International Journal of COPD Dovepress open access to scientific and medical research ORIGInAL RESEARCH Open Access Full Text Article Inspiratory drive is related to dynamic pulmonary hyperinlation in COPD patients Diego Gatta 1 Marco Fredi 2 Giovanni Aliprandi 2 Laura Pini 1 Claudio Tantucci 1 1 Respiratory Medicine Unit, Department of Medical and Surgical Sciences, University of Brescia, Brescia, Italy; 2Respiratory Rehabilitation Unit, Hospital Domus Salutis, Brescia, Italy Background: Baseline high neuromuscular drive is present in chronic obstructive pulmonary disease (COPD). In moderate-to-very severe COPD patients, both static and/or dynamic pulmonary hyperinflation have been demonstrated at rest. Aim: To assess the influence of dynamic hyperinflation on neuromuscular drive at rest. Methods: We recruited 22 patients with severe-to-very severe COPD showing resting dynamic pulmonary hyperinflation, as assessed by the baseline reduction of inspiratory capacity (IC) (,80% of predicted). IC, occlusion pressure (P0.1), maximal inspiratory pressure (MIP), and their ratio were measured at end-expiratory lung volume (EELV) before and after acute inhalation of 400 mcg of albuterol (metered-dose inhaler plus spacer). In these patients the bronchodilator response was assessed also as lung volume changes. Results: Only in COPD patients with a marked increase in IC (.12% of baseline and at least 200 mL) after bronchodilator, resting P0.1 showed a clinically significant decrease, despite the EELV diminution (P , 0.001). MIP was augmented following EELV reduction and therefore the P0.1/MIP ratio was markedly decreased (P , 0.001). In contrast, no changes in these indices were found after bronchodilator in COPD patients with insignificant variations of IC. Breathing pattern parameters did not vary in both sub-groups after albuterol. Conclusion: Following bronchodilator, significant P0.1 decrease, MIP increase, and reduction of the P0.1/MIP ratio were found only in COPD patients with a marked IC increase and these changes were closely related. These findings suggest that bronchodilators, by decreasing dynamic hyperinflation, may control exertional and/or chronic dyspnea partly through a reduction of central neuromuscular drive. Keywords: chronic obstructive pulmonary disease, control of breathing, inspiratory muscles, dynamic hyperinflation, bronchodilators Introduction Correspondence: Claudio Tantucci Medicina Interna I, University of Brescia, Spedali Civili di Brescia P.zzale Spedali Civili, 1 25123 Brescia, Italy Tel +3 90 3039 8069 Fax +3 90 3039 8069 Email tantucci@med.unibs.it submit your manuscript | www.dovepress.com Dovepress http://dx.doi.org/10.2147/COPD.S38320 In patients with moderate-to-severe chronic obstructive pulmonary disease (COPD), parameters reflecting static and dynamic pulmonary hyperinflation (DH) such as endexpiratory lung volume (EELV) or inspiratory capacity (IC) correlate better than forced expiratory volume in 1 second (FEV1) with chronic dyspnea,1 and progressive DH is thought to be the main limiting factor of their exercise capacity because of related intolerable breathlessness.2,3 In COPD patients, the occurrence of DH, either at rest or during exercise, is thought to induce dyspnea mainly by causing neuromechanical (or neuroventilatory) dissociation.3 However, a high inspiratory drive that is widely documented in severe-to-very severe COPD5 might also contribute to increased dyspnea in these patients. International Journal of COPD 2013:8 169–173 © 2013 Gatta et al, publisher and licensee Dove Medical Press Ltd. This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited. 169 Dovepress Gatta et al By increasing the expiratory flow reserve at low lung volumes, bronchodilators can reduce chronic and exertional dyspnea essentially by decreasing baseline EELV (or increasing IC) in moderate-to-severe COPD patients6–8 with DH, and better neuromechanical coupling is believed to be responsible to a large extent for such