Abstract
Intradialytic cardiac output (CO) decline normally occurs during hemodialysis (HD) and results in short-term intradialytic hypotension to longer-term increased cardiovascular morbidity and mortality in chronic HD patients. Enhanced external counter pulsation (EECP) is a novel non-invasive device that has been demonstrated to improve coronary blood flow and maintain systemic hemodynamics in patients without kidney dysfunction. This study is the first to explore the efficacy and safety of EECP application during HD on intradialytic changes of CO and other hemodynamic parameters. Stable chronic HD patients without recent cardiovascular events were randomly allocated to the EECP group (n = 7) receiving a single session of 60-min EECP therapy at the early period of 4-h online hemodiafiltration (HDF), and the control group (n = 7) obtaining standard 4-h online HDF without EECP. Interval measurements of intradialytic CO by Transonic HD03 device, intradialytic central aortic blood pressure (BP) by AtCor Medical SphygmoCor-XCEL device, and heart rate (HR) in the mid-week HD sessions were conducted. Changes in these parameters were compared with a linear mixed model. CO of the patients in the EECP group was maintained throughout the HDF session compared to a significant CO decline of 2.4 L/min after 4-h HDF in the control group (p-value 0.007). Cardiac index (CI) also changed in the same direction as CO. Central systolic BP, central diastolic BP, central mean arterial pressure, and HR were indifferent between the two groups. In 9 patients continuing the study in the subsequent 36 HDF sessions, there was a trend to prevent the increase in high-sensitivity cardiac troponin I by long-term EECP treatment. No intolerable adverse events related to EECP were reported. EECP application during online HDF could maintain CO, CI, and might reduce the risk of HD-related myocardial ischemia through various proposed mechanisms, including promoting coronary perfusion. However, larger studies on other cardiovascular outcomes are warranted.
Supplementary Information
The online version contains supplementary material available at 10.1038/s41598-025-19077-5.
Keywords: End stage kidney disease, Hemodialysis, Enhanced external counter pulsation (EECP), Cardiac output, Cardiac index, Central aortic blood pressure
Subject terms: Haemodialysis, Cardiac device therapy
Introduction
To date, the prevalence of end stage kidney disease (ESKD) requiring kidney replacement therapy (KRT) has risen markedly and results in decreased quality of life, poor survival, and increased economic burden1,2. Hemodialysis (HD), the most prescribed KRT modality, is unique in causing short-term intradialytic blood pressure fluctuation and long-term high cardiovascular events and mortality due to the intermittent and non-continuous nature of solute and volume removal compared to peritoneal dialysis or kidney transplantation3–5. Physiologically, during each HD session, cardiac output has been shown to progressively decrease from the beginning to the end of HD, which is correlated with the ultrafiltration rate6,7. This hemodynamic change partly contributes to the occurrence of intradialytic hypotension (IDH) in some patients, which has been demonstrated to be associated with various adverse outcomes, some of which could be fatal, including disturbing symptoms, inadequate dialysis, vascular access thrombosis, loss of residual kidney function or cardiovascular events8. The long-term consequence of repeatedly reduced cardiac output (CO) episodes, despite the absence of obvious decreases in blood pressure, could lead to an accelerated degenerative change of many organs in HD patients, so-called hemodialysis-induced multiorgan ischemia, including the brain, intestine, and myocardium9–11. The most-studied organ ischemia in HD patients is subclinical myocardial ischemia or myocardial stunning from decreased coronary perfusion as a consequence of decreased CO during HD, which might contribute to increased cardiovascular mortality in HD patients in addition to traditional cardiovascular risk factors such as diabetes, obesity, and smoking7,12.
