Drugs for the Prevention and Control of Syncope

Syncope is defined as a transient loss of consciousness and postural tone with spontaneous recovery and no neurologic sequelae. Regardless of its etiology, syncope results from insufficient blood flow to the reticular activating substance of the midbrain. By choosing to live in the upright posture, humans have made themselves uniquely susceptible to syncope, which is said to occur at least once in more than 3% of the population. Schematically, syncope can result from three hemodynamic abnormalities. In rising order of frequency, syncope can result from an acute increase in cerebrovascular resistance, an acute decrease in cardiac output or a fall in systemic blood pressure usually apparent in the standing position and reflecting ineffective control of peripheral vascular resistance. This last mechanism accounts for the largest number of cases encountered in clinical practice. A careful history should help differentiate between orthostatic hypotension secondary to drugs, orthostatic hypotension resulting from one of the chronic autonomic failure syndromes or the acute neurally mediated syncopal syndromes typified by vasovagal syncope and neurocardiogenic syncope. While there is little difference between vasovagal syncope and neurocardiogenic syncope, other than the clinical scenario leading to syncope, it is important that physicians evaluating patients with syncope distinguish these two entities and the chronic autonomic failure syndromes [1,2]. Young otherwise healthy individuals presenting with paroxysmal syncope are most likely to have experienced vasovagal or neurocardiogenic syncope, while older patients, often with associated medical conditions, may well display autonomic failure with supine hypertension and orthostatic hypotension leading to dizziness and/or syncope. By the same token, if physicians perform upright tilt testing, it is important that they monitor the hemodynamic response of their patients carefully. Healthy young patients with neurocardiogenic syncope will demonstrate no abnormality until the fairly abrupt onset of symptomatic hypotension and bradycardia while patients with chronic autonomic dysfunction will display gradual hemodynamic changes that may culminate more or less rapidly in syncope. Upright Tilt Testing and Natural History With the introduction of tilt testing in the mid 1980’s [3], it became possible to provoke and therefore diagnose neurocardiogenic syncope in a medical setting, prompting various therapeutic strategies to prevent recurrence. Most efforts however have been of an empirical nature, based on the use of drugs with pharmacologic actions thought to antagonize some of the physiologic changes leading to or observed during neurocardiogenic syncope. While many drugs have been reported to be effective in open label trials, when pharmacologic therapy has been subjected to double blind randomized placebo controlled trials; few therapies have demonstrated convincing benefit. Part of the difficulty has been that while tilt testing is a useful test in the evaluation of patient’s with unexplained syncope, it has not proven entirely reproducible and clearly does not constitute a reliable end point to predict therapeutic efficacy. In addition, the observation that neurocardiogenic syncope typically occurs in clusters, that a patient’s likelihood of recurrence can be predicted by historical features, and that upright tilt testing has therapeutic effects in itself were not incorporated in the design of early studies [4].