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Controlling Hyperadrenergic Activity in Neurologic Injury (CHAIN)

Primary Purpose

Traumatic Brain Injury, Dysautonomia

Status

Withdrawn

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Esmolol

Propranolol

About this trial

This is an interventional treatment trial for Traumatic Brain Injury focused on measuring Traumatic Brain Injury, Dysautonomia, Brain Injury, Sympathetic hyperactivity

Eligibility Criteria

18 Years - 100 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Johns Hopkins Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Subjects Receiving Esmolol

Subjects receiving Propranolol

Arm Description

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

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)

Outcomes

Primary Outcome Measures

Controlling heart rate in traumatic brain injured patients

Once the patient is randomized and start getting the study medication, we monitor heart rate and other vital signs for 72hrs

Secondary Outcome Measures

Full Information

NCT ID

NCT01343329

First Posted

April 26, 2011

Last Updated

April 18, 2017

Sponsor

Johns Hopkins University

1. Study Identification

Unique Protocol Identification Number

NCT01343329

Brief Title

Controlling Hyperadrenergic Activity in Neurologic Injury

Acronym

CHAIN

Official Title

Controlling Hyperadrenergic Activity in Neurologic Injury

Study Type

Interventional

2. Study Status

Record Verification Date

April 2017

Overall Recruitment Status

Withdrawn

Why Stopped

Unable to enroll subjects that fit study criteria.

Study Start Date

July 2011 (Actual)

Primary Completion Date

February 14, 2014 (Actual)

Study Completion Date

February 14, 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Johns Hopkins University

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Traumatic Brain Injury, Dysautonomia

Keywords

Traumatic Brain Injury, Dysautonomia, Brain Injury, Sympathetic hyperactivity

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

0 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Subjects Receiving Esmolol

Arm Type

Experimental

Arm Description

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

Arm Title

Subjects receiving Propranolol

Arm Type

Active Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

Esmolol

Other Intervention Name(s)

Brevibloc

Intervention Description

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

Intervention Name(s)

Propranolol

Other Intervention Name(s)

Inderal

Intervention Description

Primary Outcome Measure Information:

Title

Controlling heart rate in traumatic brain injured patients

Description

Once the patient is randomized and start getting the study medication, we monitor heart rate and other vital signs for 72hrs

Time Frame

72 hrs

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

100 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Wendy Ziai, MD

Organizational Affiliation

Johns Hopkins University

Official's Role

Principal Investigator

Facility Information:

Facility Name

Johns Hopkins Hospital

City

Baltimore

State/Province

Maryland

ZIP/Postal Code

21287

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

7391345

Citation

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.

Results Reference

background

PubMed Identifier

19115177

Citation

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.

Results Reference

background

PubMed Identifier

17099518

Citation

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.

Results Reference

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PubMed Identifier

17215730

Citation

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.

Results Reference

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PubMed Identifier

16716989

Citation

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.

Results Reference

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PubMed Identifier

8024432

Citation

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.

Results Reference

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PubMed Identifier

2702842

Citation

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.

Results Reference

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PubMed Identifier

2045626

Citation

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.

Results Reference

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PubMed Identifier

8053795

Citation

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.

Results Reference

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PubMed Identifier

11595088

Citation

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.

Results Reference

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PubMed Identifier

20091622

Citation

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.

Results Reference

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PubMed Identifier

10527224

Citation

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.

Results Reference

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Links:

URL

http://www.hopkinsmedicine.org/

Description

Main website for Johns Hopkins Hospital

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Controlling Hyperadrenergic Activity in Neurologic Injury

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