Hans C. Haverkamp

Effect of inspiratory muscle work on peripheral fatigue of locomotor muscles in healthy humans

The work of breathing required during maximal exercise compromises blood flow to limb locomotor muscles and reduces exercise performance. We asked if force output of the inspiratory muscles affected exercise‐induced peripheral fatigue of locomotor muscles. Eight male cyclists exercised at ≥ 90% peak O2 uptake to exhaustion (CTRL). On a separate occasion, subjects exercised for the same duration and power output as CTRL (13.2 ± 0.9 min, 292 W), but force output of the inspiratory muscles was reduced (−56%versus CTRL) using a proportional assist ventilator (PAV). Subjects also exercised to exhaustion (7.9 ± 0.6 min, 292 W) while force output of the inspiratory muscles was increased (+80%versus CTRL) via inspiratory resistive loads (IRLs), and again for the same duration and power output with breathing unimpeded (IRL‐CTRL). Quadriceps twitch force (Qtw), in response to supramaximal paired magnetic stimuli of the femoral nerve (1–100 Hz), was assessed pre‐ and at 2.5 through to 70 min postexercise. Immediately after CTRL exercise, Qtw was reduced −28 ± 5% below pre‐exercise baseline and this reduction was attenuated following PAV exercise (−20 ± 5%; P < 0.05). Conversely, increasing the force output of the inspiratory muscles (IRL) exacerbated exercise‐induced quadriceps muscle fatigue (Qtw=−12 ± 8% IRL‐CTRL versus−20 ± 7% IRL; P < 0.05). Repeat studies between days showed that the effects of exercise per se, and of superimposed inspiratory muscle loading on quadriceps fatigue were highly reproducible. In conclusion, peripheral fatigue of locomotor muscles resulting from high‐intensity sustained exercise is, in part, due to the accompanying high levels of respiratory muscle work.

Intrapulmonary shunting and pulmonary gas exchange during normoxic and hypoxic exercise in healthy humans

Exercise-induced intrapulmonary arteriovenous shunting, as detected by saline contrast echocardiography, has been demonstrated in healthy humans. We have previously suggested that increases in both pulmonary pressures and blood flow associated with exercise are responsible for opening these intrapulmonary arteriovenous pathways. In the present study, we hypothesized that, although cardiac output and pulmonary pressures would be higher in hypoxia, the potent pulmonary vasoconstrictor effect of hypoxia would actually attenuate exercise-induced intrapulmonary shunting. Using saline contrast echocardiography, we examined nine healthy men during incremental (65 W + 30 W/2 min) cycle exercise to exhaustion in normoxia and hypoxia (fraction of inspired O(2) = 0.12). Contrast injections were made into a peripheral vein at rest and during exercise and recovery (3-5 min postexercise) with pulmonary gas exchange measured simultaneously. At rest, no subject demonstrated intrapulmonary shunting in normoxia [arterial Po(2) (Pa(O(2))) = 98 +/- 10 Torr], whereas in hypoxia (Pa(O(2)) = 47 +/- 5 Torr), intrapulmonary shunting developed in 3/9 subjects. During exercise, approximately 90% (8/9) of the subjects shunted during normoxia, whereas all subjects shunted during hypoxia. Four of the nine subjects shunted at a lower workload in hypoxia. Furthermore, all subjects continued to shunt at 3 min, and five subjects shunted at 5 min postexercise in hypoxia. Hypoxia has acute effects by inducing intrapulmonary arteriovenous shunt pathways at rest and during exercise and has long-term effects by maintaining patency of these vessels during recovery. Whether oxygen tension specifically regulates these novel pathways or opens them indirectly via effects on the conventional pulmonary vasculature remains unclear.

Update in the Understanding of Respiratory Limitations to Exercise Performance in Fit, Active Adults

This review addresses three types of causes of respiratory system limitations to O(2) transport and exercise performance that are experienced by significant numbers of active, highly fit younger and older adults. First, flow limitation in intrathoracic airways may occur during exercise because of narrowed, hyperactive airways or secondary to excessive ventilatory demands superimposed on a normal maximum flow-volume envelope. Narrowing of the extrathoracic, upper airway also occurs in some athletes at very high flow rates during heavy exercise. Examination of the breath-by-breath tidal flow-volume loop during exercise is key to a noninvasive diagnosis of flow limitation and to differentiation between intrathoracic and extrathoracic airway narrowing. Second exercise-induced arterial hypoxemia occurs secondary to an excessively widened alveolar-arterial oxygen pressure difference. This inefficient gas exchange may be attributable in part to small intracardiac or intrapulmonary shunts of deoxygenated mixed venous blood during exercise. The existence of these shunts at rest and during exercise may be determined by using saline solution contrast echocardiography. Finally, fatigue of the respiratory muscles resulting from sustained, high-intensity exercise and the resultant vasoconstrictor effects on limb muscle vasculature will also compromise O(2) transport and performance. Exercise in the hypoxic environments of even moderately high altitudes will greatly exacerbate the negative influences of these respiratory system limitations to exercise performance, especially in highly fit individuals.

