Controlling Hyperadrenergic Activity in Neurologic Injury

NCT01343329 | Withdrawn Phase 1 DMC

• 1 other identifier: NA_00043058
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

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.

Conditions

Traumatic Brain Injury; Dysautonomia

Keywords

Traumatic Brain Injury; Dysautonomia; Brain Injury; Sympathetic hyperactivity

Outcome Measures

Primary Outcomes (1)

• 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

Study Arms (2)

Subjects Receiving Esmolol

EXPERIMENTAL

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

Drug: Esmolol

Subjects receiving Propranolol

ACTIVE COMPARATOR

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

Interventions

Esmolol 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.

Also known as: Brevibloc

Subjects Receiving Esmolol

Propranolol 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)

Also known as: Inderal

Subjects receiving Propranolol

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Johns Hopkins University: lead

Study Sites (1)

Johns Hopkins Hospital

Baltimore, Maryland, 21287, United States

Location

Related Publications (12)

• 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.

  PMID: 7391345 BACKGROUND

• 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.

  PMID: 19115177 BACKGROUND

• 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.

  PMID: 17099518 BACKGROUND

• 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.

  PMID: 17215730 BACKGROUND

• 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.

  PMID: 16716989 BACKGROUND

• 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.

  PMID: 8024432 BACKGROUND

• 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.

  PMID: 2702842 BACKGROUND

• 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.

  PMID: 2045626 BACKGROUND

• 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.

  PMID: 8053795 BACKGROUND

• 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.

  PMID: 11595088 BACKGROUND

• 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.

  PMID: 20091622 BACKGROUND

• 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.

  PMID: 10527224 BACKGROUND

Related Links

• Main website for Johns Hopkins Hospital

MeSH Terms

Conditions

Brain Injuries, Traumatic; Autonomic Nervous System Diseases; Brain Injuries

Interventions

esmolol; Propranolol

Condition Hierarchy (Ancestors)

Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Craniocerebral Trauma; Trauma, Nervous System; Wounds and Injuries

Intervention Hierarchy (Ancestors)

Phenoxypropanolamines; Propanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Propanols; Amines; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Polycyclic Compounds

Study Officials

• Wendy Ziai, MD

  Johns Hopkins University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: April 26, 2011
• First Posted: April 28, 2011
• Study Start: July 1, 2011
• Primary Completion: February 14, 2014
• Study Completion: February 14, 2014
• Last Updated: April 20, 2017

Record last verified: 2017-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)