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Respiratory 160 (2019) 105815

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Respiratory Medicine

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The effect of carotid chemoreceptor inhibition on exercise tolerance in chronic obstructive pulmonary disease: A randomized-controlled crossover trial

a,b � a,c a a Devin B. Phillips , Sophie E. Collins , Tracey L. Bryan , Eric Y.L. Wong , M. Sean McMurtry d, Mohit Bhutani a, Michael K. Stickland a,e,* a Division of Pulmonary Medicine, Faculty of Medicine and Dentistry, University of Alberta, Canada b Faculty of Kinesiology, Sport, and Recreation, University of Alberta, Canada c Faculty of Rehabilitation Medicine, University of Alberta, Canada d Division of Cardiology, Faculty of Medicine and Dentistry, University of Alberta, Canada e G.F. MacDonald Centre for Health, Covenant Health, Edmonton, Alberta, Canada

ARTICLE INFO ABSTRACT

Keywords: Background: Patients with chronic obstructive pulmonary disease (COPD) have an exaggerated ventilatory COPD response to exercise, contributing to exertional dyspnea and exercise intolerance. We recently demonstrated Exercise tolerance enhanced activity and sensitivity of the carotid chemoreceptor (CC) in COPD which may alter ventilatory and Carotid chemoreceptor cardiovascular regulation and negatively affect exercise tolerance. We sought to determine whether CC inhibi­ Dyspnea tion improves ventilatory and cardiovascular regulation, dyspnea and exercise tolerance in COPD. Methods: Twelve mild-moderate COPD patients (FEV1 83 � 15 %predicted) and twelve age- and sex-matched healthy controls completed two time-to-symptom limitation (TLIM) constant load exercise tests at 75% peak À À power output with either intravenous saline or low-dose dopamine (2 μg⋅kg 1⋅min 1, order randomized) to inhibit the CC. Ventilatory responses were evaluated using expired gas data and dyspnea was evaluated using a modified Borg scale. Inspiratory capacity maneuvers were performed to determine operating . Cardiac output was estimated using impedance cardiography and vascular conductance was calculated as cardiac output/mean arterial pressure (MAP). Results: At a standardized exercise time of 4-min and at TLIM; ventilation, operating volumes and dyspnea were unaffected by dopamine in COPD patients and controls. In COPD, dopamine decreased MAP and increased vascular conductance at all time points. In controls, dopamine increased vascular conductance at TLIM, while MAP was unaffected. Conclusion: There was no change in time to exhaustion in either group with dopamine. These data suggest that the CC plays a role in cardiovascular regulation during exercise in COPD; however, ventilation, dyspnea and exercise tolerance were unaffected by CC inhibition in COPD patients.

1. Introduction but is also related to increased mortality [4]. Previous work has sug­ gested that the observed dyspnea during incremental exercise in COPD is Chronic Obstructive Pulmonary Disease (COPD) is a respiratory the result of increased work of and diaphragmatic activity [2]. disorder characterized by progressive, partially reversible airway It has been shown that the increased work of breathing and thus dyspnea obstruction. Patients with COPD experience significant dyspnea during in COPD comes from 1) expiratory flowlimitation and resulting dynamic exertion, which has been shown to profoundly reduce exercise toler­ hyperinflation [3,5–11], and 2) an exaggerated ventilatory response to ance, physical activity, and impair patients’ ability to complete day-to- exercise (i.e. increased relative to day tasks [1–3]. The maintenance of physical activity in COPD is vital, as production, V_E/V_CO2) [1,3,12,13]. A great deal of work has focused on low physical activity in COPD is not only related to poor quality of life, improving airflow limitation in COPD; however, very little has been

* Corresponding author. 3-135 Clinical Sciences Building, Edmonton, Alberta, T6G 2J3, Canada. E-mail address: [email protected] (M.K. Stickland). https://doi.org/10.1016/j.rmed.2019.105815 Received 21 September 2019; Received in revised form 24 October 2019; Accepted 5 November 2019 Available online 6 November 2019 0954-6111/© 2019 Elsevier Ltd. All rights reserved. D.B. Phillips et al. Respiratory Medicine 160 (2019) 105815 done to understand and treat the exaggerated ventilatory response to elevated CC activity and sensitivity [13,17], which may contribute to exercise in COPD [14]. The elevated V_E/V_CO2 response to exercise ap­ the increased ventilation and dyspnea typically observed during exer­ pears to be clinically important, as it independently predicts mortality in cise. Patients with severe COPD were excluded, as they are prone to COPD and indicates that physiological abnormalities beyond airflow exercise-induced arterial hypoxemia and hypercapnea, which may have obstruction are important in determining disease severity, dyspnea and influenced CC activity [12]. Participants were carefully screened to risk of death [5,15,16]. exclude supplemental therapy, diabetes, existing CV disease, Recently, it has been shown that, in addition to the exaggerated body mass index �35, severe inflammatory disorders (such as connec­ ventilatory response to exercise, non-hypoxemic mild/moderate COPD tive tissue disease), severe risk of (STOP-Bang score > 3 patients have elevated baseline carotid chemoreceptor (CC) activity (as [24]), and none of the patients with COPD had a recent exacerbation demonstrated by the large reduction in ventilation with breathing 100% (<6 months). O2), and CC sensitivity (as demonstrated by a potentiated ventilatory response to ) [13,17]. Our recent work has demonstrated that 2.3. Pulmonary function CC inhibition with low-dose dopamine infusion reduced minute venti­ lation and improved cardiovascular function at rest in non-hypoxemic , plethysmography and for carbon COPD patients [17]. Previous work has also found that the CC can monoxide (DLCO) measurements were completed as per current guide­ play a role in ventilation as well as the sympathetic control of cardio­ lines [25–27]. Measurements were expressed as percent of predicted vascular (CV) function during exercise in health [18–20] and in chronic normal values [28]. Spirometric data was also presented as z-scores failure (CHF) [21,22]. Specifically, CC inhibition during exercise using the Global Lung Initiative 2012 equations [29]. reduced minute ventilation and muscle sympathetic nervous activity (MSNA), and increased vascular conductance in health [18,19]. In CHF, 2.4. Cardiopulmonary incremental exercise testing CC inhibition during exercise resulted in vasodilation and improved flow to working muscles in CHF [21]. Incremental exercise tests (Day 1) consisted of a 3-min steady state It is unclear if the enhanced activity and sensitivity of the CC resting period followed by 1-min of unloaded pedalling then a 20 W observed at rest 1) contributes to the exaggerated ventilatory response increase in work rate every 2-min to symptom limitation. Peak power observed during exercise in COPD, and 2) affects cardiovascular regu­ output was definedas the highest work rate that the subject was able to lation during exercise in COPD. Therefore, the purpose of this study was maintain for �30 s [30]. During the exercise tests, participants rated to examine whether CC inhibition improved ventilatory and cardio­ their perceived breathing and leg discomfort using the modified Borg vascular regulation, dyspnea and exercise tolerance in COPD. It was scale [31] at steady-state rest, within the last 30 s of every 2-min exercise hypothesized that CC inhibition would improve exercise tolerance, interval and at the end of exercise, followed by an inspiratory capacity secondary to reduced minute ventilation and dyspnea, and improved (IC) maneuver. All ventilatory and cardiovascular measurements were cardiovascular function. collected over the first 30 s of every second minute during the exercise test and were linked with the perceptual ratings and IC measurements 2. Methods collected in the final 30 s of the respective minute to avoid contamina­ tion of the expired gas data from the IC maneuvers [32]. At symptom 2.1. Study design limitation, participants completed an IC maneuver immediately fol­ lowed by the Borg ratings of breathing and leg discomfort, and venti­ The present study was a randomized, double-blind, placebo- latory and cardiovascular measurements were averaged over the last controlled crossover design and was approved by the University of 30 s of exercise. Alberta Health Research Ethics Board (Biomedical Panel Pro00043106). All exercise trials were performed on an electronically braked cycle This study is part of a larger research program examining the CC in ergometer (Ergoselect II 1200 Ergoline, Blitz, Germany) and cardiore­ health and disease. Data from nine of the control participants were spiratory data were collected using a metabolic measurement system included in a separate manuscript examining the effect of CC inhibition (Encore229 Vmax, SensorMedics, Yorba Linda, CA, USA). Operating on exercise tolerance in patients with CHF [23]. lung volumes were calculated from IC maneuvers [33]. Arterial O2 After providing written informed consent, participants completed saturation (SpO2) was estimated using finger pulse oximetry (N-595; four sessions over a 4-week period. Visit 1 included a thorough medical Nellcor Oximax, Boulder, CO, USA). was measured using history screening, a complete pulmonary function test and a symptom- electrocardiography (CardioSoft, GE Medical Systems, Milwaukee, WI, À limited incremental (20 W⋅2-min 1) cardiopulmonary cycle exercise USA). Arterial blood pressure was taken by manual auscultation. test to determine maximal work rate. Visit 2 consisted of a basal che­ moreflex assessment, which included tests to determine the ventilatory 2.5. Basal chemoreceptor assessment responses to hyperoxia, hypoxia and . Visits 3 and 4 con­ sisted of two constant work-rate cycle exercise tests to symptom limi­ Basal chemoreceptor assessments were completed as previously tation (TLIM) at 75% of the maximal work rate, on separate days, while described [17]. Briefly, CC activity was evaluated by examining the receiving either intravenous (I.V.) saline or low-dose I.V. dopamine transient reduction in minute ventilation in response to 2-min of (order randomized). Prior to all study procedures, participants were hyperoxia (FIO2 ¼ 1.0) [34]. Following a minimum 10-min break, par­ asked to abstain from caffeine, smoking, vigorous exercise, alcohol and ticipants completed a standard hyperoxic hypercapnic rebreathe test to respiratory medications for at least 12 h preceding testing. determine central medullary chemoreceptor sensitivity [35]. A 4 L rebreathing bag was filledwith a specialized gas mixture (7% CO2, 50% 2.2. Participants O2 and 43% N2). Following a brief bout of hyperoxic breathing (FIO2 ¼ 0.5), participants then began rebreathing until the end-tidal CO2 Twelve non-hypoxemic mild-moderate COPD patients (GOLD Grade values reached 55 mmHg or participants requested to stop. A 10-min I and II, with post (forced expired volume in 1 s (FEV1)/ break was given to ensure that ventilation and arterial blood pressure forced (FVC) ratio <0.7, FEV1 �50% predicted) with a returned to baseline prior to initiating the next test. CC sensitivity was smoking history >10 pack-years and 12 age- and sex-matched controls then evaluated by measuring the hypoxic ventilatory response using a with normal lung function, with minimal smoking history (<10 pack- stepwise method [13,17,22]. Briefly,participants breathed normoxic air years) were recruited. We chose to include non-hypoxemic GOLD 1 for 3-min followed by 3-min at a target SpO2 of 90% and then 3-min at a and II patients, as these types of patients previously demonstrated target SpO2 of 85%. Arterial saturation was analyzed as opposed to

