Effect of dexmedetomidine on Nociception Level Index-guided remifentanil antinociception: A randomised controlled trial.

BACKGROUND: The effect of dexmedetomidine on Nociception Level Index-guided (Medasense, Israel) antinociception to reduce intra-operative opioid requirements has not been previously investigated. OBJECTIVE: We aimed to determine if low-dose dexmedetomidine would reduce remifentanil requirements during Nociception Level Index-guided antinociception without increasing complications associated with dexmedetomidine. DESIGN: Double-blind randomised controlled trial. SETTING: Two university teaching hospitals in Brussels, Belgium. PATIENTS: American Society of Anesthesiologists 1 and 2 patients (n = 58) undergoing maxillofacial or cervicofacial surgery under propofol--remifentanil target-controlled infusion anaesthesia. INTERVENTIONS: A 30 min infusion of dexmedetomidine, or equal volume of 0.9% NaCl, was infused at 1.2 µg kg-1 h-1 immediately preceding induction and then decreased to 0.6 µg kg-1 h-1 until 30 min before ending surgery. Nociception Level Index and frontal electroencephalogram guided the remifentanil and propofol infusions, respectively. MAIN OUTCOMES: The primary outcome was the remifentanil requirement. Other outcomes included the propofol requirement, cardiovascular status and postoperative outcome. RESULTS: Mean ±â€ŠSD remifentanil (3.96 ±â€Š1.95 vs. 4.42 ±â€Š2.04 ng ml-1; P = 0.0024) and propofol (2.78 ±â€Š1.36 vs. 3.06 ±â€Š1.29 µg ml-1; P = 0.0046) TCI effect site concentrations were lower in the dexmedetomidine group at 30 min postincision and remained lower throughout surgery. When remifentanil (0.133 ±â€Š0.085 vs. 0.198 ±â€Š0.086 µg kg-1 min-1; P = 0.0074) and propofol (5.7 ±â€Š2.72 vs. 7.4 ±â€Š2.80 mg kg-1 h-1; P = 0.0228) requirements are represented as infusion rates, this effect became statistically significant at 2 h postincision. CONCLUSION: In ASA 1 and 2 patients receiving Nociception Level Index-guided antinociception, dexmedetomidine decreases intra-operative remifentanil requirements. Combined frontal electroencephalogram and Nociception Level Index monitoring can measure dexmedetomidine's hypnotic and opioid-sparing effects during remifentanil-propofol target-controlled infusion anaesthesia. TRIAL REGISTRATIONS: Clinicaltrials.gov: NCT03912740, EudraCT: 2018-004512-22.

European Society of Anaesthesiology and Intensive Care Guidelines on peri-operative use of ultrasound for regional anaesthesia (PERSEUS regional anesthesia): Peripheral nerves blocks and neuraxial anaesthesia.

Nowadays, ultrasound-guidance is commonly used in regional anaesthesia (USGRA) and to locate the spinal anatomy in neuraxial analgesia. The aim of this second guideline on the PERi-operative uSE of UltraSound (PERSEUS-RA) is to provide evidence as to which areas of regional anaesthesia the use of ultrasound guidance should be considered a gold standard or beneficial to the patient. The PERSEUS Taskforce members were asked to define relevant outcomes and rank the relative importance of outcomes following the GRADE process. Whenever the literature was not able to provide enough evidence, we decided to use the RAND method with a modified Delphi process. Whenever compared with alternative techniques, the use of USGRA is considered well tolerated and effective for some nerve blocks but there are certain areas, such as truncal blocks, where a lack of robust data precludes useful comparison. The new frontiers for further research are represented by the application of USG during epidural analgesia or spinal anaesthesia as, in these cases, the evidence for the value of the use of ultrasound is limited to the preprocedure identification of the anatomy, providing the operator with a better idea of the depth and angle of the epidural or spinal space. USGRA can be considered an essential part of the curriculum of the anaesthesiologist with a defined training and certification path. Our recommendations will require considerable changes to some training programmes, and it will be necessary for these to be phased in before compliance becomes mandatory.

