Early effects of acetazolamide on hemoglobin mass and plasma volume in chronic mountain sickness at 5100 m.

INTRODUCTION AND OBJECTIVES: Chronic Mountain Sickness (CMS) syndrome, combining excessive erythrocytosis and clinical symptoms in highlanders, remains a public health concern in high-altitude areas, especially in the Andes, with limited therapeutic approaches. The objectives of this study were to assess in CMS-highlanders permanently living in La Rinconada (5100-5300 m, Peru, the highest city in the world), the early efficacy of acetazolamide (ACZ) and atorvastatin to reduce hematocrit (Hct), as well as the underlying mechanisms focusing on intravascular volumes. MATERIALS AND METHODS: Forty-one males (46±8 years of age) permanently living in La Rinconada for 15 [10-20] years and suffering from CMS were randomized between ACZ (250 mg once-daily; N = 13), atorvastatin (20 mg once-daily; N = 14) or placebo (N = 14) uptake in a double-blinded parallel study. Hematocrit (primary endpoint) as well as arterial blood gasses, total hemoglobin mass (Hbmass) and intravascular volumes were assessed at baseline and after a mean (±SD) treatment duration of 19±2 days. RESULTS: ACZ increased PaO2 by +13.4% (95% CI: 4.3 to 22.5%) and decreased Hct by -5.2% (95% CI: -8.3 to -2.2%), whereas Hct remained unchanged with placebo or atorvastatin. ACZ tended to decrease Hbmass (-2.6%, 95% CI: -5.7 to 0.5%), decreased total red blood cell volume (RBCV, -5.3%, 95% CI: -10.3 to -0.3%) and increased plasma volume (PV, +17.6%, 95% CI: 4.9 to 30.3%). Atorvastatin had no effect on intravascular volumes, while Hbmass and RBCV increased in the placebo group (+6.1%, 95% CI: 4.2 to 7.9% and +7.0%, 95%CI: 2.7 to 11.4%, respectively). CONCLUSIONS: Short-term ACZ uptake was effective to reduce Hct in CMS-highlanders living at extreme altitude >5,000 m and was associated with both an increase in PV and a reduction in RBCV.

[Adaptation to altitude in respiratory diseases]. / Adaptation à l'altitude dans les maladies respiratoires.

The frequency of high-altitude sojourns (for work, leisure, air travel or during car/train journeys) justifies the question of their tolerance, especially in people with pre-existing respiratory disease. Reduced barometric pressure and abrupt variations in temperature and inhaled air density may be responsible for modifications affecting the respiratory system and, in fine, oxygenation. These modifications may compromise altitude tolerance, further worsen respiratory dysfunction and render physical exercise more difficult. In obstructive lung disease, altitude is associated with gas exchange impairment, increased ventilation at rest and during exercise and heightened pulmonary artery pressure through hypoxic vasoconstriction, all of which may worsen dyspnea and increase the risk of altitude intolerance (acute mountain sickness, AMS). The most severe patients require rigorous evaluation, and hypoxic testing can be proposed. People with mild to moderate intermittent asthma can plan high altitude sojourns, provided that they remain under control at night and during exercise, and follow an adequate action plan in case of exacerbation. Respiratory disease patients with pulmonary artery hypertension (PAH) and chemoreflex control abnormalities need to be identified as at risk of altitude intolerance.

Effectiveness of pulmonary rehabilitation in COVID-19 respiratory failure patients post-ICU.

INTRODUCTION: Some COVID-19 patients develop respiratory failure requiring admission to intensive care unit (ICU). We aim to evaluate the effects of pulmonary rehabilitation (PR) post-ICU in COVID-19 patients. METHODS: Twenty-one COVID-19 patients were evaluated pre- and post-PR and compared retrospectively to a non-COVID-19 group of 21 patients rehabilitated after ICU admission due to respiratory failure. RESULTS: PR induced greater 6-min walking distance improvement in COVID-19 patients (+205 ± 121 m) than in other respiratory failure patients post-ICU (+93 ± 66 m). The sooner PR was performed post-ICU, the better patients recovered. CONCLUSIONS: PR induced large functional improvements in COVID-19 patients post-ICU although significant physical and psychosocial impairments remained post-PR.

