High Ventilatory Response Research Articles

Role of raphe magnus 5-HT1A receptor in increased ventilatory responses induced by intermittent hypoxia in rats

BackgroundIntermittent hypoxia induces increased ventilatory responses in a 5-HT-dependent manner. This study aimed to explore that effect of raphe magnus serotonin 1A receptor (5-HT1A) receptor on the increased ventilatory responses induced by intermittent hypoxia.MethodsStereotaxic surgery was performed in adult male rats, and acute and chronic intermittent hypoxia models were established after recovery from surgery. The experimental group received microinjections of 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) into the raphe magnus nucleus (RMg). Meanwhile, the control group received microinjections of artificial cerebrospinal fluid instead of 8-OH-DPAT. Ventilatory responses were compared among the different groups of oxygen status. 5-HT expressions in the RMg region were assessed by immunohistochemistry after chronic intermittent hypoxia.ResultsCompared with the normoxia group, the acute intermittent hypoxia group exhibited higher ventilatory responses (e.g., shorter inspiratory time and higher tidal volume, frequency of breathing, minute ventilation, and mean inspiratory flow) (P < 0.05). 8-OH-DPAT microinjection partly weakened these changes in the acute intermittent hypoxia group. Further, compared with the acute intermittent hypoxia group, rats in chronic intermittent hypoxia group exhibited higher measures of ventilatory responses after 1 day of intermittent hypoxia (P < 0.05). These effects peaked after 3 days of intermittent hypoxia treatment and then decreased gradually. Moreover, these changes were diminished in the experimental group. 5-HT expression in the RMg region increased after chronic intermittent hypoxia, which was consistent with the changing trend of ventilatory responses. While activation of the 5-HT1A receptor in the RMg region alleviated this phenomenon.ConclusionsThe results indicate that RMg 5-HT1A receptor, via changing the expression level of 5-HT in the RMg region, is involved in the modulation of the increased ventilatory responses induced by intermittent hypoxia.

Evaluation of the Lake Louise Score for Acute Mountain Sickness and Its 2018 Version in a Cohort of 484 Trekkers at High Altitude.

Richalet, Jean-Paul, Chantal Julia, and François J. Lhuissier. Evaluation of the Lake Louise Score for acute mountain sickness and its 2018 version in a cohort of 484 trekkers at high altitude. High Alt Med Biol. 22:353-361, 2021. Background: The Lake Louise Score (LLS) is widely used in field studies and chamber studies for the diagnosis of Acute Mountain Sickness (AMS). This score aggregates symptoms that are nonspecific: headache, gastrointestinal symptoms, fatigue, dizziness and sleep disturbance can be due to a variety of causes unrelated to altitude hypoxia. The objectives of this study were to (1) reevaluate the need for a headache score >0 for the diagnosis of AMS, (2) evaluate the role of sleep disturbances, in relation with other symptoms, (3) evaluate the significance of dizziness. Materials and Methods: We analyzed LLS from 484 trekkers at high altitude. Among them, 212 suffered from moderate AMS (mAMS: 3 ≤ LLS < 6) and 115 from severe AMS (sAMS: LLS ≥ 6). Results: Cluster analysis of AMS revealed three main groups presenting the following symptoms: Group 1 includes 254 subjects who had less than 2 symptoms; Group 2 includes 137 subjects who had fatigue, sleep disturbance, and headache, corresponding to mAMS; Group 3 includes 93 subjects who had headache, fatigue, dizziness and sleep disturbance, corresponding to sAMS. A headache score of zero was found in 25% of mAMS and 5% of sAMS subjects. Only the absence of headache associated with the absence of fatigue was specific of absence of sAMS. In subjects with a dizziness score > 1, end-tidal partial pressure of carbon dioxide during a hypoxic exercise test was lower than that in subjects with a dizziness score < 2. Subjects with high ventilatory response to hypoxia may develop dizziness with high altitude exposure. Conclusion: (1) An isolated headache score > 0 should not be mandatory to define AMS, (2) sleep disruption contributes to the diagnosis of AMS, (3) gastrointestinal symptoms and dizziness are weaker contributors to the LLS, (4) dizziness might be linked to a hyperresponsiveness to hypoxia and not to AMS itself.

