Cervical Epidural Anesthesia Combined with Sedation for Neck Cancer Surgery: A Case Report.

Cervical epidural anesthesia (CEA) is a well-established technique and is suitable for various surgeries, including carotid, thyroid, airway, neck cancer, breast, and upper limb procedures. We report the case of an elderly woman with a recurrent neck mass secondary to metastatic papillary thyroid carcinoma causing neurovascular compression, who underwent surgery under CEA. Five milliliters of 0.5% bupivacaine and 5 mL of 2% lidocaine (total 10 mL) were administered into the cervical epidural space. Combined with sedation, CEA in our case provided optimal anesthetic conditions, maintaining spontaneous ventilation, preventing airway collapse, ensuring patient comfort, and facilitating surgery.

The effect of anesthetic blockade of greater occipital nerve during the withdrawal period of the medication overuse headache treatment.

Background and purpose:

Discontinua­tion of medication still remains a key element in the treatment of medication overuse headache (MOH), but there is no consensus on the withdrawal procedure. We aimed to share the promising results of anesthetic blockade of greater occipital nerve (GON), which can be an alternative to existing treatments during the early withdrawal period of MOH treatment.

This study was conducted using regular electronic medical records and headache diaries of patients diagnosed with MOH and treated with anesthetic GON blockade with 0.5% bupivacaine solution in a specia­lized headache outpatient clinic. A total of 86 patients who developed MOH while being followed up for chronic migraine were included in the study.

The treatment schemes for MOH are based on expert consensus and withdrawal strategies are the most challenging part of treatment. In our study, numerical rating scale for headache intensity, overused medication consumption per month, headache frequency (day/month) and the duration of each attack (hour/day) decreased significantly in the first month compared to pre-treatment (p < 0.01). 

Conclusion – Our study suggests that GON blockade can be used as a good alternative therapy in the treatment of MOH.

Analgesic Effectiveness of Liposomal Bupivacaine versus Plain Local Anesthetics for Abdominal Fascial Plane Blocks: A Systematic Review and Meta-analysis of Randomized Trials.

BACKGROUND: Liposomal bupivacaine is reported to prolong the duration of analgesia when used for abdominal fascial plane blocks compared to plain local anesthetics; however, evidence from randomized trials is mixed. This meta-analysis aims to compare the analgesic effectiveness of liposomal bupivacaine to plain local anesthetics in adults receiving abdominal fascial plane blocks. METHODS: Randomized trials comparing liposomal bupivacaine and plain (nonliposomal) local anesthetics in abdominal fascial plane blocks were sought. The primary outcome was area under the curve rest pain between 24 to 72 h postoperatively. Secondary outcomes included rest pain at individual timepoints (1, 6, 12, 24, 48, and 72 h); analgesic consumption at 0 to 24, 25 to 48, and 49 to 72 h; time to analgesic request; hospital stay duration; and opioid-related side effects. Data were pooled using the Hartung-Knapp-Sidik-Jonkman random effects method. RESULTS: Sixteen trials encompassing 1,287 patients (liposomal bupivacaine, 667; plain local anesthetics, 620) were included. The liposomal bupivacaine group received liposomal bupivacaine mixed with plain bupivacaine in 10 studies, liposomal bupivacaine alone in 5 studies, and both preparations in 1 three-armed study. No difference was observed between the two groups for area under the curve pain scores, with a standardized mean difference (95% CI) of -0.21 cm.h (-0.43 to 0.01; P = 0.058; I2 = 48%). Results were robust to subgroup analysis based on (1) potential conflict of interest and (2) mixing of plain local anesthetics with liposomal bupivacaine. The two groups were not different for any of the day 2 or day 3 secondary outcomes. CONCLUSIONS: This systematic review and meta-analysis suggests similar analgesic effectiveness between liposomal bupivacaine and plain local anesthetics when used for fascial plane block of the abdominal wall. The authors' analysis does not support an evidence-based preference for liposomal bupivacaine compared to plain local anesthetics for abdominal fascial plane blocks.

Absorption and pharmacokinetics of bupivacaine after bilateral topical administration in tonsillar fossae for posttonsillectomy pain relief.

