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Trial registered on ANZCTR


Registration number
ACTRN12613001042730
Ethics application status
Approved
Date submitted
17/09/2013
Date registered
19/09/2013
Date last updated
5/02/2016
Type of registration
Prospectively registered

Titles & IDs
Public title
0.9% Saline vs. Plasma Lyte (Registered Trademark)148 for Fluid Intervention Trial in Major Surgery Patients (The SPLIT- Major Surgery study)
Scientific title
A single-centred randomised double-blind pilot trial investigating acute kidney injury (RIFLE-criteria) from either 0.9% saline or Plasmalyte (Registered Trademark) 148 solutions as fluid therapy in adult patients undergoing major surgery
Secondary ID [1] 283231 0
Nil
Universal Trial Number (UTN)
U1111-1148-1333
Trial acronym
(The SPLIT- Major Surgery study)
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Adult patients undergoing major surgery 290104 0
Condition category
Condition code
Surgery 290481 290481 0 0
Other surgery
Anaesthesiology 290482 290482 0 0
Anaesthetics
Renal and Urogenital 290483 290483 0 0
Kidney disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Adult patients undergoing major surgery will be randomised to receive either intravneous Saline (0.9%) or intravenous Plasmalyte (Registered Trademark) 148 solution for all periopeartive crystalloid fluid intervention in alternating 6 week blocks. The amount of fluid adminsistered will be in keeping with standard hospital care and entirely at the discretion of all treating clinicians. All patients will be treated with the trial fluid for the duration of their hospital stay. There will be a 3 week washout period between each fluid intervention.
Intervention code [1] 287962 0
Treatment: Other
Comparator / control treatment
Patients undergoing major surgery will receive normal saline (0.9%) (control arm) or Plasmalyte (Registered Trademark) 148 solution
Control group
Active

Outcomes
Primary outcome [1] 290507 0
Acute kidney injury or failure (RIFLE-criteria)
Timepoint [1] 290507 0
Duration of hospital stay
Secondary outcome [1] 304663 0
Serum creatinine peformed as part of normal hospital care. Generally at Austin Hospital after major surgery this biochemical test is perfomed daily for 48 hours, then as clinically indicated at the discretion of the treating surgical or intensive care unit.
Timepoint [1] 304663 0
Duration of hospital stay
Secondary outcome [2] 304664 0
Serum Chloride levels peformed as part of normal hospital care. Generally at Austin Hospital after major surgery this biochemical test is perfomed daily for 48 hours, then as clinically indicated at the discretion of the treating surgical or intensive care unit.
Timepoint [2] 304664 0
Duration of hospital stay
Secondary outcome [3] 304665 0
Acid base disturbances peformed as part of normal hospital care. Generally at Austin Hospital after major surgery this biochemical test is perfomed daily for 48 hours, then as clinically indicated at the discretion of the treating surgical or intensive care unit.
Timepoint [3] 304665 0
Duration of hospital stay
Secondary outcome [4] 304666 0
Post-operative complications e.g myocardial infarction (raised cardiac troponin levels) , pneumonia (elevated white cell count and radiological changes), pulmonary embolus (radiologically confirmed), renal injury (RIFLE criteria), wound infection (positive culture from surgical wound); sepsis (internationla criteria), blood transfusion, unexpected admission to intensive care
Timepoint [4] 304666 0
Duration of hospital stay
Secondary outcome [5] 304667 0
Requirements for Intensive Care
Timepoint [5] 304667 0
Duration of hospital stay
Secondary outcome [6] 304668 0
Duration of ICU stay
Timepoint [6] 304668 0
Duration of hospital stay
Secondary outcome [7] 304669 0
Hospital length of stay
Timepoint [7] 304669 0
Duration of hospital stay
Secondary outcome [8] 304670 0
In-hospital mortality
Timepoint [8] 304670 0
Duration of hospital stay

Eligibility
Key inclusion criteria
Patients aged greater than 18 years admitted to the Austin Hospital who are undergoing surgery.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Patients who are <18 years in age
2. Raised intracranial pressure (these patients may specific fluid intervention strategies to prevent further increases in intracranial pressure)
3. Patients undergoing liver transplantation (these patients require non- lactated crystalloid solutions as part of the Austin Hospital perioperative fluid intervention protocol.
4. Patients undergoing renal transplantation, as these patients are currently part of a current randomised clinical trial.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation is not concealed.

This study utilises a novel design in order to assess the relative efficacy of two standard treatment approaches. Although this study is clearly an interventional study on the basis of conventional Guidelines, it has many features that are more akin to an observational study than an interventional one. Specifically, the study involves no departure from standard care and does not involve the collection of any data that are not already being collected for clinical and / or quality assurance purposes.

Patients will be assigned, in alternating 6 weeks blocks to use either blinded Saline (0.9%) or blinded Plasmalyte solution. There will be a three week wash-in period and a three-week wash-out period between each fluid intervention. Both solutions are considered standard of care for all crystalloid intervention at our institution.

