Angiotensin II Antagonist in Severe Sepsis
Angiotensin II Antagonist in Severe Sepsis
The investigators propose a clinical study of irbersartan for the early treatment of severe
 sepsis patients with elevated predicted risk of death between. This study will evaluate
 whether early administration of the the angiotensin receptor blocker irbersartan provides
 significant reduction of 28 days mortality and multi organ failure incidence to patients with
 severe sepsis.
Background: Angiotensin II (ANG II) is a potent vasoconstrictor and diminishes vasodilator
 responses in arteries. In addition to direct effects on vascular tone, ANG II affects
 multiple aspects of microvascular function through promotion of leukostasis, induction of
 capillary permeability and depletion of glutathione. Binding of ANG II to its receptors (in
 particular AT1) mediates intracellular free radical generation that contributes to tissue
 damage by promoting mitochondrial dysfunction.

 Angiotensin receptor blockers (ARBs) interrupt renin-angiotensin system (RAS) overactivity by
 blocking a specific receptor that mediates the pathogenic activity of angiotensin II.
 Objectives: The clinical question objective of this study is if the antiinflammatory effect
 of ARBs is relevant in sepsis management and in particular if ARBs are able to improve
 survival and reduce the incidence of Multi Organ Failure in septic patients.

 Methods:

 STUDY DESIGN: Experimental; prospective, randomized, multicenter, phase III trial.

 STUDY POPULATION: Three hundred adults within 12 hrs of recognition of severe sepsis, with
 Acute Physiology and Chronic Health Evaluation (APACHE) II-predicted risk of mortality
 between 20% and 80% are eligible.

 Settings: 5 Italian Intensive Care Units. Oral irbesartan (total dose of 75 mg) or placebo
 administered every 24 hrs for 15 days. Analysis of data performed by a blind operator.
 Expected results: about 25% reduction in 28-day mortality rate and incidence of multi organ
 failure in the study population.
Inclusion Criteria: adults within 12 hrs of recognition of severe sepsis, with Acute
 Physiology and Chronic Health Evaluation (APACHE) II-predicted risk of mortality between
 20% and 80% are eligible.

 Exclusion Criteria:Patients already treated with ACE inhibitors or ARBs will be excluded.
 Patients admitted in shock conditions (systolic blood pressure lower than 90 mmHg) will be
 excluded. Patients with severe renal failure (serum creatinine of 2.0 mg/dL or dialysis)
 will be excluded.