improvement.9 The aim of the study was to assess whether the acute reduction of resting DH possibly obtained by bronchodilator administration could influence the neuromuscular inspiratory drive and its ratio with the inspiratory muscles’ strength in stable COPD patients with marked airflow obstruction. Methods We prospectively evaluated a cohort of stable severe to very severe COPD outpatients with baseline IC values less than 80% of their predicted values, consecutively enrolled at the Respiratory Rehabilitation Unit, Hospital Domus Salutis, Brescia, Italy. The diagnosis of COPD was made according to the following criteria: (1) smoking history of more than 20 pack-years and/or the presence of other known risk factors for COPD; (2) baseline FEV1/vital capacity ratio less than the 5th percentile of normal limits;10 (3) increase of FEV1 less than 10% of the predicted value and less than 200 mL in absolute value after 400 mcg of inhaled albuterol (metered-dose inhaler plus spacer); (4) no history or evidence of other diseases with chronic airflow obstruction such as chronic asthma, bronchiectasis, constrictive bronchiolitis, tuberculosis, and cystic fibrosis. At least 24 hours after withdrawal of long-acting beta-2 agonists, short and long-acting anti-cholinergics, and slowrelease theophylline, in the absence of exacerbation in the preceding 12 weeks, the patients underwent both in baseline condition and 30 minutes after the inhalation of albuterol (400 mcg by metered-dose inhaler plus spacer) pulmonary function tests (spirometry, maximal flow/volume curve, lung volumes by N2-multibreath wash-out test) (System 1070, Medical Graphics, St Paul, MN, USA), determination of mouth pressure 100 milliseconds after the beginning of quiet inspiration during airways occlusion (P0.1) performed at EELV, and measurements of maximal inspiratory pressure (MIP) at EELV during a Muller maneuver (Resp Mech module, Medical Graphics, St Paul, MN, USA). Both P0.1 and MIP were obtained in triplicate with adequate time intervals among the different measurements and the values used for analysis were the average of the two highest ones. Subsequently, the patients were classified, according to the IC changes after acutely inhaled albuterol, in volume nonresponders (increase of IC , 12% and 200 mL of baseline: 170 submit your manuscript | www.dovepress.com Dovepress group 1) and volume responders (increase of IC  12% and 200 mL of baseline: group 2). All spirometric parameters were analyzed as percent of predicted values.10 The IC predicted values were those proposed by Tantucci et al.11 Predicted values of IC for those patients aged less than 65 were obtained by backextrapolating the reference equations. The patients were recruited and tested if able to correctly perform the pulmonary function tests according to the American Thoracic Society guidelines.12 The study was approved by the Ethics Committee of the Hospital “Spedali Civili” of Brescia and each patient signed an informed consent for collection and treatment of data. Statistical analysis Differences between groups were assessed according to an unpaired nonparametric test (Mann-Whitney test) while comparisons of functional parameters before and after albuterol within groups were performed by a paired nonparametric test (Wilcoxon test). The Pearson’s linear correlations were used to establish association between the variables of interest and the determination coefficients were also given. A P-value less than 0.05 was considered as statistically significant. The calculations were made using the SPSS 14.0 statistical package (IBM Corporation, Armonk, NY, USA). Data were expressed as mean ± standard deviation. Results Twenty-two COPD patients (18 male) with a mean age of 72 ± 6 years and FEV1 equal to 0.78 ± 0.26 L (33% ± 11% predicted) were studied. Their anthropometric and functional characteristics are shown in Table 1. At baseline, a severe reduction of FEV1 with a marked increase of residual volume and