Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12615000377538
Ethics application status
Approved
Date submitted
9/03/2015
Date registered
23/04/2015
Date last updated
23/04/2015
Type of registration
Prospectively registered

Titles & IDs
Public title
Conservative versus liberal fluid therapy in patients with liver disease admitted to the intensive care unit.
Scientific title
Efficacy and safety of conservative versus liberal fluid therapy in critically ill patients with cirrhosis admitted to the intensive care unit
Secondary ID [1] 286333 0
nil
Universal Trial Number (UTN)
Trial acronym
FliC
Linked study record

Health condition
Health condition(s) or problem(s) studied:
cirrhosis 294445 0
Condition category
Condition code
Oral and Gastrointestinal 294747 294747 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Patients admitted to intensive care with decompensated cirrhosis requiring vasoactive infusions and fluid resuscitation guided by invasive haemodynamic monitoring will be randomly allocated to a fluid administration strategy which uses either a conservative approach or a liberal approach to intravenous fluid administration. Both strategies are currently accepted approaches to managing patients with cirrhosis in the ICU and either is presently utilised according to clinician preference, with the choice currently being made in the absence of evidence that one or the other may be better. Intensive care practice involves bedside nursing staff continuously assessing a patient's haemodynamic status and titrating vasoactive infusions and intravenous fluid therapy as guided by measured circulatory parameters with advice from attending medical staff. After four days of therapy guided by the study protocol allocation, ongoing management will revert to whatever approach is preferred by the treating ICU clinicians. The study protocol will only apply during ICU based care and will cease on discharge to ward-based care if this occurs prior to four days of intensive care management.
Adherence to study protocol will be evaluated on a twice daily basis during clinical rounds.
If the patient is allocated to the ‘Liberal IV’ fluid group the following management applies:
1. Circulatory aims
a. Central venous pressure (CVP) = or greater than 12mmHg
b. Mean arterial pressure (MAP) = or greater than 65mmHg
c. After the second day in the ICU, patients are to have = or greater than 2000ml total daily positive fluid balance.
2. Management
a. If CVP < or equal to 8mmHg, administer 500ml bolus of 4% albumin regardless of MAP (unless contra-indicated by clinical status e.g. severe pulmonary oedema)
b. If MAP < or equal to 65 mmHg and CVP < or equal to 12 mmHg, administer 500ml bolus of 4% albumin
c. If MAP < or equal to 65 and CVP = or greater than 12 mmHg, titrate noradrenaline infusion via central venous catheter to achieve MAP = or greater than 65mmHg
d. Administer 100ml of 20% albumin twice daily, unless;
i. Total net fluid balance is = or greater than 8000ml over two consecutive days
ii. Serum albumin = or greater than 35 g/L
iii. Further albumin or fluid administration is contra-indicated (e.g. patient has pulmonary oedema)
3. Fluid management in the intensive care unit
a. If there is a demonstrable clinical need to modify the fluid regimen then such clinical considerations over-ride the study protocol. That is, more or less fluid of any type can be used if that is what is believed by the treating clinician to be in the patient’s best interests.

If the patient is allocated to the ‘Restrictive IV’ fluid group the following management applies:
1. Circulatory aims
a. Central venous pressure (CVP) = or less than 6mmHg
b. Mean arterial pressure (MAP) = or greater than 65mmHg
c. Cardiac index = or greater than 2.5
d. Even fluid net daily fluid balance from after the second day in ICU
2. Management
a. If CVP < 6mmHg, administer 500ml bolus of 4% albumin
b. If MAP = or greater than 65mmHg and CI = or greater than 2.5, administer no fluid except for enteral nutritional and intravenous replacement of measured/estimated losses
c. If MAP < or equal to 65mmHg and CI < 2.5, administer 500ml bolus of 4% albumin
d. If MAP < or equal to 65 mmHg and CI = or greater than 2.5, titrate noradrenaline infusion rate to achieve MAP = or greater than 65mmHg.
i. If noradrenaline infusion rate > 30 mcg/minute (or > 0.4 mcg/kg/min), give 500ml of 4% albumin and manage in accordance with clinician preference.

3. Fluid management in the intensive care unit
a. If there is a demonstrable clinical need to modify the fluid regimen then such clinical considerations over-ride the study protocol. That is, more or less fluid of any type can be used if that is what is believed by the treating clinician to be in the patient’s best interests.
All participating patients will undergo a brief echocardiography assessment;
1. at enrolment,
2. after 48 hours of protolised management,
3. prior to discharge from ICU.
Intervention code [1] 291384 0
Treatment: Other
Comparator / control treatment
Both approaches to fluid administration and circulatory support are currently accepted standards of care and clinician preferences dictate which is applied in clinical practice despite a lack of evidence that one may be better.
Control group
Active

