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Hypernatremia for the Prevention and Treatment of Cerebral Edema in Traumatic Brain Injury

Primary Purpose

Traumatic Brain Injury, Subdural Hematoma, Cerebral Contusion

Status
Withdrawn
Phase
Phase 1
Locations
Study Type
Interventional
Intervention
Induced, sustained hypernatremia using hypertonic saline
Standard of care (hypertonic saline and mannitol; serum sodium)
Sponsored by
Massachusetts General Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Traumatic Brain Injury focused on measuring Brain Injuries, Hematoma, subdural, Decompressive Craniectomy, Saline solution, hypertonic, Hypernatremia, Intracranial hemorrhages, Head Injuries, closed, Intracranial pressure, Brain edema, Critical care, Brain Diseases, Central Nervous System Diseases, Nervous System Diseases, Wounds and Injuries, Physiological Effects of Drugs, Pharmacologic Actions

Eligibility Criteria

18 Years - 60 Years (Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Adults (18 - 60 years old)
  • Severe traumatic brain injury with intracranial pressure monitoring
  • Initial GCS 5-8 (obtained free of the effects of neuromuscular blockade or sedatives)
  • Clearly defined time of injury no more than 8 hours before administration of study drug
  • Written consent obtained from legally authorized representative (LAR)
  • Severe swelling prone injury patterns:

    1. Contusion - frontal or temporal (> 20 cc)
    2. Acute convexity subdural hematoma with any evidence of midline shift

Exclusion Criteria:

  • Patients undergoing emergent (within 15 minutes) or urgent neurosurgery (within 4 hours) following emergency department arrival (bedside procedures, such as intracranial pressure monitor placement are excluded)
  • Posterior fossa lesions
  • Penetrating brain injury
  • Spinal column instability and/or spinal cord injury with neurological deficit
  • Pregnant
  • Concomitant severe nonsurvivable injury
  • Acute renal failure ; Chronic renal failure (serum creatinine of > 2.5 mg/dL, history of ongoing dialysis, glomerular filtration rate <30mL/min/1.73 m2); Severe pulmonary edema; Severe heart failure; Severe liver failure (AST, ALT, or bilirubin > 2 times normal)
  • Known use of warfarin, clopidogrel, prasugrel, cilostazol, heparin, low molecular weight heparin, heparinoids, abciximab or similar antiplatelet agents
  • Treatment with another investigational drug within the prior 30 days
  • Systolic blood pressure < 90 mm HG not responsive to fluid resuscitation
  • INR > 1.4
  • Hospitalization for brain injury or neurological disease within previous 3 years
  • Admission serum sodium < 135 mmol/L
  • > 8 hours from the time of injury to admission
  • Fix/dilated pupil suspected to be secondary to brainstem compression
  • Duret (brainstem) hemorrhage indicating brainstem herniation
  • PaO2 < 60 mmHg on admission (when blood gases are drawn as standard of care)
  • Prisoner or other persons unable to make a true, voluntary and uncoerced decision whether or not to participate in the study

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Active Comparator

    Experimental

    Arm Label

    Standard Care

    Induced Hypernatremia

    Arm Description

    Patients will be managed to maintain a goal serum sodium of > 135 mmol/L , a well recognized value in the management of severe traumatic brain injury.

    Patients will be treated with induced, sustained hypernatremia for 5 days following injury by using hypertonic saline to target a goal serum sodium of 150-160 mmol/L

    Outcomes

    Primary Outcome Measures

    Primary Efficacy Objective
    The primary efficacy objective of this study is to assess whether patients with severe TBI treated with sustained hypernatremia will show a decrease in neuroimaging defined edema compared to patients treated as the current standard of care.
    Primary Safety Objective
    The primary safety objective is to assess the safety and tolerability of sustained hypernatremia compared to the goal of avoiding hyponatremia in patients with severe traumatic brain injury. Safety will be assessed by a review of the incidence of mortality and adverse events, as well as by analysis of relevant laboratory data.

    Secondary Outcome Measures

    Short term neurological outcome
    The secondary outcome measure of this study will be assess whether patients with TBI treated with sustained hypernatremia will benefit patients in terms of short term neurological outcome - defined as need for tracheostomy during principal admission. Other secondary outcome measures will be need for delayed craniectomy and cumulative dosage of bolus dosing hyperosmolar therapy.