No previous studies have investigated the systemic absorption of bupivacaine when used topically for posttonsillectomy pain. The present study was undertaken to investigate the pharmacokinetics of bupivacaine after administration by a swab in the tonsillar fossae over 4 min after tonsillectomy. Eleven adult patients undergoing elective tonsillectomy were recruited. After removal of both tonsils, each of the two tonsillar fossae was covered with a swab moistened with 2 mL of bupivacaine 5 mg/mL, that is, a total of 20 mg bupivacaine. Blood samples were drawn after 0, 5, 10, 20, 30, 45, and 60 min. Bupivacaine was analyzed with an ultra-high-performance liquid chromatography-tandem mass spectrometry method. The highest single measured bupivacaine serum concentration was 23.2 ng/mL and took place 10 min after drug administration. Mean (±SD) Cmax was 11.4 ± 6.0 ng/mL and mean tmax was 11.3 ± 4.7 min. Mean t1/2 was 31.6 ± 9.3 min. As the toxic concentration threshold has been reported to be in the interval 1500-4500 ng/mL, the concentrations measured were well below 2% of the lowest cited toxic threshold. In conclusion, this study shows that applying 4 mL of bupivacaine 5 mg/mL by a swab in the tonsillar fossae posttonsillectomy yields very low plasma concentrations, suggesting its safe application without any risk of systemic toxic effects.

External Oblique Intercostal Plane Block Versus Port-Site Infiltration for Laparoscopic Sleeve Gastrectomy: A Randomized Controlled Study.

PURPOSE: Although laparoscopic sleeve gastrectomy (LSG) is a minimally invasive surgery, postoperative pain is common. A novel block, the external oblique intercostal (EOI) block, can be used as part of multimodal analgesia for upper abdominal surgeries. The aim of our study is to investigate the effectiveness of EOI block in patients undergoing LSG. MATERIALS AND METHODS: Sixty patients were assigned into two groups either EOI or port-site infiltration (PSI). The EOI group received ultrasound-guided 30 ml 0.25% bupivacaine, while the PSI group received 5 ml of 0.25% bupivacaine at each port sites by the surgeon. Data on clinical and demographic were collected and analyzed. RESULTS: There were no statistical differences in terms of demographic details (p > 0.05). VAS scores were statistically lower during resting at PACU, 1, 2, 4, 8, and 12 h postoperatively in the EOI group than PSI group (p < 0.05), The VAS scores were also lower during active movement at PACU, 1, 2, 4, and 8 h postoperatively in the EOI group than PSI group (p < 0.05). Twenty-four-hour fentanyl consumption was lower in the EOI than in the PSI group (505.83 ± 178.56 vs. 880.83 ± 256.78 µg, respectively, p < 0.001). Rescue analgesia was higher in PSI group than EOI group (26/30 vs. 14/30, respectively, p = 0.001). CONCLUSION: EOI block can be used as a part of multimodal analgesia due to its simplicity and effective postoperative analgesia in LSG.

Super-refractory status epilepticus, rhabdomyolysis, central hyperthermia and cardiomyopathy attributable to spinal anesthesia: a case report and review of literature.

BACKGROUND: There are only six past reports of super-refractory status epilepticus induced by spinal anesthesia. None of those patients have died. Only < 15 mg of bupivacaine was administered to all six of them and to our case. Pathophysiology ensuing such cases remains unclear. CASE PRESENTATION: A 27 year old gravida 2, para 1, mother at 37 weeks of gestation came to the operating theater for an elective cesarean section. She had no significant medical history other than controlled hypothyroidism and one episode of food allergy. Her current pregnancy was uneventful. Her American Society of Anesthesiologists (ASA) grade was 2. She underwent spinal anesthesia and adequate anesthesia was achieved. After 5-7 min she developed a progressive myoclonus. After delivery of a healthy baby, she developed generalized tonic clonic seizures that continued despite the induction of general anesthesia. She had rhabdomyolysis, one brief cardiac arrest and resuscitation, followed by stress cardiomyopathy and central hyperthermia. She died on day four. There were no significant macroscopic or histopathological changes in her brain that explain her super refractory status epilepticus. Heavy bupivacaine samples of the same batch used for this patient were analyzed by two specialized laboratories. National Medicines Quality Assurance Laboratory of Sri Lanka reported that samples failed to confirm United States Pharmacopeia (USP) dextrose specifications and passed other tests. Subsequently, Therapeutic Goods Administration of Australia reported that the drug passed all standard USP quality tests applied to it. Nonetheless, they have detected an unidentified impurity in the medicine. CONCLUSIONS: After reviewing relevant literature, we believe that direct neurotoxicity by bupivacaine is the most probable cause of super-refractory status epilepticus. Super-refractory status epilepticus would have led to her other complications and death. We discuss probable patient factors that would have made her susceptible to neurotoxicity. The impurity in the drug detected by one laboratory also would have contributed to her status epilepticus. We propose several possible mechanisms that would have led to status epilepticus and her death. We discuss the factors that shall guide investigators on future such cases. We suggest ways to minimize similar future incidents. This is an idiosyncratic reaction as well.

