Next Steps for Intradialytic Cycling Research

Abstract

Hemodialysis patients typically have extremely low physical activity levels, which contributes to poor physical function and quality of life (QOL). Numerous studies show that exercise, intradialytic cycling in particular, may improve physical and cardiovascular function and QOL. But there are also significant inconsistencies in the literature, and the benefits in many studies are modest. This may be due in part to methodological limitations in intradialytic cycling trials, including small sample sizes, short interventions, low volume, and intensity of exercise prescriptions, and/or low retention and protocol adherence rates. The goal of this review is twofold. First, we summarize the current literature on intradialytic cycling in HD patients, highlighting benefits and concerns noted in several recently published trials that were among the most robust and clinically relevant trials conducted to date. Second, we will consider strategies for moving forward with exercise and physical activity interventions in HD, including promoting intradialytic cycling as a core component of a more patient-centric and comprehensive strategy that helps progress patients towards standard physical activity guidelines. We urge researchers and exercise professionals to consider intradialytic cycling as a valuable component of a comprehensive patient-centered, lifestyle intervention, as opposed to a stand-alone exercise prescription.

1. Introduction

Individuals with end stage kidney disease (ESKD) receiving maintenance hemodialysis (HD) have very low physical activity levels and poor physical function, and this contributes to a poor quality of life (QOL) and premature mortality [1]. For several decades, clinicians and researchers globally have attempted to combat this problem by prescribing different types of exercise programs for HD patients, most typically in the form of intradialytic cycling, as part of the standard of care [2,3]. Though intradialytic resistance training, at-home walking programs, and other forms of exercise have also been prescribed [4], intradialytic cycling is often considered to be the most time efficient and popular form of exercise to implement for HD patients [5]. Intradialytic cycling has been shown to improve maximal oxygen consumption, blood pressure control, physical, cardiovascular, and cognitive function, dialysis efficiency, quality of life, and other important outcomes [6,7,8,9] but it is important to recognize that there are also several caveats in the intradialytic cycling literature. First, the benefits in many studies are modest or inconsistent, and many have significant limitations such as small sample sizes, short interventions, low volumes, and intensities of exercise, and/or low retention and protocol adherence rates that make the data difficult to interpret [10,11,12,13,14]. Moreover, there are many barriers to implementing intradialytic exercise programs [15,16], so implementation in HD clinics remains low worldwide [15,17]. As a result, sedentary behavior and poor physical function continue to be hallmarks of the disease. This suggests that standard approaches to exercise in HD, particularly intradialytic cycling, needs to be re-evaluated.

The goal of this review is twofold. First, we will summarize the current literature on exercise in HD patients, with a specific focus on benefits and concerns noted in several recently published intradialytic cycling trials that were among the largest and longest conducted to date. Second, we will consider strategies for moving forward with physical activity and exercise interventions in HD, including promoting approaches that include intradialytic cycling as a core component of a more patient-centric and comprehensive strategy that helps progress patients towards standard physical activity guidelines.

2. Recent Advances in Intradialytic Cycling Research

In recent years, several studies have been published that have addressed some of the limitations in previous intradialytic cycling trials. This includes several randomized control trials (RCTs) with more robust sample sizes (n = 70 to 335) and longer intervention durations (6 to 12 months) than most prior trials [10,18,19,20,21,22]. While there were clear methodological differences between these studies, each included an intradialytic cycling group that exercised 3 days/week at a moderate intensity supervised by research staff [10,18,19,20,21,22]. Unfortunately, none of these 4 trials were able to demonstrate statistically significant improvements in either physical function or quality of life in the intradialytic cycling group compared to controls. While there were trends for improvements in the intradialytic cycling groups in each of these studies, particularly for physical function, this data suggests that standard intradialytic cycling protocols may yield only modest benefits for many patients. This may be due in part to the low volume and intensity of exercise, as evidenced by calculated energy expenditures of <75 kcal for typical intradialytic cycling sessions [8]. Other reasons for these disappointing results include low adherence and compliance with the exercise protocols, as well as low retention/high dropout rates.