Responses to progressive exercise in subjects with chronic dyspnea and inspiratory muscle weakness

Inspiratory muscle weakness (IMW) is a potential cause of exertional dyspnea frequently under-appreciated in clinical practice. Cardiopulmonary exercise testing (CPET) is usually requested as part of the work-up for unexplained breathlessness, but the specific pattern of exercise responses ascribed to IMW is insufficiently characterized. To identify the physiological and sensorial responses to progressive exercise in dyspneic patients with IMW without concomitant cardiorespiratory or neuromuscular diseases. Twenty-three subjects (18 females, 55.2±16.9 years) complaining of chronic daily life dyspnea (mMRC = 3 [2-3]) plus maximal inspiratory pressure < the lower limit of normal and 12 matched controls performed incremental cycling CPET. FEV1/FVC<0.7, significant abnormalities in chest CT or echocardiography, and/or an established diagnosis of neuromuscular disease were among the exclusion criteria. Patients presented with reduced aerobic capacity (peak V̇O2: 79±26 vs 116±21 %predicted), a tachypneic breathing pattern (peak breathing frequency/tidal volume = 38.4 ± 22.7 vs 21.7 ± 14.2 breaths/min/L) and exercise-induced inspiratory capacity reduction (-0.17 ± 0.33 vs 0.10 ± 0.30 L) (all P < .05) compared to controls. In addition, higher ventilatory response (ΔV̇E/ΔV̇CO2 = 34.1±6.7 vs 27.0±2.3 L/L) and symptomatic burden (dyspnea and leg discomfort) to the imposed workload were observed in patients. Of note, pulse oximetry was similar between groups. Reduced aerobic capacity in the context of a tachypneic breathing pattern, inspiratory capacity reduction and preserved oxygen exchange during progressive exercise should raise the suspicion of inspiratory muscle weakness in subjects with otherwise unexplained breathlessness.

Evaluation of cardiorespiratory changes during various phases of menstrual cycle in young women before and soon after exercise

Background: Menstruation involves a cyclic expulsion of sanguinous fluid and a sloughing of uterine wall in a female and is a typical feature of the reproductive cycle in humans and subhuman primates. The variations in radial artery distensibility are typical in the natural menstrual cycle. Respiratory function is influenced by female sexual hormones, especially progesterone, which could increase ventilator at rest and soon after exercise. Objective: To study the cardiorespiratory changes during mid-follicular phase and early luteal phases of menstrual cycle before and soon after exercise. Materials and Methods: The samples were collected from young unmarried and nonpregnant women of age group 17 and 25 years from Government General Hospital, Madras Medical College. Blood was drawn during the mid-follicular phase and early luteal phase of menstrual cycle; the serum was separated and stored at 20C. The separated serum was used for quantitative determination of estradiol (E2) concentration by SMAR Test diagnostics and for progesterone determination using hormone kit. Cardiac output, peripheral blood flow, expiratory blast test, performance of isotonic exercise, and cardiac output measurement were performed, and the comparison was made between the different phases of parameters. Result: Cardiac output, peripheral blood flow, and expiratory blast test were performed, and the comparison was made between the parameters. Female subjects show higher ventilatory responses in the luteal phases than in the follicular phase without a change in VO2. Progesterone stimulates respiration and the alveolar PCO2 in women during the luteal phase of menstrual cycle, which is lower than that in men. During exercise, the muscle blood flow can increase a maximum of about 25-fold, the value being 90 mL/100g muscle/min from resting blood flow of 3.6 mL/100 g. In expiratory blast test, a normal subject can increase the mercury column to 55–100 mm or more during a single forceful expiration. Conclusion: The result suggests that cardiovascular parameters were more affected in follicular phase after exercise. Respiratory parameters were more affected in luteal phase after exercise. Change in peripheral blood flow was found to show marked effect than in cardiac output.