Methodology and reliability of respiratory muscle assessment.

The optimal method for respiratory muscle endurance (RME) assessment remains unclear. This study assessed the test-retest reliability of two RME-test methodologies. Fifteen healthy adults attended the laboratory on four occasions, separated by 5 ± 2 days, and completed each test in a random, "one on two" order. They performed spirometry testing, maximal respiratory pressure assessment and two different RME tests: an inspiratory resistive breathing (IRB) and an isocapnic hyperpnea endurance (IHE) test. Typical error, expressed as coefficient of variation, for IRB maximal inspiratory pressure (MIP) and IHE maximal ventilation were 12.21 (8.85-19.67) % and 10.73 (7.78-17.29) %, respectively. Intraclass correlation coefficients for the same parameters were 0.83 (0.46-0.94) and 0.80 (0.41-0.93), respectively. No correlations were found between RME parameters derived from the IHE and IRB tests (all p > 0.05). Significant positive correlations were found between both IRB and IHE outcomes and spirometry parameters, MIP and maximal expiratory pressure (p < 0.05). Given these results, IRB and IHE appear to be suitable for RME testing in healthy people, although they may reflect different physiological mechanisms (respiratory mechanics and respiratory muscle capacity for IHE test vs. inspiratory muscle capacity for IRB test). Future studies are therefore warranted that compare IRB and IHE tests in clinical settings.

Hypoxic conditioning and the central nervous system: A new therapeutic opportunity for brain and spinal cord injuries?

Central nervous system diseases are among the most disabling in the world. Neuroprotection and brain recovery from either acute or chronic neurodegeneration still represent a challenge in neurology and neurorehabilitation as pharmacology treatments are often insufficiently effective. Conditioning the central nervous system has been proposed as a potential non-pharmacological neuro-therapeutic. Conditioning refers to a procedure by which a potentially deleterious stimulus is applied near to but below the threshold of damage to the organism to increase resistance to the same or even different noxious stimuli given above the threshold of damage. Hypoxic conditioning has been investigated in several cellular and preclinical models and is now recognized as inducing endogenous mechanisms of neuroprotection. Ischemic, traumatic, or chronic neurodegenerative diseases can benefit from hypoxic conditioning strategies aiming at preventing the deleterious consequences or reducing the severity of the pathological condition (preconditioning) or aiming at inducing neuroplasticity and recovery (postconditioning) following central nervous system injury. Hypoxic conditioning can consist in single (sustained) or cyclical (intermittent, interspersed by short period of normoxia) hypoxia stimuli which duration range from few minutes to several hours and that can be repeated over several days or weeks. This mini-review addresses the existing evidence regarding the use of hypoxic conditioning as a potential innovating neuro-therapeutic modality to induce neuroprotection, neuroplasticity and brain recovery. This mini-review also emphasizes issues which remain to be clarified and future researches to be performed in the field. Impact statement Neuroprotection and brain recovery from either acute or chronic neurodegeneration still represent a challenge in neurology and neurorehabilitation. Hypoxic conditioning may represent a harmless and efficient non-pharmacological new therapeutic modality in the field of neuroprotection and neuroplasticity, as supported by many preclinical data. Animal studies provide clear evidence for neuroprotection and neuroplasticity induced by hypoxic conditioning in several models of neurological disorders. These studies show improved functional outcomes when hypoxic conditioning is applied and provides important information to translate this intervention to clinical practice. Some studies in humans provide encouraging data regarding the tolerance and therapeutic effects of hypoxic conditioning strategies. The main issues to address in future research include the definition of the appropriate hypoxic dose and pattern of exposure, the determination of relevant physiological biomarkers to assess the effects of the treatment and the evaluation of combined strategies involving hypoxic conditioning and other pharmacological or non-pharmacological treatments.

Absence of calf muscle metabolism alterations in active cystic fibrosis adults with mild to moderate lung disease.

