Variant responses impair the usefulness of passive upright tilt in drug research

Thirty-five male normal subjects underwent gradual passive upright tilt (1 minute at 15 degree, 2 minutes at 45 degree and 7 minutes at 85 degree) on a total of 256 occasions, in drug-free condition or after administration of placebo. Although a cardio-acceleratory and vasopressor response prevailed, seven subjects experienced imminent syncope on 9 occasions, after 2 to 7 minutes erect standing. These reactions were hypotensive in nature, and preceded by (5 instances) or concurrent with (3 instances) a sudden drop of the initially adequately rising heart rate. These reactions are likely to be of vagal origin. All reactions occurred suddenly and unexpectedly and improved rapidly when the subject was tilted back to supine position. Imminent syncopes on passive upright tilt appeared to be incidental phenomena occurring in subjects who uneventfully underwent previous or subsequent tilting, either on the same day or on another day. The potential severity of these reactions, their unpredictability and their lack of reproducibility restrict the usefulness of passive upright tilt as a test procedure in drug research. In the event that such reactions would appear after exposure to an investigational drug, it cannot be proven beyond reasonable doubt that the reaction is caused by the drug, is a variant response intrinsic to the test procedure, or a drug-related enhancement of the onset and/or severity of such a variant response.