Translating reduced oxygen consumption to impairment status to treatment considerations

 

A study from US researchers has confirmed the results of previous small studies that found people with ME/CFS respond abnormally to exertion.

84 patients with ME/CFS and 71 sedentary controls completed cardiopulmonary exercise tests (CPET) on 2 succesive days. In contrast to the healthy controls, ME/CFS patients failed to reproduce CPET-1 measures on day 2, with significant declines in work, exercise time and other measurements.

“The Fick Principle reminds that oxygen utilization for energy production is wholly dependent on blood flow and tissue oxygen extraction. This is true for any tissue (e.g., brain, skeletal muscle, liver, etc.).

Treatment considerations

With this understanding and given the disordered hemodynamic and ventilatory responses to exertion in ME/CFS, it is plausible to consider treatment approaches that may help to re-regulate ANS signaling for improved oxygen delivery to the heart, skeletal muscle, gut, brain, and other tissues impacted by ME/CFS…

Unfortunately, relatively little attention and resources have been directed toward non-pharmacological approaches to reduce symptoms of ME/CFS. Despite compelling evidence of ANS dysfunction in ME/CFS there are no randomized controlled trials to assess treatment approaches.

Here, we offer strategies proffered variously by many with ME/CFS, trial and error, practice, and some clinical evidence that center on non-pharmacological opportunities to possibly mitigate pain and inflammation, and enhance blood flow, oxygen delivery, and/or tissue oxygenation.

Compression garments
Core stability exercises
Vagus nerve stimulation (VNS)
Cryotherapy or cold therapy
Manual lymphatic drainage
Red-light therapy
Nutrition
Fasciotomy
Myofascial release therapy
Blood flow restriction training (BFR)
Activity pacing
Mindfulness training

Compression garments

Return of blood to the heart (venous return) may be assisted by use of compression garments (shorts, tights, stockings, shirt, sleeve) which are effective to aid recovery by improved blood flow in athletes and in ME/CFS for those who experience orthostatic intolerance. Massage may help to reduce depression, anxiety, stress, and perception of fatigue, and enhance overall mood and relaxation to indirectly promote blood flow, although it may not alter blood flow directly.

Core stability exercises

to maintain or improve effectiveness of muscles of the trunk and hips to support correct spinal alignment can help to improve circulation and oxygen delivery. These can be done while lying down so as not to exacerbate orthostatic symptoms. Most important when doing core stability exercises is to maintain correct spinal alignment during the exercise, more than duration or repetitions of the exercise.

The focus of core stability exercises is to improve the coordination of these muscle groups and intra-abdominal pressure regulation by the central nervous system. When first learning these exercises, working with one experienced and knowledgeable in teaching core or neuromuscular stabilization exercises , such as a physical therapist, athletic trainer, or strength/conditioning coach, would be advised to provide guidance and feedback.

As with all exercise, core stability exercises should be performed within the limitations of exertion tolerance, discussed below, so as not to exacerbate post exertion symptoms. Recognize, however, that local muscle sensitivity may arise when first beginning these types of activities which is common when first exerting muscles to perform an unfamiliar task.

Vagus nerve stimulation (VNS)

is an FDA-approved treatment for pharmacoresistant depression and epilepsy, producing clinically meaningful results. Implantation of a VNS device requires a surgical procedure and is not without risk. More recent attention has focused on transcutaneous vagus nerve stimulation (tVNS) using an external device to stimulate the vagus nerve at either the ear to access the auricular branch of the vagus nerve or the neck to target the cervical branch of the vagus nerve… For ME/CFS, preliminary findings suggest some efficacy of tVNS to reduce sympathetic stimulation of the heart, indicated by improved heart rate variability, but that ANS response varied depending on sex and tVNS stimulation parameters.

While more work is warranted to understand optimal treatment protocols, long-term effects, and other possible applications, substantial evidence indicates that tVNS can help to rebalance parasympathetic/sympathetic tone of the intrinsic cardiac nervous system to reduce heart rate.

