Neurological and histological outcomes after subarachnoid injection of a liposomal bupivacaine suspension in pigs: a pilot study.

BACKGROUND: An injectable liposomal bupivacaine suspension (EXPAREL™) is approved by the US Food and Drug Administration for analgesia by tissue infiltration and interscalene brachial plexus, but not for use in the neuraxial space. This pilot study describes neurological and histological outcomes of escalating doses of this extended-release formulation of bupivacaine after subarachnoid administration. METHODS: Twenty-five pigs (Sus scrofa domesticus) weighing 36.2 (4.4) kg were randomly assigned to one of five groups to receive a subarachnoid injection of sodium chloride 0.9%, 3 ml (negative control), preservative-free bupivacaine hydrochloride 0.5%, 3 ml (positive control), or one of three doses of liposomal bupivacaine suspension 1.33%: 1.5, 3, or 5 ml. After recovering from general anaesthesia, neurological outcomes were assessed by blinded observers. Three weeks later, the animals were sacrificed for histological evaluations of neurotoxicity. RESULTS: Animals that received sodium chloride 0.9%, bupivacaine hydrochloride, or liposomal bupivacaine 1.5 ml recovered within 2, 5, or 4 h, respectively. Animals that received liposomal bupivacaine 3 or 5 ml exhibited signs of neuraxial block (decreased nociception and proprioception) up to 32 h after injection. No histological evidence of neurotoxicity was found in any of the groups. CONCLUSIONS: Subarachnoid administration of liposomal bupivacaine in pigs exhibited a dose-response effect, and resulted in longer duration of neuraxial block than bupivacaine hydrochloride without histological evidence of neurotoxicity. Our study contributes preliminary data to inform further toxicological assessments and regulatory approval before subarachnoid administration in humans.

Neurotoxicity of perineural vs intraneural-extrafascicular injection of liposomal bupivacaine in the porcine model of sciatic nerve block.

Liposomal bupivacaine is a prolonged-release local anaesthetic, the neurotoxicity of which has not yet been determined. We used quantitative histomorphometric and immunohistochemical analyses to evaluate the neurotoxic effect of liposomal bupivacaine after perineural and intraneural (extrafascicular) injection of the sciatic nerve in pigs. In this double-blind prospective randomised trial, 4 ml liposomal bupivacaine 1.3% was injected either perineurally (n = 5) or intraneurally extrafascicularly (n = 5). Intraneural-extrafascicular injection of saline (n = 5) was used as a control. After emergence from anaesthesia, neurological examinations were conducted over two weeks. After harvesting the sciatic nerves, no changes in nerve fibre density or myelin width indicative of nerve injury were observed in any of the groups. Intraneural injections resulted in longer sensory blockade than perineural (p < 0.003) without persistent motor or sensory deficit. Sciatic nerve block with liposomal bupivacaine in pigs did not result in histological evidence of nerve injury.

The utility of three-dimensional optical projection tomography in nerve injection injury imaging.

The examination of nerve microarchitecture has hitherto been limited solely to two-dimensional imaging techniques. The objective of this study was to evaluate the ability of optical projection tomography to discern the nerve microarchitecture and injection injury in three dimensions. Five piglets were studied, whose median and lingual nerves were unilaterally injected post mortem with preset volumes of local anaesthetic, excised and subsequently made transparent with benzyl alcohol benzyl benzoate. Images were captured in three dimensions. The same contralateral nerves were used as controls. Using optical projection tomography, we observed differences between the internal organisation of the median and the lingual nerves, which potentially explain the variations in their susceptibility to injury. This was demonstrated in three dimensions as a disruption to the fascicles in the lingual nerve, and their displacement in the median nerve. This new technology offers potential for studying nerve microarchitecture topography and its tolerance to injection injury.