In patients with sickle cell disease (SCD), strenuous physical exercise has been found to be physiologically stressful, making patients severely exercise intolerant (1,2). Limitations on physical exercise in SCD may be related to (i) anemia, arterial oxyhemoglobin desaturation, hematologic abnormalities, and hemodynamic disorders, all of which disrupt oxygen supply to tissues (3,4), particularly to active skeletal muscles where oxygen demand is high, and (ii) repercussions of SCD on different organs/tissues involved in adaptation to exercise including the lungs, heart, vessels, and skeletal muscles (1,5–9). More importantly, SCD patients experience various abnormal pulmonary, circulatory, and metabolic exercise responses (1,2,5,10–14). For example, pulmonary hypertension (15,16) and diastolic dysfunction (17) affect approximately 30% and 18% (respectively) of SCD patients and constitute independent major risks of mortality, which may rise acutely during exercise, potentially resulting in cardiovascular collapse and even death (18). Strenuous exercise may also induce hemolysis, early lactate accumulation and associated acidosis, arterial desaturation, hemorheological disturbances, endothelial activation, and oxidative stress (5,12,19–22), all of which are potential triggering factors for sickling and vaso-occlusive crises (VOC). Importantly, exertion has been reported to be a major precipitating factor of VOC (23). Exercise-related aggravation of risk factors explains why physical activity is not usually recommended or is avoided for/by patients with SCD.
However, moderate-intensity physical exercise seems to be safe in SCD patients (19,20). Besides, regular physical activity is known to improve oxidative defenses, oxygen transport and utilization, muscle microvascular, energetics and structural characteristics, and overall physical fitness (24,25), suggesting that moderate-intensity endurance training may be beneficial for SCD patients (6). Improvement of physical ability is important because it reduces morbidity and improves emotional well-being, self-esteem, and social interaction (26). However, owing to the potential exercise-related risks of complications for SCD patients, the absence of recommendations for a safe protocol for physical evaluation of SCD patients, or sufficient guidelines on physical exercise programs, particularly in terms of intensity (to prevent complications), physicians are often wary of prescribing endurance training (6,20). Nevertheless, the feasibility of such an intervention has recently been demonstrated (27).
Therefore, the aim of the present study was to test in adult SCD patients the safety and usefulness of a submaximal incremental exercise evaluating physical ability as well as the feasibility and safety of endurance exercises. In particular, we hypothesized/posited that (i) stopping an incremental exercise as soon as [lactate]b reaches 4 mmol·L−1 does not elicit maximal exertion/exhaustion of patients, drastically decrease SpO2, lead to potentially harmful [lactate]b (>7 mmol·L−1 postexercise) and induce complications; (ii) the proposed protocol is useful to determine LT1, which delineates patients’ physical ability; and (iii) an individually tailored 30-min endurance exercise is feasible for the patients and does not induce major drifts in [lactate]b and SpO2, so that the proposed endurance exercise may appear safe.
Twenty SCD patients (12 men and 8 women), recruited among patients followed at the Centre de Référence des Syndromes Drépanocytaires Majeurs (AP-HP, GHU Henri-Mondor) and associated centers, participated in the study (Table 1). After having been fully informed of the purposes, procedures, and possible risks, eligible volunteers gave their written informed consent. The experiment was approved by the ethics committee and meets the standards set out in the Declaration of Helsinki. For inclusion criteria, readers should refer to ClinicalTrials.gov ID NCT02571088.
All experiments took place at GHU Henri-Mondor in Créteil (altitude 50 m/165 ft). First, blood samples were taken from participants to determine hematologic and hemoglobin parameters. Patients were also interviewed about their physical exercise habits. Then the study comprised in one or four exercise sessions. The first session consisted of a submaximal incremental exercise. The other three sessions consisted of constant-load moderate-intensity endurance exercises.
Submaximal incremental exercise
Upon arrival, patients were equipped with a 12-lead EKG, a pulse oximeter, and a face mask for gas exchange analysis. A resting blood lactate concentration ([lactate]b) measurement was performed. The cycle ergometer exercise started at 20 and 30 W for females and males, respectively. After 2 min at this load, and every 2 min thereafter, the work rate was increased by 10 and 15 W for females and males, respectively. Cardiopulmonary parameters were monitored continuously (ErgoCard, Medisoft, Belgium) or computed from the measurements taken during exercise. Approaching the end of each stage, patient’s rate of percieved exertion (RPE) (CR10 Scale®) was recorded. A blood drop (10 μL) was taken every minute from the earlobe and tested extemporaneously (within 15–20 s) for [lactate]b concentration determination (Lactate Scout+, EKF diagnostics, Cardiff, UK). Exercise was stopped as soon as [lactate]b ≥4 mmol·L−1 was recorded or if symptoms occurred. Incremental exercise was followed by 2 min of active recovery at 20 or 30 W for females and males, respectively, and then by 8 min of passive recovery. This protocol was used to identify the physiological parameters associated with (i) the first lactate threshold (LT1, defined as the first inflection point in the [lactate]b curve obtained during the submaximal incremental exercise; Fig. 1A), (ii) exercise completion, and (iii) given work rates (e.g., 50 and 75 W for women and men, respectively). LT1 indicates the transition from moderate to heavy exercise and constitutes a good marker of the patients’ physical ability and of the physical capacities required for patients’ activities of daily life.