2 D.B. Phillips et al. Respiratory Medicine 160 (2019) 105815 end-tidal O2 due to the uncertainty regarding the accuracy of estimating researcher directly conducting the exercise test were aware of the testing arterial blood gas from end-tidal expired gas in patients with lung dis­ condition. Previous research has shown that this specificdose effectively ease [36]. For the hypoxia/hyperoxia trials, inspired gas was modulated inhibits the carotid chemoreceptors in [19,48]. Dopamine does using air-oxygen (normoxia to hyperoxia) or air-nitrogen (normoxia to not cross the blood barrier and would not affect the central che­ hypoxia) blender systems. moreceptors [49]. For the chemoreceptor assessment, all data were recorded and in­ tegrated with a data acquisition system (Powerlab 16/30; ADInstru­ 2.8. Analysis ments, New South Wales, Australia) and stored for subsequent analysis using associated software (LabChart 8.0 Pro; ADInstruments). Minute The primary study outcome was the effect of dopamine on exercise ventilation was measured by a pneumotachometer (3700 series, Hans tolerance, definedas the time to symptom limitation, when compared to Rudolph, Kansas City, MO, USA) and expired CO2 and O2 were measured placebo. Secondary outcomes included the effect of dopamine on (CD-3A and S-3A; AEI Technologies, Naperville, IL, USA) continuously physiological and perceptual responses at rest and during exercise. Our from a small sample port off the mouthpiece to obtain end-tidal CO2 and previous work in mild to moderate patients with COPD demonstrated a O2. Inspired gas was humidified(HC 150; Fisher and Paykel Healthcare, 21 � 24% reduction in resting ventilation with dopamine [17]. Auckland, New Zealand) and delivered continuously using a flow- Assuming a similar effect size, we determined a priori that 12 COPD through system to prevent rebreathing of expired gas. Heart rate was patients would be sufficientto detect a significanteffect of dopamine on determined from the R-R interval with a single lead ECG (lead II, Dual exercise tolerance (α ¼ 0.05, power ¼ 0.8). Bio Amp; ADInstruments). SpO2 was estimated with -lobe pulse ox­ Data are presented as mean � standard deviation unless otherwise imetry (N-595; Nellcor Oximax, Boulder, CO, USA). stated. For all inferential analysis, statistical significancewas set a priori at p < 0.05. Unpaired t-tests were used to compare pulmonary function, 2.6. Constant work-rate exercise tests CC activity/sensitivity and CPET data between groups. Three-way repeated-measures ANOVA were used to evaluate the effect of saline The constant work-rate tests (Days 3 and 4) consisted of a 3-min vs. dopamine (factor A) during exercise on key dependent variables steady-state resting period and a 1-min period of unloaded pedaling (repeated factor) in COPD and controls (fixed factor). To interpret the followed by an immediate increase in work rate corresponding to 75% of condition by time interaction within each group, a two-way repeated- the peak work rate. Exercise endurance time was recorded from the measures ANOVA was used. Four main time points were used for eval­ onset of loaded cycle exercise to the point of symptom limitation. The uation of exercise parameters: pre-exercise baseline, a standard time of measurement procedures for the constant work-rate tests were identical 2- and 4- minutes (isotime) and TLIM. If a significant change or inter­ to the incremental exercise tests mentioned above, however, additional action effect was found, a multiple comparison Bonferroni T-test was parameters were also collected. Cardiac output was continuously completed to locate the differences for all ANOVA’s. All statistical an­ monitored beat-by-beat and recorded in 30-s averages with impedance alyses were performed using Sigma Plot Software version 13.0 (Systat cardiography (PhysioFlow, Manatec, Paris, France). Impedance cardi­ Software Inc., San Jose, CA, USA). ography provides an accurate determination of cardiac output at rest and during exercise [37,38], and is preferred over other non-invasive 3. Results techniques such as inert gas rebreathing as these can be inaccurate in lung disease. The system is used regularly in COPD [17,38–40] and is 3.1. Participants unaffected by lung hyperinflation[ 41]. Haemoglobin concentration was þ estimated using venous sampling (HemoCue 201 , HemoCue, Angel­ Descriptive participant characteristics for the COPD and control holm, Sweden). Estimations of oxygen delivery were determined using groups are displayed in Table 1. There were no between-group differ­ cardiac output, arterial O2 saturation and haemoglobin concentration ences in age, height or BMI. The COPD group had a significantlygreater data. Vascular conductance was calculated as cardiac output/mean smoking history than controls, and all but three COPD patients were ex- arterial pressure (MAP). Near infrared spectroscopy (NIRS; Oxymon MK smokers. No individuals in the control group were current smokers. III, Artinis Medical Systems, The Netherlands) was used to evaluate Medication use (not including respiratory medication) was similar tissue oxygenation following previously published methods [42–44]. Briefly,optodes were placed directly on the skin over the left thigh at the Table 1 vastus lateralis muscle, 10 cm above the patella. The optodes were held Participant characteristics. in place using double-sided tape on the optode holder and, additionally, Control COPD P value opaque adhesive tape was placed over the entire optode probe, which also aided with light shielding. Optodes were separated by 30 mm Participants 12 12 allowing for a depth of penetration of 15 mm [45]. Care was taken to Male/Female 7/5 7/5 Age (years) 63 � 11 67 � 8 0.297 ensure consistent optode placement between trials to standardize tissue Height (cm) 169.0 � 7.3 168.8 � 7.8 0.936 area sampled and minimize measurement variability. NIRS has been Mass (kg) 77.4 � 14.1 76.8 � 11.7 0.910 À shown to accurately measure the change in tissue oxygenation (index of BMI (kg⋅m 2) 27.0 � 4.1 27.2 � 4.0 0.917 Smoking history (pack years) 5 � 5 33 � 13 <0.001 local muscle blood flow and O2 extraction) in skeletal muscle during Current smoker (n) 0 3 exercise [44,46,47]. MRC dyspnea scale (1–5) 1.0 � 0.0 2.0 � 0.7 0.001 Medication use n 2.7. Dopamine/saline intervention SABA 0 8 LABA 0 9 Prior to the experimental trials (Day 3 and 4), an intravenous (I.V.) ICS 0 9 Combined ICS/LABA 0 8 catheter was inserted into the antecubital vein of the left arm. Partici­ β-blocker 2 2 pants received either isotonic I.V. saline (Day 3) or I.V. dopamine hy­ ACE-ARB 0 4 À À drochloride (2 μg⋅kg 1⋅min 1; Hospira, Lake Forest, IL, USA, Day 4) via Statins 5 4 an automated constant-infusion pump (Alaris, San Diego, CA, USA). The Data are presented as n or mean � SD. BMI: body mass index; MRC: medical order of the experimental days was randomized. Only the research research council; SABA: short-acting β-agonist; LABA: long-acting β-agonist; ICS: coordinator and supervising physician were aware of the condition inhaled corticosteroid; ACE: angiotensin converting enzyme; ARB, angiotensin (dopamine or saline). Neither the study participant nor the lead receptor blocker.

