title: Methylene blue and epinephrine: a synergetic association for anaphylactic shock treatment.
abstract: BACKGROUND
  Severe hypotension resulting from anaphylactic shock may be refractory to epinephrine and impair cerebral oxygenation and metabolism contributing to anaphylactic shock morbidity and mortality. Refractoriness to epinephrine could be corrected by nitric oxide pathway inhibitors such as methylene blue.
  
  
  OBJECTIVE
  To compare the systemic and regional (brain and skeletal muscle) effects of epinephrine and methylene blue given alone or in combination in a rat model of anaphylactic shock.
  
  
  METHODS
  Prospective laboratory study.
  
  
  METHODS
  University laboratory.
  
  
  METHODS
  Male Brown-Norway rats (n = 60).
  
  
  METHODS
  After sensitization and induction of anaphylactic shock by ovalbumin, animals received either vehicle (ovalbumin group) or a 3-mg/kg methylene blue bolus (methylene blue group) or epinephrine (epinephrine group) or both (methylene blue-epinephrine group). Sensitized control rats received only vehicle and no ovalbumin (control group).
  
  
  RESULTS
  Mean arterial pressure, cardiac output, cerebral blood flow, skeletal muscular oxygen partial pressure, cerebral oxygen partial pressure, skeletal muscular, and cerebral interstitial lactate/pyruvate ratio were measured. Cleaved caspase 3 and hypoxia-inducible factor-1α expression were analyzed in the cerebral cortex by Western blot. Without treatment, rats died rapidly within 15 mins from a decrease in cardiac output and mean arterial pressure, whereas treated rats survived until the end of the experiment. Methylene blue alone extended survival time but without significant improvement of hemodynamic variables and tissue perfusion and did not prevent neuronal injury. Epinephrine restored partially systemic hemodynamic variables and cerebral perfusion preventing glutamate-induced excitotoxicity. Compared with epinephrine alone, the methylene blue-epinephrine association avoided neuronal excitotoxicity and had an additive effect both on hemodynamic variables and for prevention of brain ischemia. Neither treatment could significantly restore cardiac output or prevent muscular compartment ischemia and microvascular leakage.
  
  
  CONCLUSIONS
  Anaphylactic shock is associated with severe impairment of cerebral blood flow despite correction of arterial hypotension. Epinephrine must still be considered as the first-line vasoconstrictive agent to treat anaphylactic shock. The epinephrine-methylene blue association was the most effective treatment to prevent cerebral ischemia and could be used in anaphylactic shock refractory to epinephrine.
authors.affiliation: Groupe Choc, Contrat AVENIR INSERM U 961, Faculté de Médecine, Nancy Université, Nancy, France.
authors.forename: Feng
authors.initials: F
authors.lastname: Zheng
authors.forename: Grégoire
authors.initials: G
authors.lastname: Barthel
authors.forename: Olivier
authors.initials: O
authors.lastname: Collange
authors.forename: Chantal
authors.initials: C
authors.lastname: Montémont
authors.forename: Simon N
authors.initials: SN
authors.lastname: Thornton
authors.forename: Dan
authors.initials: D
authors.lastname: Longrois
authors.forename: Bruno
authors.initials: B
authors.lastname: Levy
authors.forename: Gérard
authors.initials: G
authors.lastname: Audibert
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Malinovsky
authors.forename: Paul-Michel
authors.initials: PM
authors.lastname: Mertes
mesh_terms: D000707:Anaphylaxis / Q000150:complications / Q000188:drug therapy*; D000818:Animals; D002545:Brain Ischemia / Q000517:prevention & control*; D002199:Capillary Permeability / Q000187:drug effects; D002560:Cerebrovascular Circulation / Q000187:drug effects; D003161:Compartment Syndromes / Q000517:prevention & control; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D004837:Epinephrine / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008751:Methylene Blue / Q000494:pharmacology / Q000627:therapeutic use*; D018482:Muscle, Skeletal / Q000098:blood supply / Q000187:drug effects; D009569:Nitric Oxide / Q000037:antagonists & inhibitors*; D011446:Prospective Studies; D051381:Rats; D011914:Rats, Inbred BN; D014662:Vasoconstrictor Agents / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D004791:Enzyme Inhibitors; D014662:Vasoconstrictor Agents; D009569:Nitric Oxide; D008751:Methylene Blue; D004837:Epinephrine