acute ascent to 6000 m probably reflect hypoxia of the central nervous system.

E. A. Koller

Papers

Effect of coupling the breathing- and cycling rhythms on oxygen uptake during bicycle ergometry

Changes of cerebral blood flow during short-term exposure to normobaric hypoxia.

Relation between pedalling- and breathing rhythm.

Effects of hypobaric hypoxia on vascular endothelial growth factor and the acute phase response in subjects who are susceptible to high-altitude pulmonary oedema.

Effects of atropine and propranolol on the respiratory, circulatory, and ECG responses to high altitude in man.