Table 1 REstricted Fluid REsuscitation in Sepsis-associated Hypotension (REFRESH) trial Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) protocol summary

Short title

REstricted Fluid REsucitation in Sepsis-associated Hypotension (REFRESH) trial

Health condition

Sepsis

Ethics

HREC/15/Austin/486 (Austin Health, Victoria) & HREC/15/114 (South Metropolitan Health Service, WA)

Protocol version

Version 3, October 2016

Funding

Grants:

Emergency Medicine Foundation (EMSS-229R24-2015-KEIJZERS)

University of WA/University of Queensland Bilateral Research Collaboration Award

Royal Perth Hospital Medical Research Foundation

Industry:

Nil

Primary sponsor

Investigator-initiated and -driven study. Centre for Clinical Research in Emergency Medicine, University of Western Australia. Chief investigator and study contact: Dr. Stephen Macdonald, Royal Perth Hospital, PO Box X2213, Perth, WA, Australia

Email: stephen.macdonald@uwa.edu.au

Background

Sepsis is a common condition with high morbidity and mortality. Patients with sepsis can develop hypotension (low blood pressure) due to a combination of factors. The traditional first-line treatment of sepsis-associated hypotension is to give a rapid, large volume of intravenously administered fluid (fluid bolus). Emerging clinical data and advances in the understanding of fluid physiology suggest that fluid bolus may be associated with worse patient outcomes. This randomised pilot clinical trial will compare a restricted fluid-volume approach, including early use of vasopressor drugs if required, against standard (liberal fluid-volume) care to assess the feasibility and safety of this approach. An embedded laboratory study will measure the differences in a range of relevant blood markers (such as activation of the vascular endothelium) to provide mechanistic plausibility for a restricted-volume approach. Together these data will be used to inform the design of a large multicentre trial to assess clinical outcomes

Hypothesis

That a volume-restricted approach to sepsis-associated hypotension is clinically feasible; that this approach results in reduced systemic inflammation and associated biomarkers of endothelial cell activation

Study aims

1. To investigate the feasibility of delivering volume-restricted resuscitation in sepsis-associated hypotension

2. Compare the total volume of fluid administered at 6 h and 24 h

3. To assess effects on the biomarkers of the inflammatory response, endothelial activation and related pathways of interest

4. To record any differences in requirement for organ support and in clinical outcomes

Study design

• Multi-centre (Armadale, Perth/Austin, Melbourne/Fiona Stanley, Perth/Gold Coast/Royal Hobart/Royal Perth/Sir Charles Gairdner, Perth/The Prince Charles, Brisbane)

• Randomised controlled/un-blinded/feasibility

• Interventional

Setting

8 emergency departments (EDs) in Australia

Inclusion and exclusion criteria

Inclusion criteria:

 1. Suspected infection and

 2. Systolic blood pressure (SBP) < 100 mmHg, despite 1000 ml intravenously administered isotonic crystalloid administered over not more than 60 minutes and

 3. Study intervention can be administered within 2 hs of inclusion criteria being met

Exclusion criteria:

 1. Hypotension thought due to, or contributed to by, a non-sepsis cause (e.g. arrhythmia, haemorrhage)

 2. Clinical requirement for fluid replacement (e.g. gastrointestinal losses)

 3. Transfer from another hospital

 4. More than 2000 ml intravenously administered fluid has been given (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 deemed imminent and inevitable

9. Patient wishes or comorbidities such that either fluid loading or vasopressor support is not considered clinically appropriate

Intervention

Intervention arm:

Commence vasopressor infusion (± maintenance IV fluid) if SBP < 90 mmHg or mean arterial pressure (MAP) < 65 mmHg). Reassess hourly next 6 h and administer further 250-ml IV fluid bolus if required

Comparator arm:

Give a second 1000-ml fluid bolus plus further 500-ml boluses as clinically indicated until judged to be euvolaemic. Commence vasopressor infusion (± maintenance IV fluid) if SBP < 90 mmHg or MAP < 65 mmHg). Reassess hourly next 6 h and administer further 500-ml IV fluid bolus if required

Primary outcome measure

Total volume of intravenously administered fluid (including pre-randomisation) at 6 h

Secondary outcome measures

• Mortality (all-cause) at 90 days post enrolment

• ICU length of stay

• Hospital length of stay

• Hospital-free days to day 90

• Organ failure

 o Cardiovascular

  ▪ Requirement for vasopressors

  ▪ Duration of vasopressor requirement (h)

