Hemodynamic Response of Neuropathic And Non-Neuropathic POTS Patients To Adrenoreceptor Agonist And Antagonist

The pathophysiological basis of postural tachycardia syndrome (POTS) is not well elucidated. The most widely recognized primary cause of POTS is a "restricted" or "selective" peripheral neuropathy - neuropathic POTS. Several lines of evidence point to a restricted peripheral neuropathy, specifically sympathetic denervation in the lower hemibody, as a cause of POTS. These include venous denervation, impaired distal sudomotor dysfunction, lower norepinephrine spillover in the legs than the arms. However, not all POTS patients have peripheral neuropathy. Proposed pathogenic etiologies for non-neuropathic POTS include deconditioning, low-grade inflammation and oxidative stress. Neuropathic POTS is present in 33% of patients while non-neuropathic POTS is present in 67% of patients.

The most frequent neuropathic feature in the neuropathic POTS group is decreased sweat output measured by quantitative sudomotor axon reflex test. Headache and gastrointestinal symptoms (such as abdominal pain, bloating, nausea and constipation) are also more prevalent in the neuropathic than in the non-neuropathic POTS group, suggesting more global differences between the two populations.

In relation to the ambiguous pathophysiological basis, there is no definitive treatment for POTS. There are reports of improvements in hemodynamic measures and symptoms of orthostatic tolerance with pharmacologic agents that include intravenous saline, intravenous phenylephrine, midodrine, octreotide, erythropoietin, pyridostigmine, and betablockade. The therapy is however frequently disappointing. Furthermore, there are no reported long-term studies of medications to treat POTS and there are no reports of the effects of any intervention on fatigue or quality of life.

The most widely used agents to treat POTS, the alpha-adrenoreceptor agonist midodrine, and the beta blockers, paradoxically have agonistic and antagonistic effects on the autonomic nervous system. Responses to these drugs are inconsistent and there are no delineated predictors of the response in POTS patients.

The comparison of therapeutic interventions in this protocol are based on the rationale that while alpha-adrenoreceptor agonists are thought to be more effective in neuropathic POTS - a disorder characterized by a compensatory increase in sympathetic outflow in which sympatholysis may be counterproductive, beta-adrenoreceptor antagonists are thought to be more effective in non-neuropathic POTS - a disorder that could be characterized by increased central sympathetic outflow due to impaired sympathetic inhibition.

This protocol uses droxidopa, which is converted to direct adrenoreceptor agonist, norepinephrine. The protocol also uses beta-adrenoreceptor antagonist, the non-selective atenolol.

This is a randomized, double-blind, placebo-controlled, cross-over experimental study with three trial arms, according to the two medications (droxidopa and atenolol) and the placebo. The trial is performed in the Center for Autonomic and Peripheral Nerve Disorders at the Beth Israel Deaconess Medical Center.

The study consists of 10 visits:

screening visit,

testing days to define drug sensitivity

classification day

autonomic testing visits

follow-up visits

Screening visit (Visit 1) includes

Consenting procedure

Review of medical history

Review of all current medications, prescription and over the counter

Physical and neurological examinations

Measure height, weight, temperature and vital signs

12-lead ECG

Baseline autonomic tests

Blood labs

Serum pregnancy testing for women of childbearing potential

Patients are able to take PO medications

Drug Sensitivity Visit (Visit 2 and 3) On the first visit, patients receive one 100 mg droxidopa while on the second visit patients receive one 300 mg test dose of droxidopa to define their response to the drug. The drug administration is preceded and followed by heart rate and blood pressure measurements and side effect monitoring. The two consecutive visits are made within a period of 3 days. The goal of sensitivity visit is to determine if a patient has any sign of denervation supersensitivity in response to droxidopa. The patient is considered to have denervation supersensitivity if systolic blood pressure is greater than 180 mmHg or diastolic blood pressure is greater than 110 mmHg after 3 minutes of standing or after 5 minutes of sitting or the patient is unable to tolerate the side effects believed to be related to the drug.

Patient classification visit (Visit 4) includes

Quantitative Direct and Indirect testing of Sudomotor Function (QDIRT)

Quantitative Sudomotor Axon Reflex Testing (QSART)

Quantitative Sensory Testing (QST)

Punch skin biopsy

Questionnaires (Chronic Fatigue Screening Form, Fatigue Severity Scale, Chalder Fatigue Questionnaire, etc., see Questionnaires section)

Autonomic Evaluation Visits (Visit 5, 7 and 9) include

Urine pregnancy test for women of child-bearing potential

Setup and instrumentation

Blood draw for hormones and catecholamines (Visit 5 only)

Microneurography procedure

Drug/placebo administration

Deep breathing test

Paced breathing test

Modified Oxford test

Sympathetic transduction

Static exercise

Tilt table test

Primary outcome measure of autonomic evaluation visit is maximum postural tachycardia while secondary outcome measure of autonomic evaluation visit are blood pressure, heart rate, vascular resistance, muscle sympathetic nerve activity.

Follow-up testing visits (Visit 6, 8 and 10) include

Medical history

Physical examination

Vital signs

EKG

Blood pressure measurement

Tilt table test

Primary outcome measure of follow-up testing visits is the fatigue score on the Chalder Fatigue questionnaire while secondary outcome measures of follow-up testing visits are the scores on the physical functioning subscale of the SF-36 questionnaire, 7 item patient global impression of change, the Hospital Anxiety and Depression Scales, the Checklist Individual Strength (CIS), Multidimensional Fatigue Inventory (MFI), the Fatigue Severity Scale, the EuroQOL, the HADS and anxiety scores. The Orthostatic Intolerance Questionnaire - a unique validated questionnaire is used to assess orthostatic intolerance symptoms and quality of life-related to orthostatic intolerance.