Transpulmonary passage of 99mTc macroaggregated albumin in healthy humans at rest and during maximal exercise

We have demonstrated that 50-mum-diameter arteriovenous pathways exist in isolated, healthy human and baboon lungs, ventilated and perfused under physiological pressures. These findings have been confirmed and extended by demonstrating the passage of 25-microm microspheres through the lungs of exercising dogs, but not at rest. Determination of blood flow through these large-diameter intrapulmonary arteriovenous pathways would be an important first step to establish a physiological role for these vessels. Currently, we sought to estimate blood flow through these arteriovenous pathways using technetium-99m ((99m)Tc)-labeled macroaggregated albumin (MAA) in healthy humans at rest and during maximal treadmill exercise. We hypothesized that the percentage of (99m)Tc MAA able to traverse the pulmonary circulation (%transpulmonary passage) would increase during exercise. Seven male subjects without patent foramen ovale were injected with (99m)Tc MAA at rest on 1 day and during maximal treadmill exercise on a separate day (>6 days). Within 5 min after injection, subjects began whole body imaging in the supine position. Six of the seven subjects showed an increase in transpulmonary passage of MAA with maximal exercise. Using two separate analysis methods, percent transpulmonary passage significantly increased with exercise from baseline to absolute values of 1.2 +/- 0.8% (P = 0.008) and 1.3 +/- 1.0% (P = 0.016), respectively (means +/- SD; paired t-test). We conclude that MAA may be traversing the pulmonary circulation via large-diameter intrapulmonary arteriovenous conduits in healthy humans during exercise. Recruitment of these pathways may divert blood flow away from pulmonary capillaries during exercise and compromise the lungs function as a biological filter.

Inhaled salmeterol and/or fluticasone alters structure/function in a murine model of allergic airways disease

BackgroundThe relationship between airway structural changes (remodeling) and airways hyperresponsiveness (AHR) is unclear. Asthma guidelines suggest treating persistent asthma with inhaled corticosteroids and long acting β-agonists (LABA). We examined the link between physiological function and structural changes following treatment fluticasone and salmeterol separately or in combination in a mouse model of allergic asthma.MethodsBALB/c mice were sensitized to intraperitoneal ovalbumin (OVA) followed by six daily inhalation exposures. Treatments included 9 daily nebulized administrations of fluticasone alone (6 mg/ml), salmeterol (3 mg/ml), or the combination fluticasone and salmeterol. Lung impedance was measured following methacholine inhalation challenge. Airway inflammation, epithelial injury, mucus containing cells, and collagen content were assessed 48 hours after OVA challenge. Lungs were imaged using micro-CT.Results and DiscussionTreatment of allergic airways disease with fluticasone alone or in combination with salmeterol reduced AHR to approximately naüve levels while salmeterol alone increased elastance by 39% compared to control. Fluticasone alone and fluticasone in combination with salmeterol both reduced inflammation to near naive levels. Mucin containing cells were also reduced with fluticasone and fluticasone in combination with salmeterol.ConclusionsFluticasone alone and in combination with salmeterol reduces airway inflammation and remodeling, but salmeterol alone worsens AHR: and these functional changes are consistent with the concomitant changes in mucus metaplasia.

Inspiratory muscles do not limit maximal incremental exercise performance in healthy subjects

We investigated whether the inspiratory muscles affect maximal incremental exercise performance using a placebo-controlled, crossover design. Six cyclists each performed six incremental exercise tests. For three trials, subjects exercised with proportional assist ventilation (PAV). For the remaining three trials, subjects underwent sham respiratory muscle unloading (placebo). Inspiratory muscle pressure (P(mus)) was reduced with PAV (-35.9+/-2.3% versus placebo; P<0.05). Furthermore, V(O2) and perceptions of dyspnea and limb discomfort at submaximal exercise intensities were significantly reduced with PAV. Peak power output, however, was not different between placebo and PAV (324+/-4W versus 326+/-4W; P>0.05). Diaphragm fatigue (bilateral phrenic nerve stimulation) did not occur in placebo. In conclusion, substantially unloading the inspiratory muscles did not affect maximal incremental exercise performance. Therefore, our data do not support a role for either inspiratory muscle work or fatigue per se in the limitation of maximal incremental exercise.

Computational assessment of airway wall stiffness in vivo in allergically inflamed mouse models of asthma.

Allergic inflammation is known to cause airway hyperresponsiveness in mice. However, it is not known whether inflammation affects the stiffness of the airway wall, which would alter the load against which the circumscribing smooth muscle shortens when activated. Accordingly, we measured the time course of airway resistance immediately following intravenous methacholine injection in acutely and chronically allergically inflamed mice. We estimated the effective stiffness of the airway wall in these animals by fitting to the airway resistance profiles a computational model of a dynamically narrowing airway embedded in elastic parenchyma. Effective airway wall stiffness was estimated from the model fit and was found not to change from control in either the acute or chronic inflammatory groups. However, the acutely inflamed mice were hyperresponsive compared with controls, which we interpret as reflecting increased delivery of methacholine to the airway smooth muscle through a leaky pulmonary endothelium. These results support the notion that acutely inflamed BALB/c mice represent an animal model of functionally normal airway smooth muscle in a transiently abnormal lung.

