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Inspiratory loading and limb blood flow in COPD: The modulating effects of resting lung hyperinflation
Respiratory Physiology & Neurobiology 228 (2016) 25–29
Contents lists available at ScienceDirect
Respiratory Physiology & Neurobiology journal homepage: www.elsevier.com/locate/resphysiol
Inspiratory loading and limb blood flow in COPD: The modulating effects of resting lung hyperinflation Danilo C. Berton a,b,∗,1 , Marina A. de Castro a,1 , Pietro Merola a , Igor Benedetto a,b , Mariah Castilho c , Paulo J.C. Vieira c , Marli M. Knorst a,b , J. Alberto Neder d a
Graduation Program in Pulmonology, School of Medicine, Federal University of Rio Grande do Sul (UFRGS), Brazil Respiratory Division, Hospital de Clínicas de Porto Alegre (HCPA), Brazil c Exercise Pathophysiology Research Laboratory, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Brazil d Laboratory of Clinical Exercise Physiology (LACEP), Division of Respirology, Dept. of Medicine, Queen’s University and Kingston General Hospital, Kingston, Canada b
a r t i c l e
i n f o
Article history: Received 14 December 2015 Received in revised form 22 February 2016 Accepted 3 March 2016 Available online 7 March 2016 Keywords: Chronic obstructive pulmonary disease Respiratory function tests Inspiratory capacity Respiratory muscles Regional blood flow
a b s t r a c t Inspiratory resistive loading (IRL) may have deleterious cardiocirculatory effects leading to poor peripheral perfusion in severely-hyperinflated patients with COPD. Nineteen patients (13 severelyhyperinflated with inspiratory capacity/total lung capacity ratio ≤ 0.28) underwent calf blood flow (CBF) measurements by venous occlusion plethysmography at rest and during IRL at 60% maximal inspiratory pressure. Severely-hyperinflated patients had lower resting CBF and greater calf vascular resistance (CVR) than moderately-hyperinflated patients (p < 0.05). All severely-hyperinflated patients had markedly reduced CBF (p = 0.01). Opposite to our main hypothesis, however, IRL did not further reduce CBF in these patients (p > 0.05). Conversely, it significantly decreased CBF and increased CVR in moderatelyhyperinflated patients; in fact, end-trial CBF and CVR did not differ between the groups (p > 0.05). In conclusion, marked impairments in resting appendicular blood flow in severely-hyperinflated patients with COPD were seen only after acute IRL in less hyperinflated patients. These findings set the stage for studies investigating the effects of lung deflation on peripheral hemodynamics in patients with severe hyperinflation. © 2016 Elsevier B.V. All rights reserved.
1. Introduction Chronic obstructive pulmonary disease (COPD) is characterized by varied abnormalities on the airways, lung parenchyma, and pulmonary vasculature which might have important negative cardiocirculatory consequences (O’Donnell et al., 2014; Boerrigter et al., 2012; Tyberg et al., 2000). In fact, there is growing recognition that the cardiocirculatory consequences of COPD are not only relevant to patients’ functioning but also to mortality across the spectrum of disease severity (Sin and Man, 2005). Central hemodynamic consequences of lung hyperinflation (Jörgensen et al., 2003; Jorgensen et al., 2007; Barr et al., 2012; Watz et al., 2010) and sympathetically mediated peripheral
∗ Corresponding author at: Rua Ramiro Barcelos, 2350, Room 2050, Postal Code: 90035-003, Porto Alegre, RS, Brazil. E-mail address: [email protected] (D.C. Berton). 1 Authors contributed equally. http://dx.doi.org/10.1016/j.resp.2016.03.004 1569-9048/© 2016 Elsevier B.V. All rights reserved.
vasoconstriction, secondary to fatiguing contractions of respiratory muscles (St Croix et al., 2000; Sheel et al., 2001), may compromise peripheral blood flow in COPD. For instance, reduced right ventricle (RV) preload and increased RV afterload due to lung hyperinflation are known to negatively influence stroke volume and cardiac output (Jorgensen et al., 2007; Barr et al., 2012; Watz et al., 2010). In fact, static hyperinflation (inspiratory capacity/total lung capacity; IC/TLC) showed stronger associations with cardiac chamber sizes than airway obstruction or lung diffusion capacity. Patients with more severe lung hyperinflation also showed significantly impaired left ventricular diastolic filling pattern and myocardial performance (Watz et al., 2010). In addition to these negative effects of hyperinflation on central hemodynamics, volitional efforts against an inspiratory resistance have been found to increase vascular resistance and reduce resting calf blood flow (CBF) in COPD (Chiappa et al., 2014). Thus, in similarity with heathy subjects (St Croix et al., 2000; Sheel et al., 2001), fatiguing voluntary inspiratory efforts against resistance may increase muscle sympathetic nerve activity thereby decreasing blood flow to the resting limb in these patients.
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D.C. Berton et al. / Respiratory Physiology & Neurobiology 228 (2016) 25–29
Fig. 1. Calf blood flow (CBF) (panel A) and calf vascular resistance (CVR) (panel B) at baseline and at the end of inspiratory resistive loading (IRL) in severely- (closed squares) and moderately-hyperinflated (open squares) patients with COPD. Values in mean ± SE. † = End-Baseline. *p < 0.05 for intergroup comparisons at a given point.
