Phase-sensitive interaction of cardiac and respiratory timing in humans

We asked whether the heart rate response to respiratory change varied as a function of timing within the cardiac cycle. Respiratory and electrocardiographic data were collected from seven men and seven women during three weekly sessions under conditions of normal and visually paced breathing. Results revealed that, when inspiration began sooner than 500 ms before the subsequent heart beat, inspiration had little effect on the subsequent interbeat interval. However, the timing of the subsequent beat was accelerated when inspiration began later than 450 ms before this heart beat. Similar relationships were observed for expiratory onset. Results were not attributable to volitional control or rate of breathing. The modulation of respiratory sinus arrhythmia by the timing of respiratory events in the cardiac cycle has implications for the role of vagal control in the synchronization of heart rate with respiratory and behavioral actions.     

Introduction of respiratory pattern generators into models of respiratory control

We have adapted two models previously proposed as respiratory pattern generators (RPGs) into a neurochemical feed back control model of ventilation. The RPG models, non-dimensional as originally presented, consisted of oscillating circuits of either two or five interconnected neurons [Matsugu, M., Duffin, J., Poon, C.-S., 1998. Entrainment, instability, quasi-periodicity, and chaos in a compound neural oscillator. J. Comput. Neurosci. 5, 35–51; Botros, S.M., Bruce, E.N., 1990. Neural network implementation of a three-phase model of respiratory rhythm generation. Biol. Cybern. 63, 143–153]. The neurochemical model into which they were integrated [Longobardo, G., Evangelisti, C.J., Cherniack, N.S., 2002. Effects of neural drives on breathing in the awake state in humans. Respir. Physiol. 129, 317–333] included the effects of cerebral blood flow variation with CO₂, vagal stretch receptors input and a multicompartment model of carbon dioxide stores. The methodology is described whereby these neuronal oscillator networks were quantified, a necessary step for their inclusion as RPGs in broader models of the overall control of respiration. Subsequent simulations of the ventilation response to carbon dioxide with either respiratory pattern generator model exhibited only a limited range in which tidal volume and frequency increased with increasing respiratory drive. With both models, frequency peaked and then declined, as did ventilation when P_CO2 was greater than normal. The range of the models was extended if the respiratory pattern generators were considered to be composed of multiple neuronal oscillators or a single oscillator in which there was increasing phasic input that was gated or pacemaker driven.     

Change in the peripheral CO2 chemoreflex from rest to exercise

A single-breath CO₂ test of peripheral chemosensitivity has recently been described, and elaborated based on model simulations. This study was designed to measure the peripheral CO₂ chemoreflex at rest and during heavy exercise to see if carotid chemosensitivity to CO₂ increased. Ten healthy, adult males performed an incremental exercise test to determine their ventilatory anaerobic threshold (VAT), and 20 minutes of steady-state exercise at a pre-determined power output above VAT. Arterialized venous blood was obtained during each minute of incremental exercise to verify development of metabolic acidosis. Carotid chemosensitivity was tested repeatedly at rest and in steady-state exercise by the ventilatory response to a single breath of 13% CO₂ in air. The peripheral chemoreflex for CO₂ for the group of subjects doubled from rest to exercise (mean 0.0961 · s^–1 · kPa^–1) with all subjects showing an increase. We conclude that the gain of the carotid CO₂ chemoreflex increases from rest to exercise at work above the VAT.     

Pre-adaptation,adaptation and de-adaptation to high altitude in humans: cardio-ventilatory and haematological changes

The aim of this study was first to investigate cardio-ventilatory and haematological responses induced by intermittent acclimation and second to study de-adaptation from high altitude observed after descent. To achieve these objectives nine subjects were submitted to intermittent acclimation in a low barometric chamber (8 h daily for 5 days, day 1 at 4500 m, day 5 at 8500 m) before an expedition to the Himalayas. Cardio-ventilatory changes were measured during a hypobaric poikilocapnic hypoxic test (4500 m, barometric pressure = 589 hPa) and haematological changes were studied at sea level. These measurements were performed before and after acclimation, after return to sea level, but also 1 and 2 months after the expedition. In addition, partial pressures of oxygen and carbon dioxide in arterial blood (P _aO₂, P _aCO₂) and arterial erythropoietin concentration [EPO] were measured at rest during the hypoxic test. Results suggested the pre-adaptation protocol was efficient since an increased P _aO₂ (+12%, P < 0.05), a smaller difference in alveolo-arterial P0₂ ( –63%, P < 0.05) and a lower P _aCO₂ ( –11%, P < 0.05), subsequent to ventilatory changes, were observed after acclimation with a significant increase in reticulocytes and in sea level [EPO] (+44% and +62% respectively, P < 0.05). Deadaptation was characterized by a loss of these cardioventilatory changes 1 month after descent, whereas the haematological changes (increased red blood cells and packed cell volume, P < 0.05) persisted for 1 month before disappearing 2 months after descent. This study would also suggest that acute hypoxia performed after a sojourn at high altitude could induce significantly depressed EPO responses (P < 0.05).     