Exercise oscillatory ventilation in heart failure and in pulmonary arterial hypertension

BackgroundPatients with pulmonary arterial hypertension (PAH) and with heart failure (HF) have increased ventilatory responses to exercise in proportion to disease severity. Exercise-associated oscillatory ventilation (EOV) predicts poor outcome in HF. Whether EOV occurs in PAH is unknown. MethodsWe analyzed the initial cardiopulmonary exercise tests (CPETs) and right heart catheterization data of 109 patients with PAH and in 107 patients with HF consecutively referred to our center. ResultsThe PAH patients were aged 54±16years and their NYHA functional class was 2.8±0.5. The HF patients were aged 53±13years and NYHA 2.4±0.6. Hemodynamic data were obtained in only 36 of them. The patients with PAH compared to those with HF had a lower peak VO2 (13±5 vs 17±5mL/kg/min, p<0.001) and a higher ventilatory equivalent for CO2 (VE/VCO2) slope (55±21 vs 34±7, p<0.001). Mean pulmonary artery pressure was higher (50±10 vs 29±11mmHg) and wedge pressure lower (10±3 vs 19±5mmHg) in PAH patients, but cardiac output was not different (4.0±1.3 vs 4.2±1.2L/min). EOV was present in 22 patients (21%) with HF and in no patient with PAH. ConclusionsPatients with PAH compared to HF with slightly better functional class have a lower aerobic exercise capacity and higher ventilatory responses, but no EOV. An increase in pulmonary artery wedge pressure rather than a low cardiac output may be necessary condition of EOV in HF.

Oscillatory Pattern of Breathing in Healthy Humans at Exercise: Effects of Hypoxia, Hyperoxia and Hypercapnia

Periodic breathing has been rarely studied in wakefulness during exercise in healthy humans.Spectral analyses of 82 healthy subjects breath‐by‐breath ventilation (VE) signals, from hypoxia exercise tests, evidenced a periodic pattern with a period from 11.1 to 12.0 seconds. VE Peak power was higher in the group 'high ventilatory response to hypoxia at exercise' (HVRe) group (vs low HVRe, P&lt;0.001). A prospective study (25 subjects) was performed to evaluate the influence of cardiorespiratory factors on the amplitude and period of ventilation oscillations in various conditions of exercise (20 to 40% maximal aerobic power) and hypoxia (0 to 4,000m altitude). VE period was shorter during exercise (vs rest) and during hypoxia (vs normoxia) (P&lt;0.001). VE peak power was higher at exercise (P&lt;0.001) and hypoxia (P&lt;0.001). It was also positively related in hypoxia with the ventilatory response to CO2 (HCVR). We assessed respective contributions of central and peripheral chemoreceptors in hypoxia under acetazolamide (ACZ), in hyperoxia and in hypercapnic hyperoxia. ACZ reduced VE peak power (P&lt;0.001), for an unchanged period. VE Peak power remained unchanged in hyperoxia (vs normoxia), but increased in hypercapnic hyperoxia (P&lt;0.001). This novel observation suggests that healthy subjects demonstrate a spontaneous periodic breathing, triggered by hypoxic exercise, enhanced in subjects with high HVRe, high HCVR and hypercapnic conditions, suggesting that hypoxia and CO2 play a synergistic role in the modulation of these oscillations.

Exercise tolerance with helium-hyperoxiaversushyperoxia in hypoxaemic patients with COPD

The purpose of this study was to investigate whether helium-hyperoxia (HeHOx) would allow greater tolerance to maximal and submaximal exercise compared to hyperoxia (HOx) on isolation in hypoxaemic chronic obstructive pulmonary disease (COPD) patients under long-term oxygen therapy. In a double-blind study, 24 males in the Global Initiative for Chronic Obstructive Lung Disease functional class IV (forced expiratory volume in 1 s 35.2±10.1% predicted and arterial oxygen tension 56.2±7.5 mmHg) were submitted to incremental and constant load cycling at 70-80% peak work rate while breathing HOx (60% nitrogen and 40% oxygen) or HeHOx (60% helium and 40% oxygen). HeHOx improved resting airflow obstruction and lung hyperinflation in all but two patients (p<0.05). Peak work rate and time to exercise intolerance were higher with HeHOx than HOx in 17 (70.8%) out of 24 patients and 14 (66.6%) out of 21 patients, respectively (p<0.05). End-expiratory lung volumes were lower with HeHOx, despite a higher ventilatory response (p<0.05). HeHOx speeded on-exercise oxygen uptake kinetics by ∼30%, especially in more disabled and hyperinflated patients. Fat-free mass was the only independent predictor of higher peak work rate with HeHOx (r(2) = 0.66, p<0.001); in contrast, none of the resting characteristics or exercise responses were related to improvements in time to exercise intolerance (p>0.05). Helium is a valuable ergogenic aid when added to HOx for most long-term oxygen therapy-dependent patients with advanced COPD.

