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Trial registered on ANZCTR

Registration number

ACTRN12616000006448

Ethics application status

Approved

Date submitted

15/12/2015

Date registered

12/01/2016

Date last updated

6/04/2018

Type of registration

Prospectively registered

Titles & IDs

Public title

Restricted Fluid Resuscitation in Sepsis-associated Hypotension (REFRESH) Trial

Scientific title

In Sepsis with hypotension does restricted volume resuscitation lead to less endothelial cell activation and systemic inflammation?

Secondary ID [1]

None

Universal Trial Number (UTN)

Trial acronym

REFRESH trial

Linked study record

Health condition

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

Sepsis

Septic Shock

Hypotension

Condition category

Condition code

Infection

Other infectious diseases

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Restricted volume resuscitation. Patients with clinically suspected sepsis and hypotension which persists after an initial bolus of 1000mls intravenous fluids will be eligible. Particiants randomised to the restricted fluid arm will be commenced on an intravenous infusion of a vasopressor agent (noradrenaline or metaraminol as per local hospital protocol), titrated to a mean arterial pressure (MAP) of at least 65mmHg by the treating clinician. A maintenance infusion of 1-2mls/kg/hour of intravenous fluid will be started and further fluid boluses of 250mls may be administered at the discretion of treating clinician according to usual clinical practice. The trial protocol will run for 6 hours from randomisation after which treatment will continue as guided by the treating team. All administered fluids will be accurately recorded. Research blood samples will be obtained at randomisation (Time 0), and at 3 hours, 6 hours and 24 hours for biomarkers of interest.

Intervention code [1]

Treatment: Other

Comparator / control treatment

Standard volume resuscitation. Patients with clinically suspected sepsis and hypotension which persists after and initial bolus of 1000mls intravenous fluids will be eligible. Participants randomised to standard care will receive a further 1000mls intravenous fluid bolus (2000mls total) + further fluid as indicated, according to international consensus guidelines as determined by the treating clinician. Participants whose blood pressure remains inadequate following fluid resuscitation will be commenced on an intravenous infusion of a vasopressor agent (noradrenaline or metaraminol as per local hospital protocol), titrated to a mean arterial pressure (MAP) of at least 65mmHg by the treating clinician. A maintenance infusion of 1-2mls/kg/hour of intravenous fluid will be started and further fluid boluses of 500mls may be administered at the discretion of treating clinician according to usual clinical practice. The trial protocol will run for 6 hours from randomisation after which treatment will continue as guided by the treating team. All administered fluids will be accurately recorded. Research blood samples will be obtained at randomisation (Time 0), and at 3 hours, 6 hours and 24 hours for biomarkers of interest.

Control group

Active

Outcomes

Primary outcome [1]

Feasibility, defined as a at least 30% less total volume of intravenous fluid administered in the intervention group (restricted volume) during the first 6 hours of treatment.compared to the standard care group, including fluids administered prior to randomisation. This data will be prospectively collected on the case report form by research personnel and verified against fluid administration log sheets.

Timepoint [1]

6 hours from randomisation.

Secondary outcome [1]

Biomarkers
Peak values for a range of markers including:
- Atrial Natriuretic Peptide (ANP)
- Inflammatory cytokines (Interleukin-6, Interleukin-10)
- Resistin
- Neutrophil Gelatinase associated lipocalin
- Soluble Endothelial activation molecules (ICAM-1, VCAM-1, P-selectin, E-selectin)
- Soluble glycocalyx degradation molecules (Syndecan, Hyaluronin)
Biomarkers will be analysed using commercial ELISA kits or by cytometric bead array on stored sera.

Timepoint [1]

Randomisation (T0)
3 hours from randomisation (T3)
6 hours from randomisation (T6)
24 hours from randomisation (T24)

Secondary outcome [2]

Biomarkers
Pattern of expression over time for a for a range of markers including:
- Atrial Natriuretic Peptide (ANP)
- Inflammatory cytokines (Interleukin-6, Interleukin-10)
- Resistin
- Neutrophil Gelatinase associated lipocalin
- Soluble Endothelial activation molecules (ICAM-1, VCAM-1, P-selectin, E-selectin)
- Soluble glycocalyx degradation molecules (Syndecan, Hyaluronin)
Biomarkers will be analysed using commercial ELISA kits or by cytometric bead array on stored sera.