Constant-load (endurance) exercises
Eight men and seven women completed three endurance exercise sessions. Each exercise session lasted 45 min starting with a 5-min warm-up cycle, followed by 30 min of constant-load cycling at ~2.5 mmol·L−1 of [lactate]b and continued by a 5-min cooldown, and ending with 5 min of light stretching. All training sessions took place in hospital under the supervision of a cardiologist. Heart rate (HR), oxygen saturation, and [lactate]b were regularly checked. According to the [lactate]b levels measured, work rate was adjusted for the subsequent endurance exercise session (increase or decrease when [lactate]b was <2.2 mmol·L−1 and >2.8 mmol·L−1, respectively; Fig. 2A). Particular care was taken to ensure adequate hydration. In that sense, staff regularly encouraged patients to drink and continuously proposed fresh water to the cycling patients.
Parameters and Their Calculation/Estimation
The cutoff for the submaximal incremental exercise cessation was set at 4 mmol·L−1 of [lactate]b for safety purposes (see discussion). Theoretical maximal HR (HRmax-theor) was estimated based on Gellish et al. (29), who established HRmax = 207 – 0.7 × age.
Descriptive statistics are expressed as mean ± SE. Statistical significance was set at a risk α < 0.05 (i.e., P < 0.05).
All patients declared that they did not perform any physical exercise other than day-to-day activities (e.g., walking to the bus stop, housework, etc.).
Respiratory, cardiovascular, and metabolic parameters at rest
At rest, respiratory rate (fR), tidal volume (VT), and ventilation (V˙E) were 18.8 ± 1.0 min−1, 0.77 ± 0.05 L, and 14.0 ± 0.9 L·min−1, respectively. HR, systolic blood pressure (SBP), and diastolic blood pressure (DBP) as well as peripheral oxygen saturation (SpO2) were 85 ± 3 min−1 (i.e., 46.0% of HRmax-theor), 118 ± 3 mm Hg, 73 ± 2 mm Hg, and 97.1% ± 0.4%, respectively. Oxygen uptake (V˙O2), CO2 production (V˙CO2), and RER (V˙CO2/V˙O2) were 0.30 ± 0.03 L·min−1, 0.31 ± 0.02 L·min−1, and 1.05 ± 0.04, respectively. [lactate]b was 1.6 ± 0.1 mmol·L−1 (Table 2).
Respiratory, cardiovascular, and metabolic adjustments in response to incremental exercise
At LT1, work rate was 41 ± 3 W. fR, VT, and V˙E were 26.8 ± 2.1 min−1, 1.15 ± 0.08 L, and 28.3 ± 1.0 L·min−1, respectively. HR, SBP, DBP, and SpO2 were 125 ± 3 bpm (i.e., 68.2% of HRmax-theor), 135 ± 4 mm Hg, 82 ± 2 mm Hg, and 96.2% ± 0.6%, respectively. V˙O2, V˙CO2, and RER were 0.74 ± 0.05 L·min−1, 0.79 ± 0.04 L·min−1, and 1.10 ± 0.03, respectively. RPE was 1.8 ± 0.4, and [lactate]b was 2.1 ± 0.1 mmol·L−1 (Table 2).
Exercise completion occurred at 78 ± 5 W for a [lactate]b of ≥4 mmol·L−1 except in two patients who stopped exercise spontaneously complaining of respiratory discomfort and leg pain (at 3.5 and 3.6 mmol·L−1). At exercise completion, fR, VT, and V˙E were 37.1 ± 2.2 min−1, 1.41 ± 0.10 L, and 49.7 ± 2.1 L·min−1, respectively. HR, SBP, DBP, and SpO2 were 155 ± 3 bpm (i.e., 84.6% of HRmax-theor), 168 ± 4 mm Hg, 88 ± 2 mm Hg, and 95.6% ± 0.6%, respectively. V˙O2, V˙CO2, and RER were 1.02 ± 0.07 L·min−1, 1.31 ± 0.07 L·min−1, and 1.28 ± 0.02, respectively. RPE was 5.9 ± 0.7 and [lactate]b was 4.3 ± 0.1 mmol·L−1 (Table 2).