3 D.B. Phillips et al. Respiratory Medicine 160 (2019) 105815

between the control and COPD groups (Table 1). between groups, indicating that central chemoreceptor sensitivity is À similar between COPD and controls (1.2 � 1.3 vs 1.0 � 0.7 L min 1 ⋅ À 1 ¼ 3.2. Lung function and cardiopulmonary exercise test mmHg , p 0.500).

Pulmonary function and CPET data are presented in Table 2. As 3.4. Effect of dopamine on exercise endurance time expected, the COPD group had airflowobstruction, as well as increased functional residual capacity and residual volume compared to controls. In both groups, there was no significant improvement in endurance Resting IC and DLCO were lower in COPD. Exercise data show that COPD time with dopamine, when compared to saline (Control: sa­ ¼ � ¼ � ¼ patients had significantlylower peak oxygen uptake (V_O2), V_E and work line 10.9 4.8 vs dopamine 11.6 4.0 min, p 0.31; COPD: sa­ ¼ � ¼ � ¼ rate; however, there was no evidence of arterial hypoxemia at rest or line 8.5 4.7 vs dopamine 10.0 6.1 min, p 0.417). The reasons peak exercise in either group (Table 1). COPD patients demonstrated a for stopping the exercise tests are displayed in Table 3. In controls, the reduction in IC from baseline to peak exercise, which is suggestive of predominant reason for stopping was leg discomfort, regardless of dynamic hyperinflation( Table 2). COPD patients had greater ventilatory condition. In COPD patients, the predominant reason for stopping was inefficiencythan controls, as shown by the elevated V_E/V_CO2 slope and dyspnea, also regardless of condition. V_E/V_CO2 Nadir (lowest 30 s average). 3.5. Effect of dopamine on ventilation and dyspnea during exercise 3.3. Basal chemoreflex Ventilatory responses to exercise are displayed in Tables 4 and 5 and Fig. 1. As COPD patients exercised at a lower absolute intensity, V_O , Consistent with previous work [13,17], the transient reduction in 2 V_CO , and V_ , were significantly lower during exercise in COPD, when minute ventilation during hyperoxia was greater in COPD, when 2 E À compared to controls, independent of condition. As compared to con­ compared to controls (2.2 � 1.4 vs 0.2 � 1.4 L min 1, p ¼ 0.012). The trols, V_ /V_CO was significantly higher in COPD, independent of con­ slope of the ventilatory response to hypoxia was also greater in COPD E 2 dition, (p < 0.001). At isotime (2- and 4- minutes) and T , there was no patients, when compared to controls (0.27 � 0.15 vs LIM À 1 À 1 significantdifference in V_O2, V_CO2, breathing pattern or operating lung 0.07 � 0.11 L min ⋅SpO2% , p ¼ 0.001). These data suggest that volume between dopamine and saline conditions, in either group. In COPD patients have greater resting CC activity and sensitivity. There both groups, there was a condition � time interaction for V_ (p ¼ 0.049 was no difference in the hyperoxic hypercapnic ventilatory responses, E Control, p ¼ 0.016 COPD). Post hoc analysis revealed that at 2-min isotime, V_E (p ¼ 0.015 Control, p ¼ 0.028 COPD) and V_E/V_CO2 Table 2 (p ¼ 0.017 Control, p ¼ 0.011 COPD), were significantly lower with Pulmonary function and cardiopulmonary exercise test peak responses. dopamine, in both groups (Fig. 1). However, there was no difference in Control COPD P value either V_E (p ¼ 0.412 Control, p ¼ 0.214 COPD) or V_E/V_CO2 (p ¼ 0.391 Post-Bronchodilator Lung Function Control, p ¼ 0.519 COPD), at 4 min or TLIM between saline and dopa­ � � < FEV1 (L) 3.28 0.70 2.32 0.55 0.001 mine, in either group (Fig. 1). Dopamine significantlyincreased PETCO2 � � < FEV1 (% predicted) 112 13 83 15 0.001 ¼ ¼ � À � < at 4-min isotime in both groups (p 0.016 Control, p 0.036 COPD), FEV1 (z-score) 0.58 0.92 0.88 0.74 0.001 ¼ ¼ FVC (L) 4.41 � 0.87 3.88 � 0.86 0.129 but not at TLIM (p 0.785 Control, p 0.685 COPD) (Tables 4 and 5). FVC (% predicted) 112 � 13 105 � 14 0.136 SPO2 was unaffected by dopamine throughout exercise, in either group. � � FVC (z-score) 0.95 0.97 0.60 0.86 0.669 At rest, isotime, and TLIM, there were no between-group differences � � < FEV1/FVC 0.74 0.04 0.5 0.08 0.001 in mean dyspnea ratings (p ¼ 0.103) (Tables 4 and 5, Fig. 1). Further, FEV1/FVC (% predicted) 98.1 � 4.7 80.7 � 13.3 0.004 À � À � < there was no main effect for condition (dopamine vs saline) in either FEV1/FVC (z-score) 0.60 0.49 2.00 0.90 0.001 ¼ ¼ VC (% predicted) 112 � 13 105 � 13 0.226 group at rest, isotime or TLIM (p 0.182 control, p 0.448 COPD). IC (% predicted) 123 � 19 102 � 20 0.016 � � FRC (% predicted) 103 14 121 20 0.030 3.6. Effect of dopamine on cardiovascular responses to exercise RV (% predicted) 87 � 15 110 � 18 0.003 TLC (% predicted) 102 � 11 102 � 15 0.976 DLCO (% predicted) 91 � 11 66 � 22 0.002 Hemodynamic responses to exercise are displayed in Tables 4 and 5 Cardiopulmonary peak exercise responses and Fig. 2. During exercise, cardiac output was lower in COPD Work rate (W) 191 � 64 102 � 34 <0.001 (p < 0.001), likely because of the significantlylower absolute work rate. Work rate (% predicted) 132 � 45 89 � 21 <0.001 À 1 À 1 During exercise, vascular conductance was significantlylower in COPD V_O2 (ml⋅kg ⋅min ) 36.2 � 10.3 21.5 � 6.1 <0.001 À 1 patients as compared to controls (main effect p ¼ 0.04). A group by V_O2 (L⋅min ) 2.70 � 0.90 1.59 � 0.42 0.003 V_O2 (% predicted) 134 � 37 86 � 20 <0.001 condition interaction for vascular conductance was observed at 4-min _ À 1 � � VCO2 (L⋅min ) 2.94 0.9 1.71 0.44 0.002 (p ¼ 0.04). With dopamine, vascular conductance increased and MAP _ ⋅ À 1 � � VE (L min ) 97.5 35.2 61.6 18.9 0.015 decreased at all time points in COPD (main effect p < 0.001, main effect V_ (% predicted) 95 � 31 70 � 10 0.006 E p < 0.003, respectively). Vascular conductance was only increased at V_E/V_CO2peak 32.5 � 3.1 35.2 � 6.3 0.013 Nadir V_E/V_CO2 29.0 � 1.7 35.6 � 5.9 0.001 _ _ � � Slope VE/VCO2 25.3 6.61 32.6 6.2 0.013 Table 3 PETCO2 (mmHg) 33.0 � 2.6 32.9 � 3.8 0.953 À Selection frequency of reasons for stopping constant load exercise tests. HR (beats⋅min 1) 160 � 20 127 � 13 <0.001 SpO2baseline (%) 96.3 � 2.8 96.4 � 2.1 0.841 Control COPD � � SpO2peak (%) 94.3 3.7 93.9 5.0 0.723 Reasons for stopping (n) � � Dyspnea (Borg) 6.2 2.0 5.7 1.4 0.555 Dyspnea Saline 1 6 � � Leg Discomfort (Borg) 6.8 1.7 6.6 2.3 0.614 Dopamine 1 6 Δ � À � IC baseline to peak exercise (L) 0.25 0.47 0.34 0.43 0.006 Leg Discomfort Saline 6 3 Dopamine 7 1 Data are presented as mean � SD. FEV1: forced expiratory volume in 1 s; FVC: forced vital capacity; VC: vital capacity; IC: inspiratory capacity; FRC: functional Both Saline 5 3 Dopamine 4 5 residual capacity; RV; residual volume; TLC: total lung capacity; DLCO: diffusing capacity of the lung for carbon monoxide; V_O2: oxygen uptake; V_CO2: carbon In controls, the majority of individuals stopped because of leg discomfort. In dioxide production; V_E: minute ventilation; PETCO2: partial pressure of carbon COPD, the majority of patients stopped because of dyspnea. The selection fre­ dioxide; HR: heart rate; SpO2: measured by pulse oximeter. quency was similar between saline and dopamine conditions within each group.

