The Effect of Voxelotor on Exercise Capacity of Youths with Sickle Cell Anemia

Abstract Background/Hypothesis: Children and adults with sickle cell anemia (SCA) exhibit decreased cardiopulmonary fitness. Anemia is directly related to oxygen carrying capacity and is one factor that affects cardiopulmonary fitness. The new sickle cell drug voxelotor raises hemoglobin in patients with SCA treated or untreated with hydroxyurea. We hypothesized that voxelotor improves exercise capacity in youths with SCA. Methods: A single-center, open-label, single-arm longitudinal interventional pilot study was conducted for patients with SCA age > 12. Participants performed baseline Cardiopulmonary Exercise Testing (CPET#1), took 1500mg voxelotor for 2 months, then CPET was repeated (CPET#2). A modified Bruce Protocol using 2-minute stages was performed on a motorized treadmill, for a goal of 8-12 minutes of exercise. Breath by breath gas exchange data were collected and analyzed using a VMax Encore 29C metabolic cart. The metabolic test included standard monitoring of heart rate, EKG ST changes, arrhythmias, and O2 saturation. A respiratory quotient >1.1 was used as evidence of participant effort. Peak oxygen consumption (peak VO2), anaerobic threshold (AT), O2 pulse, VE/VCO2 slope, and time exercised in CPET#1 and CPET#2 were compared for each participant. The primary endpoint was peak VO2. Hemoglobin (Hgb), reticulocyte count, and bilirubin were measured before CPET#1 and CPET#2. Pill count was used to monitor medication adherence and left shift of the P50 oxygen dissociation curve was used to document biochemical effect of voxelotor. Patient Global Impression of Change (PGIC) and Clinician Global Impression of Change (CGIC) surveys were collected at the end of the study. Statistical analysis was performed using Student's paired T-test. Results: Nine SCA patients ages 12-20, including 4 males and 5 females, completed the study. All had Hgb SS and were stably maintained on hydroxyurea, which was continued without dose change during the study. After 2 months of voxelotor, all participants demonstrated expected hematologic changes, including mean rise in Hgb +1.3 g/dL (95% C.I.= 0.8, 1.7), mean decrease in reticulocyte count -2.4% (95% C.I.= -4.1, -0.8), and mean decrease in bilirubin -0.4 mg/dL (95% C.I.= -0.8, -0.1). All participants demonstrated voxelotor adherence and leftward shift of p50 (Table 1). Oxygen consumption, measured as percent predicted peak VO2 (ml/kg/min), ranged from 52% to 80% in CPET#1 and from 55% to 71% in CPET#2. The changes in peak VO2 for individual participants ranged from -10% to +10% of predicted peak VO2, with a mean difference of -2.2% (95% CI = -7.1, 2.7), which is insignificant (p=0.3). Using +/- 6% as variability in peak VO2 measurement, 5 participants exhibited no change, 3 participants had decrease in peak VO2 of -7%, -9%, and -10%, while peak VO2 increased by +10% for a single participant, who started to exercise on his own after starting voxelotor. Changes in individuals' anaerobic threshold, O2 pulse, VE/VCO2 slope, and time exercised were not significant and did not correlate with changes in peak VO2. All participants achieved respiratory quotient >1.1, assuring participant effort during CPET (Table 2). On the 7-point PGIC questionnaire evaluating activity limitations, symptoms, emotions, and overall quality of life, 7 out of 9 participants reported positive change, including "a great deal better," "definite," and "moderate" improvements. Two participants reported minimal to no change, and no participants reported worsening. In comparison, clinicians reported "minimal" to "much" improvement on CGIC for all participants. Overall, patient impression of improvement was higher than clinician impression of improvement. Conclusion: This pilot study demonstrated the feasibility of using CPET to evaluate exercise capacity longitudinally in youths with SCA. After addition of voxelotor to hydroxyurea for 2 months, all patients perceived global improvement. Peak VO2 did not change in 8 out of 9 participants and improved for 1 participant who exercised between the 2 CPETs. To increase peak VO2, higher Hgb increase, concurrent regular exercise, and longer exposure to voxelotor may be necessary. This study was funded by Global Blood Therapeutics Figure 1 Figure 1. Disclosures Larkin: Forma Therapeutics, Inc.: Research Funding. Dulman: Pfizer: Other: own stock. Kuypers: Forma Therapeutics, Inc.: Research Funding.

