Controlling Hyperadrenergic Activity in Neurologic Injury - Full Text View

Purpose

Traumatic brain injury (TBI) is frequently associated with a hyperadrenergic state accompanied by elevated levels of plasma catecholamines. In its more severe presentation, the hyperadrenergic state presents as dysautonomia, which is characterized by paroxysmal alteration in vital signs, including tachycardia. The investigators hypothesize that intravenous (IV) esmolol is as effective at controlling heart rate in hyperadrenergic states as oral propranolol, which is the standard of care. Our primary endpoint is efficacy of IV esmolol vs a PRN regimen of intermittent B-blockade in controlling heart rate below a pre-specified level (< 100 bpm) after Traumatic Brain Injury (TBI). Heart rates will be recorded continuously as well as hourly.

Condition	Intervention	Phase
Traumatic Brain Injury Dysautonomia	Drug: Esmolol Drug: Propranolol prn	Phase 1 Phase 2


Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	Controlling Hyperadrenergic Activity in Neurologic Injury

Resource links provided by NLM:

MedlinePlus related topics: Autonomic Nervous System Disorders Traumatic Brain Injury

Drug Information available for: Propranolol hydrochloride Propranolol Esmolol hydrochloride

U.S. FDA Resources

Further study details as provided by Johns Hopkins University:

Primary Outcome Measures:

Controlling heart rate in traumatic brain injured patients [ Time Frame: 72 hrs ] [ Designated as safety issue: Yes ]
Once the patient is randomized and start getting the study medication, we monitor heart rate and other vital signs for 72hrs


Estimated Enrollment:	34
Study Start Date:	July 2011
Estimated Primary Completion Date:	June 2013 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Esmolol arm The Esmolol arm is defined as a 48-hour intravenous infusion of esmolol (Brevibloc 20mg/ml), which will be started on enrollment.	Drug: Esmolol The Esmolol arm is defined as a 48-hour intravenous infusion of esmolol (Brevibloc 20mg/ml), which will be started on enrollment. The infusion rate will begin at 50 micrograms/kg/min and be adjusted to achieve heart rates between 80 and 100 beats/min with standard dosing regimens used in our Neuro intensive care unit. The infusion will be started at a rate of 0.05 milligrams/kg/min (50 micrograms/kg/min) for 5 minutes. After the 5 minutes of initial infusion, maintenance infusion may be continued at 0.05 mg/kg/min or increased stepwise (e.g. 0.1 mg/kg/min, 0.15 mg/kg/min to a maximum of 0.2 mg/kg/min) with each step being maintained for 4 or more minutes until the target heart rate is achieved. Other Name: Brevibloc
Active Comparator: Comparison arm The comparison arm will be comprised of oral propranolol, starting with 20mg PO every 6 hours prn (as needed) to reduce heart rate into target range. If 20mg is ineffective, the dose will be doubled at each dosing interval until an adequate dose is found, not to exceed 120mg four times daily. (ex: 20mg, 40mg, 80mg, 120mg)	Drug: Propranolol prn The comparison arm will be comprised of oral propranolol, starting with 20mg PO every 6 hours prn (as needed) to reduce heart rate into target range. If 20mg is ineffective, the dose will be doubled at each dosing interval until an adequate dose is found, not to exceed 120mg four times daily. (ex: 20mg, 40mg, 80mg, 120mg)

Arms

Assigned Interventions

Experimental: Esmolol arm

The Esmolol arm is defined as a 48-hour intravenous infusion of esmolol (Brevibloc 20mg/ml), which will be started on enrollment.

Drug: Esmolol

The Esmolol arm is defined as a 48-hour intravenous infusion of esmolol (Brevibloc 20mg/ml), which will be started on enrollment. The infusion rate will begin at 50 micrograms/kg/min and be adjusted to achieve heart rates between 80 and 100 beats/min with standard dosing regimens used in our Neuro intensive care unit. The infusion will be started at a rate of 0.05 milligrams/kg/min (50 micrograms/kg/min) for 5 minutes. After the 5 minutes of initial infusion, maintenance infusion may be continued at 0.05 mg/kg/min or increased stepwise (e.g. 0.1 mg/kg/min, 0.15 mg/kg/min to a maximum of 0.2 mg/kg/min) with each step being maintained for 4 or more minutes until the target heart rate is achieved.

Other Name: Brevibloc

Active Comparator: Comparison arm

The comparison arm will be comprised of oral propranolol, starting with 20mg PO every 6 hours prn (as needed) to reduce heart rate into target range. If 20mg is ineffective, the dose will be doubled at each dosing interval until an adequate dose is found, not to exceed 120mg four times daily. (ex: 20mg, 40mg, 80mg, 120mg)

Drug: Propranolol prn

The comparison arm will be comprised of oral propranolol, starting with 20mg PO every 6 hours prn (as needed) to reduce heart rate into target range. If 20mg is ineffective, the dose will be doubled at each dosing interval until an adequate dose is found, not to exceed 120mg four times daily. (ex: 20mg, 40mg, 80mg, 120mg)

Eligibility


Ages Eligible for Study:	18 Years and older (Adult, Senior)
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

TBI (Moderate/Severe TBI (GCS 12 or Head AIS>1)
Hyperadrenergic Activity: At least one paroxysmal episode (lasting at least 15 minutes) of Heart Rate 110 beats per minute during two or more consecutive days plus at least two more of the following that may not be better explained by another disease process (ex: sepsis):