Considering the key role played by hyperinflation in overloading the respiratory muscles in patients with COPD (O’Donnell et al., 2014), this phenomenon, if present, would be particularly pronounced in more hyperinflated patients. The aim of the present study, therefore, was to assess CBF during spontaneous breathing and inspiratory resistive loading (IRL) in moderate to severe COPD patients presenting with varied degrees of resting lung hyperinflation. We specifically hypothesized that, under these circumstances, CBF would be more reduced (and reciprocally calf vascular resistance (CVR) increased) in severelyhyperinflated patients with COPD. Understanding the deleterious effects of hyperinflation on the cardiovascular system is key to develop evidence-based strategies to mitigate the life-threatening cardiocirculatory consequences of COPD. 2. Material and methods 2.1. Patients This study enrolled a convenience sample of consecutive COPD patients. All patients had clinical and functional diagnosis of COPD (forced expiratory volume in 1s (FEV1 )/forced vital capacity (FVC) < 0.7 and post-bronchodilator FEV1 < 80% predicted) presenting with a long history of smoking (>20 pack-years). Patients were ex-smokers for at least 6 months and had stable disease with no exacerbations in the preceding 8 weeks. Patients were treated according to the current recommendations. (Vestbo et al., 2013) Main exclusion criteria were: current or previous cardiac disease (including previous acute coronary syndrome or known diagnosis of heart failure), long term oxygen therapy or arterial oxygen saturation <89% at rest, treatment with oral corticosteroids in the previous 3 months, neuromuscular disease, peripheral arterial disease, cancer or pulmonary rehabilitation in the preceding 12 months. The project was approved by Institutional Research Ethics Committees (No. 194.217) and all participants signed an informed consent. 2.2. Lung function tests Spirometry (including IC measurements), body plethysmography (residual volume (RV) and TLC) and measurements of transfer factor (DLCO ) were performed using automated testing equipment (Eric JaegerTM , GmbH, Wüerzburg, Germany). According to IC/TLC ratio (“inspiratory fraction”), patients were separated into severely-hyperinflated (≤0.28) or moderately-hyperinflated groups, respectively (Albuquerque et al., 2006). Maximal
Fig. 2. Association between baseline calf blood flow (CBF) (panel A) and calf vascular resistance (CVR) (panel B) with lung hyperinflation (inspiratory capacity/total lung capacity; IC/TLC).
inspiratory pressure (MIP, cmH2 O) against an occluded airway with a minor air leak (2 mm) was obtained from RV (MVD-300TM , Microhard System, Globalmed, Porto Alegre, Brazil). The highest pressure of five measurements was recorded (at least three reproducible, i.e.<10% between-maneuvers variation).
D.C. Berton et al. / Respiratory Physiology & Neurobiology 228 (2016) 25–29
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Table 1 Baseline characteristics. Variables
All (N = 19)
Severely-hyperinflated (N = 13)
Moderately-hyperinflated (N = 6)
Demographics/Anthropometrics Female sex, no. (%) Age, years Weight, kg Height, cm BMI, kg/m2
13 (68%) 63.3 ± 9.4 65.6 ± 11.5 159.0 ± 9.1 26.0 ± 3.7
8 (62%) 62.0 ± 8.6 65.8 ± 10.9 158.8 ± 9.7 26.1 ± 3.8
5 (83%) 64.5 ± 11.7 65.2 ± 13.9 158.3 ± 8.7 26.0 ± 3.9
Resting Lung Function FEV1 , L (%pred) FEV1 post BD, L (%pred) FVC, L (%pred) FVC post BD, L (%pred) FEV1 /FVC, % FEV1 /FVC post BD, % TLC, L (%pred) FRC, L (%pred) RV, L (%pred) DLCO , mL/min/mmHg (%pred) IC rest, L (%pred) MIP, cmH2 O (%pred) IC/TLC SpO2 , %
0.80 ± 0.24 (32 ± 9) 0.87 ± 0.30 (35 ± 11) 1.72 ± 0.44 (56 ± 11) 1.87 ± 0.46 (60 ± 13) 47 ± 1 46 ± 1 6.78 ± 1.51 (141 ± 21) 5.07 ± 1.81 (168 ± 52) 4.68 ± 1.38 (290 ± 73) 5.66 ± 2.30 (24 ± 10) 1.74 ± 0.46 (75 ± 23) 76 ± 22 (89 ± 28) 0.26 ± 0.06 96.2 ± 3.2
0.72 ± 0.17 (28 ± 7) 0.77 ± 0.17 (30 ± 8) 1.64 ± 0.42 (52 ± 10) 1.73 ± 0.37 (54 ± 11) 45 ± 1 45 ± 1 6.99 ± 1.76 (142 ± 20) 5.15 ± 2.17 (168 ± 62) 4.93 ± 1.57 (300 ± 78) 5.76 ± 2.82 (24 ± 11) 1.59 ± 0.49 (65 ± 14) 72 ± 22 (83 ± 28) 0.23 ± 0.04 96.2 ± 3.9
0.96 ± 0.33* (39 ± 8)* 1.10 ± 0.42* (45 ± 13)* 1.91 ± 0.48 (65 ± 7)* 2.18 ± 0.52* (72 ± 10)* 50 ± 1 49 ± 1 6.34 ± 0.66 (140 ± 24) 4.89 ± 0.74 (168 ± 28) 4.13 ± 0.63 (268 ± 62) 5.49 ± 1.23 (24 ± 7) 2.07 ± 0.16* (96 ± 26)* 86 ± 21 (104 ± 25) 0.33 ± 0.02* 96.7 ± 1.9
Data are presented as mean ± SD, unless otherwise stated. Definition of abbreviations: BMI: body mass index; FEV1: forced expiratory volume in one second; % pred: % predicted; BD: bronchodilator; FVC: forced vital capacity; TLC: total lung capacity; FRC: functional residual capacity; RV: residual volume; DLCO: diffusing capacity of the lung for carbon monoxide; IC: inspiratory capacity; MIP: maximal inspiratory pressure; SpO2: oxyhemoglobin saturation by pulse oximetry. * p < 0.05.
