Beneficial effects of intradialytic cardiopulmonary rehabilitation

Introdução: Pacientes em hemodiálise (HD) têm alta mortalidade e morbidade por complicações cardiovasculares, inclusive por redução da capacidade funcional e qualidade de vida. Objetivo: Analisar a evolução clínica e laboratorial de pacientes em HD ambulatorial submetidos à reabilitação cardiopulmonar (RCP) intradialítica. Métodos: Avaliamos 14 pacientes em um estudo prospectivo por 8 meses, utilizando protocolo de RCP com exercícios aeróbicos intradialíticos. Analisamos frequência cardíaca (FC), pressão arterial sistólica (PAS) e diastólica (PAD), saturação periférica de oxigênio (SpO2) e escala de Borg modificada em todas as sessões de HD. Avaliamos função cardíaca por ecocardiograma, capacidade funcional (CF) pelo teste de caminhada de seis minutos (TC6M), e qualidade de vida pelo Questionário SF-36, antes e depois da RCP. Dados bioquímicos e de Kt/Vsp foram coletados dos prontuários. Resultados: Durante a RCP, os resultados de FC, PAS, PAD, SpO2 e escala de Borg não mostraram alterações significativas. No TC6M observamos aumento progressivo da distância percorrida (p < 0,001) e redução na escala de Borg pós-TC6M entre D0-D180 (p = 0,009). Não houve alteração significativa nos testes bioquímicos e no KT/Vsp. Houve aumento na fração de ejeção de 65,7 ± 10,2 para 73,6 ± 10,1% (p = 0,028) e no diâmetro diastólico do ventrículo esquerdo (p = 0,027). No questionário SF-36, houve melhora significativa nos domínios: limitação física (p = 0,012), dor (p = 0,007) e vitalidade (p = 0,009). Conclusão: A RCP intradialítica nesta população foi segura e permitiu melhora objetiva da CF e tolerância ao exercício, melhora subjetiva na percepção do esforço, aumento significativo da função cardíaca, bem como melhoria na qualidade de vida em diferentes domínios. Resumo


IntRoductIon
Malnutrition and chronic inflammation of chronic kidney disease (CKD) patients on hemodialysis are closely related to muscle mass loss, with resulting decrease in the ability of routine daily activities. 1 As a consequence, in the last decade the use of CRehab in HD patients has been increasily considered. 2 However, although the majority of CRehab programs have been applied in the periods between dialysis (interdialytic period), 3 exercise during HD (intradialytic program) may be of significant impact. 2n general, intradialytic exercise is recommended for the first two hours of HD as cardiovascular instability with nausea and vomiting may occur beyond the third hour, which may affect the regularity of training.Despite evidences pointing to clear benefits of aerobic exercises for HD patients, this practice is not routinely employed in this population, differently from what is applied to chronic pulmonary obstructive disease and heart failure. 3Therefore, the present study attempted to evaluate the impact of a medium term aerobic intradialytic program, on the functional capacity, quality of life, exercise tolerance and heart function of stable renal patients on a regular HD program, methods This is a prospective, non-randomized study, involving stage 5D CKD patients on a regular HD program.Patients above 18 years old, on HD (4 hours, 3 times a week) for at least 6 months, and using arteriovenous fistula were included.Patients with cardiovascular disease, neurological, musculoskeletal and any other disability that would preclude the use of cycle ergometer or active inflammatory/infectious disease in the last 6 months, and patients becoming acutely sick needing hospitalization, were all excluded.
The initial population was composed by 24 eligible patients followed between 2011 and 2015.From these selected patients, 4 patients needed hospitalization, 1 was transplanted, 1 was transferred to another unit, 1 relapsed systemic erythematous lupus and 3 dropped out for particular reasons, with 14 patients remaining for the entire study period.

