ARISE FLUIDS: Australasian Resuscitation In Sepsis Evaluation: FLUid or Vasopressors In Emergency Department Sepsis

Sponsor

Australian and New Zealand Intensive Care Research Centre (Other)

Overall Status

Recruiting

CT.gov ID

NCT04569942

Collaborator

(none)

1,000

Enrollment

Locations

Arms

50.2

Anticipated Duration (Months)

58.8

Patients Per Site

1.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This multicentre, randomised controlled trial will enrol 1000 patients presenting with septic shock to the emergency department (ED) of participating hospitals in Australia and New Zealand. Participants will receive haemodynamic resuscitation with either a restricted fluids and early vasopressor regimen or a larger initial IV fluid volume with later introduction of vasopressors if required. Clinical care including the type of resuscitation fluid and vasopressor agent, will otherwise be in accordance with accepted standard care and according to clinician discretion. The study intervention will be delivered for at least 6 hours and up to 24 hours post-randomisation. Participants will be followed for up to 12 months and outcomes analysed on an intention-to-treat basis.

Condition or Disease	Intervention/Treatment	Phase
Shock, Septic	Drug: Vasopressor Other: Fluids	Phase 3

Detailed Description

The ARISE FLUIDS study is a multicentre, randomised, parallel group clinical trial of a restricted fluids and early vasopressor strategy compared to a larger initial IV fluid volume and later vasopressors for the haemodynamic resuscitation of patients with septic shock presenting to the ED. It will be conducted in hospitals in Australia and New Zealand with 1000 patients recruited over a 3-year period.

Each patient meeting all of the inclusion and none of the exclusion criteria will be randomised to receive haemodynamic resuscitation using either a restricted fluid and early vasopressor regimen (vasopressors arm) or a larger initial fluid resuscitation volume (fluids arm) followed by later introduction of vasopressors (if required). The intervention will be commenced in the ED and delivered for at least 6 hours, and up to 24 hours post-randomisation if admitted to the ICU or other critical care area where the study protocol can be faithfully delivered. Treatment will revert to usual care as determined by the treating clinician when the patient is transferred to a non-critical care ward. All enrolled participants will be followed up and assessed for the defined study outcomes.

Participants will be identified using a systematic approach to screening and assessment of patients with possible sepsis presenting to the ED in accordance with standard clinical practice.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

1000 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

randomized, controlled trialrandomized, controlled trial

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Australasian Resuscitation In Sepsis Evaluation: FLUid or Vasopressors In Emergency Department Sepsis

Actual Study Start Date :

Oct 26, 2021

Anticipated Primary Completion Date :

Dec 31, 2024

Anticipated Study Completion Date :

Dec 31, 2025

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Vasopressor a restricted fluids and early vasopressor strategy	Drug: Vasopressor Cease IV fluid resuscitation. If persisting hypotension and/or hypoperfusion commence a vasopressor infusion (e.g. noradrenaline) and titrate according to local practice to achieve target MAP. The target MAP will be determined by the treating clinician. Reassess at least hourly for up to 6 hours post-randomisation, then as clinically required in conjunction with the protocol. Boluses of 250ml of IV fluids are permitted if deemed indicated by the treating clinician.
Active Comparator: Fluids a larger intravenous (IV) fluid volume and later vasopressor strategy	Other: Fluids An fluid bolus of up to 1000ml will be administered over a maximum of 1 hour, if required, for persisting hypotension and/or hypoperfusion. Reassess at least hourly to 6 hours post-randomisation, then as clinically required in conjunction with the protocol. Further IV fluid boluses of 500ml are recommended as clinically indicated to achieve the target MAP. The target MAP will be determined by the treating clinician. Haemodynamic resuscitation will be guided by usual clinical assessment including vital signs, mentation, perfusion, and urine output until the treating clinician determines fluid resuscitation is no longer clinically required. A minimum of 2-3 L (30 ml/kg), including pre-randomisation fluids, is recommended within 3 hours of ED arrival consistent with the SSC guidelines, unless clinically contraindicated. Vasopressors may be commenced if blood pressure remains below target despite optimal fluid resuscitation as determined by the treating clinician.

Arm

Intervention/Treatment

Active Comparator: Vasopressor

a restricted fluids and early vasopressor strategy

Drug: Vasopressor

Cease IV fluid resuscitation. If persisting hypotension and/or hypoperfusion commence a vasopressor infusion (e.g. noradrenaline) and titrate according to local practice to achieve target MAP. The target MAP will be determined by the treating clinician. Reassess at least hourly for up to 6 hours post-randomisation, then as clinically required in conjunction with the protocol. Boluses of 250ml of IV fluids are permitted if deemed indicated by the treating clinician.

Active Comparator: Fluids

a larger intravenous (IV) fluid volume and later vasopressor strategy

Other: Fluids

An fluid bolus of up to 1000ml will be administered over a maximum of 1 hour, if required, for persisting hypotension and/or hypoperfusion. Reassess at least hourly to 6 hours post-randomisation, then as clinically required in conjunction with the protocol. Further IV fluid boluses of 500ml are recommended as clinically indicated to achieve the target MAP. The target MAP will be determined by the treating clinician. Haemodynamic resuscitation will be guided by usual clinical assessment including vital signs, mentation, perfusion, and urine output until the treating clinician determines fluid resuscitation is no longer clinically required. A minimum of 2-3 L (30 ml/kg), including pre-randomisation fluids, is recommended within 3 hours of ED arrival consistent with the SSC guidelines, unless clinically contraindicated. Vasopressors may be commenced if blood pressure remains below target despite optimal fluid resuscitation as determined by the treating clinician.