    Full Information

    First Posted
    May 22, 2012
    Last Updated
    December 9, 2016
    Sponsor
    Massachusetts General Hospital
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    1. Study Identification

    Unique Protocol Identification Number
    NCT01605357
    Brief Title
    Hypernatremia for the Prevention and Treatment of Cerebral Edema in Traumatic Brain Injury
    Official Title
    A Randomized, Open Label Clinical Trial of Sustained Hypernatremia for the Prevention and Treatment of Cerebral Edema in Traumatic Brain Injury
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    December 2016
    Overall Recruitment Status
    Withdrawn
    Why Stopped
    Never started.
    Study Start Date
    July 2012 (undefined)
    Primary Completion Date
    July 2013 (Anticipated)
    Study Completion Date
    August 2013 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Principal Investigator
    Name of the Sponsor
    Massachusetts General Hospital

    4. Oversight

    Data Monitoring Committee
    Yes

    5. Study Description

    Brief Summary
    Cerebral edema is seen heterogenous group of neurological disease states that mainly fall under the categories of metabolic, infectious, neoplasia, cerebrovascular, and traumatic brain injury disease states. Regardless of the driving force, cerebral edema is defined as the accumulation of fluid in the brain's intracellular and extracellular spaces. This occurs secondary to alterations in the complex interplay between four distinct fluid compartments within the cranium. In any human cranium; fluid is contained in the blood, the cerebrospinal fluid, interstitial fluid of the brain parenchyma, and the intracellular fluid of the neurons and glia. Fluid movement occurs normally between these compartments and depends on specific concentrations of solutes (such as sodium) and water. In brain-injured states, the normal regulation of this process is disturbed and cerebral edema can develop. Cerebral edema leads to increased intracranial pressure and mortality secondary to brain tissue compression, given the confines of the fixed-volume cranium. Additionally, secondary neuronal dysfunction or death can occur at the cellular level secondary to the disruption of ion gradients that control metabolism and function. While studies utilizing bolus dosing of hyperosmolar therapy to target signs or symptoms of increased intracranial pressure secondary to cerebral edema are numerous, there is a paucity of studies relating to continuous infusion of hyperosmolar therapy for targeted sustained hypernatremia for the prevention and treatment of cerebral edema. The investigators hypothesize that induced, sustained hypernatremia following traumatic brain injury will decrease the rate of cerebral edema formation and improve patient outcomes.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Traumatic Brain Injury, Subdural Hematoma, Cerebral Contusion, Head Injury, Cerebral Edema
    Keywords
    Brain Injuries, Hematoma, subdural, Decompressive Craniectomy, Saline solution, hypertonic, Hypernatremia, Intracranial hemorrhages, Head Injuries, closed, Intracranial pressure, Brain edema, Critical care, Brain Diseases, Central Nervous System Diseases, Nervous System Diseases, Wounds and Injuries, Physiological Effects of Drugs, Pharmacologic Actions

