Reduced fitness and abnormal cardiopulmonary responses to maximal exercise testing in children and young adults with sickle cell anemia

Robert I Liem, Madhuri Reddy, Stephanie A Pelligra, Adrienne P Savant, Bo Fernhall, Mark Rodeghier, Alexis A Thompson, Robert I Liem, Madhuri Reddy, Stephanie A Pelligra, Adrienne P Savant, Bo Fernhall, Mark Rodeghier, Alexis A Thompson

Abstract

Physiologic contributors to reduced exercise capacity in individuals with sickle cell anemia (SCA) are not well understood. The objective of this study was to characterize the cardiopulmonary response to maximal cardiopulmonary exercise testing (CPET) and determine factors associated with reduced exercise capacity among children and young adults with SCA. A cross-sectional cohort of 60 children and young adults (mean 15.1 ± 3.4 years) with hemoglobin SS or S/β(0) thalassemia and 30 matched controls (mean 14.6 ± 3.5 years) without SCA or sickle cell trait underwent maximal CPET by a graded, symptom-limited cycle ergometry protocol with breath-by-breath, gas exchange analysis. Compared to controls without SCA, subjects with SCA demonstrated significantly lower peak VO2 (26.9 ± 6.9 vs. 37.0 ± 9.2 mL/kg/min, P < 0.001). Subjects demonstrated slower oxygen uptake (ΔVO2/ΔWR, 9 ± 2 vs. 12 ± 2 mL/min/watt, P < 0.001) and lower oxygen pulse (ΔVO2/ΔHR, 12 ± 4 vs. 20 ± 7 mL/beat, P < 0.001) as well as reduced oxygen uptake efficiency (ΔVE/ΔVO2, 42 ± 8 vs. 32 ± 5, P < 0.001) and ventilation efficiency (ΔVE/ΔVCO2, 30.3 ± 3.7 vs. 27.3 ± 2.5, P < 0.001) during CPET. Peak VO2 remained significantly lower in subjects with SCA after adjusting for age, sex, body mass index (BMI), and hemoglobin, which were independent predictors of peak VO2 for subjects with SCA. In the largest study to date using maximal CPET in SCA, we demonstrate that children and young adults with SCA have reduced exercise capacity attributable to factors independent of anemia. Complex derangements in gas exchange and oxygen uptake during maximal exercise are common in this population.

Keywords: Cardiopulmonary fitness; exercise testing; sickle cell.

© 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

Figures

Figure 1
Figure 1
Differences in slopes for ΔVO2/ΔWR (upper left), ΔVO2/ΔHR (upper right), ΔVE/ΔVCO2 (lower left) and ΔVE/ΔVO2 (lower right) calculated from 10-sec averaged data from the first 3 and 5 min for subjects with SCA and controls without SCA, respectively. Cutoff values for data points were based on the minimal test time that allowed for inclusion of the same number of data points for all subjects and controls.