Cardiac Resynchronization Therapy Reduces Metaboreflex Contribution to the Ventilatory Response in Heart Failure Population

Background. Metaboreflex overactivation has been proprosed to explain exaggerated hyperventilation in heart failure population. We investigated the metaboreflex activation after cardiac resynchronization therapy (CRT). Methods. 10 heart failure patients (mean left ventricular ejection fraction (LVEF) 27 ± 4%) schedulded for CRT implantation were prospectively studied. At baseline and after 6 month follow up two maximal cardiopulmonary exercise tests with and without regional circulatory occlusion (RCO) during recovery were performed. RCO was achieved by inflation of bilateral upper thigh tourniquets 30 mmHg above peak systolic blood pressure during 3 minutes after peak exercise. Metaboreflex contribution to the ventilatory response was assessed as the difference in ventilatory data at the third minute during recovery between the two tests (Δ). Results. Patients had enhanced VE/VCO2 slope (40 ± 9) and an evident metaboreflex contribution to the high ventilatory response (ΔVE: 3 ± 4 L/min; P = 0.05, ΔRR: 4.5 ± 4/min; P = 0.003 and ΔVE/VCO2: 5.5 ± 4; P = 0.007). 6 months after CRT implantation, NYHA class, LVEF, peak VO2 and VE/VCO2 were significantly improved (1.4 ± 0.5; P < 0.001, 42 ± 7%; P < 0.001, 16.5 ± 3 mL/kg/min; P = 0.003; 33 ± 10; P = 0.01). Metaboreflex contribution to VE, RR, and VE/VCO2 was reduced compared with baseline (P = 0.08, P = 0.01 and P = 0.4 resp.). Conclusion. 6 months after CRT metaboreflex contribution to the ventilatory response is reduced.

Usefulness of the lowest VE/VCO 2 ratio measured during exercise in heart failure

We have read with great interest the paper published recently in your journal by Ingle et al.1 about VE/VCO2 measurement during exercise in patients with suspected heart failure (HF). The authors found a greater pronostic value of the lowest VE/VCO2 ratio measured during the exercise test compared with the VE/VCO2 slope. This article is of particular interest for both clinical practice and physiological understanding. Indeed, although ventilatory response evaluation is a growing approach to manage such a population and select patients for heart transplantation, there are no published guidelines concerning the method for VE/VCO2 measurement. We think that this important parameter, confirmed by this study, has to become a routine component of the exercise evaluation in HF patients. The authors confirm a new method to assess both the ventilatory response and the prognostic evaluation with higher sensitivity and specificity in HF. An enhanced ventilatory response to exercise, evaluated by a high VE/VCO2 slope, has been shown to be an independent prognostic marker of mortality and hospitalization in HF patients. The prognostic value of this parameter is not affected by beta-blocker therapy, age, obesity, or exercise capacity. However, the physiological determinants of such an exaggerated hyperventilation are not yet clear, but may involve ventilation–perfusion mismatch, depressed baroreflex, and high chemoreflex control. Of particular interest, VE/VCO2 is specially correlated with over activation of the metaboreflex as found by Piepoli et al.2, leading to high sympathetic activation. Such abnormalities probably add to the high ventilatory response during exercise but even during rest as found by authors with a higher VE/VCO2 ratio in the HF group compared with control. This observation is of particular interest concerning the pathophysiology of ventilation in this population, and confirms the influence of these determinants on ventilation at rest and during the first minutes of exercise despite a reduction in VE/VCO2 ratio. In addition, VE/VCO2 at rest is of significant prognostic interest in univariate analysis. Management, diagnosis, and prognostic evaluation of HF patients are guided by exercise information such as peak VO2. A recent study confirmed the great interest of the ventilatory response evaluation for heart transplantation.3 We hope that this article will encourage cardiologists to measure the VE/VCO2 slope and ratio using the Ingle et al. method to manage patients with HF.

A role for succinate dehydrogenase genes in low chemoresponsiveness to hypoxia?