Outcomes
Primary outcome [1] 294511 0
Change in serum creatinine as documented in clinical record
Timepoint [1] 294511 0
4 days after study enrolment
Primary outcome [2] 294599 0
Change NephroCheck test score as documented in clinical record
Timepoint [2] 294599 0
4 days after enrollment
Primary outcome [3] 294600 0
Fluid balance/weight as documented in clinical record
Timepoint [3] 294600 0
4 days post enrolment
Secondary outcome [1] 313499 0
Need for vasoactive infusions (dose, type and duration) as documented in clinical record.
Timepoint [1] 313499 0
During period of four days post-enrolment
Secondary outcome [2] 313698 0
Time on respiratory support (measured in hours including mechanical ventilation) as documented in clinical record.
Timepoint [2] 313698 0
During four days post enrolment
Secondary outcome [3] 313699 0
Extravascular lung water index (when available via PiCCO) as documented in clinical record.
Timepoint [3] 313699 0
At four days after enrolment
Secondary outcome [4] 313769 0
Primary outcome 4 Use of diuretics (daily dose) from clinical records
Timepoint [4] 313769 0
At four days post enrolment
Secondary outcome [5] 313770 0
Primary outcome 5 Acute Kidney Injury – RIFLE I (GFR decrease of >50% or doubling of serum creatinine) using data from patient records
Timepoint [5] 313770 0
at four days post enrolment
Secondary outcome [6] 313771 0
Primary outcome 6 Need for renal replacement therapy (RRT) as indicated in clinical record
Timepoint [6] 313771 0
During of ICU stay assessed from medical record
Secondary outcome [7] 313772 0
Primary Outcome 7 Echocardiographic measurements of cardiac performance; - ESV, EDV, and EF - PW Doppler of mitral valve flow (E, A, and E:A) - Tissue Doppler of mitral valve annulus (E’, A’, and E’:A”) - Calculate E:E’ (an index of left atrial pressure) undertaken as part of ICU clinical care and documented in patient clinical records
Timepoint [7] 313772 0
at entry into study, at four days after enrolment and at time of discharge from ICU
Secondary outcome [8] 313773 0
Peak serum lactate level as recorded in patient records
Timepoint [8] 313773 0
during four day period post enrolment
Secondary outcome [9] 313774 0
ICU and hospital length of as documented in patient record
Timepoint [9] 313774 0
At ICU discharge and hospital discharge
Secondary outcome [10] 313775 0
ICU and hospital mortality as documented in patient records
Timepoint [10] 313775 0
At time of death if this occurs
Secondary outcome [11] 313776 0
Mean daily fluid balance as recorded in patient clinical care record
Timepoint [11] 313776 0
Over the first four days after enrolment

Eligibility
Key inclusion criteria
1. Adults (>18 years) admitted to ICU with decompensated cirrhosis
2. Hypotension (Mean Arterial Pressure (MAP) <65mmHg)
3. Clinical need for of a Central Venous Catheter (CVC) and arterial line (capable of cardiac output measurement (e.g. PiCCO or FloTrac)
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
*Fulminant Hepatic Failure
*Oliguria requiring frusemide administration via a continuous infusion prior to or immediately on admission to ICU
*Renal failure requiring renal replacement therapy prior to or immediately on admission to ICU
*Diagnosis of Acute Respiratory Distress Syndrome (ARDS)
New, bilateral pulmonary infiltrates evident on chest X-Ray
Absence of clinical evidence for, or measured findings of left atrial hypertension
PaO2:FiO2 ratio of <200
*Severe pre-existing cardiopulmonary disease, e.g.;
NYHA class III or IV heart failure
Pulmonary hypertension
*Admission to ICU for severe bleeding (e.g. oesophageal varices complicated by haemorrhage)
*Requirement for total parenteral nutrition (TPN)

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)
Subjects will be identified at the time of admission to the ICU. If inclusion criteria are met and there are not exclusion criteria, then enrolment will occur with randomisation to therapy occurring via numbered sealed envelopes containing the allocation to liberal or conservative fluiid therapy.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computer generated random number list used to determine allocation of sealed envelopes to be used in order.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
This is a preliminary study and will seek to establish feasibility, safety and possible efficacy of the two approaches to therapy. Sample size is therefore based on convenience and anticipated feasibility.Statistical analysis will include chi-square analysis of categorical data and Mann-Whitney-U test will be used for continuous variables.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
30/04/2015
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
40
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 3556 0
Austin Health - Austin Hospital - Heidelberg

Funding & Sponsors
Funding source category [1] 290907 0
Hospital
Name [1] 290907 0
Austin Health
Country [1] 290907 0
Australia
Primary sponsor type
Individual
Name
Professor Rinaldo Bellomo
Address
145 Studley Road
Heidelberg Vic 3084
Country
Australia
Secondary sponsor category [1] 289587 0
None
Name [1] 289587 0
Address [1] 289587 0
Country [1] 289587 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 292508 0
Austin Health HREC
Ethics committee address [1] 292508 0
Ethics committee country [1] 292508 0
Australia
Date submitted for ethics approval [1] 292508 0
11/12/2014
Approval date [1] 292508 0
18/12/2014
Ethics approval number [1] 292508 0
HREC/13/Austin/186 (Old Ref: 05118)

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes
Attachments [1] 345 345 0 0
/AnzctrAttachments/368147-Clean_Updated FLIC protocol_02_Nov_2014.docx

Contacts
Principal investigator
Name 55646 0
Prof Rinaldo Bellomo
Address 55646 0
Department of Intensive Care
Austin Health
145 Studley Road
Heidelberg Vic 3084
Country 55646 0
Australia
Phone 55646 0
+61394965000
Fax 55646 0
Email 55646 0
[email protected]
Contact person for public queries
Name 55647 0
Stephen Warrillow
Address 55647 0
Department of Intensive Care
Austin Health
145 Studley Road
Heidelberg Vic 3084
Country 55647 0
Australia
Phone 55647 0
+61394965000
Fax 55647 0
Email 55647 0
[email protected]
Contact person for scientific queries
Name 55648 0
Stephen Warrillow
Address 55648 0
Department of Intensive Care
Austin Health
145 Studley Road
Heidelberg Vic 3084
Country 55648 0
Australia
Phone 55648 0
+61394965000
Fax 55648 0
Email 55648 0
[email protected]

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.