Mean values of physiological parameters measured at different stages in men and women are reported in Table 3.
Figure 1 depicts blood lactate and V˙O2 responses to submaximal incremental exercises in one of our female SCD patient. As an element of comparison, data from active adult and endurance-trained young women are also provided (personal data).
Recovery from incremental exercise
After 2 min of active recovery, fR, VT, and V˙E were 33.2 ± 2.3 min−1, 1.16 ± 0.06 L, and 36.2 ± 1.3 L·min−1, respectively. HR, SBP, DBP, and SpO2 were 134 ± 4 bpm, 164 ± 5 mm Hg, 83.0 ± 2.8 mm Hg, and 96.4% ± 0.6%, respectively. V˙O2, V˙CO2, and RER were 0.70 ± 0.04 L·min−1, 0.90 ± 0.04 L·min−1, and 1.26 ± 0.03, respectively. [lactate]b was 4.9 ± 0.2 mmol·L−1.
During passive recovery, cardiorespiratory parameters decreased progressively. After 8 min of passive recovery (10 min into recovery), fR, VT, and V˙E were 21.0 ± 1.1 min−1, 0.81 ± 0.08 L, and 16.5 ± 1.2 L·min−1, respectively. HR, SBP, DBP, and SpO2 were 97.0 ± 2.5 bpm, 126 ± 4 mm Hg, 74 ± 3.1 mm Hg, and 96.5% ± 0.5%, respectively. V˙O2, V˙CO2, and RER were 0.36 ± 0.04 L·min−1, 0.34 ± 0.03 L·min−1, and 0.96 ± 0.03, respectively. After 8 min of passive recovery, [lactate]b was 3.6 ± 0.2 mmol·L−1. No complications were reported.
Endurance exercise sessions
Table 4 reports data recorded during three endurance exercises sessions. Figure 2B reports all individual [lactate]b levels measured during these three endurance exercise sessions. No complications occurred during exercise or were reported afterward.
The first main finding of the present study was that the proposed strategy of submaximal incremental exercise allowed safe assessment of physical ability in SCD patients. The second important finding was that individually tailored endurance exercise sessions did not result in significant peripheral oxygen desaturation, blood lactate accumulation, or complications.
Protocol strategy: physiological and clinical relevance
Among the parameters indicating the physical deconditioning of SCD patients and their poor adaptation to exercise, one appears particularly critical: the early increase of [lactate]b (5,12). A rise in [lactate]b is accompanied by concomitant acidosis (30), which constitutes a real risk factor for SCD patients. Through the Bohr effect, acidosis favors dissociation of oxyhemoglobin that may trigger the cascade: HbS polymerization, sickling, and VOC. Very recently, Chatel et al. (31) reviewed in detail the deleterious effects of exercise-related acidosis on the pathophysiology of SCD and the possible complications during exercise. In the present study, we paid particular attention to this risk factor, and our protocol was specifically designed to prevent/restrict lactate-associated acidosis. During incremental exercise, [lactate]b increases sharply once 4 mmol·L−1 [lactate]b is reached. This occurs in a very short period, even with mild increases in exercise intensity (32). Furthermore, [lactate]b may continue to increase in the first minutes after exercise cessation (33). This postexercise increase in [lactate]b occurs because of the existence of a muscle-to-blood lactate gradient at exercise cessation, which drives a significant net lactate release from the previously active muscle (34) resulting in the elevation of [lactate]b in the early phase of recovery (33). This rise in [lactate]b must be anticipated because it may aggravate systemic acidosis after exercise completion. Importantly, significant disturbance to the blood acid/base balance is observed once [lactate]b exceeds ~7 mmol·L−1 (35). Therefore, a specific strategy was required to decide when to interrupt incremental exercise to prevent acid/base imbalance. To that end, the following precautions were taken: (i) regular recording of [lactate]b (in the present study, we checked [lactate]b every minute), (ii) extemporaneous testing of blood samples, (iii) a period of sampling time and analysis that was as short as possible, and (iv) anticipation of continued blood lactate accumulation during sample analysis and in the first minutes after exercise completion. In this context, we considered that stopping exercise as soon as 4 mmol·L−1 [lactate]b was reached would constitute a safe protocol to prevent deleterious blood lactate–associated acidosis during and after incremental exercise. Although the measurement of [lactate]b, as opposed to blood pH, might seem unconventional, several arguments led us to this choice. First, we considered, in full agreement with Chaudry et al. (10), the placement of an arterial cannula to be unnecessary and thus unethical. Second, even if an arterialized blood sample had been suitable, sampling and analysis times would have been too long to fulfill the need of a rapid result. Third, the close association between [lactate]b and acidosis is well documented (30,35), so [lactate]b constitutes an ideal surrogate. Fourth, the method we used in the present study is minimally invasive and requires less than 10 μL of blood by sample and 20 s of analysis allowing rapid decision. Finally, the protocol we propose is simple, reproducible, and can easily be replicated almost worldwide.