4 D.B. Phillips et al. Respiratory Medicine 160 (2019) 105815

Table 4 Physiological and perceptual parameters at isotime (4-min) during a constant-load cycle exercise test with saline or dopamine in controls and COPD.

Variable Control COPD Main Effects p value Interaction p value

Saline Dopamine Saline Dopamine Group Condition Group x Condition

Work Rate (W) 143 � 48 143 � 48 76 � 26 76 � 26 À 1 V_O2 (L⋅min ) 2.2 � 0.7 2.2 � 0.7 1.5 � 0.4 1.4 � 0.4 0.02 0.45 0.85 À 1 V_CO2 (L⋅min ) 2.3 � 0.7 2.4 � 0.7 1.4 � 0.4 1.4 � 0.4 0.02 0.75 0.85 À 1 V_E (L⋅min ) 72.4 � 20.4 68.7 � 18.8 47.5 � 10.8 45.2 � 10.3 0.008 0.24 0.58 V_E/V_CO2 30.6 � 2.6 29.4 � 2.4 37.3 � 6.9 36.5 � 7.1 0.001 0.15 0.64 PETCO2 (mmHg) 35.4 � 3.1 37.1 � 2.8* 33.0 � 3.9 34.6 � 4.4* 0.17 0.04 0.95 SpO2 (%) 97.6 � 1.3 96.3 � 1.3 93.8 � 3.2 92.7 � 3.7 0.07 0.14 0.69 VT (L) 2.50 � 0.51 2.53 � 0.58 1.71 � 0.50 1.84 � 0.48 0.02 0.39 0.68 À 1 fB (breaths⋅min ) 28.1 � 7.6 27.4 � 5.8 29.4 � 8.0 27.3 � 5.8 0.82 0.25 0.35 IC (L) 3.20 � 0.76 3.22 � 0.70 2.40 � 0.66 2.36 � 0.45 0.04 0.35 0.93 IRV (L) 0.85 � 0.76 0.74 � 0.38 0.59 � 0.38 0.59 � 0.38 0.45 0.24 0.52 À Q (L⋅min 1) 12.5 � 2.4 12.8 � 2.7 8.9 � 2.7 8.9 � 2.4 0.01 0.30 0.21 À HR (beats⋅min 1) 146 � 17 146 � 17 119 � 17 120 � 21 0.02 0.68 0.82 À SV (ml⋅beat 1) 85 � 14 88 � 17 75 � 17 74 � 17 0.26 0.35 0.18 MAP (mmHg) 118 � 10 113 � 7 105 � 15 91 � 15* 0.02 < 0.001 0.01 À À Q/MAP (ml⋅min 1 mmHg 1) 107 � 17 114 � 20 85 � 21 101 � 27* 0.04 0.01 0.04 Dyspnea (Borg) 4.3 � 1.7 3.8 � 1.4 3.8 � 1.4 3.4 � 1.0 0.85 0.60 0.86 Leg Discomfort (Borg) 4.9 � 1.7 4.8 � 1.7 4.6 � 1.4 4.0 � 1.4 1.00 0.18 1.00

Data are presented as mean � SD. V_O2, oxygen consumption; V_CO2, carbon dioxide production; V_E, minute ventilation; PETCO2, pressure of end-tidal carbon dioxide; SpO2: oxygen saturation measured by pulse oximeter; VT, ; fB, breathing frequency; IC, inspiratory capacity; IRV, inspiratory reserve volume Q, cardiac output; HR, heart rate; SV, stroke volume; MAP, mean brachial arterial pressure; Q/MAP, vascular conductance. *p < 0.05 between conditions within group.

