Bernard Chalon

H2S induced hypometabolism in mice is missing in sedated sheep.

On the basis of studies performed in mice that showed H(2)S inhalation decreasing dramatically the metabolic rate, H(2)S was proposed as a means of protecting vital organs from traumatic or ischemic episodes in humans. Hypoxia has in fact also long been shown to induce hypometabolism. However, this effect is observed solely in small-sized animals with high VO2 kg(-1), and not in large mammals. Thus, extrapolating the hypometabolic effect of H(2)S to large mammals is questionable and could be potentially dangerous. We measured metabolism in conscious mice (24 g) exposed to H(2)S (60 ppm) at an ambient temperature of 23-24 degrees C. H(2)S caused a rapid and large (50%) drop in gas exchange rate, which occurred independently of the change in body temperature. The metabolic response occurred within less than 3 min. In contrast, sheep, sedated with ketamine and weighing 74 kg did not exhibit any decrease in metabolic rate during a similar challenge at an ambient temperature of 22 degrees C. While a part of H(2)S induced hypometabolism in the mice is related to the reduction in activity, we speculate that the difference between sheep and mice may rely on the nature and the characteristics of the relationship between basal metabolic rate and body weight thus on the different mechanisms controlling resting metabolic rate according to body mass. Therefore, the proposed use of H(2)S administration as a way of protecting vital organs should be reconsidered in view of the lack of hypometabolic effect in a large sedated mammal and of H(2)S established toxicity.

Femoral vascular occlusion and ventilation during recovery from heavy exercise

Ventilation and cardiac output subside gradually following cessation of exercise, which is commonly linked to the slow wash-out of materials from the recovering muscles. The effect of hindering the removal of the metabolic products of heavy cycle exercise on the kinetics of ventilation and gas exchange was studied in 5 subjects by occluding the femoral circulation with cuffs during the first 2 min of recovery (15 tests). Fifteen undisturbed recoveries served as controls. Compared to spontaneous recovery, circulatory obstruction induced an immediate (from the first breath) decrease in minute ventilation (VE), while end-tidal CO2 (PETCO2) as well as lactate and K+ in venous blood at forearm did not change significantly. A ventilatory deficit of 27 +/- 9 L was observed from the 2 min of occlusion. Following cuff deflation, VE rose 2-3 breaths after PETCO2 began to increase in every subject. The mechanisms of the normocapnic reduction of VE during occlusion, as well as the rise of ventilation following cuff release, are still unclear. However, these results argue against any significant role for hyperpnea-inducing intramuscular chemoreception, or point to muscular perfusion as a prerequisite of such a mechanism to operate.

The control of ventilation is dissociated from locomotion during walking in sheep

This study was designed to test the hypothesis that the frequency response of the systems controlling the motor activity of breathing and walking in quadrupeds is compatible with the idea that supra‐spinal locomotor centres could proportionally drive locomotion and ventilation. The locomotor and the breath‐by‐breath ventilatory and gas exchange (CO2 output (V̇  CO 2 ) and O2 uptake (V̇  O 2 )) responses were studied in five sheep spontaneously walking on a treadmill. The speed of the treadmill was changed in a sinusoidal pattern of various periods (from 10 to 1 minute) and in a step‐like manner. The frequency and amplitude of the limb movements, oscillating at the same period as the treadmill speed changes, had a constant gain with no phase lag (determined by Fourier analysis) regardless the periods of oscillations. In marked contrast, when the periods of speed oscillations decreased, the amplitude (peak‐to‐mean) of minute ventilation (V̇E) oscillations decreased sharply and significantly (from 6.1 ± 0.4 l min−1 to 1.9 ± 0.2 l min−1) and the phase lag between ventilation and treadmill speed oscillations increased (to 105 ± 25 ° during the 1 min oscillation periods). V̇E response followed V̇  CO 2 very closely. The drop in V̇E amplitude ratio was proportional to that in V̇  CO 2 (from 149 ± 48 ml min−1 to 38 ± 5 ml min−1) with a slightly longer phase lag for ventilation than for V̇  CO 2. These results show that beyond the onset period of a locomotor activity, the amplitude and phase lag of the V̇E response depends on the period of the walking speed oscillations, tracking the gas exchange rate, regardless of the amplitude of the motor act of walking. Locomotion thus appears unlikely to cause a simple parallel and proportional increase in ventilation in walking sheep.