The detection of hypoxia by the carotid bodies elicits a ventilatory response of utmost importance for tolerance to high altitude. Germline mutations in three genes encoding subunit B, C and D of succinate dehydrogenase (SDHB, SDHC and SDHD) have been associated with paragangliomas of the carotid body. We hypothesized that SDH dysfunction within the carotid body could result in low chemoresponsiveness and intolerance to high altitude. The frequency of polymorphisms of SDHs, hypoxia-inducible factor type 1 (HIF1alpha) and angiotensin converting enzyme (ACE) genes was compared between 40 subjects with intolerance to high altitude and a low hypoxic ventilatory response at exercise (HVRe < or = 0.5 ml min(-1) kg(-1); HVR- group) and 41 subjects without intolerance to high altitude and a high HVRe (> or = 0.80 ml min(-1) kg(-1); HVR+). We found no significant association between low or high HVRe and (1) the allele frequencies for nine single nucleotide polymorphisms (SNPs) in the SDHD and SDHB genes, (2) the ACE insertion/deletion polymorphism and (3) four SNPs in the HIF1alpha gene. However, a marginal significant association was found between the synonymous polymorphism c.18A>C of the SDHB gene and chemoresponsiveness: 8/40 (20%) in the HVR- group and 3/41 (7%) in the HVR+ group (p = 0.12). A principal component analysis showed that no subject carrying the 18C allele had both high ventilatory and cardiac response to hypoxia. In conclusion, no clear association was found between gene variants involved in oxygen sensing and chemoresponsiveness, although some mutations in the SDHB and SDHD genes deserve further investigations in a larger population.

Does exercise have deleterious consequences for the lungs of patients with chronic heart failure?

Changes in lung function in patients with chronic heart failure (CHF), usually reported at rest, may be exacerbated during exercise and induce post-exercise effects. We investigated the hypothesis that post-exercise induced changes in lung function in CHF patients are due to the consequences of left atrial overload. Twenty-one CHF patients and six healthy subjects (Ctrl) participated in this study. Transfer lung capacity for carbon monoxide (T(LCO)) and maximal expiratory flows (V (max)) were measured before a maximal exercise test and 1h, 2h and 20h afterwards. CHF patients were divided in two groups according to their ventilatory response to the maximal exercise test (V(E) vs. V(CO(2)) relationship slopes above or below 34, i.e., CHF>34 and CHF<34). Compared with the Ctrl group, in CHF groups resting T(LCO) and V(max) were lower. After exercise, further changes in T(LCO) and V(max) were observed in CHF>34. T(LCO) per unit volume (K(CO)) was increased 1h post-exercise while maximal expiratory flow between 25 and 75% of forced vital capacity was decreased 2h and 20h post-exercise. We observed a negative correlation between the delta T(LCO) 1h post-exercise from rest and the delta T(LCO) 2h post-exercise from rest. The decreases in pulmonary V(max) we observed well after exercise following increases in K(CO) in patients with high ventilatory response to exercise (CHF>34) might indicate bronchial congestion resulting from increased left atrial pressure during exercise. We propose that endurance training should be prescribed cautiously for these patients.

Relationship between individual ventilatory response and acute renal water excretion at high altitude

We tested the hypothesis that the individual ventilatory adaptation to high altitude (HA, 5050 m) may influence renal water excretion in response to water loading. In 8 healthy humans (33+/-4 S.D. years) we studied, at sea level (SL) and at HA, resting ventilation (VE), arterial oxygen saturation (SpO2), urinary output after water loading (WL, 20 mL/kg), and total body water (TBW). Ventilatory response to HA was defined as the difference in resting VE over SpO2 (DeltaVE/DeltaSpO2) from SL to HA. At HA, a significant increase in urinary volume after the first hour from WL (%WLt0-60) was observed. Significant correlations were found between DeltaVE/DeltaSpO2 versus %WLt0-60 at HA and versus changes in TBW, from SL to HA. In conclusion, in healthy subjects the ventilatory response to HA influences water balance and correlates with kidney response to WL. A higher ventilatory response at HA, allowing a more efficient water renal handling, is likely to be a protective mechanisms from altitude illness.

