Angiotensin in Septic Kidney Injury Trial

Sepsis Clinical Trial

— ASK-IT  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT00711789
• Other study ID #: TNH 23/08
• Status: Recruiting
• Phase: Phase 2
• First received: July 7, 2008
• Last updated: June 22, 2011
• Start date: February 2010

Study information

• Verified date: January 2009
• Source: Austin Health
• Contact: Michael C Reade, MBBS DPhil
• Phone: +61394964838
• Email: michael.reade[@]austin.org.au
• Is FDA regulated: No
• Health authority: Australia: Department of Health and Ageing Therapeutic Goods Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 12
• Est. primary completion date: February 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Acute Kidney Injury
• Acute Renal Failure
• Renal Insufficiency
• Sepsis
• Septic Shock
• Shock, Septic

Intervention

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
• 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.

Locations

Country	Name	City	State
Australia	Northern Hospital	Epping	Victoria
Australia	The Western Hospital	Footscray	Victoria

Sponsors (3)

Lead Sponsor	Collaborator
Austin Health	Northern Health and Social Care Trust, Western Hospital, Australia

Country where clinical trial is conducted

Australia, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Urine output		During the 24 hours of infusion of study drug	No
Primary	Arterial blood pressure		During the 24 hour infusion of study drug	Yes
Secondary	Serum creatinine		At the end of the 24 hour infusion of study drug	No
Secondary	Serum urea		At the end of the 24 hour infusion of study drug	No
Secondary	Serum Cystatin C		At the end of the 24 hour infusion of study drug	No
Secondary	Serum neutrophil gelatinase associated lipocalin (NGAL)		At the end of the 24 hour infusion of study drug	No
Secondary	Urinary cystatin C		At the end of the 24 hour infusion of study drug	No
Secondary	Urinary NGAL		At the end of the 24 hour infusion of study drug	No
Secondary	Urinary IL-18		At the end of the 24 hour infusion of study drug	No
Secondary	Need for renal replacement therapy		During ICU admisison	No
Secondary	Mortality		ICU and 28 days	No