Despite these negative results, there are also some reasons for optimism regarding intradialytic cycling, particularly related to its positive effects on cardiovascular structure and function seen in a few recent studies [19,21,22]. For example, the primary finding in the CYCLE trial [19] was that 6 months of intradialytic cycling significantly reduced left ventricular mass, despite failing to improve physical function or quality of life (secondary outcomes) [19]. And in contrast to the studies by Koh et al. and Jeong et al. [10,18], the CYCLE trial also found significant reductions in arterial stiffness in their intradialytic cycling group. A primary difference in the CYCLE study was that magnetic resonance imaging (MRI) was used to measure changes in these cardiovascular parameters, as opposed to ultrasound and arterial tonometry, which has typically been used to measure changes in cardiovascular structure and function in most previous intradialytic cycling studies. Another novel cardiovascular benefit from intradialytic cycling seen in recent studies is a reduction in myocardial stunning, which is a frequent problem during hemodialysis [21,22]. It is caused in part by ultrafiltration-induced intradialytic hypotension, which causes ischemia and cardiac dysfunction [21,22]. Two recent pilot studies demonstrated that a single bout of intradialytic cycling significantly reduced intradialytic myocardial stunning, particularly toward the end of the treatment [21,22]. These preliminary findings have the potential to be highly clinically significant if replicated in robust intervention trials. It should also be noted that intradialytic cycling has been demonstrated to be very safe. While some guidelines have suggested special contraindications to exercise for dialysis patients, including electrolyte abnormalities, excessive interdialytic weight gain, lung congestion, peripheral edema and others [23], these concerns appear to be hypothetical, as there is very little evidence of adverse events from intradialytic exercise in published clinical trials. This suggests that intradialytic cycling is safe and should be promoted in all clinics where possible [24,25,26,27].

In summary, while there are many potential benefits of intradialytic cycling, several of the most robust interventions published to date have failed to significantly improve physical function, strength, physical activity levels, and QOL in HD patients [19,21,22]. This is likely contributing to the poor implementation of exercise programs in HD clinics. Another barrier to implementation is that most clinics are unable to employ exercise professionals to run a program, while clinic staff and nephrologists have limited training relative to exercise prescription [28]. Exercise and physical activity guidelines for HD patients are also unclear on specifics of frequency, intensity, type and timing or the focus on endurance, resistance, balance, and flexibility training in this population [29]. Perhaps because of these concerns, the US Kidney Disease Outcomes Quality Initiative (K/DOQI) removed its exercise recommendations in 2015 as part of their clinical practice guidelines for HD [30]. Without policy change or guidelines to support change, the implementation of exercise programs in HD clinics will remain low, and physical activity levels in HD patients will remain poor. It is important that we consider new approaches to implementing exercise in HD patients, given that the decades-long experience with using intradialytic cycling as the cornerstone of exercise programs has not provided more robust outcomes, as displayed in

Table 1. Types of exercise interventions implemented in hemodialysis patients.

Exercise Mode	Selected Citations	Comment
Intradialytic Cycling	Goldberg, et al. (1986) [6]
	Painter, et al. (1986) [7]
	Moore, et al. (1998) [31] Kopple, et al. (2007) [14] Toussaint, et al. (2008) [32] Bohm, et al. (2014) [33] Jeong, et al. (2018) [34] McGuire, et al. (2019) [22] Penny, et al. (2019) [21] Graham-Brown, et al. (2019) [19] Greenwood, et al. (2021) [20]	Intradialytic cycling has been predominant form of exercise in HD patients worldwide since 1980′s. While many studies have demonstrated modest benefits in a variety of health-related outcomes, the benefits have often been modest or inconsistent.
Intradialytic Resistance Training	Cheema, et al. (2007) PEAK 1 & 2 [35]
	Kopple, et al. (2007) [14] Johansen, et al. (2009) [1] Chen, et al. (2010) [36] Kirkman, et al. (2014) [37]	Consistent improvements in strength; marginal/inconsistent benefits in physical function and body composition
Intradialytic Cycling + Resistance Training	Anding, et al. (2015) [38]	Modest benefits, concerns with
	Thompson, et al. (2016) [39]	adherence/feasibility
Intradialytic Cycling + Nutrition Support	Prado, et al. (2007) [40] Hristea, et al. (2016) [41] Martin-Alemany, et al. (2016) [42] Jeong, et al. (2019) [18]	Exercise with concomitant nutrition support does not appear to have have additive benefits
Intradialytic Resistance Training + Nutrition Support	Dong, et al. (2011) [43] Molsted, et al. (2013) [44]	Modest additive benefits
Home Walking Programs	Koh, et al. (2010) [10] Manfredini, et al. (2017) [45] Baggatta, et al. (2018) [46]	Low intensity led to modest physical function improvements
Home Resistance Training	Headley, et al. (2002) [11]	Modest physical function benefits
Pedometers/Accelerometers	Gomes, et al. (2015) [47] Kittiskulnam, et al. (2019) [48]	Highlights the sedentary behaviors and PA levels within HD patients
Other (Activities of Daily Living, Laughter Yoga, Zumba, VR/Gaming)	Tawney, et al. (2000) * [49] Bennett, et al. (2012) [50] Bennet, et al. (2015) [51] Segura-Orti, et al. (2019) [52]	Small trials, modest benefits, likely difficult to implement

* This table provides examples of different types of interventions that have been implemented in HD population. Most show modest benefits, but there are limitations with each, and with few exceptions (Tawney, et al.) [49], almost none provide patients autonomy to choose their preferred type of activity.