  ▪ Vasopressor-free days to day 28

 o Respiratory

  ▪ Requirement for ventilation (NIV/IPPV)

  ▪ Duration of ventilator support (h)

  ▪ Ventilator-free days to day 28

 o Renal

  ▪ Requirement for renal replacement therapy (RRT)

  ▪ Duration of RRT

  ▪ RRT-free days to day 28

  ▪ AKIN score to day 7

Laboratory/mechanistic outcome measures

Peak values, as well as patterns of expression over time (T0–T24), will be analysed for a range of biomarkers and compared between the groups including:

• Atrial natriuretic peptide

• Troponin

• Inflammatory cytokines

 o IL-6, IL-10, resistin

• NGAL (a biomarker of renal injury)

• Endothelial cell activation biomarkers

 o sVCAM, sICAM, sE-Selectin, sFlt-1

• Soluble markers of glycocalyx degradation

 o Heparan sulphate, syndecan-1, hyaluronan

Feasibility outcome measures

• Proportion of eligible patients enrolled

• Randomisation errors

• Compliance – protocol violations

• Proportion with completely recorded data

• Proportion with complete study blood sampling

Sample size

50 per arm/100 total

Randomisation

Eligible participants in whom a consent process has been commenced will be randomised to either the fluid-volume restricted or the fluid-liberal (standard-care arm)

Randomisation procedure

• Eligibility assessment and randomisation conducted by clinical staff with support by research personnel (in person or by telephone)

• Computer-generated randomisation sequence

• Real-time web-based randomisation

• 1:1 randomisation in blocks of 2 or 4

Blinding

• Un-blinded to patients and to treating team

• Blinding of laboratory staff and data analysts

Data collection methods

• Paper CRF completed for each participant

• CRF populated by research staff in real time or from clinical record

• Subsequent data entry into secure database by trained research assistant

• Audit of data entry against source documentation

Data collected

• All fluids administered pre-randomisation

• All fluids administered post randomisation – 6 h (recorded hourly)

• All fluids administered over 6–24 h

• Urine output to 24 h

• Vital signs at enrolment and hourly until 6 h

• Antimicrobials – agent, dose and time administered

• Corticosteroid administration

• Source of sepsis (suspected/proven)

• Charlson Comorbidity Score

• Microbiological/serological results from samples obtained in first 24 h

• Sequential Organ Failure Assessment (SOFA) score at admission and at 24 h

• Acute Physiology and Chronic Health Evaluation (APACHE) II score (peak first 24 h)

• Acute Kidney INjury (AKIN) score up to 7 days

• Study blood sampling at enrolment (T0), 3 h (T3), 6 h (T6) and 12–24 h (T24)

Statistical analysis

• Intention-to-treat analysis

• Statistician blinded to treatment allocation

Data and safety monitoring

• DSMC – emergency physician, intensive care physician, statistician

• SAE reporting to study coordination centre within 24 h

• DSMC review all SAE

• Periodic data review by DSMC and recommendations to PI in event of study conduct of SAE issues

• Trial coordinator will monitor trial conduct at each site at regular intervals

Ethics and governance

• HREC approvals obtained for all sites

• Clinical governance (site-specific authority) procedures in place for all sites

• Any subsequent protocol amendments to be submitted to lead ethics site with appropriate dissemination to participating study sites

• The study will be conducted in accordance with GCP

Consent

• Where possible, prospective informed consent will be obtained

• Due to the time-critical nature of the condition, approval in place for verbal consent to randomise and initiate care followed by formal written consent process

• Some participants will lack capacity so consent will be sought from next of kin

• Where next of kin not immediately available, provision in place for enrolment under initial waiver of consent (or procedural authorisation) followed by delayed consent to continue in the trial

Confidentiality

• All data will be de-identified

• Data (paper and electronic) will be stored securely

Dissemination

• Trial results to be presented at relevant scientific meetings and published in peer-reviewed journal

Study status

• Opened to recruitment July 2016 (Protocol V2)

• Protocol amended October 2016 (Protocol V3) after 6 participants enrolled

• As at 22 June 2017, 42 participants enrolled at 6 of 7 sites active

• Anticipated to complete enrolment of 100 participants within 12 months