2.3. Venous occlusion plethysmography
2.5. Statistical analysis
CBF was measured by venous occlusion plethysmography (HokansonTM , TL-400, Bellevue, WA, USA) as previously described (Arnold et al., 1990). Briefly, the right lower limb was positioned above the heart (being supported at the level of thigh and ankle) in order to ensure proper venous drainage. A mercury rubber strain gauge was positioned on the right calf at the point of maximum circumference. During the entire protocol, a cuff on the thigh was alternately inflated to 60 mm Hg and deflated in 10s cycles. Additionally, another cuff was placed on the ankle and inflated to suprasystolic levels (240 mmHg) to occlude foot circulation. CBF (mL/100 mL/min) was determined manually on the basis of a minimum of three separate readings. CBF < 1 mL/100 mL/min indicated severely-reduced peripheral blood flow based on the previous results of Chiappa et al. (2008). CVR was calculated as mean arterial pressure (MAP)/CBF (mmHg/mL/100 mL/min).
Continuous variables were compared using parametric (Student t tests) or correlate nonparametric tests according their distribution. Fisher’s Exact test was used for categorical comparison. Pearson product-moment or Spearman’s rank correlation coefficients assessed linear association, as appropriate. A p value ≤0.05 was considered to be significant.
2.4. Inspiratory resistive loading (IRL) Patients wore a nose clip and breathed to task failure through a 2-way low-resistance Lloyd valve (Warren E. Collins, Inc., Braintree, Massachusetts, USA) connected in series to a POWERbreatheTM Inspiratory Muscle Trainer (Southam, United Kingdom). Inspiratory pressure was set at 60% MIP, a relative intensity previously found to elicit significant reduction in CBF as measured by venous occlusion plethysmography (Chiappa et al., 2008). Patients followed a metronome in order to maintain a breathing frequency of 15 breaths/min with a duty cycle (inspiratory time/total respiratory cycle) of 0.3. Heart rate (HR, bpm), MAP (mmHg) (Dinamap 1846 SX/PTM , Critikon, Tampa, Florida), CBF and CVR were measured at the end of a 3-min resting unloaded breathing period, every minute during IRL and at test cessation. End-tidal partial pressure for carbon dioxide (PETCO2 ) and oxyhemoglobin saturation by pulse oximetry (SpO2 ) were also continuously assessed (Takaoka OxicapTM , São Paulo, Brazil).
3. Results Nineteen patients completed all study procedures: 13 patients were severely-hyperinflated. Patients in both groups exhibited moderate to severe airflow obstruction with increased static lung volumes and substantial reductions in DLCO . As expected, severely-hyperinflated presented more advanced airflow obstruction (Table 1). At baseline, severely-hyperinflated had lower resting CBF and greater CVR than their counterparts (p < 0.05) (Fig. 1). IC/TLC ratio was significantly correlated with resting CBF and, marginally, with CVR (Fig. 2). Nine of 13 (69%) severelyhyperinflated patients had severely reduced resting peripheral blood flow (CBF <1 mL/100 mL/min) while all patients with moderate hyperinflation had resting CBF above this value (p = 0.011). Furthermore, patients with severely-reduced CBF were significantly more hyperinflated compared to those with resting CBF above 1 mL/100 mL/min: 0.22 ± 0.04 vs. 0.30 ± 0.04; p < 0.01. During inspiratory muscle loading, PETCO2 and SpO2 did not differ from baseline in both groups. Time to task failure was also similar (488 ± 261 vs. 375 ± 59s for severely- and moderatelyhyperinflated patients, respectively; p = 0.31). CVR increased (and CBF decreased) at greater extent in moderately- than severelyhyperinflated patients; in fact, end-trial CBF and CVR did not differ between the groups (p > 0.05) (Fig. 1).
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4. Discussion
exercise stress remains unknown and deserves further investigation.