Outcome Measures

Primary Outcome Measures

Days alive and out of hospital [From randomisation until 90 days post- randomization]
the number of days alive and out of hospital at 90 days post randomization

Secondary Outcome Measures

Mortality [From randomisation until 90 days post- randomization]
All-cause mortality
Time from randomization until death [From randomisation until 90 days post- randomization]
Time from randomization until death
Days alive and at home [From randomisation until 90 days post- randomization]
Days alive and at home at 90 days post-randomisation
Ventilator-free days to day 28 [From randomisation until 28 days post- randomization]
Number of days not on invasive mechanical ventilation
Vasopressor-free days to day 28 [From randomisation until 28 days post- randomization]
Number of days not on vasopressors
Renal replacement therapy-free days to day 28 [From randomisation until 28 days post- randomization]
Number of days not on renal replacement therapy
Death or disability at 6 months [at 6 months post randomization]
Death or disability as measured by the World Health Organization Disability Assessment Schedule (WHODAS)
Death or disability at 12 months [at 12 months post randomization]
Death or disability as measured by the World Health Organization Disability Assessment Schedule (WHODAS)

Other Outcome Measures

Incidence of invasive mechanical ventilation [From randomisation until 90 days post- randomization]
Incidence of invasive mechanical ventilation
Duration of invasive mechanical ventilation [From randomisation until 90 days post- randomization]
Duration of invasive mechanical ventilation
Incidence of acute renal replacement therapy [From randomisation until 90 days post- randomization]
Incidence of acute renal replacement therapy
Duration of acute renal replacement therapy [From randomisation until 90 days post- randomization]
Duration of acute renal replacement therapy
Incidence of vasopressor support [From randomisation until 90 days post- randomization]
Incidence of vasopressor support
Duration of vasopressor support [From randomisation until 90 days post- randomization]
Duration of vasopressor support
Emergency Department length of stay [From randomisation until 90 days post- randomization]
Emergency Department length of stay
Intensive care unit length of stay [From randomisation until 90 days post- randomization]
Intensive care unit length of stay
Hospital length of stay [From randomisation until 90 days post- randomization]
Hospital length of stay
In hospital mortality [From randomisation until 90 days post- randomization]
Patients who die in hospital
Mortality at 6 months [6 Months post- randomization]
mortality at 6 months
Mortality at 12 months [1 year post- randomization]
mortality at 12 months
Quality of life at 6 months [6 months post- randomization]
Patient quality of life as measured by the EuroQol Group 5 dimensions 5 levels survey (EQ-5D-5L)
Quality of life at 12 months [1 year post- randomization]
Patient quality of life as measured by the EuroQol Group 5 dimensions 5 levels survey (EQ-5D-5L)
Cost-effectiveness measured as cost/quality-adjusted life year (QALY) [1 year post- randomization]
cost effectiveness measured as cost per quality-adjusted life year

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Clinically suspected infection;
Systolic blood pressure (SBP) <90 mm Hg or mean arterial pressure (MAP) <65 mm Hg, despite a ⩾1000ml cumulative total bolus of IV fluid administered over a maximum of 60 minutes; including pre-hospital boluses;
Arterial or venous blood lactate >2.0 mmol/L;
At least one dose of an intravenous antimicrobial has been commenced.

Exclusion Criteria:

Age <18 years;
Confirmed or suspected pregnancy;
Transferred from another acute care facility;
Hypotension suspected to be due to a non-sepsis cause;
2L total IV fluid administered (including prehospital fluids but excluding drugs and flushes);
More than 6 hours has elapsed since presentation to the ED or more than 2 hours has elapsed since last inclusion criterion has been met;
Treating clinician considers that one or both of the treatment regimens are not suitable for the patient or the study protocol cannot be delivered e.g. limitation of care, requirement for immediate surgery;
Death is considered imminent or inevitable;
Underlying disease that makes survival to 90 days unlikely;
Inability to follow patient up to day-90 e.g. unstable accommodation, overseas visitor;
Previously enrolled in this study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Bankstown Hospital	Bankstown	New South Wales	Australia	2200
2	Royal Prince Alfred Hospital	Camperdown	New South Wales	Australia	2050
3	John Hunter Hospital	New Lambton Heights	New South Wales	Australia	2305
4	Royal North Shore Hosptial	Sydney	New South Wales	Australia	2065
5	Mackay Base Hospital	Mackay	Queensland	Australia	4740
6	Robina Hospital	Robina	Queensland	Australia	4226
7	Gold Coast University Hospital	Southport	Queensland	Australia	4215
8	Toowoomba Hospital	Toowoomba	Queensland	Australia	4350
9	The Queen Elizabeth Hospital	Adelaide	South Australia	Australia	5011
10	Bendigo Hospital	Bendigo	Victoria	Australia	3550
11	Box Hill Hospital	Box Hill	Victoria	Australia	3128
12	Angliss Hospital	Ferntree Gully	Victoria	Australia	3156
13	Austin Health	Heidelberg	Victoria	Australia	3084
14	Alfred Hospital	Melbourne	Victoria	Australia	3004
15	Maroondah Hospital	Ringwood East	Victoria	Australia	3135
16	St John of God Murdoch Hospital	Murdoch	Western Australia	Australia	6150
17	Royal Perth Hospital	Perth	Western Australia	Australia	6000