This CO decline and reduced coronary perfusion have been a major challenge in HD patients. Although there was a study demonstrating that hemodiafiltration (HDF) modality can reduce the incidence of IDH and result in hemodynamic stability during the session, as compared with conventional HD, CO still declines significantly throughout the HDF session and is not different from that of the conventional HD7,13. In patients who developed IDH refractory to standard therapy, mechanical intervention such as non-invasive external pneumatic pressure cuffs around the lower extremities has been explored with satisfactory results in these patients14. However, the device applied a cuff pressure that did not synchronize with the cardiac cycle, so the mechanism might be mostly due to the increased venous return. If external cuff pressure is combined with the cardiac cycle, there could be an additional positive effect on CO from improved cardiac function. This is the rationale for a novel device called enhanced external counter pulsation (EECP). The principle of this equipment is that the inflatable cuffs applied around the thigh and leg can inflate or deflate synchronously with a cardiac cycle guided by an electrocardiogram. In the diastolic phase, the cuff inflates sequentially from the distal leg to the proximal thigh, in order to increase central aortic blood flow and central aortic blood pressure, the so-called ‘diastolic augmentation’. In the end-diastolic to systolic phase, the fully inflated cuffs deflate rapidly in all parts to decrease systemic vascular resistance (SVR), which could finally decrease the cardiac energy demand. Physiological benefits of EECP include increased cardiac output, decreased cardiac ischemia, increased vascular wall shear stress, decreased vascular inflammation, and decreased SVR15.
Considering the beneficial effects of EECP on both cardiac and peripheral vascular functions16. The device has been successfully introduced as adjunctive therapy in patients with cardiovascular disease for decades with the established protocol of a 35-h course (1 h per day for 35–36 days for a duration of 6-weeks) in patients without contraindications15. Theoretically, the mechanism of EECP application could maintain hemodynamic tone, ameliorate CO decline during HD or HDF, and decrease cardiac dysfunction in these patients. Nevertheless, previous clinical studies on a classic EECP device in patients with kidney disease are scarce, and none of the studies exploring the effect of this device on hemodynamic change during HD17. Our study aimed to investigate the hemodynamic maintaining effect of EECP in patients receiving maintenance online HDF, which could be the initial step to maximize the benefits of this device among these patients.
Methods
Participants
All prevalent stable patients with HD three times a week in the HD unit of King Chulalongkorn Memorial Hospital with arteriovenous vascular access between December 2019 and March 2020 were screened and included in this open-label randomized controlled trial. Patients included must be in euvolemic status, as confirmed by the dry weight confirmed by the bioelectrical impedance analysis, which is routinely conducted in our center, and should achieve adequate dialysis as assessed by Kt/V18. We excluded pregnant patients and those with recent or active cardiovascular diseases, including obstructive heart disease, atrial flutter, atrial fibrillation, severe or unstable conditions requiring specific therapy, and patients who might be at risk from EECP therapy such as significant vascular disease of the lower extremities, bleeding diathesis, uncontrolled hypertension, or aortic aneurysm (Supplementary Table 1). To achieve this comprehensive screening, all potential eligible patients received a detailed clinical evaluation, echocardiography, and abdominal ultrasonography within 1 year before enrollment.
Randomization and intervention
After screening, consecutive subjects were randomly assigned in a 1:1 ratio using a simple random method to an EECP group or a control group. Patients in the EECP group received a single session of EECP application (PSK-Health Sci-tech Development, Chongqing, China) within the second hour of the online HDF session using compression pressure of 300 mmHg synchronized with the cardiac cycle for 60 min, based on physiologically favorable cuff pressure from a previous study19, after stabilization of hemodynamics and clinical evaluation in the first hour. The midweek HDF session was chosen in the study due to its stable volume status20. Patients in both groups received standard therapy that included routine laboratory monitoring, proper medication, and nutritional counseling from physicians and nutritionists. HD modality utilized in our center is a post-dilution online HDF with Fresenius 5008H (Fresenius Medical Care, Bad Homburg, Germany) machine and reused high-flux dialyzer for all patients. The investigator who analyzed the data was blinded to the allocated group. After completing the investigational session, patients in the EECP group were invited to continue the intervention in subsequent HD sessions in a ‘extension phase’ for a total of 36 sessions according to the original established 36-h EECP protocol in the general population. Pre-dialysis high-sensitivity cardiac troponin I (hs-TropI) was measured in the 18th and 35th EECP sessions in the patients in this extension phase along with the regular blood drawn for other HD laboratory measurements without additional cost. Hs-TropI was also measured in patients in the control group who were willing to participate in the extension phase in the same interval after the initial trial. This study has been approved by the institutional review board and all methods were performed in accordance with the relevant guidelines and regulations. The clinical trial registry number for this study is NCT06608953 (registration date 23/09/2024). Informed consent was obtained from all included patients.
