Controlling Hyperadrenergic Activity in Neurologic Injury

NCT ID: NCT01343329

Last Updated: 2017-04-20

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

Get a concise snapshot of the trial, including recruitment status, study phase, enrollment targets, and key timeline milestones.

Recruitment Status

WITHDRAWN

Clinical Phase

PHASE1/PHASE2

Study Classification

INTERVENTIONAL

Study Start Date

2011-07-31

Study Completion Date

2014-02-14

Brief Summary

Review the sponsor-provided synopsis that highlights what the study is about and why it is being conducted.

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) or hemorrhagic neurologic injury. Heart rates will be recorded continuously as well as hourly.

Detailed Description

Dive into the extended narrative that explains the scientific background, objectives, and procedures in greater depth.

Conditions

See the medical conditions and disease areas that this research is targeting or investigating.

Traumatic Brain Injury Dysautonomia

Study Design

Understand how the trial is structured, including allocation methods, masking strategies, primary purpose, and other design elements.

Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

Review each arm or cohort in the study, along with the interventions and objectives associated with them.

Subjects Receiving Esmolol

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

Group Type EXPERIMENTAL

Esmolol

Intervention Type DRUG

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.

Subjects receiving Propranolol

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)

Group Type ACTIVE_COMPARATOR

Propranolol

Intervention Type DRUG

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)

Interventions

Learn about the drugs, procedures, or behavioral strategies being tested and how they are applied within this trial.

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.

Intervention Type DRUG

Propranolol

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)

Intervention Type DRUG

Other Intervention Names

Discover alternative or legacy names that may be used to describe the listed interventions across different sources.

Brevibloc Inderal

Eligibility Criteria

Check the participation requirements, including inclusion and exclusion rules, age limits, and whether healthy volunteers are accepted.

Inclusion Criteria

* TBI (Moderate/Severe TBI (GCS 12 or Head AIS\>1) or hemorrhagic neurologic injury
* 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
Minimum Eligible Age

18 Years

Maximum Eligible Age

100 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

Meet the organizations funding or collaborating on the study and learn about their roles.

Johns Hopkins University

OTHER

Sponsor Role lead

Responsible Party

Identify the individual or organization who holds primary responsibility for the study information submitted to regulators.

Wendy Ziai

Associate Professor

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

Learn about the lead researchers overseeing the trial and their institutional affiliations.

Wendy Ziai, MD

Role: PRINCIPAL_INVESTIGATOR

Johns Hopkins University

Locations

Explore where the study is taking place and check the recruitment status at each participating site.

Johns Hopkins Hospital

Baltimore, Maryland, United States

Site Status

Countries

Review the countries where the study has at least one active or historical site.

United States

References

Explore related publications, articles, or registry entries linked to this study.

Hortnagl H, Hammerle AF, Hackl JM, Brucke T, Rumpl E, Hortnagl H. The activity of the sympathetic nervous system following severe head injury. Intensive Care Med. 1980 May;6(3):169--7. doi: 10.1007/BF01757299.

Reference Type BACKGROUND
PMID: 7391345 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 19115177 (View on PubMed)

Fernandez-Ortega JF, Prieto-Palomino MA, Munoz-Lopez A, Lebron-Gallardo M, Cabrera-Ortiz H, Quesada-Garcia G. Prognostic influence and computed tomography findings in dysautonomic crises after traumatic brain injury. J Trauma. 2006 Nov;61(5):1129-33. doi: 10.1097/01.ta.0000197634.83217.80.

Reference Type BACKGROUND
PMID: 17099518 (View on PubMed)

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. doi: 10.1097/TA.0b013e31802d02d0.

Reference Type BACKGROUND
PMID: 17215730 (View on PubMed)

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. doi: 10.1080/02699050600664715.

Reference Type BACKGROUND
PMID: 16716989 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 8024432 (View on PubMed)

Chiolero RL, Breitenstein E, Thorin D, Christin L, de Tribolet N, Freeman J, Jequier E, Schutz Y. Effects of propranolol on resting metabolic rate after severe head injury. Crit Care Med. 1989 Apr;17(4):328-34. doi: 10.1097/00003246-198904000-00006.

Reference Type BACKGROUND
PMID: 2702842 (View on PubMed)

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. doi: 10.1177/088307389100600204.

Reference Type BACKGROUND
PMID: 2045626 (View on PubMed)

Silver JK, Lux WE. Early onset dystonia following traumatic brain injury. Arch Phys Med Rehabil. 1994 Aug;75(8):885-8. doi: 10.1016/0003-9993(94)90113-9.

Reference Type BACKGROUND
PMID: 8053795 (View on PubMed)

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. doi: 10.1080/02699050110065277.

Reference Type BACKGROUND
PMID: 11595088 (View on PubMed)

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;2010(1):CD007185. doi: 10.1002/14651858.CD007185.pub2.

Reference Type BACKGROUND
PMID: 20091622 (View on PubMed)

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. doi: 10.1016/s1053-0770(99)90007-1.

Reference Type BACKGROUND
PMID: 10527224 (View on PubMed)

Related Links

Access external resources that provide additional context or updates about the study.

http://www.hopkinsmedicine.org/

Main website for Johns Hopkins Hospital

Other Identifiers

Review additional registry numbers or institutional identifiers associated with this trial.

NA_00043058

Identifier Type: -

Identifier Source: org_study_id

More Related Trials

Additional clinical trials that may be relevant based on similarity analysis.

Propranolol for the Treatment of Traumatic Brain Injury
NCT06262061 NOT_YET_RECRUITING EARLY_PHASE1