For example, assume:

GROUP ONE: Saline

GROUP TWO: Plasmalyte

Three weeks prior to commencement, blinded Saline will be introduced into all theatres, intensive care and surgical wards for a 3 week wash-in period. GROUP ONE subjects will then receive Saline for 6 weeks. This will be followed by a 3-week wash-out period of Saline. Plasmalyte solution will then be washed-in for 3 weeks. GROUP TWO subjects will then receive Plasmalyte solution for a 6 week period. Plasmalyte solution will be washed-out for 3 weeks and the study will stop.

Total study duration: 24 weeks

Any patients who remains in hospital throughout an entire cross over period will continue to receive the fluid that they were originally assigned to. Thus blinded fluid will be made available as the only crystalloid fluid in all surgical wards and in the intensive care unit.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (i.e. computer sequence generation) computer sequence will be performed for this study.

This study utilises a novel design in order to assess the relative efficacy of two standard treatment approaches. Although this study is clearly an interventional study on the basis of conventional Guidelines, it has many features that are more akin to an observational study than an interventional one. Specifically, the study involves no departure from standard care and does not involve the collection of any data that are not already being collected for clinical and / or quality assurance purposes.

Patients will be assigned, in alternating 6 weeks blocks to use either blinded Saline (0.9%) or blinded Plasmalyte solution. There will be a three week wash-in period and a three-week wash-out period between each fluid intervention. Both solutions are considered standard of care for all crystalloid intervention at our institution.

For example, assume:

GROUP ONE: Saline

GROUP TWO: Plasmalyte

Three weeks prior to commencement, blinded Saline will be introduced into all theatres, intensive care and surgical wards for a 3 week wash-in period. GROUP ONE subjects will then receive Saline for 6 weeks. This will be followed by a 3-week wash-out period of Saline. Plasmalyte solution will then be washed-in for 3 weeks. GROUP TWO subjects will then receive Plasmalyte solution for a 6 week period. Plasmalyte solution will be washed-out for 3 weeks and the study will stop.

Total study duration: 24 weeks

Any patients who remains in hospital throughout an entire cross over period will continue to receive the fluid that they were originally assigned to. Thus blinded fluid will be made available as the only crystalloid fluid in all surgical wards and in the intensive care unit.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Other
Other design features
In this study, whether or not patients receive saline or Plasmalyte as default crystalloid fluid therapies will be determined, on the basis of whether they are cared for during a particular period. No controls will be placed on the use of colloidal fluid therapy, blood products (red blood cells, platelets, cryoprecipitate or fresh frozen plasma, or any other fluid non-crystalloid fluid intervention e.g. dextrose, bicarbonate.

All patients in this study will receive standard treatment except that the default therapy that they receive will be randomly allocated according to the 6-week block in which they are admitted to the study hospital.


Phase
Phase 4
Type of endpoint(s)
Safety
Statistical methods / analysis
A recently published open label sequential period study of chloride-liberal vs. chloride-restrictive fluid administration demonstrated a reduction in the incidence of injury and failure based on RIFLE criteria from 14% (95% CI, 11% - 16%) to 8.4% (95% CI, 6.4% - 10%); P<0.001) with the introduction of a chloride-restrictive fluid regime.

We have conservatively estimated, we can study over 1000 subjects over a 24 week period, our sample size will still provide more than 90% power with an alpha of 0.01 to detect a difference of this magnitude.


All analyses will be conducted on an intention-to-treat basis.

The primary analyses will be unadjusted analyses in which binary outcomes will be compared using relative risks with 95% confidence intervals and chi square tests and continuous outcomes will be compared with the use of mean differences and un-paired T-tests assuming that normality assumptions are meet. If normality assumptions are not met then we plan to attempt simple data transformation, such as a logarithm transformation, and if this fails to proceed to a Mann-Whitney rank based test. Adjusted analyses will be performed using Poisson regression for binary outcomes and linear regression for continuous outcomes. Baseline covariates will include age, gender, elective vs. emergency surgery, surgical specialty of admission, type of operation, and baseline serum creatinine level. Survival times will be compared using log-rank tests and presented as Kaplan-Meier curves.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 1528 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [2] 1529 0
Austin Health - Heidelberg Repatriation Hospital - Heidelberg West
Recruitment postcode(s) [1] 7366 0
3084 - Heidelberg