This study demonstrated that higher resting pulmonary hyperinflation (lower IC/TLC) is associated with lower limb blood flow in moderate to severe COPD patients. In fact, marked impairments in resting appendicular blood flow in severely-hyperinflated patients with COPD were seen only after acute inspiratory muscle loading in less hyperinflated patients. Severe hyperinflation has long been associated with impaired central hemodynamics (Nakhjavan et al., 1966) which could help explain lower CBF in our severely-hyperinflated patients (Fig. 1). For instance, ventricular dimensions have been inversely related to severity of airflow obstruction and emphysema extent. (Jorgensen et al., 2007; Barr et al., 2012) Strategies aimed at reducing lung volumes (bronchodilators (Saito et al., 1999) or lung volume reduction surgery (Lammi et al., 2012); LVRS) were able to increase oxygen pulse, a surrogate of cardiac stroke volume. LVRS may increase left ventricular end-diastolic dimensions and filling, and improve stroke volume. Left ventricular compression from right ventricular overfilling, higher positive pleural pressure during expiration, and increased intra-thoracic pressure can also contribute to impaired cardiac output and poor peripheral perfusion (O’Donnell et al., 2014). Contrary to our main hypothesis, IRL did not further decrease CBF (or significantly increased CVR) in severely-hyperinflated patients. It is conceivable that there was less “room” for further hemodynamic compromise (or further sympathetic overexcitation) in these patients. Accordingly, lung hyperinflation was significantly associated with central hemodinamic parameters (Watz et al., 2010) and airflow obstruction (measured by FEV1 ) correlated with autonomic dysfunction (Stein et al., 1998). It also remains open to investigation whether lower cardiac output (due to cardiopulmonary interactions) or sympathetically-mediated peripheral vasoconstriction may chronically impair resting CBF in severely-hyperinflated patients with COPD. As stated above, the respiratory muscles are likely chronically overloaded in more hyperinflated patients. Thus, 60% MIP may have been insufficient to further impair peripheral hemodynamics in these patients. Moderate (Faisal et al., 2016) or severe (Laveneziana et al., 2014) COPD patients usually do not develop inspiratory muscle fatigue or the relative inspiratory pressure demand (60% of maximal inspiratory pressure) even during high-intensity exercise to potentially elicit limb vasoconstriction (Sheel et al., 2002). In fact, time to task failure did not differ between the groups which suggest some degree of inspiratory muscle “training” secondary to chronic overloading. On the other hand, static inspiratory pressures were measured from a higher RV in more hyperinflated patients. It is therefore possible that we might have underestimated “true” intrinsic maximal inspiratory muscle strength in this particular group. We also cannot rule out the hypothesis that venous occlusion plethysmography was insensitive to detect further decreases in already-compromised CBF in severely-hyperinflated patients. Lack of measurements of work of breathing or demonstration of respiratory muscle fatigue precluded stronger mechanistic associations between the degree of inspiratory muscle (de)activation and the observed peripheral hemodynamic consequences of IRL. Nevertheless, despite the lack of cardiac output and sympathetic nerve activity measurements, it is noteworthy that CVR was greater in severely-hyperinflated patients (Fig. 1). This might indicate increased resting sympathetic tonus in these patients (Andreas et al., 2005). Finally, the current experiments were performed at rest, presenting less potential for blood flow competition between respiratory and locomotor muscles (as patients’ peripheral muscles were at rest without the influence of functional sympatholysis or higher concentration of local vasodilators). Therefore, the modulation of lung hyperinflation on peripheral blood flow during IRL and
5. Conclusions Severe lung hyperinflation was associated with lower calf blood flow and increased calf vascular resistance in COPD patients. Similar peripheral hemodynamic abnormalities were elicited by acute inspiratory muscle loading in less hyperinflated patients. These findings set the stage for interventional studies to assess the effects of lung deflation on appendicular blood flow in severely hyperinflated patients with COPD. Contributions All authors played a role in the content of the manuscript and approved its final version. In addition: DCB, JAN, MMK had input into the study design and conception; MAC, PM, MC, IB and DCB collected the data; DCB, MAC and MC performed data analysis. DCB and JAN prepared the first draft of the manuscript. Sources of support The study was supported by a grant received from Incentive Fund of Research of HCPA (FIPE). MAC received a CAPES Fellowship, Graduation Program in Pulmonology, Universidade Federal do Rio Grande do Sul (UFRGS) (2013–2014). References Albuquerque, A.L., Nery, L.E., Villaca, D.S., Machado, T.Y., Oliveira, C.C., Paes, A.T., Neder, J.A., 2006. Inspiratory fraction and exercise impairment in COPD patients GOLD stages II-III. Eur. Respir. J. 28, 939–944. Andreas, S., Anker, S.D., Scanlon, P.D., et al., 2005. Neurohumoral activation as a link to systemic manifestation of chronic lung disease. Chest 128, 3618–3624. Arnold, J.M., Ribeiro, J.P., Colucci, W.S., 1990. Muscle blood flow during forearm exercise in patients with severe heart failure. Circulation 82, 465–472. Barr, R.G., Bluemke, D.A., Ahmed, F.S., et al., 2012. Percent emphysema, airflow obstruction, and impaired left ventricular filling. N. Engl. J. Med. 362, 217–227. Boerrigter, B., Trip, N.P., Bogaard, H.J., et al., 2012. Right atrial pressure affects the interaction between lung mechanics and right ventricular function in spontaneously breathing COPD patients. PLoS One 7, e30208. Chiappa, G.R., Roseguini, B.T., Vieira, P.J., Alves, C.N., Tavares, A., Winkelmann, E.R., Ferlin, E.L., Stein, R., Ribeiro, J.P., 2008. Inspiratory muscle training improves blood flow to resting and exercising limbs in patients with chronic heart failure. J. Am. Coll. Cardiol. 