Title: Early Vasopressors in Sepsis (EVIS)
Funder: Chief Scientist Office, Scotland

Abstract: The aim of this research study is to compare two treatments (fluid and blood pressure medication via a drip) for patients in hospital with sepsis, a life-threatening condition caused by the overreaction of the body’s immune system to infection. We plan to see if one approach is better than the other, in terms of survival, time spent in hospital and quality of life - outcomes that are important to both the patient and NHS. _x000D_ Background _x000D_ Globally, 27 million people develop sepsis every year occurring in all ages and social groups. 1 in 5 patients with sepsis die in the UK and if they are critically unwell with low blood pressure, “shock”, this increases to 1 in every 3 patients dying. Survivors can face lifelong complications including depression, weakness and chronic pain. Like heart attacks and strokes, sepsis needs to be treated quickly after it develops. Current UK and international guidelines focus on the public and professionals recognising sepsis early and delivering early treatment with antibiotics, fluids via a drip into a vein and other treatments. Medication to improve blood pressure (vasopressors) are also recommended later in treatment guidelines after initial attempts to stabilise the patient. There is evidence based on observations looking back at previous patients that using vasopressors earlier in the patient journey may be beneficial. There has been no prospective clinical study looking at whether these potential benefits remain when vasopressors are given via a small drip in the arm as part of early treatment when the patient arrives in hospital. _x000D_ Design and methods _x000D_ The study will investigate two different approaches to early treatment, in very unwell patients who have sepsis. Patients will either receive standard treatment with early intravenous fluid resuscitation and later use of vasopressors as required, or early use of vasopressors with additional intravenous fluid resuscitation as required._x000D_ Patients who meet the study entry criteria will be asked to be involved by trained clinical or research staff. If they consent they will be randomly allocated to either standard treatment or early vasopressor treatment for the first 48 hours after the start of the study. All other care will be decided by the clinician in communication with the patient. Patients will be free to withdraw from the study at any time. This type of clinical study design, known as randomised, is the best study design to allow us to decide if there is any difference between these two approaches. _x000D_ Patient and public involvement (PPI)_x000D_ We have PPI during the study design including a PPI co-applicant from the charity Sepsis Research. Our PPI engagement has shaped the choice of outcomes used and the group has reviewed relevant documentation. We will continue to work with our existing sepsis PPI group when the study is running, when the results are available and during the write up of the study. Lastly we anticipate significant PPI in sharing the results with health care professionals, charities and guideline groups._x000D_ Dissemination _x000D_ The trial findings will be publicised via conference presentations, journal publications and research summaries. It will be sent to major relevant professional and charitable organisations and to UK and international guideline development groups. Our team includes extensive experience in the use of social medical platforms for medical education, public engagement and dissemination at a national level.

Lay abstract: Population: Adults presenting to an ED, AMU or SAU with signs or symptoms of community acquired sepsis and a SBP < 90 mmHg or MAP < 65mmHg and a venous lactate of > 2mmol/l_x000D_ Intervention: Intravenous Norepinephrine infusion administered via a peripheral intravenous cannula in the first 48 hrs after randomisation to a target MAP>65mmHg. _x000D_ Control group treatment: Intravenous crystalloid administered as 250-1000ml boluses up to 30ml/kg in the first 3 hours after randomisation, and thereafter according to national guidelines for remaining 45 hours to a target MAP>65mmHg._x000D_ Outcome: 30 day mortality_x000D_ Design: open label two-arm, multicentre, pragmatic, parallel group definitive randomised trial of adult patients with community acquired septic shock recruited from the ED, AMU or SAU. There will be an internal pilot with progression from pilot to main study assessed on (a) recruitment feasibility and (b) protocol adherence._x000D_ Setting: 60 ED and AMU within NHS hospitals with patient case mix typical of UK acute care, with a proven track record of successful participation in NIHR Portfolio national clinical trials._x000D_ Population: Adult patients who present to UK NHS hospitals with community acquired septic shock_x000D_ Inclusion criteria _x000D_ A. Adults (18 years and older); _x000D_ B. Suspected or confirmed infection causing acute illness; _x000D_ C. SBP < 90 mmHg or MAP < 65 mmHg AND serum lactate>2;_x000D_ D. Hospital presentation within last 6hrs. _x000D_ Exclusion criteria_x000D_ A. >1000ml of iv fluid prior to screening; _x000D_ B. Requirement for Immediate surgery; _x000D_ C. Established chronic renal replacement therapy; _x000D_ D. Confirmed pregnancy/lactation; _x000D_ E. Known allergy/adverse reaction to NE; _x000D_ F. No medical history that might, in the opinion of the attending clinician, put the patient at significant risk if he/she were to participate in the trial _x000D_ G. Previous recruitment in the trial_x000D_ Secondary outcomes during first 48 hours: volume of iv fluid delivered in each arm in the first 6,12,24,48hrs; rate of lactate clearance at 3,6hrs; SOFA score at 0, 24,48hrs; total dose of NE delivered in first 6,12,24,48hrs. Vasopressor ucontrol arm. _x000D_ Protocol Adherence: Proportion of patients who have PVI discontinued for non-clinical reasons after recruitment to intervention arm; _x000D_ Safety: proportion of patients developing vasopressor extravasation, worsening acute kidney injury or pulmonary oedema_x000D_ Process evaluation: embedded qualitative research to: (a) establish the extent to which the intervention is implemented as intended; (b) ascertain how feasible and acceptable the intervention is to clinical staff; and (c) identify any facilitators and barriers to recruitment. This will consist of a rapid ethnographic assessment._x000D_ Longer term follow up: 90 day mortality, length of hospital stay for index admission; readmission in first 30 days after discharge; critical care stay and interventions_x000D_ Health Economic evaluation: This will be conducted from the perspective of the NHS and PSS in line with NICE guidance. Data on healthcare resource use will include inpatient and community care health services. Unit costs will be obtained from standard sources. HRQoL will be assessed at baseline, 30 days and 6 months using EQ5D-5L. Patient-level costs and quality adjusted life years (QALYs) will be estimated. Within trial and a model-based analyses will be undertaken based on six-month and lifetime horizon, respectively. All appropriate deterministic and probabilistic sensitivity analyses will be carried out

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION;INFLAMMATORY AND IMMUNE SYSTEM