Nevrološka ocena in nevrotoksičnost liposomalnega bupivakaina po intratekalni aplikaciji pri prašiču

Žel, Jurij (author), Stopar Pintarič, Tatjana (mentor), Seliškar, Alenka (co-mentor)

Suspenzija liposomalnega bupivakaina (Exparel, Pacira Pharmaceuticals, Inc., San Diego, CA, ZDA) je formulacija s podaljšanim sproščanjem bupivakaina, ki je odobrena za infiltracijo v mehka tkiva in interskaleni blok brahialnega pleksusa pri ljudeh, ne pa za nevraksialno uporabo. Namen te raziskave je ugotoviti nevrološke posledice in histopatološke spremembe pri naraščajočih odmerkih liposomalnega bupivakaina, apliciranega intratekalno. Petindvajsetim prašičem, težkim 36,2 ± 4,4 kg, naključno razdeljenim v pet skupin, smo intratekalno aplicirali naslednje testne učinkovine: 3 ml 0,9-% raztopine natrijevega klorida (negativna kontrola), 3 ml 0,5-% bupivakain HCl (pozitivna kontrola) ali enega od treh odmerkov 1,33-% suspenzije liposomalnega bupivakaina (1,5, 3 ali 5 ml oziroma 20, 39 ali 66 mg). Po okrevanju iz anestezije smo ocenjevali nevrološki status živali in tri tedne po aplikaciji testnih učinkovin prašiče žrtvovali. Možno nevrotoksičnost testnih učinkovin smo ocenjevali s histopatološko preiskavo hrbtenjače in hrbtenjačnih živcev ter z analizo cerebrospinalne tekočine, ki smo jo odvzeli pred aplikacijo testnih učinkovin in pred žrtvovanjem. Prašiči, ki so prejeli 0,9-% natrijev klorid, 3 ml 0,5-% bupivakain HCl ali 1,5 ml 1,33-% (20 mg) liposomalnega bupivakaina, so okrevali v 2, 5 ali 4 urah po aplikaciji. Prašiči, ki so prejeli 3 ali 5 ml 1,33-% (39 ali 66 mg) liposomalnega bupivakaina, so kazali znake nevraksialnega bloka do 32 ur po aplikaciji. Histopatološke analize niso potrdile sprememb, ki bi kazale na nevrotoksičnost, rezultati analize cerebrospinalne tekočine pa so bili nejasni. Nevraksialni blok po intratekalni aplikaciji liposomalnega bupivakaina pri prašiču je odvisen od odmerka in traja dlje kot po aplikaciji bupivakain HCl. S histopatološko preiskavo hrbtenjače in hrbtenjačnih živcev nismo opazili sprememb, ki bi kazale na nevrotoksičnost liposomalnega bupivakaina.

• Language: Slovenian
• Keywords: analgezija, živalski modeli, bupivakain – toksičnost, zdravila s podaljšanim sproščanjem – farmakologija, liposomi, spinalna injekcija – škodljivi učinki, hrbtenjača – anatomija in histologija, spinalni živci – anatomija in histologija, prašiči
• Work type: Doctoral dissertation
• Organization: VF - Veterinary Faculty
• Year: 2020
• PID: 20.500.12556/RUL-125168
• Publication date in RUL: 05.03.2021

Secondary language

• Language: English
• Title: Neurological evaluation and neurotoxicity of Liposome Bupivacaine after intrathecal injection in pig)

Abstract

Bupivacaine liposome injectable suspension (Exparel, Pacira Pharmaceuticals, Inc., San Diego, CA, USA) is an extended-release formulation of bupivacaine. It is approved for analgesia via tissue infiltration and interscalene brachial plexus in man, but not for use in neuraxial space. The aim of this study is to establish neurologic and histopathologic outcomes of escalating dosages of liposome bupivacaine suspension administered intrathecally. Twenty-five pigs, weighing 36.2 ± 4.4 kg, were randomly assigned to one of five groups to receive intrathecal injections of 3 ml 0.9% sodium chloride (negative control), 3 ml 0.5% bupivacaine hydrochloride (positive control), or one of three doses of 1.33% liposome injectable suspension: 1.5, 3 or 5 ml (20, 39 or 66 mg). After recovering from general anaesthesia, the pigs were assessed for neurological outcome study by blinded observers. Three weeks later, the animals were sacrificed for histopathologic evaluations of neurotoxicity. The samples of cerebrospinal fluid were analysed before the application of tested substances and three weeks later. Pigs that received 0.9% sodium chloride, bupivacaine hydrochloride 3 ml or 1.5 ml of 1.33% (20 mg) liposome bupivacaine recovered within 2, 5 and 4 hours, respectively. Pigs that received 3 and 5 ml of 1.33% (39 and 66 mg) liposome bupivacaine, respectively, exhibited signs of neuraxial block up to 32 hours after injection. No histopathologic evidence of neurotoxicity was found in any of the groups, results of the cerebrospinal fluid analysis were inconclusive. Intrathecal administration of liposome bupivacaine injectable suspension in pigs resulted in a dose-response pattern of longer duration of neuraxial block than bupivacaine hydrochloride without histopathologic evidence of neurotoxicity.

• Keywords: Analgesia, models, animal, bupivacain – toxicity, delayed-action preparation – pharmacology, liposomes, injections, spinal – adverse effects, spinal cord – anatomy and histology, spinal nerve – anatomy and histology, swine