Cryotherapy or cold therapy

is a therapeutic modality to decrease pain, reduce chronic and acute inflammation, and to aid recovery in athletes, among other applications. Cold exposure of the whole body stimulates ANS responses to increase core temperature toward normal body temperature by redirecting blood flow away from the skin and toward the heart and viscera. In doing so, a very brief, intensely cold whole-body exposure is believed to provoke ANS re-regulation toward homeostasis or stable equilibrium, and thereby improve symptoms of ME/CFS associated with cardiovascular autonomic dysregulation.

Coupling brief whole-body cryotherapy with static stretching improved symptoms of ME/CFS related to fatigue, sleep, and cognitive function. More work is needed to better elucidate the mechanisms involved in the effectiveness of whole-body cryotherapy, although preliminary data suggests a promising approach to consider for symptom mitigation.

Manual lymphatic drainage

Evidence of structural and functional abnormalities in the brain of some with ME/CFS may be related to accumulation of toxins associated with glymphatic dysfunction. Similarly, the primary respiratory mechanism, typically dysregulated in those with ME/CFS, is suggested to be synchronous with the rhythmic pulsation of lymphatic drainage from the brain and spinal cord, or neuraxis, induced by sympathetic nervous system activity.

Consequently, impaired cranial rhythmic impulse could lead to respiratory dysfunction, chronic fatigue, and other symptoms of ME/CFS. Some evidence indicates that a specific manual lymphatic drainage intervention may reduce fatigue symptoms in long COVID and chronic venous insufficiency which share many symptoms with ME/CFS.

Red-light therapy

Although not fully understood, photobiomodulation, also known as low-level laser therapy (LLLT) or red-light therapy, has been in existence for more than a half century. It is known to affect mitochondrial function by altering cytochrome c oxidase which is particularly able to absorb light in the near-infrared region, increasing electron transport activity and ultimately adenosine triphosphate production. More commonly used now in sport medicine and orthopedic rehabilitative settings to enhance recovery and repair, LLLT has been reported to decrease soreness, inflammatory markers, lactic acid, and oxidative stress, and enhance glucose uptake to support aerobic metabolism.

Nutrition

An additional approach to modulate systemic inflammation involves selection and timing of body fuels. Nutritional considerations to reduce inflammation include an anti-inflammatory diet, reduced consumption of refined sugar, a gluten-free diet, or intermittent fasting. A nutritional approach to ‘feed’ the gut microbiome can help with energy balance, glycemic control, and inflammation.

Fasciotomy

It has long been known, but possibly underappreciated, that the integrity of fascia in the maintenance of muscle tension and interstitial pressure is integral to healthy muscle function and force production, independent of muscle fatigue. As such, fasciotomy, the common approach to relieve the pain of muscle compartment syndrome by cutting the surrounding fascia, unfortunately also reduces muscle force output by 50% or more. However, fascia that is unusually restricted or foreshortened may increase neural tension and contribute to pain, altering muscle recruitment patterns, reducing muscle force production and intra-neural blood flow, and releasing inflammatory factors.

Myofascial release therapy

In those with ME/CFS, longitudinal strain to the nerves and soft tissue of the lower limb increased pain and many symptoms of PEM, including difficulty concentrating. Prolonged sitting, reclining bed rest, or driving with arms outstretched and right leg extended are examples of activities that could contribute to increased mechanical tension to the nervous system.

Efforts to reduce fascial restriction and mechanical tension using myofascial release therapy effectively decreased pain and improved range of motion and functionality in women following breast cancer surgery. Both the subcutaneous and subserous fascial planes slide independently but fuse at specific locations, particularly in the area of the pelvis, abdominal wall, and aperture of the thorax, suggesting that impingement of fascia in one area can ‘tug’ on an adjacent or even distal area provoking symptoms that seem unrelated to the point of restriction.