51, 1663–1671. Chiappa, G.R., Vieira, P.J., Umpierre, D., Corrêa, A.P., Berton, D.C., Ribeiro, J.P., Neder, J.A., 2014. Inspiratory resistance decreases limb blood flow in COPD patients with heart failure. Eur. Respir. J. 43, 1507–1510. Faisal, A., Alghamdi, B.J., Ciavaglia, C.E., Elbehairy, A.F., Webb, K.A., Ora, J., Neder, J.A., O’Donnell, D.E., 2016. Common mechanisms of dyspnea in chronic interstitial and obstructive lung disorders. Am. J. Respir. Crit. Care Med. 193, 299–309. Jörgensen, K., Houltz, E., Westfelt, U., Nilsson, F., Scherstén, H., Ricksten, S.E., 2003. Effects of lung volume reduction surgery on left ventricular diastolic filling and dimensions in patients with severe emphysema. Chest 124, 1863–1870. Jorgensen, K., Muller, M.F., Nel, J., Upton, R.N., Houltz, E., Ricksten, S.E., 2007. Reduced intrathoracic blood volume and left and right ventricular dimensions in patients with severe emphysema: an MRI study. Chest 131, 1050–1057. Lammi, M.R., Ciccolella, D., Marchetti, N., Kohler, M., Criner, G.J., 2012. Increased oxygen pulse after lung volume reduction surgery is associated with reduced dynamic hyperinflation. Eur. Respir. J. 40, 837–843. Laveneziana, P., Webb, K.A., Wadell, K., Neder, J.A., O’Donnell, D.E., 2014. Does expiratory muscle activity influence dynamic hyperinflation and exertional dyspnea in COPD. Respir. Physiol. Neurobiol. 199, 24–33. Nakhjavan, F.K., Palmer, W.H., McGregor, M., 1966. Influence of respiration on venous return in pulmonary emphysema. Circulation 33, 8–16. O’Donnell, D.E., Laveneziana, P., Webb, K., Neder, J.A., 2014. Chronic obstructive pulmonary disease: clinical integrative physiology. Clin. Chest Med. 35, 51–69. Saito, S., Miyamoto, K., Nishimura, M., Aida, A., Saito, H., Tsujino, I., Kawakami, Y., 1999. Effects of inhaled bronchodilators on pulmonary hemodynamics at rest and during exercise in patients with COPD. Chest 115, 376–382. Sheel, A.W., Derchak, P.A., Morgan, B.J., Pegelow, D.F., Jacques, A.J., Dempsey, J.A., 2001. Fatiguing inspiratory muscle work causes reflex reduction in resting leg blood flow. J. Physiol. (Lond.) 537, 277–289. Sheel, A.W., Derchak, P.A., Pegelow, D.F., Dempsey, J.A., 2002. Threshold effects of respiratory muscle work on limb vascular resistance. Am. J. Physiol. Heart Circ. Physiol. 282, H1732–H1738. Sin, D.D., Man, S.F., 2005. Chronic obstructive pulmonary disease as a risk factor for cardiovascular morbidity and mortality. Proc. Am. Thorac. Soc. 2, 8–11.
D.C. Berton et al. / Respiratory Physiology & Neurobiology 228 (2016) 25–29 St Croix, C.M., Morgan, B.J., Wetter, T.J., Dempsey, J.A., 2000. Fatiguing inspiratory muscle work causes reflex sympathetic activation in humans. J. Physiol. (Lond.) 529, 493–504. Stein, P.K., Nelson, P., Rottman, J.N., et al., 1998. Heart rate variability reflects severity of COPD in PiZ ␣1-antitrypsin deficiency. Chest 113, 327–333. Tyberg, J.V., Grant, D.A., Kingma, I., et al., 2000. Effects of positive intrathoracic pressure on pulmonary and systemic hemodynamics. Respir. Physiol. 119 (2–3), 71–179.
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Vestbo, J., Hurd, S.S., Agustí, A.G., Jones, P.W., Vogelmeier, C., Anzueto, A., Barnes, P.J., Fabbri, L.M., Martinez, F.J., Nishimura, M., Stockley, R.A., Sin, D.D., Rodriguez-Roisin, R., 2013. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: gOLD executive summary. Am. J. Respir. Crit. Care Med. 187, 347–365. Watz, H., Waschki, B., Meyer, T., et al., 2010. Decreasing cardiac chamber sizes and associated heart dysfunction in COPD: role of hyperinflation. Chest 138, 32–38.
Contents lists available at ScienceDirect
Respiratory Physiology & Neurobiology journal homepage: www.elsevier.com/locate/resphysiol
Inspiratory loading and limb blood flow in COPD: The modulating effects of resting lung hyperinflation Danilo C. Berton a,b,∗,1 , Marina A. de Castro a,1 , Pietro Merola a , Igor Benedetto a,b , Mariah Castilho c , Paulo J.C. Vieira c , Marli M. Knorst a,b , J. Alberto Neder d a
Graduation Program in Pulmonology, School of Medicine, Federal University of Rio Grande do Sul (UFRGS), Brazil Respiratory Division, Hospital de Clínicas de Porto Alegre (HCPA), Brazil c Exercise Pathophysiology Research Laboratory, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Brazil d Laboratory of Clinical Exercise Physiology (LACEP), Division of Respirology, Dept. of Medicine, Queen’s University and Kingston General Hospital, Kingston, Canada b
a r t i c l e
i n f o
Article history: Received 14 December 2015 Received in revised form 22 February 2016 Accepted 3 March 2016 Available online 7 March 2016 Keywords: Chronic obstructive pulmonary disease Respiratory function tests Inspiratory capacity Respiratory muscles Regional blood flow
a b s t r a c t Inspiratory resistive loading (IRL) may have deleterious cardiocirculatory effects leading to poor peripheral perfusion in severely-hyperinflated patients with COPD. Nineteen patients (13 severelyhyperinflated with inspiratory capacity/total lung capacity ratio ≤ 0.28) underwent calf blood flow (CBF) measurements by venous occlusion plethysmography at rest and during IRL at 60% maximal inspiratory pressure. Severely-hyperinflated patients had lower resting CBF and greater calf vascular resistance (CVR) than moderately-hyperinflated patients (p < 0.05). All severely-hyperinflated patients had markedly reduced CBF (p = 0.01). Opposite to our main hypothesis, however, IRL did not further reduce CBF in these patients (p > 0.05). Conversely, it significantly decreased CBF and increased CVR in moderatelyhyperinflated patients; in fact, end-trial CBF and CVR did not differ between the groups (p > 0.05). In conclusion, marked impairments in resting appendicular blood flow in severely-hyperinflated patients with COPD were seen only after acute IRL in less hyperinflated patients. These findings set the stage for studies investigating the effects of lung deflation on peripheral hemodynamics in patients with severe hyperinflation. © 2016 Elsevier B.V. All rights reserved.