European Society of Anaesthesiology guidelines on peri-operative use of ultrasound-guided for vascular access (PERSEUS vascular access).

: Ultrasound for diagnostic and procedural purposes is becoming a standard in daily clinical practice including anaesthesiology and peri-operative medicine. The project of European Society of Anaesthesiology (ESA) Task Force for the development of clinical guidelines on the PERioperative uSE of Ultra-Sound (PERSEUS) project has focused on the use of ultrasound in two areas that account for the majority of procedures performed routinely in the operating room: vascular access and regional anaesthesia. Given the extensive literature available in these two areas, this paper will focus on the use of ultrasound-guidance for vascular access. A second part will be dedicated to peripheral nerve/neuraxial blocks. The Taskforce identified three main domains of application in ultrasound-guided vascular cannulation: adults, children and training. The literature search were performed by a professional librarian from the Cochrane Anaesthesia and Critical and Emergency Care Group in collaboration with the ESA Taskforce. The Grading of Recommendation Assessment (GRADE) system for assessing levels of evidence and grade of recommendations were used. For the use of ultrasound-guided cannulation of the internal jugular vein, femoral vein and arterial access, the level evidence was classified 1B. For other accesses, the evidence remains limited. For training in ultrasound guidance, there were no studies. The importance of proper training for achieving competency and full proficiency before performing any ultrasound-guided vascular procedure must be emphasised.

Opioid-free anesthesia: a different regard to anesthesia practice.

PURPOSE OF REVIEW: In the past two decades, opioids have been prescribed increasingly for the treatment of various chronic pain conditions and during the perioperative period. Perioperative opioid administration is associated with well known adverse effects and recently to long-term use and poor surgical outcomes. In this context, the anesthesiologists have to face their responsibilities. The review discusses the neurophysiological basis of opioid-free anesthesia (OFA), the rational supporting its use in perioperative medicine as well as barriers and future challenges in the field. RECENT FINDINGS: OFA has gained in popularity as a way to enhance early recovery and to spare opioids for the postoperative period. Whether it is possible to deliver safe and stable anesthesia without intraoperative opioids to many patients undergoing various surgical procedures, OFA still raises questions. Accurate monitoring to measure intraoperative nociception and guide the use of adjuvants are not available. There is a need for the development of procedure-specific strategies as well as indications and contraindications to the technique. Finally, objective assessment of OFA use on patient outcomes should be recorded in large multicenter studies. SUMMARY: OFA stands as a new paradigm, which questions anesthesiology practice and might help to rationalize perioperative opioids use.

The nerve: A fragile balance between physiology and pathophysiology.

Regarding nerves as simple cables and electrical conduits is a gross error that does not allow us to understand the anomalies and disorders observed postoperatively. Instead, nerves should be seen as a living tissue of which physiological regulation is as complex as that of the blood-brain barrier. This review describes the basic structure and functions of this blood-nerve barrier and highlights the mechanisms of its breakdown and the resultant disorders. For clinical practice, it is important to note that the diffusion of molecules from the perineurium or from the blood is very limited, and so the blood-nerve barrier is a major pharmacologic barrier. Any stress upon neural physiological balance, particularly the terminal vascular blood supply, will induce the classic inflammatory cascade. Due to the complexity of the vascular system, nerve ischaemia will occur more quickly when the terminal blood supply is compromised. This blood supply can adapt in a variety of ways but when these possibilities of adaptation are exceeded, tissue ischaemia may be more extensive. Also, even after the initial injury has subsided, inflammation can cause a secondary insult. This could be particularly important in some patients with subclinical neuropathy.

The pneumatic tourniquet: mechanical, ischaemia-reperfusion and systemic effects.