Outcomes and measurement
Changes in cardiac output (CO), cardiac index (CI), central blood pressure, and heart rate (HR) compared to values at the start of online HDF were compared between the groups. We measured all outcomes at the start of online HDF, at the 60th minute (before applying EECP in the EECP group), at the 90th minute (30 min after applying EECP in the EECP group), at the 120th minute (after completing EECP therapy in the EECP group), and at the end of the session. CO and CI were determined by an ultrasonic dilution technique following the standard protocol via arteriovenous access with a Transonic HD03 monitor4. Central aortic blood pressure was measured peripherally and calculated with programmed equipment by AtCor Medical SphygmoCor-XCEL (Fig. 1) under a controlled condition stated by a previous study21. Hs-TropI was measured by the hospital central laboratory with a standardized electrochemiluminescence immunoassay. Any adverse events and episodes of intradialytic hypotension in the study period were collected.
Fig. 1.
Application of an Enhanced External Counter Pulsation Device (EECP) and Other Measurement Equipment during the Hemodialysis Session (Hemodiafiltration Mode) (A) and a Diagram Explaining the Application of EECP in a Hemodialysis Patient (B).
Statistical analysis
Categorical data, normally distributed continuous data, and non-normally distributed continuous data were presented in frequency (percentage), mean (standard deviation), and median [interquartile range], respectively. Repeated measurements of hemodynamic parameters throughout the HDF session were compared with the linear mixed model. Sample size calculation for repeated measurements with the web-based program GLIMMPSE based on cardiac index data from previous literature, assuming normal distribution, and power of 80%, revealed at least 14 subjects for the study6,22. The statistical tests were conducted by STATA version 15 with a significant p-value of less than 0.05.
Results
Baseline characteristics
Of 27 eligible patients, 13 were excluded due to their comorbidities, uncontrolled blood pressure, bleeding diathesis, abnormal echocardiography, or presence of abdominal aortic aneurysm (Supplementary Fig. S1). Patients in the EECP group were younger, comprised of more males, had higher body weight, had more left atrial volume, and had more left ventricular volume with a slightly lower stroke volume index. More diastolic dysfunction was present in the control group. Other baseline characteristics were comparable in both groups, as shown in Table 1. No subject with moderate to severe valvular disease was included in the study. All patients achieved the target weight at the end of the study session.
Table 1.
Baseline characteristics of the included subjects. Categorical data, normally distributed continuous data, and non-normally distributed continuous data were presented in frequency, mean (standard deviation), and median [interquartile range], respectively.
| EECP group (N = 7) | Control group (N = 7) | Total (N = 14) | |
|---|---|---|---|
| Age, year | 56 [39, 68] | 65 [52, 72] | 57 [52, 71] |
| Men, number | 4 | 2 | 6 |
| Comorbidity or primary kidney disease, number | |||
| Diabetes | 2 | 2 | 4 |
| Hypertension | 5 | 5 | 10 |
| Dyslipidemia | 3 | 3 | 6 |
| ADPKD | 1 | 2 | 3 |
| History of coronary CAD | 1 | 2 | 3 |
| History of heart failure | 0 | 1 | 1 |
| History of stroke | 0 | 3 | 3 |
| Dry body weight, kg | 64.2 [53.6, 65.5] | 53.6 [48.4, 61.0] | 55.2 [51.0, 64.5] |
| Ultrafiltration of the studied hemodialysis session, L | 2.35 (0.94) | 2.13 (1.02) | 2.24 (0.92) |
| Ultrafiltration rate of the studied hemodialysis session, mL/kg/h | 9.8 (4.0) | 9.4 (4.8) | 9.6 (4.2) |
| Laboratory parameters | |||
| Hemoglobin, g/dL | 10.1 (2.2) | 10.9 (2.2) | 10.5 (2.1) |
| Serum albumin, g/dL | 4.1 (0.2) | 3.8 (0.3) | 3.9 (0.3) |
| Serum sodium, mmol/L | 139 (1) | 141 (2) | 140 (2) |
| Serum potassium, mmol/L | 4.8 (0.7) | 4.3 (0.9) | 4.5 (0.8) |