1. Introduction Chronic obstructive pulmonary disease (COPD) is characterized by varied abnormalities on the airways, lung parenchyma, and pulmonary vasculature which might have important negative cardiocirculatory consequences (O’Donnell et al., 2014; Boerrigter et al., 2012; Tyberg et al., 2000). In fact, there is growing recognition that the cardiocirculatory consequences of COPD are not only relevant to patients’ functioning but also to mortality across the spectrum of disease severity (Sin and Man, 2005). Central hemodynamic consequences of lung hyperinflation (Jörgensen et al., 2003; Jorgensen et al., 2007; Barr et al., 2012; Watz et al., 2010) and sympathetically mediated peripheral
∗ Corresponding author at: Rua Ramiro Barcelos, 2350, Room 2050, Postal Code: 90035-003, Porto Alegre, RS, Brazil. E-mail address: [email protected] (D.C. Berton). 1 Authors contributed equally. http://dx.doi.org/10.1016/j.resp.2016.03.004 1569-9048/© 2016 Elsevier B.V. All rights reserved.
vasoconstriction, secondary to fatiguing contractions of respiratory muscles (St Croix et al., 2000; Sheel et al., 2001), may compromise peripheral blood flow in COPD. For instance, reduced right ventricle (RV) preload and increased RV afterload due to lung hyperinflation are known to negatively influence stroke volume and cardiac output (Jorgensen et al., 2007; Barr et al., 2012; Watz et al., 2010). In fact, static hyperinflation (inspiratory capacity/total lung capacity; IC/TLC) showed stronger associations with cardiac chamber sizes than airway obstruction or lung diffusion capacity. Patients with more severe lung hyperinflation also showed significantly impaired left ventricular diastolic filling pattern and myocardial performance (Watz et al., 2010). In addition to these negative effects of hyperinflation on central hemodynamics, volitional efforts against an inspiratory resistance have been found to increase vascular resistance and reduce resting calf blood flow (CBF) in COPD (Chiappa et al., 2014). Thus, in similarity with heathy subjects (St Croix et al., 2000; Sheel et al., 2001), fatiguing voluntary inspiratory efforts against resistance may increase muscle sympathetic nerve activity thereby decreasing blood flow to the resting limb in these patients.
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D.C. Berton et al. / Respiratory Physiology & Neurobiology 228 (2016) 25–29
Fig. 1. Calf blood flow (CBF) (panel A) and calf vascular resistance (CVR) (panel B) at baseline and at the end of inspiratory resistive loading (IRL) in severely- (closed squares) and moderately-hyperinflated (open squares) patients with COPD. Values in mean ± SE. † = End-Baseline. *p < 0.05 for intergroup comparisons at a given point.
Considering the key role played by hyperinflation in overloading the respiratory muscles in patients with COPD (O’Donnell et al., 2014), this phenomenon, if present, would be particularly pronounced in more hyperinflated patients. The aim of the present study, therefore, was to assess CBF during spontaneous breathing and inspiratory resistive loading (IRL) in moderate to severe COPD patients presenting with varied degrees of resting lung hyperinflation. We specifically hypothesized that, under these circumstances, CBF would be more reduced (and reciprocally calf vascular resistance (CVR) increased) in severelyhyperinflated patients with COPD. Understanding the deleterious effects of hyperinflation on the cardiovascular system is key to develop evidence-based strategies to mitigate the life-threatening cardiocirculatory consequences of COPD. 2. Material and methods 2.1. Patients This study enrolled a convenience sample of consecutive COPD patients. All patients had clinical and functional diagnosis of COPD (forced expiratory volume in 1s (FEV1 )/forced vital capacity (FVC) < 0.7 and post-bronchodilator FEV1 < 80% predicted) presenting with a long history of smoking (>20 pack-years). Patients were ex-smokers for at least 6 months and had stable disease with no exacerbations in the preceding 8 weeks. Patients were treated according to the current recommendations. (Vestbo et al., 2013) Main exclusion criteria were: current or previous cardiac disease (including previous acute coronary syndrome or known diagnosis of heart failure), long term oxygen therapy or arterial oxygen saturation <89% at rest, treatment with oral corticosteroids in the previous 3 months, neuromuscular disease, peripheral arterial disease, cancer or pulmonary rehabilitation in the preceding 12 months. The project was approved by Institutional Research Ethics Committees (No. 194.217) and all participants signed an informed consent. 2.2. Lung function tests Spirometry (including IC measurements), body plethysmography (residual volume (RV) and TLC) and measurements of transfer factor (DLCO ) were performed using automated testing equipment (Eric JaegerTM , GmbH, Wüerzburg, Germany). According to IC/TLC ratio (“inspiratory fraction”), patients were separated into severely-hyperinflated (≤0.28) or moderately-hyperinflated groups, respectively (Albuquerque et al., 2006). Maximal
Fig. 2. Association between baseline calf blood flow (CBF) (panel A) and calf vascular resistance (CVR) (panel B) with lung hyperinflation (inspiratory capacity/total lung capacity; IC/TLC).
inspiratory pressure (MIP, cmH2 O) against an occluded airway with a minor air leak (2 mm) was obtained from RV (MVD-300TM , Microhard System, Globalmed, Porto Alegre, Brazil). The highest pressure of five measurements was recorded (at least three reproducible, i.e.<10% between-maneuvers variation).
