Introduction Results Methods References Discussion
Effects of perineural and intraneural injection of water- and lipid-soluble bupivacaine on rat sciatic nerve Jacob Benrud,
1 MD ,
1 PhD ,
Victor Ruiz-Velasco,
Kristi L. Helke DVM,
2 PhD ,
Sanjib Adhikary,
1 MD
1. Penn State Milton S. Hershey Medical Center, Department of Anesthesiology and Perioperative Medicine, Hershey, PA 17033 2. Medical University of South Carolina, Department of Comparative Medicine, Charleston, SC 29425
Introduction
Results
• EXPAREL®, bupivacaine encapsulated in a lipid-soluble DepoFoam®, was approved for clinical use in 2011 by the FDA for local infiltration or field blocks1 • EXPAREL® is currently the only single-dose local analgesic that can provide up to 72h post-operative pain relief • Lipid-soluble bupivacaine has not been approved for peripheral nerve blocks because of lack of safety information • Nerve injury from regional anesthesia ranges anywhere from 0.5 to 15%2 and is dependent upon a number of factors2-4 including: • Location of injection • Type of block • Mechanical injury • Chemical effects of the injectate • To our knowledge, till now there has only been one small study examining the effects lipid-soluble bupivacaine on the structure of peripheral nerves5 • We hypothesized that intraneural injection of lipid-soluble bupivacaine would exert greater structural damage on sciatic nerve versus its watersoluble counterpart
• There is no obvious statistical difference between or among groups • Inflammation scores were higher, regardless of the injection type, in the day 1 group of rats • More damage was evident with intra- vs. perineural injections • More damage was evident at day 21, yet less inflammation was present • More nerve damage was evident at day 21 with both lipid-soluble and water-soluble bupivacaine • In all groups, there was decreased inflammation at day 21 as trauma from the injection healed • There is less damage with lipid-soluble vs. water-soluble bupivacaine
control boiled liposomal bupivicaine
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bupivicaine liposomal lysosomalbupivacaine bupivicaine
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• Sprague Dawley rats were anesthetized using isoflurane • Rat sciatic nerves (n=108) were injected in vivo with 100µl of injectate using an intra- or perineural approach after direct visualization was obtained by surgical exposure • Rats were separated into different groups based on which injectate they received including: lipid-soluble bupivacaine, water-soluble bupivacaine, saline control, or liposomal carrier control • Rats were sacrificed at time points day 1, day 3, and day 21. For each treatment group at each time point n=12 and for each control group at each time point n=6 • After sacrifice, each sciatic nerve was dissected, fixed in formalin, and stained with hematoxylin and eosin • A section was taken from the site of injection and also proximal to and distal to the site of injection • Slides were then graded by a histopathologist who was blinded to the intervention using a validated scoring system for inflammation and neuronal damage
in
Methods
nerveScores damage Nerve Damage
Graph 1. Nerve damage scores among groups. Scores were given based on degree of cell or axon separation, myelin splitting, evidence of myelin and axonal loss.
Fig 1. Intraneural injection with water- Fig 2. Intraneural injection with lipidsoluble bupivacaine soluble bupivacaine
A
B
Fig 3A. Normal appearing nerve tissue from section of rat sciatic nerve. Fig 3B. Demonstrates severe separation of axons and abundant clear space indicative of inflammatory damage.
Discussion
• Our results did not show any statistical difference of inflammation and nerve damage between treatment groups • Inflammation was higher in the period immediately following injection but significantly improved by day 21 • Nerve damage was more evident at day 21 both with water-soluble and lipid-soluble bupivacaine but more so with the widely used water-soluble bupivacaine, although statistically insignificant • Although both forms of bupivacaine can cause nerve damage, there was no statistically significant difference between the two when used to inject rat sciatic nerves
References 1. Haas, E, Onel E, Miller H, Ragupathi M, White PF. A double-blind, randomized, activecontrolled study for post-hemorrhoidectomy pain management with liposome bupivacaine, a novel local analgesic formulation. Am Surg 2012. 78(5): 574-581. 2. Liguori GA. Complications of regional anesthesia: Nerve injury and peripheral neural blockade. J Neurosurg Anesthesiol 2004;16: 84-86. 3. Jeng CL and Rosenblatt MA. Intraneural injections and regional anesthesia: the known and the unknown. Minerva Anesthesiol 2011; 77(1): 54–58. 4. Sondekoppam, RV and Tsui, BCH. Factors Associated With Risk of Neurologic Complications After Peripheral Nerve Blocks: A Systematic Review. Anesthesia & Analgesia. 2017;124(2):645-660. 5. Damjanovska M, Cvetko E, Hadzic A, et al. Neurotoxicity of perineural vs intraneural– extrafascicular injection of liposomal bupivacaine in the porcine model of sciatic nerve block. Anaesthesia. 2015;70(12):1418-1426.
