Delayed orthostatic hypotension: Severity of clinical symptoms and response to medical treatment
Introduction
“Classic” orthostatic hypotension (OH) is defined as a systolic blood pressure (SBP) drop of at least 20 mmHg or a diastolic blood pressure (DBP) drop of at least 10 mmHg within 3 min of standing or upright tilt table testing to 60° (Freeman et al., 2011). However, the blood pressure (BP) drop commonly occurs beyond 3 min; when this occurs, it is referred to as delayed OH. OH can be clinically classified into several categories, and delayed OH is recognized as a potential etiology of orthostatic intolerance (Freeman et al., 2011; Cheshire Jr, 2017).
Among 230 patients with orthostatic intolerance enrolled in a previous study, less than half (46%) exhibited a BP drop within 3 min, 15% had a BP drop between 3 and 10 min, and 39% had a BP drop after 10 min (Gibbons and Freeman, 2006). A retrospective analysis of 270 participants with OH showed that 43% of patients experienced a BP drop within 3 min, and 91% experienced a drop within 30 min (Gurevich et al., 2014).
Several pathophysiological mechanisms have been suggested to explain the delayed BP drop, including increased peripheral venous pooling, increased fluid transudation, or gradual failure of neural and humoral counteraction against redistributed blood volume (Gibbons and Freeman, 2006). Progressive decrease in total peripheral resistance (Podoleanu et al., 2009) or inadequate calf muscle tone (Madhavan et al., 2008) was also suggested to be a contributor of delayed OH. A recent report suggests that delayed OH is an earlier, milder form of classic OH (Gibbons and Freeman, 2015) based on milder sympathetic adrenergic dysfunction during the Valsalva maneuver (Gibbons and Freeman, 2006).
Evaluation of patients with delayed OH has focused primarily on their orthostatic BP or heart rate (HR) changes or on laboratory autonomic function test results. Although the main reason for a clinic visit in these patients is orthostatic intolerance, its impact on quality of life has not been evaluated in detail. Whether delayed OH can reduce health-related quality of life (HRQOL) or cause depression is unclear. Moreover, the necessity of medical treatment that is known to improve orthostatic BP changes and associated symptoms in classic OH (Singer et al., 2006; Byun et al., 2017), including midodrine and pyridostigmine, has not been properly evaluated in delayed OH.
Delayed OH can cause hypotensive symptoms, such as dizziness, pre-syncope, weakness, fatigue, and palpitation (Streeten and Anderson Jr., 1992). Fatigue was even more common in patients with delayed OH than in those with classic OH. We hypothesized that the patients with delayed OH may also have similar disturbances as classic OH, which can be relieved after medical treatment. Therefore, we first performed a cross-sectional study to assess OH-related symptom severity in delayed OH and to compare it with that of classic OH. Then, we performed an observational study to evaluate the efficacy of treatment with midodrine and pyridostigmine for up to 3 months in patients with delayed OH.
Section snippets
Study participants and ethics
This was an adjunctive study of a randomized, open-label clinical trial of midodrine and pyridostigmine for OH, which was registered at ClinicalTrials.gov (NCT02308124) (Byun et al., 2017). Previously, we enrolled 120 consecutive patients with symptomatic OH within 10 min of standing and reported the medical treatment outcome in 87 of those with classic OH (Byun et al., 2017). This study analyzed 17 of the patients who were excluded for having delayed OH, which was defined as a SBP reduction of
Clinical features and baseline characteristics
The mean age of the patients with delayed OH was 51.5 years, and 7 (41.2%) were male. The mean BMI of the patients was 23.2 kg/m2. Baseline characteristics were similar between the patients with delayed and classic OH. Six of them had non-diabetic peripheral autonomic neuropathy, and 11 had an unspecified etiology.
Baseline supine vital signs and nadir BP during 10 min of standing were similar between those with classic and delayed OH. However, the maximal orthostatic SBP drop within 10 min
Discussion
This study showed that patients with delayed OH, despite having less of an orthostatic BP drop, have a similar severity of orthostatic intolerance as those with classic OH. Overall depressive symptoms and HRQOL were also comparable between the classic and delayed OH groups. Moreover, this study was the first to evaluate the efficacy of medical treatment with midodrine or pyridostigmine in patients with delayed OH, and the results showed improvement in the standing BP drop and associated
Perspectives
Patients with delayed OH showed similar orthostatic intolerance symptoms despite a lower degree of orthostatic BP drop than those with classic OH. This study suggests that medical treatment with midodrine may be of benefit for the rapid amelioration of symptoms associated with delayed OH. However, determination of the necessity of prolonged treatment and whether the treatment may be effective in preventing progression to degenerative disease or improving the mortality rate requires further
Acknowledgements
None.
Funding
This study was supported by funds from JW Pharma (C1411-4), SK Plasma (0620164080) and Daiichi Sankyo Korea (06-2014-3970).
Conflict of interest
The authors declare that there are no conflicts of interest to disclose.
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The first two authors contributed equally to this work.