D.C. Berton et al. / Respiratory Physiology & Neurobiology 228 (2016) 25–29
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Table 1 Baseline characteristics. Variables
All (N = 19)
Severely-hyperinflated (N = 13)
Moderately-hyperinflated (N = 6)
Demographics/Anthropometrics Female sex, no. (%) Age, years Weight, kg Height, cm BMI, kg/m2
13 (68%) 63.3 ± 9.4 65.6 ± 11.5 159.0 ± 9.1 26.0 ± 3.7
8 (62%) 62.0 ± 8.6 65.8 ± 10.9 158.8 ± 9.7 26.1 ± 3.8
5 (83%) 64.5 ± 11.7 65.2 ± 13.9 158.3 ± 8.7 26.0 ± 3.9
Resting Lung Function FEV1 , L (%pred) FEV1 post BD, L (%pred) FVC, L (%pred) FVC post BD, L (%pred) FEV1 /FVC, % FEV1 /FVC post BD, % TLC, L (%pred) FRC, L (%pred) RV, L (%pred) DLCO , mL/min/mmHg (%pred) IC rest, L (%pred) MIP, cmH2 O (%pred) IC/TLC SpO2 , %
0.80 ± 0.24 (32 ± 9) 0.87 ± 0.30 (35 ± 11) 1.72 ± 0.44 (56 ± 11) 1.87 ± 0.46 (60 ± 13) 47 ± 1 46 ± 1 6.78 ± 1.51 (141 ± 21) 5.07 ± 1.81 (168 ± 52) 4.68 ± 1.38 (290 ± 73) 5.66 ± 2.30 (24 ± 10) 1.74 ± 0.46 (75 ± 23) 76 ± 22 (89 ± 28) 0.26 ± 0.06 96.2 ± 3.2
0.72 ± 0.17 (28 ± 7) 0.77 ± 0.17 (30 ± 8) 1.64 ± 0.42 (52 ± 10) 1.73 ± 0.37 (54 ± 11) 45 ± 1 45 ± 1 6.99 ± 1.76 (142 ± 20) 5.15 ± 2.17 (168 ± 62) 4.93 ± 1.57 (300 ± 78) 5.76 ± 2.82 (24 ± 11) 1.59 ± 0.49 (65 ± 14) 72 ± 22 (83 ± 28) 0.23 ± 0.04 96.2 ± 3.9
0.96 ± 0.33* (39 ± 8)* 1.10 ± 0.42* (45 ± 13)* 1.91 ± 0.48 (65 ± 7)* 2.18 ± 0.52* (72 ± 10)* 50 ± 1 49 ± 1 6.34 ± 0.66 (140 ± 24) 4.89 ± 0.74 (168 ± 28) 4.13 ± 0.63 (268 ± 62) 5.49 ± 1.23 (24 ± 7) 2.07 ± 0.16* (96 ± 26)* 86 ± 21 (104 ± 25) 0.33 ± 0.02* 96.7 ± 1.9
Data are presented as mean ± SD, unless otherwise stated. Definition of abbreviations: BMI: body mass index; FEV1: forced expiratory volume in one second; % pred: % predicted; BD: bronchodilator; FVC: forced vital capacity; TLC: total lung capacity; FRC: functional residual capacity; RV: residual volume; DLCO: diffusing capacity of the lung for carbon monoxide; IC: inspiratory capacity; MIP: maximal inspiratory pressure; SpO2: oxyhemoglobin saturation by pulse oximetry. * p < 0.05.
2.3. Venous occlusion plethysmography
2.5. Statistical analysis
CBF was measured by venous occlusion plethysmography (HokansonTM , TL-400, Bellevue, WA, USA) as previously described (Arnold et al., 1990). Briefly, the right lower limb was positioned above the heart (being supported at the level of thigh and ankle) in order to ensure proper venous drainage. A mercury rubber strain gauge was positioned on the right calf at the point of maximum circumference. During the entire protocol, a cuff on the thigh was alternately inflated to 60 mm Hg and deflated in 10s cycles. Additionally, another cuff was placed on the ankle and inflated to suprasystolic levels (240 mmHg) to occlude foot circulation. CBF (mL/100 mL/min) was determined manually on the basis of a minimum of three separate readings. CBF < 1 mL/100 mL/min indicated severely-reduced peripheral blood flow based on the previous results of Chiappa et al. (2008). CVR was calculated as mean arterial pressure (MAP)/CBF (mmHg/mL/100 mL/min).
Continuous variables were compared using parametric (Student t tests) or correlate nonparametric tests according their distribution. Fisher’s Exact test was used for categorical comparison. Pearson product-moment or Spearman’s rank correlation coefficients assessed linear association, as appropriate. A p value ≤0.05 was considered to be significant.
2.4. Inspiratory resistive loading (IRL) Patients wore a nose clip and breathed to task failure through a 2-way low-resistance Lloyd valve (Warren E. Collins, Inc., Braintree, Massachusetts, USA) connected in series to a POWERbreatheTM Inspiratory Muscle Trainer (Southam, United Kingdom). Inspiratory pressure was set at 60% MIP, a relative intensity previously found to elicit significant reduction in CBF as measured by venous occlusion plethysmography (Chiappa et al., 2008). Patients followed a metronome in order to maintain a breathing frequency of 15 breaths/min with a duty cycle (inspiratory time/total respiratory cycle) of 0.3. Heart rate (HR, bpm), MAP (mmHg) (Dinamap 1846 SX/PTM , Critikon, Tampa, Florida), CBF and CVR were measured at the end of a 3-min resting unloaded breathing period, every minute during IRL and at test cessation. End-tidal partial pressure for carbon dioxide (PETCO2 ) and oxyhemoglobin saturation by pulse oximetry (SpO2 ) were also continuously assessed (Takaoka OxicapTM , São Paulo, Brazil).
