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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| high sodium infusion fluid | Active Comparator | 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. |
|
| low sodium infusion fluid | Active Comparator | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 0.9% Sodium-chloride | Drug | 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. |
| 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) |
| 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 |
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Inclusion Criteria:
All adult patients suffering from non-traumatic subarachnoid haemorrhage.
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Anna S Messmer, MD | Contact | +41316322111 | 0041 | anna.messmer@insel.ch |
| Research Nurses Department of Intensive Care | Contact | +41316322111 | 0041 | kim.researchnurses@insel.ch |
| Name | Affiliation | Role |
|---|---|---|
| Anna S Messmer, MD | Department of Intensive Care, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Department of perioperative Intensive Care Medicine | Recruiting | Sankt Gallen | Canton of St. Gallen | 9007 | Switzerland |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 41107997 | Background | Messmer AS, Pitteloud M, Quintard H, Pietsch U, Muller M, Filipovic M, Jakob SM, Z'Graggen WJ, Schefold JC, Pfortmueller CA. CRYSTALLBrain: crystalloid fluid choice and neurological outcome in patients with non-traumatic subarachnoid haemorrhage-a study protocol for a multi-centre randomised double-blind clinical trial. Trials. 2025 Oct 17;26(1):422. doi: 10.1186/s13063-025-09099-9. | |
| 39379751 |
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Information will be available upon request.
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Multi-center investigator-initiated randomized-controlled double blind clinical trial comparing to already established treatment protocols.
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double-blind randomized
| Ringer's Lactate | Drug | 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. |
|
| 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) |
| Department of Intensive Care, Bern University Hospital and University of Bern, Bern, Switzerland | Recruiting | Bern | 3010 | Switzerland |
|
| Department of Intensive Care Medicine | Recruiting | Geneva | 1205 | Switzerland |
|
| Derived |
| Mistry AM. Which Intravenous Isotonic Fluid Offers Better Outcomes for Patients with a Brain Injury? Neurocrit Care. 2025 Apr;42(2):715-721. doi: 10.1007/s12028-024-02139-3. Epub 2024 Oct 8. |
| ID | Term |
|---|---|
| D013345 | Subarachnoid Hemorrhage |
| D016638 | Critical Illness |
| ID | Term |
|---|---|
| D020300 | Intracranial Hemorrhages |
| D002561 | Cerebrovascular Disorders |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D006470 | Hemorrhage |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D020969 | Disease Attributes |
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| ID | Term |
|---|---|
| D012965 | Sodium Chloride |
| D000077325 | Ringer's Lactate |
| ID | Term |
|---|---|
| D002712 | Chlorides |
| D006851 | Hydrochloric Acid |
| D017606 | Chlorine Compounds |
| D007287 | Inorganic Chemicals |
| D017670 | Sodium Compounds |
| D000077324 | Crystalloid Solutions |
| D007552 | Isotonic Solutions |
| D012996 | Solutions |
| D004364 | Pharmaceutical Preparations |
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