Early Vasopressors in Sepsis

NCT ID: NCT05179499

Last Updated: 2025-03-06

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

RECRUITING

Clinical Phase

PHASE3

Total Enrollment

1005 participants

Study Classification

INTERVENTIONAL

Study Start Date

2022-10-11

Study Completion Date

2027-10-31

Brief Summary

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Sepsis is a life-threatening reaction to an infection. It happens when the immune system overreacts to an infection and starts to damage the body's tissues and organs.

The aim of this research study is to compare the two different ways to treat sepsis, in the early phase of treatment immediately after the participants arrive in hospital. The standard approach is to give a salt solution fluid through a drip in the participants arm to start with, then adding in a medication that increases the blood flow to the participants vital organs (a vasopressor mediation called norepinephrine) if required. The alternative approach is to start the vasopressor medication immediately, and then add in extra salt solution fluid via a drip if required. Vasopressors work by increasing the blood pressure which allows a better blood flow to the internal organs. The investigators plan to see which approach is better and to see if they have a role in improving a patient's recovery time, reducing complications, the length of time they stay in hospital and longer term poor health.

Based on research that has already been done, the investigators believe treating patients with vasopressors when they arrive in the Emergency Department, may have potential advantages over the standard fluids used today. However, the evidence is not clear and that is why this research is being done.

Detailed Description

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Sepsis results from overwhelming reactions to microbial infections where the immune system initiates dysregulated responses that lead to remote organ dysfunction, shock and ultimately death. Sepsis remains a significant global issue - as well as direct mortality, survivors suffer long term reductions in patient centred outcomes, with reduced quality of life and functional status. Patients with hypotension and organ hypoperfusion as a result of sepsis have poorer outcomes by dysregulated inflammation, endothelial dysfunction, immune suppression, and organ dysfunction. Current guidelines highlight the importance of early fluid resuscitation, but the association of early fluid therapy with improved outcomes is unclear. In the resuscitation phase, current practice is to give intravenous (IV) fluid and intermittent vasopressor boluses if required, before, for some patients, continuous vasopressor infusion via a central venous line in Intensive Care (ICU). An alternative, early continuous peripheral vasopressor infusion (PVI) is not routine practice in the UK.

Current practice in the UK is guided by NICE Sepsis guidance and the international Surviving Sepsis Campaign (SSC) consensus recommendations. Both specify intravenous fluid administration as a central tenet of early resuscitation of patients with septic shock, with intravenous vasopressor administration recommended after intravenous fluid resuscitation. NICE recommend boluses of 500ml of crystalloid and "refer to critical care for review of management including need for central venous access and initiation of vasopressors". SSC recommend 30ml/kg crystalloid in first hour, followed by vasopressors to maintain MAP\>65.

The current NICE fluid resuscitation guideline, November 2020, continues to emphasise 500ml boluses of crystalloid as usual care. A recent international survey of 100 critical care and EM physicians regarding intravenous fluid resuscitation practice, confirmed that an initial bolus of 1000ml of crystalloid, followed by 500ml boluses of crystalloid remained the most common management strategy for the initial treatment of septic shock. This persisted despite the lack of benefit demonstrated in three landmark trials of protocolised sepsis management.

In recent years, there has been increasing acceptance of peripheral administration of norepinephrine, based on evidence of safety and efficacy. The Intensive Care Society published guidance on peripheral vasopressor infusion in November 2020. We have recently conducted a survey amongst ED and ICU clinicians in the UK regarding attitudes and current practice related to the use of intravenous peripheral vasopressors. Eighty two respondents provided the following answers

1. Experience of use of any intravenous vasopressor in ED was high (81%);
2. Exclusive PVI made up 23% of all vasopressor use in ED;
3. Norepinephrine (norepinephrine) was the most common vasopressor (54%);
4. Barriers to PVI were local protocols and an appropriate level of care in the destination ward for a patient on vasopressor infusion.

Conditions

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Sepsis

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Open label, two arm, multicentre, pragmatic parallel group sequential randomised trial with an internal pilot
Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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Intervention Arm

Participants will receive peripheral vasopressor infusion of norepinephrine (16 micrograms/ml) during the initial 48 hour study period. All other care will be as per local protocol.

Group Type ACTIVE_COMPARATOR

Norepinephrine

Intervention Type DRUG

Norepinepherine should be prepared and delivered at a concentration of 16 micrograms/ml

Standard care

Participants allocated to the control arm will receive standard care as defined by the UK NICE guidelines and the Surviving Sepsis Campaign guidelines during the 48 hour study period post randomisation. All other care will be as per local protocol.