Incidence and factors associated with failed spinal anaesthesia among patients undergoing surgery: a multi- center prospective observational study.

BACKGROUND: Failed spinal anaesthesia causes prolonging of operation time, insufficient analgesia for surgery and needs repeating spinal anaesthesia which in turn causes local anaesthesia toxicity, high spinal and total spinal, and conversion to general anaesthesia. However, the problem remains unexplored in Amhara regional state comprehensive specialized hospitals. OBJECTIVE: To determine incidence and factors associated with failed spinal anaesthesia among patients undergoing surgery in selected Amhara National Regional State comprehensive specialized hospitals, Northwest Ethiopia, 2023. METHODS: Multi-center prospective observational study was conducted. Data was collected using questionnaire and checklist. All consecutive scheduled emergency and elective patients were included in the study. Data was transformed from Epi data to SPSS and logistic regression analysis was done. Both crude and adjusted odds ratio were used to assess the strength of association. Variables with a p-value of less than 0.05 were considered as statistically significant. RESULTS: A total of 532 patients were included in this study with a response rate of 98%. Incidence of failed spinal anaesthesia was 22.4% (CI = 19-25.9). Emergency surgery (AOR = 7.01, CI = 4.5-12.7), dose of bupivacaine of ≤ 10 mg (AOR = 3.02, CI = 1.3-10.2), work experience of anaesthetist < 2 years (AOR = 3.1, CI = 1.7-5.72), bloody CSF (AOR = 8.5, CI = 2.53-18.5), hyperbaric local anaesthetic drug (AOR = 3.3, 95% CI = 3.2-8.2) and local anaesthetist without adjuvants (AOR = 5.25, CI = 2.62-14.2) were associated failed spinal anaesthesia. CONCLUSION AND RECOMMENDATION: The incidence of failed spinal anaesthesia was high in Amhara Region comprehensive specialized hospitals. We suggest that anaesthesia providers should minimize failure by using adjuvants and appropriate dose of local anaesthetic. Additionally, simulation training should be given for anaesthesia trainees to improve their skills and to produce competent professionals.

Dose safety and pharmacodynamics of subcutaneous bupivacaine in a novel extended-release microparticle formulation: A phase 1, dose-ascending study in male volunteers.

A novel microparticle-based extended-release local anaesthetic containing a bupivacaine/poly-lactic-co-glycolic acid (PLGA; LIQ865A) or plain bupivacaine (LIQ865B) was examined in a first-in-human trial. The objectives were to examine the dose safety/tolerability and pharmacodynamics. Randomized subcutaneous injections of LIQ865A (n = 16) or LIQ865B (n = 12) and diluent, contralaterally, were administered in a dose-ascending manner (150- to 600-mg bupivacaine). Subjects were admitted 24 h post-injection and followed for 30 days post-injection. The risk ratios (RRs; 95% CI) of erythematous reactions for LIQ865A versus diluent was 9.00 (1.81-52.23; P = 0.006) and for LIQ865B versus diluent 2.50 (0.69-9.94; P = 0.37). The RR for the development of hematomas (LIQ865A versus diluent) were 3.25 (1.52-8.16; P = 0.004) and 4.00 (0.72-24.89; P = 0.32) (LIQ865B versus diluent). Subcutaneous indurations persisting for 4-13 weeks were seen in 6/16 subjects receiving LIQ865A. One subject receiving LIQ865A (600-mg bupivacaine) developed intermittent central nervous system (CNS) symptoms of local anaesthetic systemic toxicity (85 min to 51 h post-injection) coinciding with plasma peak bupivacaine concentrations (490-533 ng/ml). Both LIQ865 formulations demonstrated dose-dependent hypoesthesia and hypoalgesia. The duration of analgesia ranged between 37 and 86 h. The overall number of local adverse events, however, prohibits clinical application without further pharmacological modifications.