Temperature of 38.5C Respiratory Rate 20 breaths per minute Agitation Diaphoresis Dystonia Stimulus responsive ("triggering of paroxysm")

- Informed Consent obtained

Exclusion Criteria:

Patients that do not meet criteria for dysautonomia (as stated above)
Age <18 years
Pregnancy
Hypotension - requiring pressor therapy to maintain baseline adequate CPP or mean arterial pressure
Cardiac arrhythmia - sinus bradycardia (HR <60), 2nd or 3rd degree AV block
Hemodynamic contraindications to intravenous beta-blockade such as a documented history of congestive heart failure (CHF), dependency on cardiac inotropes or documented bronchospastic disease
Any patient on chronic beta blockade as an outpatient.
Life expectancy < 48 hours or patients with "do not resuscitate orders"
Ongoing seizure activity
Informed consent not obtained

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01343329

Locations


United States, Maryland
Johns Hopkins Hospital	Not yet recruiting
Baltimore, Maryland, United States, 21287
Contact: Satish B Chandolu, MBBS, MHA 410-955-6488 satish@jhu.edu
Contact: Elizabeth White, RN, CCRP 4105026367 ewhite11@jhmi.edu
Principal Investigator: Wendy Ziai, MD

Sponsors and Collaborators

Johns Hopkins University

More Information

Additional Information:

Related Info This link exits the ClinicalTrials.gov site

Publications:

Hörtnagl H, Hammerle AF, Hackl JM, Brücke T, Rumpl E, Hörtnagl H. The activity of the sympathetic nervous system following severe head injury. Intensive Care Med. 1980 May;6(3):169--7.

Baguley IJ. Autonomic complications following central nervous system injury. Semin Neurol. 2008 Nov;28(5):716-25. doi: 10.1055/s-0028-1105971. Epub 2008 Dec 29. Review.

Fernández-Ortega JF, Prieto-Palomino MA, Muñoz-López A, Lebron-Gallardo M, Cabrera-Ortiz H, Quesada-García G. Prognostic influence and computed tomography findings in dysautonomic crises after traumatic brain injury. J Trauma. 2006 Nov;61(5):1129-33.

Cotton BA, Snodgrass KB, Fleming SB, Carpenter RO, Kemp CD, Arbogast PG, Morris JA Jr. Beta-blocker exposure is associated with improved survival after severe traumatic brain injury. J Trauma. 2007 Jan;62(1):26-33; discussion 33-5.

Baguley IJ, Heriseanu RE, Felmingham KL, Cameron ID. Dysautonomia and heart rate variability following severe traumatic brain injury. Brain Inj. 2006 Apr;20(4):437-44.

Meythaler JM, Stinson AM 3rd. Fever of central origin in traumatic brain injury controlled with propranolol. Arch Phys Med Rehabil. 1994 Jul;75(7):816-8.

Chioléro RL, Breitenstein E, Thorin D, Christin L, de Tribolet N, Freeman J, Jéquier E, Schutz Y. Effects of propranolol on resting metabolic rate after severe head injury. Crit Care Med. 1989 Apr;17(4):328-34.

Pranzatelli MR, Pavlakis SG, Gould RJ, De Vivo DC. Hypothalamic-midbrain dysregulation syndrome: hypertension, hyperthermia, hyperventilation, and decerebration. J Child Neurol. 1991 Apr;6(2):115-22.

Silver JK, Lux WE. Early onset dystonia following traumatic brain injury. Arch Phys Med Rehabil. 1994 Aug;75(8):885-8.

Cuny E, Richer E, Castel JP. Dysautonomia syndrome in the acute recovery phase after traumatic brain injury: relief with intrathecal Baclofen therapy. Brain Inj. 2001 Oct;15(10):917-25.

Chen JM, Heran BS, Perez MI, Wright JM. Blood pressure lowering efficacy of beta-blockers as second-line therapy for primary hypertension. Cochrane Database Syst Rev. 2010 Jan 20;(1):CD007185. doi: 10.1002/14651858.CD007185.pub2. Review.

Harwood TN, Butterworth J, Prielipp RC, Royster RL, Hansen K, Plonk G, Dean R. The safety and effectiveness of esmolol in the perioperative period in patients undergoing abdominal aortic surgery. J Cardiothorac Vasc Anesth. 1999 Oct;13(5):555-61.


Responsible Party:	Wendy Ziai, MD, Assistant Professor, Neuroanesthesiology and Critical Care, Johns Hopkins University
ClinicalTrials.gov Identifier:	NCT01343329 History of Changes
Other Study ID Numbers:	NA_00043058
Study First Received:	April 26, 2011
Last Updated:	April 27, 2011
Health Authority:	United Sates: Institutional Review Board

Keywords provided by Johns Hopkins University:


Traumatic Brain Injury Dysautonomia Brain Injury Sympathetic hyperactivity

Additional relevant MeSH terms:


Wounds and Injuries Brain Injuries Primary Dysautonomias Autonomic Nervous System Diseases Brain Diseases Central Nervous System Diseases Nervous System Diseases Craniocerebral Trauma Trauma, Nervous System Propranolol Esmolol	Adrenergic beta-Antagonists Adrenergic Antagonists Adrenergic Agents Neurotransmitter Agents Molecular Mechanisms of Pharmacological Action Physiological Effects of Drugs Anti-Arrhythmia Agents Antihypertensive Agents Vasodilator Agents Adrenergic beta-1 Receptor Antagonists

ClinicalTrials.gov processed this record on September 28, 2016

Controlling Hyperadrenergic Activity in Neurologic Injury (CHAIN)