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3. The Future of Intradialytic Cycling

While intradialytic cycling has some obvious limitations, there is overwhelming evidence that it is safe, and it is still viewed as the most practical to administer and monitor compared to other types of exercise. As a result, it is likely to remain a significant component of future exercise programs for HD patients. So, the question remains: what can we do to address the primary concerns and limitations with intradialytic cycling, as well as improve implementation? Two needs are apparent: (1) more research is still needed to improve the evidence base regarding the efficacy of intradialytic exercise; and (2) the role of intradialytic cycling as a stand-alone intervention needs to be re-evaluated. Instead, intradialytic cycling should be considered a valuable component of a more comprehensive, patient-centered approach to increasing physical activity in HD patients. These issues are considered more thoroughly below.

In terms of research, more is needed to address gaps in the literature with intradialytic cycling. This includes a more thorough evaluation of its cardiovascular benefits, especially related to myocardial stunning. To date, the only studies to investigate this were two pilot studies demonstrating that a single bout of intradialytic cycling reduced myocardial stunning compared to a dialysis session without exercise [21,22]. Additional studies are needed to determine if sustained intradialytic cycling programs produce even greater reductions in myocardial stunning or other cardiovascular benefits. We must also improve our understanding of how the timing of intradialytic cycling (e.g., exercise during the 1st vs. 3rd or 4th hour of dialysis) affects its safety and efficacy. Only a few studies have examined this question, including two small pilot studies [31,34]. In the study by Moore, et al., exercise in the 3rd hour of dialysis caused intradialytic hypotension (IDH) but there were several important limitations in this study, including a small sample size (n = 8), and over half of the patients enrolled had high ultrafiltration rates which may have attributed to the hemodynamic instability during the third hour of cycling [31]. By contrast, Jeong, et al. showed that cycling during the 3rd hour of dialysis did not increase the risk of IDH or other intradialytic symptoms compared to cycling in the 1st hour [34]. This is an important finding that deserves further scrutiny, as exercise in the 3rd or 4th hour of dialysis is often contraindicated due to concerns with hemodynamic instability, cramping, and other symptoms [23]. Given how challenging it can be for patients to adhere to intradialytic cycling programs, this restriction may be serving as an unnecessary barrier to exercise for some patients.

There also needs to be more research examining the impact of intradialytic cycling on patient-related outcomes (PROs). To date, few studies have addressed this issue, but a recent review by Hargrove, et al. demonstrated intradialytic cycling improved PROs symptoms related to muscle cramping, fatigue, and restless leg syndrome [53]. One concern is that the assessment tools for measuring PROs are limited, so further development of these tools will be important [54].

There is also limited research evaluating the impact of intradialytic cycling on hard outcomes (e.g., hospitalization, mortality) and the cost-effectiveness of exercise programs, though a few recent studies have begun to examine these issues. For example, a secondary analysis of the CYCLE study showed there was a reduction in health care utilization costs in patients enrolled in an intradialytic cycling program compared to non-exercising controls, indicating the approach is potentially cost-effective [19]. However, more research is needed to demonstrate that intradialytic cycling, or any exercise program in general, can improve hard-outcomes and/or is cost-effective for dialysis patients.

4. Moving beyond the Bike

In our opinion, a second critical need is that researchers and clinicians need to stop relying on intradialytic cycling as a stand-alone exercise intervention. Intradialytic cycling programs have been around for more than 40 years. If they were going to work, we would have robust research evidence by now demonstrating feasibility and efficacy. Despite a few promising programs around the world [55] widespread implementation is lacking [8]. Instead, we believe intradialytic cycling should be considered a valuable component of a more comprehensive physical activity program for HD patients. Programs need to be developed that provide patients the autonomy to choose the types of activities they can engage in, instead of specific activities like intradialytic cycling being mandated. In addition, the volume and intensity of the activities should attempt to progress patients towards the standard physical activity guidelines, as appropriate for the individual. There are hypothetical advantages and limitations related to both intradialytic cycling as well as more personalized approaches to exercise prescription. We have described some of these in

Table 2. Advantages and limitations of Intradialytic Exercise vs the proposed “Patient-Centered” approach to exercise.

