Safety and Efficacy of Intravenous Norepinephrine for Orthostatic Hypotension

Patients with chronic autonomic failure (CAF) often have disabling orthostatic hypotension (OH). OH in CAF patients is often associated with supine hypertension (hypertension while lying down), 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 way to maintain blood pressure during standing without worsening hypertension while lying down. The research question is will a drug (norepinephrine) given intravenously (IV) prevent blood pressure from falling in patients with orthostatic hypotension.

This is a placebo controlled, blinded study of 15 patients with neurogenic orthostatic hypotension. The study consists of two experimental days per participant. On a day before the day of norepinephrine (NE) infusion, the patient undergoes head-up tilting 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.

• Study Weblinks:
  • Autonomic Disorders Consortium
• Study Design:
  • Interventional
• Study Type:
  • Interventional
  • Clinical Trial
  • Placebo-Controlled
  • Randomized
• Total number of consented subjects: 6
• Subject Sample Telemetry Report (SSTR)

Inclusion 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:

• 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 experienced 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

• Study activated March 9, 2011
• First accrual August 29, 2011
• Study final closed September 24, 2012

• Primary Phenotype: Pure Autonomic Failure
• Parkinson Disease
• Hypotension, Orthostatic

• BioProject
• PubMed
• MeSH
• PMC

• Study Chairs
  • David S. Goldstein, MD, PhD. National Institute of Health Clinical Center, Bethesda, MD, USA.
• Participating Site Principal Investigators
  • LaToya Sewell. National Institute of Neurological Disorders and Stroke, National Institute of Health, Bethesda, MD, USA.
  • Courtney Holmes. National Institute of Neurological Disorders and Stroke, National Institute of Health, Bethesda, MD, USA.
  • Andre Diedrich. Vanderbilt University, Nashville, TN, USA.
  • David Robertson. Vanderbilt University, Nashville, TN, USA.
• Current Funding Sources
  • U54NS065736-06. National Institutes of Health, Bethesda, MD, USA.