Pathophysiological adaptations to walking and cycling in primary pulmonary hypertension

Exercise tolerance inversely correlates with the severity of the disease in patients with idiopathic pulmonary arterial hypertension (IPAH). Cycling and walking protocols are commonly utilized in the evaluation of exercise intolerance in IPAH, but little information exists on possible differences in ventilatory and gas exchange adaptations to these exercise modalities. In a group of patients with moderate to severe IPAH (n = 13), we studied the ventilatory, cardiovascular and gas exchange adaptations to maximal incremental walking (W) and maximal incremental cycling (C). During W, compared to C, the ventilatory equivalents for CO(2) output (V'(E)/V'CO(2)) were significantly higher either expressed as the rate of increment (56 +/- 5 vs. 45 +/- 3; P < 0.0001) or as the absolute values at anaerobic threshold (AT) and at peak exercise. At AT, the increase in V'(E)/V'CO(2) during W was associated with a significant lower value of end-tidal carbon dioxide. At peak W, compared to peak C, dyspnea sensation was higher and arterial oxygen saturation (SpO(2)) was lower (87 +/- 2 vs. 91 +/- 2, P < 0.001). In patients with IPAH the physiologic information obtained with W are different from those obtained with C. Tolerance to W exercise is limited by high ventilatory response and dyspnea sensation. W should be used to assess the degree of lung gas exchange inefficiency and arterial O(2) desaturation during exercise.

Maintained inspiratory activity during proportional assist ventilation in surfactant-depleted cats early after surfactant instillation: phrenic nerve and pulmonary stretch receptor activity

BackgroundInspiratory activity is a prerequisite for successful application of patient triggered ventilation such as proportional assist ventilation (PAV). It has recently been reported that surfactant instillation increases the activity of slowly adapting pulmonary stretch receptors (PSRs) followed by a shorter inspiratory time (Sindelar et al, J Appl Physiol, 2005 [Epub ahead of print]). Changes in lung mechanics, as observed in preterm infants with respiratory distress syndrome and after surfactant treatment, might therefore influence the inspiratory activity when applying PAV early after surfactant treatment.ObjectiveTo investigate the regulation of breathing and ventilatory response in surfactant-depleted young cats during PAV and during continuous positive airway pressure (CPAP) early after surfactant instillation in relation to phrenic nerve activity (PNA) and the activity of PSRs.MethodsSeven anesthetized, endotracheally intubated young cats were exposed to periods of CPAP and PAV with the same end-expiratory pressure (0.2–0.5 kPa) before and after lung lavage and after surfactant instillation. PAV was set to compensate for 75% of the lung elastic recoil.ResultsTidal volume and respiratory rate were higher with lower PaCO2 and higher PaO2 during PAV than during CPAP both before and after surfactant instillation (p < 0.05; both conditions). As an indicator of breathing effort, esophageal deflection pressure and PNA were lower during PAV than during CPAP in both conditions (p < 0.02). Peak PSR activity was higher and occurred earlier during PAV than during CPAP (p < 0.01), and correlated linearly with PNA duration in all conditions studied (p < 0.001). The inspiratory time decreased as tidal volume increased when CPAP was changed to PAV, with the highest correlation observed after surfactant instillation (r = -0.769). No apneic periods could be observed.ConclusionPSR activity and the control of breathing are maintained during PAV in surfactant-depleted cats early after surfactant instillation, with a higher ventilatory response and a lower breathing effort than during CPAP.

Hypoxic ventilatory response in successful extreme altitude climbers

A very high ventilatory response to hypoxia is believed necessary to reach extreme altitude without oxygen. Alternatively, the excessive ventilation could be counterproductive by exhausting the ventilatory reserve early on. To test these alternatives, 11 elite climbers (2004 Everest-K2 Italian Expedition) were evaluated as follows: 1) at sea level, and 2) at 5,200 m, after 15 days of acclimatisation at altitude. Resting oxygen saturation, minute ventilation, breathing rate, hypoxic ventilatory response, maximal voluntary ventilation, ventilatory reserve (at oxygen saturation = 70%) and two indices of ventilatory efficiency were measured. Everest and K2 summits were reached 29 and 61 days, respectively, after the last measurement. Five climbers summited without oxygen, the other six did not, or succeeded with oxygen (two climbers). At sea level, all data were similar. At 5,200 m, the five summiters without oxygen showed lower resting minute ventilation, breathing rate and ventilatory response to hypoxia, and higher ventilatory reserve and ventilatory efficiency, compared to the other climbers. Thus, the more successful climbers had smaller responses to hypoxia during acclimatisation to 5,200 m, but, as a result, had greater available reserve for the summit. A less sensitive hypoxic response and a greater ventilatory efficiency might increase ventilatory reserve and allow sustainable ventilation in the extreme hypoxia at the summit.

