Clinical trial NCT05179499: Early Vasopressors in Sepsis
Official title: Early Vasopressors in Sepsis
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Sepsis
Keywords: Sepsis
Resuscitation
Norepinephrine
Intravenous fluids
Emergency Medicine
Critical Care
Lead sponsor: NHS Greater Glasgow and Clyde
Sponsor class: OTHER
Collaborators: name: University of Edinburgh
name: Northern Care Alliance NHS Foundation Trust
name: University of Manchester
name: University of Glasgow
name: NHS Lothian
name: Chelsea and Westminster NHS Foundation Trust
First posted: 2022-01-05
Enrollment: 1005
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Open label, two arm, multicentre, pragmatic parallel group sequential randomised trial with an internal pilot
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: The primary objective is to determine whether early PVI (within 12 hours of admission) targeted to MAP of ≥65 mmHg improves clinical effectiveness in hospitalised adult patients with septic shock compared with usual care, in the first 48 hours.
timeFrame: 90 days post randomisation
Secondary outcomes:
measure: Accumulated Total Volume of IV fluid
timeFrame: 6,12, 24, 48 and 72 hours post randomisation
measure: Lactate clearance from baseline
timeFrame: 6, 12, 24, 48 & 72 hours post randomisation
measure: Organ Dysfunction Score
timeFrame: 0, 24, 48 and 72 hours post randomisation
measure: Total Dose of Norepinephrine
timeFrame: 6, 12, 24, 48 and 72 hours post randomisation
measure: Proportion of patients who receive vasopressors
timeFrame: 6, 12, 24 and 48 hours after recruitment to the control arm
measure: Proportion of patients who require central venous access
timeFrame: 24 and 48 hours post randomisation
measure: Proportion of patients developing acute kidney injury
timeFrame: During the first 72 hours post randomisation
measure: Proportion of patients receiving parenteral corticosteroid
timeFrame: 24, 48 & 72 hours post randomisation
measure: Length of hospital stay for index admission
timeFrame: up to hospital discharge
measure: Proportion of participants needing renal replacement therapy during index hospital admission
timeFrame: index admission
measure: Proportion of participants needing non-invasive ventilation during index hospital admission
timeFrame: index admission
measure: Proportion of participants needing advanced respiratory support (ICNARC definition)
timeFrame: index admission
measure: Total dose of other vasopressor
timeFrame: 6, 12, 24, 48, 72 hours post randomisation
measure: All-cause mortality during index hospital admission and at 30 and 90 days
timeFrame: index admission and at 30 & 90 days post randomisation
measure: Readmission in first 30 days and 90 days
timeFrame: 30 & 90 days post randomisation
Other outcomes:
measure: Patient Centred Outcome
timeFrame: 30 days post randomisation
measure: Protocol Adherence
timeFrame: 48 hours post randomisation
measure: Protocol Adherence
timeFrame: 48 hours post randomisation
measure: Proportion of patients developing vasopressor extravasation
timeFrame: 72 hours post randomisation
measure: Proportion of patients developing pulmonary oedema
timeFrame: index admission
Locations:
city: Aintree
country: United Kingdom
facility: Aintree University Hospital
city: Blackburn
country: United Kingdom
facility: Royal Blackburn Hospital
city: Bury
country: United Kingdom
facility: Fairfield General Hospital
city: Derby
country: United Kingdom
facility: Royal Derby Hospital
city: Edinburgh
country: United Kingdom
facility: Royal Infirmary of Edinburgh
city: Fife Keith
country: United Kingdom
facility: Victoria Hospital
city: Glasgow
country: United Kingdom
facility: Glasgow Royal Infirmary
city: Glasgow
country: United Kingdom
facility: Queen Elizabeth University Hospital
city: Hull
country: United Kingdom
facility: Hull Royal Infirmary
city: Kettering
country: United Kingdom
facility: Kettering General
city: Kilmarnock
country: United Kingdom
facility: University Hospital Crosshouse
city: Lanark
country: United Kingdom
facility: University Hospital Monklands
city: Leicester
country: United Kingdom
facility: Leicester Royal Infirmary
city: Liverpool
country: United Kingdom
facility: Royal Liverpool University Hospital
city: London
country: United Kingdom
facility: Royal London Hospital
city: London
country: United Kingdom
facility: St George's
city: London
country: United Kingdom
facility: University Hospital Lewisham
city: Oxford
country: United Kingdom
facility: John Radcliffe Hospital
city: Paisley
country: United Kingdom
facility: Royal Alexandra Hospital
city: Peterborough
country: United Kingdom
facility: Peterborough City Hospital
city: Reading
country: United Kingdom
facility: Royal Berkshire Hospital
city: Romford
country: United Kingdom
facility: Queens Hospital Barking
city: Salford
country: United Kingdom
facility: Salford Royal
Study officials:
References: