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ORIGINAL ARTICLES
Respiratory, Neuromuscular, and Cardiovascular Effects of Neosaxitoxin in Isoflurane-Anesthetized Sheep
  1. Matthew C. Wylie, MD*,
  2. Victor M. Johnson, MA*,
  3. Elizabeth Carpino, MA*,
  4. Kathryn Mullen, LVT†,
  5. Kimberlie Hauser, LVT†,
  6. Arthur Nedder, DVM†,
  7. John N. Kheir, MD‡,
  8. Alberto J. Rodriguez-Navarro, MD§∥,
  9. David Zurakowski, PhD* and
  10. Charles B. Berde, MD, PhD*
  1. From the *Department of Anesthesiology, Perioperative and Pain Medicine,
  2. †Animal Resources and
  3. ‡Department of Cardiology, Children’s Hospital Boston, Boston, MA;
  4. §Instituto de Ciencias Biomedicas, ICBM, Programa de Fisiología y Biofisica, Universidad de Chile; and
  5. ∥Proteus SA, Santiago, Chile.
  1. Address correspondence to: Charles B. Berde, MD, PhD, Department of Anesthesiology, Perioperative and Pain Medicine, Children’s Hospital Boston, 333 Longwood Ave, Boston, MA 02115 (e-mail: charles.berde{at}childrens.harvard.edu).

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.

http://dx.doi.org/10.1097/AAP.0b013e3182424566

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    Footnotes

    • Children’s Hospital Boston and Proteus SA are in collaboration for commercial development of NeoSTX as a prolonged-duration local anesthetic. Dr. Berde and Children’s Hospital Boston have an issued patent concerning uses of site-1 sodium-channel blockers as prolonged-duration local anesthetics. In the event of future commercial development, Dr. Berde, other colleagues, and Children’s Hospital Boston could all receive royalties. Dr. Rodriguez-Navarro holds stock options in Proteus SA and, in the event of future commercial development, could receive stock-related income and royalties.

    • Financial support was provided by grants to Dr. Berde from Children’s Hospital Boston’s Technology and Innovation Development Office and the Sara Page Mayo Endowment for Pain Research.