Angiotensin in Septic Kidney Injury Trial (ASK-IT)

Study Description

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Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Acute Renal Failure; Sepsis; Septic Shock	Drug: Angiotensin II; Drug: Saline placebo	Phase 2

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 Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	12 participants
Allocation:	Randomized
Intervention Model:	Crossover Assignment
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:	Treatment
Official Title:	A Pilot Crossover Randomised Controlled Trial of Angiotensin II in Critically Ill Patients With Severe Sepsis and Acute Renal Failure
Study Start Date :	February 2010
Estimated Primary Completion Date :	February 2013

Arms and Interventions

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Arm	Intervention/treatment
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
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.

Outcome Measures

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Primary Outcome Measures :

1. Urine output [ Time Frame: During the 24 hours of infusion of study drug ]
2. Arterial blood pressure [ Time Frame: During the 24 hour infusion of study drug ]

Secondary Outcome Measures :

1. Serum creatinine [ Time Frame: At the end of the 24 hour infusion of study drug ]
2. Serum urea [ Time Frame: At the end of the 24 hour infusion of study drug ]
3. Serum Cystatin C [ Time Frame: At the end of the 24 hour infusion of study drug ]
4. Serum neutrophil gelatinase associated lipocalin (NGAL) [ Time Frame: At the end of the 24 hour infusion of study drug ]
5. Urinary cystatin C [ Time Frame: At the end of the 24 hour infusion of study drug ]
6. Urinary NGAL [ Time Frame: At the end of the 24 hour infusion of study drug ]
7. Urinary IL-18 [ Time Frame: At the end of the 24 hour infusion of study drug ]
8. Need for renal replacement therapy [ Time Frame: During ICU admisison ]
9. Mortality [ Time Frame: ICU and 28 days ]

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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.

Contacts and Locations

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Contacts

Contact: Michael C Reade, MBBS DPhil	+61394964838	michael.reade@austin.org.au
Contact: Forbes McGain, MBBS FJFICM	+613 8345 6639	forbes.mcgain@wh.org.au

Locations

Australia, Victoria
Northern Hospital	Recruiting
Epping, Victoria, Australia, 3074
Contact: Michael C Reade, MBBS DPhil +61394964838 michael.reade@austin.org.au
Contact: Graeme Duke, MD FJFICM +613 8405 8000 graeme.duke@nh.org.au
Principal Investigator: Michael C Reade, MBBS DPhil
Sub-Investigator: Graeme Duke, MD FJFICM
Sub-Investigator: Mary Park, RN
The Western Hospital	Recruiting
Footscray, Victoria, Australia, 3011
Contact: Forbes McGain, MBBS FJFICM +613 8345 6639 forbes.mcgain@wh.org.au
Contact: Craig French, MBBS FJFICM +613 8345 6639 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

Sponsors and Collaborators

Austin Health

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

More Information

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Responsible Party:	Assoc. Prof. Michael C. Reade, The Northern Hospital
ClinicalTrials.gov Identifier:	NCT00711789 History of Changes
Other Study ID Numbers:	TNH 23/08
First Posted:	July 9, 2008
Last Update Posted:	June 23, 2011
Last Verified:	January 2009

Keywords provided by Austin Health:

Acute renal failure; Septic shock; angiotensin II; neutrophil gelatinase associated lipocalin (NGAL); cystatin C

Additional relevant MeSH terms:

Sepsis; Renal Insufficiency; Shock, Septic; Acute Kidney Injury; Infection; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Kidney Diseases	Urologic Diseases; Shock; Angiotensin II; Angiotensinogen; Vasoconstrictor Agents; Serine Proteinase Inhibitors; Protease Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action