Clinical Hemorheology and Microcirculation 49 (2011) 151–163 DOI 10.3233/CH-2011-1465 IOS Press
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Exercise limitation, exercise testing and exercise recommendations in sickle cell anemia Philippe Connesa,b,∗ , Roberto Machadoc , Olivier Huea and Harvey Reidd a
Laboratory ACTES, Department of Physiology, University of the French West Indies, Pointe a Pitre, Guadeloupe, French West Indies b Inserm, Pointe-`a-Pitre, Guadeloupe, Universit´e des Antilles et de la Guyane, Pointe-`a-Pitre, France c Section of Pulmonary, Critical Care Medicine, Sleep and Allergy, University of Illinois Chicago, Chicago, USA d Department of Basic Medical Sciences (Physiology Section), Faculty of Medical Sciences, University of the West Indies, Mona Campus, Kingston, Jamaica, West Indies
Abstract. Sickle cell anemia (SCA or SS homozygous sickle cell disease) is an inherited blood disorder caused by single nucleotide substitution in the -globin gene that renders their hemoglobin (HbS) much less soluble than normal hemoglobin (HbA) when deoxygenated. The polymerization of HbS upon deoxygenation is the basic pathophysiologic event leading to RBC sickling, hemolysis, vasoocclusion and ultimately to chronic organ damage. The metabolic changes imposed by exercise may initiate sickling and vaso-occlusive episodes. Further, in patients with SCA, exercise limitation may be related to anemia or chronic complications such as pulmonary vascular disease, congestive heart failure and chronic parenchymal lung disease. Few studies have investigated the cardiorespiratory responses of patients with SCA during either symptom-limited maximal exercise test on cyclo-ergometer or during a six minute walk test. Therefore, patients are advised to start exercise slowly and progressively, to maintain adequate hydration during and after exercise, to avoid cold exposure or sudden change in temperature, and to avoid sports associated with mechanical trauma. There are, however, lack of evidence to allow practitioners to prescribe an exercise program for patients with SCA, and individuals are usually encouraged to exercise on a symptom-limited basis. Finally, this review will also highlight the basic principles that are often used for exercise practice and could be used for exercise prescription and rehabilitation in patients with sickle cell anemia. Keywords: Sickle cell disease, exercise rehabilitation, exercise testing, clinical complications, physical fitness
1. Sickle cell anemia and pathophysiologic mechanisms African traditional medicine knew sickle cell anemia (SCA) for centuries. During the cold season, a part of the African population experienced chronic rheumatisms. In 1910, James Herrick was the first scientist to describe sickle red blood cells [50] and the mutation causing HbS was described in 1977 by Marotta et al. [67-68]. The gene defect is a mutation of a single nucleotide (A −→ T) on the ∗
Corresponding author: Philippe Connes, Laboratory ACTES (EA 3596), Department of Physiology, University of the French West Indies, 97159 Pointe a Pitre, Guadeloupe, French West Indies. Tel.: 590 690 36 76 28; Fax: 590 590 83 05 13; E-mail:
[email protected]. 1386-0291/11/$27.50 © 2011 – IOS Press and the authors. All rights reserved
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-globin chain, which results in the substitution of valine for glutamic acid in the sixth position of the beta chain of the hemoglobin S (HbS). The hydrophobic residues of valine at position 6 of the beta chain in hemoglobin are able to associate with the hydrophobic patch, causing HbS molecules to aggregate and form fibrous precipitates under deoxygenated condition. Such a phenomenon is called “polymerisation of HbS” [81, 88] and is usually reversible on reoxygenation. However, after many repeated cycles of deoxygenation/reoxygenation, RBCs become and remain irreversibly sickled [16, 59, 61]. The term, sickle cell disease (SCD), refers to the homozygous state (HbSS) or SCA, and also to compound heterozygous states in which other hemoglobin disorders are inherited together with HbS, such as sickle-hemoglobin C disease (SC), sickle-+ thalassemia and sickle-0 thalassemia. More than 50 million of persons are affected by this disease worldwide [8]. When red cells from patients with SCA become deoxygenated in the capillaries, the HbS polymerizes inducing the sickling process, which decreases the deformability of the red blood cells (RBC). Rigid cells fail to move through the small blood vessels, hence blocking local blood flow in the microvasculature [54, 66]. The abnormal rheology of the sickled red cells contributes to tissue hypoxia, vaso-occlusive crisis and ultimately organ damage. Moreover, these rigid RBCs are more fragile than normal RBCs, hence promoting hemolytic episodes and often severe anemia [39]. It is known that the percentages of HbS and HbF determine the polymerization tendency and thus can modulate the severity of SCA [83]. However, the pathophysiology of HbS polymerization is insufficient to explain the extreme variable phenotypic expression of SCA and its multiple complications such as vaso-occlusive painful crisis, acute chest syndrome, pulmonary hypertension and stroke. Although SCA is a monogenic disorder, the pathophysiologic mechanisms involved are complex. Recent data have elucidated some of the mechanisms and events associated with the vasooclusive crisis. For example, the following has been observed: – abnormal rheologic properties of RBCs [5, 13, 16, 20, 29, 94] – predilection of sickle red cells for adherence to the vascular endothelium [48, 56] – existence of a pro-inflammatory vascular environment with circulating activated endothelial cells, neutrophils and monocytes [38, 41, 55, 88, 90] – marked endothelial dysfunction related to decreased nitric oxide (NO) bio-availability [55, 60] – imbalance between hemostasic/fibrinolytic activities [43] – alterations in the autonomic nervous system activity [5, 30, 51, 76, 86]. Hence, the morbidity and severity of SCA are modulated by several factors, such as inflammation, cellular activation mechanisms and adhesion processes, endothelial dysfunction, and abnormal blood rheology [16, 56, 88]. 2. Risks of exercise Health care providers are often questioned whether patients with SCA should participate in sports or strenuous physical activity. The major question faced by health care professionals and exercise physiologists involved in SCA management is the safe level of physical activity they should recommend for their patients. Exercise and physical activity are known to induce marked metabolic changes, such as lactic acid production by active muscles. The presence of anemia is responsible for a faster transition from aerobic to anaerobic metabolism during exercise, which may stimulate the polymerization of HbS and lead RBCs to sickle and promote microvascular occlusions [73]. An added consideration is the dehydration
