Water and Sudafed in Autonomic Failure

NCT ID: NCT02149901

Last Updated: 2021-05-05

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: EARLY_PHASE1
• Total Enrollment: 35 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-10-31
• Study Completion Date: 2020-12-31

Brief Summary

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.

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.

Conditions

Shy-Drager Syndrome; Multiple System Atrophy

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: OTHER
• Blinding Strategy: NONE

Study Groups

Pseudoephedrine + 480 ml water

Pseudoephedrine 30 mg PO 45 minutes before water 480 ml

Group Type: EXPERIMENTAL

Pseudoephedrine + 480 ml water

Intervention Type: DRUG

30 mg pseudoephedrine to be given with a pressor dose (480 ml) of drinking water

Pseudoephedrine + 50 ml water

Pseudoephedrine 30 mg PO 45 minutes before water 50 ml

Group Type: PLACEBO_COMPARATOR

Pseudoephedrine + 50 ml water

Intervention Type: DRUG

Pseudoephedrine given with a non-pressor (50 ml) dose of drinking water

Placebo + 480 ml water (optional)

Placebo PO 45 minutes before water 480 ml

Group Type: EXPERIMENTAL

Placebo + 480 ml water (optional)

Intervention Type: OTHER

placebo PO with a pressor (480 ml) dose of drinking water

Placebo + 50 ml water (optional)

Placebo PO 45 minutes before water 50 ml

Group Type: PLACEBO_COMPARATOR

Placebo + 50 ml water (optional)

Intervention Type: OTHER

placebo PO with a non-pressor (50 ml) dose of drinking water

Interventions

Pseudoephedrine + 480 ml water

30 mg pseudoephedrine to be given with a pressor dose (480 ml) of drinking water

Intervention Type: DRUG

Pseudoephedrine + 50 ml water

Pseudoephedrine given with a non-pressor (50 ml) dose of drinking water

Intervention Type: DRUG

Placebo + 480 ml water (optional)

placebo PO with a pressor (480 ml) dose of drinking water

Intervention Type: OTHER

Placebo + 50 ml water (optional)

placebo PO with a non-pressor (50 ml) dose of drinking water

Intervention Type: OTHER

Other Intervention Names

Sudafed; drinking water; Sudafed; drinking water; drinking water; drinking water

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

National Center for Advancing Translational Sciences (NCATS)

NIH

Sponsor Role: collaborator

Vanderbilt University

OTHER

Sponsor Role: lead

Responsible Party

Emily M. Garland

Research Associate Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Emily M Garland, PhD, MSCI

Role: PRINCIPAL_INVESTIGATOR

Vanderbilt University Medical Center

Locations

Vanderbilt University

Nashville, Tennessee, United States

Countries

United States

References

Jordan J, Shannon JR, Grogan E, Biaggioni I, Robertson D. A potent pressor response elicited by drinking water. Lancet. 1999 Feb 27;353(9154):723. doi: 10.1016/S0140-6736(99)99015-3. No abstract available.

Reference Type: BACKGROUND

PMID: 10073520 (View on PubMed)

Jordan J, Shannon JR, Black BK, Ali Y, Farley M, Costa F, Diedrich A, Robertson RM, Biaggioni I, Robertson D. The pressor response to water drinking in humans : a sympathetic reflex? Circulation. 2000 Feb 8;101(5):504-9. doi: 10.1161/01.cir.101.5.504.

Reference Type: BACKGROUND

PMID: 10662747 (View on PubMed)

Jordan J, Shannon JR, Diedrich A, Black B, Robertson D, Biaggioni I. Water potentiates the pressor effect of ephedra alkaloids. Circulation. 2004 Apr 20;109(15):1823-5. doi: 10.1161/01.CIR.0000126283.99195.37. Epub 2004 Apr 5.

Reference Type: BACKGROUND

PMID: 15066944 (View on PubMed)

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Reference Type: BACKGROUND

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Reference Type: BACKGROUND

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Reference Type: BACKGROUND

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Reference Type: BACKGROUND

PMID: 7507589 (View on PubMed)

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Reference Type: BACKGROUND

PMID: 2161310 (View on PubMed)

Other Identifiers

P01HL056693

Identifier Type: NIH

Identifier Source: secondary_id

View Link

UL1TR000445

Identifier Type: NIH

Identifier Source: secondary_id

View Link

140547

Identifier Type: -

Identifier Source: org_study_id