Table 5 Physiological and perceptual parameters at time to symptom limitation (TLIM) during a constant-load cycle exercise test with saline or dopamine in controls and COPD. Variable Control COPD Main Effects p value Interaction p value

Saline Dopamine Saline Dopamine Group Condition Group x Condition

Work Rate (W) 143 � 166 143 � 166 76 � 80 76 � 80 Endurance Time (Min) 10.9 � 4.8 11.6 � 4.0 8.5 � 4.7 10.0 � 6.1 0.26 0.30 0.64 À 1 V_O2 (L⋅min ) 2.5 � 0.7 2.5 � 1.0 1.5 � 0.4 1.4 � 0.4 < 0.001 0.89 0.97 À 1 V_CO2 (L⋅min ) 2.6 � 1.0 2.6 � 1.0 1.5 � 0.4 1.4 � 0.4 0.002 0.30 0.56 À 1 V_E (L⋅min ) 84.8 � 27.0 86.6 � 28.3 52.0 � 10.8 55.0 � 15.2 0.004 0.15 0.52 V_E/V_CO2 35.1 � 4.1 35.1 � 3.4 39.1 � 5.2 39.1 � 5.2 0.05 0.98 0.98 PETCO2 (mmHg) 31.0 � 3.4 30.8 � 3.4 31.6 � 4.5 31.3 � 4.5 0.88 0.74 0.73 SpO2 (%) 95.1 � 2.4 94.8 � 2.8 93.0 � 6.2 91.7 � 5.8 0.22 0.22 0.48 VT (L) 2.43 � 0.48 2.35 � 0.51 1.76 � 0.51 1.75 � 0.42 0.03 0.36 0.60 À 1 fB (breaths⋅min ) 36.6 � 7.3 36.9 � 7.3 31.0 � 8.3 32.5 � 6.9 0.16 0.08 0.78 IC (L) 3.24 � 0.73 3.27 � 0.63 2.30 � 0.73 2.43 � 0.55 0.03 0.58 0.35 IRV (L) 0.82 � 0.35 0.90 � 0.45 0.69 � 0.69 0.62 � 0.42 0.41 1.00 0.50 À Q (L⋅min 1) 13.9 � 2.2 14.8 � 3.3 9.5 � 2.5 9.6 � 2.9 0.02 0.18 0.21 À HR (beats⋅min 1) 155 � 14 157 � 19 125 � 19 131 � 2 0.02 0.17 0.51 À SV (ml⋅beat 1) 90. � 14 96 � 2 75 � 17 73 � 19 0.06 0.38 0.17 MAP (mmHg) 120 � 14 114 � 14 106 � 19 92 � 19* 0.02 0.004 0.19 À À Q/MAP (ml⋅min 1 mmHg 1) 118 � 27 128 � 41* 92 � 31 108 � 42* 0.08 0.01 0.77 À 1 O2 Delivery (mlO2⋅min ) 2837 � 826 3098 � 1062* 1855 � 557 1883 � 689 0.006 0.16 0.03 Dyspnea (Borg) 7.8 � 1.9 7.9 � 1.9 6.8 � 1.8 7.1 � 2.2 0.62 0.84 0.85 Leg Discomfort (Borg) 8.8 � 1.7 9.0 � 1.7 7.1 � 1.9 7.6 � 2.0 0.38 1.00 1.00

Data are presented as mean � SD. V_O2, oxygen consumption; V_CO2, carbon dioxide production; V_E, minute ventilation; PETCO2, pressure of end-tidal carbon dioxide; SpO2: oxygen saturation measured by pulse oximeter; VT, tidal volume; fB, breathing frequency; IC, inspiratory capacity; IRV, inspiratory reserve volume Q: cardiac output; HR: heart rate; SV: stroke volume; MAP: mean brachial arterial pressure; Q/MAP: vascular conductance. *p < 0.05 between conditions within group.

TLIM in controls (p ¼ 0.048). These data suggest that dopamine had a 4. Discussion greater effect on vascular conductance in COPD patients than controls. Despite improved vascular conductance with dopamine, there was no To date, this is the firstknown study to examine the effect of carotid effect for condition (saline vs dopamine) in cardiac output (p ¼ 0.661 chemoreceptor inhibition during whole-body exercise in non- control, p ¼ 0.607 COPD), vastus-lateralis total oxygenation (p ¼ 0.719 hypoxemic patients with mild-moderate COPD and the major findings control, p ¼ 0.464 COPD) or perceived leg discomfort (p ¼ 0.460 con­ are twofold. First, carotid chemoreceptor inhibition with low-dose trol, p ¼ 0.461 COPD) at rest, isotime and TLIM. Estimated O2 delivery dopamine increased vascular conductance during exercise in COPD was not different between conditions at TLIM (p ¼ 0.334) in COPD, patients and, to a lesser extent, healthy controls. These data demonstrate however, there was a small but significant increase in controls at TLIM the importance of the CC in contributing to vascular regulation during (p ¼ 0.04). In controls, the increased O2 delivery, with dopamine, was whole-body exercise in health and in patients with COPD; however, this secondary to a larger increase in venous concentration, did not translate into an improvement in exercise tolerance. Second, no from baseline to TLIM, when compared to the saline condition (dopa­ consistent reduction in exercise ventilation (i.e. lower V_E/V_CO2 or V_E), À mine: 1.4 � 1.0 vs. saline: 0.6 � 0.8 g dL 1, p ¼ 0.007). was observed in COPD patients with dopamine and, as a result, dyspnea was unaffected. These findingsindicate that the exaggerated ventilatory response to exercise typically observed in COPD patients is likely not

5 D.B. Phillips et al. Respiratory Medicine 160 (2019) 105815

Fig. 1. Mean � SEM minute ventilation (V_E), ventilatory equivalent to carbon dioxide production (V_E/V_CO2) and exertional dyspnea at rest and during constant-load cycle ergometry in controls (left column) and COPD (right column). *p < 0.05 saline vs dopamine within group. explained by the heightened activity and sensitivity of the CC. either group. The observed reduction in V_E 2-min into exercise parallels the findings of Boetger and Ward, which suggests that CC inhibition 4.1. Ventilatory responses to exercise with dopamine slows the initial ventilatory response to whole-body exercise in both COPD and controls [20]. As exercise ventilation was largely unaffected Although the is complex, it is well accepted by dopamine, it is not surprising that operating lung volume and dys­ that afferent feedback from the CC, and central medullary chemore­ pnea were not different between saline and dopamine conditions in ceptors are key influences at rest and during exercise [50]. Work by COPD or controls. The findingsfrom our study suggest that the elevated Boetger and Ward demonstrated a blunted ventilatory response to cycle basal activity/sensitivity of the CC, in COPD, does not explain the ergometry exercise in young, apparently healthy individuals when the exaggerated ventilatory response to exercise typically observed in mild À À CC was inhibited with 3 μg⋅kg 1⋅min 1 I.V. dopamine [20]. Specifically, to moderate non-hypoxemic patients with COPD [3,13]. Although our the authors found that, although the transient ventilatory response was intervention (dopamine) did not translate to improvements in exercise tolerance, the current study helps to better understand the role of the CC slower, (as evident by a lower V_E in the first 90-s of exercise), the steady-state ventilatory response (>2-min of exercise) was unaffected by in ventilatory control during exercise in patients with COPD. dopamine, when compared to placebo. Although COPD patients in the current study demonstrated elevated resting CC activity and sensitivity, 4.2. Cardiovascular responses to exercise with dopamine as well as an exaggerated ventilatory response to exercise, CC inhibition did not consistently affect ventilation (i.e. V_E and V_E/V_CO2) during During exercise, sympathetic nervous activity (SNA) increases, constant-load cycle exercise. While a reduction in V_E at 2-min of exercise which causes vasoconstriction in the kidneys and GI tract, and competes was observed with dopamine in both groups, there was no consistent with local vasodilatory influences to manage blood pressure and loco­ reduction in V_E throughout the exercise tests (4-min isotime and TLIM) in motor muscle blood flow [51,52]. It is generally assumed that the

6 D.B. Phillips et al. Respiratory Medicine 160 (2019) 105815

Fig. 2. Mean � SEM cardiac output (Q), mean arterial pressure (MAP), vascular conductance and vastus lateralis tissue oxygentation (Total Hemoglobin (Hb)) at rest and during constant-load cycle ergometry in controls (left column) and COPD (right column). *p < 0.05 saline vs dopamine within group. increased MSNA during exercise is the result of feed-forward mecha­ Recently, we have demonstrated that CC inhibition reduced MSNA nisms such as feedback from muscle metaboreceptors, central command and central arterial stiffness, and improved vascular conductance, at and the resetting of systemic [53]. However, emerging rest, in mild to moderate non-hypoxemic COPD patients [17]. In the research has clearly demonstrated that the CC is a key contributor to present study, as compared to the saline control condition, CC inhibition increased SNA and vasoconstrictor mediated restraint of exercising with dopamine increased vascular conductance and reduced MAP dur­ muscle blood flow, such that CC inhibition during exercise resulted in ing exercise in COPD. A small but significant increase in vascular reduced SNA, vasodilation and increased blood flowto working muscle conductance was observed in controls at TLIM, however, MAP was un­ in health [18,19] and CHF [21]. affected by dopamine throughout exercise. Despite evidence of