BACKGROUND: Specific alterations in skeletal muscle related to genetic defects may be present in adults with cystic fibrosis (CF). Limb muscle dysfunction may contribute to physical impairment in CF. AIMS AND OBJECTIVES: We hypothesized that adults with CF would have altered calf muscle metabolism during exercise. METHODS: Fifteen adults with CF and fifteen healthy controls matched for age, gender and physical activity performed a maximal cycling test and an evaluation of calf muscle energetics by 31P magnetic resonance spectroscopy before, during and after plantar flexions to exhaustion. RESULTS: Maximal cycling test revealed lower exercise capacities in CF (VO2peak 2.44±0.11 vs. 3.44±0.23L·Min-1, P=0.03). At rest, calf muscle phosphorus metabolites and pHi were similar in CF and controls (P>0.05). Maximal power output during plantar flexions was significantly lower in CF compared to controls (7.8±1.2 vs. 6.6±2.4W; P=0.013). At exhaustion, PCr concentration was similarly reduced in both groups (CF -33±7%, controls -34±6%, P=0.44), while PCr degradation at identical absolute workload was greater in CF patients (P=0.04). These differences disappeared when power output was normalized for differences in calf size (maximal power output: 0.10±0.02 vs. 0.10±0.03W/cm2; P=0.87). Pi/PCr ratio and pHi during exercise as well as PCr recovery after exercise were similar between groups. CONCLUSION: Similar metabolic calf muscle responses during exercise and recovery were found in CF adults and controls. Overall, muscle anabolism rather than specific metabolic dysfunction may be critical regarding muscle function in CF.

Physiological characteristics of elite high-altitude climbers.

Factors underlying the amplitude of exercise performance reduction at altitude and the development of high-altitude illnesses are not completely understood. To better describe these mechanisms, we assessed cardiorespiratory and tissue oxygenation responses to hypoxia in elite high-altitude climbers. Eleven high-altitude climbers were matched with 11 non-climber trained controls according to gender, age, and fitness level (maximal oxygen consumption, VO2 max ). Subjects performed two maximal incremental cycling tests, in normoxia and in hypoxia (inspiratory oxygen fraction: 0.12). Cardiorespiratory measurements and tissue (cerebral and muscle) oxygenation were assessed continuously. Hypoxic ventilatory and cardiac responses were determined at rest and during exercise; hypercapnic ventilatory response was determined at rest. In hypoxia, climbers exhibited similar reductions to controls in VO2 max (climbers -39 ± 7% vs controls -39 ± 9%), maximal power output (-27 ± 5% vs -26 ± 4%), and arterial oxygen saturation (SpO2 ). However, climbers had lower hypoxic ventilatory response during exercise (1.7 ± 0.5 vs 2.6 ± 0.7 L/min/%; P < 0.05) and lower hypercapnic ventilatory response (1.8 ± 1.4 vs 3.8 ± 2.5 mL/min/mmHg; P < 0.05). Finally, climbers exhibited slower breathing frequency, larger tidal volume and larger muscle oxygenation index. These results suggest that elite climbers show some specific ventilatory and muscular responses to hypoxia possibly because of genetic factors or adaptation to frequent high-altitude climbing.

Impact of salbutamol on muscle metabolism assessed by ³¹P NMR spectroscopy.

The potential ergogenic effects of oral salbutamol intake were demonstrated for decades but the underlying mechanisms remain to elucidate. We hypothesized that improved exercise performance after acute oral salbutamol administration is associated with changes in muscle metabolism. Twelve healthy, nonasthmatic, moderately trained, male subjects were recruited to compare in a double-blind crossover randomized study, an oral dose of salbutamol (4 mg) and a placebo. After treatment administration, subjects performed repetitive plantar flexions to exhaustion in a 3T magnet. Continuous (31) P nuclear magnetic resonance spectroscopy assessment of the calf muscles was performed at rest, during exercise, and during recovery. No significant difference between treatments was detected in metabolite concentration at rest (P > 0.05). Creatine phosphate and inorganic phosphate changes during and immediately after exercise were similar between treatments (P > 0.05). Intramuscular pH (pHi) was significantly higher at rest, at submaximal exercise but not at exhaustion with salbutamol (pHi at 50% of exercise duration, 6.8 ± 0.1/6.9 ± 0.1 for placebo and salbutamol, respectively, P < 0.05). The maximal power (28 ± 7 W/23 ± 7 W; P = 0.001) and total work (1702 ± 442 J/1381 ± 432 J; P = 0.003) performed during plantar flexions were significantly increased with salbutamol. Salbutamol induced significant improvement in calf muscle endurance with similar metabolic responses during exercise, except slight differences in pHi. Other mechanisms than changes in muscle metabolism may be responsible for the ergogenic effect of salbutamol administration.

