Bruno Chenuel

Influence of cerebrovascular function on the hypercapnic ventilatory response in healthy humans

An important determinant of [H+] in the environment of the central chemoreceptors is cerebral blood flow. Accordingly we hypothesized that a reduction of brain perfusion or a reduced cerebrovascular reactivity to CO2 would lead to hyperventilation and an increased ventilatory responsiveness to CO2. We used oral indomethacin to reduce the cerebrovascular reactivity to CO2 and tested the steady‐state hypercapnic ventilatory response to CO2 in nine normal awake human subjects under normoxia and hyperoxia (50% O2). Ninety minutes after indomethacin ingestion, cerebral blood flow velocity (CBFV) in the middle cerebral artery decreased to 77 ± 5% of the initial value and the average slope of CBFV response to hypercapnia was reduced to 31% of control in normoxia (1.92 versus 0.59 cm−1 s−1 mmHg−1, P < 0.05) and 37% of control in hyperoxia (1.58 versus 0.59 cm−1 s−1 mmHg−1, P < 0.05). Concomitantly, indomethacin administration also caused 40–60% increases in the slope of the mean ventilatory response to CO2 in both normoxia (1.27 ± 0.31 versus 1.76 ± 0.37 l min−1 mmHg−1, P < 0.05) and hyperoxia (1.08 ± 0.22 versus 1.79 ± 0.37 l min−1 mmHg−1, P < 0.05). These correlative findings are consistent with the conclusion that cerebrovascular responsiveness to CO2 is an important determinant of eupnoeic ventilation and of hypercapnic ventilatory responsiveness in humans, primarily via its effects at the level of the central chemoreceptors.

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.

Organ dysfunction and muscular disability in myotonic dystrophy type 1.

Myotonic dystrophy type 1 (DM1) is a multisystemic disorder characterized by muscle weakness and multiple organ impairment, especially the eyes, lung, and heart. We conducted the current study to analyze the prevalence and intercorrelation among these disorders and their respective relationships with muscular disability. We assessed medical history, anthropometric data, lung volumes, arterial and venous blood samples, surface 12-lead electrocardiogram, echocardiography, ophthalmologic examination, and muscular impairment rating scale (MIRS) in 106 patients (48 male and 58 female) with DM1, aged 43.7 ± 12.8 years. Obesity, hypertriglyceridemia, and diabetes were found in respectively 25.6%, 47.6%, and 17.1% of patients. Disabling cataract was found in 43.4%, and was independently predicted by age and MIRS. Restrictive lung disease was noted in 34%, and was predicted by MIRS, CTG repeat expansion, and body mass index. Conduction disorders were found in 30.2% of patients and were predicted by left ventricular ejection fraction, MIRS, and CTG repeat expansion. We found significant relationships between cataract, restrictive lung disease, and conduction disorders: patients with cataract and those with conduction disorders exhibited more severe restrictive lung disease than the other patients. Conversely, the relative risk of restrictive lung disease was 2.42 (1% confidence interval [CI], 1.06-5.51) in patients with cataract and 2.54 (1% CI, 1.26-5.07) in patients with conduction disorders. Multivariate analysis revealed that MIRS was the only independent predictor for conduction disorders and restrictive lung disease. MIRS ≥3 and MIRS ≥4 were the best simple cutoff values to predict, respectively, lung and cardiac involvements. To conclude, muscular disability, ophthalmologic, and cardiac and pulmonary involvement are strongly correlated. Particular attention should be given to these entities in patients with distal or proximal muscular weakness. Abbreviations: BMI = body mass index, CI = confidence interval, DM1 = myotonic dystrophy type 1, ECG = surface 12-lead electrocardiogram, FEV1 = forced expiratory volume in 1 second, FSH = follicle-stimulating hormone, IgG = immunoglobulin G, LVEF = left ventricular ejection fraction, MIRS = muscular impairment rating scale, PaCO2 = arterial CO2 partial pressure, PaO2 = arterial O2 partial pressure, RNA = ribonucleic acid, RR = relative risk, RV = residual volume, TLC = total lung capacity, VC = vital capacity.