It is also important to note that our interest in [lactate]b and the 4 mmol·L−1 value was not exclusively driven by developing acidosis. First, rapid elevation in [lactate]b also reflects a reduction in lactate uptake by the liver (36) as [lactate]b approaches 4 mmol·L−1 because of reduced splanchnic blood flow. Given the significant abnormalities reported in viscera in SCD, a reduction of splanchnic blood flow may constitute an additional risk factor we expected to limit by our method. Second, the submaximal nature of the incremental exercise may also contribute to limit/restrict hemolysis, arterial desaturation, hemorheological disturbances, endothelial activation, and oxidative stress known as potential triggering factors of VOC (3,21,22).
Submaximal incremental exercise
LT1 occurred very early (at a low work rate), indicating the particularly poor physical ability of SCD patients. At LT1, none of the physiological parameters measured displayed abnormal values except for RER, which was relatively high, suggesting the need to expel excess CO2, despite normal [lactate]b. The low level of hemoglobin in SCD patients might explain this result. Hemoglobin constitutes an important buffering system, and anemia in SCD patients may increase the share of H+ buffered by blood bicarbonate, leading to excessive CO2 production (V˙CO2) and increase in RER.
At exercise completion, [lactate]b and HR reached 4.30 ± 0.09 mmol·L−1 and 155 ± 3 min−1 (85% of maximal theoretical HR), respectively. Interestingly, analogous HR values were recorded in healthy subjects (158–159 min−1) for similar [lactate]b, at 65%–70% of maximal oxygen uptake (32). This finding demonstrates that at completion, exercise was still submaximal in the present study. Similarly, RPE reported at exercise completion was 5.9 ± 0.7, with exhaustion expected at 10. However, some physiological parameters recorded at exercise completion were approaching critical levels. This was the case for RER (vide supra), SBP, and fR. These latter results reinforce our choice of a submaximal incremental exercise protocol. Furthermore, in the context of SCD, it is also important to consider SpO2 during exercise. Desaturation increases adherence of sickle erythrocytes to endothelium, sickling, and, hence, the risk of VOC (4). In the present study, 12 patients presented SpO2 values >95% at exercise completion, 5 patients presented values ≥93% and ≤95%, and 2 patients exhibited SpO2 values of 89% and 90%. Most of the patients did not present desaturation (defined as a decrease in SpO2 > 3%) in response to exercise, except for two patients for whom SpO2 dropped by 5% (from 98% to 93%) and 10% (from 99% to 89%). For these two patients, exercise completion at that point seemed warranted.
As expected, peak [lactate]b occurred during the early phase of recovery. The highest value recorded was 6.1 mmol·L−1. This shows that our strategy to prevent high levels of blood lactate accumulation was adequate. No complications occurred after exercise cessation or within the following 5 d, suggesting that this type of exercise was safe.
Endurance exercise sessions
The blood lactate curve traced during incremental exercise provides useful information in managing endurance exercise intensity (37). During endurance exercise below and up to the intensity of the LT1, blood lactate concentrations remain low, close to the resting level (37). At these low exercise intensities, exercise is safe and sustainable/feasible for pathophysiological patients, including in SCD (19,20). However, at such exercise intensities, the stimulus for muscle adaptations is rather limited. Beyond the workload corresponding to 4 mmol·L−1, lactate accumulates (37) and acidosis develops (33), which is highly deleterious (31). For these two reasons (to avoid acidosis and to sufficiently stimulate pulmonary, cardiovascular, and muscle adaptations), we chose a training intensity between the LT1 (1.8–2.0 mmol·L−1) and the 4 mmol·L−1 cutoff (which delineates an unsteady state in [lactate]b) already discussed. Furthermore, because (i) a [lactate]b of ~2.5 mmol·L−1 is a common target intensity used for endurance training, (ii) in very untrained subjects, to not say totally deconditioned/unfit patients, it would have been probably unfeasible to sustain 30 min of endurance exercise at higher intensity (for instance at 3.5–4 mmol·L−1), we hypothesized that exercising for 30 min at ~2.5 mmol·L−1 may constitute adequate endurance training sessions in SCD patients. However, it remained to test the feasibility and the safety of the proposed endurance exercise sessions in SCD patients.