Combined segmental spinal epidural for major spine surgery: a case report.

A woman in her mid-50s, hesitant about general anaesthesia due to a difficult airway, opted for neuraxial anaesthesia for L4 laminectomy with pedicle screw fixation (L3-L5). Preoperatively, she received 150 µg buprenorphine and 1 mg midazolam. In lateral position, a T8-T9 epidural catheter was placed, followed by segmental spinal anaesthesia (2.5 mL 0.5% hyperbaric bupivacaine+30 µg clonidine) at T10-T11. Prone positioning was executed using standard techniques. During the 6-7 hours surgery, three 7 mL epidural top-ups (2% lignocaine epinephrine) were administered at 90 min intervals. Haemodynamics remained stable with 2.5 L crystalloids, 350 mL packed red cells and three ephedrine doses (6 mg each). Sedation included 150 µg buprenorphine and two 1 mg midazolam doses. Postoperatively, she received epidural 0.25% bupivacaine for 2 days, systemic analgesics and was discharged on the sixth day.

Paracervical block before laparoscopic total hysterectomy: A randomized controlled trial.

OBJECTIVE: To test the hypothesis that paracervical block with 0.5 % bupivacaine decreases postoperative pain after total laparoscopic hysterectomy (TLH). MATERIALS AND METHOD: This randomized double-blind placebo control trial included 152 women. We injected 10 mL 0.5 % bupivacaine (study group, n = 75) or 10 mL normal saline (control group, n = 77) at the 3 and 9 o'clock positions of the uterine cervix. The primary outcome was the visual analog scale score (VAS) determined 1 h (h) postoperatively. RESULTS: The 152 patients did not differ in their baseline demographics or perioperative characteristics. The mean VAS 1 h postoperatively was significantly lower in the study group than in controls (5.7 ± 1.2 vs. 6.8 ± 1.1, P < 0.001). The average VAS at 30 min, 3 h, and 6 h postoperatively was also significantly lower in the study group. Patients in the study group had a significantly lower analgesic requirement than did controls during the first 24 h postoperatively (6 [7.8 %] vs. 16 [21 %], P = 0.021). Total QoR-40 questionnaire scores were higher in patients who received bupivacaine. CONCLUSION: Paracervical bloc with 0.5 % bupivacaine just before TLH is an effective and safe method to reduce pain and lower postoperative analgesic requirement. URL LINK THAT LEADS DIRECTLY TO THE TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT05341869?cond=NCT05341869&draw=2&rank=1.

YTHDF1-mediated sphingosine kinase 2 upregulation alleviates bupivacaine-induced neurotoxicity via the PI3K/AKT axis.

BACKGROUND: Bupivacaine (BUP), a long-acting local anesthetic, has been widely used in analgesia and anesthesia. However, evidence strongly suggests that excessive application of BUP may lead to neurotoxicity in neurons. Sphingosine kinase 2 (SPHK2) has been reported to exert neuroprotective effects. In this study, we intended to investigate the potential role and mechanism of SPHK2 in BUP-induced neurotoxicity in dorsal root ganglion (DRG) neurons. METHODS: DRG neurons were cultured with BUP to simulate BUP-induced neurotoxicity in vitro. CCK-8, LDH, and flow cytometry assays were performed to detect the viability, LDH activity, and apoptosis of DRG neurons. RT-qPCR and western blotting was applied to measure gene and protein expression. Levels. MeRIP-qPCR was applied for quantification of m6A modification. RIP-qPCR was used to analyze the interaction between SPHK2 and YTHDF1. RESULTS: SPHK2 expression significantly declined in DRG neurons upon exposure to BUP. BUP challenge substantially reduced the cell viability and increased the apoptosis rate in DRG neurons, which was partly abolished by SPHK2 upregulation. YTHDF1, an N6-methyladenosine (m6A) reader, promoted SPHK2 expression in BUP-treated DRG neurons in an m6A-dependent manner. YTHDF1 knockdown partly eliminated the increase in SPHK2 protein level and the protection against BUP-triggered neurotoxicity in DRG neurons mediated by SPHK2 overexpression. Moreover, SPHK2 activated the PI3K/AKT signaling to protect against BUP-induced cytotoxic effects on DRG neurons. CONCLUSIONS: In sum, YTHDF1-mediated SPHK2 upregulation ameliorated BUP-induced neurotoxicity in DRG neurons via promoting activation of the PI3K/AKT signaling pathway.