Effects of Altered Airway Function on Exercise Ventilation in Asthmatic Adults

PURPOSE Variable airway function is a central feature of the asthmatic condition. Thus, habitually active asthmatics are certain to exercise under conditions of variable airway (dys)function. The purpose of this study was to determine the effects of variable preexercise airway function on ventilation during whole-body exercise in asthmatic adults. METHODS Eight mild asthmatic (age = 26 yr; V˙O2peak = 49 mL·kg·min) and nine nonasthmatic (age = 30 yr; V˙O2peak = 46 mL·kg·min) adults performed constant workrate cycling exercise to exhaustion after four separate interventions: 1) a control trial (CON); 2) inhalation of fast-acting β2-agonist (BD); 3) eucapnic voluntary hyperpnea challenge (BC); and 4) sham to the hyperpnea (SHAM). Pulmonary function was assessed at baseline and after each intervention. Exercise ventilation and operating lung volumes were compared among the four exercise trials in both control and asthmatic subjects. RESULTS Baseline pulmonary function was significantly lower in asthmatic subjects compared with control subjects. In asthmatic subjects, postintervention (i.e., preexercise) forced expiratory volume 1.0 s was significantly different among the four exercise trials (CON = 3.5 ± 0.4, BD = 4.1 ± 0.4, SHAM = 3.6 ± 0.3, BC = 2.8 ± 0.3 L, P < 0.05), whereas it was not different in control subjects. There were no differences in exercise ventilation or operating lung volumes during exercise among the four trials either within asthmatic subjects or between control and asthmatic subjects. CONCLUSIONS These findings suggest that the state of airway function-whether bronchodilated or bronchoconstricted-before exercise in the mild asthmatic does not affect the exercise ventilatory response. Thus, ventilatory system function in the asthmatic appears to be responsive to the acute requirement for increased airflow during whole-body exercise.

Quantifying the shape of the maximal expiratory flow–volume curve in mild COPD

Maximal expiratory flow-volume (MEFV) curve evaluation using absolute and percent predicted values of flow and volume are used to diagnose respiratory disease, but the shape of the curve is rarely used. Three mathematical methods were used to quantify shape of MEFV curves in subjects with mild COPD (n=19) and matched healthy controls (n=15). Those with mild COPD had a significantly greater slope-ratio (SR) (1.90 ± 0.24 vs. 1.28 ± 0.32) and Beta-angle (160 ± 6.7 vs. 186 ± 15.0) compared to healthy individuals (p<0.05). The flow-ratio method showed no difference between groups. A significant positive SR-volume relationship during expiration was observed in a greater number of mild COPD subjects (94%) compared to controls (20%) (p<0.001). With its increased spatial resolution and the potential to discern etiology behind specific curvature, we suggest using the SR method when available. The change in SR throughout expiration could help identify those who fall within the lower limit of normal lung function and those who may have pathological obstruction.

No effect of elevated operating lung volumes on airway function during variable workrate exercise in asthmatic humans

In asthmatic adults, airway caliber fluctuates during variable intensity exercise such that bronchodilation (BD) occurs with increased workrate whereas bronchoconstriction (BC) occurs with decreased workrate. We hypothesized that increased lung mechanical stretch would prevent BC during such variable workrate exercise. Ten asthmatic and ten nonasthmatic subjects completed two exercise trials on a cycle ergometer. Both trials included a 28-min exercise bout consisting of alternating four min periods at workloads equal to 40 % (Low) and 70% (High) peak power output. During one trial, subjects breathed spontaneously throughout exercise (SVT), such that tidal volume (VT) and end-inspiratory lung volume (EILV) were increased by 0.5 and 0.6 liters during the high compared with the low workload in nonasthmatic and asthmatic subjects, respectively. During the second trial (MVT), VT and EILV were maintained constant when transitioning from the high to the low workload. Forced exhalations from total lung capacity were performed during each exercise workload. In asthmatic subjects, forced expiratory volume 1.0 s (FEV1.0) increased and decreased with the increases and decreases in workrate during both SVT (Low, 3.3 ± 0.3 liters; High, 3.6 ± 0.2 liters; P < 0.05) and MVT (Low, 3.3 ± 0.3 liters; High, 3.5 ± 0.2 liters; P < 0.05). Thus increased lung stretch during MVT did not prevent decreases in airway caliber when workload was reduced. We conclude that neural factors controlling airway smooth muscle (ASM) contractile activity during whole body exercise are more robust determinants of airway caliber than the ability of lung stretch to alter ASM actin-myosin binding and contraction.