title: Respiratory, neuromuscular, and cardiovascular effects of neosaxitoxin in isoflurane-anesthetized sheep.
abstract: BACKGROUND
  Neosaxitoxin (NeoSTX) is a potent site-1 sodium-channel blocker being developed as a local anesthetic. Doses of 100 μg have been used by local infiltration in anesthetized adult humans without adverse effect. We hypothesized that similar doses could cause significant respiratory, neuromuscular, and cardiovascular impairment and sought to test this hypothesis in sheep.
  
  
  METHODS
  Procedures were approved by the Institutional Animal Care and Use Committee. In neuromuscular/respiratory experiments, 33 intubated, isoflurane-anesthetized sheep were randomized to 6 NeoSTX treatment groups: saline control, 1 μg/kg subcutaneous (SC), 1 μg/kg intravenous (IV), 2 μg/kg SC, 2 μg/kg SC with bupivacaine 0.25%, and 3 μg/kg SC. Primary outcome measures were doxapram-stimulated inspired volume (DSIV) and quantitative limb acceleration. In cardiovascular experiments, 8 sheep received escalating IV doses of NeoSTX (1, 2, and 3 μg), with hemodynamic and electrocardiographic measurements. Data were analyzed using repeated-measures analysis of variance with post hoc Bonferroni-corrected comparisons.
  
  
  RESULTS
  NeoSTX 1 μg/kg IV and SC produced no significant reduction in DSIV or limb acceleration compared with baseline. NeoSTX 2 μg/kg SC produced clinically mild reduction in twitch and DSIV; animals recovered well postoperatively. Coadministration of bupivacaine did not worsen these effects. NeoSTX 3 μg/kg produced severe and prolonged impairment of DSIV and limb acceleration. Escalating IV doses of NeoSTX produced mild decrements in heart rate, systemic arterial pressure, and systemic vascular resistance; cardiac output was maintained. Transient interventricular conduction delay occurred without cardiac arrest or ventricular ectopy.
  
  
  CONCLUSIONS
  In our sheep model, neuromuscular, respiratory, and cardiovascular effects of NeoSTX were dose dependent and mild using the dose range anticipated for clinical use.
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, Children's Hospital Boston, Boston, MA 02115, USA.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Wylie
authors.forename: Victor M
authors.initials: VM
authors.lastname: Johnson
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Carpino
authors.forename: Kathryn
authors.initials: K
authors.lastname: Mullen
authors.forename: Kimberlie
authors.initials: K
authors.lastname: Hauser
authors.forename: Arthur
authors.initials: A
authors.lastname: Nedder
authors.forename: John N
authors.initials: JN
authors.lastname: Kheir
authors.forename: Alberto J
authors.initials: AJ
authors.lastname: Rodriguez-Navarro
authors.forename: David
authors.initials: D
authors.lastname: Zurakowski
authors.forename: Charles B
authors.initials: CB
authors.lastname: Berde
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004562:Electrocardiography; D006439:Hemodynamics / Q000187:drug effects*; D007530:Isoflurane / Q000008:administration & dosage*; D053580:Muscle Strength / Q000187:drug effects*; D011897:Random Allocation; D015656:Respiratory Mechanics / Q000187:drug effects*; D012530:Saxitoxin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D012756:Sheep
chemical_list: D012530:Saxitoxin; C034902:neosaxitoxin; D007530:Isoflurane