Population genetic aspects and phenotypic plasticity of ventilatory responses in high altitude natives

Highland natives show unique breathing patterns and ventilatory responses at altitude, both at rest and during exercise. For many ventilatory traits, there is also significant variation between highland native groups, including indigenous populations in the Andes and Himalaya, and more recent altitude arrivals in places like Colorado. This review summarizes the literature in this area with some focus on partitioning putative population genetic differences from differences acquired through lifelong exposure to hypoxia. Current studies suggest that Tibetans have high resting ventilation (V (E)), and a high hypoxic ventilatory response (HVR), similar to altitude acclimatized lowlanders. Andeans, in contrast, show low resting V (E) and a low or "blunted" HVR, with little evidence that these traits are acquired via lifelong exposure. Resting V (E) of non-indigenous altitude natives is not well documented, but lifelong hypoxic exposure almost certainly blunts HVR in these groups through decreased chemosensitivity to hypoxia in a process known as hypoxic desensitization (HD). Together, these studies suggest that the time course of ventilatory response, and in particular the origin or absence of HD, depends on population genetic background i.e., the allele or haplotype frequencies that characterize a particular population. During exercise, altitude natives have lower V (E) compared to acclimatized lowland controls. Altitude natives also have smaller alveolar-arterial partial pressure differences P(AO2) - P(aO2) during exercise suggesting differences in gas exchange efficiency. Small P(AO2) - P(aO2) in highland natives of Colorado underscores the likely importance of developmental adaptation to hypoxia affecting structural/functional aspects of gas exchange with resultant changes in breathing pattern. However, in Andeans, at least, there is also evidence that low exercise V (E) is determined by genetic background affecting ventilatory control independent of gas exchange. Additional studies are needed to elucidate the effects of gene, environment, and gene-environment interaction on these traits, and these effects are likely to differ widely between altitude native populations.     

On the interaction between respiratory compartments during passive expiration in ARDS patients

Relaxed expiratory volume-time profile has been frequently analysed by fitting exponential functions of time to one- or two-compartment models. In the latter case, the two exponential constants are assumed as representing the time constants of both compartments. Least-square fittings on the experimental data of five consecutive mechanically ventilated supine patients with acute respiratory distress syndrome (ARDS) were performed using rate-constants (flow/volume ratio) as parameters in order to obtain the model matching. Passive expiratory volume-time curves were recorded under PEEP = 0 and 13.6 +/- 3.3 S.D. cmH2O conditions. Model matching was optimal with significant, reliable parameter values. As a result, the use of a PEEP in ARDS patients: (a) delayed expiration; (b) decreased the percentage initial volume contribution of the slow-emptying compartment; and, (c) modified the interaction between compartments. The volume-time profile of the second compartment was found to increase at the beginning of expiration, and, then, progressively decayed towards zero, showing a maximum, although the overall curve decreased throughout expiration.     

Changes in respiratory control after 5 days at altitude

These experiments examined changes in the chemoreflex control of breathing and acid-base balance after 5 days at altitude (3480 m) in six healthy males. The partial pressures of carbon dioxide (P(CO2)) at which ventilation increased during isoxic hypoxic and hyperoxic modified rebreathing tests at sea level fell significantly at altitude by mean+/-S.E.M. of 12.8+/-2.51 mmHg and 9.5+/-1.77 mmHg, respectively, but response slopes above threshold were unchanged. Altitude exposure produced a respiratory alkalosis evidenced by a decrease in mean resting end-tidal P(CO2) from 41+/-0.84 mmHg at sea level to 32+/-2.04 mmHg at altitude, but pH did not increase significantly from its sea level value. Blood samples were analyzed to discover acid-base changes, using a modification of the equations for acid-base balance proposed by [Stewart, P.A., 1983. Modern quantitative acid-base chemistry. Can. J. Physiol. Pharmacol. 61, 1444-1461]. While strong ion difference at altitude was not significantly different from its sea level value, albumin concentration was increased significantly from 38.6+/-0.30 g L(-1) to 49.8+/-0.76 g L(-1). We suggest that the respiratory alkalosis was produced by a fall in the chemoreflex threshold and pH was corrected by an elevation in the concentration of weakly dissociated protein anions.     

