Subarachnoid HemorrhageCRYSTALLBrainNCT04043598
Crystalloid Fluid Choice and Neurological Outcome in Patients After Subarachnoid Haemorrhage
A study testing 0.9% Sodium-chloride and Ringer's Lactate in people with Subarachnoid Hemorrhage and Critical Illness, run by Insel Gruppe AG, University Hospital Bern at 3 sites in Switzerland.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 16 years and older
- Conditions the study is for
- Subarachnoid Hemorrhage, Critical Illness, Infusion Fluid
- What is being tested?
- 0.9% Sodium-chloride and Ringer's Lactate
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 320 participants
- Where
- 3 sitesSwitzerland
- Study dates
- 24 May 2022to Dec 2027
- Phase
- Interventional
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 16 years and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- All adult patients suffering from non-traumatic subarachnoid haemorrhage.
Who cannot join
- 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
Trial locations and contacts
3 sites in 1 country. Contact the study team or a site near you to ask about taking part.
Research Nurses Department of Intensive Care contact
Switzerland3 sites, 3 recruiting
- Recruiting
Department of Intensive Care, Bern University Hospital and University of Bern, Bern, Switzerland
Bern, 3010
Anna S Messmer, MD, 0041316322111, anna.messmer@insel.ch
- Recruiting
Department of Intensive Care Medicine
Geneva, 1205
Hervé Quintard, Prof. Dr. med., +41 223727460, Herve.Quintard@hcuge.ch
- Recruiting
Department of perioperative Intensive Care Medicine
Sankt Gallen, Canton of St. Gallen, 9007
Urs Pietsch, PD Dr. med., +41 71 494 93 21, urs.pietsch@kssg.ch
About this study
Official title: 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.
Read the 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.
- Being tested
- 0.9% Sodium-chloride, Ringer's Lactate
- Medical subject headings
- Subarachnoid Hemorrhage, Critical Illness
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
0.9% Sodium-chlorideDrug
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.
Ringer's LactateDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: Drug: 0.9% Sodium-chloride |
| 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. Receives: Drug: Ringer's Lactate |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of patients with clinically relevant vasospasms
Defined as new neurologic deficit requiring immediate intervention
Measured: From ICU admission until discharge (usually within the first 21 days)
Secondary outcomes (9)
Number of ICU deaths
Death on the ICU
Measured: From ICU admission until discharge (usually within the first 21 days)
Number of In-hospital deaths
Death during hospital stay
Measured: 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
Measured: 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
Measured: 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)
Measured: At day 90 and 180
Difference in Glasgow Outcome Scale
Scale ranges from 1-8 (1 is dead 7 good recovery)
Measured: 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)
Measured: At day 90 and 180
Difference in Long-term mortality
Death at 90 and 180 day
Measured: At day 90 and 180
Length of stay
Length of hospital stay
Measured: ICU stay and hospital stay (usually between 1-30days)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Aug 2019
- Study start24 May 2022
- Primary completionJul 2027 (estimated)
- Study completionDec 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Subarachnoid HemorrhageStudies of the same condition, open and under way.
- More trials run by Insel Gruppe AG, University Hospital BernThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Other
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Multi-center investigator-initiated randomized-controlled double blind clinical trial comparing to already established treatment protocols.
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 320 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Insel Gruppe AG, University Hospital Bern
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Anna S Messmer, MD, Principal investigator, Department of Intensive Care, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04043598
- Sponsor's protocol ID
- CRYSTALLBrain
- Acronym
- CRYSTALLBrain
- Status last verified
- Apr 2026
- First submitted
- 31 Jul 2019
- Last updated
- 29 Apr 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No: Information will be available upon request.
Publications
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.
PubMed 41107997Mistry 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.
PubMed 39379751
Study at a glance
From the registry record, last updated by the sponsor on 29 Apr 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Crystalloid Fluid Choice and Neurological Outcome in Patients After Subarachnoid Haemorrhage - a Multi-center Randomized Double-blind Clinical Trial
- ClinicalTrials.gov ID
- NCT04043598
- Acronym / sponsor ID
- CRYSTALLBrain / CRYSTALLBrain
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 320 participants (estimated)
- Lead sponsor
- Insel Gruppe AG, University Hospital BernUniversity, hospital or other
- Study start
- 24 May 2022 (actual)
- Primary completion
- Jul 2027 (estimated)
- Study completion
- Dec 2027 (estimated)
- First posted
- 2 Aug 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Primary purpose
- Other
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
- Model description
- Multi-center investigator-initiated randomized-controlled double blind clinical trial comparing to already established treatment protocols.
| Arm | Type | Receives |
|---|---|---|
| high sodium infusion fluid | Active comparator | Drug: 0.9% Sodium-chloridePatients 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 | Drug: Ringer's LactatePatients will exclusively receive lactated Ringer's (sodium content 130mmol/l) for fluid maintenance and resuscitation from study inclusion until ICU/intermediate care (IMC) discharge. |
Who may qualify
- Ages
- 16 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (1 listed)
- All adult patients suffering from non-traumatic subarachnoid haemorrhage.
Key exclusion criteria (5 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| 0.9% Sodium-chlorideWe will compare two already established treatment protocols: the use of normal saline versus lactated Ringer's for fluid therapy in patients with subarachnoid hemorrhage. | Drug | high sodium infusion fluid |
| Ringer's LactateWe will compare two already established treatment protocols: the use of normal saline versus lactated Ringer's for fluid therapy in patients with subarachnoid hemorrhage. | Drug | low sodium infusion fluid |
Primary outcome
Number of patients with clinically relevant vasospasms
Time frame: From ICU admission until discharge (usually within the first 21 days)
Defined as new neurologic deficit requiring immediate intervention
9 secondary outcomes
Number of ICU deaths
Time frame: From ICU admission until discharge (usually within the first 21 days)
Number of In-hospital deaths
Time frame: From hospital admission to hospital discharge (usually within the first 21 days)
Number of severe vasospasms requiring endovascular treatment
Time frame: From hospital admission to hospital discharge (usually within the first 21 days)
Number of patients needing decompressive hemicraniectomy
Time frame: From hospital admission to hospital discharge (usually within the first 21 days)
Difference in modified RankingScale
Time frame: At day 90 and 180
Difference in Glasgow Outcome Scale
Time frame: At day 90 and 180
Difference in mini Montreal Cognitive Assessment
Time frame: At day 90 and 180
Difference in Long-term mortality
Time frame: At day 90 and 180
Length of stay
Time frame: ICU stay and hospital stay (usually between 1-30days)
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 Apr 2026.
- Background: PubMed 41107997Messmer 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.
- Derived from this study: PubMed 39379751Mistry 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.
- Individual participant dataSharing planned: No. Information will be available upon request.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Research Nurses Department of Intensive Care contact
Anna S Messmer, MD principal investigator
Department of Intensive Care, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing 0.9% Sodium-chloride and Ringer's Lactate in people with Subarachnoid Hemorrhage and Critical Illness, run by Insel Gruppe AG, University Hospital Bern at 3 sites in Switzerland.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 29 Apr 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in Switzerland. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Anna S Messmer, MD (+41316322111 ext. 0041, anna.messmer@insel.ch), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of patients with clinically relevant vasospasms (time frame: From ICU admission until discharge (usually within the first 21 days)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04043598, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Apr 2026.