Alcides Rocha

Physiological and clinical relevance of exercise ventilatory efficiency in COPD

Exercise ventilation (V′E) relative to carbon dioxide output (V′CO2) is particularly relevant to patients limited by the respiratory system, e.g. those with chronic obstructive pulmonary disease (COPD). High V′E−V′CO2 (poor ventilatory efficiency) has been found to be a key physiological abnormality in symptomatic patients with largely preserved forced expiratory volume in 1 s (FEV1). Establishing an association between high V′E−V′CO2 and exertional dyspnoea in mild COPD provides evidence that exercise intolerance is not a mere consequence of detraining. As the disease evolves, poor ventilatory efficiency might help explaining “out-of-proportion” breathlessness (to FEV1 impairment). Regardless, disease severity, cardiocirculatory co-morbidities such as heart failure and pulmonary hypertension have been found to increase V′E−V′CO2. In fact, a high V′E−V′CO2 has been found to be a powerful predictor of poor outcome in lung resection surgery. Moreover, a high V′E−V′CO2 has added value to resting lung hyperinflation in predicting all-cause and respiratory mortality across the spectrum of COPD severity. Documenting improved ventilatory efficiency after lung transplantation and lung volume reduction surgery provides objective evidence of treatment efficacy. Considering the usefulness of exercise ventilatory efficiency in different clinical scenarios, the V′E−V′CO2 relationship should be valued in the interpretation of cardiopulmonary exercise tests in patients with mild-to-end-stage COPD. Ventilatory efficiency is a key measurement for the interpretation of cardiopulmonary exercise testing in COPD http://ow.ly/1nsY307pbz8

Exercise Ventilation in COPD: Influence of Systolic Heart Failure

ABSTRACT Systolic heart failure is a common and disabling co-morbidity of chronic obstructive pulmonary disease (COPD) which may increase exercise ventilation due to heightened neural drive and/or impaired pulmonary gas exchange efficiency. The influence of heart failure on exercise ventilation, however, remains poorly characterized in COPD. In a prospective study, 98 patients with moderate to very severe COPD [41 with coexisting heart failure; ‘overlap’ (left ventricular ejection fraction < 50%)] underwent an incremental cardiopulmonary exercise test (CPET). Compared to COPD, overlap had lower peak exercise capacity despite higher FEV1. Overlap showed lower operating lung volumes, greater ventilatory inefficiency and larger decrements in end-tidal CO2 (PETCO2) (P < 0.05). These results were consistent with those found in FEV1-matched patients. Larger areas under receiver operating characteristic curves to discriminate overlap from COPD were found for ventilation (E)-CO2 output CO2) intercept, E-CO2 slope, peak E/CO2 ratio and peak PETCO2. Multiple logistic regression analysis revealed that CO2 intercept ≤ 3.5 L/minute [odds ratios (95% CI) = 7.69 (2.61–22.65), P < 0.001] plus E-CO2 slope ≥ 34 [2.18 (0.73–6.50), P = 0.14] or peak E/CO2 ratio ≥ 37 [5.35 (1.96–14.59), P = 0.001] plus peak PETCO2 ≤ 31 mmHg [5.73 (1.42–23.15), P = 0.01] were indicative of overlapping. Heart failure increases the ventilatory response to metabolic demand in COPD. Variables reflecting excessive ventilation might prove useful to assist clinical interpretation of CPET responses in COPD patients presenting heart failure as co-morbidity.

