title: Cardiovascular effects of the nitric oxide synthase inhibitor NG-methyl-L-arginine hydrochloride (546C88) in patients with septic shock: results of a randomized, double-blind, placebo-controlled multicenter study (study no. 144-002).
abstract: OBJECTIVE
  To assess the hemodynamic effects of the nitric oxide synthase inhibitor 546C88 in patients with septic shock, although this was not a stated aim of the protocol. The predefined primary efficacy objective of the protocol was resolution of shock determined at the end of a 72-hr treatment period.
  
  
  METHODS
  Multicentered, randomized, placebo-controlled, safety and efficacy study.
  
  
  METHODS
  Forty-eight intensive care units in Europe, North America, and Australia.
  
  
  METHODS
  A total of 312 patients with septic shock diagnosed within 24 hr before randomization.
  
  
  METHODS
  Patients were randomly allocated to receive either 546C88 or placebo (5% dextrose) by intravenous infusion for up to 72 hrs. Conventional vasoactive therapy was restricted to norepinephrine, dopamine, and dobutamine. Study drug was initiated at 0.1 mL/kg/hr (5 mg/kg/hr 546C88) and titrated according to response up to a maximum rate of 0.4 mL/kg/hr with the objective to maintain mean arterial pressure at 70 mm Hg while attempting to withdraw any concurrent vasopressor(s).
  
  
  RESULTS
  Requirement for vasopressors, systemic and pulmonary hemodynamics, indices of oxygen transport, and plasma concentrations of arginine and nitrate were assessed over time. The median mean arterial pressure for both groups was maintained > or =70 mm Hg. There was an early increase in systemic and pulmonary vascular tone and oxygen extraction, whereas both cardiac index and oxygen delivery decreased for patients in the 546C88 cohort. Although these parameters subsequently returned toward baseline values, the observed differences between the treatment groups, except for pulmonary vascular resistance and oxygen extraction, persisted throughout the treatment period, despite a reduced requirement for vasopressors in the 546C88 cohort. These changes were associated with a reduction in plasma nitrate concentrations, which were elevated in both groups before the start of therapy.
  
  
  CONCLUSIONS
  The nitric oxide synthase inhibitor 546C88 can reduce the elevated plasma nitrate concentrations observed in patients with septic shock. In this study, treatment with 546C88 for up to 72 hrs was associated with an increase in vascular tone and a reduction in both cardiac index and oxygen delivery. The successful maintenance of a target mean arterial blood pressure > or =70 mm Hg was achieved with a reduction in the requirement for, or withdrawal of, conventional inotropic vasoconstrictor agents (i.e., dopamine and norepinephrine). There were no substantive untoward consequences accompanying these hemodynamic effects. An international, randomized, double-blind, placebo-controlled phase III study has since been conducted in patients with septic shock. Recruitment into the study was discontinued due to the emergence of increased mortality in the 546C88-treated group.
authors.affiliation: Department of Intensive Care, Homerton Hospital, London, UK.
authors.forename: David
authors.initials: D
authors.lastname: Watson
authors.forename: Robert
authors.initials: R
authors.lastname: Grover
authors.forename: Antonio
authors.initials: A
authors.lastname: Anzueto
authors.forename: Jose
authors.initials: J
authors.lastname: Lorente
authors.forename: Mark
authors.initials: M
authors.lastname: Smithies
authors.forename: Rinaldo
authors.initials: R
authors.lastname: Bellomo
authors.forename: Kalpalatha
authors.initials: K
authors.lastname: Guntupalli
authors.forename: Steven
authors.initials: S
authors.lastname: Grossman
authors.forename: Jill
authors.initials: J
authors.lastname: Donaldson
authors.forename: Jean-Roger
authors.initials: JR
authors.lastname: Le Gall
mesh_terms: D000328:Adult; D000368:Aged; D002302:Cardiac Output / Q000187:drug effects; D002319:Cardiovascular System / Q000187:drug effects*; D003422:Critical Care; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007362:Intensive Care Units; D008297:Male; D008875:Middle Aged; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D011336:Probability; D011652:Pulmonary Circulation / Q000187:drug effects; D012016:Reference Values; D018570:Risk Assessment; D012720:Severity of Illness Index; D012772:Shock, Septic / Q000188:drug therapy* / Q000382:microbiology* / Q000401:mortality; D016019:Survival Analysis; D016896:Treatment Outcome; D014662:Vasoconstrictor Agents / Q000008:administration & dosage*; D019323:omega-N-Methylarginine / Q000008:administration & dosage*
chemical_list: D014662:Vasoconstrictor Agents; D019323:omega-N-Methylarginine; D019001:Nitric Oxide Synthase