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Trial registered on ANZCTR

Registration number

ACTRN12620000137998

Ethics application status

Approved

Date submitted

17/01/2020

Date registered

12/02/2020

Date last updated

26/06/2024

Date data sharing statement initially provided

12/02/2020

Type of registration

Prospectively registered

Titles & IDs

Public title

20% Human Albumin Solution Fluid Bolus Administration Therapy in Patients after Cardiac Surgery-II

Scientific title

20% Human Albumin Solution Fluid Bolus Administration Therapy in Patients after Cardiac Surgery-II (HAS FLAIR-II): a phase II multicentre randomised controlled trial to determine whether fluid resuscitation with 20% albumin (Albumex®20) in patients after cardiac surgery decreases the duration of vasopressor requirement compared to usual care.

Secondary ID [1]

None

Universal Trial Number (UTN)

U1111-1242-2469

Trial acronym

HAS FLAIR-II

Linked study record

Health condition

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

Cardiac Surgery

Critical illness

Condition category

Condition code

Anaesthesiology

Anaesthetics

Surgery

Other surgery

Cardiovascular

Other cardiovascular diseases

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Intravenous fluid bolus therapy (FBT)* with 20% albumin will administered by the treating team until one of the following criteria for treatment cessation is met:
- Initial (index) vasopressor dependence resolves

[The resolution of vasopressor dependence is defined as the patient being alive and all vasopressors being discontinued for at least 4 consecutive hours in the presence of a MAP>65 mmHg, or a target MAP set by the clinician in charge of the patient’s care, during the index vasopressor period (subsequent vasopressor periods will not contribute to the primary outcome)]

- Patient is discharged from ICU
- 7 days have passed since randomisation
- Contraindications to 20% albumin or crystalloid therapy arise
- Death occurs
- Serious adverse events suspected to be related to a study medication develops

*FBT will be defined as a volume of at least 100 mL of intravenous fluid administered over one hour or less at a rate of 2 ml/min or greater to increase or maintain intravascular volume. The FBT would be in addition to maintenance fluids, or specific fluids used to replace non-physiological fluid losses.

N.B FBT is a common intervention for the optimisation of cardiac output and the treatment of hypotension after cardiac surgery. However there are no consensus diagnostic criteria to identify whether a patient is appropriate for FBT after being admitted to ICU following cardiac surgery. Thus, the decision to administer FBT is based on clinical judgment.

Intervention code [1]

Treatment: Other

Intervention code [2]

Treatment: Drugs

Comparator / control treatment

The control will be ‘standard care’ which is fluid bolus therapy with a crystalloid solution for at least the first 1000 mL followed by whatever other fluids clinicians consider appropriate and no use of 20% albumin in the first 7 days post randomisation.

Control group

Active

Outcomes

Primary outcome [1]

Duration of vasopressor therapy (in hours) censored at day 7. Defined by discontinuation of all vasopressors for at least 4 consecutive hours in the presence of a MAP>65mmHg or target MAP set by the clinician in charge of the patient’s care for the same 24-hour period.

Timepoint [1]

at day 7

Secondary outcome [1]

Volume of resuscitation fluid per calendar day as documented on the ICU fluid balance chart

Timepoint [1]

Until discharge from ICU or day 7 post randomisation whichever occurs first

Secondary outcome [2]

Volume of study and non-study fluid administered, but not as fluid bolus therapy, censored per calendar day as documented on the ICU fluid balance chart

Timepoint [2]

Until discharge from ICU or day 7 post randomisation whichever occurs first

Secondary outcome [3]

Total intravenous fluid input censored per calendar day as documented on the ICU fluid balance chart

Timepoint [3]

Until discharge from ICU or day 7 post randomisation whichever occurs first

Secondary outcome [4]

Fluid output (mediastinal drain(s) and urine output) censored per calendar day as documented on the ICU fluid balance chart

Timepoint [4]

Cumulative fluid balance censored per calendar day while in ICU

Secondary outcome [5]

Number of FBTs administered per calendar day while in ICU as documented on the ICU fluid balance chart

Timepoint [5]

Until discharge from ICU or day 7 post randomisation whichever occurs first

Secondary outcome [6]

Duration and cumulative dose of vasopressor therapy by type (e.g. noradrenaline, vasopressin) in the first 7 days as documented on the ICU observation chart

