Controlling Hyperadrenergic Activity in Neurologic Injury

Traumatic Brain Injury Clinical Trial

— CHAIN  

Official title:

Controlling Hyperadrenergic Activity in Neurologic Injury

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT01343329
• Other study ID #: NA_00043058
• Status: Withdrawn
• Phase: Phase 1/Phase 2
• First received: April 26, 2011
• Last updated: April 18, 2017
• Start date: July 2011
• Est. completion date: February 14, 2014

Study information

• Verified date: April 2017
• Source: Johns Hopkins University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: February 14, 2014
• Est. primary completion date: February 14, 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 100 Years

Eligibility

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

Related Conditions & MeSH terms

• Autonomic Nervous System Diseases
• Brain Injuries
• Dysautonomia
• Primary Dysautonomias
• Traumatic Brain Injury
• Wounds and Injuries

Intervention

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.
• 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)

Locations

Country	Name	City	State
United States	Johns Hopkins Hospital	Baltimore	Maryland

Sponsors (1)

Lead Sponsor	Collaborator
Johns Hopkins University

Country where clinical trial is conducted

United States, 

References & Publications (12)

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. — View 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. Review. — View 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. Review. — View Citation

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. — View 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. — View 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. — View Citation

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. — View 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. — View Citation

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. — View 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. — View 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. — View Citation

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

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	72 hrs

External Links

•   Main website for Johns Hopkins Hospital