Group Type PLACEBO_COMPARATOR

Balanced Crystalloid

Intervention Type OTHER

IV fluids administered as per standard care

Interventions

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Norepinephrine

Norepinepherine should be prepared and delivered at a concentration of 16 micrograms/ml

Intervention Type DRUG

Balanced Crystalloid

IV fluids administered as per standard care

Intervention Type OTHER

Eligibility Criteria

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Inclusion Criteria

* Age \>18 years
* Clinically suspected or proven infection resulting in principal reason for acute illness
* SBP \< 90 mmHg or MAP of \< 65 mmHg (within an hour of eligibility assessment)
* Measured serum lactate of \> 2 mmol/L. The serum lactate should be measured 2 hours prior to determination of eligibility, where possible. Longer timeframes may be used and justified within the medical notes if, in the opinion of the investigator, the clinical status of the patient has not significantly improved in the time interval between lactate measurement and eligibility assessment. Lactate measurements more than 4 hours prior to eligibility assessment should not normally be used.
* Hospital presentation within last 12 hours

Exclusion Criteria

* \>1500ml of intravenous fluid prior to screening
* Clinically judged to require immediate surgery (within one hour of eligibility assessment)
* Immediate (\< 1 hour) requirement for central venous access
* Chronic renal replacement therapy
* Known allergy/adverse reaction to norepinephrine
* Palliation / end of life care (explicit decision by patient/family/carer in conjunction with clinical team that active treatment beyond symptomatic relief is not appropriate)
* Previous recruitment in the trial
* Patients with permanent incapacity
* Pregnancy. All women of childbearing potential (WoCBP) must have a negative urine or serum pregnancy test result completed as part of screening requirements.

WoCBP are defined as fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.

* Other primary causes of shock (e.g. suspected cardiogenic shock, haemorrhagic shock, etc)
* History or evidence of any other medical, neurological or psychological condition that would expose the subject to an undue risk of a significant Adverse Effect as determined by the clinical judgement of the investigator
* Participation in other clinical trials of investigational medicinal products
Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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University of Edinburgh

OTHER

Sponsor Role collaborator

Northern Care Alliance NHS Foundation Trust

OTHER

Sponsor Role collaborator

University of Manchester

OTHER

Sponsor Role collaborator

University of Glasgow

OTHER

Sponsor Role collaborator

NHS Lothian

OTHER_GOV

Sponsor Role collaborator

Chelsea and Westminster NHS Foundation Trust

OTHER

Sponsor Role collaborator

NHS Greater Glasgow and Clyde

OTHER

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Locations

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Aintree University Hospital

Aintree, , United Kingdom

Site Status NOT_YET_RECRUITING

Royal Blackburn Hospital

Blackburn, , United Kingdom

Site Status RECRUITING

Fairfield General Hospital

Bury, , United Kingdom

Site Status ACTIVE_NOT_RECRUITING

Royal Derby Hospital

Derby, , United Kingdom

Site Status RECRUITING

Royal Infirmary of Edinburgh

Edinburgh, , United Kingdom

Site Status RECRUITING

Victoria Hospital

Fife Keith, , United Kingdom

Site Status RECRUITING

Glasgow Royal Infirmary

Glasgow, , United Kingdom

Site Status ACTIVE_NOT_RECRUITING

Queen Elizabeth University Hospital

Glasgow, , United Kingdom

Site Status ACTIVE_NOT_RECRUITING

Hull Royal Infirmary

Hull, , United Kingdom

Site Status RECRUITING

Kettering General

Kettering, , United Kingdom

Site Status RECRUITING

University Hospital Crosshouse

Kilmarnock, , United Kingdom

Site Status NOT_YET_RECRUITING

University Hospital Monklands

Lanark, , United Kingdom

Site Status RECRUITING

Leicester Royal Infirmary

Leicester, , United Kingdom

Site Status ACTIVE_NOT_RECRUITING

Royal Liverpool University Hospital

Liverpool, , United Kingdom

Site Status NOT_YET_RECRUITING

Royal London Hospital

London, , United Kingdom

Site Status RECRUITING

St George's

London, , United Kingdom

Site Status RECRUITING

University Hospital Lewisham

London, , United Kingdom

Site Status NOT_YET_RECRUITING

John Radcliffe Hospital

Oxford, , United Kingdom

Site Status ACTIVE_NOT_RECRUITING

Royal Alexandra Hospital

Paisley, , United Kingdom

Site Status RECRUITING

Peterborough City Hospital

Peterborough, , United Kingdom

Site Status RECRUITING

Royal Berkshire Hospital

Reading, , United Kingdom

Site Status RECRUITING

Queens Hospital Barking

Romford, , United Kingdom

Site Status ACTIVE_NOT_RECRUITING

Salford Royal

Salford, , United Kingdom

Site Status RECRUITING

Countries

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United Kingdom

Central Contacts

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Hannah Greenwood

Role: CONTACT

0141 314 4366

Alasdair Corfield

Role: CONTACT

Other Identifiers

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2021-006886-39

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

GN20AE342

Identifier Type: -

Identifier Source: org_study_id

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