7 D.B. Phillips et al. Respiratory Medicine 160 (2019) 105815

vasodilation, there was no effect of dopamine on cardiac output, total confound the current results [59,60]. Although individual dosing may oxygen delivery or locomotor muscle (i.e. vastus lateralis) tissue have provided a more effective intervention to inhibit the CC, we chose a oxygenation, as assessed by NIRS, in COPD. Further, the observed single, conservative dose of I.V. dopamine a priori because of the vasodilation did not translate to improved exercise tolerance. These data complexity of physiological experiments in COPD and the risk of suggest that, although CC inhibition may not acutely improve oxygen alpha-adrenergic stimulation. delivery and blood flowto working muscles, the CC is a key contributor Despite the mean change in exercise endurance (94 � 400 s) nearly to vascular regulation during exercise in patients with mild to moderate achieving the minimal clinically important difference of 101 s [61], only COPD. 2 of the 12 COPD patients within the study achieved a 101 s improve­ ment in exercise endurance time with dopamine. Based on our observed 4.3. Considerations and limitations effect size and variability in the change in exercise endurance time from saline to dopamine, 158 COPD patients would be required to detect a Despite evidence of improved vascular conductance during exercise significanteffect of CC inhibition on exercise endurance time (α ¼ 0.05, with dopamine, we did not observe a significant reduction in minute β ¼ 0.2, power ¼ 80%, Effect Size ¼ 0.235). We acknowledge the small ventilation and dyspnea during exercise with dopamine in patients with sample size of our study, however, the inability to detect a significant COPD. Multiple studies have used high oxygen (i.e. breathing hyperoxia) effect on the primary outcome is largely due to the small observed effect as a physiological intervention aimed at reducing ventilation and dys­ size and not an inadequate sample size. pnea and improving exercise tolerance in non-hypoxemic COPD patients [54–57]. A limitation of breathing hyperoxia during exercise is that any 4.4. Conclusion potential effect of reducing CC activity on ventilation cannot be distin­ guished from the secondary effects of hyperoxia such as the increase in Inhibition of the CC with dopamine improved vascular conductance arterial O2 content and resulting increase in O2 delivery. For this reason, during exercise in COPD, although, no consistent changes in ventilation, the present study used a low-dose dopamine intervention, as it has been dyspnea or exercise tolerance were observed. Our findings suggest that shown to be an effective method to inhibit the CC, without the autor­ the exaggerated ventilatory response typically observed in COPD is not egulatory and metabolic effects typically observed with hyperoxia [17, explained by heightened activity/sensitivity of the CC. However, the CC 19,48]. appears to be a modulator of vasoconstrictor outflowduring exercise in It is often assumed that low-dose dopamine causes vasodilation non-hypoxemic COPD patients. through stimulation of dopamine-1 vascular receptors. However, low- dose dopamine does not cause vasodilation in healthy controls [17,19, Disclaimer 22], while vasodilation is observed in conditions of high CC activity/­ sensitivity such as CHF [21,22] and COPD [17]. It is acknowledged that The views expressed in the submitted article are of our own and not the vasodilation observed with dopamine in COPD could be due to the an official position of the institution. direct peripheral vasodilatory actions of dopamine (via direct stimula­ tion of dopamine-1 vascular receptors); however, any direct peripheral Sources of support vascular effects of dopamine would have also been consistently observed in controls at rest and during exercise. Further, dopamine reduced Canadian Institutes of Health Research. ventilation at rest in COPD patients, and at the onset of exercise in both controls and COPD. These observations strongly suggest that dopamine Funding inhibited the CC. Further, direct stimulation of vascular dopamine-1 receptors would not be expected to affect ventilation. When com­ This study was supported by the Canadian Institutes of Health bined, these results suggest that the cardiovascular effects observed in Research (CIHR). DBP was supported by a graduate scholarship from the � the current study are secondary to CC inhibition and not a peripheral Lung Association of Alberta/Northwest Territories (AB/NWT). SEC was vascular effect. supported by the Motyl Endowment Studentship in Cardiac Sciences. Patients with COPD demonstrate elevated deadspace during whole- The funders had no role in the study design, data collection and analysis, body exercise, even in patients with mild airflow obstruction [3]. In or preparation of the manuscript. the current study, it is unclear if deadspace was affected by dopamine, as arterial blood gas data were not obtained. However, no consistent Declaration of competing interest changes in breathing pattern, operating lung volume or PETCO2 were observed during exercise in COPD and it is unlikely that deadspace was There are no conflicts of interest. affected by dopamine. Further these data would suggest that the elevated deadspace, typically observed in COPD, is not a direct result of References elevated CC activity/sensitivity. μ ⋅ À 1⋅ À 1 In the current study, dopamine was infused at 2 g kg min as [1] D. Ofir, P. Laveneziana, K.A. Webb, Y.M. Lam, D.E. O’Donnell, Mechanisms of this dose has been previously shown to inhibit the CC in humans [19, dyspnea during cycle exercise in symptomatic patients with GOLD stage I chronic 48]. Limberg et al. showed substantial variability in the dose-specific obstructive pulmonary disease, Am. J. Respir. Crit. Care Med. 177 (6) (2008) 622–629. effect of dopamine on CC sensitivity in young healthy individuals, as [2] J.A. Guenette, R.C. Chin, S. Cheng, P.B. Dominelli, N. Raghavan, K.A. Webb, J. evaluated by the hypoxic ventilatory response (HVR) at varying infusion A. Neder, D.E. O’Donnell, Mechanisms of exercise intolerance in global initiative À À rates (1–4 μg⋅kg 1⋅min 1) [58]. The author’s concluded that no uniform for chronic obstructive lung disease grade 1 COPD, Eur. Respir. J. 44 (5) (2014) – dose is ideal to inhibit the CC and reduce HVR, and suggested that in­ 1177 1187. À 1 À 1 [3] A.F. Elbehairy, C.E. Ciavaglia, K.A. Webb, J.A. Guenette, D. Jensen, S.M. Mourad, dividual dosing (between 1 and 4 μg⋅kg ⋅min ) should be used when J.A. Neder, D.E. O’Donnell, Canadian Respiratory Research Network, Pulmonary designing experiments focused on the independent contribution of the abnormalities in mild chronic obstructive pulmonary disease. CC on integrative physiological effects. It is plausible that, had indi­ implications for dyspnea and exercise intolerance, Am. J. Respir. Crit. Care Med. 191 (12) (2015) 1384–1394. vidualized dosing of dopamine been used in the current study, a [4] B. Waschki, A. Kirsten, O. Holz, K.C. Muller, T. Meyer, H. Watz, H. Magnussen, consistent reduction in exercise V_E and dyspnea may have been Physical activity is the strongest predictor of all-cause mortality in patients with – observed. Importantly, moderate dose dopamine (i.e. COPD: a prospective cohort study, Chest 140 (2) (2011) 331 342. ⋅ À 1⋅ À 1 [5] J.A. Neder, A. Alharbi, D.C. Berton, M.C. Alencar, F.F. Arbex, D.M. Hirai, K. ~5 μg kg min ) can stimulate alpha-adrenergic receptors, which A. Webb, D.E. O’Donnell, Ventilatory inefficiency adds to lung function in would result in vasoconstriction, reducing conductance and would predicting mortality in COPD, COPD 13 (4) (2016) 416–424.