Timepoint [2]

Randomisation (T0)
3 hours from randomisation (T3)
6 hours from randomisation (T6)
24 hours from randomisation (T24)

Secondary outcome [3]

Ventilator-free days by review of hospital records

Timepoint [3]

28 days from enrollment

Secondary outcome [4]

Duration of ventilator support by review of hospital records

Timepoint [4]

28 days from enrollment

Secondary outcome [5]

Cardiovascular support-free days by review of hospital records

Timepoint [5]

28 days from enrollment

Secondary outcome [6]

Duration of cardiovascular support by review of hospital records

Timepoint [6]

28 days from enrollment

Secondary outcome [7]

Renal replacement therapy-free days by review of hospital records

Timepoint [7]

28 days from enrollment

Secondary outcome [8]

Duration of renal replacement therapy by review of hospital records

Timepoint [8]

28 days from enrollment

Secondary outcome [9]

ICU-free days by review of hospital records

Timepoint [9]

28 days from enrollment

Secondary outcome [10]

Duration of ICU stay by review of hospital records

Timepoint [10]

28 days from enrollment

Secondary outcome [11]

Hospital-free days by review of hospital records

Timepoint [11]

28 days from enrollment

Secondary outcome [12]

Duration of hospital stay by review of hospital records

Timepoint [12]

28 days from enrollment

Secondary outcome [13]

In hospital mortality by review of hospital records

Timepoint [13]

28 days from enrollment

Secondary outcome [14]

All cause mortality by electronic database query and telephone follow up with patient/carer/primary care physician

Timepoint [14]

90 days from enrollment

Eligibility

Key inclusion criteria

1. Suspected infection
2. Systolic blood pressure <100mmHg after at least 1000mls intravenous isotonic crystalloid administered over maximum 60 minutes
3. Randomisation within 2 hours of meeting inclusion criteria

Minimum age

18 Years

Maximum age

No limit

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

1. Hypotension thought due to, or contributed to by, a non-sepsis cause (e.g. arrhythmia, haemorrhage)
2. Clinical indication for further fluid replacement replacement (e.g. GI losses)
3. Transfer from another hospital
4. More than 2000mL of intravenous fluid has been given (either pre-hospital, in ED or both)
5. Likely requirement for immediate surgery
6. Age<18 years
7. Pregnancy (confirmed or suspected)
8. Patient in extremis or death is deemed imminent and inevitable
9. Patient wishes or comorbidities such that fluid loading or vasopressor support is not considered to be clinically appropriate.

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)

Central online computerised randomisation performed only after decision to enroll participant

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

1:1 allocation by real-time online randomisation

Masking / blinding

Open (masking not used)

Who is / are masked / blinded?

Intervention assignment

Parallel

Other design features

Patients and treating clinician will be aware of treatment allocation
Biomarker analyses will be performed by laboratory staff blinded to treatment allocation

Phase

Not Applicable

Type of endpoint/s

Safety/efficacy

Statistical methods / analysis

The primary outcome (feasibility) is a 30% reduction in fluid administered over the first 6 hours. In a recent Australian clinical trial (the ARISE trial) in this population the control arm received a mean volume of 4200 +/-2650 mls of fluid in the initial 6 hours. A clinically meaningful reduction would be 2800 +/-1800mls. A total of 86 participants will have 80% power to detect this difference with alpha 0.05. The trial will enroll a total of 100 participants to allow a 'margin of safety'.

Differences in continuous variables will be analysed using the t-test or Wilcoxon rank sum test depending upon the distribution. Chi squared or Fishers exact test will be used for categorical data.

For biomarker analyses, those which are normally distributed or can be transformed, linear mixed models with maximum likelihood estimation will be employed to analyse the pattern of biomarkers over time. Differences in the pattern of biomarkers over time between the restricted volume and the standard volume groups will be tested by the interaction of time and group in the model. Additional covariates will be added to adjust for treating centre, illness severity and comorbidities. For biomarkers with skewed distributions resistant to successful transformation, quantile regression with per person cluster adjustment will be used.

Recruitment

Recruitment status

Active, not recruiting

Date of first participant enrolment

Anticipated

27/06/2016

Actual

3/10/2016

Date of last participant enrolment

Anticipated

31/01/2017

Actual

8/03/2018

Date of last data collection

Anticipated

6/06/2018

Actual

Sample size

Target

104

Accrual to date

Final

100

Recruitment in Australia

Recruitment state(s)

QLD,TAS,WA,VIC

Recruitment hospital [1]

Armadale Kelmscott Memorial Hospital - Armadale

Recruitment hospital [2]

Austin Health - Austin Hospital - Heidelberg

Recruitment hospital [3]

Fiona Stanley Hospital - Murdoch

Recruitment hospital [4]

Gold Coast Hospital - Southport

Recruitment hospital [5]

Royal Hobart Hospital - Hobart

Recruitment hospital [6]

Royal Perth Hospital - Perth

Recruitment hospital [7]

The Prince Charles Hospital - Chermside

Recruitment hospital [8]

