Vasopressin Versus Catecholamines for Cerebral Perfusion Pressure Control in Brain Injured Trauma Patients (AVP)

Traumatic brain injury (TBI) is among the leading causes of trauma death and disability in both civilian and military populations. The damage that occurs at the instant of trauma cannot be modified; the secondary injuries that occur afterward are the impediments to recovery and can be influenced by the physician. Cerebral ischemia is the most important secondary event that determines outcome following TBI. To minimize ischemic episodes once the patient has arrived at the hospital, most treatments are aimed at optimizing cerebral perfusion pressure (CPP). The cornerstones of these treatments include mannitol, to reduce intracranial pressure (ICP), and catecholamines, such as phenylephrine (PE), to increase mean arterial pressure (MAP), but these agents have undesired side effects. Nevertheless, once they lose potency, there are few alternatives. The main objective of this proposal to develop a new therapeutic option for CPP management in TBI patients using arginine vasopressin (AVP).

AVP is the endogenous anti-diuretic hormone. It is FDA-approved for use in the diagnosis and treatment of diabetes insipidus, for the prevention and treatment of post-operative abdominal distention, and in abdominal radiography to dispel interfering gas shadows. It has been used off-label for several other conditions. There is minimal information on its therapeutic potential after TBI. The investigators have demonstrated that AVP during fluid resuscitation rapidly restored hemodynamics, CPP, and improves acute survival in a clinically-relevant model of TBI. The investigators observed similar short term benefits after chest and liver trauma. Nevertheless, AVP has actions that could mask any short term benefit. The investigators have already defined risks and benefits of AVP therapy, relative to PE, in four different clinically-relevant laboratory model. The investigators now plan to evaluate this new therapy relative to the current evidence-based guideline for CPP management in TBI patients.

The working hypothesis is that the risk/benefit profile for AVP is equal, or superior to, PE at equi-effective doses for the management of CPP following TBI. A corollary is that a higher CPP can be safely tolerated with AVP vs catecholamines.

THE INVESTIGATORS AIM TO: Determine whether AVP is safe and effective to maintain CPP = 60 mm Hg in TBI patients.

Study Overview

• Status: Completed
• Conditions: Traumatic Brain Injury
• Intervention / Treatment: Drug: arginine vasopressin; Drug: Standard catecholamine

Detailed Description

This is a randomized, controlled, open-label clinical trial comparing vasopressin and catecholamines for cerebral perfusion pressure (CPP) control after a traumatic brain injury (TBI).

Once a neurosurgeon is consulted for a patient presenting with a TBI, they will review entry criteria and refer to study personnel to obtain informed consent.

After informed consent, subjects will be randomized into one of the 2 groups to receive either a catecholamine at the discretion of the attending physicians or vasopressin (AVP). A 6 hour dose of non-study drug will be permitted prior to initiation of study drug. The amount of study drug will be titrated to maintain cerebral perfusion pressure within normal limits. Subjects will be followed until they can maintain their CPP without vasopressor medication. Data collection will include amount and duration of vasopressor therapy and resulting cerebral perfusion pressure and time until successful weaning from vasopressor therapy.

All subsequent clinical care will be at the discretion of the attending physician.

The standard protocol/procedure for the discontinuation of drugs in each arm of the study is as follows: Vasopressors are discontinued in a step-wise fashion, regardless of the specific agent or the specific ICU patient population. In patients with severe traumatic brain injury (TBI), cerebral perfusion pressure (CPP) is maintained between 60 and 70 mmHg with vasopressors. When intracranial pressure (ICP) begins to correct (decrease), vasopressors are titrated downward slowly to maintain CPP. This continues until ICP is normalized and systemic hemodynamics are able to support a normal CPP. At this point, vasopressors are withdrawn completely. This process is standard regardless of the choice of vasopressor.

• Study Type: Interventional
• Enrollment (Actual): 96
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Florida
    • Miami, Florida, United States, 33136
      • Ryder Trauma Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age >/= 18 yrs,
• Primary admission to the hospital within 8 h after injury
• Closed head injury
• Potential for intracranial pressure monitoring

Exclusion Criteria:

• Pregnant or nursing women
• Hemodynamic instability after initial resuscitation
• Vasopressor therapy for greater than 6 hours

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: AVP, arginine vasopressin; Vasopressin	Drug: arginine vasopressin; Titrated to cerebral perfusion pressure greater than 60 mm Hg
Active Comparator: Standard Catecholamine; levophed, dopamine, phenylephrine)	Drug: Standard catecholamine; Titrated catecholamine of attending physicians preference to cerebral perfusion pressure greater than 60 mm Hg.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time ICP >20	The number of hours that participants remained with intracranial pressure above 20 mmHg	The number of hours during the first 5 days of intracranial pressure monitoring

Collaborators and Investigators

• Sponsor: University of Miami
• Investigators: Principal Investigator: Kenneth G Proctor, PhD, University of Miami

Publications and helpful links

General Publications

• Dudkiewicz M, Proctor KG. Tissue oxygenation during management of cerebral perfusion pressure with phenylephrine or vasopressin. Crit Care Med. 2008 Sep;36(9):2641-50. doi: 10.1097/CCM.0b013e3181847af3.
• Sanui M, King DR, Feinstein AJ, Varon AJ, Cohn SM, Proctor KG. Effects of arginine vasopressin during resuscitation from hemorrhagic hypotension after traumatic brain injury. Crit Care Med. 2006 Feb;34(2):433-8. doi: 10.1097/01.ccm.0000196206.83534.39.
• Feinstein AJ, Cohn SM, King DR, Sanui M, Proctor KG. Early vasopressin improves short-term survival after pulmonary contusion. J Trauma. 2005 Oct;59(4):876-82; discussion 882-3. doi: 10.1097/01.ta.0000187654.24146.22.
• Feinstein AJ, Patel MB, Sanui M, Cohn SM, Majetschak M, Proctor KG. Resuscitation with pressors after traumatic brain injury. J Am Coll Surg. 2005 Oct;201(4):536-45. doi: 10.1016/j.jamcollsurg.2005.05.031.

Study record dates

Study Major Dates

• Study Start: September 1, 2008
• Primary Completion (Actual): September 1, 2014
• Study Completion (Actual): September 1, 2014

Study Registration Dates

• First Submitted: November 20, 2008
• First Submitted That Met QC Criteria: November 20, 2008
• First Posted (Estimate): November 21, 2008

Study Record Updates

• Last Update Posted (Estimate): December 12, 2014
• Last Update Submitted That Met QC Criteria: December 11, 2014
• Last Verified: December 1, 2014

More Information

Terms related to this study

• Keywords: TBI, trauma, brain
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Wounds and Injuries; Craniocerebral Trauma; Trauma, Nervous System; Brain Injuries; Brain Injuries, Traumatic; Physiological Effects of Drugs; Natriuretic Agents; Hemostatics; Coagulants; Vasoconstrictor Agents; Antidiuretic Agents; Vasopressins; Arginine Vasopressin
• Other Study ID Numbers: 20060949