Autonomic Nervous System and Chronic Fatigue Syndrome
Condition: Chronic Fatigue Syndrome; Orthostatic Intolerance; Postural Tachycardia Syndrome
MeSH terms: Fatigue Syndrome, Chronic; Postural Orthostatic Tachycardia Syndrome; Orthostatic Intolerance; Tachycardia; Syndrome; Fatigue
Study type: Interventional
Phase: Phase 1

Summary: 
      The investigators propose to test the hypothesis that the sympathetic nervous system
      contributes to the cardiovascular and inflammatory abnormalities present in the chronic
      fatigue syndrome (CFS) and, in particular in the subset of patients characterized by postural
      tachycardia syndrome (POTS). CFS and POTS are seen mostly in otherwise normal young women,
      and are the cause of significant disability. A substantial proportion of patients referred
      for evaluation of POTS met diagnostic criteria for CFS and, conversely, a subset of patients
      referred for treatment for CFS have POTS. The investigators hypothesize that sympathetic
      activation underlies the pathophysiology of patients in whom CFS and POTS overlap (CFS-P).
    

Detailed description: 
      In Specific Aim 1, the investigators will use state-of-the-art measurements of sympathetic
      activity (autonomic function tests, response to trimethaphan, direct nerve sympathetic
      traffic recordings with microneurography, plasma norepinephrine, and intraneuronal
      metabolites), inflammatory mediators (C-reactive protein, inflammatory cytokines), and
      oxidative stress (isoprostanes) in patients with CFS-P. It is important that appropriate
      control groups be included, and we will also study patients with CFS without orthostatic
      tachycardia, patients with POTS without CFS, and normal controls.

      The investigators have documented abnormalities in volume regulation in POTS patients.
      Hypovolemia can contribute to sympathetic activation and, vice versa, sympathetic activation
      can contribute to hypovolemia. Interrupting this vicious circle with acute saline infusion is
      the most effective treatment to improve symptoms in POTS patients. Not surprisingly, many
      POTS patients followed by the investigators, and CFS patients followed by Dr. David Bell, are
      using saline pulse therapy as a way to alleviate symptoms. However, the efficacy and safety
      of this approach has not been proven. The investigators propose to validate this treatment in
      Specific Aim 2.

      This group studies show that nitric oxide is arguably the most important metabolic factor
      involved in cardiovascular regulation. Abnormalities in nitric oxide have been proposed to
      contribute to CFS and POTS, but proving this has been challenging in part due to its
      interaction with the sympathetic nervous system. In Specific Aim 3, the investigators propose
      to investigate the importance of nitric oxide in CFS-P patients using an experimental
      approach developed in our laboratory to eliminate nitric oxide/autonomic interactions.

      Finally, in Specific Aim 4, they propose a proof-of-concept study to test the hypothesis that
      sympathetic activation contributes to many of the abnormalities found in CFS patients. If our
      hypothesis is correct, inhibition of sympathetic tone will result in improvement of the
      abnormalities described in volume, inflammation, and oxidative stress. More importantly, it
      will result in symptomatic improvement in these patients. The investigators believe,
      therefore, that the studies proposed in this application will improve the understanding of
      the pathophysiology of CFS, and provide a rationale approach to the treatment of this
      disabling condition.
    

Intervention name(s): Autonomic Function Testing; Saline infusions; L-NMMA trimethaphan; methyldopa
Intervention type(s): Other; Other; Drug; Drug
Intervention description(s): The autonomic function tests include asking the subject to breathe deeply for two minutes and breathing as fast and as hard as they can for 30 seconds, maintaining a handgrip for 3 minutes, breathing against pressure for 15 seconds, placing one hand in ice water for 1 minute and an orthostatic test. All these tests are meant to stimulate the autonomic nervous system to produce changes in blood pressure and heart rate of short duration that reflect how well the involuntary nervous system is working. In addition, a 24-hour blood pressure monitoring and exercise test may be also performed in some subjects.; The effects of continuous IV infusion or pulse IV administration of saline in increasing total blood volume and fatigue score will be evaluated; Trimethaphan IV infusion for approximately 60 minutes at a dose of 4-6 mg/min L-NMMA IV infusion for approximately 45 minutes at 125, 250, and 500 mg/kg/min for 15 minutes each; Aldomet oral twice a day for 12 weeks
Other intervention name(s): Aldomet
Intervention MeSH terms: Methyldopa; Trimethaphan; Trimethaphan camsylate
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Keywords: Chronic fatigue syndrome; Postural tachycardia syndrome; Autonomic nervous system