Study deSign
Patients were evaluated during 3 phases with total length of 240 days.All were submitted to transthoracic echocardiography, functional capacity evaluation by walk test of six minutes (6MWT, m) 4 and SF-36 quality of life Survey (SF-36). 5Laboratory data were collected from medical records.The 3 phases are described in Figure 1.Phase II: Total of 120 days with intradialytic CRehab in all HD sessions.The CRehab was performed, beginning after the first hour of HD.During the procedure the patients were monitored for arterial systolic (SBP) and diastolic (DBP) blood pressure, heart rate (HR), peripheral oxygen saturation (SpO 2 ) measured by usual oxymeter (Octivetech 300C, Clinical Guard, Atlanta, USA) and modified Borg scale, 6 all in 4 moments (0, 10, 20 and 30 min).The 6MWT was performed at day 180.
Phase III: Total of 60 days without intradialytic CRehab.Patients were regularly dialyzed and submitted to routine Lab tests, ECHO and SF-36.The 6MWT was performed at day 240.

intradialytic crehab protocol
According to National 7 and International 8,9 guidelines for CRehab, the patients were submitted to aerobic exercise in lower limbs for 30 minutes.The use of the cycle ergometer (Original Pedlar, Battle Creek, Fremont, USA) for CRehab was always initiated after the first 60 minutes of HD.On some patients with lower functional capacity according to 6MWT, the weekly progression of time was introduced until reaching the total time of 30 minutes.In order to define the dose of the exercise, the Karvonen formula was applied to calculate the training heart rate (THR), through a maximal heart rate (MHR) 10 and using 50-80% of reserve heart rate (RHR). 11In addition, to assure patient safety during the procedures, the modified Borg scale was used each 10 minutes for measuring the effort perception.

Functional capacity (Fc) test
The evaluation of functional capacity was performed using 6MWT in the interdialytic period according to the American Thoracic Society and European Respiratory Society Recommendations. 4 The test could be stopped in case of thoracic pain, shortness of breath, cramps, paleness or dizziness.Before and after the procedure, vital signs, Borg scale and SpO 2 were examined.In case the patients presented high levels of SBP (> 180 mmHg) and or DBP (> 110 mmHg), the test would not be done.

laboratory teStS, cardiac function and quality of life
Data for serum biochemistry, hemoglobin, electrolytes and C-reactive protein (CRP) were obtained from routine Lab tests.The values for KT/V were calculated from usual formula 12 for days 0, 60, 180 and 240.The evaluation of cardiac function was done using thoracic bidimensional echocardiography (Acuson X300, Siemens, München, Germany).The following parameters were described: left ventricle systolic (LVSD) and diastolic (LVDD) diameter; left ventricle posterior wall (LVPW); ejection fraction (EF).The SF-36 5 was used for quality of life evaluation.

StatiStical analySiS
All the values obtained were presented as mean ± standard deviation (SD) or median (interquartile interval: 25%, 75%) according to symmetric or asymmetric distribution of variables.The values were analyzed by Student`s t test (paired and non-paired) for quantitative symmetric distribution, and Mann-Whitney and Wilcoxon for asymmetric distribution variables.Such tests were used for 2-groups comparison.For comparative analysis of 3 or more groups, one-way ANOVA repeated measures was used for symmetric distribution and Friedman test for asymmetric distribution variables.Holm-Sidak was used for comparison between pairs of groups as post-test.Results were considered significant when p < 0.05.