人体呼吸系统数学模型

建立人体呼吸系统的模型，其包含有五个房室和通气率、血率量的控制系统。通过建立模型，能够了解氧气和二氧化碳在人体中的运输、交换、贮存的过程，并能仿真在低氧状太必高碳酸状态下，氧气和二氧化碳在人体各处的动态变化过程和静态数值，为研究体内外气体交换提供依据。     

Protocol to measure acute cerebrovascular and ventilatory responses to isocapnic hypoxia in humans

This study describes a protocol to determine acute cerebrovascular and ventilatory (AHVR) responses to hypoxia. Thirteen subjects undertook a protocol twice, 5 days apart. The protocol started with 8 min of eucapnic euoxia (end-tidal P(CO2) (PET(CO2)= 1.5 Torr) above rest; end-tidal P(O2) (PET(O2)) = 88 Torr) followed by six descending 90 s hypoxic steps (PET(O2) = 75.2, 64.0, 57.0, 52.0, 48.2, 45.0 Torr). Then, PET(O2) was elevated to 300 Torr for 10 min while PET(O2) remained at eucapnia (5 min) then raised by 7.5 Torr (5 min). Peak blood flow velocity in the middle cerebral artery (MCA) and regional cerebral oxygen saturation (Sr(O2)) were measured with transcranial Doppler ultrasound and near-infrared spectroscopy, respectively, and indices of acute hypoxic sensitivity were calculated (AHR(CBF) and AHRSr(O2)). Values for AHR(CBF), AHRSr(O2) and AHVR were 0.43 cm s(-1) % desaturation(-1), 0.80% % desaturation(-1) and 1.24l min(-1) % desaturation(-1), respectively. Coefficients of variation for AHR(CBF), AHRSr(O2) and AHVR were small (range = 8.0-15.2%). This protocol appears suitable to quantify cerebrovascular and ventilatory responses to acute isocapnic hypoxia.     

Facial cooling and peripheral chemoreflex mechanisms in humans

Aim: Reductions in arterial oxygen partial pressure activate the peripheral chemoreceptors which increase ventilation, and, after cessation of breathing, reduce heart rate. We tested the hypothesis that facial cooling facilitates these peripheral chemoreflex mechanisms. Methods: Chemoreflex control was assessed by the ventilatory response to hypoxia (10% O₂ in N₂) and the bradycardic response to voluntary end‐expiratory apnoeas of maximal duration in 12 young, healthy subjects. We recorded minute ventilation, haemoglobin O₂ saturation, RR interval (the time between two R waves of the QRS complex) and the standard deviation of the RR interval (SDNN), a marker of cardiac vagal activity throughout the study. Measurements were performed with the subject’s face exposed to air flow at 23 and 4 °C. Results: Cold air decreased facial temperature by 11 °C (P < 0.0001) but did not affect minute ventilation during normoxia. However, facial cooling increased the ventilatory response to hypoxia (P < 0.05). The RR interval increased by 31 ± 8% of the mean RR preceding the apnoea during the hypoxic apnoeas in the presence of cold air, compared to 17 ± 5% of the mean RR preceding the apnoea in the absence of facial cooling (P < 0.05). This increase occurred despite identical apnoea durations and reductions in oxygen saturation. Finally, facial cooling increased SDNN during normoxia and hypoxia, as well as during the apnoeas performed in hypoxic conditions (all P < 0.05). Conclusion: The larger ventilatory response to hypoxia suggests that facial cooling facilitates peripheral chemoreflex mechanisms in normal humans. Moreover, simultaneous diving reflex and peripheral chemoreflex activation enhances cardiac vagal activation, and favours further bradycardia upon cessation of breathing.     