References

    1. Alpert BS, Gilman PA, Strong WB, Ellison MF, Miller MD, McFarlane J, et al. Hemodynamic and ECG responses to exercise in children with sickle cell anemia. Am. J. Dis. Child. 1981;135:362–366.
    1. Anthi A, Machado RF, Jison ML, Taveira-Dasilva AM, Rubin LJ, Hunter L, et al. Hemodynamic and functional assessment of patients with sickle cell disease and pulmonary hypertension. Am. J. Respir. Crit. Care Med. 2007;175:1272–1279.
    1. Armstrong N, Williams J, Balding J, Gentle P. Kirby B. The peak oxygen uptake of British children with reference to age, sex and sexual maturity. Eur. J. Appl. Physiol. 1991;62:369–375.
    1. Barker AR, Williams CA, Jones AM. Armstrong N. Establishing maximal oxygen uptake in young people during a ramp cycle test to exhaustion. Br. J. Sports Med. 2011;45:498–503.
    1. Barst RJ, Mubarak KK, Machado RF, Ataga KI, Benza RL, Castro O, et al. Exercise capacity and haemodynamics in patients with sickle cell disease with pulmonary hypertension treated with bosentan: results of the ASSET studies. Br. J. Haematol. 2010;149:426–435.
    1. van Beers EJ, van der Plas MN, Nur E, Bogaard HJ, van Steenwijk RP, Biemond BJ, et al. Exercise tolerance, lung function abnormalities, anemia, and cardiothoracic ratio in sickle cell patients. Am. J. Hematol. 2014;89:819–824.
    1. Blair SN, Kampert JB, Barlow HW, 3rd, Kohl CE, Macera CA, Paffenbarger RS, Jr, et al. Influences of cardiorespiratory fitness and other precursors on cardiovascular disease and all-cause mortality in men and women. JAMA. 1996;276:205–210.
    1. Brittain JE. Parise LV. Cytokines and plasma factors in sickle cell disease. Curr. Opin. Hematol. 2007;14:438–443.
    1. Callahan LA, Woods KF, Mensah GA, Ramsey LT, Barbeau P. Gutin B. Cardiopulmonary responses to exercise in women with sickle cell anemia. Am. J. Respir. Crit. Care Med. 2002;165:1309–1316.
    1. Carnethon MR, Gulati M. Greenland P. Prevalence and cardiovascular disease correlates of low cardiorespiratory fitness in adolescents and adults. JAMA. 2005;294:2981–2988.
    1. Charache S, Bleecker ER. Bross DS. Effects of blood transfusion on exercise capacity in patients with sickle-cell anemia. Am. J. Med. 1983;74:757–764.
    1. Charlot K, Waltz X, Hedreville M, Sinnapah S, Lemonne N, Etienne-Julan M, et al. Impaired oxygen uptake efficiency slope and off-transient kinetics of pulmonary oxygen uptake in sickle cell anemia are associated with hemorheological abnormalities. Clin. Hemorheol. Microcirc. 2014 Epub ahead of print.
    1. Chaudry RA, Bush A, Rosenthal M. Crowley S. The impact of sickle cell disease on exercise capacity in children. Chest. 2013;143:478–484.
    1. Cooper DM, Leu SY, Galassetti P. Radom-Aizik S. Dynamic interactions of gas exchange, body mass, and progressive exercise in children. Med. Sci. Sports Exerc. 2014;46:877–886.
    1. Covitz W, Eubig C, Balfour IC, Jerath R, Alpert BS, Strong WB, et al. Exercise-induced cardiac dysfunction in sickle cell anemia. A radionuclide study. Am. J. Cardiol. 1983;51:570–575.
    1. Das BB, Sobczyk W, Bertolone S. Raj A. Cardiopulmonary stress testing in children with sickle cell disease who are on long-term erythrocytapheresis. J. Pediatr. Hematol. Oncol. 2008;30:373–377.
    1. Davies CT, Barnes C. Godfrey S. Body composition and maximal exercise performance in children. Hum. Biol. 1972;44:195–214.
    1. Godfrey S, Davies CT, Wozniak E. Barnes CA. Cardio-respiratory response to exercise in normal children. Clin. Sci. 1971;40:419–431.
    1. Gordeuk VR, Minniti CP, Nouraie M, Campbell AD, Rana SR, Luchtman-Jones L, et al. Elevated tricuspid regurgitation velocity and decline in exercise capacity over 22 months of follow up in children and adolescents with sickle cell anemia. Haematologica. 2011;96:33–40.
