Assessing the Efficacy of Midodrine in Improving Orthostatic Tolerance Using Lower Body Negative Pressure plus Tilt-Table Testing

Syncope (“fainting”) is defined as a transient loss of consciousness due to reduced cerebral blood flow (1) It is a major clinical problem in the U.S. population. It is estimated that approximately 3% of emergency department visits and 2-6% of hospital admissions are for syncope (1), with more than 500,000 new patients experiencing syncope per year (2) and costing the health care system over $2 billion annually (3). Although the causes of syncope are numerous, and include disorders of vascular tone or blood volume, cardiovascular disorders, and cerebrovascular disorders, the type of syncope to which this study pertains is orthostatic intolerance, or syncope resulting from the stress of standing erect (e.g. orthostatic stress) due to excess blood “pooling” in the veins of the lower extremities, thus reducing systemic and cerebral blood flow and inducing syncope. When a healthy person stands erect, this venous pooling is compensated by three physiologic mechanisms, largely regulated by the autonomic nervous system: constriction of arterioles and venules, increased heart rate, and contraction of the leg muscles, which serve as a pump to increase venous return. However, patients with orthostatic tolerance are deficient in one of these mechanisms, and thus can not compensate effectively when standing and are prone to syncope. Orthostatic intolerance can further be grouped into three categories. The first is acute orthostatic hypotension, during which the patient experiences an acute drop in blood pressure when standing that can eventually lead to syncope. The second category is dysautonomic syncope, where the patient experiences a slower, progressive drop in blood pressure that eventually leads to a syncopal event. The final category is vasovagal syncope, which occurs when a patient initially experiences appropriate responses to a decreased systemic blood volume, such as the normal compensatory mechanisms outlined above, but eventually very low ventricular volumes lead to mechanoreceptor activation and an increased parasympathetic stimulus called the Bezold-Jarisch reflex, which then leads to decreased heart rate, decreased vascular resistance, and eventually syncope (4). This is the disorder which we will examine in our study. Traditionally, head-up tilting has been used as a model for orthostatic stress, in that the patient is tilted from a supine to a standing position and then remains standing for a specified time period (usually from 20-60 minutes). Patients that experience syncope during this procedure are usually given a diagnosis of orthostatic intolerance. Patients not prone to this disorder can be expected to be asymptomatic during the period of tilting and thus have a negative (normal) tilt-table test. While the tilt-table test is of widespread use in the evaluation of syncope, there is a significant drawback to using this test in that there is a low incidence of symptomatic hypotension, and thus positive tilt-table tests (5). In healthy subjects, the incidence of positive tests is usually very low, and one study by Hainsworth and Al-Shamma reported no positive tests in 66 healthy subjects when tilted to 60 degrees for 20 minutes (6). As a result, these subjects are producing no data with which to evaluate their predisposition to syncope, and the study loses power by not having data for these subjects. Furthermore,