Does impaired O2 delivery during exercise accentuate central and peripheral fatigue in patients with coexistent COPD-CHF?

Impairment in oxygen (O2) delivery to the central nervous system ("brain") and skeletal locomotor muscle during exercise has been associated with central and peripheral neuromuscular fatigue in healthy humans. From a clinical perspective, impaired tissue O2 transport is a key pathophysiological mechanism shared by cardiopulmonary diseases, such as chronic obstructive pulmonary disease (COPD) and chronic heart failure (CHF). In addition to arterial hypoxemic conditions in COPD, there is growing evidence that cerebral and muscle blood flow and oxygenation can be reduced during exercise in both isolated COPD and CHF. Compromised cardiac output due to impaired cardiopulmonary function/interactions and blood flow redistribution to the overloaded respiratory muscles (i.e., ↑work of breathing) may underpin these abnormalities. Unfortunately, COPD and CHF coexist in almost a third of elderly patients making these mechanisms potentially more relevant to exercise intolerance. In this context, it remains unknown whether decreased O2 delivery accentuates neuromuscular manifestations of central and peripheral fatigue in coexistent COPD-CHF. If this holds true, it is conceivable that delivering a low-density gas mixture (heliox) through non-invasive positive pressure ventilation could ameliorate cardiopulmonary...

Assessement of quadriceps strength, endurance and fatigue in FSHD and CMT: benefits and limits of femoral nerve magnetic stimulation.

OBJECTIVES: To (i) evaluate the feasibility and the reliability of a test assessing quadriceps strength, endurance and fatigue in patients with fascioscapulohumeral dystrophy (FSHD) and Charcot-Marie-Tooth disease (CMT), (ii) compare quadriceps function between patients and healthy controls. METHODS: Controls performed the test once and patients twice on two separate visits. It involved progressive sets of 10 isometric contractions each followed by neuromuscular assessments with FNMS. RESULTS: Volitional assessment of muscle strength, endurance and fatigue appeared to be reliable in FSHD and CMT patients. Supramaximal FNMS was achieved in ∼70% of FSHD patients and in no CMT patients. In FSHD patients, Femoral nerve magnetic stimulation (FNMS) provided reliable assessment of central (typical error as a coefficient of variation (CVTE)<8% for voluntary activation) and peripheral (CVTE<10% and intraclass coefficient correlation >0.85 for evoked responses) function. Patients and controls had similar reductions in evoked quadriceps responses, voluntary activation and similar endurance. CONCLUSIONS: This test provides reliable evaluation but FNMS exhibits limitations due to insufficient stimulation intensity particularly in neurogenic conditions. It showed similar central and peripheral quadriceps fatigability in patients and controls. SIGNIFICANCE: This test may be a valuable tool for patient follow-up although further development of magnetic stimulation devices is needed to extend its applicability.

Hypoxia, energy balance and obesity: from pathophysiological mechanisms to new treatment strategies.

High altitude exposure is often accompanied by weight loss. Postulated mechanisms are a reduction of nutritional energy intake, a reduction of intestinal energy uptake from impaired intestinal function and increased energy expenditure. Beyond the field of altitude, there are good reasons for renewed interest in the relationship between hypoxia and energy balance. The increasing prevalence of obesity and associated comorbidities represent a major health concern. Obesity is frequently associated with sleep disorders leading to intermittent systemic hypoxia with deleterious cardiovascular and metabolic consequences. Hypoxic regions may be present within hypertrophic white adipose tissue leading to chronic systemic inflammation. Among the increasing number of people commuting to altitude for work or leisure, obesity is a risk factor for acute mountain sickness. Paradoxically, exposure to intermittent hypoxia might be considered as a means to lose body mass and to improve metabolic risk factors. Daytime exposure to intermittent hypoxia has been used to treat hypertension in former Soviet Union countries and is now being experimented elsewhere. Such intermittent hypoxic exposure at rest or during exercise may lead to improvement in body composition and health status with improved exercise tolerance, metabolism and systemic arterial pressure. Future research should confirm whether hypoxic training could be a new treatment strategy for weight loss and comorbidities in obese subjects and elucidate the underlying mechanisms and signalling pathways.