    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
    Standard Care
    Arm Type
    Active Comparator
    Arm Description
    Patients will be managed to maintain a goal serum sodium of > 135 mmol/L , a well recognized value in the management of severe traumatic brain injury.
    Arm Title
    Induced Hypernatremia
    Arm Type
    Experimental
    Arm Description
    Patients will be treated with induced, sustained hypernatremia for 5 days following injury by using hypertonic saline to target a goal serum sodium of 150-160 mmol/L
    Intervention Type
    Drug
    Intervention Name(s)
    Induced, sustained hypernatremia using hypertonic saline
    Intervention Description
    Patients in the experimental arm will receive hypertonic saline to target a serum sodium goal of 150 - 160 mmol/L. All hypertonic saline will be administered intravenously. Loading phase: Upon enrollment 23.4 % hypertonic saline (volume 20 cc) will be administered via a central venous catheter. A continuous infusion of 3% hypertonic saline will be administered at a rate of 30 cc per hour and titrated every six hours to target a serum sodium goal of 150-160 mmol/L. Maintenance phase: Titrate serum sodium to 150-160 mmol/L using continuous 3% hypertonic saline infusion. Discontinuation phase: After 5 days of completed therapy, begin to wean 3% hypertonic saline rate by 10cc every 6 hours. Discontinue hypertonic saline infusion after infusing at a rate of 20cc an hour for 6 hours. Bolus dosing of hypertonic saline and mannitol are to be administered at the discretion of the provider to treat elevated intracranial pressure based on practice guidelines
    Intervention Type
    Drug
    Intervention Name(s)
    Standard of care (hypertonic saline and mannitol; serum sodium)
    Intervention Description
    Bolus dosing of hypertonic saline and mannitol are to be administered at the discretion of the provider to treat elevated intracranial pressure based on practice guidelines. Hyponatremia ( serum sodium < 135 mmol/L) is to be corrected at the discretion of the provider.
    Primary Outcome Measure Information:
    Title
    Primary Efficacy Objective
    Description
    The primary efficacy objective of this study is to assess whether patients with severe TBI treated with sustained hypernatremia will show a decrease in neuroimaging defined edema compared to patients treated as the current standard of care.
    Time Frame
    72 hours ; 120 hours ; 30 days
    Title
    Primary Safety Objective
    Description
    The primary safety objective is to assess the safety and tolerability of sustained hypernatremia compared to the goal of avoiding hyponatremia in patients with severe traumatic brain injury. Safety will be assessed by a review of the incidence of mortality and adverse events, as well as by analysis of relevant laboratory data.
    Time Frame
    Through 30 days
    Secondary Outcome Measure Information:
    Title
    Short term neurological outcome
    Description
    The secondary outcome measure of this study will be assess whether patients with TBI treated with sustained hypernatremia will benefit patients in terms of short term neurological outcome - defined as need for tracheostomy during principal admission. Other secondary outcome measures will be need for delayed craniectomy and cumulative dosage of bolus dosing hyperosmolar therapy.
    Time Frame
    30 days

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Maximum Age & Unit of Time
    60 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: Adults (18 - 60 years old) Severe traumatic brain injury with intracranial pressure monitoring Initial GCS 5-8 (obtained free of the effects of neuromuscular blockade or sedatives) Clearly defined time of injury no more than 8 hours before administration of study drug Written consent obtained from legally authorized representative (LAR) Severe swelling prone injury patterns: Contusion - frontal or temporal (> 20 cc) Acute convexity subdural hematoma with any evidence of midline shift Exclusion Criteria: Patients undergoing emergent (within 15 minutes) or urgent neurosurgery (within 4 hours) following emergency department arrival (bedside procedures, such as intracranial pressure monitor placement are excluded) Posterior fossa lesions Penetrating brain injury Spinal column instability and/or spinal cord injury with neurological deficit Pregnant Concomitant severe nonsurvivable injury Acute renal failure ; Chronic renal failure (serum creatinine of > 2.5 mg/dL, history of ongoing dialysis, glomerular filtration rate <30mL/min/1.73 m2); Severe pulmonary edema; Severe heart failure; Severe liver failure (AST, ALT, or bilirubin > 2 times normal) Known use of warfarin, clopidogrel, prasugrel, cilostazol, heparin, low molecular weight heparin, heparinoids, abciximab or similar antiplatelet agents Treatment with another investigational drug within the prior 30 days Systolic blood pressure < 90 mm HG not responsive to fluid resuscitation INR > 1.4 Hospitalization for brain injury or neurological disease within previous 3 years Admission serum sodium < 135 mmol/L > 8 hours from the time of injury to admission Fix/dilated pupil suspected to be secondary to brainstem compression Duret (brainstem) hemorrhage indicating brainstem herniation PaO2 < 60 mmHg on admission (when blood gases are drawn as standard of care) Prisoner or other persons unable to make a true, voluntary and uncoerced decision whether or not to participate in the study
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Brian P Walcott, MD
    Organizational Affiliation
    Massachusetts General Hospital
    Official's Role
    Study Chair
    First Name & Middle Initial & Last Name & Degree
    Brian V Nahed, MD
    Organizational Affiliation
    Massachusetts General Hospital
    Official's Role
    Principal Investigator
    First Name & Middle Initial & Last Name & Degree
    Sameer A Sheth, MD PhD
    Organizational Affiliation
    Massachusetts General Hospital
    Official's Role
    Study Director

    12. IPD Sharing Statement

    Learn more about this trial

    Hypernatremia for the Prevention and Treatment of Cerebral Edema in Traumatic Brain Injury

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