The pneumatic tourniquet is frequently used for upper and lower limb surgery to reduce bleeding, improve visualisation of important structures and expedite surgical procedures. Despite advances in technology, localised tissue damage secondary to cuff compression, ischaemia-reperfusion injuries and systemic complications still occur. The combination of these problems may affect outcome and contribute to prolonged hospitalisation. Use of the correct pneumatic tourniquet cuff size and a patient-specific cuff pressure with careful control of the duration of inflation may help reduce the incidence of these injuries. The efficacy of ischaemic preconditioning or postconditioning, and experimental treatments such as free radical scavenging, and use of nitric oxide synthetase inhibitors on endothelial dysfunction, systemic neutrophil activation and coagulation reactions needs to be established.

Lessons from the Analysis of a Retrospective Cohort of Patients Who Underwent Large Open Abdominal Surgery Under Total Intravenous Opioid-Free Anesthesia.

BACKGROUND: Opioid-free anesthesia (OFA) is a new method of anesthesia based on a paradigm shift. Under general anesthesia, the physiology and/or the pathophysiological variations clinically observed are more a reflection of a systemic reaction to the stress (surgical and anesthesia stresses) than a true reflection of pain. OBJECTIVE: To report the results of a large monocenter, retrospective, non-interventional observational study of all consecutive patients who received a total intravenous (IV)-OFA protocol for the surgical management of major open abdominal and urological surgery. PATIENTS AND METHODS: We retrospectively extracted the anesthesia files of 311 consecutive patients (regional anesthesia excluded). No opioids were administered to any of these patients during the surgery. IV morphine administered in the recovery room was the primary endpoint of the study. The secondary endpoints included the amount of opioid required during the first two postoperative days, as well as the maximum pain intensity. RESULTS: Only very small doses of IV morphine were administered. The mean total morphine titration was 2 mg (1.9 ± 2.9 mg), corresponding to control of the maximal level of pain to 2.1 ± 2.6 as evaluated with a numerical scale in the postoperative care unit. Similarly, we observed a very low level of morphine consumption during the first two postoperative days. CONCLUSIONS: These results highlight the safety and the feasibility of our total IV-OFA protocol, thus confirming this new paradigm. Under general anesthesia, the cardiovascular and inflammatory response to the stress could be reliably managed through a multimodal approach without a need for opioids. In the postoperative period, very low doses of opioids were required.

Effects of a bupivacaine nerve block on the axonal transport of Tumor Necrosis Factor-alpha (TNF-alpha) in a rat model of carrageenan-induced inflammation.

Many pro-inflammatory cytokines are involved in the process of inflammatory pain. Bi directional axonal transport of Tumor Necrosis Factor-alpha (TNF-alpha) occurs in case of neuropathic pain induced by nerve ligation. We used an in vivo preparation with injection of carrageenan and fluorescent TNF-alpha in the territory of the saphenous nerve of rats to study this transport. We have shown that retrograde transport of TNF-alpha occurs after an inflammatory insult caused by the injection of carrageenan. This transport was likely mediated by the TNF receptor 1. A nerve block with bupivacaine totally abolishes the expression of the receptor in the dorsal root ganglion and the retrograde transport of TNF-alpha. In addition, bupivacaine at low concentrations (1-10 microM) was able to stop the axonal transport ex vivo. Tetrodotoxin was less efficacious for inhibiting the TNF-alpha transport and the rise in receptor expression and for inhibiting the axonal transport ex vivo. This may partly explain the efficacy of nerve blocks with bupivacaine to decrease the neurogenic inflammation and in a lower extent the long-term inhibition of hyperalgesic phenomenon observed in animals and in humans.

[Guiding opioid-free intravenous antinociception with the Analgesia Nociception Index: a case report]. / Antinocicepção intravenosa sem opioides orientada pelo Índice de Analgesia/Nocicepção: relato de caso.