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Chronic Pain Is An Independent Predictor of Lower 6 Minute Walk Distance In Patients with Sickle Cell Disease: Results From Walk-PHaSST Study

Blood ◽

10.1182/blood.v116.21.2658.2658 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2658-2658

Author(s):

Lakshmanan Krishnamurti ◽

Ruchika Goel ◽

Oswaldo Castro ◽

Robyn J. Barst ◽

Erika Berman Rosenzweig ◽

...

Keyword(s):

Chronic Pain ◽

Exercise Capacity ◽

Sickle Cell ◽

Acute Pain ◽

Research Funding ◽

History Of ◽

Pain Crisis ◽

The Mean ◽

Minute Walk Distance ◽

Minute Walk

Abstract Abstract 2658 Introduction: Six minute walk distance (6MWD), is a measure of exercise capacity commonly used as an endpoint in pulmonary hypertension (PH) clinical trials. Many patients with sickle cell disease (SCD) have acute pain crises or chronic pain syndromes that impair their quality of life. While patients with SCD who are undergoing screening for PH are generally screened in steady state, i.e., when they have not had a recent pain crisis, the impact of chronic pain on exercise capacity in this group of patients has not been previously evaluated. Methods: walk-PHaSST was a multi-center screening study designed to identify subjects with SCD at increased risk for symptomatic PH, defined by a tricuspid regurgitant velocity (TRV) ≥ 2.7 m/sec and 6MWD between 150–500 meters, for enrollment in a double-blind placebo controlled trial of sildenafil. The primary endpoint was the change in 6MWD after 16 weeks of treatment. We examined the relationship between subjects' self-reported acute and chronic pain and baseline 6MWD in the screened SCD patients in walk-PHaSST. Results: For 90% of subjects, the information about pain was reported by the patient or parent/family member. Documentation of pain management and utilization of services was verified from medical records in 10% of subjects. Ninety four percent of all subjects reported having a history of acute sickle cell pain crises; 6% reported never having had an acute pain crisis. For the subjects who reported a history of acute pain crises, the ‘typical’ acute pain rating on a scale of 0 to 10 was ≥ 7 (maximum 10) for 77% of this subset of subjects. A total of 342 (50%) subjects reported not having had any pain crises in the preceding week. Of 720 subjects screened medical history and 6 MWD was available in 673 patients. Of these 633 (94%) subjects did not report having had a pain crisis requiring an emergency department visit or hospitalization in the preceding week. A total of 39% of subjects reported chronic sickle cell related pain; no rating was reported for chronic pain. 88% of patients reported using medications for pain control while 15% reported using non-drug therapy including physical therapy in 3%, alternative therapy in 2%, acupuncture in 2% and hypnosis in < 1% of patients. The mean 6MWD for the screened population was 439 meters (median 438 m, range 123–713 m). A total of 171/673 (26%) subjects had a 6MWD >500 meters, which was above the screening cut-off for enrollment in the main interventional trial. By univariate analysis, subjects reporting chronic pain had a significant lower odds ratio for walking > 500 meters (OR 0.637, 95% C.I 0.44–0.99); a similar observation was seen with those subjects with a history of acute pain crises (OR 0.47, 95% C.I 0.24–0.91). Multivariable logistic regression analysis revealed a significant inverse relationship between chronic pain but not acute pain and 6MWD after adjusting for age, TRV, gender, hematocrit and smoking history (See Table 1). The mean 6MWD decreased by 27 meters with self reported chronic pain after adjusting for TRV, age, gender, hematocrit and 6MWD. Conclusions: TRV is a known predictor of 6MWD. However, these data suggest that patient self reported sickle cell related chronic pain is also an independent predictor of 6MWD. This relationship raises interesting questions about the potentially confounding effects of pain on exercise capacity as assessed by the 6MW test. Further study is warranted to investigate an association between chronic pain and exercise capacity in SCD as well as exploration of appropriate endpoints for future clinical trials in patients with SCD and suspected symptomatic PH. Disclosures: Barst: Pfizer: Consultancy, Research Funding. Rosenzweig:Pfizer: Research Funding. Badesch:Pfizer: Honoraria, Research Funding. Hassell:Novartis: Research Funding.