Control of breathing and muscle perfusion in humans

Very brief and intense exercise triggers a biphasic metabolic and respiratory response with a second phase that occurs after the cessation of the muscular activity. The effects on minute ventilation (VE) produced by manipulation of the peripheral circulation in metabolically active muscles could thus be studied without the confounding effects of painful contractions. The second phase of breath‐by‐breath VE and pulmonary gas exchange responses to a brief change in work rate (400 W for 12 s) were studied in six healthy male subjects on four occasions (24 tests). An upper thigh cuff inflation was randomly applied either above or below the systolic blood pressure (200 or 90 Torr, respectively) for 90 s just after the cessation of the contractions prior to the delayed rise in pulmonary gas exchange (eight tests in each subject). Total occlusion produced a significant reduction in the delayed rise in VE (‐29 ± 3%) which normally occurred 20–25 s after the cessation of the contractions. In contrast, cuff inflation at a level predominantly impeding venous return while partially maintaining the arterial supply reduced the rise in pulmonary gas exchange in similar proportion to that during total obstruction but with a slight but not significant reduction in ventilation (‐9 ± 5%). VE during partial occlusion was if anything higher than in control tests with similar oxygen uptake (280 W), despite a higher blood pressure (BP) during occlusion (+7 Torr). It is concluded that the factors resulting from a reduction in venous return or from the involvement of the arterial baroreflex are not responsible for the changes in VE produced by the obstruction of the circulation to and from metabolically active muscles. It is proposed that factors related to the level of the perfusion pressure in hyperaemic muscles, possibly located at the venular end of the microcirculation, could account for the changes in VE observed.

Isolation of the arterial supply to the carotid and central chemoreceptors in the sheep.

The aim of our study was to develop and validate a simple surgical model in the sheep which allows control of the gas composition of the blood supplying the carotid and central chemosensitive area independently of the rest of the body. This approach was made possible due to the specific features of the cranial circulation in the sheep. An extracorporeal circuit, consisting of a pump and a gas exchanger, was placed at the level of the two common carotid arteries to create a pressure gradient between the carotid and the systemic systems and to reverse blood flow in the vertebral vessels via the occipital arteries. When a pressure gradient of about 40 Torr was created between the systemic and carotid circulation, we found that no blood could reach the carotid bodies and the medulla without passing though the extracorporeal circulation. This was established (1) by measuring vertebral blood flow; and (2) by injecting either a coloured suspension or particles labelled with 99m*Tc into the systemic or the carotid circulation. The slope of the relationship between minute ventilation (V̇E) and systemic arterial PCO2 (Pa,CO2) during high CO2 inhalation in seven hyperoxic vagotomised and anaesthetised sheep was dramatically reduced, but remained above zero, when Pa,CO2 was maintained constant in the cephalic circuit (0.11 ± 0.15 vs. 0.70 ± 0.35 l min−1 Torr−1 for the control tests). This residual V̇E response to CO2 inhalation remains to be explained since it could not be accounted for by any of the chemical or circulatory changes occurring in the cephalic circulation. Nevertheless, this preparation provides an easy method of maintaining chemical and circulatory homeostasis at the chemoreceptor level.

Ventilatory dynamics in children and adults during sinusoidal exercise

SummaryThe ventilatory response to sinusoidally varying exercise was studied in five adults and seven prepubertal children to determine whether the faster kinetics of ventilation observed in children during abrupt changes in exercise intensity remained more rapid when exercise intensity varied continuously. Each subject exercised on a cycle ergometer first against a constant load and then against a load fluctuating over six different periods ranging from 0.75 to 10 min. The pedal rate was kept constant for all loads. The inspiratory minute ventilation was determined breath-by-breath. Amplitude (A) and phase angle (ϕ) of the fundamental component and the first harmonics of the ventilatory response were calculated by Fourier analysis for an integer number of waves for each period. From the relationship between A, ϕ and frequency, dynamic parameters of a first order model with and without delay were compared between adults and children. Firstly we found that the ventilatory time constant was significantly faster in children: 49.7 (SD 9.1) s vs 74.6 (SD 11.1) s (P<0.01). Secondly, the change in A and ϕ with the frequency was not however characteristic of a first order system without delay in most of the subjects ϕ > 90° for the shorter periods). Thirdly, even when the ventilatory control system was described as a first order model with a positive delay, time constants remained significantly shorter in children: 45.6 (SD 5.7) s vs 67.4 (SD 13) s (P<0.01). The ability to increase ventilation faster in children appeared to be a characteristic of the ventilatory control system during exercise independent of the type of drive used.

