Angiotensin in Septic Kidney Injury Trial (ASK-IT)
Recruitment status was: Recruiting
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.
|Acute Renal Failure Sepsis Septic Shock||Drug: Angiotensin II Drug: Saline placebo||Phase 2|
|Study Design:||Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double Blind (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|
- Urine output [ Time Frame: During the 24 hours of infusion of study drug ]
- Arterial blood pressure [ Time Frame: During the 24 hour infusion of study drug ]
- Serum creatinine [ Time Frame: At the end of the 24 hour infusion of study drug ]
- Serum urea [ Time Frame: At the end of the 24 hour infusion of study drug ]
- Serum Cystatin C [ Time Frame: At the end of the 24 hour infusion of study drug ]
- Serum neutrophil gelatinase associated lipocalin (NGAL) [ Time Frame: At the end of the 24 hour infusion of study drug ]
- Urinary cystatin C [ Time Frame: At the end of the 24 hour infusion of study drug ]
- Urinary NGAL [ Time Frame: At the end of the 24 hour infusion of study drug ]
- Urinary IL-18 [ Time Frame: At the end of the 24 hour infusion of study drug ]
- Need for renal replacement therapy [ Time Frame: During ICU admisison ]
- Mortality [ Time Frame: ICU and 28 days ]
|Study Start Date:||February 2010|
|Estimated Primary Completion Date:||February 2013 (Final data collection date for primary outcome measure)|
|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.
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00711789
|Contact: Michael C Reade, MBBS DPhilfirstname.lastname@example.org|
|Contact: Forbes McGain, MBBS FJFICM||+613 8345 email@example.com|
|Epping, Victoria, Australia, 3074|
|Contact: Michael C Reade, MBBS DPhil +61394964838 firstname.lastname@example.org|
|Contact: Graeme Duke, MD FJFICM +613 8405 8000 email@example.com|
|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 firstname.lastname@example.org|
|Contact: Craig French, MBBS FJFICM +613 8345 6639 email@example.com|
|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|
|Principal Investigator:||Michael C Reade, MBBS DPhil||Northern Hospital, Epping, Victoria, Australia|
|Principal Investigator:||Forbes McGain, MBBS FJFICM||Western Hospital, Footscray, Victoria. Australia|