Tilt testing with combined lower body negative pressure: a "gold standard" for measuring orthostatic tolerance

Orthostatic tolerance (OT) refers to the ability to maintain cardiovascular stability when upright, against the hydrostatic effects of gravity, and hence to maintain cerebral perfusion and prevent syncope (fainting). Various techniques are available to assess OT and the effects of gravitational stress upon the circulation, typically by reproducing a presyncopal event (near-fainting episode) in a controlled laboratory environment. The time and/or degree of stress required to provoke this response provides the measure of OT. Any technique used to determine OT should: enable distinction between patients with orthostatic intolerance (of various causes) and asymptomatic control subjects; be highly reproducible, enabling evaluation of therapeutic interventions; avoid invasive procedures, which are known to impair OT(1). In the late 1980s head-upright tilt testing was first utilized for diagnosing syncope(2). Since then it has been used to assess OT in patients with syncope of unknown cause, as well as in healthy subjects to study postural cardiovascular reflexes(2-6). Tilting protocols comprise three categories: passive tilt; passive tilt accompanied by pharmacological provocation; and passive tilt with combined lower body negative pressure (LBNP). However, the effects of tilt testing (and other orthostatic stress testing modalities) are often poorly reproducible, with low sensitivity and specificity to diagnose orthostatic intolerance(7). Typically, a passive tilt includes 20-60 min of orthostatic stress continued until the onset of presyncope in patients(2-6). However, the main drawback of this procedure is its inability to invoke presyncope in all individuals undergoing the test, and corresponding low sensitivity(8,9). Thus, different methods were explored to increase the orthostatic stress and improve sensitivity. Pharmacological provocation has been used to increase the orthostatic challenge, for example using isoprenaline(4,7,10,11) or sublingual nitrate(12,13). However, the main drawback of these approaches are increases in sensitivity at the cost of unacceptable decreases in specificity(10,14), with a high positive response rate immediately after administration(15). Furthermore, invasive procedures associated with some pharmacological provocations greatly increase the false positive rate(1). Another approach is to combine passive tilt testing with LBNP, providing a stronger orthostatic stress without invasive procedures or drug side-effects, using the technique pioneered by Professor Roger Hainsworth in the 1990s(16-18). This approach provokes presyncope in almost all subjects (allowing for symptom recognition in patients with syncope), while discriminating between patients with syncope and healthy controls, with a specificity of 92%, sensitivity of 85%, and repeatability of 1.1±0.6 min(16,17). This allows not only diagnosis and pathophysiological assessment(19-22), but also the evaluation of treatments for orthostatic intolerance due to its high repeatability(23-30). For these reasons, we argue this should be the "gold standard" for orthostatic stress testing, and accordingly this will be the method described in this paper.