Funding & Sponsors
Funding source category [1] 287977 0
Commercial sector/Industry
Name [1] 287977 0
Baxter Healthcare
Address [1] 287977 0
PO Box 88, Toongabbie, NSW, 2146
Country [1] 287977 0
Australia
Primary sponsor type
Hospital
Name
Austin Hospital
Address
Studley Road, Heidelberg, 3084, Victoria
Country
Australia
Secondary sponsor category [1] 286699 0
Commercial sector/Industry
Name [1] 286699 0
Baxter Healthcare
Address [1] 286699 0
PO Box 88, Toongabbie, NSW, 2146
Country [1] 286699 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 289905 0
Austin Health Research Ethics Unit
Ethics committee address [1] 289905 0
Studley road, Heidelberg, Victoria, 3084
Ethics committee country [1] 289905 0
Australia
Date submitted for ethics approval [1] 289905 0
24/09/2013
Approval date [1] 289905 0
17/07/2014
Ethics approval number [1] 289905 0

Summary
Brief summary
The administration of intravenous crystalloid fluid (also known as fluid therapy) is a ubiquitous intervention in patients undergoing surgery. Worldwide, the most commonly used crystalloid fluids available for patients undergoing major surgery include Saline (0.9%) or the balanced fluid solutions - Hartmann’s and Plasmalyte. Choice of fluid therapy is based frequently dependent on geography, and choice of fluid amongst anaesthetists at Austin Hospital is similar to worldwide practices.

Saline has been used in clinical practice for fluid therapy since the late 1800s. While it is the most commonly used IV fluid in the world recent data raise the possibility that it might increase the risk of developing kidney damage in acutely unwell patients compared to fluids with lower concentrations of chloride such as Plasmalyte. While this increased risk of kidney damage with the use of saline is plausible, current data are insufficient to recommend clinical practice change and data from an interventional trial are urgently needed. However, the design of such a Trial requires sufficient pilot data to establish feasibility, safety power calculations and define an optimal study protocol.

This study aims are to provide high quality pilot data in a rapid time frame to address this important question and to help decide whether a pivotal randomized controlled trial is justified. Thus, all patients undergoing surgery at Austin Hospital will be assigned to receive either Saline (0.9%) or the balanced crystalloid solution Plasmalyte as the primary crystalloid fluid in a blinded fashion during two study periods.

The study will be conducted over a 4-month period allowing including two periods of 6 weeks each where all patients will receive the intervention, with a three week wash-in and a three week wash-out period for each group. Blinded study fluid will be used for all crystalloid therapy in all participants. Austin Hospital staff specialists in anaesthesia agree that on the basis of current evidence, Saline (0.9%) and Plasmalyte are equally acceptable for crystalloid fluid therapy in every situation requiring major surgery with the exclusion of surgery for liver transplantation, renal transplantation and patients with raised intracranial pressure, where specific hospital perioperative fluid protocols are used in these settings.

Both Saline (0.9%) and Plasmalyte will be available for open-label administration in the rare situations, where, in the opinion of the treating anaesthetist or clinician, there is a clinical indication for one fluid or the other. This may occur, for example, in the setting of severe acidosis where the higher chloride content of saline may make this fluid problematic because it may increase the severity of such acidosis.

All adult patients who receive blinded or open-label fluid during one of the two-month study blocks will be analysed. The primary outcome will be the proportion of patients with kidney injury or failure based on established criteria. Secondary outcomes will include delta creatinine (the difference between baseline and peak creatinine), serum electrolyte levels, bicarbonate level, requirement for renal replacement therapy, complications and in-hospital mortality.

All of the data required for this study are collected routinely as part of standard clinical care and/or quality assurance activities.

The study will establish the pilot feasibility, safety and preliminary efficacy evidence base for the design of a large interventional trial to inform clinicians looking after major surgery patients as to whether Saline (0.9%) or Plasmalyte or solution is the preferred crystalloid fluid in this setting.

Hospitals involved: Austin Hospital

Number of participants: Given the current theatre workload at Austin Hospital, approximately 1000 participants will be recruited in each group. A total of 2000 participants are expected.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 43010 0
Dr Laurence Weinberg
Address 43010 0
Department of Anaesthesia
Austin Hospital
145 Studley Rd, Heidelberg, Vic 3084
Country 43010 0
Australia
Phone 43010 0
+61, 3, 9496 5000
Fax 43010 0
+61, 3, 94596421
Email 43010 0
Laurence.Weinberg@austin.org.au
Contact person for public queries
Name 43011 0
Dr Laurence Weinberg
Address 43011 0
Department of Anaesthesia
Austin Hospital
145 Studley Rd, Heidelberg, Vic 3084
Country 43011 0
Australia
Phone 43011 0
+61, 3, 9496 5000
Fax 43011 0
+61, 3, 94596421
Email 43011 0
Laurence.Weinberg@austin.org.au
Contact person for scientific queries
Name 43012 0
Dr Laurence Weinberg
Address 43012 0
Department of Anaesthesia
Austin Hospital
145 Studley Rd, Heidelberg, Vic 3084
Country 43012 0
Australia
Phone 43012 0
+61, 3, 9496 5000
Fax 43012 0
+61, 3, 94596421
Email 43012 0
Laurence.Weinberg@austin.org.au

No data has been provided for results reporting
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary