Early Vasopressors in Sepsis

Study Overview
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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 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.

Official Title
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Early Vasopressors in Sepsis

Conditions
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Sepsis

Intervention / Treatment
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* Drug: Norepinephrine
* Other: Balanced Crystalloid


Participation Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Open label, two arm, multicentre, pragmatic parallel group sequential randomised trial with an internal pilot
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Intervention Arm<br>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. | Drug: Norepinephrine<br>* Norepinepherine should be prepared and delivered at a concentration of 16 micrograms/ml<br>|
| Placebo Comparator: Standard care<br>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. | Other: Balanced Crystalloid<br>* IV fluids administered as per standard care<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All cause mortality | All cause mortality at 30 days | 30 days post randomisation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Accumulated Total Volume of IV fluid | Accumulated volume of IV fluid delivered in each arm - excluding fluid volumes less than 100ml | 6,12, 24, 48 and 72 hours post randomisation | 
| Lactate clearance from baseline | Blood lactate value - arterial or venous | 6, 12 and 24 hours post randomisation | 
| Organ Dysfunction Score | Organ dysfunction score (SOFA) calculated at each time point | 0, 24, 48 and 72 hours post randomisation | 
| Total Dose of Norepinephrine | Total dose of norepinephrine delivered by any route (peripheral or central) at each timepoint | 6, 12, 24, 48 and 72 hours post randomisation | 
| Proportion of patients who receive vasopressors | Proportion of patients recruited to control arm who receive any vasopressor (norepinephrine, vasopressin, metarminol, epinephrine) at each time point | 6, 12, 24 and 48 hours after recruitment to the control arm | 
| Proportion of patients who require central venous access | Decision to treat based on treating clinician judgement | 24 and 48 hours post randomisation | 
| Proportion of patients developing acute kidney injury | 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 | During the first 72 hours post randomisation | 
| Proportion of patients receiving parenteral corticosteroid | defined as new prescription of parenteral corticosteroid | 24 and 48 hours post randomisation | 
| Length of hospital stay for index admission | Proportion of patients admitted to and length of stay in critical care (level 2 or 3) during hospital admission | up to hospital discharge | 
| Proportion of participants needing renal replacement therapy during index hospital 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 | index admission | 
| Proportion of participants needing non-invasive ventilation during index hospital 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 | index admission | 
| Proportion of participants needing advanced respiratory support (ICNARC definition) | 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 | index admission | 
| Total dose of other vasopressor | Total dose of other vasopressors delivered by any route (peripheral or central) at each timepoint | 6, 12, 24, 48, 72 hours post randomisation | 
| All-cause mortality during index hospital admission and at 90 days | All-cause mortality during index hospital admission and at 90 days | index admission and at 90 days post randomisation | 
| Readmission in first 30 days after discharge | Readmission in first 30 days after discharge | 30 days after discharge | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sepsis, Resuscitation, Norepinephrine, Intravenous fluids, Emergency Medicine, Critical Care