Results
A total of fourteen patients, being 8 women and 6 men, were evaluated.Mean age was 50.2 ± 15.2.The patients were ethnically diverse with 3 white, 8 black and 3 brown or mulattos.The causes of renal diseases were as follows: arterial hypertension (6), diabetes mellitus (4), chronic glomerulonephritis (2), unknown (2).Mean time on HD was 23 ± 10 months.Body weight (kg) and BMI (kg/m 2 ) were not significantly different comparing before and after the study (67 ± 22 and 66 ± 18 kg, 22 ± 12 and 21 ± 10, respectively).The results from blood tests and KT/Vsp values are expressed in Table 1 for the periods D0, D60, D180 and D240.There was no significant difference among all these parameters.
Table 2 depicts all vital signs, modified Borg scale and SpO 2 with data from all HD sessions at each 10 minutes during intradialytic CRehab.There was no significant alteration observed in all parameters analyzed.Figure 2 describes the results for FC test as analyzed by the distances covered during 6MWT.It was observed a significant increase of the covered distance in the CRehab period.
On the other hand, after CRehab interruption (D180 to D240), there was a significant decrease of covered distance.It is noteworthy that at day 240, the patients were still able to walk for longer distance when compared with moments D0 and D60.Table 3 shows comparative analysis of HR, SpO 2 and Borg scale at pre and post 6MWT on periods D0, D60, D180 and D240.Values of HR showed significant increase between pre and post 6MWT, at all moments, except on D60.
However, when analyzing pre-test moments, a significant decrease was observed between moments D0 and D240 (p = 0.009) and between D60 and D240 (p = 0.01).Values for modified Borg scale were all different when comparing pre and post 6MWT.The comparison between moments pre-test revealed that the values were not significantly different, whereas on moments post-test there was a significant reduction between moments D0 and D180 (p = 0.009).
The values for SpO 2 did not show significant difference between values pre and post in all moments.However, when comparing pre-test values, we observed significant increase between moments D60 and D240 (p = 0.009).The post-test values were different  when moments D0 and D180 were compared (p < 0.05).The results pointed to a progressive decrease in the values of HR and Borg scale pre 6MWT on the periods examined.The echocardiographic data revealed significant increase in left ventricular diastolic diameter (LVDD) and ejection fraction (EF) when comparing pre and post CRehab moments (D0 and D180).Results from SF-36 survey also demonstrated increased domains for physical role functioning, bodily pain and vitality.Results of cardiac function from ECHO and SF-36 are depicted on Table 4.