BACKGROUND: Opioid-free anesthesia decreases the incidence of opioid adverse events, but its optimal antinociceptive depth has not been clearly defined. Personalizing intraoperative opioid-free infusions with a nociception monitor may be the solution. CASE REPORT: We describe the feasibility and potential limitations of titrating opioid-free antinociception during major abdominal surgery using the Analgesia Nociception Index (Mdoloris, Lille, France) in an obese patient. After stabilizing the patient's nociception-antinociception balance intraoperatively we quickly reversed anesthesia and the patient did not require postoperative opioids. CONCLUSION: Personalizing opioid-free antinociception with a nociception monitor is feasible. It may optimize intraoperative antinociception and improve postoperative comfort.

Outpatient Robot-assisted Radical Prostatectomy: A Feasibility Study.

OBJECTIVE: To evaluate the feasibility of routine outpatient management after robotic-assisted radical prostatectomy (RARP). Prostate cancer is indeed the second most common cancer in men. Surgical technics have evolved from open surgery to robot-assisted surgery with a reduction of postoperative complications. Such technical improvements associated with modern anesthesia allow outpatient surgery in various types of procedures. MATERIAL AND METHODS: After approval of the IRB, this observational prospective and monocentric study was performed in the urology unit at Rennes University Hospital between December 2015 and October 2017. All patients scheduled for RARP performed by one experienced surgeon were consecutively included. The possibility of discharge was evaluated using the Post Anesthesia Discharge Scoring System (PADSS) score until patients had a score of 9 or higher allowing their discharge. Risk factors of delayed discharge were secondarily assessed RESULTS: Ninety-seven patients scheduled for RARP performed by one experienced surgeon were consecutively included. Only 1 patient had a PADSS score ≥ 9 the day of the surgery (day 0). Seventy-four percent of the patients achieved discharge criteria 1 day after surgery whereas, 33% and 66% of the population was effectively discharged on day 2 and day 3, respectively. Patients with a PADSS score ≥ 9 at day 1 experienced significantly less postoperative nausea and vomiting than patients with a PADSS score ≥ 9 at day 2 or 3 (7% vs 28%, P = .01). CONCLUSION: Outpatient RARP was not feasible in most patients. However, routine discharge at day 1 seems conceivable. Improving the management of postoperative nausea and vomiting may even allow outpatient management. This progress remains to be confirmed by further studies.

Preparation, characterization and in vitro evaluation of 50% enantiomeric excess bupivacaine (S75-R25)-loaded microspheres.

BACKGROUND AND OBJECTIVES: Microspheres can be used as a controlled delivery system to prolong the duration of action of local anesthetics. The objective of this study was the preparation, characterization and analysis of the in vitro release of 50% enantiomeric excess bupivacaine (S75-R25)-loaded microspheres. METHODS: Microspheres were prepared using the copolymer of polylactide-co-glycolic acid by the spray-dryed method. RESULTS: Characterization of microspheres regarding their size and content were similar to the theoretical values. The in vitro release demonstrated a biphasic pattern. CONCLUSIONS: Manufacturing of 50% enantiomeric excess bupivacaine-loaded microspheres by the spray-dryed method with results similar to bupivacaine-loaded microspheres can be done.

Epidural, intrathecal pharmacokinetics, and intrathecal bioavailability of ropivacaine.

BACKGROUND: Ropivacaine is used by the epidural route for postoperative pain management with various neuraxial techniques. Given the widespread use of these techniques and the relative paucity of data on spinal disposition of local anesthetics, we evaluated through an experimental animal model, the spinal disposition of ropivacaine, allowing further studies of factors influencing their intrathecal bioavailability. METHODS: Sheep received an IV bolus dose of ropivacaine (50 mg), and 1 wk after, an intrathecal dose of ropivacaine (20 mg) followed 3 h later by epidural ropivacaine (100 mg). A simultaneous microdialysis technique was used to measure epidural and intrathecal drug concentrations after both epidural and intrathecal administrations. RESULTS: Absorption-time plots showed a large variability in the systemic absorption after both intrathecal and epidural administration, with an apparent faster systemic absorption after intrathecal administration. In the intrathecal space, the elimination clearance was around three-times higher than the distribution clearance. In the epidural space, the relative contribution of elimination and distribution to ropivacaine disposition was different, indicating a more pronounced influence of the distribution process. The intrathecal bioavailability after epidural administration was 11.1% +/- 7.6%. CONCLUSIONS: Using an animal model, we showed that drug dispositions in the intrathecal and epidural compartments are different, and that the intrathecal bioavailability of ropivacaine after epidural administration is low, and highly variable.