8 D.B. Phillips et al. Respiratory Medicine 160 (2019) 105815

[6] J.A. Guenette, K.A. Webb, D.E. O’Donnell, Does dynamic hyperinflationcontribute [32] D. Jensen, K. Amjadi, V. Harris-McAllister, K.A. Webb, D.E. O’Donnell, to dyspnoea during exercise in patients with COPD? Eur. Respir. J. 40 (2) (2012) Mechanisms of dyspnoea relief and improved exercise endurance after furosemide 322–329. in COPD, Thorax 63 (7) (2008) 606–613. [7] D.E. O’Donnell, K.A. Webb, The major limitation to exercise performance in COPD [33] J.A. Guenette, R.C. Chin, J.M. Cory, K.A. Webb, D.E. O’Donnell, Inspiratory is dynamic hyperinflation, J. Appl. Physiol. 105 (2) (2008) 753–755. capacity during exercise: measurement, analysis, and interpretation, Pulm. Med. [8] P. Laveneziana, K.A. Webb, K. Wadell, J.A. Neder, D.E. O’Donnell, Does expiratory 2013 (2013) 956081. muscle activity influencedynamic hyperinflationand exertional dyspnea in COPD? [34] P. Dejours, Chemoreflexes in breathing, Physiol. Rev. 42 (1962) 335–358. Respir. Physiol. Neurobiol. 199 (2014) 24–33. [35] D. Read, A clinical method for assessing the ventilatory response to carbon dioxide, [9] D.E. O’Donnell, J.A. Guenette, F. Maltais, K.A. Webb, Decline of resting inspiratory Australas. Ann. Med. 16 (1967) 20–32. capacity in COPD: the impact on breathing pattern, dyspnea, and ventilatory [36] N.L. Jones, D.G. Robertson, J.W. Kane, Difference between end-tidal and arterial capacity during exercise, Chest 141 (3) (2012) 753–762. PCO2 in exercise, J. Appl. Physiol. 47 (5) (1979) 954–960. [10] P. Laveneziana, K.A. Webb, J. Ora, K. Wadell, D.E. O’Donnell, Evolution of dyspnea [37] A. Charloux, E. Lonsdorfer-Wolf, R. Richard, E. Lampert, M. Oswald-Mammosser, during exercise in chronic obstructive pulmonary disease: impact of critical volume B. Mettauer, B. Geny, J. Lonsdorfer, A new impedance cardiography device for the constraints, Am. J. Respir. Crit. Care Med. 184 (12) (2011) 1367–1373. non-invasive evaluation of cardiac output at rest and during exercise: comparison [11] J.A. Guenette, D. Jensen, K.A. Webb, D. Ofir, N. Raghavan, D.E. O’Donnell, Sex with the “direct” Fick method, Eur. J. Appl. Physiol. 82 (4) (2000) 313–320. differences in exertional dyspnea in patients with mild COPD: physiological [38] Z. Louvaris, S. Spetsioti, V. Andrianopoulos, N. Chynkiamis, H. Habazettl, mechanisms, Respir. Physiol. Neurobiol. 177 (3) (2011) 218–227. H. Wagner, S. Zakynthinos, P.D. Wagner, I. Vogiatzis, Cardiac output measurement [12] J.A. Neder, F.F. Arbex, M.C. Alencar, C.D. O’Donnell, J. Cory, K.A. Webb, D. during exercise in COPD: a comparison of dye dilution and impedance E. O’Donnell, Exercise ventilatory inefficiency in mild to end-stage COPD, Eur. cardiography, Clin. Res. J 13 (4) (2019) 222–231. Respir. J. 45 (2) (2015) 377–387. [39] C.C. Oliveira, C.R. Carrascosa, A. Borghi-Silva, D.C. Berton, F. Queiroga Jr., E. [13] M.K. Stickland, D.P. Fuhr, H. Edgell, B.W. Byers, M. Bhutani, E.Y. Wong, C. M. Ferreira, L.E. Nery, J.A. Neder, Influence of respiratory pressure support on D. Steinback, Chemosensitivity, cardiovascular risk, and the ventilatory response to hemodynamics and exercise tolerance in patients with COPD, Eur. J. Appl. Physiol. exercise in COPD, PLoS One 11 (6) (2016), e0158341. 109 (4) (2010) 681–689. [14] D.E. O’Donnell, J.A. Neder, A.F. Elbehairy, Physiological impairment in mild [40] D.M. Hirai, J.H. Jones, J.T. Zelt, M.L. da Silva, R.F. Bentley, B.A. Edgett, B.J. Gurd, COPD, Respirology 21 (2) (2016) 211–223. M.E. Tschakovsky, D.E. O’Donnell, J.A. Neder, Oral N-acetylcysteine and exercise [15] D.E. O’Donnell, A.F. Elbehairy, A. Faisal, K.A. Webb, J.A. Neder, D.A. Mahler, tolerance in mild chronic obstructive pulmonary disease, J. Appl. Physiol. 122 (5) Exertional dyspnoea in COPD: the clinical utility of cardiopulmonary exercise (2017) 1351–1361. testing, Eur. Respir. Rev. 25 (141) (2016) 333–347. [41] A.T. Edmunds, S. Godfrey, M. Tooley, Cardiac output measured by transthoracic [16] R. Torchio, A. Mazzucco, M. Guglielmo, R. Giardino, C. Ciacco, F. Ardissone, impedance cardiography at rest, during exercise and at various lung volumes, Clin. Minute ventilation to carbon dioxide output (V’E/V’CO2 slope) is the strongest Sci. 63 (1982) 107–113. death predictor before larger lung resections, Monaldi Arch. Chest Dis. 87 (3) [42] B. Shadgan, J.A. Guenette, A.W. Sheel, W.D. Reid, Sternocleidomastoid muscle (2017). deoxygenation in response to incremental inspiratory threshold loading measured [17] D.B. Phillips, C.D. Steinback, S.E. Collins, T.L. Bryan, E.Y.L. Wong, V. Tedjasaputra, by near infrared spectroscopy, Respir. Physiol. Neurobiol. 178 (2) (2011) 202–209. M. Bhutani, M.K. Stickland, The carotid chemoreceptor contributes to the elevated [43] R. Boushel, H. Langberg, J. Olesen, J. Gonzales-Alonza, J. Bulow, M. Kjaer, arterial stiffness and vasoconstrictor outflow in COPD, J. Physiol. 15 (2018) Monitoring tissue oxygen availability with near infrared spectroscopy (NIRS) in 3233–3244. health and disease, Scand. J. Med. Sci. Sport. 11 (2001) 213–222. [18] M.K. Stickland, B.J. Morgan, J.A. Dempsey, Carotid chemoreceptor modulation of [44] B. Grassi, V. Quaresima, C. Marconi, M. Ferrari, P. Cerretelli, Blood lactate sympathetic vasoconstrictor outflowduring exercise in healthy humans, J. Physiol. accumulation and muscle deoxygenation during incremental exercise, J. Appl. 586 (6) (2008) 1743–1754. Physiol. 87 (1) (1999) 348–355. [19] M.K. Stickland, D.P. Fuhr, M.J. Haykowsky, K.E. Jones, D.I. Paterson, J. [45] S. Homma, T. Fukunaga, A. Kagaya, Influence of adipose tissue thickness on near A. Ezekowitz, M.S. McMurtry, Carotid chemoreceptor modulation of blood flow infrared spectroscopic signal in the measurement of muscle, J. Biomed. Opt. during exercise in healthy humans, J. Physiol. 589 (Pt 24) (2011) 6219–6230. 1 (1996) 418–424. [20] C.L. Boetger, D.S. Ward, Effect of dopamine on transient ventilatory response to [46] R. Boushel, F. Pott, P. Madsen, G. Radegran, M. Nowak, B. Qustorff, N.H. Secher, exercise, J. Appl. Physiol. 