Exercise Method	Advantages	Limitations
Standard Approach: Intradialytic Exercise	Captive Audience Efficient Less patient burden Higher compliance Exercise monitoring	Restricted movement/mobility Boredom/uninterested Less patient autonomy
Proposed Approach: Patient-Centered, personalized exercise prescription	Unlimited exercise types
	More patient autonomy Fewer exercise restrictions based on patient ability	Unsupervised exercise Exercise resources are limited by financial & environment access

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For a physical activity program to succeed, the implementation must consider how patients view the barriers and benefits to exercise and include an individualized patient-centered comprehensive lifestyle approach to exercise prescription. The term “patient-centered” empowers patients to become active participants in their health care needs [56]. Patient-centered care has the potential to create an efficient way for clinicians to address specific challenges patients encounter [57]. Instead, current research approaches are typically “clinician-centered”, which often assess clinical measures pertaining to physiological function [58]. While these measures are important, patients may disagree on their priority in relation to their needs. To implement a program that is patient-centered, clinicians and researchers must welcome patients to assert their humanity and individuality in their treatment plan [59]. A patient-centered exercise program incorporates the patient’s voice in the design and implementation of programs. In addition, it is essential for studies to target patient reported outcomes measures pertaining to fatigue, pain and other symptoms associated with the disease and HD treatment. By providing more autonomy to HD patients to choose their preferred types of physical activity, it is more likely that we will reduce sedentary behavior increase in physical activity participation, and subsequently reduce symptoms of fatigue and other factors that improve patient’s perceived wellness and quality of life.

Several recent reviews have advocated for a paradigm shift towards a comprehensive lifestyle intervention supported by members of the patient care team and family targeting the “patient-centered” approach [8,60,61]. This patient-centered exercise prescription consists of combining intradialytic exercise, light-intensity activities of daily living, and high-intensity exercise as an individualized approach to embody the lifestyle of the HD patient. Thus, the specific aim to increase physical activity is achieved and clinical outcomes are more likely to improve [55].

There is evidence from other clinical populations that comprehensive lifestyle interventions can be successful. These programs implement counseling, comprehensive behavior change, and goal setting techniques which allow individuals the autonomy to decide and prioritize their path to make a change in their wellness [62,63]. An example of this concept was IDES study which involved enrolling 300 individuals with type 2 diabetes and measured the change in physical activity volume and time spent participating in exercises using an accelerometer over 3 years. The participants were randomized to two groups: (1) a control/standard care group which received the American Diabetes Association recommended guidelines; and (2) a behavioral intervention that received 16 individual counseling sessions to help participants set and achieve goals pertaining to diet, exercise, and behavior modifications. The primary outcome was that the behavioral group experienced an increase in physical activity and a decrease in sedentary time compared to the control group. The study had a high retention rate in both groups (89%) and was a successful model for implementing a comprehensive lifestyle program rather than ‘exercise’ only. Unfortunately, multifactorial models including behavior modifications or social factors in tandem have not been widely implemented in HD patients.

For this approach to work, it is evident that clinics must employ exercise professionals who will motivate patients to prioritize exercise as part of their care. HD patients indicate that there is a lack of clinic staff expertise to oversee exercise in the clinic, and this is a significant barrier to implementing programs [64]. Furthermore, international organizations including the Global Renal Exercise (GREX) Network [17] and the UK Renal Association [24] have also suggested that exercise programs for all individuals with ESKD/CKD be designed by appropriately trained staff. Unfortunately, there is a lack of funding to achieve this in most dialysis centers around the world, and significant policy barriers need to be addressed for this to happen [65].

5. Conclusions

Intradialytic cycling has been the primary component of exercise programs for HD patients worldwide since the 1980′s. It is demonstrated to be safe, and recent research suggests it may provide unique benefits such as a reduction in specific intradialytic symptoms (e.g., cramping, intradialytic hypotension, and myocardial stunning). However, its effects on other important outcomes, including physical function and quality of life, are questionable. Because of this, research groups around the world have begun moving away from intradialytic cycling as a stand-alone intervention and including it instead as a component of a more comprehensive, patient-centered approach to increasing dialysis patients’ physical activity levels. However, most of these comprehensive programs are in their initial phases, and more research will be needed to demonstrate the most feasible approaches and those that have the greatest promise for improving the health and quality of life of this critically ill patient population.