Timepoint [6]

at day 7

Secondary outcome [7]

Change in serum creatinine from baseline to peak level in the first 7 days

Timepoint [7]

at day 7

Secondary outcome [8]

Incidence of acute kidney injury (KDIGO classification) in the first 7 days after randomisation

Timepoint [8]

at day 7

Secondary outcome [9]

Proportion of patients newly treated with renal replacement therapy during index hospital admission as documented in the patient notes

Timepoint [9]

at day 30 or discharge from hospital whichever occurs first

Secondary outcome [10]

Ventilator free hours at day 7 as calculated from the patient observation chart

Timepoint [10]

at day 7

Secondary outcome [11]

Days at home up to 30 days after surgery (DAH30) as ascertained through patient level data linkage to the recruitment sites admission databases and the Australian & New Zealand Society of Cardiac & Thoracic Surgeons dataset

Timepoint [11]

at day 30

Eligibility

Key inclusion criteria

The treating clinician wishes to administer fluid bolus therapy (FBT) after cardiac surgery.

Minimum age

18 Years

Maximum age

No limit

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

Age less than 18 years
Pregnancy
Patients who have previously received a FBT prescribed in the ICU after cardiac surgery (NB patients who have received FBT in the ICU prior to surgery remain eligible).
Contraindication to study fluid e.g. patients with known or suspected allergy to albumin or crystalloid fluid
Documented refusal of any study fluid (i.e. a patient may refuse to receive Human Albumin Solution which is in 20% and 4% albumin)
Death is deemed to be imminent or inevitable during this admission, and either the attending physician, patient or substitute decision-maker is not committed to active treatment
Off pump cardiac surgery
Patient who have previously been enrolled in this study

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)

ICU patients will be enrolled as soon as possible after fulfilling the criteria for randomisation. A permuted block randomisation method with variable block sizes of 2, 4 and 6 and stratified by site and the presence of a vasopressor at the time of randomisation will be used to allocate eligible patients to either the treatment or usual care group in a 1:1 ratio. Randomisation will be performed by the randomisation module in Research Electronic Data Capture (REDCap), which is a secure web application for managing online data collection.

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

The random allocation sequence is generated using a computer software program by coordinating investigators at the coordinating centre and embedded into the REDCap system. Site investigators, site research coordinators, or statisticians in co-ordinating centre do not have access to the allocation sequence.

Masking / blinding

Open (masking not used)

Who is / are masked / blinded?

Intervention assignment

Parallel

Other design features

Phase

Phase 2

Type of endpoint/s

Efficacy

Statistical methods / analysis

We assumed a pooled standard deviation of vasopressor therapy duration of 32 hours. It was estimated that 200 patients per group would have 80% power (2-sided alpha = 0.05) to detect a difference in the cumulative hours of vasopressor therapy of 9 hours. The difference of 9 hours was two-thirds of the effect observed in the previous HAS FLAIR-I study, and we considered a 9-hour reduction in the duration of vasopressor therapy to represent a meaningful difference. As the distribution of the primary outcome was expected to be nonparametric, the sample size was inflated by 15%. To further account for withdrawal from the trial and refusing to allow retention of data (5%), we planned to enrol 480 patients.

Statistical analysis will be performed by a statistician. Data will be presented as n (95% CI), mean (SD) or median [IQR] as appropriate. The main analyses will be conducted on an intention to treat basis using standard statistical methods for categorical and continuous data.

Recruitment

Recruitment status

Completed

Date of first participant enrolment

Anticipated

23/03/2020

Actual

31/08/2020

Date of last participant enrolment

Anticipated

Actual

31/08/2022

Date of last data collection

Anticipated

Actual

5/09/2022

Sample size

Target

480

Accrual to date

Final

480

Recruitment in Australia

Recruitment state(s)

SA,VIC

Recruitment hospital [1]

Austin Health - Austin Hospital - Heidelberg

Recruitment hospital [2]

Royal Melbourne Hospital - City campus - Parkville

Recruitment hospital [3]

Monash Medical Centre - Clayton campus - Clayton

Recruitment hospital [4]

Barwon Health - Geelong Hospital campus - Geelong

Recruitment hospital [5]

Flinders Medical Centre - Bedford Park

Recruitment hospital [6]