Lipid emulsion treatment for local anesthetic systemic toxicity in pediatric patients: A systematic review.

BACKGROUND: Local anesthetic systemic toxicity (LAST) is rare, but fatal; the current widely used treatment is lipid emulsion (LE). The goal of this study was to analyze and review case reports on LE treatment for LAST in pediatric patients. METHODS: We performed a systematic review using case reports on LE treatment for LAST in pediatric patients, searching PubMed and Scopus databases to March 2023 using the following keywords: ("local anesthetic toxicity" OR "local anesthetic systemic toxicity" OR LAST") AND ("newborn" OR "infant" OR "child" OR "children" OR "adolescent" OR "pediatric") AND ("lipid emulsion" OR "Intralipid"). RESULTS: Our search yielded 21 cases, revealing that nearly 43% patients with LAST were less than 1 year old, and most cases were caused by bupivacaine (approximately 67% cases). "Inadvertent intravascular injection" by anesthesiologists and "overdose of local anesthetics" mainly by surgeons were responsible for 52% and 24% cases of LAST, respectively. LAST occurred in the awake state (52%) and under general anesthesia (48%), mainly causing seizures and arrhythmia, respectively. Approximately 55% of patients received LE treatment in <10 minutes after LAST, mainly improving cardiovascular symptoms. A 20% LE (1.5 mL/kg) dose followed by 0.25 mL/kg/minutes dose was frequently used. LE and anticonvulsants were mainly used in the awake state, whereas LE with or without vasopressors was mainly used under general anesthesia. LE treatment led to full recovery from LAST in 20 cases; however, 1 patient died due to underlying disease. CONCLUSION: Consequently, our findings reveal that LE is effective in treating pediatric LAST.

Chitosan Membranes Stabilized with Varying Acyl Lengths Release Cis-2-Decenoic Acid and Bupivacaine at Controlled Rates and Inhibit Pathogenic Biofilm.

BACKGROUND: Adherence of complex bacterial biofilm communities to burned tissue creates a challenge for treatment, with infection causing 51% of burn victim deaths. This study evaluated the release of therapeutics from wound care biomaterials and their antimicrobial activity against pathogens Staphylococcus aureus, Acinetobacter baumannii, and Pseudomonas aeruginosa. METHODS: Electrospun chitosan membranes (ESCMs) were fabricated and acylated with chain lengths ranging from 6-10 carbons then loaded with 0.15 mg of anti-biofilm agent, cis-2-decenoic acid (C2DA), and 0.5 mg of local anesthetic, bupivacaine. RESULTS: Combinations of therapeutics released from modified ESCMs at a cumulative amount of 45-70% of bupivacaine and less than 20% of C2DA. Results from bacterial studies suggest that this combination reduced biofilm 10-fold for S. aureus, 2-fold for Acinetobacter baumannii, and 2-3-fold for Pseudomonas aeruginosa by 24 hours. Additionally, dual loaded groups reduced planktonic Staphylococcus aureus ~4-fold by 24 hours as well as Acinetobacter baumannii ~3-fold by 48 hours. CONCLUSIONS: The combination of therapeutics used has a significant role in biofilm prevention for selected strains via direct contact or diffusion in aqueous solutions.

Follow-up of Serum Creatine Phosphokinase Levels after Ultrasound Guided Suprainguinal Fascia Iliaca Block with Bupivacaine in Total Knee Arthroplasty Patients: An Observational, Controlled Study.

OBJECTIVE: To determine the myotoxicity of bupivacaine on muscles after suprainguinal fascia iliaca block for postoperative analgesia in total knee arthroplasty (TKA) patients through changes in serum creatine phosphokinase (CPK) levels during the perioperative period. STUDY DESIGN: Observational study. Place and Duration of the Study: Postoperative Recovery Room department of Anaesthesiology and Reanimation, Samsun University, Samsun, Training and Research Hospital, Samsun, Turkiye, between December 2022 and February 2023. METHODOLOGY: Patients undergoing for the procedure of TKA surgery were recruited. (40 controls and 42 SIFIB groups). Serum CPK levels were evaluated preoperatively, at postoperative 6th hour and 24th hour. RESULTS:  From total 82 patients, 42 of them who received SIFIB as a component of multimodal analgesia had serum CPK levels comparable to those in the control group at all time points (p>0.05). While the increase in CPK level at 6th hour relative to baseline was significant in both groups (p<0.05), only the block group demonstrated a statistically significant difference between the 6th and 24th hours (p<0.05). CONCLUSION: SIFIB administration did not result in severe bupivacaine-induced myotoxicity in comparison to the control group. SIFIB administration is a safe option when used as part of multimodal analgesia in TKA. KEY WORDS:  Bupivacaine, Creatine phosphokinase, Myotoxicity, Regional anaesthesia.

