title: Multicenter, randomized, placebo-controlled phase III study of pyridoxalated hemoglobin polyoxyethylene in distributive shock (PHOENIX).
abstract: OBJECTIVE
  To compare the effectiveness and safety of the hemoglobin-based nitric oxide scavenger, pyridoxalated hemoglobin polyoxyethylene, against placebo in patients with vasopressor-dependent distributive shock.
  
  
  METHODS
  Multicenter, randomized, placebo-controlled, open-label study.
  
  
  METHODS
  Sixty-one participating ICUs in six European countries (Austria, Belgium, Germany, the Netherlands, Spain, and United Kingdom).
  
  
  METHODS
  All patients admitted with distributive shock, defined as the presence of at least two systemic inflammatory response syndrome criteria, persisting norepinephrine dependence and evidence of organ dysfunction/hypoperfusion despite adequate fluid resuscitation.
  
  
  METHODS
  Patients were randomized to receive 0.25 mL/kg/hr pyridoxalated hemoglobin polyoxyethylene (20 mg Hb/kg/hr) or an equal volume of placebo, infused for up to 150 hours, in addition to conventional vasopressor therapy.
  
  
  RESULTS
  The study was stopped after interim analysis showed higher mortality in the pyridoxalated hemoglobin polyoxyethylene group and an increased prevalence of adverse events. At this time, 377 patients had been randomized to pyridoxalated hemoglobin polyoxyethylene (n = 183) or placebo (n = 194). Age, gender, type of patient (medical/surgical), and Acute Physiology and Chronic Health Evaluation II scores were similar between groups. Twenty-eight-day mortality rate was 44.3% in the pyridoxalated hemoglobin polyoxyethylene group versus 37.6% in the placebo group (OR, 1.29; 95% CI, 0.85-1.95; p = 0.227). In patients with higher organ dysfunction scores (Sepsis-related Organ Failure Assessment > 13), mortality rates were significantly higher in the pyridoxalated hemoglobin polyoxyethylene group when compared with those in placebo-treated patients (60.9% vs 39.2%; p = 0.014). Survivors who received pyridoxalated hemoglobin polyoxyethylene had a longer vasopressor-free time (21.3 vs 19.7 d; p = 0.035).
  
  
  CONCLUSIONS
  In this randomized, controlled phase III trial in patients with vasopressor-dependent distributive shock, administration of a pyridoxalated hemoglobin solution decreased the need for vasopressors but was associated with a trend to increased mortality.
authors.affiliation: 1Department of Intensive Care, Erasme Hospital, Université libre de Bruxelles, Brussels, Belgium. 2Apex Bioscience, Inc., Chapel Hill, NC. 3Bloomsbury Institute of Intensive Care Medicine, University College London, London, United Kingdom. 4CIBER Enfermedades Respiratorias, Getafe University Hospital, Universidad Europea, Madrid, Spain. 5Curacyte AG, Munich, Germany. 6Department of Anesthesiology, Intensive Care Medicine and Pain Management, HELIOS Klinikum Erfurt GmbH, Erfurt, Germany. 7Klinik fur Kardiologie, Angiologie and Konservative Intensivmedizin, Vivantes Klinikum Neukoelln, Berlin, Germany. 8Intensive Care Department, Hospital Universitari Mútua Terrassa, Terrassa, Barcelona, Spain. 9CIBER Enfermedades Respiratorias, Terrassa, Barcelona, Spain. 10Department of Intensive Care (ICU), Hospital Universitari Dr. Josep Trueta, Girona, Spain. 11Department of Intensive Care, RWTH University Hospital Aachen, Aachen, Germany.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Vincent
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Privalle
authors.forename: Mervyn
authors.initials: M
authors.lastname: Singer
authors.forename: José A
authors.initials: JA
authors.lastname: Lorente
authors.forename: Erwin
authors.initials: E
authors.lastname: Boehm
authors.forename: Andreas
authors.initials: A
authors.lastname: Meier-Hellmann
authors.forename: Harald
authors.initials: H
authors.lastname: Darius
authors.forename: Ricard
authors.initials: R
authors.lastname: Ferrer
authors.forename: Josep-Maria
authors.initials: JM
authors.lastname: Sirvent
authors.forename: Gernot
authors.initials: G
authors.lastname: Marx
authors.forename: Joseph
authors.initials: J
authors.lastname: DeAngelo
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006454:Hemoglobins / Q000627:therapeutic use*; D006801:Humans; D007902:Length of Stay / Q000706:statistics & numerical data; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000037:antagonists & inhibitors; D011092:Polyethylene Glycols / Q000627:therapeutic use*; D012121:Respiration, Artificial / Q000706:statistics & numerical data; D012769:Shock / Q000188:drug therapy* / Q000401:mortality; D016019:Survival Analysis; D055815:Young Adult
chemical_list: D006454:Hemoglobins; C050907:pyridoxalated-hemoglobin-polyethylene glycol conjugate; D009569:Nitric Oxide; D011092:Polyethylene Glycols