Intravenous lidocaine.

Lidocaine has analgesic effect and antihyperalgesic and anti-inflammatory properties, which enable its use as a general anesthetic adjuvant. Lidocaine can reduce nociception and/or cardiovascular responses to surgical stress, postoperative pain, and/or analgesic requirements. However, its mechanisms of action remain unclear, despite its different known properties. Although the exact mechanism of action remains uncertain, initial bolus followed by a continuous lidocaine infusion has clear analgesic benefits. Lidocaine is one of the major drugs for opioid-reduced anesthesia or opioid-free anesthesia procedures. It clearly improves the postoperative outcomes with increased patient satisfaction. Such procedures should be included wisely in the enhanced recovery after surgery protocols. By using the recommended protocols, a high safety and efficacy of lidocaine can be achieved.

Tolerance and efficacy of a polyamine-deficient diet for the treatment of perioperative pain.

BACKGROUND: Polyamines have been identified as pain agonists and interact with N-methyl-D-aspartate receptors. A prospective, randomized, multicenter, and blinded phase II clinical trial was conducted to evaluate a polyamine-deficient diet for the treatment of perioperative pain in patients during spinal surgery. METHODS: All analyses followed the intention-to-treat principle. The trial was designed to evaluate the dose-ranging effect of a low polyamine diet with respect to a total (group 1) or partial (group 2) polyamine diet on perioperative pain (7 d before and 5 d after surgery). Pain (numerical scale at rest and motion), quality of life questionnaires (Brief Pain Inventory, EIFEL questionnaire, and Short Form-12 acute questionnaire), and tolerance of and compliance with the nutritional program were measured. RESULTS: Compliance (preoperatively: 100% in group 1 and 83% in group 2; postoperatively: 83% in group 1 and 71% in group 2) and tolerance were good. After 7 d following the diet before surgery, decreased pain was observed in group 1 whereas no effect was observed in group 2 (P = 0.144). This analgesic effect became significant in group 1 in the subgroup of patients with initial high levels of pain (NS ≥ 4) at rest (P = 0.03) and during motion (P = 0.011). Quality of life was significantly improved in group 1 (P = 0.0465). In the postoperative period, pain was significantly decreased in group 1 compared to group 2 at rest (P = 0.022) and during motion (P = 0.029). The effect was significantly better on patients with higher initial pain both at rest (P = 0.013) and during motion (P = 0.005) in group 1 compared to group 2. CONCLUSION: Suppression of polyamines from the diet offers a nutrition-based treatment option for perioperative pain reduction independent of and complementary to typical analgesic approaches.

An evaluation of a polyamine-deficient diet for the treatment of inflammatory pain.