Systemic oxygen transport in rats artificially selected for running endurance

The relative contribution of genetic and environmental influences to individual exercise capacity is difficult to determine. Accordingly, animal models in which these influences are carefully controlled are highly useful to understand the determinants of intrinsic exercise capacity. Studies of systemic O(2) transport during maximal treadmill exercise in two diverging lines of rats artificially selected for endurance capacity showed that, at generation 7, whole body maximal O(2) uptake ((.)V(O(2)(max)) was 12% higher in high capacity (HCR) than in low capacity runners (LCR) during normoxic exercise. The difference in (.)V(O(2)(max) between HCR and LCR was larger during hypoxic exercise. Analysis of the linked O(2) conductances of the O(2) transport system showed that the higher (.)V(O(2)(max) was not due to a higher ventilatory response, a more effective pulmonary gas exchange, or an increased rate of O(2) delivery to the tissue by blood. The main reason for the higher (.)V(O(2)(max) of HCR was an increased tissue O(2) extraction, due largely to a higher tissue diffusive O(2) conductance. The enhanced tissue O(2) diffusing capacity was paralleled by an increased capillary density of a representative locomotory skeletal muscle, the gastrocnemius, in HCR. Activities of skeletal muscle oxidative enzymes citrate synthase and beta-HAD were also higher in HCR than LCR. Thus, the functional characteristics observed during exercise are consistent with the structural and biochemical changes observed in skeletal muscle that imply an enhanced capacity for muscle O(2) uptake and utilization in HCR. The results indicate that the improved (.)V(O(2)(max) is solely due to enhanced muscle O(2) extraction and utilization. However, the question arises as to whether it is possible to maintain a continually expanding capacity for O(2) extraction at the tissue level with successive generations, without a parallel improvement in the capacity to deliver O(2) to the exercising muscles.

Exercise hyperventilation in chronic heart failure is not caused by systemic lactic acidosis

Patients with heart failure have an abnormally high ventilatory response to exercise associated with gas exchange defects and reduced arterial pCO(2). We examined the possibility of lactic acidosis as the stimulus to this increased ventilation that abnormally depresses pCO(2) during exercise in heart failure. We studied 18 patients with chronic heart failure. We measured VE/VCO(2) slope during exercise, arterial blood gases and lactate concentrations during cardiopulmonary exercise testing (rest, peak exercise and one minute after the end of exercise). Neither VE/VCO(2) slope nor arterial pCO(2) were related to arterial lactate concentrations at peak exercise (r = -0.16, p = 0.65 and r = -0.15, p = 0.6). During early recovery, patients with a high VE/VCO(2) slope had a particularly pronounced rise in arterial lactate and hydrogen ion concentrations (r = 0.57, p < 0.05 and r = 0.84, p < 0.0001) and yet their arterial pCO(2) rose rather than fell (r = 0.79, p < 0.001). The rise in arterial pCO(2) correlated with the increase in arterial hydrogen concentration (r = 0.78, p < 0.001) and with arterial pCO(2) at peak exercise (r = -0.76, p < 0.001). In heart failure VE/VCO(2) slope and low arterial pCO(2) at peak exercise are not related to the degree of systemic lactic acidosis. Lactic acidosis is therefore not a plausible mechanism of exercise induced hyperventilation.

