Intravenous Norepinephrine for Orthostatic Hypotension

Background: - Orthostatic hypotension is a fall in blood pressure when standing up. Normally, a reflex action of the automatic nervous system makes blood vessels tighten when people stand up. The nervous system releases the chemical norepinephrine, which tightens blood vessels and keeps blood pressure in check. In orthostatic hypotension, the nervous system does not release enough norepinephrine when a person stands up, which can cause fainting or falling. Researchers are interested in determining whether norepinephrine given as a drug by vein can help maintain blood pressure during changes in body position. Objectives: - To determine whether intravenous norepinephrine can maintain blood pressure in people with orthostatic hypotension. Eligibility: - Individuals at least 18 years of age who have been diagnosed with orthostatic hypotension related to Parkinson's disease or pure autonomic failure. Design: This study will require a 2-day inpatient admission to the NIH Clinical Center. The first day will involve laboratory evaluation and the second day will involve testing with norepinephrine. The second day requires an overnight stay. Participants will be screened with a medical history and physical examination, blood samples, and an electrocardiogram or echocardiogram. Participants who are on medications may be asked to taper or discontinue one or more medications for the purposes of this study. Participants may not take aspirin or any drugs that slow blood clotting for 7 days before study participation. Day 1: Participants will have a clear liquid breakfast, and will have a 1-hour baseline tilt table test to monitor blood flow, skin temperature, sweating, and blood pressure. Body temperature and breathing will also be monitored. Day 2: Participants will have a clear liquid breakfast, and will have a 2-hour tilt table test. Initial blood pressure readings will be taken, and an intravenous line will be placed. Participants will then receive norepinephrine or saline, followed by additional position changes of the tilt table to measure blood pressure differences before returning to the starting position. After about 10 minutes, the tilt table testing and infusion will be repeated with the other drug (saline or norepinephrine). Participants will be discharged 24 hours after the testing is complete.

Objective: Patients with chronic autonomic failure (CAF) often have disabling orthostatic hypotension (OH). In CAF, OH results from deficient baroreflex-mediated release of norepinephrine (NE) from sympathetic nerves. In patients with pure autonomic failure (PAF) or Parkinson disease (PD) with OH, cardiac and extra-cardiac noradrenergic denervation exacerbates effects of baroreflex failure. OH in CAF patients is often associated with supine hypertension, which can be severe. Drugs to treat OH worsen supine hypertension. Therefore, the combination of OH with supine hypertension poses a difficult therapeutic challenge. This protocol is a first step toward development of a prosthetic baroreceptor system to maintain blood pressure during orthostasis without worsening supine hypertension. In patients with PAF or PD+OH NE is infused i.v. at doses titrated individually to maintain blood pressure during head-up tilt at increasing angles from horizontal. Blood pressure is monitored continuously directly via an intra-arterial catheter. Because of the phenomenon of denervation supersensitivity, we anticipate that patients with OH associated with sympathetic noradrenergic denervation, as in PAF and PD, should be especially responsive to i.v. norepinephrine. Study Population: Patients with Parkinson disease and orthostatic hypotension or with pure autonomic failure. Design: This is a placebo controlled study that consists of two experimental days per participant. On a day before the day of norepinephrine (NE) infusion, the patient undergoes head-up tilting (typically at 15, 30, 45, and 60 degrees from horizontal) while blood pressure is monitored. Tilt angles are increased until the patient has orthostatic symptoms, systolic pressure decreases to less than 90 mm Hg, or systolic pressure decreases by more than 80 mm Hg. On the day of NE infusion patients, receive NE and placebo with the sequence of treatments randomized. If the patient has severe supine hypertension (more than 200 mm Hg systolic), then NE is infused beginning with the patient at whatever tilt angle is required for baseline pressure to be less than 200 mm Hg. NE is infused at doses titrated to keep directly recorded systolic blood pressure at or above the baseline value during exposure to higher tilt angles. When placebo is given, angles of tilt are increased until the patient has orthostatic symptoms, systolic pressure decreases to less than 90 mm Hg, or systolic pressure decreases by more than 80 mm Hg. Outcome Measures: The extent to which NE infusion can maintain blood pressure is tested by comparison of the fractional changes in systolic blood pressure at the same tilt angles during NE infusion vs. placebo infusion. Primary: Blood pressures (systolic, diastolic, mean) Symptoms of orthostatic intolerance Secondary: Hemodynamics (e.g., total peripheral resistance) Arterial plasma levels of norepinephrine and related neurochemicals Comparison: Patients undergo head-up tilt at the same angles to verify orthostatic hypotension if norepinephrine is not infused. Participating Sites: The study is done in the NIH Clinical Center in Bethesda, MD. Contact Information: The Principal Investigator is David S. Goldstein, MD PhD, Chief, Clinical Neurocardiology Section, CNP/DIR/NINDS/NIH, phone 301-496-2103, e-mail goldsteind@ninds.nih.gov. The contact for patient care coordination is Tereza Jenkins, phone 301-496-1115, e-mail jenkinst@ninds.nih.gov. The research contact (e.g., for database coordination) is Sandra Pechnik, phone 301-435-5166, e-mail pechniks@ninds.nih.gov.

