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Trial registered on ANZCTR


Registration number
ACTRN12614000866606
Ethics application status
Approved
Date submitted
4/08/2014
Date registered
13/08/2014
Date last updated
13/08/2014
Type of registration
Retrospectively registered

Titles & IDs
Public title
Chloride-Liberal versus Chloride-Restrictive Intravenous Fluid Administration and Acute Kidney Injury: An Extended Analysis
Scientific title
A comparison of chloride-liberal and chloride-restrictive intravenous fluid administration on acute kidney injury in adult intensive care unit patients
Secondary ID [1] 284782 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Critically ill patients 292158 0
Acute Kidney Injury 292728 0
Condition category
Condition code
Renal and Urogenital 292493 292493 0 0
Kidney disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is an extended analysis of an earlier study, Chloride High Level of Resuscitation Infusion Delivered Evaluation (CHLORIDE), registered with the ClinicalTrials.gov; NCT 00885404. The study was conducted in the 22-bed multidisciplinary ICU of the Austin Hospital, Heidelberg, Victoria.

In the original prospective sequential study, the sequence consisted of a 6 month control period followed by a 6 month 'washout' period that included staff education and a 6 month intervention period. During the intervention period, ICU clinicians were not allowed to use chloride-rich fluids - 0.9% saline, Gelofusine, or Albumex 4 (4% albumin) - in their routine practice. In replacement, they were encouraged to use existing lower chloride fluids - Hartmann’s solution, Plasma-Lyte 148, and Albumex 20. However, chloride-rich fluids were allowed under exclusive and specific prescription by an ICU specialist for conditions which might be considered likely to benefit from their use (e.g., hyponatremia, cerebral edema, marked hypochloremic alkalosis).

Adherence to the intervention was ensured through close coordination with the Pharmacy Unit. The Unit strictly supplied only low-chloride intravenous fluids during the intervention period. The only high chloride solution bags available in the ICU during this period were stored in an ICU specialist's room, released after specific prescriptions described above.

For this study, the chloride-restrictive intravenous fluid intervention had been maintained in the same ICU for the subsequent 6 months, extending the intervention period to 1 year. We now have a longer intervention period when the most common prescribers (ICU residents and fellows) had not received any specific training and simply rotated through the ICU when only low chloride fluids were available.
Intervention code [1] 289572 0
Treatment: Drugs
Comparator / control treatment
During the first 6 month of the original study, the control period; ICU clinicians were free to use any intravenous fluids based on clinical preference. None of the clinicians was aware of the plan to conduct a trial involving removal of chloride-rich fluids from ICU practice. The fluids available included 0.9% saline, Gelofusine, Albumex 4 (4% albumin), Hartmann’s solution, Plasma-Lyte 148, and Albumex 20 (20% albumin).

We now prolong the the control period to include the preceding 6 months; extending the control period to 1 year. This would not have affected the study protocol as the control arm was a standard intravenous practice period without clinician awareness.
Control group
Historical

Outcomes
Primary outcome [1] 292371 0
Incidence of Acute Kidney Injury (AKI) according to the Kidney Disease: Improving Global Outcome (KDIGO) creatinine definitions
Timepoint [1] 292371 0
Duration of ICU stay
Secondary outcome [1] 308807 0
The need for Renal Replacement Therapy (RRT)
Timepoint [1] 308807 0
Duration of ICU stay
Secondary outcome [2] 308808 0
Length of stay in Intensive Care Unit and Hospital
Timepoint [2] 308808 0
Duration of hospital stay
Secondary outcome [3] 308809 0
Intensive Care Unit and Hospital survival
Timepoint [3] 308809 0
Duration of hospital stay

Eligibility
Key inclusion criteria
1. All consecutive ICU admissions for the 1 year control period from 18 August 2007 through 17 August 2008.
2. All consecutive ICU admissions for the 1 year intervention period from 18 February 2009 through 17 February 2010.
Minimum age
No limit
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
No exclusion criteria to this study because intravenous fluids were part of standard patient care in the ICU.

Study design
Purpose of the study
Prevention
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Prospective open label sequential period (before-and-after) study
Phase
Phase 4
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
We will perform baseline comparisons using Chi-square tests for equal proportion with results reported as numbers, percentages, and 95% confidence intervals. We will present continuously normally distributed variables as means (95%CI) and compare using student t-tests. We will analyze acute kidney injury (defined by KDIGO) and the need for RRT using logistic regression and report the results as odds ratios (ORs) with 95% confidence intervals. We will present time-to-event analysis using Kaplan-Meier curves and perform comparisons using log-rank tests.

We will perform multivariable logistic regression analysis on all outcomes, adjusting for the pre–defined covariates of sex, APACHE III score, diagnosis, operative status, and admission type (elective or emergency).

We will perform further sensitivity analysis by comparing outcomes during each 6-month period of this extended study: the original control, the extended control, the original intervention and the extended intervention periods. We will compare the incidence of KDIGO-defined AKI stages 2 and 3, and the need for RRT between these 4 groups also adjusting for the above variables. To further determine if the treatment effect was consistent across periods, we plan to fit interaction between treatment (intervention vs control) and period (original vs extended).

To reduce the chance of a type I error due to reporting multiple outcomes, we will use a two-sided P value of <0.01 to indicate statistical significance.