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Biochemical Surrogate Markers of Hemolysis Do Not Correlate with Directly Measured Erythrocyte Survival in Sickle Cell Anemia

Blood ◽

10.1182/blood.v128.22.2484.2484 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2484-2484

Author(s):

Charles T. Quinn ◽

Eric P. Smith ◽

Shahriar Arbabi ◽

Paramjit Khera ◽

Christopher J. Lindsell ◽

...

Keyword(s):

Stable Isotope ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Research Funding ◽

Total Bilirubin ◽

Reticulocyte Count ◽

Human Study ◽

Surrogate Marker ◽

Blood Levels ◽

Surrogate Markers

Abstract Introduction: Hemolysis has been proposed as a cause of several complications of sickle cell anemia (HbSS), including pulmonary hypertension, priapism, leg ulcers, and stroke. No human study of the role of hemolysis in these complications has directly quantified hemolysis; all used surrogate markers. We applied a recently validated stable isotope glycine red blood cell (RBC) labeling method (Am J Hematol. 2015;90:50-5) to measure RBC survival, a direct measure of the rate of hemolysis, to determine whether commonly used surrogate markers of hemolysis accurately estimate RBC survival in HbSS. Methods: Orally administered stable isotope-labeled glycine (15N-glycine), a metabolic precursor of heme, was used to track an age cohort of RBCs in participants with HbSS. The atomic excess of 15N in heme extracted from blood over time was monitored by mass spectrometry to calculate mean RBC survival. We also measured complete blood counts, reticulocyte counts, fetal hemoglobin (HbF), blood levels of biochemical surrogates of hemolysis (LDH, AST, bilirubin, and plasma free Hb), alpha-globin genotype, and tricuspid jet regurgitant velocity (TRV) by echocardiography. Results: There were 5 males and 6 females; mean age was 23 years (range 16-41). Two participants completed the study twice for a total of 13 labeling studies. Mean RBC survival was 31.9 days (S.D. 12.0; range 14.1-53.6). Mean RBC survival was inversely correlated with absolute reticulocyte count (ARC; r = -0.84, P < 0.001; Panel A) and percentage of reticulocytes (r = -0.78, P = 0.002). There was also a positive correlation between mean RBC survival and percent HbF (r = 0.58, P = 0.038; Panel B). The commonly used biochemical surrogate markers of hemolysis, AST, LDH, total bilirubin, indirect bilirubin, and plasma free Hb, were not correlated with directly measured RBC survival (Panels C & D). The "hemolytic index" or "hemolytic component" [derived from the combination of LDH, AST, total bilirubin and reticulocyte count (Blood. 2009;114:4639-44)] was not more strongly correlated with mean RBC survival than ARC (r = -0.73, P = 0.004). That is, the hemolytic component provided no more information about mean RBC survival than ARC alone. We found a correlation between TRV and LDH (r = 0.62, P = 0.03; Panel E), as previously described, but no correlation between TRV and directly measured RBC survival in the same participants (r = 0.09, P = 0.79; Panel F). This indicates that the relationship between TRV and LDH, while valid and reproducible, is not readily explained by hemolytic rate. Conclusions: RBC labeling with orally administered 15N-glycine is a safe and practical method to measure RBC survival directly, and thereby quantify hemolysis. Commonly used biochemical surrogate markers of hemolytic rate (LDH, AST, bilirubin, and plasma free Hb) did not correlate with directly measured RBC survival. These markers should be interpreted cautiously in HbSS. Only reticulocyte count and HbF level correlated with directly measured RBC survival. Although ARC appears to be a reasonable surrogate marker of hemolysis, it is indirect and explains only 70% of the variation in RBC survival. If greater accuracy is required for physiological studies or clinical trials, 15N-glycine RBC labeling can directly and accurately quantify hemolysis. Disclosures Quinn: Amgen: Research Funding; Eli Lilly: Research Funding; Silver Lake Research Corporation: Consultancy. Joiner:Global Blood Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Improvement in Red Blood Cell Physiology in Children with Sickle Cell Anemia Receiving Voxelotor

Blood ◽

10.1182/blood-2019-129351 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2281-2281 ◽

Cited By ~ 1

Author(s):

Satheesh Chonat ◽

Earl Fields ◽

Hannah Baratz ◽

Amanda Watt ◽

Mira Pochron ◽

...

