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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Withdrawn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)

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

NCT ID

NCT01605357

First Posted

May 22, 2012

Last Updated

December 9, 2016

Sponsor

Massachusetts General Hospital

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

Time Frame

72 hours ; 120 hours ; 30 days

Title

Primary Safety Objective

Description

Time Frame

Through 30 days

Secondary Outcome Measure Information:

Title

Short term neurological outcome

Description

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

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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