VENTILATORY SUPPORT DURING TRAINING IMPROVES TRAINING BENEFIT IN SEVERE CHRONIC AIRWAY OBSTRUCTION

BACKGROUND One mechanism that may limit training effect in chronic obstructive pulmonary disease is the ventilatory limitation and associated dyspnea. OBJECTIVES To minimize ventilatory limitation during training of patients with severe COPD by applying bi-level positive pressure ventilation during training in order to augment training intensity (and effect). METHODS The study group comprised 19 patients (18 males, 1 female) with a mean age of 64 +/- 9 years. Mean forced expiratory volume in 1 second was 32 +/- 4% of predicted, and all were ventilatory-limited (exercise breathing reserve 3 +/- 9 L/min, normal > 15 L/min). The patients were randomized: 9 were assigned to training with BiPAP and 10 to standard training. All were trained on a treadmill for 2 months, twice a week, 45 minutes each time, at maximal tolerated load. Incremental maximal unsupported exercise test was performed before and at the end of the training period. RESULTS BiPAP resulted in an increment of 94 +/- 53% in training speed during these 2 months, as compared to 41 +/- 19% increment in the control group (P < 0.005). Training with BiPAP yielded an average increase in maximal oxygen uptake of 23 +/- 16% (P < 0.005), anaerobic threshold of 11 +/- 12% (P < 0.05) and peak O2 pulse of 20 +/- 19% (P < 0.05), while peak exercise lactate concentration was not higher after training. Interestingly, in the BiPAP group, peak exercise ventilation was also 17 +/- 20% higher after training (P < 0.05). Furthermore, contrary to our expectation, at any given work rate, ventilation (and tidal volume) in the BiPAP group was higher in the post-training test as compared to the pre-training test, and the end tidal partial pressure of CO2 at 55 watts was lower, 40 +/- 4 and 38 +/- 4 mmHg respectively (P < 0.05). No improvement in exercise capacity was observed after this short training period in the control group. CONCLUSION Pressure-supported ventilation during training is feasible in patients with severe COPD and it augments the training effect. The improved exercise tolerance was associated with higher ventilatory response and therefore lower P(ET)CO2 at equal work rates after training.

Lack of a relation between serum potassium concentration and exercise hyperpnea in patients with chronic heart disease.

Exertional dyspnea, a major symptom of patients with chronic heart failure, mainly stems from an abnormally high ventilatory response to exercise. However, there has been considerable controversy surrounding the mechanisms of respiratory control during exercise, especially regarding the role of serum potassium. We investigated the relation between serum potassium concentration [K+] and ventilation (VE) during exercise before and after oral supplements of potassium chloride in cardiac patients. Thirteen patients with chronic heart disease performed a 6-min constant-work-rate exercise (65.8+/-11.1 W) with respiratory gas measurements before initiating oral supplements of potassium chloride, 4 weeks after continued supplements, and 4 weeks after discontinuing supplements. Blood was sampled from a forearm vein at rest before exercise and at the end of exercise for measurement of [K+] and blood gases. The [K+] at rest was 3.66+/-0.30 mmol/L before oral supplements of potassium and significantly increased to 4.08+/-0.31 mmol/L (p<0.01) after supplements. In spite of the significant increases in the [K+], resting VE was not changed. While serum [K+] during exercise was significantly higher after potassium supplements than before, exercise VE was not influenced by the changes in [K+] throughout the study period. The findings of the present study strongly suggest that the chronic increase in the serum [K+] has no influence on the resting or exercise VE in patients with heart disease.

Normoxic ventilatory response in lowlander and Sherpa elite climbers

The differences in ventilatory response to exercise of some highland ethnic communities is a controversial issue. We have evaluated the differences in ventilatory response to exercise at sea level between two groups of elite climbers, four Himalayan Sherpas (S) and four Caucasian lowlanders (C), after descent from extreme altitude. All of them performed a progressive-intensity exercise test on a treadmill under normoxic conditions. Pulmonary gas exchange was obtained until exhaustion by means of an automatic gas-analyzer system. Significant differences in expired ventilation and carbon dioxide production were found between the two groups, the V ̇ e · V ̇ O 2 −1 being lower in the S at rest (41.9±5) in comparison with C (48.7±9) ( P<0.05), higher at medium loads of the test (S=28.2±4 vs. C=25.7±2; P<0.05) and reaching similar values at higher loads (S=34.5±2 vs. C=35.6±4; NS). We conclude that the special ventilatory response observed in these highlanders could explain their adaptation to altitude, allowing higher oxygen blood saturation at medium working loads and reducing the risk of neurological injury caused by a high ventilatory response when exercising at high intensity effort under extreme altitude environment.