Keyword(s):

Shear Stress ◽

Pilot Study ◽

Sickle Cell ◽

Research Funding ◽

Advisory Board ◽

Red Cell ◽

Employment Equity ◽

Oxygen Dissociation ◽

Equity Ownership ◽

Dissociation Curves

Background: Sickle hemoglobin (HbS) under conditions of deoxygenation polymerizes to cause sickling of red blood cells (RBCs) and other rheological abnormalities. Voxelotor has been previously shown in a preclinical model of sickle cell disease (SCD) to increase HbS affinity to oxygen, thus reducing its polymerization and sickling with subsequent increase in the half-life of RBCs. We hypothesized that given this mechanism of action, we would observe improvements in RBC physiology in patients receiving voxelotor. In the Phase 3 GBT HOPE trial, the use of voxelotor in patients with SCD caused a significant reduction in markers of hemolysis and anemia. Ektacytometry is considered the gold standard to study deformability of RBCs with membrane protein disorders. The deformability of RBCs can be assessed using a defined value of shear stress with an increasing osmotic gradient (osmoscan) as well as with a newer technology to subject these cells to gradual deoxygenation (oxygenscan). Both assays can be measured using the Laser Optical Rotational Red Cell Analyzer (LORRCA, RR Mechatronics, NL). In this pilot study, we analyzed samples from patients with SCD receiving voxelotor, before and 12 weeks after starting therapy to assess the benefits of voxelotor on RBC physiology. Methods: Our pilot study obtained whole blood from children ages 4-11 years with SCD, who were enrolled in the IRB approved GBT 440-007 clinical trial (NCT02850406; a study evaluating multiple doses of voxelotor at 1500 mg/day equivalent exposure to adults based on body weight) at Emory University/Children's Healthcare of Atlanta. All participants in this cohort continued their stable, optimal hydroxyurea dose during treatment with voxelotor. The below measurements were performed on the pre-dose and Week 12 visit samples. Deformability of RBCs was performed at a shear stress of 30 Pa and varying osmolality gradients (0-600 mOsm/Kg) for Osmoscan. Omin corresponds to the value of the hypotonic osmolality, where 50% of the cells hemolyze in an osmotic fragility assay and provides information on the initial surface area:volume ratio. Maximal deformability or Elongation Index (EImax) near isotonic osmolality informs us of the RBC cytoskeleton mechanics and Ohyper, the osmolality corresponding to 50% of the Elmax, provides information regarding the cytoplasmic viscosity. Oxygenscan was performed but under controlled deoxygenation using nitrogen. Point of Sickling (POS) is a point on the curve during deoxygenation when sickling begins, and EImin corresponds when sickle RBCs can least elongate. Oxygen dissociation curves were obtained using a HemOx Analyzer (TCS Scientific). Complete blood count parameters were determined on a clinical laboratory hematology analyzer (ADVIA, Siemens). Data was analyzed with Prism using a paired T-test. Results: Both pre-dose and Week 12 visit samples were available for 10 participants. Mean hemoglobin at baseline was 9.0 g/dL (7.6-10.0) and at 12 weeks, 10.3 g/dL (8.2-12.3). Six out of 10 participants had a hemoglobin response at Week 12 (defined as an increase in Hb from baseline by >1 g/dL), of which 5 had hemoglobin over 10 g/dL. Mean % change in percentage of reticulocytes was -17.0%. Significant improvement in EImax on osmoscan was noted at Week 12 (p=0.0147), suggesting RBCs were more deformable with improved cytoskeleton mechanics. In addition, oxygenscan curves shifted upwards towards normal with a significant increase in EImax (p=0.0347) and EImin (p=0.0079). These findings combined with a decrease in POS (p=0.0001) during deoxygenation suggests that at low oxygen tension, voxelotor treated RBCs were more deformable possibly from reduced HbS polymer inside these cells. Significant reductions in P50 (p=0.0011) and P20 (p=0.0001) with a left shift of the oxygen dissociation curve further demonstrates the effect of voxelotor on RBCs. Discussion: Voxelotor therapy in children with HbSS is associated with reductions in anemia and reticulocyte response, and recovery in RBC health as early as 12 weeks of treatment. Voxelotor's ability to inhibit HbS polymerization and RBC sickling is associated with specific modulation in red cell rheology at normoxic and deoxygenating conditions. Left shifted oxygen dissociation curves confirm voxelotor's ability to increase oxygen affinity. These findings suggest that voxelotor improves RBC deformability and anemia and delays the initiation of RBC sickling. Figure Disclosures Chonat: Alexion: Other: advisory board; Agios Pharmaceuticals, Inc.: Other: advisory board. Baratz:Prolong Pharmacuticals: Honoraria; Global Blood Therapeutics: Research Funding. Pochron:Global Blood Therapeutics: Employment, Equity Ownership. Dixon:Global Blood Therapeutics: Employment, Equity Ownership. Tonda:Global Blood Therapeutics: Employment, Equity Ownership. Lehrer-Graiwer:Global Blood Therapeutics: Employment, Equity Ownership. Brown:Pfizer: Research Funding; Novartis, Inc: Research Funding; Imara, Inc: Consultancy, Research Funding; Global Blood Therapeutics, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Archer:AstraZeneca: Research Funding; Prolong Pharmaceuticals: Consultancy; Global Blood Therapeutics: Consultancy, Research Funding.