Control of arterial PCO2 by somatic afferents in sheep

The ventilatory response to electrically induced rhythmic muscle contractions (ERCs) was studied in six urethane–chloralose‐anaesthetized sheep, while arterial oxygen and carbon dioxide pressure (P  a,O 2 and P  a,CO 2) and perfusion pressure were maintained constant at the known chemoreception sites. With cephalic P  a,CO 2 held constant, the response to inhaled CO2 was virtually abolished (0.03 ± 0.04 l min−1 Torr−1). During low‐current ERC, which doubled the metabolic rate ( increased from 192 ± 23 to 317 ± 84 ml min−1, P < 0.01), followed the change in closely (from 5.24 ± 1.81 to −9.27 ± 3.60 l min−1, P < 0.01) in the absence of any chemical error signal occurring at carotid and central chemoreceptor level (Δcephalic P  a,CO 2=−0.75 ± 1 Torr). Systemic P  a,CO 2 decreased by −2.47 ± 1.9 Torr (P < 0.01). Both heart rate and systemic blood pressure increased significantly by 18.6 ± 5.5 beats min−1 and 7.0 ± 9.3 mmHg, respectively. When the CO2 flow to the central circulation was reduced during ERC by blocking venous return ( decreased by 102 ± 45 l min−1, P < 0.01), ventilation was stimulated (from 11.99 ± 4.11 to 13.01 ± 4.63 l min−1, P < 0.05). The opposite effect was observed when the arterial supply was blocked. Finally, raising the CO2 content and flow in the systemic blood did not significantly stimulate ventilation provided that the peripheral and central chemoreceptors were unaware of the changes in blood CO2/H+ composition. Our results support the existence of a system capable of controlling blood P  a,CO 2 homeostasis when the metabolism increases independently of peripheral and central respiratory chemoreceptors. Information from the skeletal muscles related to the local vascular response provides the central nervous system with a respiratory stimulus proportional to the rate at which gases are exchanged in the muscles, thereby coupling ventilation to the metabolic rate.

Interactions between volitional and automatic breathing during respiratory apraxia

The sites and forms of interactions between voluntary breathing acts and automatic respiratory rhythm generation are the subject of considerable research interest. We report here observations of the control of breathing in a patient suffering from an advanced form of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome). This patient demonstrated a severely compromised ability to perform volitional respiratory acts upon command, despite exacerbated behavioural and automatic control of respiration. The presence of residual volitional control of breathing in this patient provided interesting insights concerning the interaction between the automatic and the voluntary control of respiration. We observed that (1) when the subjects was asked to inspire voluntarily he could at best mobilize a volume similar to spontaneous VT and only very slowly; (2) automatic breathing movements persisted, superimposed onto the active voluntary movements, with an amplitude that decreased when the inspiratory activity, albeit weak, reached its maximal level; (3) during breath holding both the amplitude and the frequency of the basal spontaneous rhythmic activity were depressed. This observation therefore supports the idea of a strong interaction between volitional and automatic breathing in the form of an inhibition of automatic activity during voluntary breathing. Although, the site of interaction (spinal versus supraspinal) could not be determined during volitional inspiration, the effect of breath holding on the frequency of the spontaneous breathing activity supports the view that a volitional breathing arrest has some inhibitory effects on the respiratory oscillator at the medullary level. Finally, in an attempt to reconcile the persistence of a rhythmic activity during voluntary inspiration and expiration with previous data from the literature, it is proposed that the normal suppression of the automatic activity during voluntary inspiration relies on cortical and sub-cortical structures involved in the planning, i.e. the praxic component, of a respiratory task rather than on projections originating from the primary motor cortex.

In-Vivo Interactions Between Cobalt or Ferric Compounds and the Pools of Sulphide in the Blood During and After H2s Poisoning

Hydrogen sulphide (H2S), a chemical hazard in oil and gas production, has recently become a dreadful method of suicide, posing specific risks and challenges for the first responders. Currently, there is no proven effective treatment against H2S poisoning and its severe neurological, respiratory or cardiac after-effects. We have recently described that H2S is present in various compartments, or pools, in the body during sulphide exposure, which have different levels of toxicity. The general goals of our study were to (1) determine the concentrations and kinetics of the various pools of hydrogen sulphide in the blood, i.e., gaseous (CgH2S) versus total sulphide, i.e., reacting with monobromobimane (CMBBH2S), during and following H2S exposure in a small and large mammal and (2) establish the interaction between the pools of H2S and a methemoglobin (MetHb) solution or a high dose of hydroxocobalamin (HyCo). We found that CgH2S during and following H2S infusion was similar in sedated sheep and rats at any given rate of infusion/kg and provoked symptoms, i.e., hyperpnea and apnea, at the same CgH2S. After H2S administration was stopped, CgH2S disappeared within 1 min. CMBBH2S also dropped to 2-3μM, but remained above baseline levels for at least 30 min. Infusion of a MetHb solution during H2S infusion produced an immediate reduction in the free/soluble pool of H2S only, whereas CMBBH2S increased by severalfold. HyCo (70 mg/kg) also decreased the concentrations of free/soluble H2S to almost zero; CgH2S returned to pre-HyCo levels within a maximum of 20 min, if H2S infusion is maintained. These results are discussed in the context of a relevant scenario, wherein antidotes can only be administered after H2S exposure.

