Angiotensin in Septic Kidney Injury Trial - Full Text View

Purpose

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	Intervention	Phase
Acute Renal Failure Sepsis Septic Shock	Drug: Angiotensin II Drug: Saline placebo	Phase 2


Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Crossover Assignment Masking: Double Blind (Subject, Caregiver, 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

Resource links provided by NLM:

MedlinePlus related topics: Sepsis Shock

U.S. FDA Resources

Further study details as provided by Austin Health:

Primary Outcome Measures:

Urine output [ Time Frame: During the 24 hours of infusion of study drug ] [ Designated as safety issue: No ]
Arterial blood pressure [ Time Frame: During the 24 hour infusion of study drug ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

Serum creatinine [ Time Frame: At the end of the 24 hour infusion of study drug ] [ Designated as safety issue: No ]
Serum urea [ Time Frame: At the end of the 24 hour infusion of study drug ] [ Designated as safety issue: No ]
Serum Cystatin C [ Time Frame: At the end of the 24 hour infusion of study drug ] [ Designated as safety issue: No ]
Serum neutrophil gelatinase associated lipocalin (NGAL) [ Time Frame: At the end of the 24 hour infusion of study drug ] [ Designated as safety issue: No ]
Urinary cystatin C [ Time Frame: At the end of the 24 hour infusion of study drug ] [ Designated as safety issue: No ]
Urinary NGAL [ Time Frame: At the end of the 24 hour infusion of study drug ] [ Designated as safety issue: No ]
Urinary IL-18 [ Time Frame: At the end of the 24 hour infusion of study drug ] [ Designated as safety issue: No ]
Need for renal replacement therapy [ Time Frame: During ICU admisison ] [ Designated as safety issue: No ]
Mortality [ Time Frame: ICU and 28 days ] [ Designated as safety issue: No ]


Estimated Enrollment:	12
Study Start Date:	February 2010
Estimated Primary Completion Date:	February 2013 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
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.

Arms

Assigned Interventions

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.

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.

Eligibility


Ages Eligible for Study:	18 Years and older (Adult, Senior)
Genders Eligible for Study:	Both
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

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00711789

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


Responsible Party:	Assoc. Prof. Michael C. Reade, The Northern Hospital
ClinicalTrials.gov Identifier:	NCT00711789 History of Changes
Other Study ID Numbers:	TNH 23/08
Study First Received:	July 7, 2008
Last Updated:	June 22, 2011
Health Authority:	Australia: Department of Health and Ageing Therapeutic Goods Administration

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

ClinicalTrials.gov processed this record on September 28, 2016

Angiotensin in Septic Kidney Injury Trial (ASK-IT)