61 (6) (1986) 2102–2107. Muscle metabolism from near infrared spectroscopy during rhythmic handgrip in [21] M.K. Stickland, J.D. Miller, C.A. Smith, J.A. Dempsey, Carotid chemoreceptor humans, Eur. J. Appl. Physiol. 79 (1998) 41–48. modulation of regional blood flow distribution during exercise in health and [47] J.R. Wilson, D.M. Mancini, K. McCully, N. Ferraro, V. Lanoce, B. Chance, chronic heart failure, Circ. Res. 100 (9) (2007) 1371–1378. Noninvasive detecetion of skeletal muscle underperfusion with near infrared [22] H. Edgell, M.S. McMurtry, M.J. Haykowsky, I. Paterson, J.A. Ezekowitz, J.R. Dyck, spectroscopy in patients with heart failure, Circulation 80 (1989) 1668–1674. M.K. Stickland, Peripheral chemoreceptor control of cardiovascular function at rest [48] S. Lahiri, T. Nishino, A. Mokashi, E. Mulligan, Interaction of dopamine and and during exercise in heart failure patients, J. Appl. Physiol. 118 (7) (2015) haloperidol with O2 and CO2 chemoreception in , J. Appl. Physiol. 49 839–848. (1) (1980) 45–51. [23] S.E. Collins, D.B. Phillips, M.S. McMurtry, T.L. Bryan, D.I. Paterson, E.Y.L. Wong, J. [49] B.V. Zlokovic, The blood-brain barrier in health and chronic neurodegenerative A. Ezekowitz, M.A. Forhan, M.K. Stickland, The effects of carotid chemoreceptor disorders, 57 (2) (2008) 178–201. inhibition on exercise tolerance in chronic heart failure, Front. Physiol. (2019). [50] J.A. Dempsey, C.A. Smith, Pathophysiology of human ventilatory control, Eur. Submitted for publication. Respir. J. 44 (2) (2014) 495–512. [24] F. Chung, H.R. Abdullah, P. Liao, STOP-bang questionnaire: a practical approach to [51] M.J. Joyner, L.A. Naus, M.A. Warner, D.O. Warner, Sympathetic modulation of screen for obstructive sleep apnea, Chest 149 (3) (2016) 631–638. blood flow and O2 uptake in rhythmically contracting human forearm muscles, [25] J. Wanger, J.L. Clausen, A. Coates, O.F. Pedersen, V. Brusasco, F. Burgos, Am. J. Physiol. 263 (4 Pt 2) (1992) H1078–H1083. R. Casaburi, R. Crapo, P. Enright, C.P. van der Grinten, P. Gustafsson, [52] J.B. Buckwalter, P.S. Clifford, Alpha-adrenergic vasoconstriction in active skeletal J. Hankinson, R. Jensen, D. Johnson, N. Macintyre, R. McKay, M.R. Miller, muscles during dynamic exercise, Am. J. Physiol. 277 (1 Pt 2) (1999) H33–H39. D. Navajas, R. Pellegrino, G. Viegi, Standardisation of the measurement of lung [53] L.B. Rowell, D.S. O’Leary, Reflex control of the circulation during exercise: volumes, Eur. Respir. J. 26 (3) (2005) 511–522. chemoreflexes and mechanoreflexes, J. Appl. Physiol. 69 (2) (1990) 407–418. [26] M.R. Miller, J. Hankinson, V. Brusasco, F. Burgos, R. Casaburi, A. Coates, R. Crapo, [54] N.D. Eves, S.R. Petersen, M.J. Haykowsky, E.Y. Wong, R.L. Jones, Helium- P. Enright, C.P. van der Grinten, P. Gustafsson, R. Jensen, D.C. Johnson, hyperoxia, exercise, and respiratory mechanics in chronic obstructive pulmonary N. MacIntyre, R. McKay, D. Navajas, O.F. Pedersen, R. Pellegrino, G. Viegi, disease, Am. J. Respir. Crit. Care Med. 174 (7) (2006) 763–771. J. Wanger, A.E.T. Force, Standardisation of spirometry, Eur. Respir. J. 26 (2) [55] M.M. Peters, K.A. Webb, D.E. O’Donnell, Combined physiological effects of (2005) 319–338. and hyperoxia on exertional dyspnoea in normoxic COPD, Thorax [27] N. Macintyre, R.O. Crapo, G. Viegi, D.C. Johnson, C.P. van der Grinten, 61 (7) (2006) 559–567. V. Brusasco, F. Burgos, R. Casaburi, A. Coates, P. Enright, P. Gustafsson, [56] D.E. O’Donnell, D.J. Bain, K.A. Webb, Factors contributing to relief of exertional J. Hankinson, R. Jensen, R. McKay, M.R. Miller, D. Navajas, O.F. Pedersen, breathlessness during hyperoxia in chronic airflow limitation, Am. J. Respir. Crit. R. Pellegrino, J. Wanger, Standardisation of the single-breath determination of Care Med. 155 (2) (1997) 530–535. carbon monoxide uptake in the lung, Eur. Respir. J. 26 (4) (2005) 720–735. [57] A. Somfay, J. Porszasz, S.M. Lee, R. Casaburi, Effect of hyperoxia on gas exchange [28] C.A. Gutierrez, R.H. Ghezzo, R.T. Abboud, M.G. Cosio, J.R. Dill, R.R. Martin, D. and lactate kinetics following exercise onset in nonhypoxemic COPD patients, S. McCarthy, J.L. Morse, N. Zamel, Reference values of pulmonary function tests Chest 121 (2) (2002) 393–400. for Canadian Caucasians, Eur. Respir. J. 11 (6) (2004) 12. [58] J.K. Limberg, B.D. Johnson, W.W. Holbein, S.M. Ranadive, M.T. Mozer, M. [29] P.H. Quanjer, S. Stanojevic, T.J. Cole, X. Baur, G.L. Hall, B.H. Culver, P.L. Enright, J. Joyner, Interindividual variability in the dose-specific effect of dopamine on J.L. Hankinson, M.S. Ip, J. Zheng, J. Stocks, E.R.S.G.L.F. Initiative, Multi-ethnic carotid chemoreceptor sensitivity to hypoxia, J. Appl. Physiol. 120 (2) (2016) reference values for spirometry for the 3-95-yr age range: the global lung function 138–147. 2012 equations, Eur. Respir. J. 40 (6) (2012) 1324–1343. [59] B. Hoffman, R. Lefkowitz, Catecholamines and sympathomimetic , in: [30] D. Jensen, A. Alsuhail, R. Viola, D.J. Dudgeon, K.A. Webb, D.E. O’Donnell, Inhaled A. Gilman, T. Rall, A. Nies, P. Taylor (Eds.), Goodman and Gilman’s the fentanyl citrate improves exercise endurance during high-intensity constant work rate cycle exercise in chronic obstructive pulmonary disease, J. Symptom Manag. 43 (4) (2012) 706–719. [31] G.A.V. Borg, Psychophysical bases of perceived exertion, Med. Sci. Sport. Exerc. 14 (5) (1982) 377–381.

9 D.B. Phillips et al. Respiratory Medicine 160 (2019) 105815

Pharmacological Basis of Therapeutics, Pergamon Press, New York, 1990, [61] L. Puente-Maestu, F. Villar, J. de Miguel, W.W. Stringer, P. Sanz, M.L. Sanz, J.G. de pp. 187–220. Pedro, Y. Martinez-Abad, Clinical relevance of constant power exercise duration [60] A. Ciarka, J.L. Vincent, P. van de Borne, The effects of dopamine on the respiratory changes in COPD, Eur. Respir. J. 34 (2) (2009) 340–345. system: friend or foe? Pulm. Pharmacol. Ther. 20 (6) (2007) 607–615.

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