title: Combination of intravenously infused methylene blue and inhaled nitric oxide ameliorates endotoxin-induced lung injury in awake sheep.
abstract: OBJECTIVE
  To evaluate the effects of a combination of methylene blue, an inhibitor of the nitric oxide pathway, and inhaled nitric oxide on endotoxin-induced acute lung injury in awake sheep.
  
  
  METHODS
  Prospective, randomized, controlled experimental study.
  
  
  METHODS
  University animal laboratory.
  
  
  METHODS
  Twenty-four yearling, awake sheep.
  
  
  METHODS
  The sheep were anesthetized and instrumented with vascular catheters. After 1 wk of recovery, the animals underwent tracheotomy and were subjected to intravenous infusions of endotoxin 10 ng x kg-1 x min-1 and isotonic saline 3 mL x kg-1 x hr-1 for 8 hrs. The sheep were randomly assigned to three groups of eight animals each: a) the control group received endotoxin and saline; b) the INO group received endotoxin, saline, and inhaled nitric oxide 40 ppm for 5 hrs; and c) the MB/INO group received endotoxin, saline, and methylene blue 3 mg/kg as an intravenous bolus injection followed by a continuous infusion of 3 mg x kg-1 x min-1 for 6 hrs in combination with inhaled nitric oxide 40 ppm for 5 hrs.
  
  
  RESULTS
  Hemodynamic variables and blood gases were determined hourly. In the early phase of endotoxemia (0-2 hrs), methylene blue/inhaled nitric oxide reduced the increments in pulmonary arterial pressure, pulmonary microvascular pressure, and pulmonary vascular resistance index by 60% compared with the controls and to a greater extent than did inhaled nitric oxide alone. During the late phase, all the preceding variables returned closely to baseline following inhaled nitric oxide or methylene blue/inhaled nitric oxide but remained remarkably elevated in the control group. Inhaled nitric oxide and methylene blue/inhaled nitric oxide reduced the increase in extravascular lung water by 40% and 80%, respectively. Inhaled nitric oxide transiently attenuated the increase in venous admixture and did not prevent a decrease in arterial oxygenation. In the methylene blue/inhaled nitric oxide group, blood gases remained unchanged from baseline.
  
  
  CONCLUSIONS
  In sheep, methylene blue/inhaled nitric oxide protects more efficiently against acute lung injury than inhaled nitric oxide alone, as indicated by a milder pulmonary hypertension, less extravascular lung water accumulation, and maintained gas exchange.
authors.affiliation: Department of Anesthesiology, Faculty of Medicine, University of Tromsø, Norway.
authors.forename: Mikhail Y
authors.initials: MY
authors.lastname: Kirov
authors.forename: Oleg V
authors.initials: OV
authors.lastname: Evgenov
authors.forename: Lars J
authors.initials: LJ
authors.lastname: Bjertnaes
mesh_terms: D000280:Administration, Inhalation; D000704:Analysis of Variance; D000818:Animals; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D015633:Extravascular Lung Water / Q000187:drug effects; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D007262:Infusions, Intravenous; D008751:Methylene Blue / Q000494:pharmacology / Q000627:therapeutic use*; D009569:Nitric Oxide / Q000494:pharmacology / Q000627:therapeutic use*; D011652:Pulmonary Circulation / Q000187:drug effects; D011897:Random Allocation; D012128:Respiratory Distress Syndrome / Q000188:drug therapy*; D012756:Sheep; D014665:Vasodilator Agents / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D004791:Enzyme Inhibitors; D014665:Vasodilator Agents; D009569:Nitric Oxide; D008751:Methylene Blue