Stimulation of the motor cortex and corticospinal tract to assess human muscle fatigue.

This review aims to characterize fatigue-related changes in corticospinal excitability and inhibition in healthy subjects. Transcranial magnetic stimulation (TMS) has been extensively used in recent years to investigate modifications within the brain during and after fatiguing exercise. Single-pulse TMS reveals reduction in motor-evoked potentials (MEP) when measured in relaxed muscle following sustained fatiguing contractions. This modulation of corticospinal excitability observed in relaxed muscle is probably not specific to the fatigue induced by the motor task. During maximal and submaximal fatiguing contractions, voluntary activation measured by TMS decreases, suggesting the presence of supraspinal fatigue. The demonstration of supraspinal fatigue does not eliminate the possibility of spinal contribution to central fatigue. Concomitant measurement of TMS-induced MEP and cervicomedullary MEP in the contracting muscle, appropriately normalized to maximal muscle compound action potential, is necessary to determine the relative contribution of cortical and spinal mechanisms in the development of central fatigue. Recent studies comparing electromyographic (EMG) responses to paired-pulse stimuli at the cortical and subcortical levels suggest that impaired motoneuron responsiveness rather than intracortical inhibition may contribute to the development of central fatigue. This review examines the mechanical and EMG responses elicited by TMS (single- and paired-pulse) and cervicomedullary stimulation both during and after a fatiguing exercise. Particular attention is given to the muscle state and the type of fatiguing exercise when assessing and interpreting fatigue-induced changes in these parameters. Methodological concerns and future research interests are also considered.

Potential interests and limits of magnetic and electrical stimulation techniques to assess neuromuscular fatigue.

Neuromuscular function can change under different conditions such as ageing, training/detraining, long-term spaceflight, environmental conditions (e.g. hypoxia, hyperthermia), disease, therapy/retraining programs and also with the appearance of fatigue. Neuromuscular fatigue can be defined as any decrease in maximal voluntary strength or power. There is no standardized method to induce fatigue and various protocols involving different contraction patterns (such as sustained or intermittent submaximal isometric or dynamic contractions on isokinetic or custom chairs) have been used. Probably due to lack of motivation/cooperation, results of fatigue resistance protocols are more variable in patients than in healthy subjects. Magnetic and electrical stimulation techniques allow non-invasive assessment of central and peripheral origins of fatigue. They also allow investigation of different types of muscle fatigue when combining various types of stimulation with force/surface EMG measurements. Since maximal electrical stimuli may be uncomfortable or even sometimes painful, several alternative methods have been recently proposed: submaximal muscle stimulation, low/high-frequency paired pulses instead of tetanic stimuli and the use of magnetic stimulation at the peripheral level.

Time-dependent effect of acute hypoxia on corticospinal excitability in healthy humans.

Contradictory results regarding the effect of hypoxia on cortex excitability have been reported in healthy subjects, possibly depending on hypoxia exposure duration. We evaluated the effects of 1- and 3-h hypoxia on motor corticospinal excitability, intracortical inhibition, and cortical voluntary activation (VA) using transcranial magnetic stimulation (TMS). TMS to the quadriceps cortex area and femoral nerve electrical stimulations were performed in 14 healthy subjects. Motor-evoked potentials (MEPs at 50-100% maximal voluntary contraction; MVC), recruitment curves (MEPs at 30-100% maximal stimulator power output at 50% MVC), cortical silent periods (CSP), and VA were measured in normoxia and after 1 (n = 12) or 3 (n = 10) h of hypoxia (Fi(O(2)) = 0.12). One-hour hypoxia did not modify any parameters of corticospinal excitability but reduced slightly VA, probably due to the repetition of contractions 1 h apart (96 ± 4% vs. 94 ± 4%; P = 0.03). Conversely, 3-h hypoxia significantly increased 1) MEPs of the quadriceps muscles at all force levels (+26 ± 14%, +24 ± 12%, and +27 ± 17% at 50, 75, and 100% MVC, respectively; P = 0.01) and stimulator power outputs (e.g., +21 ± 14% at 70% maximal power), and 2) CSP at all force levels (+20 ± 18%, +18 ± 19%, and +14 ± 22% at 50, 75, and 100% MVC, respectively; P = 0.02) and stimulator power outputs (e.g., +9 ± 8% at 70% maximal power), but did not modify VA (98 ± 1% vs. 97 ± 3%; P = 0.42). These data demonstrate a time-dependent hypoxia-induced increase in motor corticospinal excitability and intracortical inhibition, without changes in VA. The impact of these cortical changes on physical or psychomotor performances needs to be elucidated to better understand the cerebral effects of hypoxemia.

