A Study of Stellate Ganglion Block and / or Reserpine in Group 2 Pulmonary Hypertension

A Phase I Study of Stellate Ganglion Block and / or Reserpine in Group 2 Pulmonary Hypertension

Pulmonary hypertension Group 2 (PH 2) associated with left-sided heart disease is relatively common, is associated with a poor prognosis, and unfortunately there are no proven medical treatments beyond attempts at correcting the left sided heart disease. Many PH 2 patients have evidence of active constriction of blood vessels from increased nerve traffic. Use of agents or procedures which produce a reversible chemical blockage of this nerve traffic have not been systematically tested in PH 2. The investigators will test whether acute interruption of sympathetic nervous system tone, which local anesthetic block of the stellate ganglion in the neck, will improve PH2, and also test whether the high blood pressure drug reserpine, which blocks sympathetic nerve activity, will do so during a one month trial period.

Study Overview

• Status: Withdrawn
• Conditions: Pulmonary Artery Hypertension
• Intervention / Treatment: Drug: reserpine; Procedure: stellate ganglion block; Drug: lidocaine

Detailed Description

Background. Pulmonary hypertension Group 2 (PH 2) associated with left-sided heart disease is relatively common, is associated with a poor prognosis, and unfortunately there are no proven medical treatments beyond attempts at correcting the left sided heart disease. Many PH 2 patients have evidence of vasoconstriction and increased sympathetic nervous system activity. Use of agents or procedures which produce a reversible chemical sympathectomy have not been systematically tested in PH 2.

Methods. Two groups will be eligible for participation: Group 1 (n=10): Patients with PH 2 previously documented by echocardiography (echo), 6 minute walk test, biomarkers, and right heart catheterization (RHC) will receive reserpine, 0.05 mg per day for two weeks, then, 0.1 mg per day for an additional two weeks. After one month, patients will be reassessed for New York Heart Association (NYHA) class and drug side effects, echocardiography, 6 minute walk assessment, and brain natriuretic peptide (BNP). Group 2 patients (n=10) will have clinically suspected PH 2 and be scheduled to undergo clinically indicated RHC. If during RHC PH 2 is confirmed, after assessment of nitric oxide responsiveness, their baseline hemodynamics will be re-established over 10 minutes, and a left stellate ganglion block with lidocaine will be performed, and immediate hemodynamic responsiveness assessed. Four hours post-procedure, a side effect questionnaire will be obtained. Group 2 patients who complete RHC will then begin reserpine treatment in the same manner as Group I patients.

Hypothesis and Impact. PH 2 is the most common type of pulmonary hypertension. The current diagnostic and therapeutic strategy aims to treat the left sided heart disease in attempt to normalize pulmonary artery pressure. The place of selective pulmonary vasodilators is undefined. The investigator's approach addresses inhibition of adverse pulmonary vasoconstriction mediated by the sympathetic nervous system in PH 2.

• Study Type: Interventional
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic Florida

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 98 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

• Prior right heart catheterization, with mean pulmonary artery pressure > 25 mm Hg, pulmonary capillary wedge pressure > 15 mm Hg, and diastolic pressure gradient (pulmonary artery diastolic pressure - mean pulmonary capillary wedge pressure) ≥ 7 mm Hg OR clinically suspected group 2 pulmonary hypertension from non-invasive testing with planned right heart catheterization (RHC).
• On stable diuretic therapy
• Able to attend end-study visit 4 weeks after study entry

Exclusion criteria:

• Anticipated surgery to correct heart lesion responsible for pulmonary hypertension
• Need for heparinization for right heart catheterization (not standard practice, but sometimes utilized)
• History of depression, or treatment with tricyclic anti-depressant, serotonin uptake inhibitor, monamine oxidase inhibitor
• Severe renal or hepatic impairment, creatinine clearance < 30 ml/minute or renal replacement therapy or post-kidney transplant, abnormal liver function with elevated enzymes> 1.5 times the upper limit of normal or prior liver transplant.
• Systolic blood pressure <100 mm Hg
• Heart rate < 60 beats per minute
• Inability to independently complete telephone follow-up at two weeks, and clinic end-study visit at 4 weeks.
• Pulmonary edema
• Infiltrative cardiomyopathy - amyloidosis
• Symptomatic orthostatic hypotension
• Women of childbearing age who have not had surgical sterilization and are not using oral contraceptives, or who's spouse has not had surgical sterilization will be excluded due to the length of the trial and the possibility that they could become pregnant after entry.
• Uncontrolled heartburn
• Prior surgery to the left neck, for example, carotid endarterectomy, or other surgery which would increase the risk of stellate ganglion block
• Known sensitivity, allergy, or contraindication to lidocaine, any local anesthetic, or reserpine