Excess Ventilation in Chronic Obstructive Pulmonary Disease–Heart Failure Overlap. Implications for Dyspnea and Exercise Intolerance

Rationale: An increased ventilatory response to exertional metabolic demand (high &OV0312;e/&OV0312;co2 relationship) is a common finding in patients with coexistent chronic obstructive pulmonary disease and heart failure. Objectives: We aimed to determine the mechanisms underlying high &OV0312;e/&OV0312;co2 and its impact on operating lung volumes, dyspnea, and exercise tolerance in these patients. Methods: Twenty‐two ex‐smokers with combined chronic obstructive pulmonary disease and heart failure with reduced left ventricular ejection fraction undertook, after careful treatment optimization, a progressive cycle exercise test with capillary (c) blood gas collection. Measurements and Main Results: Regardless of the chosen metric (increased &OV0312;e‐&OV0312;co2 slope, &OV0312;e/&OV0312;co2 nadir, or end‐exercise &OV0312;e/&OV0312;co2), ventilatory inefficiency was closely related to PcCO2 (r values from −0.80 to −0.84; P < 0.001) but not dead space/tidal volume ratio. Ten patients consistently maintained exercise PcCO2 less than or equal to 35 mm Hg (hypocapnia). These patients had particularly poor ventilatory efficiency compared with patients without hypocapnia (P < 0.05). Despite the lack of between‐group differences in spirometry, lung volumes, and left ventricular ejection fraction, patients with hypocapnia had lower resting PaCO2 and lung diffusing capacity (P < 0.01). Excessive ventilatory response in this group was associated with higher exertional PcO2. The group with hypocapnia, however, had worse mechanical inspiratory constraints and higher dyspnea scores for a given work rate leading to poorer exercise tolerance compared with their counterparts (P < 0.05). Conclusions: Heightened neural drive promoting a ventilatory response beyond that required to overcome an increased “wasted” ventilation led to hypocapnia and poor exercise ventilatory efficiency in chronic obstructive pulmonary disease‐heart failure overlap. Excessive ventilation led to better arterial oxygenation but at the expense of earlier critical mechanical constraints and intolerable dyspnea.

Does Exercise Ventilatory Inefficiency Predict Poor Outcome in Heart Failure Patients With COPD

PURPOSE: To investigate whether the opposite effects of heart failure (HF) and chronic obstructive pulmonary disease (COPD) on exercise ventilatory inefficiency (minute ventilation [ E]-carbon dioxide output [ CO2] relationship) would negatively impact its prognostic relevance. METHODS: After treatment optimization and an incremental cardiopulmonary exercise test, 30 male patients with HF-COPD (forced expiratory volume in 1 second [FEV1] = 57% ± 17% predicted, ejection fraction = 35% ± 6%) were prospectively followed up during 412 ± 261 days for major cardiac events. RESULTS: Fourteen patients (46%) had a negative outcome. Patients who had an event had lower echocardiographically determined right ventricular fractional area change (RVFAC), greater ventilatory inefficiency (higher E/ CO2 nadir), and lower end-tidal CO2 (PETCO2) (all P < .05). Multivariate Cox models revealed that E/ CO2 nadir >36, &Dgr;PETCO2(PEAK-REST)≥2 mm Hg, and PETCO2PEAK⩽33 mm Hg added prognostic value to RVFAC⩽45%. Kaplan-Meyer analyses showed that although 18% of patients with RVFAC>45% had a major cardiac event after 1 year, no patient with RVFAC>45% and E/ CO2 nadir ⩽36 (or PETCO2PEAK>33 mm Hg) had a negative event. Conversely, although 69% of patients with RVFAC⩽45% had a major cardiac event after 1 year, all patients with RVFAC⩽45% and &Dgr;PETCO2(PEAK-REST)≥2 mm Hg had a negative event. CONCLUSION: Ventilatory inefficiency remains a powerful prognostic marker in HF despite the presence of mechanical ventilatory constraints induced by COPD. If these preliminary findings are confirmed in larger studies, optimal thresholds for outcome prediction are likely greater than those traditionally recommended for HF patients without COPD.

