Elsevier

Autonomic Neuroscience

Volume 213, September 2018, Pages 81-85
Autonomic Neuroscience

Delayed orthostatic hypotension: Severity of clinical symptoms and response to medical treatment

https://doi.org/10.1016/j.autneu.2018.06.005Get rights and content

Highlights

  • Patients with delayed OH had less severe orthostatic BP drop than the classic OH.

  • Patients with delayed OH exhibited orthostatic intolerance similar to that of classic OH.

  • Medical treatment improved standing BP drop and associated symptoms in patients with delayed OH.

Abstract

Introduction

Severity of orthostatic intolerance and the benefit of medical treatment in patients with delayed OH have not been elucidated. This study aimed to compare the symptom severity between classic and delayed OH and evaluate the efficacy of midodrine or pyridostigmine in patients with delayed OH.

Methods

This was an adjunctive study of previously reported randomized, open-label clinical trials evaluating the efficacy and safety of midodrine or pyridostigmine for classic OH. Seventeen patients with delayed OH were enrolled and also received midodrine (2.5 mg twice a day) or pyridostigmine (30 mg twice a day) alone or combined. Result of initial orthostatic vital sign and questionnaires were compared between the patients with delayed OH and previously reported 87 patients with classic OH. Delayed OH patients were followed up at 1 and 3 months post-treatment and the vital sign measurements and questionnaires were repeated during the follow-up period.

Results

Questionnaire scores regarding OH-related symptoms, depression and health-related quality of life (HRQOL) were comparable between the classic and delayed OH patients at baseline. OH-related symptoms and depression were significantly improved after 3 months of medical treatment.

Conclusion

Patients with delayed OH exhibited orthostatic intolerance similar to that of classic OH. This study shows that these patients may benefit from medical treatment with either midodrine or pyridostigmine.

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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1

The first two authors contributed equally to this work.

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