    1. Hackney AC, Hezier W, Gulledge TP, Jones S, Strayhorn D, Busby M, et al. Effects of hydroxyurea administration on the body weight, body composition and exercise performance of patients with sickle-cell anaemia. Clin. Sci. (Lond.) 1997;92:481–486.
    1. Hebbel RP, Osarogiagbon R. Kaul D. The endothelial biology of sickle cell disease: inflammation and a chronic vasculopathy. Microcirculation. 2004;11:129–151.
    1. Janz KF, Burns TL, Witt JD. Mahoney LT. Longitudinal analysis of scaling VO2 for differences in body size during puberty: the Muscatine Study. Med. Sci. Sports Exerc. 1998;30:1436–1444.
    1. Krahenbuhl GS, Skinner JS. Kohrt WM. Developmental aspects of maximal aerobic power in children. Exerc. Sport Sci. Rev. 1985;13:503–538.
    1. Mancini DM, Katz SD, Lang CC, LaManca J, Hudaihed A. Androne AS. Effect of erythropoietin on exercise capacity in patients with moderate to severe chronic heart failure. Circulation. 2003;107:294–299.
    1. Martin GR, Ongkingo JR, Turner ME, Skurow ES. Ruley EJ. Recombinant erythropoietin (Epogen) improves cardiac exercise performance in children with end-stage renal disease. Pediatr. Nephrol. 1993;7:276–280.
    1. McConnell ME, Daniels SR, Lobel J, James FW. Kaplan S. Hemodynamic response to exercise in patients with sickle cell anemia. Pediatr. Cardiol. 1989;10:141–144.
    1. Metra M, Cannella G, La Canna G, Guaini T, Sandrini M, Gaggiotti M, et al. Improvement in exercise capacity after correction of anemia in patients with end-stage renal failure. Am. J. Cardiol. 1991;68:1060–1066.
    1. Miller GJ, Serjeant GR, Sivapragasam S. Petch MC. Cardio-pulmonary responses and gas exchange during exercise in adults with homozygous sickle-cell disease (sickle-cell anaemia) Clin. Sci. 1973;44:113–128.
    1. Myers J, Prakash M, Froelicher V, Do D, Partington S. Atwood JE. Exercise capacity and mortality among men referred for exercise testing. N. Engl. J. Med. 2002;346:793–801.
    1. Panepinto JA, O'Mahar KM, DeBaun MR, Loberiza FR. Scott JP. Health-related quality of life in children with sickle cell disease: child and parent perception. Br. J. Haematol. 2005;130:437–444.
    1. Pianosi P, D'Souza SJ, Charge TD, Beland MJ, Esseltine DW. Coates AL. Cardiac output and oxygen delivery during exercise in sickle cell anemia. Am. Rev. Respir. Dis. 1991a;143:231–235.
    1. Pianosi P, D'Souza SJ, Esseltine DW, Charge TD. Coates AL. Ventilation and gas exchange during exercise in sickle cell anemia. Am. Rev. Respir. Dis. 1991b;143:226–230.
    1. Reiter CD, Wang X, Tanus-Santos JE, Hogg N, Schechter RO, 3rd, Cannon AN, et al. Cell-free hemoglobin limits nitric oxide bioavailability in sickle-cell disease. Nat. Med. 2002;8:1383–1389.
    1. Rutenfranz J, Lange Andersen K, Seliger V, Ilmarinen J, Klimmer F, Kylian H, et al. Maximal aerobic power affected by maturation and body growth during childhood and adolescence. Eur. J. Pediatr. 1982;139:106–112.
    1. Sachdev V, Kato GJ, Gibbs JS, Barst RJ, Machado RF, Nouraie M, et al. Echocardiographic markers of elevated pulmonary pressure and left ventricular diastolic dysfunction are associated with exercise intolerance in adults and adolescents with homozygous sickle cell anemia in the United States and United Kingdom. Circulation. 2011;124:1452–1460.
    1. Solovey A, Lin Y, Browne P, Choong S, Wayner E. Hebbel RP. Circulating activated endothelial cells in sickle cell anemia. N. Engl. J. Med. 1997;337:1584–1590.
    1. Waltz X, Romana M, Hardy-Dessources MD, Lamarre Y, Divialle-Doumdo L, Petras M, et al. Hematological and hemorheological determinants of the six-minute walk test performance in children with sickle cell anemia. PLoS One. 2013;8:e77830.
    1. Wei M, Kampert JB, Barlow CE, Nichaman MZ, Gibbons LW, Paffenbarger RS, Jr, et al. Relationship between low cardiorespiratory fitness and mortality in normal-weight, overweight, and obese men. JAMA. 1999;282:1547–1553.

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