Ventilatory Inefficiency and Exertional Dyspnea in Early Chronic Obstructive Pulmonary Disease

&NA; Exertional dyspnea is present across the spectrum of chronic obstructive pulmonary disease (COPD) severity. However, without realizing it themselves, patients may decrease daily physical activity to avoid distressing respiratory sensations. Dyspnea also may be associated with deconditioning. Cardiopulmonary exercise testing can uncover exertional dyspnea and its physiological determinants in patients with preserved or only mildly reduced FEV1. Dyspnea in mild COPD can largely be explained by increased “wasted” ventilation in the physiological dead space, which heightens the drive to breathe and worsens the inspiratory mechanical constraints. During incremental exercise testing, this is readily identified as an excessive ventilation‐to‐metabolic demand, that is, a high ventilation (Symbole) to carbon dioxide output (Symbolco2) relationship. Linking increases in Symbole/Symbolco2 to exertional dyspnea may provide objective evidence that a patients poor exercise tolerance is not just a consequence of deconditioning. This information should prompt a proactive therapeutic approach to increase the available ventilatory reserve by, for example, giving inhaled bronchodilators. Considering that the structural determinants of ventilatory inefficiency (early emphysema, ventilation‐perfusion mismatching, and microvascular disease) may progress despite only modest changes in FEV1, serial Symbole/Symbolco2 measurements might also prove valuable to track disease progression in these symptomatic patients. Symbol. No caption available.

The peripheral–central chemoreflex interaction: where do we stand and what is the next step?

It has been known for more than a century that two distinct set of chemosensitive mechanisms contribute to human ventilatory control. This tightly controlled chemoreflex system operate via a negative feedback loop, mediating cardiorespiratory responses, which maintains arterial blood gases and acid–base balance within normal limits in a healthy organism under most circumstances. In contrast, dysfunctional chemoreflex sensitivity contributes to abnormal ventilatory control, turning this mechanism into a key point in the pathophysiology of highly prevalent diseases, like chronic heart failure (CHF), hypertension, chronic obstructive pulmonary disease (COPD), and obstructive sleep apnoea (OSA) (Kara et al. 2003). Peripherally, the chemoreflex control of ventilation is mediated by polymodal receptors (mainly in the carotid body; CB), which are sensitive to changes in the concentration of various substances in the arterial blood, such as carbon dioxide (CO2), hydrogen ions (H+), lactate, potassium, glucose, insulin and angiotensin. However, the major stimulus to peripheral chemoreceptors is the reduction in partial pressure of oxygen in the arterial blood (PaO2 ). Centrally, receptors are located in many brainstem areas, including the nucleus of the solitary tract (NTS), raphe, locus coeruleus and cerebellar fastigial nucleus. But, more recently, evidence from Guyenet et al. (2010) and Stornetta et al. (2006) (cited by Dempsey & Smith, 2014) has emphasized that the retrotrapezoid nucleus (RTN), which is characterized by glutamatergic interneurons expressing Phox2b, is the major potential site of central CO2/H+ chemoresponsiveness. Despite the existence of separate chemosensitive areas, with different stimulus characteristics, peripheral and central chemoreflexes do not act independently of each other. The discovery of important sites of convergence between CB and brainstem chemoreceptors in the NTS and RTN supports the idea of peripheral–central chemoreflex interdependence (Stornetta et al. 2006; cited by Dempsey & Smith, 2014). However, how these receptors interact to provide coordinated control of ventilation remains controversial. Previous studies provided evidence of different forms of peripheral–central interaction, i.e. (1) hypoadditive, where the stimulation of one reflex attenuate the response of the other, (2) additive, where both reflexes do not interact in a significant way, or (3) hyperadditive, where the stimulation of one reflex results in increased response of the other (also known as synergism). The controversy over the nature of this interaction has been attributed to heterogeneous protocols, preparations and species involved in previous studies. For example, some of these studies included decerebrated, vagotomized and anaesthetized animals (Day & Wilson, 2009), which is a highly controlled preparation, but could per se reduce the ventilatory response in face of central and/or peripheral stimulation or inhibition. Consequently, it may not reflect the real ventilatory control of an intact awake animal or human. Others investigated the interaction in humans, via non-invasive studies, which is limited to interpreting the function of each reflex separately. Based on the unclear nature of the chemoreflexes interaction, Smith et al. (2015) published a recent study in The Journal of Physiology using an intricate invasive preparation in intact, non-anaesthetized, awake dogs, which allowed independent peripheral and central stimulation or inhibition. The left CB was denervated and the right carotid sinus was prepared with a vascular occluder and catheter allowing reversible isolation and extracorporeal perfusion of the intact CB. Then, the intact CB was exposed to three different conditions: (1) normal stimuli to the CB, with pH, PaO2 and PaCO2 concentrations matching a given dog’s eupnoeic values; (2) CB inhibition with hypocapnic normoxic blood; and (3) CB stimulation with hypercapnic normoxic blood. In the steady-state of each CB perfusion, fractional inspired CO2 (F ICO2 ) was progressively increased to stimulate central chemoreceptors and changes in ventilation, diaphragm electromyography (EMG), blood gases and arterial pressure were quantified. The main finding of Smith et al. (2015) was that the increase in the slope of minute ventilation and inspiratory flow rate vs. changes in central PCO2 was 2to 4-fold greater when the isolated CB was exposed to hypercapnia vs. hypocapnia, and 2-fold greater during normocapnia vs. hypocania. Thus, specific CB stimulation or inhibition by hypercapnia/hypocapnia, while central chemoreceptors were stimulated by increased F ICO2 , resulted in hyperadditive interaction. Noteworthy, the present findings corroborate those previously reported by Dr Dempsey’s lab (Blain et al. 2010) using the same dog preparation. Earlier, authors demonstrated that inhibition or stimulation of vascularly isolated CB with changes in O2 levels also affected the magnitude of the ventilatory response to central hypercapnia in a hyperadditive fashion. Therefore, based on current and previous findings, Smith et al. (2015) suggest that changes in PO2 and PCO2 at the CB have similar effects on peripheral–central interaction for the control of ventilation. Results reported by Smith et al. (2015) are unique, since they were obtained in intact, unanaesthesized, awake animals, which is probably the best method used so far to translate results to spontaneously breathing humans. Nevertheless, they should be interpreted in light of some limitations. One is the use of systemic hypercapnia, which may not only stimulate central chemoreceptors, but may directly modify the activity of other receptors, such as pulmonary stretch receptors, or even the activity of neurons from the ‘central respiratory controller’, where supposedly all inputs that regulate ventilation are integrated. Unfortunately, it is impossible to exclusively manipulate the central chemoreceptors in intact, unanaesthesized and awake animals without systemic effects. To avoid systemic effects, Day & Wilson (2009), for example,

