Water and Sudafed in Autonomic Failure

April 29, 2021 updated by: Emily M. Garland, Vanderbilt University

Effect of Drinking Water on the Pressor Response to Pseudoephedrine in Patients With Autonomic Failure

The specific aim of this study is to determine whether water ingestion potentiates the pressor response to pseudoephedrine in patients with primary disorders of autonomic failure. The study design will enable us to also evaluate the pressor response to water alone and to pseudoephedrine alone. In a secondary analysis, we will compare the results in patients with two autonomic disorders, pure autonomic failure (PAF) and multiple system atrophy (MSA). We hypothesize that drinking water following a dose of pseudoephedrine will lead to a greater increase in blood pressure than pseudoephedrine alone.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed Description

The maximal pressor response to water is reached when other pressor agents are only beginning to act. In addition to the therapeutic value of water ingestion alone, the blood pressure-raising effects of agents that increase sympathetic nervous system tone, such as phenylpropanolamine, are potentiated by water drinking. These drug interaction effects can be exploited in the treatment of orthostatic hypotension with the combination of water and a sympathomimetic potentially able to increase blood pressure to a greater extent and for a longer period of time than either water or the medication alone. However, the interaction can also lead to potentially dangerous blood pressure surges.

This protocol requires an initial screening history and physical of study participants, including safety labs and EKGs, and evaluation of their autonomic nervous system status following the consent process. If the patient meets study criteria and is willing to undergo study testing, the 4-way crossover protocol will follow.

Study Testing days 1 and 2 Arm 1: Pseudoephedrine 30 mg PO + 50 ml water Arm 2: Pseudoephedrine 30 mg PO + 480 ml water

  • Testing will be performed at the same time of day for all studies, at least 2 hours after a meal to avoid any confounding effects from postprandial hypotension.
  • A saline lock will be inserted for blood sampling at least 30 minutes before baseline data collection.
  • Participants will be asked to empty their bladders before beginning the test to avoid any effect of a full urinary bladder on peripheral sympathetic activity.
  • Participants will be seated comfortably in a chair. They will be asked to remain in the seated position for the duration of the study.
  • The Dinamap electrocardiographic and blood pressure (brachial cuff) recorder will be attached to the patient and set up for measurements every 5 minutes throughout the study with digital download into the ADC (Autonomic Dysfunction Center) BP database.
  • Participants will also be instrumented with EKG, finger cuff and sensor for continuous monitoring of blood pressure, heart rate, respiration, SpO2, stroke volume, systemic vascular resistance, and cardiac output, using a Nexfin system and Ivy Biomedical Vital-Guard monitor.
  • After a 30 minute baseline monitoring period (time -30 min to 0 min), 4 ½ teaspoons of blood will be collected for osmolality measurement and assays of hormones that regulate blood pressure.
  • The subject will then be given 30 mg of pseudoephedrine PO (time 0 min). Monitoring will be continued for 45 minutes.
  • At 45 minutes, the participant will be asked to drink 50 ml (Arm 1) or 480 ml (Arm 2) of water.
  • Additional blood samples (4 ½ teaspoons) for osmolality and BP-regulating hormones will be collected 30 and 60 minutes after water (+75 and +105 minutes of study).
  • Monitoring will be continued until + 135 min.
  • At 135 minutes, the study will end for the day. The timing of pseudoephedrine administration relative to water ingestion and the duration of the monitoring period are based on previous results3 and pharmacokinetic data7 reporting a Tmax for pseudoephedrine between 1 and 2 hours. Testing on study day 2 will be identical with the participant consuming the alternate water volume.

Study Testing days 3 and 4 are optional Arm 3: Placebo PO + 50 ml water Arm 4: Placebo PO + 480 ml water Testing will be performed according to the same schedule as for Arms 1 and 2. Instrumentation will be limited to the Dinamap electrocardiographic and blood pressure (brachial cuff) recorder set up for measurements every 5 minutes throughout the study for Arms 3 and 4.

