ANZCTR - Registration

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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]

Nil

Universal Trial Number (UTN)

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Critically ill patients

Acute Kidney Injury

Condition category

Condition code

Renal and Urogenital

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]

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]

Incidence of Acute Kidney Injury (AKI) according to the Kidney Disease: Improving Global Outcome (KDIGO) creatinine definitions

Timepoint [1]

Duration of ICU stay

Secondary outcome [1]

The need for Renal Replacement Therapy (RRT)

Timepoint [1]

Duration of ICU stay

Secondary outcome [2]

Length of stay in Intensive Care Unit and Hospital

Timepoint [2]

Duration of hospital stay

Secondary outcome [3]

Intensive Care Unit and Hospital survival

Timepoint [3]

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

Sex

Both males and females

Can healthy volunteers participate?

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

18/08/2007

Actual

18/08/2007

Date of last participant enrolment

Anticipated

17/02/2010

Actual

17/02/2010

Date of last data collection

Anticipated

Actual

Sample size

Target

3000

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

VIC

Recruitment hospital [1]

Austin Health - Austin Hospital - Heidelberg

Recruitment postcode(s) [1]

3084 - Heidelberg

Funding & Sponsors

Funding source category [1]

Hospital

Name [1]

Austin Health

Address [1]

Studley Road, Heidelberg, 3084, Victoria

Country [1]

Australia

Primary sponsor type

Hospital

Name

Austin Health

Address

Studley Road, Heidelberg, 3084, Victoria

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Other collaborator category [1]

Other Collaborative groups

Name [1]

Australia and New Zealand Intensive Care Research Centre (ANZIC-RC)

Address [1]

The Alfred Centre
Level 6 (Lobby B)
99 Commercial Road
Melbourne Victoria 3004

Country [1]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Austin Health Human Research Ethics Committee

Ethics committee address [1]

Studley road, Heidelberg, Victoria, 3084

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

26/11/2008

Approval date [1]

15/01/2009

Ethics approval number [1]

H2008/03445

Ethics committee name [2]

Austin Health Human Research Ethics Committee

Ethics committee address [2]

Studley Road, Heidelberg, Victoria 3084

Ethics committee country [2]

Australia

Date submitted for ethics approval [2]

07/07/2014

Approval date [2]

25/07/2014

Ethics approval number [2]

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]

/AnzctrAttachments/366520-JAMA 2012; 308 (15)1566-1572.pdf

Attachments [2]

/AnzctrAttachments/366520-Crit Care Med 2011;39(11)2419-2424.pdf

Contacts

Principal investigator

Name

Dr Nor'azim Mohd Yunos

Address

Clinical School of Johor Bahru,
Monash University Malaysia,
8, Jalan Masjid Abu Bakar,
80100 Johor Bahru

Country

Malaysia

Phone

+ 60 7 2190 640

Fax

nor.azim@monash.edu

Contact person for public queries

Name

Rinaldo Bellomo

Address

Department of Intensive Care,
Austin Health,
145 Studley Road, Heidelberg,
Victoria 3084, Australia

Country

Australia

Phone

+ 61 3 9496 5992

Fax

rinaldo.bellomo@austin.org.au

Contact person for scientific queries

Name

Rinaldo Bellomo

Address

Department of Intensive Care,
Austin Health,
145 Studley Road, Heidelberg,
Victoria 3084, Australia

Country

Australia

Phone

+ 61 3 9496 5992

Fax

rinaldo.bellomo@austin.org.au

No information has been provided regarding IPD availability

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No Supporting Document Provided

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