Baseline values measured at various tilt angles, so that each participant may serve as their own control.

Subjects received a saline IV infusion as a placebo, while measurements were taken at various tilt angles.

Subjects were given an norepinephrine infusion at various tilt angles, while measurements were taken.

The extent to which norepinephrine infusion maintains blood pressure, by comparison with the changes in systolic pressure at varying tilt angles during baseline and saline infusion.

The extent to which norepinephrine infusion maintains blood pressure, by comparison with the changes in diastolic pressure at varying tilt angles during baseline and saline infusion.

The extent to which norepinephrine infusion maintains average blood pressure, by comparison with the fractional changes in blood pressure at varying tilt angles during baseline and saline infusion.

The extent to which norepinephrine infusion affects heart rate, by comparison of beat-to-beat heart rate at varying tilt angles during baseline and saline infusion.

The extent to which norepinephrine infusion affects cardiac stroke volume, by comparison of cardiac stroke volume at varying tilt angles during baseline and saline infusion.

The extent to which norepinephrine infusion affects cardiac output, by comparison of cardiac output at varying tilt angles during baseline and saline infusion.

The extent to which norepinephrine infusion affected total peripheral resistance, by comparison of total peripheral resistance at varying tilt angles during baseline and saline infusion.

INCLUSION CRITERIA: A candidate subject is eligible for inclusion if he or she satisfies all of the following criteria: Aged 18 years or over. A confirmed diagnosis of neurogenic orthostatic hypotension related to Parkinson disease or pure autonomic failure. Able to provide informed consent EXCLUSION CRITERIA: A candidate subject is ineligible for inclusion if he or she satisfies any of the following criteria: Receiving medications expected to augment or attenuate blood pressure responses to i.v. norepinephrine (such as tricyclic antidepressants or alpha-adrenoceptor blockers). Has heart block (unless a functioning cardiac pacemaker is in place or the patient is cleared by a cardiologist). Raynaud's phenomenon or other findings in the medical history suggest a tendency to vasospasm. History of myocardial infarction or current evidence of symptomatic congestive heart failure or symptomatic coronary ischemia. Current evidence of ventricular arrhythmias or frequent premature ventricular contractions. Renal failure. History of mesenteric ischemia. History of cerebrovascular ischemic disease, unless corrected (e.g., by stent). Technical or medicinal limitations that obviate safe placement of arm intravenous and intra-arterial catheters for drug infusion and blood drawing. Examples of medicinal limitations are required daily aspirin ingestion and previously documented lidocaine allergy. Pregnant or lactating or a female of child bearing potential who refuses to have a blood test for pregnancy. (Urine pregnancy tests can yield false-negative results, due to incorrect test preparation, urine that is too dilute, or interference by several medications. We have experience with the NIH Clinical Pathology Department not calling a urine test for pregnancy positive or negative because the urine was dilute. Serum pregnancy tests do not have these limitations.) Unable to tolerate lying supine on a tilt table. Closed angle glaucoma.

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