Hypertonic Saline vs. Mannitol for Elevated Intercranial Pressure

This study examines the role of osmotic agents in controlling brain swelling in brain injured individuals. Two osmotic agents -- mannitol and hypertonic saline -- are in common use, and they will be compared in the context of a randomized clinical trial. The goal is to determine if these agent differ in their ability to control episodes of brain swelling.

Study Overview

• Status: Terminated
• Conditions: Traumatic Brain Injury; Elevated Intracranial Pressure
• Intervention / Treatment: Drug: Mannitol; Drug: Hypertonic Saline

Detailed Description

This single-center, randomized, open label trial will compare (i) 0.9% normal saline infusion and boluses of mannitol (control group) with (ii) 3% hypertonic saline, with intermittent boluses as needed, to treat elevated intracranial pressure (ICP) following severe traumatic brain injury.

Patients will be randomized to one of the two study arms following placement of an ICP monitor. Raised ICP will be defined as an ICP greater than 20 mmHG for 20 minutes or longer. In the event of such an event, the appropriate treatment will be administered.

The primary endpoint will be success in ICP control, operationalized as the proportion of time during which ICP is less than or equal to 20 mmHg during the first 120 hours following initiation of monitoring. Secondary endpoints include therapy intensity level, incidence of pre-determined severe adverse events, and long-term outcomes measured at 3 and 6 months post-injury.

• Study Type: Interventional
• Enrollment (Actual): 5
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• closed traumatic brain injury
• either (i) GCS score 3-8 (inclusive), or (ii) GCS motor score of 5 or less AND abnormal admission CT scan showing intracranial pathology
• hemodynamically stable with systolic blood pressure greater than 90 mmHg
• at least 1 reactive pupil
• age between 18y and 70y (inclusive)
• INR less than 1.5

Exclusion Criteria:

• actively on hypertonic saline or mannitol
• hypernatremia (>145 meq/L)
• anuric or with creatinine greater than or equal to 2.5
• known seizure disorder
• penetrating head trauma
• suspected anoxic events
• history of, or CT confirmation of, previous brain injury
• any injury that, in the opinion of the Principal Investigator, has a high likelihood of death with the first 72 hours post-injury
• any treatment, condition, or injury that contraindicates treatment with hypertonic saline

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: Mannitol; 0.9% normal saline infusion and boluses of mannitol	Drug: Mannitol; 0.9% normal saline infusion and boluses of mannitol
Active Comparator: Hypertonic Saline; 3% hypertonic saline continuous infusion, with intermittent boluses as needed	Drug: Hypertonic Saline; 3% hypertonic saline continuous infusion, with intermittent boluses as needed

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of time during which ICP is less than or equal to 20 mmHg during the first 120 hours following initiation of ICP monitoring. In the case where a patient is weaned from infusion, full ICP control will be assumed.	ICP will be recorded continuously and the proportion of time during which ICP is uncontrolled will be calculated. Specifically, this will be measured as any period during which ICP > 20 mmHg for 600 seconds or longer.	120 hours post initiation of monitoring

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Therapy Intensity Level (TIL), reflecting the amount and duration of therapy required to control ICP. TIL incorporates, among others, variables such as degree of head elevation, level of sedation, volume of CSF drainage, and hypocapnia.		Daily
Long-term outcomes measured by Disability Rating Scale and Glasgow Outcome Scale-Extended		3 and 6 months post-injury
Incidence of pre-determined severe adverse events (SAEs): brain hypoxia, delayed decompression, pulmonary edema, renal failure, respiratory complications, seizures, systemic hypoxia, and uncontrollable ICP	For each patient, we will count the number of SAEs in each category. Total SAEs by category and average number of SAEs per patient will be compared between the two study treatments.	Each occurence of an SAE during the patient's hospital stay will be recorded.

Collaborators and Investigators

• Sponsor: University of Cincinnati
• Collaborators: United States Department of Defense
• Investigators: Principal Investigator: Lori Shutter, MD, Department of Neurology College of Medicine University of Cincinnati

Publications and helpful links

General Publications

• Zornow MH. Hypertonic saline as a safe and efficacious treatment of intracranial hypertension. J Neurosurg Anesthesiol. 1996 Apr;8(2):175-7. doi: 10.1097/00008506-199604000-00021. No abstract available.
• Doyle JA, Davis DP, Hoyt DB. The use of hypertonic saline in the treatment of traumatic brain injury. J Trauma. 2001 Feb;50(2):367-83. doi: 10.1097/00005373-200102000-00030. No abstract available.
• Qureshi AI, Suarez JI. Use of hypertonic saline solutions in treatment of cerebral edema and intracranial hypertension. Crit Care Med. 2000 Sep;28(9):3301-13. doi: 10.1097/00003246-200009000-00032.
• Gunnar W, Jonasson O, Merlotti G, Stone J, Barrett J. Head injury and hemorrhagic shock: studies of the blood brain barrier and intracranial pressure after resuscitation with normal saline solution, 3% saline solution, and dextran-40. Surgery. 1988 Apr;103(4):398-407.
• Ogden AT, Mayer SA, Connolly ES Jr. Hyperosmolar agents in neurosurgical practice: the evolving role of hypertonic saline. Neurosurgery. 2005 Aug;57(2):207-15; discussion 207-15. doi: 10.1227/01.neu.0000166533.79031.d8.

Study record dates

Study Major Dates

• Study Start: April 1, 2010
• Primary Completion (Actual): November 1, 2010
• Study Completion (Actual): November 1, 2010

Study Registration Dates

• First Submitted: April 22, 2010
• First Submitted That Met QC Criteria: April 26, 2010
• First Posted (Estimate): April 27, 2010

Study Record Updates

• Last Update Posted (Estimate): March 5, 2013
• Last Update Submitted That Met QC Criteria: March 4, 2013
• Last Verified: March 1, 2013

More Information

Terms related to this study

• Keywords: intracranial pressure; traumatic brain injury; hypertonic saline therapy
• 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; Intracranial Hypertension; Physiological Effects of Drugs; Natriuretic Agents; Diuretics, Osmotic; Diuretics; Mannitol
• Other Study ID Numbers: Shutter-2010-01