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.

Fatal cardiac arrhythmia following voluntary caffeine overdose in an amateur body-builder athlete☆

Caffeine (1,3,7-trimethylxanthine, CAS 58-08-2) is one of the most commonly consumed substances in the world and is well known to have extensive effects on physiological functions, especially on the cardiovascular system. We report a fatal cardiac arrhythmia following voluntary caffeine overdose in an amateur body-builder athlete.

High-dose hydroxocobalamin administered after H2S exposure counteracts sulfide-poisoning-induced cardiac depression in sheep

Abstract Context. Severe H2S poisoning leads to death by rapid respiratory and cardiac arrest, the latter can occur within seconds or minutes in severe forms of intoxication. Objectives. To determine the time course and the nature of H2S-induced cardiac arrest and the effects of high-dose hydroxocobalamin administered after the end of sulfide exposure. Materials and methods. NaHS was infused in 16 sedated mechanically ventilated sheep to reach concentrations of H2S in the blood, which was previously found to lead to cardiac arrest within minutes following the cessation of H2S exposure. High-dose hydroxocobalamin (5 g) or saline solution was administered intravenously, 1 min after the cessation of NaHS infusion. Results. All animals were still alive at the cessation of H2S exposure. Three animals (18%) presented a cardiac arrest within 90 s and were unable to receive any antidote or vehicle. In the animals that survived long enough to receive either hydroxocobalamin or saline, 71% (5/7) died in the control group by cardiac arrest within 10 min. In all instances, cardiac arrest was the result of a pulseless electrical activity (PEA). In the group that received the antidote, intravenous injection of 5 g of hydroxocobalamin provoked an abrupt increase in blood pressure and blood flow; PEA was prevented in all instances. However, we could not find any evidence for a recovery in oxidative metabolism in the group receiving hydroxocobalamin, as blood lactate remained elevated and even continued to rise after 1 h, despite restored hemodynamics. This, along with an unaltered recovery of H2S kinetics, suggests that hydroxocobalamin did not act through a mechanism of H2S trapping. Conclusion. In this sheep model, there was a high risk for cardiac arrest, by PEA, persisting up to 10 min after H2S exposure. Very high dose of hydroxocobalamin (5 g), injected very early after the cessation of H2S exposure, improved cardiac contractility and prevented PEA.

Lack of correlation between the ventilatory response to CO2 and lung function impairment in myotonic dystrophy patients: Evidence for a dysregulation at central level

Myotonic dystrophy Type 1 (DM1) is the most common muscular dystrophy in adults. Respiratory failure is common but clinical findings support a dysregulation of the control of breathing at central level, furthermore contributing to alveolar hypoventilation independently of the severity of respiratory weakness. We therefore intended to study the relationship between the ventilatory response to CO2 and the impairment of lung function in DM1 patients. Sixty-nine DM1 patients were prospectively investigated (43.5 ± 12.7 years). Systematic pulmonary lung function evaluation including spirometry, plethysmography, measurements of respiratory muscle strength, arterial blood gas analysis and ventilatory response to CO2 were performed. Thirty-one DM1 patients (45%) presented a ventilatory restriction, 38 (55%) were hypoxaemic and 15 (22%) were hypercapnic. Total lung capacity decline was correlated to hypoxaemia (p = 0.0008) and hypercapnia (p = 0.0013), but not to a decrease in ventilatory response to CO2 (p = 0.194). Ventilatory response to CO2 was reduced to 0.85 ± 0.67 L/min/mmHg and not correlated to respiratory muscle weakness. Ventilatory response to CO2 was neither different among restricted/non-restricted patients (p = 0.2395) nor among normoxaemic/hypoxaemic subjects (p = 0.6380). The reduced ventilatory response to CO2 in DM1 patients appeared independent of lung function impairment and respiratory muscle weakness, suggesting a central cause of CO2 insensitivity.