Polyamines are thought to be involved in the regulation of numerous metabolic and electrophysiological processes in the nervous system. In this study we evaluated the effect of a synthetic polyamine-deficient diet on pain in a carrageenan (Car)-induced inflammatory rat model. Inflammation was induced with a unilateral subcutaneous injection of Car in a plantar hindpaw in rats fed without (control group) or with (deficiency group) a polyamine-deficient diet. Ipsilateral and contralateral hyperalgesia was evaluated using the Randall-Sellito pressure test. Heart rate changes were also recorded under general anesthesia. Then, the effects of a bupivacaine sciatic nerve block and subcutaneous injection of naloxone or ketamine were evaluated for Car-induced hyperalgesia. Data were analyzed using analysis of variance followed by unpaired Student's t-test (significance P < 0.05). Before Car injection, no significant difference was observed in response to mechanical stimuli between the control and the deficiency groups (n = 114 in pooled data). Car injection induced significant ipsilateral and contralateral hyperalgesia in the control groups, whereas a significant analgesic effect appeared in the deficient groups on both the ipsilateral and contralateral hindpaws. This analgesic effect was confirmed by the electrocardiogram recording that showed a significant increase in heart rate in the control group after Car injection compared with the deficiency group that showed a decrease in heart rate under general anesthesia. Bupivacaine sciatic nerve block had no significant effect on hypoalgesia phenomena induced by polyamine deficiency. Naloxone administration had no effect in the control group but reversed the analgesic effect in the deficiency group. Ketamine administration induced a significant analgesic effect in the control group and partly reversed the analgesic effect in the deficiency group. In conclusion, a synthetic polyamine-deficient diet had a significant general analgesic effect on Car-induced mechanical hyperalgesia. The mechanism of analgesic action remains to be elucidated.

Guiding opioid-free intravenous antinociception with the Analgesia Nociception Index: a case report / Antinocicepção intravenosa sem opioides orientada pelo Índice de Analgesia/Nocicepção: relato de caso

Abstract Background: Opioid-free anesthesia decreases the incidence of opioid adverse events, but its optimal antinociceptive depth has not been clearly defined. Personalizing intraoperative opioid-free infusions with a nociception monitor may be the solution. Case report: We describe the feasibility and potential limitations of titrating opioid-free antinociception during major abdominal surgery using the Analgesia Nociception Index (Mdoloris, Lille, France) in an obese patient. After stabilizing the patient's nociception-antinociception balance intraoperatively we quickly reversed anesthesia and the patient did not require postoperative opioids. Conclusion: Personalizing opioid-free antinociception with a nociception monitor is feasible. It may optimize intraoperative antinociception and improve postoperative comfort.

Resumo Introdução A anestesia sem opioides diminui a incidência de eventos adversos associados aos opioides, mas a profundidade antinociceptiva ideal dessa abordagem não está claramente definida. Personalizar a infusão intraoperatória sem opioides com o uso de monitor de nocicepção pode ser a solução. Relato de caso Descrevemos a viabilidade e as eventuais limitações da titulação da antinocicepção sem opioides por meio do uso do Índice de Analgesia/Nocicepção (Mdoloris, Lille, França) durante cirurgia abdominal de grande porte em paciente com obesidade. Depois de estabilizar o equilíbrio nocicepção-antinocicepção da paciente no intraoperatório, revertemos rapidamente a anestesia e a paciente não precisou de opioides no pós-operatório. Conclusão A personalização da antinocicepção sem opioides por meio do emprego de monitor de nocicepção é factível. A abordagem pode otimizar a antinocicepção intraoperatória e melhorar o conforto pós-operatório.

Population Pharmacokinetics of Amitriptyline After Intrathecal, Epidural, and Intravenous Administration in Sheep.