Current challenges in managing comorbid heart failure and COPD

ABSTRACT Introduction: Heart failure (HF) with reduced ejection fraction and chronic obstructive pulmonary disease (COPD) frequently coexist, particularly in the elderly. Given their rising prevalence and the contemporary trend to longer life expectancy, overlapping HF–COPD will become a major cause of morbidity and mortality in the next decade. Areas covered: Drawing on current clinical and physiological constructs, the consequences of negative cardiopulmonary interactions on the interpretation of pulmonary function and cardiopulmonary exercise tests in HF–COPD are discussed. Although those interactions may create challenges for the diagnosis and assessment of disease stability, they provide a valuable conceptual framework to rationalize HF–COPD treatment. The impact of COPD or HF on the pharmacological treatment of HF or COPD, respectively, is then comprehensively discussed. Authors finalize by outlining how the non-pharmacological treatment (i.e. rehabilitation and exercise reconditioning) can be tailored to the specific needs of patients with HF–COPD. Expert commentary: Randomized clinical trials testing the efficacy and safety of new medications for HF or COPD should include a sizeable fraction of patients with these coexistent pathologies. Multidisciplinary clinics involving cardiologists and respirologists trained in both diseases (with access to unified cardiorespiratory rehabilitation programs) are paramount to decrease the humanitarian and social burden of HF–COPD.