The Exercise Response to Pharmacologic Cholinergic Stimulation in Myalgic Encephalomyelitis / Chronic Fatigue Syndrome
Condition: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome; Chronic Fatigue Syndrome; Myalgic Encephalomyelitis; Exercise Intolerance; Dysautonomia; Low Ventricular Filling Pressures (Preload Failure); Postural Orthostatic Tachycardia Syndrome; Orthostatic Hypotension; Fibromyalgia
MeSH terms: Encephalomyelitis; Fibromyalgia; Fatigue Syndrome, Chronic; Myalgia; Hypotension, Orthostatic; Primary Dysautonomias; Postural Orthostatic Tachycardia Syndrome; Hypotension; Tachycardia; Syndrome; Fatigue
Study type: Interventional
Phase: Phase 2

Summary: 
      Myalgic encephalomyelitis/Chronic fatigue syndrome (ME/CFS), otherwise known as Chronic
      fatigue syndrome (CFS) or myalgic encephalomyelitis (ME), is an under-recognized disorder
      whose cause is not yet understood. Suggested theories behind the pathophysiology of this
      condition include autoimmune causes, an inciting viral illness, and a dysfunctional autonomic
      nervous system caused by a small fiber polyneuropathy. Symptoms include fatigue, cognitive
      impairments, gastrointestinal changes, exertional dyspnea, and post-exertional malaise. The
      latter two symptoms are caused in part by abnormal cardiopulmonary hemodynamics during
      exercise thought to be due to a small fiber polyneuropathy. This manifests as low
      biventricular filling pressures throughout exercise seen in patients undergoing an invasive
      cardiopulmonary exercise test (iCPET) along with small nerve fiber atrophy seen on skin
      biopsy.

      After diagnosis, patients are often treated with pyridostigmine (off-label use of this
      medication) to enhance cholinergic stimulation of norepinephrine release at the
      post-ganglionic synapse. This is thought to improve venoconstriction at the site of
      exercising muscles, leading to improved return of blood to the heart and increasing filling
      of the heart to more appropriate levels during peak exercise. Retrospective studies have
      shown that noninvasive measurements of exercise capacity, such as oxygen uptake, end-tidal
      carbon dioxide, and ventilatory efficiency, improve after treatment with pyridostigmine. To
      date, there are no studies that assess invasive hemodynamics after pyridostigmine
      administration.

      It is estimated that four million people suffer from ME/CFS worldwide, a number that is
      thought to be a gross underestimate of disease prevalence. However, despite its potential for
      debilitating symptoms, loss of productivity, and worldwide burden, the pathophysiology behind
      ME/CFS remains unknown and its treatment unclear. By evaluating the exercise response to
      cholinergic stimulation, this study will shed further light on the link between the autonomic
      nervous system and cardiopulmonary hemodynamics, potentially leading to new therapeutic
      targets.
    

Detailed description: 
      The hypothesis of our study is that hemodynamic, ventilatory and oxygen exchange variables
      such biventricular filling pressures and systemic oxygen extraction can be improved by
      cholinergic stimulation in patients with ME/CFS.

      The objective of this study is to examine the exercise response to pharmacologic cholinergic
      stimulation in ME/CFS patients already undergoing a clinically indicated invasive
      cardiopulmonary exercise test (iCPET). This will be achieved by inhibiting
      acetylcholinesterase with pyridostigmine, thus increasing acetylcholine levels, downstream
      levels of norepinephrine, and enhancing vascular regulation.

      To test our hypothesis, we propose the following specific aims:

      Define the response of peak oxygen uptake(VO2) to pyridostigmine. Define the gas exchange
      responses, such as end-tidal carbon dioxide(CO2) and ventilatory efficiency to
      pyridostigmine.

      Define the hemodynamic responses, such as right atrial pressures, pulmonary artery pressure,
      pulmonary capillary wedge pressures, cardiac output, heart rate, stroke volume, pulmonary
      vascular resistance and systemic vascular resistance to pyridostigmine.

      Evaluate the response of skeletal muscle oxygen extraction and lactate to pyridostigmine.

      These determinations will occur during a clinically indicated iCPET, which includes
      exercising on a stationary cycle with a right heart catheter (RHC) and a radial arterial line
      in place. To stimulate the cholinergic response, a single dose of an oral
      acetylcholinesterase inhibitor, pyridostigmine, versus placebo will be given after the iCPET.
      Recovery cycling will be performed after a rest period of 50 minutes. This will be
      administered in a randomized, double-blind, placebo-controlled trial.
    

Intervention name(s): Pyridostigmine Bromide; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Pyridostigmine Bromide 60 mg capsule by mouth as a one time dose; Placebo (Cellulose microcrystalline) capsule by mouth as a one time dose
Other intervention name(s): Mestinon; Cellulose microcrystalline
Intervention MeSH terms: Bromides; Pyridostigmine Bromide
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Subjects will be assigned randomly to receive either pyridostigmine or placebo, both study participants and investigators will be blinded.
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: Myalgic encephalomyelitis/Chronic fatigue syndrome; Myalgic encephalomyelitis; Chronic fatigue syndrome; Pyridostigmine; Exercise Intolerance; Invasive Cardiopulmonary Exercise Test