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occurring during exercise together with the acute episodes of tissue hypoxia, which may also contribute to the sickling of RBCs. Exposure to moderate temperature changes during exercise may also trigger vaso-occlusive crisis. Furthermore, although regular exercise may improve immune function, acute bouts of exercise may cause a temporary immune dysfunction with transient increase in several circulating cytokines [45, 85] which may also trigger vaso-occlusive crisis through an activation of several adhesion molecules and circulating blood cells [65] which may reduce blood flow in the microcirculation. The genesis of reactive oxygen species during intense exercise could also promote endothelial dysfunction and RBCs alterations. It is often thought that prolonged endurance exercise is more stressful than short periods of exercise in patients with SCA, however greater efforts should also be paid to the effects of short intense exercise. For example, intense exercise, such as that which involves repeated jumping, may increase the risks for muscle and joint injuries [49]. Contact sports, including American football, hockey, and similar events, should be avoided, particularly by patients with splenomegaly, given the high risk of splenic rupture [52]. All these considerations stimulate fear from physicians about exercise recommendations in SCA patients. However, as developed later in this article, recent evidences suggest that SCA patients may practice physical activities even if specific recommendations about exercise duration and intensity is needed.
3. Physical fitness 3.1. Physical activity/daily practice SCA is often associated with poor nutritional status and delayed growth in adolescents [84]. These conditions have been shown to be associated with a 10–20% greater resting energy expenditure (REE) than is seen in healthy subjects, resulting from higher protein turnover and higher cardiac output [18, 19, 22, 87]. Indeed, to maintain their daily total energy expenditure at the same level as that of healthy adolescents, SCA adolescents decrease their physical activity energy expenditure (PAEE) [23]. The reason for lower physical activity in SCA patients compared with normal subjects may be attributable to the chronic anemia [23]. Millis et al. [72] investigated the differences in performance of routine physical activities between SCA children and children with normal hemoglobin. Each subject swam 20-yd then 40-yd followed by a 100-yd “potato” foot-racing event. The results showed significantly reduced performance in SCA children compared with the control group. Another study investigated the ability to perform simple physical exercise by children with SCA and compared with children either having the sickle cell trait or normal hemoglobin genotype (HbA) [73]. The exercises undertaken were a vertical jump to determine the anaerobic power of leg muscles, a grip, back and leg strength, and a treadmill running test of 5 min duration at 5 km/h. The different strengths studied and the anaerobic power were decreased in SCA children as compared with the two other groups. The heart rate measured during the treadmill exercise was significantly higher in SCA children than in the other children and blood lactate levels at the beginning and at the end of exercise were greater in SCA children. The greater heart rate found in SCA children may be interpreted as physiologic adaptation to compensate for the decreased blood oxygen transport capacity related to anemia and microcirculatory impairment. However, results from Moheeb et al. [73] also indicated a greater energetic cost and a greater anaerobic contribution in SCA children than in healthy children for a low intensity exercise. These data are in accordance with the recent findings of
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Balayssac-Syransy et al. [14] where a group of SCA patients and a control group performed a cycling exercise test of 20 min duration at 50 Watts in supine position. Although the exercise intensity proposed was moderate, SCA patients exhibited a greater cardiorespiratory stress than control subjects with heart rate and ventilation being higher in the former group. The higher ventilation, as well as the lack of steady-state ventilation, during the submaximal exercise was probably related to the greater lactic acid production by exercising muscles in the SCA group [14]. All these information must be considered by physicians when they recommend physical activity to SCA patients. 3.2. Exercise as a tool for functional and physical fitness assessment Several studies have examined the mechanisms responsible for the exercise intolerance in SCA patients. Multiple factors could contribute to this intolerance and they include: – – – – –
reduced oxygen carrying capacity related to low Hb level, functional and structural cardiac adaptations resulting from chronic anemia [6, 21], pulmonary parenchymal dysfunction caused by repeated episodes of acute chest syndrome [27], pulmonary vascular disease [24, 37] and peripheral vascular impairments due to frequent and repeated microvascular occlusion [24].