| Serum phosphate, mg/dL | 3.8 (0.8) | 4.4 (0.7) | 4.1 (0.8) |
| Serum calcium, mg/dL | 9.3 (0.5) | 8.9 (0.7) | 9.1 (0.6) |
| Serum bicarbonate, mmol/L | 25 (3) | 24 (2) | 24 (2) |
| hs-Troponin I (ng/L) | 28.7 [19.3, 66.9] | 18.9 [14.1, 28.3] | 19.4 [16.3, 52.4] |
| Medications, number | |||
| ACEI/ARB | 2 | 3 | 5 |
| Dihydropyridine CCB | 3 | 3 | 6 |
| Beta-blockers | 3 | 4 | 7 |
| Alpha-blockers | 2 | 2 | 4 |
| Initial systolic blood pressure, mmHg | 135 (10) | 130 (23) | 133 (18) |
| Initial diastolic blood pressure, mmHg | 83 (8) | 75 (11) | 79 (10) |
| Initial heart rate, beats per minute | 75 (17) | 72 (14) | 73 (16) |
| Echocardiographic parameters | |||
| LV ejection fraction (%) | 56 (7) | 64 (5) | 61 (7) |
| Stroke volume index (mL/m2) | 43.0 (12.4) | 49.6 (5.1) | 46.9 (9.3) |
| Diastolic dysfunction and grade, n | 1 (grade II) | 3 (2 with grade I, 1 with grade II) | 4 (2 with grade I, 2 with grade II) |
| LV mass index (g/m2) | 151.1 (47.2) | 148.0 (35.8) | 149.3 (40.7) |
| LV diastolic internal diameter, cm | 5.3 (0.1) | 4.5 (0.7) | 4.8 (0.6) |
| LV systolic internal diameter, cm | 3.7 (0.3) | 2.8 (0.5) | 3.1 (0.6) |
| Left atrial volume index, mL/m2 | 63.8 (15.6) | 36.2 (12.2) | 47.2 (19.2) |
ACEI angiotensin converting enzyme inhibitor, ADPKD autosomal dominant polycystic kidney disease, ARB angiotensin receptor blocker, CAD coronary artery disease, CHF congestive heart failure, EECP enhanced external counter pulsation, hs-Troponin I high-sensitivity troponin I, LV left ventricle.
Changes in CO and CI
In the control group, CO and CI decreased significantly from the start to the end of the HDF session at a rate of 0.6 L/min/h (95% confidence interval 1.0–0.2 L/min/h) and 0.4 L/min/m2/h (95% confidence interval 0.6–0.1 L/min/m2/h), respectively. As a result, CO and CI at the end of the HDF session were 2.4 L/min and 1.6 L/min/m2, both of which were lowered than the initial values without EECP application. In the EECP group, CO and CI were relatively stable across the study session with the p-value of difference from the control group of 0.007 and 0.015, respectively (Fig. 2).
Fig. 2.
Results of the linear mixed model that demonstrate cardiac output, cardiac index, systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate changes from baseline throughout a single hemodialysis (HD) session in the control group and the experimental group receiving enhanced external counter pulsation (EECP) application in the early hour of the HD session. The 95% confidence interval bars are also shown. The EECP application time in experimental group was between hour 1 and hour 2 of the HD sessions (red bar). (*) represents the difference between groups with a p-value of less than 0.05.
Changes in central aortic blood pressure and heart rate
As shown in Fig. 2, central systolic blood pressure was slightly lower, and central diastolic blood pressure and heart rate were slightly higher in the EECP group, although they did not reach a statistically significant level. There were 2 records of ultrasonic blood volume monitoring by the Fresenius 5008H machine in 2 patients from the EECP group, as shown in Supplementary Fig. S2, which demonstrated amelioration of blood volume decline during the EECP application in one patient but not demonstrated in another.
Change in Hs-TropI after 35 EECP sessions
Nine patients (4 in the EECP group, 5 in the control group) participated in the extension phase of the study. The changes in hs-TropI in the subsequent 36 HD sessions with and without EECP application are shown in Table 2 and Fig. 3. Due to the three-weekly HD schedule, the completion of 36 sessions lasts for 12 weeks. Most of the patients in the EECP group (3 of 4) have decreased hs-TropI at the end of the intervention compared to the baseline level, while most of the patients in the control group (4 of 5) have increased hs-TropI. The final hs-TropI in 1 patient in the EECP group with increased hs-TropI is still lower than the laboratory cut-off level due to the low initial level.