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Associations between spleen volume and exercise capacity in advanced heart failure patients with left ventricular assist device

European Heart Journal ◽

10.1093/ehjci/ehaa946.1094 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

H Hiraiwa ◽

T Okumura ◽

A Sawamura ◽

S Kazama ◽

Y Kimura ◽

...

Keyword(s):

Exercise Capacity ◽

Left Ventricular ◽

Advanced Heart Failure ◽

Cardiac Preload ◽

Spleen Volume ◽

Assist Device ◽

Ventricular Assist ◽

Peak Vo2 ◽

Left Ventricular Assist ◽

O2 Pulse

Abstract Background The spleen has been recognized as an important organ with several functions such as a reservoir of blood volume, and an involvement in iron metabolism by processing of aged red blood cells and recycling iron. During exercise, spleen contracts, and red blood cells pooled in the spleen are recruited into the systemic circulation. So far, we reported that spleen size changed in advanced heart failure (HF) with left ventricular assist device (LVAD). In addition, spleen volume was related to pulmonary capillary wedge pressure (PCWP) or right atrial pressure (RAP) as parameters of cardiac preload. However, it remains unclear about the relationship between spleen volume and exercise capacity in advanced HF with LVAD. Purpose The purpose of this study was to investigate the associations between spleen volume and exercise capacity in advanced HF patients with LVAD. Methods We enrolled 27 HF patients (21 males, 45±12 years) with LVAD (HeartMate II™; Abbott, Chicago, IL, USA) for use as a bridge to heart transplantation. All patients underwent blood test, echocardiography, right heart catheterization, computed tomography (CT) and cardiopulmonary exercise testing (CPET). Spleen size was measured by CT volumetry. We excluded patients with splenic infarction or aortic valve closure surgery. Results At baseline, body mass index, blood brain natriuretic peptide levels, hemoglobin levels, left ventricular ejection fraction were 21.4±3.1 kg/m2, 73.8 (51.9–165.8) pg/mL, 12.1 (10.6–13.4) g/dL, 24.8±14.7%, respectively. Total cardiac output (CO), the sum of pump flow and CO of native heart was 4.6±0.9 L/min, and spleen volume was 184.9±48.8 mL. As for parameters of CPET, peak heart rate (HR), peak VO2, and peak O2 pulse were 128±25 beats/min, 14.2±3.3 mL/kg/min, and 6.6±1.9 mL/beat. At rest, there were significant correlations between spleen volume and PCWP (r=0.382, p=0.049), RAP (r=0.406, p=0.035) or pulsatility index (r=0.384, p=0.047), despite no correlations with total CO or pump flow. During exercise, there were significant interrelations of spleen volume with peak VO2 (r=0.451, p=0.018) and peak O2 pulse (r=0.427, p=0.026). Furthermore, peak VO2 was interrelated with peak HR (r=0.481, p=0.011) or hemoglobin levels (r=0.649, p<0.001). Remarkably, spleen volume was significantly correlated with hemoglobin levels (r=0.391, p=0.043) (Figure). Interpreting these results based on Fick's formula, the proportion of native CO to total CO is very small at rest, but increases during exercise. The spleen during exercise may contribute to increased native CO, especially stroke volume. Moreover, the spleen may be related to both cardiac preload and oxygen carrying capacity, resulting in a significant association between spleen volume and peak VO2. Conclusion Spleen volume could be a useful predictor of exercise capacity in advanced HF patients with LVAD, reflecting splenic function to modulate cardiac preload and blood hemoglobin levels. Spleen volume and exercise parameters Funding Acknowledgement Type of funding source: None

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Computerized cognitive training in pediatric sickle cell disease: A randomized controlled pilot study.