All [lactate]b measurements taken during endurance exercises were lower than 4 mmol·L−1. Furthermore, SpO2 remained within an acceptable range. SpO2 was ≥94% except (i) in three patients during the first endurance session who displayed SpO2 of 92% and (ii) in one patient during the second session who displayed SpO2 of 93%. For the third session, none of the patients displayed SpO2 lower than 94%. Finally, HR and RPE values clearly indicate the acceptable, sustainable, and feasible nature of endurance exercise. No complications took place after exercise cessation or within the following 5 d. As a whole, the data from this study suggest that patients with SCD may undertake moderate-intensity endurance exercise without significant blood lactate accumulation, peripheral oxygen desaturation, or complications, confirming previous studies which found that low-intensity endurance exercise appears feasible and safe for SCD (19,20).
Recommendations for further research and exercise testing in SCD patients
On the basis of the feasibility and apparent safety of endurance exercise sessions performed in the present study, we are confident in the possibility of conducting a moderate-intensity endurance training program in patients with SCD. However, we noticed significant variation in the physical/physiological condition of the patients from one day to the next (often related to changes in weather, fatigue, and stress), so we would recommend monitoring/checking HR, [lactate]b, and/or SpO2 at each exercise session. On the basis of exercise sessions and empirical precautionary adjustments to work rate, one possibility is to adjust exercise intensity from one session to the next as per the strategy depicted in Figure 2A. The purpose of this strategy is to keep endurance exercise as safe as possible, while allowing sufficient stimulation to induce pulmonary, cardiovascular, and muscular adaptations. Particular care must always be taken to keep patients hydrated before, during, and after exercise (6).
In the present study, [lactate]b was checked every minute as a safety procedure, and it turned out it was an appropriate strategy because [lactate]b increased early and relatively abruptly (Fig. 1). This strategy is all the more recommended as patients are living and tested in mild or moderate altitude where the risks for the patients seem to be increased (38). On the basis of our experience and the results of the present study, an adapted version of the submaximal incremental exercise protocol used here might be implemented. In that sense, women and men might start the submaximal incremental exercise at 15 and 30 W, respectively, and increase the power output every minute by 5 W. LT1 would be reached in ~4–6 min and exercise completion (4 mmol·L−1 cutoff) would occur in ~8–12 min of exercise in both sexes.
One limitation of the present study is that this protocol was applied to a small population of adult SCD patients without severe complications. Further studies would be necessary to document the feasibility and interest of this approach/protocol to a larger and wider population including more severe patients. Along the same line, there is no evidence that this protocol is adapted for children. In healthy subjects, physiological adaptations to exercise (e.g., HR, oxygen uptake kinetics, and lactate accumulation) as well as muscle characteristics (e.g., glycolytic and oxidative enzymes) are different in children (39), and it is probable that differences also exist between adult and young SCD patients. Further studies in children will be necessary.
The first main finding of the present study was that the proposed strategy of submaximal incremental exercise constituted a safe procedure to assess parameters indicative of physical ability of SCD patients, including the LT1. The second important finding was that physical ability of the SCD patients was particularly low. Finally, 30-min moderate-intensity endurance exercise sessions did not lead to significant peripheral oxygen desaturation, blood lactate accumulation, or complications and, therefore, appeared safe. These results suggest that endurance training programs might be prescribed to adult SCD patients and that the method proposed in the present study may be helpful in that regard.
This study is part of a larger experiment. Part of the results presented here have been submitted for publication elsewhere for other purpose (Gellen et al., unpublished data).
This study was supported by grants from the association L’Harmony, the French Cardiology Society, and the IRMES (INSEP Paris), which support the present research.
The authors thank all the patients for their interest and voluntary participation in the study.
L. A. M., B. G., F. G., P. B., and L. F. designed the study. J. B., F. G., and P. B. included the patients. L. A. M., B. G., S. P., T. R., J. M., A. P., P.B., and L. F. and L. F. performed the experiment and the data acquisition. L. A. M. and R. L. analyzed the data. L. A. M. drafted the work. L. A. M., B. G., R. L., S. P., T. R., J. M., A. P., J. B., F. G., P. B., and L. F. critically revised and approved the present version of the manuscript.
The authors declare no conflict of interest or financial interests. The results of the present study do not constitute endorsement by the American College of Sports Medicine. The results of the study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation.
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