Early Vasopressors in Sepsis (EVIS)

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

Intervention: Intravenous Norepinephrine infusion administered via a peripheral intravenous cannula in the first 48 hrs after randomisation to a target MAP>65mmHg.

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. Outcome: 30 day mortality

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.

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. Population: Adult patients who present to UK NHS hospitals with community acquired septic shock Inclusion criteria

A. Adults (18-years and older); B. Suspected or confirmed infection causing acute illness; C. SBP < 90 mmHg or MAP < 65 mmHg AND serum lactate>2; D. Hospital presentation within last 6hrs. Exclusion criteria A. >1000ml of iv fluid prior to screening; B. Requirement for Immediate surgery; C. Established chronic renal replacement therapy;

D. Confirmed pregnancy/lactation; E. Known allergy/adverse reaction to NE;

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 G. Previous recruitment in the trial

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.

Protocol Adherence: Proportion of patients who have PVI discontinued for non-clinical reasons after recruitment to intervention arm; Safety: proportion of patients developing vasopressor extravasation, worsening acute kidney injury or pulmonary oedema

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.

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

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