Callahan et al. [24] investigated whether one or more of these factors could be involved in the reduced exercise capacity of 17 SCA patients in the steady-state condition. An important observation was that all the patients were able to complete the symptom-limited cardiopulmonary exercise testing (CPET) on ergocycle with intensity being incremental every 2 min, without any complications. Nevertheless, all the patients showed abnormal exercise responses (VO2 ) responses, i.e. with at least one of the following abnormalities: peak VO2 less than 80% predicted, anaerobic threshold (AT) less than predicted, low oxygen (O2 ) pulse (i.e. the ratio of VO2 to heart rate which mimics the stroke volume) or low VO2 -work rate ratio. The low AT suggested that transition from aerobic to anaerobic exercise was faster in SCA patients than in the healthy subjects. All the patients from the study of Callahan et al. [24] had high ventilatory reserve indicating the absence of mechanical ventilation impairment. All the gas exchange and cardiac responses were carefully analysed by the authors and 3 main mechanisms for the exercise limitation in SCA were proposed: a. Anemia which can cause low peak VO2 , low AT, low O2 pulse, elevated heart rate for level of work and increased respiratory equivalent in carbon dioxide (i.e. elevated VE/VCO2 with VE corresponding to ventilation) [98]. The authors observed that exercise limitation could be fully explained by the anemia in only 3 patients. b. Pulmonary vascular disease was also involved in exercise limitation in about two third of patients. These patients showed gas exchange abnormalities such as: alveolar-arterial oxygen tension difference [P(A-a)O2 ] >30 mmHg, abnormal dead-space to tidal volume ratio (VD/VT) in association with a widening of the arterial-end-tidal carbon dioxide difference suggesting ventilation-perfusion mismatch, and very high values of VE/VCO2 ) [24]. These gas exchange abnormalities were not related to anemia and could be due to the presence of pulmonary vascular disease. c. Peripheral vascular disease and/or myopathy. In 3 patients, the reduced exercise responses were not fully explained by anemia or impairment in gas exchange. In addition to low VO2 response and high ventilatory reserve, these patients had a high heart rate reserve, which is not the case in patients with anemia alone [24]. The authors suggested that micro-vascular occlusion in skeletal muscles
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and repeated ischemia-reperfusion in those organs might have contributed to the development of peripheral vascular disease/myopathy. 4. Exercise as a clinical tool for identifying clinical complications and for clinical survey Although SCA patients have impaired aerobic fitness, exercise testing may provide important information about medical problems, which may not be apparent in resting conditions but may be uncovered by exercise. Table 1 summarizes the most frequently used cardiorespiratory parameters that have been used for screening for SCA’ associated diseases. It has been shown that exercise testing could be useful in the following cases. 4.1. Screening for pulmonary or peripheral vascular disease The study of cardiorespiratory parameters and blood gas homeostasis during a symptom limited CPET with steps increment individualized is a powerful tool to objectively determine the presence or absence of pulmonary/peripheral vascular disease [24, 82]. Although less rich in information, the study of exercise response during a 6-min walk test (speed and distance covered) in association with the measurement of dyspnea [3, 40] and pulmonary function tests (notably spirometry and diffusion capacity of carbon Table 1 Interpretation of CPET and 6-min walking test data [10, 24, 36, 69] Classification
Criteria
Abnormal
Limited exercise capacity
Low peak VO2 Low anaerobic threshold Low maximum O2 pulse Low VO2 -work rate ratio Low distance covered during a 6-min walking test
Abnormal gas exchange
Abnormal lung function studies (at rest and after exercise)* Increased P(A-a)O2 Increased VE/VCO2 Abnormal VD/VT Presence of dyspnea Low breathing reserve High heart rate reserve ST segment depression Elevated double product