Effect of exercise on lung-perfusion scanning in patients with bronchogenic carcinoma

The aim of this study was to determine whether perfusion-scintillation scanning, used as a predictive pre-operative index of lung functionality in patients with lung cancer, is affected by the level of pulmonary blood flow (PBF). Twenty patients with primary lung cancer underwent spirometry and a radionuclide-perfusion scan (macroaggregated albumin particles labelled with 99mTechnetium) both at rest and during the last minute of a ramp-like increase in work rate until exhaustion. On average, the perfusion of the lung with the tumour was significantly reduced by the same magnitude at rest and during exercise (mean±sd: −9±6% versus −10±4% of the cardiac output), regardless of the extent of the tumour. However, subject-by-subject analysis revealed that in two patients, a larger decrease in the perfusion of the lung with the tumour was observed during exercise than at rest (−11% and −17%, respectively). This leads to an underestimation of predictive postoperative functional parameters if resting values are used in these patients. The use of perfusion scintigraphy at rest therefore gives a clear picture of the functionality of the lung before resection in most patients requiring surgery.

Heart rate dynamics during sinusoidal exercise: comparison of the control system between children and adults

The aim was to model the dynamics of heart rate (HR) response to sinusoidal work rate (WR) forcing in children and adults. Seven pre-pubertal boys (aged 10-13) and five adult males (aged 22-37) were studied. Continuous ECG recordings were obtained during the following physiological manoeuvres: five constant amplitude ergometer exercises with WR varying sinusoidally with periods of 0.75, 1, 2, 3.5, and 5 min duration, and one step exercise at a constant WR equal to the midpoint of the sinusoid amplitude. The amplitude ratio (AR; standardized by WR) of the fundamental harmonic of the HR response and the phase shift (phi) between the WR to HR were calculated by Fourier analysis. The HR dynamic parameters (gain and time constant (tau)) of a first order model with or without delay (Td) were also estimated. The AR in children was always higher than that in adults, in absolute terms, but not as a function of body weight. The phi was more delayed in the children than the adults only for the shortest period, i.e. 0.75 min. The tau for the first order model, either without or with Td, was found to be no difference between children and adults (44.7 vs. 45.9 s (without Td), 34.9 vs. 42.3 s (with Td)). Td, however, was longer in the children (6.6 vs. 2.3 s). The goodness of fit for the first order model with Td was better than that without Td in children, i.e. due to the difference of phi for 0.75 min period, whereas the HR dynamics in adults was appropriately described by first order model without Td. It is concluded that the fundamental control of HR to sinusoidal exercise between children and adults was not appreciably different, except for a small Td difference at high sinusoidal frequency.

Distention of Venous Structures in Muscles as a Controller of Respiration

The search for a Coe flow-related control mechanism of ventilation (VE) that could account for PaCO2 homeostasis1– remains rather disappointing. Indeed, although activation of chemoreceptors or mechanoreceptors located in specific sites of the cardiovascular system, i.e. the right heart6,7,8, the pulmonary circulation9,10, the carotid bifurcation or the ascending aorta11 can trigger ventilatory reflexes, their role in adjusting ventilation to the rate of incoming blood flow, when metabolism varies, is far from being established3,12. It remains therefore unclear what afferent information reaching the central nervous system could adjust the level of ventilation to the rate of CO2 removed from the tissues and reaching the lungs, to maintain constant arterial PCO2. The possible role of the peripheral circulation, mainly in the muscles, as a possible controller of respiration has been more recently proposed13–16, since a large proportion of the mechanosensitive group III and IV muscle afferent fibers, which have long been shown to stimulate ventilation17–18, are located in the adventitia of the venules. Based on human19–24 and animal13,14 studies in which the peripheral circulation was either impeded or increased, it was argued that during a peripheral vasodilatation, the change in volume of the post-capillary and/or venous network could be a source of VE stimulation15. Such a mechanism places therefore the circulation in the tissues as a possible site of mediation between peripheral gas exchange and ventilatory control.

Frequency response of the input reaching the respiratory centres during moderate intensity exercise.

It has been suggested that the intrinsic properties of the brainstem respiratory neurones, responsible for a short term potentiation phenomenon, could slow and magnify the effects of an immediate and steady centrally mediated stimulus to breathe during exercise1,2,3. Worth of note is that this phenomenom has been described mainly during and following stimulation of somatic afferent fibres or the sinus nerve3. Such a short term potentiation phenomenon was put forward to try to reconcile the traditional description of the dynamics of the \( \dot v \) E on and off-transient response to exercise, which has a 60 second time constant and follows the \( \dot VO_2 \) and \( \dot VCO_2 \) time course4,5,6.