The clinical burden of sickle cell anemia (SCA) has a tremendous impact on physical functioning, including cardiopulmonary fitness, among affected individuals. However, the physiologic basis of exercise limitation remains poorly understood in this population. The objective of our study was to characterize the cardiopulmonary response to maximal exercise and to delineate the physiologic mechanisms responsible for decreased fitness among children and young adults with SCA.
We prospectively performed maximal cardiopulmonary exercise testing (CPET) on 60 subjects with SCA (hemoglobin SS or S/β0 thalassemia) and 20 controls without SCA or sickle cell trait matched for race and gender. CPET was completed using a graded, symptom-limited cycle ergometry protocol with breath-by-breath, gas exchange analysis and pre/post spirometry. The primary outcome of fitness was defined by weight-adjusted, peak oxygen consumption (peak VO2). Slopes for determining oxygen uptake kinetics and ventilatory efficiency were calculated using 10-second averages of data points. We used the V-slope method to determine ventilatory threshold. Bivariate comparisons of continuous data were performed using Student's t-test for independent samples (IBM, SPSS V20). We used multivariate analysis to derive a model for determining independent contributors to peak VO2 in subjects.
There was no difference in gender distribution among subjects and controls, but subjects were older (15.1 ± 3.44 vs. 13.2 ±2.9 years, p = 0.03) and had lower hemoglobin (8.8 ±1.3 vs. 12.8 ±1.5 g/dL, p < 0.0001). All subjects met criteria for a maximal test as defined by a respiratory exchange ratio (RER) ≥ 1.1, and in all, testing was terminated due to excessive fatigue. No major adverse events occurred during CPET in any subject. Only 1/60 (1.7%) subjects developed vaso-occlusive pain requiring hospitalization in the 2-week follow-up period after testing. Nearly all of the major indicators of CPET performance and gas exchange were adversely affected in our subjects. Compared to controls, subjects demonstrated significantly lower mean peak VO2 (26.9 ±6.9 vs. 40.6 ±8.2 mL/kg/min, p < 0.0001), even after adjustment for age and hemoglobin. Average total test time (5.6 ±1.3 vs. 7.8 ±2.2 min, p = 0.012) and peak work rate (108 ±37 vs. 151 ±57 watts, p = 0.011) were similarly reduced as was ventilatory threshold (1.01 ±0.29 vs. 1.34 ±0.34 L/min, p < 0.0001), indicating earlier transition to anaerobic metabolism during exercise. Heart rate reserve, the difference between achieved maximal and baseline heart rates, was significantly lower (99 ±14 vs. 111 ±15, p = 0.002) in subjects. Slopes calculated using minute ventilation (VE), expired CO2 (VCO2), VO2 and work rate also indicated significantly reduced ventilatory efficiency (ΔVE/ΔVCO2), oxygen delivery (ΔVO2/ΔWR) and oxygen uptake (ΔVO2/ΔVE) kinetics in subjects versus controls. To examine the physiologic contributors to peak VO2 in subjects with SCA alone, we developed a multivariate model that included age, baseline hemoglobin, heart rate reserve, maximal VE, pre-exercise forced expiratory volume in 1 second, and ventilatory threshold. This model explained 67% of the variability observed in peak VO2 in subjects, with age, maximal VE and ventilatory threshold retaining independent contributions to peak VO2 and ventilatory threshold making the largest contribution with an non-standardized β coefficient of 11.9 (SE ±3.2), p < 0.0001.
Maximal CPET is safe in children and young adults with SCA, suggesting that acute exercise challenge is well tolerated in this population even at high levels of exercise intensity and physical exertion. When compared to their peers, children and young adults with SCA demonstrate significantly reduced fitness levels. Exercise limitation in SCA may be attributed to complex derangements in the cardiopulmonary and metabolic responses to exercise that are independent of anemia. Our findings highlight the need to develop targeted exercise training strategies aimed at improving fitness in this population and to assess its impact on overall disease severity.
No relevant conflicts of interest to declare.
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