This trial has been completed.

Conditions chronic fatigue syndrome, orthostatic intolerance, postural tachycardia syndrome
Treatments autonomic function testing, saline infusions, l-nmma trimethaphan, methyldopa
Phase phase 1
Sponsor Vanderbilt University
Start date April 2007
End date January 2017
Trial size 58 participants
Trial identifier NCT00580619, 060662, CRC-1636, CRC-1705


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).

United States No locations recruiting
Other countries No locations recruiting

Study Design

Allocation non-randomized
Endpoint classification efficacy study
Intervention model parallel assignment
Masking open label
To evaluate if the various indices of sympathetic activity (Autonomic Function Testing) differ between patients with chronic fatigue syndrome and postural tachycardia syndrome (CFS-P), and CFS without POTS.
autonomic function testing
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.
To test the null hypothesis that there is no difference between two saline therapies (pulse saline vs. sham saline) in improving both the fatigue score and postural tachycardia syndrome.Saline infusions
saline infusions
The effects of continuous IV infusion or pulse IV administration of saline in increasing total blood volume and fatigue score will be evaluated
Response to nitric oxide inhibition in the presence and absence of an intact autonomic nervous system will be evaluated. L-NMMA trimethaphan will be used for NO inhibition and autonomic blockade, respectively.
l-nmma trimethaphan
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
(Active Comparator)
The effects of chronic autonomic withdrawal on improving symptoms of chronic fatigue and postural tachycardia syndrome will be evaluated
methyldopa Aldomet
Aldomet oral twice a day for 12 weeks

Primary Outcomes

Heart rate
time frame: Duration of the intervention

Secondary Outcomes

Blood Pressure
time frame: Duration of the intervention

Eligibility Criteria

All participants from 18 years up to 65 years old.

Inclusion Criteria: - Meet CDC diagnostic criteria of CFS (Fukuda et al., 1994) - Meet diagnostic criteria of POTS (Raj et al., 2005) - Age between 18-65 years - Male and female are eligible (although the majority of patients with CFS-P are female) Exclusion Criteria: - Presence of medical conditions that can explain postural tachycardia syndrome (e.g., dehydration, medications) - Presence of medical or psychiatric conditions known to cause fatigue (Fukuda et al., 1994). Inability to give, or withdrawal of, informed consent - Inability to acquire or maintain adequate long-term intravenous access (peripheral indwelling catheter, PIC) - Pregnancy - Other factors which in the investigator's opinion would prevent the subject from completing the protocol - Patients who are bedridden or chair-ridden

Additional Information

Official title Autonomic Nervous System and Chronic Fatigue Syndrome
Principal investigator Italo Biaggioni, MD
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.
Trial information was received from ClinicalTrials.gov and was last updated in January 2017.
Information provided to ClinicalTrials.gov by Vanderbilt University Medical Center.