Water and Sudafed in Autonomic Failure
| Status: | Active, not recruiting |
|---|---|
| Conditions: | Other Indications |
| Therapuetic Areas: | Other |
| Healthy: | No |
| Age Range: | 18 - 80 |
| Updated: | 4/6/2019 |
| Start Date: | October 2014 |
| End Date: | December 2019 |
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.
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.
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.
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.
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
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