Table 2.
Absolute level of pre-dialysis high-sensitivity cardiac troponin I and percentage change in hs-Troponin I compared to baseline level in the extension phase of the study. The cut-off point for high-sensitivity cardiac troponin I for this study is 15.6 ng/L.
| Subject | Absolute level of high-sensitivity cardiac troponin I (ng/L) and [percentage change from baseline] | ||
|---|---|---|---|
| Baseline | 18th session | 36th session | |
| EECP 1 | 86.2 | 91.6 [6.3%] | 76.5 [− 11.3%] |
| EECP 2 | 19.5 | 17.7 [− 9.2%] | 17.3 [− 11.3%] |
| EECP 3 | 37.8 | 25.8 [− 31.7%] | 27.3 [− 27.8%] |
| EECP 4 | 4.9 | 2.9 [− 40.8%] | 6.5 [32.7%] |
| Control 1 | 19.0 | 14.1 [− 25.8%] | 21.9 [15.3%] |
| Control 2 | 9.5 | 12.2 [28.4%] | 13.9 [46.3%] |
| Control 3 | 28.3 | 31.3 [10.6%] | 51.0 [80.2%] |
| Control 4 | 19.3 | 11.4 [− 40.9%] | 17.3 [− 10.4%] |
| Control 5 | 66.9 | 74.4 [11.2%] | 70.0 [4.6%] |
EECP enhanced external counter pulsation.
Fig. 3.
Absolute level of high-sensitivity cardiac troponin I (hs-TropI) and percentage change in hs-Troponin I compared to baseline level in each patient in the extension phase of the study over 36 hemodialysis sessions. Each line represents each patient; thick blue lines indicate patients receiving enhanced external counter pulsation (EECP) intervention throughout the study, and dashed red lines indicate control group patients. All measurements were collected in pre-dialysis period.
Adverse events
There were 5 episodes of mild fatigue at the end of the 60-min EECP therapy in 2 patients across the study period, which spontaneously resolved after resting for 4–6 h, and 1 episode of muscle cramp in a patient in the control group, which improved by reducing the ultrafiltration rate and infusing normal saline solution. Intradialytic hypotension, which can be managed by dialysate cooling and infusion of normal saline, occurred 2 times equally in both groups. No serious adverse events or uncontrolled blood pressure were found in all patients across the 12-week study period.
Discussion
This study is the first to explore the hemodynamic effects of a single EECP application during a 4-h online HDF and indirect evaluation of cardiac function for a longer-term EECP intervention in patients receiving maintenance HDF. In our control group, changes in CO and CI were supported by the findings of a previous study, which were progressive declines throughout the HD session4. In the group receiving EECP in the early hours of the HDF session, CO and CI were significantly maintained throughout the session. This is compatible with the physiological effects of EECP that have been demonstrated in cardiac patients, including increased CO output through increased venous return from external cuff pressure to the lower extremities and improved cardiac perfusion due to diastolic augmentation23. Although we applied EECP in the online HDF modality, the device could also benefit patients who receive conventional HD in a similar pattern due to the known similar patterns of CO decline during the session7. The caution in considering the result is that, due to the small sample size, the higher decrease in cardiac output in the control group might be partly affected by the unequal baseline characteristics, since the patients in the control groups were older and had more underlying cardiac comorbidities. The changes in central aortic blood pressure and heart rate were not significantly different between the groups in our study despite the postulated mechanism of EECP that it might increase diastolic blood pressure and slightly decrease systolic blood pressure due to the negative suction effect of rapid deflation of the cuff during the systolic phase23. The effects of EECP therapy on blood pressure in patients with cardiac disease consist of increased CO and increased diastolic blood pressure that result in increased coronary blood flow and myocardial perfusion through processes collectively called diastolic augmentation16,19. A point to consider is the low-to-moderate interdialytic weight gain and ultrafiltration rate in our patients. This might explain the indifference in blood pressure and the absence of IDH in both groups. The application of EECP in patients with higher weight gain could result in different responses and require further study. In addition, patients with significant hypervolemia or unstable heart failure should be contraindicated for the application of EECP according to the original protocol, as increased venous return could worsen hypertension or cardiac decompensation15.
