Angiotensin in Septic Kidney Injury Trial (ASK-IT)

A Pilot Crossover Randomised Controlled Trial of Angiotensin II in Critically Ill Patients With Severe Sepsis and Acute Renal Failure

The purpose of this study is to determine the effect of a systemic infusion of angiotensin II on haemodynamics and urine output in critically ill patients with severe sepsis/septic shock and acute renal failure.

It will also help determine the feasibility of conducting a definitive and adequately powered randomised controlled trial of angiotensin II in such patients that would assess mortality and need for renal replacement therapy as endpoints.

Study Overview

• Status: Unknown
• Conditions: Sepsis; Septic Shock; Acute Renal Failure
• Intervention / Treatment: Drug: Angiotensin II; Drug: Saline placebo

Detailed Description

Sepsis is the most common cause of ARF in the ICU. In last 50 years there have been no significant advances in our understanding of the pathogenesis, prevention or treatment of septic ARF, except for the use of renal replacement therapy (RRT) once it is established.

It has been assumed that hypotension induced by severe sepsis results in organ hypoperfusion and subsequent kidney ischaemia. This ischaemia has been believed to be one of the main factors, if not the principal factor, contributing to development of ARF in severe sepsis. Surprisingly, there is little evidence to support this assumption. Rather, emerging evidence seriously questions this traditional ischaemic-acute tubular necrosis (ATN) paradigm of septic ARF. Patients with severe sepsis have been found to have increased, rather than decreased, renal blood flow, and post mortem examination of kidneys from patients who have died with septic acute renal failure rarely show the appearance of ATN. An animal model of septic ARF found that renal blood flow was increased, while glomerular filtration rate was decreased.

These facts lead us to hypothesise that profound efferent arteriolar vasodilatation may be the cause of the observed decrease in GFR in septic ARF. The only logical explanation for the observation that RBF increases while GFR falls is that both efferent and afferent arterioles dilate, but that efferent vasodilation is greater. A selective efferent arteriolar vasoconstrictor would be expected to restore GFR. Angiotensin II is the most selective known efferent vasoconstrictor.

We hypothesise that early therapeutic intervention with angiotensin II in critically ill patients with severe sepsis/septic shock and kidney dysfunction may improve kidney function such that the need for renal replacement therapy is avoided. This would represent a significant improvement in the care of critically ill patients with severe sepsis/septic shock and ARF, a condition for which no interventions short of RRT have been shown to improve outcome. Novel and successful therapeutic interventions in this patient population would have widespread clinical implications, including improved survival and less need for long-term dialysis, with consequent resource savings.

• Study Type: Interventional
• Enrollment (Anticipated): 12
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • Victoria
    • Epping, Victoria, Australia, 3074
      • Recruiting
      • Northern Hospital
      • Contact: Michael C Reade, MBBS DPhil; Phone Number: +61394964838; Email: michael.reade@austin.org.au
      • Contact: Graeme Duke, MD FJFICM; Phone Number: +613 8405 8000; Email: graeme.duke@nh.org.au
      • Principal Investigator: Michael C Reade, MBBS DPhil
      • Sub-Investigator: Graeme Duke, MD FJFICM
      • Sub-Investigator: Mary Park, RN
    • Footscray, Victoria, Australia, 3011
      • Recruiting
      • The Western Hospital
      • Contact: Forbes McGain, MBBS FJFICM; Phone Number: +613 8345 6639; Email: forbes.mcgain@wh.org.au
      • Contact: Craig French, MBBS FJFICM; Phone Number: +613 8345 6639; Email: craig.french@wh.org.au
      • Principal Investigator: Forbes McGain, MBBS FJFICM
      • Sub-Investigator: Craig French, MBBS FJFICM
      • Sub-Investigator: John Mulder, MBBS FJFICM
      • Sub-Investigator: Sathyajith Velandy-Koottayi, MBBS FJFICM
      • Sub-Investigator: Heike Raunow, RN

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• age ≥ 18 years
• within the first 24 hours of ICU admission
• an expected duration of ICU admission of at least 72 hours
• informed consent by patient or by proxy (i.e. next of kin)
• diagnosis of severe sepsis/septic shock
• diagnosis of kidney dysfunction (minimum RIFLE criteria - 'R'); and
• presence of a central venous catheter.