For example, a head injury may later contribute to pain lower in the body due to adhesions that ‘pull’ on the longitudinal axis of the fascia causing pain elsewhere. Approaches that may bring relief by way of liberating fascia include appropriate physical therapy, body work, breathing exercises, gentle stretches, stress reduction, acupuncture, foam rolling, FasciaBlaster®, heating pad or hot water bottle, and/or nutritional support for fascia. In addition to circumstances described above involving prolonged stationary positions, those who have experienced injury, surgery, or some type of bodily trauma that could cause fascial adhesions may want to consider these approaches.

Blood flow restriction training (BFR)

involves restriction of blood flow to arms or legs to trap blood in the local musculature during low-intensity resistance exercise, eliciting a strong hemodynamic response. It has been reported to increase strength and muscle size in healthy adults and reduce characteristics evident in chronic heart failure including muscle atrophy, shortness of breath, fatigue, increased ventilation, and sympathetic stimulation.

Exercise with BFR may also promote more angiogenesis-related factors mRNA expression and improve vascular function. Collectively, these findings suggest that BFR training may be of benefit to those with ME/CFS to mitigate muscle loss but also to improve functional performance. More work is warranted to better understand the mechanisms of action with BFR, as well as an appropriate protocol for use in ME/CFS to avoid possible dizziness that has been reported in some cases, but it appears to be a promising approach to reduce fatigue and improve muscle function.

Activity pacing

is a goal-directed behavioral approach that involves decision-making and planning to effectively manage available energy resources to reduce fatigue and symptoms of PEM in those with ME/CFS. It is an approach that has gained acceptance, not only for ME/CFS, but for other disabling conditions, including long COVID. The goal of pacing, as opposed to graded exercise therapy, is symptom reduction to improve well-being and overall function through self-regulatory behavior.

Effective pacing can reduce fatigue, psychological distress, depression, and improve overall physical function. Activity pacing relies on basic journaling of symptoms and activities to provide a ‘look-back’ in instances where PEM symptoms emerge to understand possible triggers of symptom exacerbation and inform future pacing-related decisions. Additionally, it is helpful to have an objective indicator of exertional threshold to provide on-going feedback. Based on data from the present study, it is evident that exertion above VAT provokes abnormal hemodynamic and ventilatory responses. The VAT level of energy production can be ascertained during a submaximal cardiopulmonary exercise test. When heart rate that corresponds to VAT (HR@VAT) is known, use of a simple heart rate monitor with an alarm set to 10 bpm below heart rate at VAT provides objective, auditory feedback to reduce exertion below threshold to avoid symptoms of PEM.

When heart rate at VAT is not known, RPE may provide an estimate of VAT. An upper exertion limit RPE of 10–12 (for a 6–20 scale) or RPE of 2–3 (for a 1–10 scale) are consistent with ranges in perceived exertion from ‘light and easy – non-taxing, very gentle and easy to maintain a conversation – could continue for hours’ to ‘comfortable pace – able to maintain a conversation without getting out of breath’. Pacing should begin with a conservative estimate of exertional threshold (e.g., 10/20 or 2/10, or less if indicated) while using journal entries from the previous 1 to 2 days to assess if the exertional limit is effectively mitigating symptom exacerbation. If not, then the exertional limit should be lowered, recognizing also that the cyclic nature of symptoms in ME/CFS may alter exertional tolerance levels at times.

Another exertional metric to begin pacing when heart rate at VAT is not known can be estimated by adding 15 bpm to resting heart rate (RHR + 15). Resting heart rate should be measured after 5 min of seated or supine rest in a quiet environment. Preliminary data from the Workwell Foundation suggests that RHR + 15 is a useful metric to guide pacing when HR@VAT is not known, with more information about pacing at www.workwellfoundation.org. A positive and protracted adaptation to, and familiarity with pacing is necessary before venturing to raise the exertional tolerance level. Effective pacing over time may allow for a very gradual escalation of physical and cognitive activities. Emergence of post-exertional symptoms is always an indicator that prior exertional levels exceeded exertional tolerance.