Sir Charles Gairdner Hospital - Nedlands

Funding & Sponsors

Funding source category [1]

Charities/Societies/Foundations

Name [1]

Queensland Emergency Medicine Research Foundation

Address [1]

1/15 Lang Parade
Milton QLD 4064

Country [1]

Australia

Primary sponsor type

University

Name

University of Western Australia

Address

35 Stirling Highway
Crawley WA 6009

Country

Australia

Secondary sponsor category [1]

Hospital

Name [1]

Royal Perth Hospital

Address [1]

GPO Box 2213
Perth WA6000

Country [1]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

South Metropolitan Health Service Human Research Ethics Committee

Ethics committee address [1]

Southern Integrated Research Organisation
Locked Bag 100
Palmyra DC WA6961

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

01/09/2015

Approval date [1]

13/10/2015

Ethics approval number [1]

15-114

Summary

Brief summary

Sepsis can occur when a person becomes unwell due to an infection. It is caused by inflammation throughout the body and affects the functions of organs such as the heart, lungs and kidneys. Sepsis can cause low blood pressure and impaired blood flow to the body’s tissues. This is sometimes called ‘septic shock’.

First line treatment of septic shock is to give intravenous fluid to help restore the circulation. Standard guidelines recommend at least 30ml/kg initially, or approximately 2 litres in an adult. Often up to 5 litres is given in the first 6 hours. However, the volume required varies between individual patients, and calculating the correct amount can be difficult. There is emerging evidence that giving too much fluid can be harmful by leaking into the tissues (such as lungs), impairing organ function, delaying recovery and increasing the risk of complications.

Other research suggests that giving excessive fluid affects the body’s immune responses. In particular this can lead to adverse effects on the normal function of small blood vessels within tissues. This may be one mechanism by which too much fluid leads to harm.

An alternative means of restoring adequate blood pressure is to use a drug called noradrenaline. This is a chemical produced naturally by the body, which causes blood vessels to constrict, raising blood pressure. Noradrenaline, given by a continuous infusion through a drip, has been routinely used for decades for this purpose and is known to be safe and effective. Normally noradrenaline is commenced in patients whose blood pressure does not improve after 2-3 litres of intravenous fluid.

While our current guidelines recommend initial generous fluid administration for septic shock, it has been suggested that using lower volumes of fluid may result in less inflammation and harmful effects, particularly on the cells which line the walls of blood vessels and control their function. This study aims to test this hypothesis.

We propose comparing an approach where patients receive a smaller volume of fluid in their initial resuscitation, against the standard guideline-recommended volume. Participants will be randomised to one or other group. We will measure the blood levels of certain chemical markers of inflammation and blood vessel function. We aim to demonstrate that giving a lower amount of fluid in the initial resuscitation phase is feasible clinically, and results in less alteration of blood vessel function and inflammation in the body.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Dr Stephen Macdonald

Address

Centre for Clinical Research in Emergency Medicine
Harry Perkins Institute of Medical Research
Emergency Department
Royal Perth Hospital
GPO Box X2213
Perth WA6001

Country

Australia

Phone

+61 8 9224 8458

Fax

+61 8 9224 1494

stephen.macdonald@health.wa.gov.au

Contact person for public queries

Name

Stephen Macdonald

Address

Centre for Clinical Research in Emergency Medicine
Harry Perkins Institute of Medical Research
Emergency Department
Royal Perth Hospital
GPO Box X2213
Perth WA6001

Country

Australia

Phone

+61 8 9224 8458

Fax

+61 8 9224 1494

stephen.macdonald@health.wa.gov.au

Contact person for scientific queries

Name

Stephen Macdonald

Address

Centre for Clinical Research in Emergency Medicine
Harry Perkins Institute of Medical Research
Emergency Department
Royal Perth Hospital
GPO Box X2213
Perth WA6001

Country

Australia

Phone

+61 8 9224 8458

Fax

+61 8 9224 1494

stephen.macdonald@health.wa.gov.au

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

Type	Is Peer Reviewed?	DOI	Citations or Other Details	Attachment
Plain language summary	No		There were 99 participants (50 restricted volume a... [More Details]

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	Clinical trials in acute respiratory distress syndrome: challenges and opportunities.	2017	https://dx.doi.org/10.1016/S2213-2600%2817%2930188-1
Embase	REstricted Fluid REsuscitation in Sepsis-associated Hypotension (REFRESH): Study protocol for a pilot randomised controlled trial.	2017	https://dx.doi.org/10.1186/s13063-017-2137-7
Embase	Restricted fluid resuscitation in suspected sepsis associated hypotension (REFRESH): a pilot randomised controlled trial.	2018	https://dx.doi.org/10.1007/s00134-018-5433-0

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

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