functional residual capacity and reduction of IC were observed in these patients who exhibited, as expected, high values of P0.1. No significant differences, however, were found at rest for spirometric parameters, lung volumes, neuromuscular drive, and maximal isometric force of inspiratory muscles between volume non-responders (group 1: increase of IC , 12% and 200 mL of baseline) and volume responders (group 2: increase of IC  12% and 200 mL of baseline) (Table 1). Following inhalation of albuterol, FEV1 increased by 50 ± 50 mL (from 0.87 ± 0.25 L to 0.92 ± 0.22 L) in group 1 and by 130 ± 70 mL (from 0.74 ± 0.27 L to 0.87 ± 0.28 L) in group 2. P0.1, MIP, and their ratio (P0.1/MIP%) are displayed in Table 2, before and after albuterol for all patients and those International Journal of COPD 2013:8 Inspiratory drive and dynamic hyperinlation in COPD Dovepress neuromuscular drive at rest (r2 = 0.59; P , 0.01). A similar relationship was found between changes in IC (as a percentage of baseline) and P0.1/MIP% ratio, as shown in Figure 1, panel B (r2 = 0.56; P , 0.01). No variations of the breathing pattern parameters such as tidal volume (Vt), respiratory rate (RR), inspiratory (Ti) and expiratory time (Te), mean inspiratory flow (VT/Ti), and duty cycle (Ti/Ttot) were observed before and after albuterol administration in both groups of COPD patients. Table 1 Anthropometric and functional characteristics observed in all patients and two groups of them, divided according to the absence (n = 7) or presence (n = 15) of signiicant change of IC (.12% from baseline and 200 mL) after acute bronchodilator at rest n Age (year) Gender (M/F) Smoke exposure (pack years) SVC (% pred) FEV1 (% pred) FVC (% pred) FEV1/FVC % IC (% pred) RV (% pred) TLC (% pred) P0.1 (cm H2O) MIP (cm H2O) PaO2 (mmHg) PaCO2 (mmHg) 22 68 ± 8 18/4 45 ± 22 7 71 ± 6 7/0 43 ± 20 15 66 ± 10 11/4 46 ± 23 ns / ns 78 ± 20 33 ± 10 74 ± 19 35 ± 9 55 ± 18 190 ± 63 121 ± 24 4.7 ± 1.2 69 ± 19 66 ± 10 44 ± 5 77 ± 23 33 ± 9 73 ± 20 36 ± 12 59 ± 27 183 ± 60 115 ± 23 4.2 ± 0.5 78 ± 20 64 ± 7 42 ± 7 79 ± 20 33 ± 11 74 ± 19 34 ± 7 54 ± 14 193 ± 67 124 ± 25 4.9 ± 1.4 65 ± 18 67 ± 11 45 ± 6 ns ns ns ns ns ns ns ns ns ns ns Discussion The results of this study indicate that in stable COPD patients at rest the neuromuscular output to inspiratory muscles is related to the degree of pulmonary hyperinflation and the reduction of DH possibly achieved by bronchodilator induces a significant decrease of inspiratory drive. Since bronchodilators have been shown to limit exertional and chronic dyspnea in COPD mainly by decreasing DH, our findings suggest that this may occur partly because of reduction on central motor output to inspiratory muscles. It has been demonstrated that COPD patients have a high neural drive even at rest, as reflected by the increased baseline P0.1.5 Many factors have been implicated to explain this elevated motor command to inspiratory muscles. Included among them are increased airflow resistance, abnormal gas exchange, weak respiratory muscles, and high ventilatory requirements.13 Much evidence has been collected showing that distressing breathlessness in moderate-to-severe COPD patients is mostly linked to the occurrence of DH.3 The imbalance between the volume displacement and the muscular effort required to achieve it, known as neuromechanical or neuroventilatory dissociation, is thought to be the main mechanism by which DH causes chronic and exertional dyspnea in COPD.9 Other mechanisms, however, have been invoked in COPD patients as able to generate dyspnea and Note: Data are mean ± SD. Abbreviations: IC, inspiratory capacity; SVC, slow vital capacity; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; RV, residual volume; TLC, total lung capacity; P0.1, mouth pressure 100 milliseconds after the beginning of quiet inspiration during airways occlusion; MIP, maximal inspiratory pressure; SD, standard deviation. with and without significant increase of IC (as a percentage of