Local anesthesia enhanced with increasing high-frequency ultrasound intensity
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ORIGINAL ARTICLE
Local anesthesia enhanced with increasing high-frequency ultrasound intensity Kathleen Cullion 1,2 & Laura C. Petishnok 1,2 & Tao Sun 3 & Claudia M. Santamaria 1 & Grant L. Pemberton 1 & Nathan J. McDannold 3 & Daniel S. Kohane 1,4
# Controlled Release Society 2020
Abstract The effect of local anesthetics, particularly those which are hydrophilic, such as tetrodotoxin, is impeded by tissue barriers that restrict access to individual nerve cells. Methods of enhancing penetration of tetrodotoxin into nerve include co-administration with chemical permeation enhancers, nanoencapsulation, and insonation with very low acoustic intensity ultrasound and microbubbles. In this study, we examined the effect of acoustic intensity on nerve block by tetrodotoxin and compared it to the effect on nerve block by bupivacaine, a more hydrophobic local anesthetic. Anesthetics were applied in peripheral nerve blockade in adult Sprague-Dawley rats. Insonation with 1-MHz ultrasound at acoustic intensity greater than 0.5 W/cm2 improved nerve block effectiveness, increased nerve block reliability, and prolonged both sensory and motor nerve blockade mediated by the hydrophilic ultra-potent local anesthetic, tetrodotoxin. These effects were not enhanced by microbubbles. There was minimal or no tissue injury from ultrasound treatment. Insonation did not enhance nerve block from bupivacaine. Using an in vivo model system of local anesthetic delivery, we studied the effect of acoustic intensity on insonation-mediated drug delivery of local anesthetics to the peripheral nerve. We found that insonation alone (at intensities greater than 0.5 W/cm2) enhanced nerve blockade mediated by the hydrophilic ultra-potent local anesthetic, tetrodotoxin. Keywords Drug delivery . Insonation . Peripheral nerve . Tetrodotoxin . Acoustic intensity Abbreviations TTX Tetrodotoxin S1SCB Site-one sodium channel blocker PBS Phosphate-buffered saline CPE Chemical permeation enhancer Electronic supplementary material The online version of this article (https://doi.org/10.1007/s13346-020-00760-1) contains supplementary material, which is available to authorized users. * Daniel S. Kohane [email protected] 1
Laboratory for Biomaterials and Drug Delivery, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
2
Department of Medical Critical Care, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
3
Focused Ultrasound Laboratory, Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
4
Department of Anesthesiology, Critical Care, and Pain Management, Boston Children’s Hospital, Harvard Medical School, 300 Longwood Ave, Enders Building, Room 361, Boston, MA 02115, USA
Introduction Administration of anesthetics locally to peripheral nerves (i.e., peripheral nerve blocks) can be an effective adjunct to perioperative pain management and can significantly reduce the use of systemic therapies, such as opioids [1]. The effect of local anesthetics on the function of
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