dIscussIon
Chronic renal patients on HD present considerable less functional capacity when compared to normal subjects, which directly impacts on morbidity and mortality. 13,14In addition, the sedentary behavior, normally adopted by renal patients on dialysis, may contribute to the decline on physical activity, generating functional incapacity and inactivity. 15The present study attempted to apply an intradialysis CRehab program in order to examine the effect of the proposed procedure on physical conditioning, including cardiac function and psychosocial aspects linked to the quality of life.Historically, the first CRehab for patients on dialysis was applied and described by Goldberg et al.
in 1983 16 with beneficial results for arterial pressure control and serum hemoglobin levels.Ever since, several studies have been done using different modalities of exercises between sessions of HD, with interesting results on functional capacity, cardiac function and arterial pressure control, anemia and quality of life. 17,18n hemodialysis patients, the majority of CRehab programs have been applied in the interdialytic period.Nevertheless, it has been suggested that the intradialytic exercise can be more beneficial since it might promote better clearance of solutes due to increased blood flow systemically. 2,3,19,20Our results on arterial pressure control revealed no change on regular levels previously recorded from the patients, although there was a tendency to decrease the levels.These results are in variance with previous studies that showed significant decrease on baseline SBP and DBP in protocols using 4 to 7 months of CRehab. 16,17,21,22In only one study, however, the protocol was applied for a period of 3 months. 23he 6MWT used in our study to examine FC is accessible and cost-effective, given the possibility of correlation between covered distance and the peak VO 2 . 17,24Our study showed a significant improvement on functional capacity of HD patients, as seen by the increase of distance covered.][27][28] On the other hand, the study by Segura-Ortí et al. 27 , was not able to show a better FC using the same test, albeit close assessment of supervision during CRehab by the physiotherapist.By contrast, in the studies by Koh et al. 28 and Fitts, 29 there could not be observed better FC, although supervision during CRehab did not occur.Other aspects on the evaluation of FC using 6MWT deal with SpO 2 , HR and modified Borg scale.These parameters were only examined in the study by Reboredo et al., 30 which was in agreement with our results showing reduction on modified Borg scale in the post-test moments.
The analysis of clinical laboratory data did not reveal significant findings when comparing all moments.In addition, data of KT/Vsp were not significantly different after CRehab, which opposes data from other studies showing increases from 11 to 38%. 17,23,30,31The studies by Momeni et al. 32 and Musavian et al. 33 and showed significant reduction of serum potassium after 16 and 12 weeks of CRehab, respectively.Likewise, Goldberg et al. 16 observed a significant increase of 29% on serum hemoglobin, while in the study by Musavian et al. 33 the increase was up to 0.6 mmol/L.
Regarding the results on serum levels of calcium, phosphorus and sodium, to our knowledge, no study showed significant alterations.In addition, two recent studies have examined these electrolytes, with no relevant results. 34,35Finally, the results on serum CRP levels were shown to decrease after an 8-week protocol in 21 patients. 36Our results did not show this decrease on CRP and this cannot be explained at this moment.Nevertheless, one can consider that different results may be accounted by the different populations examined.
In the present study we documented a clear significant improvement on cardiac function as we could observe an increase in LVDD and EF after CRehab (Table 4).In fact, few studies have examined cardiac function using ECHO after this protocol.The previous study by Deligiannis et al. 21applied intradialytic aerobic exercises during 3 months for 30 minutes with 60 to 70% MHR and observed increase of EF.In addition, Momeni et al. 32 used the same protocol of the group of Deligiannis et al. 21observed increase of EF, systolic and diastolic VE function.
The explanation for these results may reside on better conditioning of the heart with adaptation to aerobic exercise, regularly observed in normal individuals.Moreover, the patients of this study presented arterial pressure in the normal range before the procedures (Table 2), and also EF levels on normal values (Table 4).All these results give support to the notion of preserved ventricular mass, still able to react as into Frank Starling mechanism of adaptation to the proposed exercise stress and aerobic demand.
Finally, the results on the evaluation of quality of life by SF-36 survey demonstrated that CRehab protocol was of great benefit as it promoted a significant improvement in three domains: physical role functioning, bodily pain and vitality (Table 4).Previous studies from other groups also encountered positive results with the same domains. 2,17,22,37Among these studies, only two of them presented significant results on emotional role function and general health perception. 22,37In fact, one can speculate about the new feeling of well-being after the progress achieved on physical conditioning and true cardiac function improvement.Nevertheless, more specific studies are needed to address this issue.
In conclusion, the present study applying a proposed cardiopulmonary rehabilitation intradialytic protocol to patients on hemodialysis, with controlled supervised aerobic exercises, clearly demonstrated a beneficial effect on functional capacity, cardiac function with increase of EF and LVDD, and subjective signs of improvement on quality of life.These findings strongly suggest that a careful, supervised program of cardiopulmonary rehabilitation on renal patients on dialysis may be more intensively applied in order to decrease the incidence of cardiovascular morbidity and mortality, and to improve the quality of life of these patient population.

Figure 2 .
Figure 2. Comparison of distance covered during the 6min Walk Test in different moments of rehabilitation (baseline, 60 days, 180 days and 240 days).Statistical analyses were performed by Holm-Sidak test pos-repeated measured ANOVA.

tAble 1
laboratory parameterS and hd doSe (kt/vSp) at different timeS of the Study (baSeline, 60 dayS, 180 dayS, 240 dayS)

tAble 3
compariSon between clinical parameterS hr (heart rate), Spo 2 (peripheral oxygen Saturation) and borg Scale pre e poSt 6min walk teSt in different momentS (baSeline, 60 dayS, 180 dayS and 240 dayS) Results expressed in mean ± standard deviation or median (25%;75%) according to symmetric or asymmetric distribution of variables.Statistical analyses were performed by paired t-test or Wilcoxon signed rank test.

tAble 4
parameterS of echocardiogram and Sf-36 Survey befrore and after rehabilitation = left ventricular diastolic diameter; LVSD = left ventricular systolic diameter; LVPW = left ventricular posterior wall diameter; EF = ejection fraction.results expressed in mean ± standard deviation or median (25%;75%) according to symmetric or asymmetric distribution of variables.statistical analyses were performed by paired t-test teste t or Wilcoxon signed rank test. LVDD