3. Results Nineteen patients completed all study procedures: 13 patients were severely-hyperinflated. Patients in both groups exhibited moderate to severe airflow obstruction with increased static lung volumes and substantial reductions in DLCO . As expected, severely-hyperinflated presented more advanced airflow obstruction (Table 1). At baseline, severely-hyperinflated had lower resting CBF and greater CVR than their counterparts (p < 0.05) (Fig. 1). IC/TLC ratio was significantly correlated with resting CBF and, marginally, with CVR (Fig. 2). Nine of 13 (69%) severelyhyperinflated patients had severely reduced resting peripheral blood flow (CBF <1 mL/100 mL/min) while all patients with moderate hyperinflation had resting CBF above this value (p = 0.011). Furthermore, patients with severely-reduced CBF were significantly more hyperinflated compared to those with resting CBF above 1 mL/100 mL/min: 0.22 ± 0.04 vs. 0.30 ± 0.04; p < 0.01. During inspiratory muscle loading, PETCO2 and SpO2 did not differ from baseline in both groups. Time to task failure was also similar (488 ± 261 vs. 375 ± 59s for severely- and moderatelyhyperinflated patients, respectively; p = 0.31). CVR increased (and CBF decreased) at greater extent in moderately- than severelyhyperinflated patients; in fact, end-trial CBF and CVR did not differ between the groups (p > 0.05) (Fig. 1).
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4. Discussion
exercise stress remains unknown and deserves further investigation.
This study demonstrated that higher resting pulmonary hyperinflation (lower IC/TLC) is associated with lower limb blood flow in moderate to severe COPD patients. In fact, marked impairments in resting appendicular blood flow in severely-hyperinflated patients with COPD were seen only after acute inspiratory muscle loading in less hyperinflated patients. Severe hyperinflation has long been associated with impaired central hemodynamics (Nakhjavan et al., 1966) which could help explain lower CBF in our severely-hyperinflated patients (Fig. 1). For instance, ventricular dimensions have been inversely related to severity of airflow obstruction and emphysema extent. (Jorgensen et al., 2007; Barr et al., 2012) Strategies aimed at reducing lung volumes (bronchodilators (Saito et al., 1999) or lung volume reduction surgery (Lammi et al., 2012); LVRS) were able to increase oxygen pulse, a surrogate of cardiac stroke volume. LVRS may increase left ventricular end-diastolic dimensions and filling, and improve stroke volume. Left ventricular compression from right ventricular overfilling, higher positive pleural pressure during expiration, and increased intra-thoracic pressure can also contribute to impaired cardiac output and poor peripheral perfusion (O’Donnell et al., 2014). Contrary to our main hypothesis, IRL did not further decrease CBF (or significantly increased CVR) in severely-hyperinflated patients. It is conceivable that there was less “room” for further hemodynamic compromise (or further sympathetic overexcitation) in these patients. Accordingly, lung hyperinflation was significantly associated with central hemodinamic parameters (Watz et al., 2010) and airflow obstruction (measured by FEV1 ) correlated with autonomic dysfunction (Stein et al., 1998). It also remains open to investigation whether lower cardiac output (due to cardiopulmonary interactions) or sympathetically-mediated peripheral vasoconstriction may chronically impair resting CBF in severely-hyperinflated patients with COPD. As stated above, the respiratory muscles are likely chronically overloaded in more hyperinflated patients. Thus, 60% MIP may have been insufficient to further impair peripheral hemodynamics in these patients. Moderate (Faisal et al., 2016) or severe (Laveneziana et al., 2014) COPD patients usually do not develop inspiratory muscle fatigue or the relative inspiratory pressure demand (60% of maximal inspiratory pressure) even during high-intensity exercise to potentially elicit limb vasoconstriction (Sheel et al., 2002). In fact, time to task failure did not differ between the groups which suggest some degree of inspiratory muscle “training” secondary to chronic overloading. On the other hand, static inspiratory pressures were measured from a higher RV in more hyperinflated patients. It is therefore possible that we might have underestimated “true” intrinsic maximal inspiratory muscle strength in this particular group. We also cannot rule out the hypothesis that venous occlusion plethysmography was insensitive to detect further decreases in already-compromised CBF in severely-hyperinflated patients. Lack of measurements of work of breathing or demonstration of respiratory muscle fatigue precluded stronger mechanistic associations between the degree of inspiratory muscle (de)activation and the observed peripheral hemodynamic consequences of IRL. Nevertheless, despite the lack of cardiac output and sympathetic nerve activity measurements, it is noteworthy that CVR was greater in severely-hyperinflated patients (Fig. 1). This might indicate increased resting sympathetic tonus in these patients (Andreas et al., 2005). Finally, the current experiments were performed at rest, presenting less potential for blood flow competition between respiratory and locomotor muscles (as patients’ peripheral muscles were at rest without the influence of functional sympatholysis or higher concentration of local vasodilators). Therefore, the modulation of lung hyperinflation on peripheral blood flow during IRL and
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