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Prior right heart catheterization; Patients with qualifying hemodynamics from prior right heart catheterization will receive open label reserpine, 0.05 mg by mouth daily for two weeks, then 0.10 mg by mouth daily for two weeks, and then have repeat non-invasive assessments of status.	Drug: reserpine; Patients with qualifying hemodynamics from prior right heart catheterization will receive open label reserpine, 0.05 mg by mouth daily for two weeks, then 0.10 mg by mouth daily for two weeks, and then have repeat non-invasive assessments of status
Experimental: Scheduled for right heart catheterization; Patients with suspected group 2 pulmonary hypertension by clinical and non-invasive assessments and are scheduled to undergo clinically indicated right heart catheterization will have pulmonary artery pressures measured. If qualifying severity of group 2 pulmonary hypertension is present, after clinically indicated assessment of inhaled nitric oxide, their baseline hemodynamics will be allowed to re-equilibrate over 10 minutes, and then ultrasound guided left stellate ganglion block with lidocaine will be performed, and hemodynamics reassessed 10 minutes afterward	Procedure: stellate ganglion block; Patients with suspected group 2 pulmonary hypertension by clinical and non-invasive assessments and are scheduled to undergo clinically indicated right heart catheterization will have pulmonary artery pressures measured. If qualifying severity of group 2 pulmonary hypertension is present, after clinically indicated assessment of inhaled nitric oxide, their baseline hemodynamics will be allowed to re-equilibrate over 10 minutes, and then ultrasound guided left stellate ganglion block with lidocaine will be performed, and hemodynamics reassessed 10 minutes afterward; Drug: lidocaine; Patients with suspected group 2 pulmonary hypertension by clinical and non-invasive assessments and are scheduled to undergo clinically indicated right heart catheterization will have pulmonary artery pressures measured. If qualifying severity of group 2 pulmonary hypertension is present, after clinically indicated assessment of inhaled nitric oxide, their baseline hemodynamics will be allowed to re-equilibrate over 10 minutes, and then ultrasound guided left stellate ganglion block with lidocaine will be performed, and hemodynamics reassessed 10 minutes afterward

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0	Adverse events of interest are for stellate ganglion block: pulmonary edema, bradycardia requiring treatment, hypotension requiring treatment, arrhythmia, pneumothorax, hoarseness, dysphagia, globus, left upper extremity weakness. For reserpine, heart failure hospitalization, syncope, all cause hospitalization, bradycardia requiring treatment, hypotension requiring treatment, new arrhythmia, edema requiring an increase in diuretics, depression, lethargy, nasal stuffiness, dizziness, orthostatic hypotension, falls, nightmares, sexual dysfunction, anxiety, dyspepsia. Adverse events classed as serious: Life threatening serious adverse events including acute coronary syndrome with active ischemia, fatal arrhythmias, myocardial infarction, acute kidney injury, cardiogenic shock, stroke, pulmonary embolization, arterial and/or venous thrombosis, systemic embolization, severe hypotension, respiratory failure and death; Prolonged hospitalization or rehospitalization	one month

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with successful stellate ganglion block	Stellate block: frequency of the occurrence of ptosis and conjunctival flushing.	One hour
Effect of stellate ganglion block on heart rate	Heart rate before and after stellate ganglion block	One hour
Change in 6 minute walk distance from one month of reserpine therapy	Six minute walk distance, meters, baseline compared to one month	One month
Change in brain natriuretic peptide (BNP) from one month of reserpine therapy	BNP, pg/ml, baseline compared to one month	One month
Change in Doppler derived mean pulmonary artery pressure from one month of reserpine therapy	Mean pulmonary artery pressure estimate, mm Hg	One month
Change in blood pressure from one month of reserpine therapy	Blood pressure, mm Hg, baseline versus one month	One month
Change in Minnesota Living with heart failure questionnaire from one month of reserpine therapy	Minnesota Living with heart failure questionnaire aggregate score, baseline versus one month	One month
Hemodynamic effect of stellate ganglion block	Blood pressure, mm Hg, before and after stellate ganglion block	One hour
Hemodynamic effect of stellate ganglion block	Pulmonary artery pressure, mm Hg, before and after stellate ganglion block	One hour
Hemodynamic effect of stellate ganglion block	Pulmonary capillary wedge pressure, mm Hg, before and after stellate ganglion block	One hour
Hemodynamic effect of stellate ganglion block	right atrial pressure, mm Hg, before and after stellate ganglion block	One hour
Hemodynamic effect of stellate ganglion block	Cardiac output, liters per minute, before and after stellate ganglion block	One hour
Change in heart rate from one month of reserpine therapy	Heart rate, baseline versus one month	One month

Collaborators and Investigators

• Sponsor: Mayo Clinic
• Investigators: Principal Investigator: Joseph Blackshear, MD, Mayo Clinic

Publications and helpful links

Helpful Links

• Mayo Clinic Clinical Trials

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2016
• Primary Completion (Actual): July 1, 2016
• Study Completion (Actual): July 1, 2016

Study Registration Dates

• First Submitted: February 4, 2016
• First Submitted That Met QC Criteria: February 17, 2016
• First Posted (Estimate): February 18, 2016

Study Record Updates

• Last Update Posted (Actual): May 22, 2019
• Last Update Submitted That Met QC Criteria: May 20, 2019
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Hypertension; Pulmonary Arterial Hypertension; Hypertension, Pulmonary; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Central Nervous System Depressants; Peripheral Nervous System Agents; Sensory System Agents; Anesthetics; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Anesthetics, Local; Voltage-Gated Sodium Channel Blockers; Sodium Channel Blockers; Adrenergic Uptake Inhibitors; Lidocaine; Reserpine
• Other Study ID Numbers: 16-000928