Central and peripheral fatigue kinetics during exhaustive constant-load cycling.

The kinetics of central and peripheral fatigue development during an intensive constant-load cycling exercise was evaluated to better understand the mechanisms of task failure. Thirteen males cycled to exhaustion at 80% of maximal power output in intermittent bouts of 6 min of exercise with 4-min break between bouts to assess quadriceps fatigue with maximal voluntary contractions and single (1 Hz), paired (10 and 100 Hz) potentiated and interpolated magnetic stimulations of the femoral nerve (TwQ). Surface electromyographic signals (EMG) of the quadriceps muscles were recorded during stimulations and cycling. Total cycling duration (TCD) was 27 min 38 s±7 min 48 s. The mechanical response evoked by magnetic stimulation decreased mostly during the first half of TCD (TwQ1 Hz reduction: -34.4±12.2% at 40% TCD and -44.8±9.2% at exhaustion; P<0.001), while a reduction in maximum voluntary activation was present toward the end of exercise only (-5.4±4.8% and -6.4±5.6% at 80% TCD and exhaustion, respectively; P<0.01). The increase in quadriceps EMG during cycling was significantly correlated to the TwQ reduction for the rectus femoris (r(2) =0.20 at 1 Hz, r(2) =0.47 at 100 Hz, all P≤0.001). We conclude that peripheral fatigue develops early during constant-load intense cycling and is compensated by additional motor drive, while central fatigue appears to be associated with task failure.

Respiratory muscle endurance training in obese patients.

OBJECTIVE: Increased respiratory muscle work is associated with dyspnea and poor exercise tolerance in obese patients. We evaluated the effect of respiratory muscle endurance training (RMET) on respiratory muscle capacities, symptoms and exercise capacity in obese patients. DESIGN: A total of 20 obese patients hospitalized for 26 ± 6 days to follow a low-calorie diet and a physical activity program were included in this case-control study. Of them, 10 patients performed RMET (30-min isocapnic hyperpnea at 60-80% maximum voluntary ventilation, 3-4 times per week during the whole hospitalization period: RMET group), while the other 10 patients performed no respiratory training (control (CON) group). RMET and CON groups were matched for body mass index (BMI) (45 ± 7 kg m(-2)) and age (42 ± 12 years). Lung function, respiratory muscle strength and endurance, 6-min walking distance, dyspnea (Medical Research Council scale) and quality of life (short-form health survey 36 questionnaire) were assessed before and after intervention. RESULTS: Similar BMI reduction was observed after hospitalization in the RMET and CON groups (-2 ± 1 kg m(-2), P < 0.001). No significant change in lung function and respiratory muscle strength was observed except for vital capacity, which increased in the RMET group (+0.20 ± 0.26 l, P = 0.039). Respiratory muscle endurance increased in the RMET group only (+52 ± 27%, P < 0.001). Compared with the CON group, the RMET group had greater improvement in 6MWT (+54 ± 35 versus +1 ± 7 m, P = 0.007), dyspnea score (-2 ± 1 versus -1 ± 1 points, P = 0.047) and quality of life (total score: +251 ± 132 versus +84 ± 152 points, P = 0.018) after hospitalization. A significant correlation between the increase in respiratory muscle endurance and improvement in 6MWT distance was observed (r (2) = 0.36, P = 0.005). CONCLUSIONS: The present study indicates that RMET is feasible in obese patients and can induce significant improvement in dyspnea and exercise capacity. RMET may be a promising tool to improve functional capacity and adherence to physical activities in this population, but further studies are needed to confirm these results.