Crystalloid Fluid Choice and Neurological Outcome in Patients After Subarachnoid Haemorrhage (CRYSTALLBrain)

Crystalloid Fluid Choice and Neurological Outcome in Patients After Subarachnoid Haemorrhage - a Multi-center Randomized Double-blind Clinical Trial

Patients with subarachnoid hemorrhage are prone to suffer from dysnatriemia. Evidence shows that hyponatriemia is associated with increased incidence of vasospasm, brain swelling and mortality in these patients. Patients with subarachnoid hemorrhage often require large amounts of iv fluids in order to maintain euvolemia and support cardiocirculatory function. Prior evidence shows that the type of infusion fluid significantly influences blood sodium content. Hence, this study evaluated whether the sodium content of the infusion solution impacts mortality and morbidity in patients with subarachnoid hemorrhage.

Study Overview

• Status: Recruiting
• Conditions: Critical Illness; Subarachnoid Hemorrhage; Sodium Disorder; Infusion Fluid
• Intervention / Treatment: Drug: 0.9% Sodium-chloride; Drug: Ringer's Lactate

Detailed Description

Background: Despite ongoing advances in critical care mortality and morbidity of patients with subarachnoid hemorrhage remains high. Secondary brain injuries related to cerebral vasospasm and consecutive ischemic brain injury and intracerebral edema are the main contributors to mortality and morbidity in these patients. Evidence points towards low serum sodium levels being one of the significant risk factors for of secondary brain injury in this population. Previous studies show that fluid resuscitation with normal saline results in higher serum sodium levels and higher serum osmolality when compared to balanced infusates in patients with subarachnoid hemorrhage.

Aim: The primary objective of this study is to evaluate whether the use of a sodium-rich infusion (normal saline) results in better clinical outcome when compared to a sodium-depleted infusion (lactated Ringer's) in patients with subarachnoid hemorrhage. The primary endpoint will be the occurrence of clinically relevant vasospasm requiring immediate treatment. In addition, the investigators will assess other relevant complications such as long and short-term mortality, significant brain edema requiring conservative therapy or/and operative hemicraniectomy, as well as further patient-relevant outcomes such as days on organ support, postoperative infections, length of stay and long-term disability/mortality.

Study intervention: All patients admitted to a participating hospital with the diagnosis of intracerebral bleeding will be screened and if eligible, randomized to one of the study arms. Individual patient's consent will be sought. Thereafter, patients will receive only the allocated study fluid for fluid maintenance and resuscitation from study inclusion until ICU/intermediate care (IMC) discharge. Neurological evaluation will be performed hourly for the initial phase and thereafter two hourly. Serum sodium, osmolality, fluid, water and electrolyte balance as well as acid-base homeostasis will be evaluated daily. Further, specific assessment of renal, cardiac and immune function takes place at 5 pre-specified time-points (day 1,3,7,10 and at ICU/IMC discharge).

After ICU/IMC discharge patients will be followed for evaluation of secondary endpoints. Long-term disability will be assessed by telephone interview based on the modified the Rankin-Scale and the Glasgow Outcome Scale Extended.

Sample Size: Sample size calculation was based upon the investigators' ICU's registry data. In 2017, 44.38% patients with subarachnoid hemorrhage reached the predefined endpoint of clinically relevant vasospasm requiring immediate intervention. A clinically relevant effect size was determined to be an improvement in outcome of 15%. Based on these results a patient number of n = 160 for each group was determined under estimation of a 15% drop out rate.