1 MD ,
1 PhD ,
Victor Ruiz-Velasco,
Kristi L. Helke DVM,
2 PhD ,
Sanjib Adhikary,
1 MD
1. Penn State Milton S. Hershey Medical Center, Department of Anesthesiology and Perioperative Medicine, Hershey, PA 17033 2. Medical University of South Carolina, Department of Comparative Medicine, Charleston, SC 29425
Introduction
Results
• EXPAREL®, bupivacaine encapsulated in a lipid-soluble DepoFoam®, was approved for clinical use in 2011 by the FDA for local infiltration or field blocks1 • EXPAREL® is currently the only single-dose local analgesic that can provide up to 72h post-operative pain relief • Lipid-soluble bupivacaine has not been approved for peripheral nerve blocks because of lack of safety information • Nerve injury from regional anesthesia ranges anywhere from 0.5 to 15%2 and is dependent upon a number of factors2-4 including: • Location of injection • Type of block • Mechanical injury • Chemical effects of the injectate • To our knowledge, till now there has only been one small study examining the effects lipid-soluble bupivacaine on the structure of peripheral nerves5 • We hypothesized that intraneural injection of lipid-soluble bupivacaine would exert greater structural damage on sciatic nerve versus its watersoluble counterpart
• There is no obvious statistical difference between or among groups • Inflammation scores were higher, regardless of the injection type, in the day 1 group of rats • More damage was evident with intra- vs. perineural injections • More damage was evident at day 21, yet less inflammation was present • More nerve damage was evident at day 21 with both lipid-soluble and water-soluble bupivacaine • In all groups, there was decreased inflammation at day 21 as trauma from the injection healed • There is less damage with lipid-soluble vs. water-soluble bupivacaine
control boiled liposomal bupivicaine
10
bupivicaine liposomal lysosomalbupivacaine bupivicaine
5
1
pe
rin
eu
ra l
d2
d2 1
ur al
3 in
tr an e
eu r
al d
3 rin pe
tr an
eu ra ld
al d eu r in
pe
rin
eu ra ld
1
0 1
cumulative damage score
15
tr an
• Sprague Dawley rats were anesthetized using isoflurane • Rat sciatic nerves (n=108) were injected in vivo with 100µl of injectate using an intra- or perineural approach after direct visualization was obtained by surgical exposure • Rats were separated into different groups based on which injectate they received including: lipid-soluble bupivacaine, water-soluble bupivacaine, saline control, or liposomal carrier control • Rats were sacrificed at time points day 1, day 3, and day 21. For each treatment group at each time point n=12 and for each control group at each time point n=6 • After sacrifice, each sciatic nerve was dissected, fixed in formalin, and stained with hematoxylin and eosin • A section was taken from the site of injection and also proximal to and distal to the site of injection • Slides were then graded by a histopathologist who was blinded to the intervention using a validated scoring system for inflammation and neuronal damage
in
Methods
nerveScores damage Nerve Damage
Graph 1. Nerve damage scores among groups. Scores were given based on degree of cell or axon separation, myelin splitting, evidence of myelin and axonal loss.
Fig 1. Intraneural injection with water- Fig 2. Intraneural injection with lipidsoluble bupivacaine soluble bupivacaine
A
B
Fig 3A. Normal appearing nerve tissue from section of rat sciatic nerve. Fig 3B. Demonstrates severe separation of axons and abundant clear space indicative of inflammatory damage.
Discussion
• Our results did not show any statistical difference of inflammation and nerve damage between treatment groups • Inflammation was higher in the period immediately following injection but significantly improved by day 21 • Nerve damage was more evident at day 21 both with water-soluble and lipid-soluble bupivacaine but more so with the widely used water-soluble bupivacaine, although statistically insignificant • Although both forms of bupivacaine can cause nerve damage, there was no statistically significant difference between the two when used to inject rat sciatic nerves
References 1. Haas, E, Onel E, Miller H, Ragupathi M, White PF. A double-blind, randomized, activecontrolled study for post-hemorrhoidectomy pain management with liposome bupivacaine, a novel local analgesic formulation. Am Surg 2012. 78(5): 574-581. 2. Liguori GA. Complications of regional anesthesia: Nerve injury and peripheral neural blockade. J Neurosurg Anesthesiol 2004;16: 84-86. 3. Jeng CL and Rosenblatt MA. Intraneural injections and regional anesthesia: the known and the unknown. Minerva Anesthesiol 2011; 77(1): 54–58. 4. Sondekoppam, RV and Tsui, BCH. Factors Associated With Risk of Neurologic Complications After Peripheral Nerve Blocks: A Systematic Review. Anesthesia & Analgesia. 2017;124(2):645-660. 5. Damjanovska M, Cvetko E, Hadzic A, et al. Neurotoxicity of perineural vs intraneural– extrafascicular injection of liposomal bupivacaine in the porcine model of sciatic nerve block. Anaesthesia. 2015;70(12):1418-1426.