One indicator of successful symptom mitigation over time may be the measure of heart rate variability (HRV). This is the measure of variability in time between each heartbeat and is an indirect indicator of ANS tone. Increasing evidence suggests that the ANS regulates the inflammatory response. A decrease in HRV indicates an abnormal predominance of sympathetic activity and has been observed in patients with ME/CFS, fibromyalgia pain, post-traumatic stress disorder, type 2 diabetes, and as a general indicator of stress and health. Neuroimaging studies indicate a relationship between HRV and regional cerebral blood flow, suggesting that the interpretation of external phenomena as threat or negative (ie., ‘fight or flight’ response) can alter higher brain messaging to the brainstem and subsequent ANS signaling to the heart.

Additionally, one’s interpretation of psychosocial stress can be quantified by measuring cortisol release, which is closely associated with HRV, as an indicator of the physiological response to the stress [170]. In this way, HRV can be used to track changes in autonomic tone over time and as an indicator of productive symptom management in ME/CFS.

Breathing and circulation are related. Impaired respiratory function is universal in ME/CFS and so must be addressed to improve circulation of blood with oxygen to tissues for energy metabolism and circulation of lymph to remove metabolic byproducts. Although breathing is an involuntary process, intervention using voluntary slow or diaphragmatic breathing can effectively improve vagally-mediated HRV with only a little training. Slow breathing can reduce blood pressure in low-risk hypertensive and prehypertensive patients, hypertensive diabetics, and improve respiratory function in chronic obstructive pulmonary disease, reduce stress, anxiety, constipation, migraine, and other ANS-associated maladies. Among other effects, the diaphragm also influences postural stability, elimination, birthing, metabolic balance, cardiovascular and lymphatic systems. Given the broad reaching impact of improved breathing mechanics, this low-risk, low-cost, non-pharmacological approach to symptom mitigation should be a first-line approach.

Mindfulness training

Finally, ANS function is intimately associated with neurophysiological responses, including ‘fight or flight’, immune activation, pain sensitivity, and many other stress-related impacts. Understanding this is at the core of integrative approaches to help move away from ‘sickness’ and toward ‘health’. There is increasing evidence of the efficacy of some types of ‘mindfulness training’ to transcend the state of ‘ill’ and move toward a state of ‘well’ with regard to many diseases.

Recent work demonstrated the efficacy of meditation as an adjuvant therapy to alter bloodborne factors and resiliency to viral infection in the treatment of COVID-19 and has been reviewed elsewhere with promise for long COVID and ME/CFS. A multi-symptom disease such as ME/CFS is often addressed with a poly-pharmaceutical approach to symptom management. Consideration by both patient and physician of the approaches discussed herein could reduce the efforts to pharmacologically control one’s physiology through the understanding that many, if not all symptoms of ME/CFS implicate ANS dysfunction and may be positively influenced with non-pharmacological approaches. The body-brain axis is proving to be highly influential in control and regulation of energy metabolism.

Advice to physicians

The relationships between peak oxygen consumption, impairment severity, and patient responses on the MOS SF-36 questionnaire suggests that a first-line assessment by physicians might begin with completion of the MOS SF-36.”

Cardiopulmonary and metabolic responses during a 2-day CPET in myalgic encephalomyelitis/chronic fatigue syndrome: translating reduced oxygen consumption to impairment status to treatment considerations, by Betsy Keller, Candace N. Receno, Carl J. Franconi, Sebastian Harenberg, Jared Stevens, Xiangling Mao, Staci R Stevens, Geoff Moore, Susan Levine, John Chia, Dikoma Shungu & Maureen R Hanson in Journal of Translational Medicine 05 July 2024

See also:

Health rising: Biggest 2-Day Exercise Study Ever Validates the Energy Problems in ME/CFS: Pt. I