• Study Type: Interventional
• Enrollment (Estimated): 320
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Anna S Messmer, MD; Phone Number: 0041 +41316322111; Email: anna.messmer@insel.ch
• Study Contact Backup: Name: Research Nurses Department of Intensive Care; Phone Number: 0041 +41316322111; Email: kim.researchnurses@insel.ch

Study Locations

• Switzerland
  • Bern, Switzerland, 3010
    • Recruiting
    • Department of Intensive Care, Bern University Hospital and University of Bern, Bern, Switzerland
    • Contact: Anna S Messmer, MD; Phone Number: 0041316322111; Email: anna.messmer@insel.ch
  • Geneva, Switzerland, 1205
    • Recruiting
    • Department of Intensive Care Medicine
    • Contact: Hervé Quintard, Prof. Dr. med.; Phone Number: +41 223727460; Email: Herve.Quintard@hcuge.ch

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

All adult patients suffering from non-traumatic subarachnoid haemorrhage.

Exclusion Criteria:

• Patients with major intra-cranial trauma
• Diagnosis of an AV-malformation as the source of subarachnoid hemorrhage on the primary CT/MRI or angiography
• More than 24 hours after diagnosis of subarachnoid haemorrhage as diagnosed by cerebral imaging (CT scan or MRI)
• Patients with clear limitation to therapy at hospital admission (eg ICU admission for evaluation of organ donation)
• Declining of informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: high sodium infusion fluid; Patients will exclusively receive 0.9% saline (sodium content 154mmol/l) for fluid maintenance and resuscitation from study inclusion until ICU/intermediate care (IMC) discharge.	Drug: 0.9% Sodium-chloride; We will compare two already established treatment protocols: the use of normal saline versus lactated Ringer's for fluid therapy in patients with subarachnoid hemorrhage.
Active Comparator: low sodium infusion fluid; Patients will exclusively receive lactated Ringer's (sodium content 130mmol/l) for fluid maintenance and resuscitation from study inclusion until ICU/intermediate care (IMC) discharge.	Drug: Ringer's Lactate; We will compare two already established treatment protocols: the use of normal saline versus lactated Ringer's for fluid therapy in patients with subarachnoid hemorrhage.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients with clinically relevant vasospasms	Defined as new neurologic deficit requiring immediate intervention	From ICU admission until discharge (usually within the first 21 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of ICU deaths	Death on the ICU	From ICU admission until discharge (usually within the first 21 days)
Number of In-hospital deaths	Death during hospital stay	From hospital admission to hospital discharge (usually within the first 21 days)
Number of severe vasospasms requiring endovascular treatment	Number of severe vasospasms requiring endovascular treatment	From hospital admission to hospital discharge (usually within the first 21 days)
Number of patients needing decompressive hemicraniectomy	Operative intervention needed for high intracranial pressure	From hospital admission to hospital discharge (usually within the first 21 days)
Difference in modified RankingScale	Scale ranges from 0-5 (0 = no symptoms; 5= severe disability)	At day 90 and 180
Difference in Glasgow Outcome Scale	Scale ranges from 1-8 (1 is dead 7 good recovery)	At day 90 and 180
Difference in mini Montreal Cognitive Assessment	Max score depends on age and education (the higher the score the better the cognition)	At day 90 and 180
Difference in Long-term mortality	Death at 90 and 180 day	At day 90 and 180
Length of stay	Length of hospital stay	ICU stay and hospital stay (usually between 1-30days)

Collaborators and Investigators

• Sponsor: Insel Gruppe AG, University Hospital Bern
• Investigators: Principal Investigator: Anna S Messmer, MD, Department of Intensive Care, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland

Study record dates

Study Major Dates

• Study Start (Actual): May 24, 2022
• Primary Completion (Estimated): December 1, 2025
• Study Completion (Estimated): July 1, 2026

Study Registration Dates

• First Submitted: July 31, 2019
• First Submitted That Met QC Criteria: July 31, 2019
• First Posted (Actual): August 2, 2019

Study Record Updates

• Last Update Posted (Actual): December 12, 2023
• Last Update Submitted That Met QC Criteria: December 11, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Disease Attributes; Intracranial Hemorrhages; Hemorrhage; Critical Illness; Subarachnoid Hemorrhage
• Other Study ID Numbers: CRYSTALLBrain

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Information will be available upon request.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No