The Effect of Vasopressor Therapy on Renal Perfusion in Septic Shock (REPERFUSE)

The Effect of Vasopressor Therapy on Renal Perfusion in Patients With Septic Shock - a Mechanistically Focussed Randomized Control Study

Acute kidney injury (AKI) is a common complication of septic shock and together these conditions carry a high mortality risk. In septic patients who develop severe AKI renal cortical perfusion is deficient despite normal macrovascular organ blood flow. This intra-renal perfusion abnormality may be amenable to pharmacological manipulation, which may offer mechanistic insight into the pathophysiology of septic AKI. The aim of the current study is to investigate the effects of vasopressin and angiotensin II on renal microcirculatory perfusion in a cohort of patients with septic shock.

Study Overview

• Status: Recruiting
• Conditions: Septic Shock; Acute Kidney Injury
• Intervention / Treatment: Drug: Angiotensin II; Drug: Norepinephrine; Drug: Vasopressin

• Study Type: Interventional
• Enrollment (Estimated): 45
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Sam Hutchings; Phone Number: 02032994957; Email: sam.hutchings@nhs.net

Study Locations

• United Kingdom
  • London, United Kingdom, SE5 9RS
    • Recruiting
    • King's College Hospital
    • Contact: Sam Hutchings; Phone Number: 02032994957; Email: sam.hutchings@nhs.net

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Within 48 hours of intensive care admission
• Evidence of suspected or confirmed infection
• Sequential Organ Failure (SOFA) score increase of 2 or more (assuming a baseline of 0 if no previous measures)
• Requirement for norepinephrine infusion as the sole vasopressor agent in a dose of >0.1mcg/kg/min
• Lactate >2mmol/L at any stage prior to randomisation

Exclusion Criteria:

• Known intolerance to Sonovue™ contrast medium, vasopressin or angiotensin II
• Patients receiving other vasoactive drugs in addition to norepinephrine
• Patients with known chronic kidney disease (CKD) stage 4 or 5 (baseline glomerular filtration rate (GFR) <30mls/min)
• Patients receiving extra corporal membrane oxygenation (ECMO)
• Patients with acute occlusive coronary syndromes requiring intervention
• Patients with mesenteric ischaemia
• Patients with a history or presence of aortic dissection or abdominal aortic aneurysm
• Patients with Raynaud's syndrome or acute vaso-occlusive conditions
• Pregnancy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Angiotensin II Infusion; Angiotensin II infusion commenced alongside standard care vasopressor therapy (norepinephrine). Angiotensin II up titrated in a protocolised manner to a target/maximum dose of 40 ng/kg/min whilst noradrenaline down titrated in order to achieve/maintain target mean arterial pressure (MAP) as directed by attending clinician.	Drug: Angiotensin II; Angiotensin II infusion; Drug: Norepinephrine; Standard care vasopressor therapy, norepinephrine infusion
Experimental: Vasopressin Infusion; Vasopressin infusion commenced alongside standard care vasopressor therapy (norepinephrine). Vasopressin up titrated in a protocolised manner to a target/maximum dose of 0.04 IU/min whilst noradrenaline down titrated in order to achieve/maintain target mean arterial pressure (MAP) as directed by attending clinician.	Drug: Norepinephrine; Standard care vasopressor therapy, norepinephrine infusion; Drug: Vasopressin; Vasopressin infusion
Active Comparator: Norepinephrine Infusion; Standard care vasopressor therapy which recruited participants already receiving, titrated to achieve/maintain target mean arterial pressure (MAP) as directed by attending clinician.	Drug: Norepinephrine; Standard care vasopressor therapy, norepinephrine infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cortical mean transit time (mTT) measured in seconds	Contrast enhanced ultrasound measure of renal cortical tissue blood flow	Measured at +24 hours following study vasopressor infusion starting

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cortical mean transit time (mTT) measured in seconds	Contrast enhanced ultrasound measures of renal cortical tissue blood flow	Measured at +1 hour and +24 hours following study vasopressor infusion starting
Cortical perfusion index (PI) measured in arbitrary units	Contrast enhanced ultrasound measures of renal cortical tissue blood flow	Measured at +1 hour and +24 hours following study vasopressor infusion starting
Cortical wash in rate (WiR) measured in arbitrary units	Contrast enhanced ultrasound measures of renal cortical tissue blood flow	Measured at +1 hour and +24 hours following study vasopressor infusion starting
Urinary oxygen tension (pO2) across 24 hours study period measured in millimetres of mercury (mmHg)	Mean urinary pO2	Across 24 hours study period
Tissue inhibitor of metalloproteinases-2 (TIMP-2) and insulin-like growth factor binding protein-7 (IGFBP-7). Both measured in nanograms per millilitre (ng/ml)	Biomarker analysis - regulatory proteins involved in initiating cell cycle arrest and associated with AKI	Measured at baseline and +24 hours following study vasopressor infusion starting

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Perfused vessel density (PVD) measured in millimetres per square millimetre	Incident dark field video microscopy measures of the systemic microcirculation	Measured at +1 hour and +24 hours following study vasopressor infusion starting
Microvascular flow index (MFI) (unitless score from 0 to 3 where 3 is the value see in health).	Incident dark field video microscopy measures of the systemic microcirculation	Measured at +1 hour and +24 hours following study vasopressor infusion starting
Syndecan 1, angiopoietin 1 & 2, Interleukin 6 & 8 (IL-6, IL-8) and tissue necrosis factor (TNF). All measured in nanograms per millilitre (ng/ml)	Biomarker analysis - markers of inflammation and endothelial activation/function	Measured at baseline and +24 hours following study vasopressor infusion starting

Collaborators and Investigators

• Sponsor: King's College Hospital NHS Trust
• Collaborators: European Society of Intensive Care Medicine; Royal Centre for Defence Medicine

Study record dates

Study Major Dates

• Study Start (Actual): January 5, 2024
• Primary Completion (Estimated): January 1, 2026
• Study Completion (Estimated): July 1, 2026

Study Registration Dates

• First Submitted: January 3, 2024
• First Submitted That Met QC Criteria: January 28, 2024
• First Posted (Actual): January 31, 2024

Study Record Updates

• Last Update Posted (Actual): April 4, 2025
• Last Update Submitted That Met QC Criteria: April 1, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urogenital Diseases; Pathologic Processes; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Infections; Sepsis; Systemic Inflammatory Response Syndrome; Inflammation; Renal Insufficiency; Acute Kidney Injury; Shock; Shock, Septic; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Protease Inhibitors; Enzyme Inhibitors; Hemostatics; Coagulants; Neurotransmitter Agents; Adrenergic alpha-Agonists; Adrenergic Agonists; Adrenergic Agents; Natriuretic Agents; Serine Proteinase Inhibitors; Sympathomimetics; Vasoconstrictor Agents; Antidiuretic Agents; Giapreza; Norepinephrine; Vasopressins; Arginine Vasopressin; Angiotensin II; Angiotensinogen
• Other Study ID Numbers: 328797

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No