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] 2627 0
Austin Health - Austin Hospital - Heidelberg
Recruitment postcode(s) [1] 8292 0
3084 - Heidelberg

Funding & Sponsors
Funding source category [1] 289414 0
Hospital
Name [1] 289414 0
Austin Health
Address [1] 289414 0
Studley Road, Heidelberg, 3084, Victoria
Country [1] 289414 0
Australia
Primary sponsor type
Hospital
Name
Austin Health
Address
Studley Road, Heidelberg, 3084, Victoria
Country
Australia
Secondary sponsor category [1] 288096 0
None
Name [1] 288096 0
Address [1] 288096 0
Country [1] 288096 0
Other collaborator category [1] 278000 0
Other Collaborative groups
Name [1] 278000 0
Australia and New Zealand Intensive Care Research Centre (ANZIC-RC)
Address [1] 278000 0
The Alfred Centre
Level 6 (Lobby B)
99 Commercial Road
Melbourne Victoria 3004
Country [1] 278000 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 291174 0
Austin Health Human Research Ethics Committee
Ethics committee address [1] 291174 0
Studley road, Heidelberg, Victoria, 3084
Ethics committee country [1] 291174 0
Australia
Date submitted for ethics approval [1] 291174 0
26/11/2008
Approval date [1] 291174 0
15/01/2009
Ethics approval number [1] 291174 0
H2008/03445
Ethics committee name [2] 291482 0
Austin Health Human Research Ethics Committee
Ethics committee address [2] 291482 0
Studley Road, Heidelberg, Victoria 3084
Ethics committee country [2] 291482 0
Australia
Date submitted for ethics approval [2] 291482 0
07/07/2014
Approval date [2] 291482 0
25/07/2014
Ethics approval number [2] 291482 0
LNR/14/Austin/369

Summary
Brief summary
Intravenous fluid therapy may influence outcomes in critically ill patients. Some of these outcomes have been linked to the contents of intravenous fluids, including colloid source and electrolyte compositions. The chloride content of intravenous fluids has recently emerged as an area of interest in terms of renal injury.

For example, a double-blind randomized controlled trial in healthy volunteers showed significantly better renal cortical tissue perfusion following a 2L infusion of a low-chloride fluid (Plasma-Lyte-Registered Trade Mark) compared with a high-chloride fluid (0.9% saline) (Chowdhury et al 2012). Similar effects were seen with the administration of hydroxyethyl starch (HES) in a low chloride solution compared to HES in saline (Chowdhury et al 2014). These studies suggest that excess chloride administration may modulate renal perfusion in man. However, the clinical implications of reducing chloride administration remain poorly understood. We previously reported the findings of a before-and-after study of restrictive vs. liberal intravenous chloride administration in a tertiary intensive care unit (ICU). Although our study found a beneficial renal effect of restricting chloride administration, it was suggested that a Hawthorne effect induced by preparation and education for the before-and-after study may have accounted for the findings .

Accordingly, to mitigate the impact of such a putative Hawthorne effect, we extended the control and the intervention periods of our study from 6 months to 1 year to include a longer control period and an intervention period when the most common prescribers (ICU residents and fellows) had not received any specific training and simply rotated through the ICU when only low chloride fluids were available. We hypothesize that extending the study period will not affect our earlier finding of decreased incidence of acute kidney injury with chloride-restrictive intravenous fluid strategy compared with chloride-liberal strategy.
Trial website
Trial related presentations / publications
1. Yunos NM, Kim IB, Bellomo R, Bailey M, Story D, Ho L, Gutteridge GA, Hart GK. The Biochemical Effects of Restricting Chloride-Rich Fluids in Intensive Care (ClinicalTrials.gov NCT 00885404) Crit Care Med 2011;39(11):2419-2424

2. Yunos NM, Bellomo R, Hegarty C, Story D, Ho L, Bailey M.
Association between a chloride-liberal vs. chloride-restrictive intravenous fluid administration strategy and kidney injury in critically ill adults. JAMA 2012; 308 (15):1566-1572
Public notes
This is an extended analysis of an earlier study, Chloride High Level of Resuscitation Infusion Delivered Evaluation (CHLORIDE), registered with the ClinicalTrials.gov; NCT 00885404. The study was conducted in the 22-bed multidisciplinary ICU of the Austin Hospital, Heidelberg, Victoria. The ethics approval for both original and extended studies were from Austin Health Human Research Ethics Committee. The committee acknowledged that the control group, recruited prior to ethics approval, received only standard intravenous practice without clinician awareness.
Attachments [1] 83 83 0 0

Contacts
Principal investigator
Name 49138 0
Dr Nor'azim Mohd Yunos
Address 49138 0
Clinical School of Johor Bahru,
Monash University Malaysia,
8, Jalan Masjid Abu Bakar,
80100 Johor Bahru
Country 49138 0
Malaysia
Phone 49138 0
+ 60 7 2190 640
Fax 49138 0
Email 49138 0
nor.azim@monash.edu
Contact person for public queries
Name 49139 0
Prof Rinaldo Bellomo
Address 49139 0
Department of Intensive Care,
Austin Health,
145 Studley Road, Heidelberg,
Victoria 3084, Australia
Country 49139 0
Australia
Phone 49139 0
+ 61 3 9496 5992
Fax 49139 0
Email 49139 0
rinaldo.bellomo@austin.org.au
Contact person for scientific queries
Name 49140 0
Prof Rinaldo Bellomo
Address 49140 0
Department of Intensive Care,
Austin Health,
145 Studley Road, Heidelberg,
Victoria 3084, Australia
Country 49140 0
Australia
Phone 49140 0
+ 61 3 9496 5992
Fax 49140 0
Email 49140 0
rinaldo.bellomo@austin.org.au

No information has been provided regarding IPD availability
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