Warringal Private Hospital - Heidelberg

Recruitment postcode(s) [1]

3084 - Heidelberg

Recruitment postcode(s) [2]

3050 - Parkville

Recruitment postcode(s) [3]

3168 - Clayton

Recruitment postcode(s) [4]

3220 - Geelong

Recruitment postcode(s) [5]

5042 - Bedford Park

Recruitment postcode(s) [6]

3084 - Heidelberg

Funding & Sponsors

Funding source category [1]

Hospital

Name [1]

Austin Health

Address [1]

Intensive Care Unit
Austin Campus
145 Studley Road
Heidelberg
VIC 3084

Country [1]

Australia

Primary sponsor type

Hospital

Name

Austin Health

Address

Austin Campus
145 Studley Road
Heidelberg
VIC 3084

Country

Australia

Secondary sponsor category [1]

Individual

Name [1]

Professor Rinaldo Bellomo

Address [1]

Department of Intensive Care
Austin Hospital
145 Studley Road
Heidelberg VIC 3084

Country [1]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Austin Health Human Research Ethics Committee

Ethics committee address [1]

Ethics and Research Governance Unit
Level 8, Harold Stokes Building 
Austin Health
PO Box 5555
Heidelberg
Victoria
3084

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

16/10/2019

Approval date [1]

05/12/2019

Ethics approval number [1]

HREC/57780/Austin-2019

Summary

Brief summary

HAS FLAIR-II is a multi-centre, randomised controlled trial, looking at patients who require fluid bolus therapy (FBT) after cardiac surgery. FBT after cardiac surgery is a common intervention used to correct hypotension +/- optimise cardiac function.

There are several types of intravenous fluid used for fluid resuscitation, which are broadly classified into crystalloids and colloids. After cardiac surgery, patients receive a combination of crystalloid and the colloid albumin in the form of 4% albumin. 20% albumin corrects low blood volume more rapidly and requires less volume to do so than crystalloid fluids and 4% albumin, and by doing so reduces the amount of chloride and fluid the body receives. This
may avoid harm associated with chloride and large fluid administrations.

Participants will be allocated in a 1:1 ratio to either the treatment group (FBT with 20% albumin) or to usual care (FBT with whatever fluid the treating clinicians consider appropriate and no use of 20% albumin in the first 7 days). We will evaluate the duration of vasopressor use in those who received 20% albumin compared to those that received usual care. We plan to enroll 470 patients post cardiac surgery from Intensive Care Units in Australia.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Dr Geoffrey Wigmore

Address

Department of Intensive Care
Austin Health
Austin Campus
145 Studley Road
Heidelberg
VIC 3084

Country

Australia

Phone

+61 3 9496 5000

Fax

[email protected]

Contact person for public queries

Name

Glenn Eastwood

Address

Department of Intensive Care
Austin Health
Austin Campus
145 Studley Road
Heidelberg
VIC 3084

Country

Australia

Phone

+61 3 9496 4835

Fax

+61 3 9496 3932

[email protected]

Contact person for scientific queries

Name

Geoffrey Wigmore

Address

Department of Intensive Care
Austin Health
Austin Campus
145 Studley Road
Heidelberg
VIC 3084

Country

Australia

Phone

+61 3 9496 5000

Fax

[email protected]

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

No/undecided IPD sharing reason/comment

What supporting documents are/will be available?

Doc. No.	Type	Citation	Link	Email	Other Details	Attachment
5412	Statistical analysis plan	Wigmore G, Deane AM, Anstey J, Bailey M, Bihari S, Eastwood G, Ghanpur R, Maiden MJ, Presneill JJ, Raman J, Bellomo R, investigators HF-It, (2022) Study protocol and statistical analysis plan for the 20% Human Albumin Solution Fluid Bolus Administration Therapy in Patients after Cardiac Surgery-ll (HAS FLAIR-II) trial. Crit Care Resusc 24: 309-318	https://doi.org/10.51893/2022.4.OA1

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

Source	Title	Year of Publication	DOI
Dimensions AI	Albumin as a drug: its biological effects beyond volume expansion	2020	https://doi.org/10.1016/s1441-2772(23)00394-0

N.B. These documents automatically identified may not have been verified by the study sponsor.

Trial Review

Documents added manually

Documents added automatically