EVIS: Early Vasopressors in Sepsis

Sponsor

NHS Greater Glasgow and Clyde (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05179499

Collaborator

University of Glasgow (Other), University of Edinburgh (Other), Northern Care Alliance NHS Foundation Trust (Other), Imperial College London (Other), St George's, University of London (Other)

3,286

Enrollment

Arms

Anticipated Duration (Months)

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Sepsis	Drug: Norepinephrine Other: Balanced Crystalloid	Phase 3

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

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

Study Design

Study Type:

Interventional

Anticipated Enrollment :

3286 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Open label, two arm, multicentre, pragmatic parallel group randomised trial with an internal pilotOpen label, two arm, multicentre, pragmatic parallel group randomised trial with an internal pilot

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Early Vasopressors in Sepsis

Anticipated Study Start Date :

Mar 1, 2022

Anticipated Primary Completion Date :

Jul 1, 2023

Anticipated Study Completion Date :

Jul 30, 2025

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Peripheral Vasopressor Infusion Arm Participants will receive peripheral vasopressor infusion of norepinepherine (16 micrograms/ml) All other care will be as per local protocol	Drug: Norepinephrine Norepinepherine should be prepared and delivered at a concentration of 16 micrograms/ml
Placebo Comparator: Standard care Participants will receive standard care as per UK national guidelines on Sepsis. All other care will be as per local protocol	Other: Balanced Crystalloid IV fluids administered as per standard care

Arm

Intervention/Treatment

Active Comparator: Peripheral Vasopressor Infusion Arm

Participants will receive peripheral vasopressor infusion of norepinepherine (16 micrograms/ml) All other care will be as per local protocol

Drug: Norepinephrine

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

Placebo Comparator: Standard care

Participants will receive standard care as per UK national guidelines on Sepsis. All other care will be as per local protocol

Other: Balanced Crystalloid

IV fluids administered as per standard care

Outcome Measures

Primary Outcome Measures

All cause mortality [30 days post randomisation]
All cause mortality at 30 days

Secondary Outcome Measures

Accumulated Total Volume of IV fluid [72 hours post randomisation]
Accumulated volume of IV fluid delivered in each arm - excluding fluid volumes less than 100ml
Lactate [0, 6, 12 and 24 hours]
Blood lactate value - arterial or venous
Organ Dysfunction Score [0, 24, 48 and 72 hours]
Organ dysfunction score (SOFA) calculated at each time point
Total Dose of Norepinephrine [6, 12, 24, 48 and 72 hours]
Total dose of norepinephrine delivered by any route (peripheral or central) at each timepoint
Total dose of vasopressor [6, 12, 24 and 48 hours after recruitment to the control arm]
Proportion of patients recruited to control arm who receive any vasopressor (norepinephrine, vasopressin, metarminol, epinephrine) at each time point
Proportion of patients who require central venous access [24 and 48 hours]
Decision to treat based on treating clinician judgement
Proportion of patients developing acute kidney injury [First 72 hours]
Acute kidney injury in line with the (p) RIFLE (paediatric Risk, Injury, Failure, Loss, End stage renal disease, AKIN (Acute kidney injury network) or KDIGO (Kidney Disease: Improving Global Outcomes) definitions by using any of the following criteria a rise in serum creatinine of 26 micromol/litre or greater within 48 hours a 50% or greater rise in serum creatinine known or presumed to have occurred within the past 7 days a fall in urine output to less than 0.5 ml/kg/hour for more than 6 hours in adults
Proportion of patients receiving parenteral corticosteroid [24 and 48 hours]
defined as new prescription of parenteral corticosteroid
Length of hospital stay for index admission [up to hospital discharge]
index hospital admission ends when the patient is discharged from the facility providing definitive treatment for the episode of sepsis leading to inclusion of the study
Proportion of patients admitted to and length of stay in critical care (level 2 or 3) during index admission [index admission]
level 2 care is for patients requiring more detailed observation or intervention including support for a single failing organ system or post-operative care and those 'stepping down' from higher levels of care; level 3 care is for patients requiring advanced respiratory support alone or monitoring and support for two or more organ systems. This level includes all complex patients requiring support for multi-organ failure
Proportion of participants needing renal replacement therapy during index hospital admission [index admission]
decision to treat based on treating clinician judgement; participants who receive new renal replacement therapy; participants with chronic renal replacement initiated prior to the index admission will not be eligible to meet this endpoint
Proportion of participants needing non-invasive ventilation during index hospital admission [index admission]
decision to treat based on treating clinician judgement; defined as admissions receiving mask/hood CPAP or mask/hood BiPAP or non-invasive ventilation; admissions receiving CPAP via a tracheostomy
Proportion of participants needing advanced respiratory support (ICNARC definition) [index admission]
decision to treat based on treating clinician judgement; Patients who receive one or more of the following: A. Patients who receive invasive mechanical ventilation via endotracheal or tracheostomy tube, except those intubated solely for a procedure and extubated within 24 hours B. BiPAP (bilevel positive airway pressure) applied via a trans-laryngeal tracheal tube or applied via a tracheostomy C. CPAP (continuous positive airway pressure) via a translaryngeal tune of applied via a tracheostomy D. extracorporeal respiratory support

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Age >18 years
Clinically suspected or proven infection resulting in principal reason for acute illness
SBP <90mmHg or MAP <65mmHg and measured serum lactate of >2mmol/L at the time of eligibility assessment
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 (< 1hour) 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