丹红注射液延迟缺氧性呼吸抑制的发生及其机制

 目的：探讨丹红注射液对缺氧性呼吸抑制的作用及其相关机制。方法：记录膈肌肌电观察缺氧后呼吸的变化,通过免疫组化的方法检测缺氧大鼠脑干酸敏感离子通道1a (ASIC1a)的表达。结果：大鼠对缺氧的呼吸反应为先兴奋后抑制。缺氧后30 min,单纯缺氧组大鼠呼吸较缺氧前表现为明显的抑制（P<0.05）,而缺氧加丹红保护组大鼠呼吸依然兴奋（P<0.05）,尚未表现出明显的抑制。大鼠脑干ASIC1a的表达主要在孤束核和斜方体核,缺氧后大鼠ASIC1a的表达较对照组明显增加（P<0.05）,但缺氧加丹红保护组大鼠ASIC1a的表达较单纯缺氧组明显减少（P<0.05）。结论：丹红注射液能明显延迟缺氧后呼吸抑制的发生,在缺氧性呼吸抑制时保护机体。ASIC1a可能参与了这一过程。     

Effect of acetazolamide on respiratory muscle fatigue in humans

Previous studies have demonstrated that carbonic anhydrase inhibition with acetazolamide reduces exercise capacity. The mechanism responsible for this early fatigue is unclear, but may be partly mediated by impaired respiratory muscle function. Inspiratory muscle strength and endurance were assessed in seven healthy men (age 28 ± 5 yrs, ±SD) by measuring maximal inspiratory pressure (MIP) and time to task failure during a constant-load breathing test (CLBT), respectively, under control (CON) and acetazolamide (ACZ; 500 mg/8 h po for 3 days) conditions that were separated by two weeks and randomized between subjects. In addition, MIP was measured before and after moderate-intensity cycling exercise to fatigue while pulmonary gas exchange, plasma pH, and ventilation were measured during exercise. ACZ did not alter pulmonary function (FVC, FEV1, MVV) or MIP measured at rest (CON, −157 ± 47 vs. ACZ, −154 ± 45 cmH₂O, p > 0.05), but decreased time to task failure during the CLBT (CON, 1340 ± 820 vs. ACZ, 698 ± 434 s; p = 0.01). Exercise duration during cycling exercise was reduced (p = 0.003) with ACZ (1090 ± 254 s) compared to CON (1944 ± 532 s) in the presence of a significantly lower plasma pH and higher ventilation compared to control (p < 0.05). Compared to resting values, MIP was reduced (p = 0.03) in ACZ but not CON at exhaustion. In conclusion, carbonic anhydrase inhibition with ACZ is associated with impaired respiratory muscle function at rest and following constant load cycling which may contribute to reduced exercise tolerance with carbonic anhydrase inhibition.     

Accounting for flow dependence of respiratory resistance during exercise

Studies of airway function during exercise have produced conflicting results both in healthy and diseased subjects. Respiratory resistance (Rrs) was measured using an impulse oscillation technique. A flow/resistance curve was established for each of 16 healthy males during voluntary hyperventilation (VHV) at rest. Then, Rrs and flow were measured immediately (t(0)) and 90 sec (t(90)) after exercise on a cycle ergometer at 60, 70, and 80% of maximal aerobic power. The flow/resistance relationship at rest during VHV was used to assess the flow dependence of Rrs. Rrs at t(0) was higher than at rest (P <0.01) but lower than Rrs obtained at matched flow during VHV (P <0.05). In healthy subjects, the linear increase in Rrs with VHV indicates airflow dependency of Rrs following Rohrer's equation. The relative decrease in Rrs with exercise suggests bronchodilation. The bronchodilating effect disappeared promptly when exercise was stopped suggesting that it may have been related to a reflex mechanism.     

A comprehensive simulator of the human respiratory system: Validation with experimental and simulated data

A comprehensive model of oxygen (O₂) and carbon dioxide (CO₂) exchange, transport, and storage in the adult human is presented, and its ability to provide realistic responses under different physiological conditions is evaluated. The model comprises three compartments (i.e., lung, body tissue, and brain tissue) and incorporates a controller that adjusts alveolar ventilation and cardiac output dynamically integrating stimuli coming from peripheral and central chemoreceptors. A new realistic CO₂ dissociation curve based on a two-buffer model of acid-base chemical regulation is included. In addition, the model explicitly considers relevant physiological factors such as buffer base, the nonlinear interaction between the O₂ and CO₂ chemoreceptor responses, pulmonary shunt, dead space, variable time delays, and Bohr and Haldane effects. Model simulations provide results consistent with both dynamic and steady-state responses measured in subjects undergoing inhalation of high CO₂ (hypercapnia) or low O₂ (hypoxia) and subsequent recovery. An analysis of the results indicates that the proposed model fits the experimental data of ventilation and gas partial pressures as some meaningful simulators now available and in a very large range of gas intake fractions. Moreover, it also provides values of blood concentrations of CO₂, HCO⁻ ₃, and hydrogen ions in good agreement with more complex simulators characterized by an implicit formulation of the CO₂ dissociation curve. In the experimental conditions analyzed, the model seems to represent a single theoretical framework able to appropriately describe the different phenomena involved in the control of respiration.     