Study Type

Interventional

Enrollment (Anticipated)

35

Phase

  • Early Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Tennessee
      • Nashville, Tennessee, United States, 37232
        • Vanderbilt University

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 80 years (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Age 18-80 years, with
  • Neurogenic orthostatic hypotension, ≥30 mmHg drop in SBP within 5 minutes of standing,
  • Associated with impaired autonomic reflexes, as determined by absence of blood pressure overshoot during phase IV of the valsalva maneuver,
  • Absence of other identifiable causes of autonomic neuropathy, and
  • Able and willing to provide informed consent

Exclusion Criteria

  • Pregnancy
  • Current smoking habit
  • Systemic illnesses known to produce autonomic neuropathy, including but not limited to diabetes mellitus, amyloidosis, monoclonal gammopathy of unknown significance, and autoimmune neuropathies.
  • Known intolerance to pseudoephedrine
  • Pre-existing sustained severe hypertension (BP > 180/110 mmHg in the sitting position)
  • Clinically unstable coronary artery disease or major cardiovascular or neurological event in the past 6 months.
  • Any other significant systemic, hepatic, cardiac or renal illness
  • Use of MAO-I (i.e. selegiline; rasagiline - Azilect, linezolid and others) within 14 days
  • Known closed-angle glaucoma
  • Clinically meaningful arrhythmias
  • Other factors which in the investigator's opinion would prevent the participant from completing the protocol, including poor compliance during previous studies or an unpredictable schedule

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: OTHER
  • Allocation: RANDOMIZED
  • Interventional Model: CROSSOVER
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Pseudoephedrine + 480 ml water
Pseudoephedrine 30 mg PO 45 minutes before water 480 ml
Drug: Pseudoephedrine + 480 ml water
30 mg pseudoephedrine to be given with a pressor dose (480 ml) of drinking water
Other Names:
  • Sudafed
  • drinking water
Placebo Comparator: Pseudoephedrine + 50 ml water
Pseudoephedrine 30 mg PO 45 minutes before water 50 ml
Drug: Pseudoephedrine + 50 ml water
Pseudoephedrine given with a non-pressor (50 ml) dose of drinking water
Other Names:
  • Sudafed
  • drinking water
Experimental: Placebo + 480 ml water (optional)
Placebo PO 45 minutes before water 480 ml
Other: Placebo + 480 ml water (optional)
placebo PO with a pressor (480 ml) dose of drinking water
Other Names:
  • drinking water
Placebo Comparator: Placebo + 50 ml water (optional)
Placebo PO 45 minutes before water 50 ml
Other: Placebo + 50 ml water (optional)
placebo PO with a non-pressor (50 ml) dose of drinking water
Other Names:
  • drinking water

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
The primary outcome measure in each Aim will be the peak increase in systolic blood pressure after pseudoephedrine or placebo relative to baseline (delta SBP).
Time Frame: between 60 and 120 minutes after pseudoephedrine or placebo
between 60 and 120 minutes after pseudoephedrine or placebo

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in diastolic blood pressure relative to baseline
Time Frame: between 60 and 120 minutes after pseudoephedrine or placebo
between 60 and 120 minutes after pseudoephedrine or placebo
Change in heart rate relative to baseline
Time Frame: between 60 and 120 minutes after pseudoephedrine or placebo
between 60 and 120 minutes after pseudoephedrine or placebo
Absolute systolic blood pressure after treatment
Time Frame: between 60 and 120 minutes after pseudoephedrine and placebo
between 60 and 120 minutes after pseudoephedrine and placebo
Absolute diastolic blood pressure after treatment
Time Frame: between 60 and 120 minutes after pseudoephedrine or placebo
between 60 and 120 minutes after pseudoephedrine or placebo
area under the curve for systolic blood pressure from baseline to 135 minutes post-treatment
Time Frame: from baseline to 135 minutes after pseudoephedrine or placebo
Area under the curve can better measure an extension of the duration of response.
from baseline to 135 minutes after pseudoephedrine or placebo
Peak plasma norepinephrine concentration after treatment
Time Frame: between baseline and 135 minutes after pseudoephedrine or placebo
between baseline and 135 minutes after pseudoephedrine or placebo

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Vanderbilt University

Collaborators

National Heart, Lung, and Blood Institute (NHLBI)
National Center for Advancing Translational Sciences (NCATS)

Investigators

  • Principal Investigator: Emily M Garland, PhD, MSCI, Vanderbilt University Medical Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

October 1, 2014

Primary Completion (Actual)

December 1, 2020

Study Completion (Actual)

December 1, 2020

Study Registration Dates

First Submitted

May 26, 2014

First Submitted That Met QC Criteria

May 26, 2014

First Posted (Estimate)

May 29, 2014

Study Record Updates

Last Update Posted (Actual)

May 5, 2021

Last Update Submitted That Met QC Criteria

April 29, 2021

Last Verified

April 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 140547
  • UL1TR000445 (U.S. NIH Grant/Contract)
  • P01HL056693 (U.S. NIH Grant/Contract)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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