BACKGROUND: Amitriptyline (AMI) is a lipophilic, tricyclic antidepressant with analgesic properties that could potentially be used for epidural (EPI) analgesia. However, no pharmacokinetic data are available for AMI in spinal spaces. The objective of this study was to evaluate the spinal disposition and intrathecal (IT) bioavailability of AMI after IT and EPI administration. METHODS: Six Lacaune ewes received 3 consecutive administrations of AMI. They initially received 10 mg of AMI administered intravenously, then 5 mg of AMI administered intrathecally, and 50 mg of AMI injected into the EPI space. Consecutive administrations were separated by intervals of 2 hours. A simultaneous microdialysis technique was used to determine the EPI and IT concentrations of AMI. Population analysis with S-ADAPT software was used to evaluate the pharmacokinetic parameters. RESULTS: Following intravenous administration, the clearance and central compartment (Vc) in plasma were 1.32 L/min and 147 L, respectively. Concentration-time profiles for the IT and EPI compartments were highly variable after transmeningeal diffusion. The IT Vc after IT administration and the EPI Vc after EPI administration were 2.4 and 48.9 mL, respectively. Less AMI transferred from the EPI to the IT space than from the IT to the EPI compartment, with bioavailabilities of 1.3% and 55%, respectively. CONCLUSIONS: Simultaneous population analysis for AMI demonstrated differences in EPI and IT pharmacokinetics following the EPI and IT administration of this drug. The IT bioavailability of AMI after EPI administration is relatively low.

Effect of preoperative oral sustained-release morphine sulfate on postoperative morphine requirements in elective spine surgery.

Sustained-release morphine sulfate (SRMS) is a painkiller used in oncology. The purpose of our study was to assess its efficacy on postoperative morphine requirements in elective spine surgery. This was a placebo-controlled, randomized, double-blind study. Adults scheduled for spine surgery under general anesthesia were orally administered SRMS (30 mg) or a placebo 2 h before surgery. Primary endpoint was postoperative cumulated morphine consumption through patient-controlled analgesia (PCA) during the 12 h following extubation. Statistical analysis was performed using a sequential method, the triangular test. The study was stopped after the sixth analysis (51 patients had been included; placebo: 26, SRMS: 25). Age, weight, sex ratio, type of surgery, intra-operative sufentanil consumption, anesthesia duration and time to extubation were similar in the two groups. Morphine consumption through PCA during the 12 h following extubation was significantly lower in the SRMS group (mean +/- SD: 10.5 +/- 7.6 mg) compared with placebo group (15.6 +/- 6.0 mg, P = 0.016, sequential analysis). Corresponding unbiased median estimates were 10.6 and 15.8 mg in SRMS and placebo groups, respectively. Morphine consumption through PCA during the 24 h following extubation was also significantly lower in the SRMS group (15.9 +/- 12.7 mg) compared with the placebo group (23.8 +/- 10.9 mg, P = 0.032). Vigilance, nausea and respiratory rate 3 and 6 h after extubation were similar in the two groups. A preoperative oral administration of SRMS (30 mg) induces a 33% reduction of postoperative morphine requirements in patients scheduled for spine surgery without inducing side effects.

Spray-dryed bupivacaine-loaded microspheres: in vitro evaluation and biopharmaceutics of bupivacaine following brachial plexus administration in sheep.

Microspheres could be used as a drug delivery system to prolong the duration of action of bupivacaine and to reduce its systemic absorption leading to high plasma concentrations related to central nervous and cardiovascular toxicity. Bupivacaine-loaded microspheres were made by spray-drying using polylactide-co-glycolide polymers from different sources and with different bupivacaine-polymer ratio. The characterization of microspheres concerned the shape and size, the bupivacaine drug-content (DC) and the cumulative release profiles. We evaluated in sheep the bupivacaine pharmacokinetics: (i) after short intravenous infusion of 75 mg bupivacaine solution; and (ii) following brachial nerve plexus injections of 75 mg bupivacaine solution alone, with the addition of 75 microg epinephrine, with the addition of 150 microg epinephrine and of bupivacaine (750 mg)-loaded microspheres. Release profiles showed a biphasic pattern whatever the DC. After i.v. infusion the mean clearance value was 1.53+/-0.53 l/min and the mean elimination half-life was 120.5+/-73.1 min. Following brachial plexus nerve injection, bupivacaine C(max) were lower than 100 ng/ml following either solution or microspheres administration. Ninety percent of the 75 mg bupivacaine given as a solution were absorbed in 5.8+/-1.0 h (bupivacaine alone) compared to 24.6+/-1.2 h following microsphere administration.