baseline). Despite the reduction of EELV as reflected by the increase of IC, P0.1 was significantly reduced in volume responder COPD patients (P , 0.001). Since MIP values increased with decreasing EELV, P0.1/MIP% was markedly decreased in volume responder COPD patients after albuterol. In contrast, marginal changes in P0.1 and no changes in MIP and P0.1/MIP% were observed in volume non-responder COPD patients after bronchodilator. Changes in IC (as a percentage of baseline) and P0.1 following acute administration of albuterol are plotted in Figure 1, panel A, showing a close direct correlation between reduction of DH (as reflected by the IC increase) and decreased Table 2 Resting values of IC and P0.1, MIP, and their ratio before (Pre-Br) and after (Post-Br) acute administration of bronchodilator P ΔIC , 12% bas n IC (L) ΔIC . 12% bas P Pre-Br Post-Br Pre-Br Post-Br 7 7 15 15 1.77 ± 0.45 1.88 ± 0.48 1.30 ± 0.46 1.66 ± 0.49 ,0.05 6±4 ,0.001 ΔIC (% bas) P0.1 (cm H2O) 30 ± 13 4.2 ± 0.5 4.0 ± 0.6 3.8 ± 1.4 ,0.001 78 ± 20 79 ± 20 ,0.05 ns 4.9 ± 1.4 MIP (cm H2O) 65 ± 18 70 ± 20 ,0.01 P0.1/MIP% 5.5 ± 1.1 5.1 ± 1.1 ns 8.2 ± 3.0 5.8 ± 2.0 ,0.01 Notes: Clinically signiicant improvement of P0.1 and MIP and P0.1/MIP ratio were observed only in COPD patients with signiicant increase in IC. Data are mean ± SD. Abbreviations: IC, inspiratory capacity; P0.1, mouth pressure 100 millseconds after the beginning of quiet inspiration during airways occlusion; MIP, maximal inspiratory pressure; COPD, chronic obstructive pulmonary disease; Pre-Br, pre-bronchodilator; Post-Br, post-bronchodilator; bas, baseline; SD, standard deviation. International Journal of COPD 2013:8 submit your manuscript | www.dovepress.com Dovepress 171 Dovepress Gatta et al A B 8 3 r2 = 0.56 P < 0.01 −∆ P0.1/MIP (%) −∆ P0.1 (cm H2O) r2 = 0.59 P < 0.01 2 1 0 −10 0 10 20 30 40 50 60 ∆IC (% baseline) 6 4 2 0 −10 0 10 20 30 40 50 60 ∆IC (% baseline) Figure 1 Relationship between changes in IC and P0.1 (A) and P0.1/MIP% (B), following bronchodilator in groups of stable severe-to-very severe COPD patients at rest. Note: The vertical lines indicate the threshold of a signiicant increase in IC. Abbreviations: IC, inspiratory capacity; P0.1, mouth pressure 100 millseconds after the beginning of quiet inspiration during airways occlusion; MIP, maximal inspiratory pressure; COPD, chronic obstructive pulmonary disease. particularly an increased sense of work/effort following stimuli such as increased ventilatory requirements, elevated EELV, and a related increase in elastic inspiratory threshold load due to intrinsic positive end-expiratory pressure.3,9,14 A high inspiratory neural drive, especially in the presence of functionally or intrinsically weakened inspiratory muscles is in fact associated with a greater respiratory effort.15 The neural pathways underlying the sense of work/effort include corollary discharge from motor cortical and bulbar centers16 and possibly multiple afferences from mechanical and metabolic receptors of respiratory and skeletal muscles to the sensory cortex that are believed to contribute to the dyspnea sensation.13 In our work we showed a clear link between neuromuscular output level and severity of DH at rest in stable COPD patients and the possibility of significantly reducing it when an effective desufflation is achievable, in this case after acute bronchodilator inhalation, as indicated by a marked IC increase. The effect on the reduction of respiratory drive observed in COPD patients who significantly increase IC after bronchodilator is likely even greater than we have shown, given the corresponding reduction in EELV that per se should increase, not decrease P0.1 because of better force-length relationship of the inspiratory muscles. In fact, although we did not measure directly EELV, with the reasonable assumption that total lung capacity remains unchanged after acute inhalation of albuterol, the IC variation specularly reflects the EELV change. 