Safety and Feasibility of Hypertonic Saline Solution After Aneurysmal Subarachnoid Hemorrhage: (HS3)

Hypertonic Saline Solution in Aneurysmal Subarachnoid Hemorrhage: A Randomized - Phase II Single Blinded Clinical Trial

Subarachnoid hemorrhage (SAH) occurs after rupture of cerebral aneurysms. Treatment of SAH focuses on avoiding medical complications including cerebral vasospasm, which may result in limited circulation to the brain. Cerebral vasospasm, or thinning of the arteries of the brain, is a feared complication that could potentially cause stroke and worst outcomes after SAH. Hypertonic saline (HTS) is a compound that may be used to prevent vasospasm following SAH by enhancing the circulation in the brain. This study will evaluate if a protocol of volume expansion with HTS is safe and effective in patients with subarachnoid hemorrhage for the prevention of cerebral vasospasm.

Study Overview

• Status: Unknown
• Conditions: Subarachnoid Hemorrhage; Hyponatremia; Cerebral Vasospasm
• Intervention / Treatment: Drug: HTS 3%; Drug: Standard fluid management

Detailed Description

This is a prospective, single-center, interventional, randomized, parallel, two-arm (1:1) phase II clinical trial with blinded end-point ascertainment designed to determine the safety and feasibility of a protocol of 3% hypertonic saline (HTS) as a "volume expander" administered within 72-hours of admission and up to 7-days in SAH patients compared to standard fluid management, in individuals with aneurysmal SAH. A common sequela of aneurysmal SAH is vasospasm, which causes significant morbidity and mortality. In addition, 30% of patients with SAH develop hypovolemic hyponatremia (serum sodium [Na] <130mEq/L), predisposing them to develop cerebral ischemia. Current guidelines for the management of aneurysmal SAH recommend: (1) maintaining euvolemia in order to prevent delayed cerebral ischemia (DCI) and (2) using HTS as a treatment option for the prevention and treatment of hypovolemic hyponatremia. Treatment for vasospasm includes induction of hypertension, along with systemic and/or intra-arterial administration of calcium channel blockers, or angioplasty. The investigators will (1) measure the incidence of severe adverse events from our protocol of HTS, (2) measure the incidence of cerebral vasospasm in patients treated with our protocol of HTS as compared to patients treated with standard fluid therapy; and (3) assess the burden of hypovolemic hyponatremia.

• Study Type: Interventional
• Enrollment (Anticipated): 50
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Recruiting
      • Thomas Jefferson University Hospital
      • Contact: Jan Jager, RN; Phone Number: 215-955-7301; Email: Jan.Jager@jefferson.edu
      • Principal Investigator: Fred Rincon, MD, MSc

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 66 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age 18 to 70 inclusive
2. Hunt-Hess score of 1-5
3. Glascow Come Scale 4-15
4. Modified Fisher Grade 1-4
5. At least one reactive pupil
6. A brain CT/ MRI demonstrating SAH
7. DSA (digital subtraction angiogram) or CTA confirmed presence of intracranial aneurysm
8. The patient can be started on HTS within 72 hours of onset of symptoms of SAH
9. Previously placed central line or having other indication for central line placement

Exclusion Criteria:

1. Pregnancy, or inability to rule out pregnancy with a pregnancy test
2. A normal head CT scan or a CT scan showing a bleed that is not SAH
3. Spinal cord injury or other serious noncerebral injury
4. Known seizure disorder
5. Known brain disease (eg tumor, metastasis) or major psychiatric disorders (eg schizophrenia)
6. Renal insufficiency (baseline Cr>1.5 mg/dl, CrCl<30 ml/min, CKD)
7. Acute systolic dysfunction or congestive heart failure (CHF), with EF <30%
8. Hematologic abnormalities or coagulopathy (PT>20, PTT>50, INR>1.5, or bleeding time>10sec)
9. Clinically significant cardiovascular, hepatic or pulmonary disease that, in the opinion of the investigator, would compromise patient safety
10. Other life-threatening injury that compromises patient survival through duration of study
11. Patient unlikely to be available for follow-up at 6 months after trial conclusion
12. Any concurrent relevant condition that makes the patient unsuitable for participation or follow-up
13. Serum sodium > 155 mEq/L

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Hypertonic saline (HTS); A protocol of prophylactic 3% HTS as a volume expander with bolus (over 30 minutes) of 3% HTS at a dose of 250 ml every 6 hours for 7 days. This will be given through a central line as soon as possible and within 72 hours of onset of SAH symptoms.	Drug: HTS 3%; 3% HTS at a dose of 250 ml every 6 hours for 7 days
Active Comparator: Standard fluid; Routine fluid management strategy as pre-specified by our SAH management protocol at Jefferson University Hospital according to the American Heart Association and Neurocritical Care Guidelines for the management of SAH (this includes conventional intravenous fluids or normal saline solutions to maintain a normal hydration status and guided by the treating doctor and daily assessments of fluid balance).	Drug: Standard fluid management; Routine fluid management strategy as pre-specified by our SAH management protocol.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety (adverse events)	Incidence or proportion of serious adverse events	21 days
Feasibility (Proportion of patients treated according to the protocol)	Proportion of patients treated according to the protocol	21 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Vasospasm (Incidence of cerebral vasospasm defined as clinical deterioration)	Incidence of cerebral vasospasm defined as clinical deterioration (focal deficit or decline in Glasgow Coma Scale (GCS) score of >/=2 points by neurological exam), or transcranial doppler (TCD) velocity increase with mean blood flow > 120 cm/sec, or arterial narrowing (mod-sec) on DSA or CTA.	21 days
Hyponatremia (Incidence of hypovolemic hyponatremia defined as Na <135)	Incidence of hypovolemic hyponatremia defined as Na <135	21 days

Collaborators and Investigators

• Sponsor: Thomas Jefferson University

Study record dates

Study Major Dates

• Study Start: January 1, 2015
• Primary Completion (Anticipated): January 1, 2017

Study Registration Dates

• First Submitted: March 10, 2015
• First Submitted That Met QC Criteria: May 1, 2015
• First Posted (Estimate): May 4, 2015

Study Record Updates

• Last Update Posted (Estimate): February 11, 2016
• Last Update Submitted That Met QC Criteria: February 10, 2016
• Last Verified: February 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Metabolic Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Intracranial Hemorrhages; Water-Electrolyte Imbalance; Hemorrhage; Subarachnoid Hemorrhage; Hyponatremia; Vasospasm, Intracranial
• Other Study ID Numbers: 14D.557