In the short term, the intermittent nature of an ultrafiltration process and solute removal during maintenance HD and HDF could lead to IDH in some patients, which could result in inadequate dialysis, disturbing symptoms, or significant morbidities8,24. As mentioned earlier, the application of EECP in patients with an ultrafiltration rate higher than in our study might demonstrate the potential reduction in IDH from this device. Moreover, this non-physiological rapid removal has been shown to be associated with chronic organ ischemia, especially myocardial stunning4,7. Therefore, chronic EECP applications might positively affect cardiac function in HD patients, who are at extremely high cardiovascular risk25. Although assessing myocardial stunning during HD mostly requires peri-dialysis echocardiogram or cardiac magnetic resonance imaging conducted in a dedicated research laboratory, cardiac enzyme which is partially elevated due to the myocardial stunning process has also been proven to be a simpler tool to predict cardiac events related to HD in the longer term7,26,27. We have also evaluated changes in hs-TropI, which is more specific in HD patients than other cardiac enzymes, after chronic application of EECP adapted from the original EECP protocol in the non-HD population, in chronic HDF patients in the extension phase of this study28. Despite the smaller sample size than the main study, the results demonstrate a trend in preventing the normally increasing hs-TropI across the time in HD by EECP application, which require proving in larger studies.
Since this study is a proof-of-concept study that focuses primarily on the immediate effect of a single EECP session, studies with longer follow-up times are required to explore possible longer-term benefits or even morbidity and mortality. The cuff pressure and the machine settings in this study comply with those stated in the established protocol17. This emphasizes the feasibility of applying this novel intervention in patients with HD or HDF. Regarding the safety of EECP in patients with HD, there was only mild self-remitting and tolerable fatigue after the application of EECP, which was also demonstrated in previous studies of EECP in patients without kidney disease15.
The strengths of this study are the randomized controlled design and that we measured hemodynamic parameters more frequently than in previous studies. Moreover, we utilized acceptable and reliable measurements for hemodynamic parameters in HD patients based on pre-existing literature21,29. However, there are some limitations to our study. First, it was an open-label study without sham intervention in the control group due to the limited number of EECP machines. However, the lack of sham-controlled might not significantly affect the measurement of outcomes which are all rigid parameters. Secondly, despite the non-violation to sample size calculation, the sample size was still relatively small due to the complexity of collecting various hemodynamic parameters along with applying the EECP device during HD treatment. Therefore, the interpretation of the primary finding, other rare outcomes including an adverse effect require further studies with a larger sample size and a longer-term application of EECP. Finally, the linear mixed model might not be able to depict the changing trends of parameters that did not change linearly, so a time variate analysis in future work might be considered. In addition, future exploration of other biomarkers of cardiac injury or volume status, such as echocardiography, and hemodynamic parameters, such as systemic vascular resistance, could provide more insight into the mechanism of this therapy.
Conclusions
An EECP application during online HDF with the cuff pressure proposed in previous studies has shown promising acute hemodynamic effects, namely maintenance of CO and CI, and might ameliorate myocardial stunning in the longer term without intolerable adverse events. This is consistent with the beneficial effect of EECP in patients without kidney disease.
Supplementary Information
Author contributions
T.T., S.S. and K.T.: conceptualization. T.T. and K.T.: investigation, methodology, and writing the original draft. S.S., W.K., S.E., S.E., and Y.A.: validation, review, and editing.
Funding
This study received grants supported by the Kidney Foundation of Thailand and Ratchadapisek research funds from the Faculty of Medicine, Chulalongkorn University. The funder had no role in the design, data collection, data analysis, and reporting of this study.
Data availability
All data generated or analyzed during this study are included in this article and its supplementary material files. Further enquiries can be directed to the corresponding author.
Declarations
Statement of ethics
This study protocol was reviewed and approved by the institutional review board of the Faculty of Medicine of Chulalongkorn University, with approval number IRB246/62 (initial approval date 13/02/2020). Written informed consent was obtained from all participants. We did not include vulnerable patients in our study.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Data Availability Statement
All data generated or analyzed during this study are included in this article and its supplementary material files. Further enquiries can be directed to the corresponding author.