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.

Evaluation of oscillometric blood pressure monitor BLT M9000 VET in anaesthetised healthy adult dogs.

To examine agreement in anaesthetised dogs between invasive blood pressure measurements and measurements obtained with an oscillometric blood pressure monitor. MATERIALS AND METHODS: Paired invasive and oscillometric measurements were taken in 24 dogs every 5 minutes during anaesthesia (9 to 37 measurements per dog). Agreement between measurement methods was explored using Bland-Altman plots. To determine the accuracy of the oscillometric measurements, the results were compared with the guidelines recommended by the American College of Veterinary Internal Medicine and the Association for the Advancement of Medical Instrumentation. RESULTS: In total, 493 paired readings were obtained: 98·6% of oscillometric readings were successful. Biases (±standard deviation) for oscillometric readings of systolic arterial blood pressure and mean arterial blood pressure were 2·1 (±11·5) and -9·8 (±7·6) mm Hg, indicating slight over- and under-estimation, respectively, versus invasive measurements. More than 50% and 80% of systolic arterial and mean arterial pressure measurements were within 10 and 20 mmHg of invasively measured values, respectively. A large negative bias (-14·1 ±9·2 mmHg) against invasive measurements revealed that the oscillometric measures of diastolic arterial blood pressure measurements were under-estimated. CLINICAL SIGNIFICANCE: In healthy adult anaesthetised dogs, this oscillometric monitor met the American College of Veterinary Internal Medicine requirements for systolic arterial and mean arterial pressure measurement but failed to meet the requirements for the measurement of diastolic arterial pressure.

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.

Total intravenous anaesthesia with propofol or propofol/ketamine in spontaneously breathing dogs premedicated with medetomidine.

The cardiorespiratory parameters, the depth of anaesthesia and the quality of recovery were evaluated in six spontaneously breathing dogs that had been premedicated with medetomidine (40 microg/kg, supplemented with 20 microg/kg an hour later), administered with either propofol (1 mg/kg followed by 0.15 mg/kg/minute, intravenously), or with ketamine (1 mg/kg followed by 2 mg/kg/hour, intravenously) and propofol (0.5 mg/kg followed by 0.075 mg/kg/minute, intravenously). The dogs' heart rate and mean arterial blood pressure were higher and their minute volume of respiration and temperature were lower when they were anaesthetised with propofol plus ketamine, and a progressive hypercapnia leading to respiratory acidosis was more pronounced. When the dogs were anaesthetised with propofol/ketamine they recovered more quickly, but suffered some unwanted side effects. When the dogs were anaesthetised with propofol alone they recovered more slowly but uneventfully.

Selective recording of neuroelectric activity from the peripheral nerve.

Electroneurograms (ENGs) from superficial regions of the sciatic nerve of a dog, innervating the tibialis anterior (TA) and gastrocnemius muscles (GM), arising mainly from muscle spindles and Golgi tendon organs were recorded selectively with an implanted 33-electrode spiral cuff (cuff). Relative positions of superficial regions within the cuff were defined by delivering stimulating pulses on groups of three electrodes (GTEs) within the cuff which were in contact with them. It was found that GTEs eliciting maximum contractions of muscles were GTE No. 3 for the TA muscle and GTE No. 8 for the GM muscle. In the first experiment the implanted leg was mounted into a special electronic brace. Extending forces were applied to the ankle rotating it by up to +/-37 degrees according to the neutral position, thus eliciting torques in the TA muscle of up to 1.2 Nm. Channel 1 of the 4-channel preamplifier was connected to GTE No. 8, channel 2 to GTE No. 2, channel 3 to GTE No. 11 and channel 4 to GTE No. 5. Results show that only ENG recorded with GTE No. 8, being close to the region innervating the TA muscle, correspond to the mechanical load. In the second experiment the calcanean tendon (CT) of an implanted leg was dissected. The proximal end of the CT was connected to a force transducer and repetitive pull forces (about 12 N) were applied to the CT. Channel 1 of the preamplifier was connected to GTE No. 5, channel 2 to GTE No. 1, channel 3 to the GTE No. 11 and channel 4 to GTE No. 8. Results show that only ENG recorded with GTE No. 5, being close to the region innervating the GM muscle, correspond to the mechanical load applied on CT.

Regeneration of the radial nerve in a dog influenced by electrical stimulation.

The effect of biphasic electric fields on nerve regeneration that follows injury to the left radial nerve of a dog was examined using electromyography (EMG). The left and right radial nerves were crushed with a serrated hemostat and the stimulating electrodes were positioned proximally and distally relative to the site of the injury. The left nerves received rectangular, biphasic current pulses (30 microA, 0.5 Hz) through the lesion for two months. The right radial nerves were treated as controls and regenerated without electrical stimulation. EMG activity was recorded intramuscularly from left and right musculus extensor digitorum (from Medical dictionary) communis (MEDC). Results obtained at the end of the two-month stimulation period showed a significant difference between the EMG activity of the stimulated and the unstimulated MEDC suggesting that the electrical treatment enhanced the nerve regeneration.

Regeneration of the radial nerve in a dog influenced by electrical stimulation.

The effect of biphasic electric fields on nerve regeneration that follows injury to the left radial nerve of a dog was examined using electromyography (EMG). The left and right radial nerves were crushed with a serrated hemostat and the stimulating electrodes were positioned proximally and distally relative to the site of the injury. The left nerves received rectangular, biphasic current pulses (30µA, 0.5Hz) through the lesion for two months. The right radial nerves were treated as controls and regenerated without electrical stimulation. EMG activity was recorded intramuscularly from left and right musculus extensor digitorum (from Medical dictionary) communis (MEDC). Results obtained at the end of the two-month stimulation period showed a significant difference between the EMG activity of the stimulated and the unstimulated MEDC suggesting that the electrical treatment enhanced the nerve regeneration.

Influence of electrical stimulation on regeneration of the radial nerve in dogs.

The effects of biphasic electric fields on nerve regeneration that follows injury to the left radial nerve were studied in dogs by electromyography (EMG). Left and right radial nerves were crushed with a serrated haemostat. Stimulating electrodes were positioned proximally and distally to the site of the injury. The left nerves received rectangular, biphasic and current pulses (30 microA, 0.5 Hz) through the injury for two months. The right radial nerves were treated as controls and regenerated without electrical stimulation. EMG activities were recorded intramuscularly from the left and right musculus extensor digitalis communis (MEDC). Results obtained at the end of the two-month stimulation period showed a significant difference in EMG activity between the left (stimulated) and the right (non-stimulated) MEDC, suggesting that electrical treatment enhanced nerve regeneration.