Exclusion Criteria:

• inability to provide or obtain consent;
• patient is moribund with expected death within 24 hours;
• known chronic kidney disease (CKD) or end-stage renal disease (ESRD) receiving chronic RRT;
• confirmed or suspected acute glomerulonephritis, acute interstitial nephritis, renal vasculitis or post-renal aetiology for kidney dysfunction;
• patient is already receiving (or is about to start) CRRT for acute renal failure at the time of enrolment;
• known or documented allergy to angiotensin II;
• MAP consistently > 100 mmHg with no pressor support and no easily treatable cause (eg. pain); and
• enrolling physician's belief that the study drug could not be administered for the expected study duration.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Placebo	Drug: Saline placebo; Saline placebo will be given by continuous infusion according to a blood-pressure base protocol. This protocol will also incorporate noradrenaline for blood pressure control (as is true in the active drug arm), such that blood pressure targets will be rapidly achieved in both arms of the study; the only difference being that in the active drug arm, at least part of the pressor effect will be provided by angiotensin II.
ACTIVE_COMPARATOR: Angiotensin II	Drug: Angiotensin II; Angiotensin II will be given by continuous infusion for 24 hours starting at a dose of 5ng/kg/min and then titrated to a maximum dose of 15 ng/kg/min according to a blood pressure based protocol

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Urine output	During the 24 hours of infusion of study drug
Arterial blood pressure	During the 24 hour infusion of study drug

Secondary Outcome Measures

Outcome Measure	Time Frame
Serum creatinine	At the end of the 24 hour infusion of study drug
Serum urea	At the end of the 24 hour infusion of study drug
Serum Cystatin C	At the end of the 24 hour infusion of study drug
Serum neutrophil gelatinase associated lipocalin (NGAL)	At the end of the 24 hour infusion of study drug
Urinary cystatin C	At the end of the 24 hour infusion of study drug
Urinary NGAL	At the end of the 24 hour infusion of study drug
Urinary IL-18	At the end of the 24 hour infusion of study drug
Need for renal replacement therapy	During ICU admisison
Mortality	ICU and 28 days

Collaborators and Investigators

• Sponsor: Austin Health
• Collaborators: Northern Health and Social Care Trust; Western Hospital, Australia
• Investigators: Principal Investigator: Michael C Reade, MBBS DPhil, Northern Hospital, Epping, Victoria, Australia; Principal Investigator: Forbes McGain, MBBS FJFICM, Western Hospital, Footscray, Victoria. Australia

Study record dates

Study Major Dates

• Study Start: February 1, 2010
• Primary Completion (ANTICIPATED): February 1, 2013

Study Registration Dates

• First Submitted: July 7, 2008
• First Submitted That Met QC Criteria: July 8, 2008
• First Posted (ESTIMATE): July 9, 2008

Study Record Updates

• Last Update Posted (ESTIMATE): June 23, 2011
• Last Update Submitted That Met QC Criteria: June 22, 2011
• Last Verified: January 1, 2009

More Information

Terms related to this study

• Keywords: Acute renal failure; Septic shock; cystatin C; angiotensin II; neutrophil gelatinase associated lipocalin (NGAL)
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Kidney Diseases; Urologic Diseases; Systemic Inflammatory Response Syndrome; Inflammation; Shock; Sepsis; Shock, Septic; Renal Insufficiency; Acute Kidney Injury; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Serine Proteinase Inhibitors; Vasoconstrictor Agents; Angiotensin II; Giapreza; Angiotensinogen
• Other Study ID Numbers: TNH 23/08