Ventilatory responses to exercise and carbon dioxide in elderly and younger humans

Summary The present investigation examined the relationship between CO₂ sensitivity [at rest (S _R) and during exercise (S _E)] and the ventilatory response to exercise in ten elderly (61–79 years) and ten younger (17–26 years) subjects. The gradient of the relationship between minute ventilation and CO₂ production ( _E/ CO₂) of the elderly subjects was greater than that of the younger subjects [mean (SEM); 32.8 (1.6) vs 27.3 (0.4); P<0.01]. At rest, S _R was lower for the elderly than for the younger group [10.77 (1.72) vs 16.95 (2.13) 1 · min^–1 · kPa^–1; 1.44 (0.23) vs 2.26 (0.28) 1 · min^–1 · mmHg^–1; P<0.05], but S _E was not significantly different between the two groups [17.85 (2.49) vs 19.17 (1.62) l · min^–1 · kPa^–1; 2.38 (0.33) vs 2.56 (0.21) 1 · min^–1 · mmHg^–1]. There were significant correlations between both S _R and S _E, and _E/ CO₂ (P<0.05; P<0.001) for the younger group, bot none for the elderly. The absence of a correlation for the elderly supports the suggestion that _E/ CO₂ is not an appropriate index of the ventilatory response to exercise for elderly humans.     

Influence of the viscoelastic properties of the respiratory system on the energetically optimum breathing frequency

We hypothesized that the viscoelastic properties of the respiratory system should have significant implications for the energetically optimal frequency of breathing, in view of the fact that these properties cause marked dependencies of overall system resistance and elastance on frequency. To test our hypothesis we simulated two models of canine and human respiratory system mechanics during sinusoidal breathing and calculated the inspiratory work ( ) and pressure-time integral (PTI) per minute under both resting and exercise conditions. The two models were a two-compartment viscoelastic model and a single-compartment model. Requiring minute alveolar ventilation to be fixed, we found that both models predicted almost identical optimum breathing frequencies. The calculated PTI was very insensitive to increases in breathing frequency above the optimal frequencies, while was found to increase slowly with frequency above its optimum. In contrast, both and PTI increased sharply as frequency decreased below their respective optima. A sensitivity analysis showed that the model predictions were very insensitive to the elastance and resistance values chosen to characterize tissue viscoelasticity. We conclude that the criterion for choosing the frequency of breathing is compatible with observations in nature, whereas the optimal frequency predictions of the PTI are rather too high. Both criteria allow for a fairly wide margin of choice in frequency above the optimum values without incurring excessive additional energy expenditure. Furthermore, contrary to our expectations, the viscoelastic properties of the respiratory system tissues do not pose a noticeable problem to the respiratory controller in terms of energy expenditure.     

Activation of respiratory afferents by resistive loaded breathing modifies somatosensory evoked potentials to median nerve stimulation in humans

The cortical projections of respiratory afferents (vagus and respiratory muscle nerves) are well documented in humans. It is also shown that their activation during loaded breathing modifies the perception of tactile sensation as well as the motor drive to skeletal muscles. The effects of expiratory or inspiratory loaded breathing on somatosensory evoked potentials (SEPs) elicited by median nerve stimulation were studied in eight healthy subjects. No significant changes occurred in latencies of N20, N30 and P40 throughout the expiratory loading period, except for a significant lengthening in P1 latency compared with unloaded breathing. However, inspiratory loading induced a significant increase in peak latency of N20, N30 and P40 components. We suggest that projections of inspiratory afferents from the diaphragm and the intercostal muscles, activated by inspiratory loading, could be responsible for the lengthened latency of median nerve SEP components. Thus, respiratory afferents very likely interact with pathways of the somatosensory system.