172 submit your manuscript | www.dovepress.com Dovepress Therefore, the decrease of neuromuscular output at rest in COPD patients after bronchodilating drugs may reflect an effective desufflation in the absence of important FEV1 change also when the lung volumes and IC measurements cannot be adequately performed. Drugs or non-pharmacological interventions that are effective in decreasing DH may diminish both the degree of neuromuscular uncoupling and the amount of neuromuscular drive. It is conceivable that either mechanism can contribute to reduce chronic and exertional dyspnea in COPD. Finally, our results could be useful to explain the wide range of resting values of P0.1 observed in COPD patients with apparently similar severity of airflow obstruction, as measured by spirometry, taking into account the possible effect of different degrees of pulmonary hyperinflation. Some limits of the study need to be addressed. The amount of neural drive is indirectly assessed by the P0.1 measurement at the mouth. The dynamically hyperinflated COPD patients have some intrinsic positive end-expiratory pressure. Thus, changes of esophageal P0.1 (that truly reflect the neuromuscular output) occur before those of mouth P0.1 and the two measurements correspond only when the initial pressure decay is linear, as it usually is. The inspiratory muscles in COPD can be intrinsically weak (myopathy, sarcopenia, etc) and P0.1 could be influenced by the force developed at the beginning of inspiration, without carefully reflecting the central neural drive. However, this seems unlikely because early (the first 100 milliseconds) contraction of inspiratory muscles is not impaired under these circumstances, as found in several neuromuscular diseases.17,18 International Journal of COPD 2013:8 Inspiratory drive and dynamic hyperinlation in COPD Dovepress Although baseline parameters were not significantly different between volume and non-volume responders, the first group tends to be younger with more females, showing slightly higher P0.1 and lower MIP. Since the sample size is small, we cannot exclude that these differences could be relevant when larger cohorts are examined. In conclusion, a large P0.1 decrease, MIP increase, and reduction of the P0.1/MIP ratio were found after bronchodilator only in COPD patients with a marked IC increase. More interestingly, the improvement of DH and the decrease in neuromuscular drive were closely related. These findings indicate that decreasing DH by bronchodilators is associated with a reduction of the central neuromuscular drive and effort/work related sensation, suggesting that corollary discharge linked to an augmented central inspiratory output is an adjunctive mechanism promoting dyspnea in COPD patients with dynamic hyperinflation. Disclosure The authors report no conflicts of interest in this work. References 1. Eltayara L, Becklake MR, Volta CA, Milic-Emili J. Relationship between chronic dyspnea and expiratory flow limitation in patients with chronic obstructive pulmonary disease. 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Chest. 1994;105(4):1163–1170. International Journal of COPD Dovepress Publish your work in this journal The International Journal of COPD is an international, peer-reviewed journal of therapeutics and pharmacology focusing on concise rapid reporting of clinical studies and reviews in COPD. Special focus is given to the pathophysiological processes underlying the disease, intervention programs, patient focused education, and self management protocols. This journal is indexed on PubMed Central, MedLine and CAS. The manuscript management system is completely online and includes a very quick and fair peer-review system, which is all easy to use. Visit http://www.dovepress.com/testimonials.php to read real quotes from published authors. Submit your manuscript here: http://www.dovepress.com/international-journal-of-copd-journal International Journal of COPD 2013:8 submit your manuscript | www.dovepress.com Dovepress 173