Clinical Practice in Pediatric Psychology ◽

10.1037/cpp0000313 ◽

2020 ◽

Vol 8 (4) ◽

pp. 390-401 ◽

Cited By ~ 1

Author(s):

Taryn M. Allen ◽

Lindsay M. Anderson ◽

Samuel M. Brotkin ◽

Jennifer A. Rothman ◽

Melanie J. Bonner

Keyword(s):

Pilot Study ◽

Sickle Cell Disease ◽

Cognitive Training ◽

Sickle Cell ◽

Cell Disease ◽

Computerized Cognitive Training ◽

Randomized Controlled ◽

Pediatric Sickle Cell Disease

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P391 Changes in QRS duration during exercise are associated with maximal exercise capacity and peak oxygen consumption in adults with repaired tetralogy of Fallot

European Heart Journal ◽

10.1016/s0195-668x(03)93829-2 ◽

2003 ◽

Vol 24 (5) ◽

pp. 49

Author(s):

W BUDTS

Keyword(s):

Oxygen Consumption ◽

Tetralogy Of Fallot ◽

Exercise Capacity ◽

Maximal Exercise ◽

Peak Oxygen Consumption ◽

Repaired Tetralogy Of Fallot ◽

Qrs Duration ◽

Maximal Exercise Capacity

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VEGF Promoter Region 18-bp Insertion-Deletion Polymorphism in Sickle Cell Disease Patients with Microalbuminuria: A Pilot Study

Indian Journal of Hematology and Blood Transfusion ◽

10.1007/s12288-018-1018-x ◽

2018 ◽

Vol 35 (2) ◽

pp. 278-283

Author(s):

Dnyanesh B. Amle ◽

Rachana L. Patnayak ◽

Varsha Verma ◽

Gajendra Kumar Singh ◽

Vijaylakshmi Jain ◽

...

Keyword(s):

Pilot Study ◽

Sickle Cell Disease ◽

Sickle Cell ◽

Promoter Region ◽

Cell Disease ◽

Deletion Polymorphism

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Role of ventilatory response to exercise in determining exercise capacity in COPD

Journal of Applied Physiology ◽

10.1152/jappl.1995.79.6.1870 ◽

1995 ◽

Vol 79 (6) ◽

pp. 1870-1877 ◽

Cited By ~ 19

Author(s):

O. Bauerle ◽

M. Younes

Keyword(s):

Body Mass Index ◽

Oxygen Consumption ◽

Exercise Capacity ◽

Body Mass ◽

Ventilatory Response ◽

Inspiratory Flow ◽

Peak Oxygen Consumption ◽

Chronic Obstructive ◽

Inspiratory Capacity ◽

Response To Exercise

The progression of chronic obstructive pulmonary disease (COPD) is generally associated with decreased exercise capacity. Differences in forced expired volume in 1 s (FEV1) among patients account for only a fraction of the variability in maximal oxygen consumption (VO2max). We hypothesized that variability in ventilatory response to exercise and in inspiratory mechanics and body mass index contributes importantly to variability in VO2max in this disease. We analyzed the files of 53 patients with established diagnosis of COPD who underwent a recent symptom-limited exercise test. We used inspiratory capacity and maximum inspiratory flow as measures of variability in inspiratory mechanics. The minute ventilation (VE) at the subject's VO2max was divided by the predicted in a normal subject at the same VO2 to obtain a ratio (VE,max/VE,pred). The ventilatory response during exercise provided the best correlation with peak VO2 (r = 0.62). FEV1 and inspiratory capacity also correlated with peak oxygen consumption but not as well as the ventilatory response (r = 0.49 and r = 0.46, respectively). Maximum inspiratory flow and body mass index showed only weak positive correlations (r = 0.23, not significant). The stepwise analysis generated the following equation: VO2max (%predicted) = (77.26 x VE,pred/VE,max) + [0.45 x FEV1 (%predicted)] - 23.66; r = 0.76, P < 0.001. We conclude that variability in the ventilatory response during exercise is one of the main determinants of variability in exercise capacity in COPD patients.

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