Bupivacaine-fentanyl isobaric spinal anesthesia reduces the risk of ICU admission in elderly patients undergoing lower limb orthopedic surgery.

BACKGROUND: To evaluate if bupivacaine-fentanyl isobaric spinal anesthesia could reduce the risk of ICU admission compared with general anesthesia in elderly patients undergoing lower limb orthopedic surgery. METHODS: This study comprised a retrospective review of all lower limb orthopedic surgeries performed at our hospital between January 2013 and December 2019. According to anesthesia methods, patients were divided into the spinal anesthesia group (n = 1,728) and the general anesthesia group (n = 188). The primary outcome evaluated was the occurrence of ICU admission. Secondary outcomes included hemodynamic changes, postoperative complications, and mortality. RESULTS: Repeated measure analysis of variance indicated that the difference between the two groups in the systolic blood pressure (SBP) was not significant before anesthesia (T0), immediately after anesthesia (T1), and before leaving the operation room (T8) (P > 0.05), but significant (P < 0.01) from 5 min after anesthesia (T2) to after operation (T7). The proportions of ICU admission (6.4% vs. 23.8%, P < 0.01) and unplanned intubation (0.1% vs. 3.8%, P < 0.01) were significantly lower in the spinal anesthesia group compared with those in the general anesthesia group. Multivariate logistic regression revealed that after controlling for potential confounding factors, the odds of ICU admission for patients in the spinal anesthesia group was 0.240 times (95% CI 0.115-0.498; P < 0.01) than those in the general anesthesia group. CONCLUSIONS: Bupivacaine-fentanyl isobaric spinal anesthesia significantly reduced the risk of ICU admission and unplanned intubation, and provided better intraoperative hemodynamics in elderly patients undergoing lower limb orthopedic surgery. TRIAL REGISTRATION: This study has been registered in the Chinese Clinical Trial Registry (ChiCTR2000033411).

The 90% effective dose of intrathecal hyperbaric bupivacaine for Cesarean delivery under combined spinal-epidural anesthesia in parturients with super obesity: an up-down sequential allocation study.

PURPOSE: To determine the 90% effective dose (ED90) of intrathecal hyperbaric bupivacaine for Cesarean delivery under combined spinal-epidural anesthesia (CSE) in parturients with super obesity (body mass index [BMI] ≥ 50 kg·m-2). METHODS: We enrolled parturients with BMI ≥ 50 kg·m-2 with term, singleton vertex pregnancies undergoing elective Cesarean delivery under CSE. An independent statistician generated the 0.75% hyperbaric bupivacaine dosing regimen in increments of 0.75 mg using a biased-coin up-down sequential allocation technique. This was combined with 15 µg fentanyl, 150 µg morphine, and normal saline to a volume of 2.05 mL. The initial and maximum doses were 9.75 mg and 12 mg, respectively. Participants, clinical team, and outcome assessors were blinded to the dose. The primary outcome was block success, defined as T6 block to pinprick within ten minutes and no intraoperative analgesic supplementation within 90 min of spinal injection. We determined the ED90 using logistic regression. RESULTS: We enrolled 45 parturients and included 42 in the analysis. All doses achieved a T6 level within ten minutes, and the primary outcome occurred in 0/1 (0%) of the 9.75-mg doses, 2/3 (67%) of the 10.5-mg doses, 21/27 (78%) of the 11.25-mg doses, and 11/11 (100%) of the 12-mg doses. The ED90 of hyperbaric bupivacaine was 11.56 mg (95% confidence interval, 11.16 to 11.99). Four parturients (9.5%) had sensory level higher than T2, but none was symptomatic or required general anesthesia. CONCLUSION: The estimated ED90 of hyperbaric bupivacaine with fentanyl and morphine in parturients with super obesity undergoing Cesarean delivery under CSE was approximately 11.5 mg. STUDY REGISTRATION: ClinicalTrials.gov (NCT03781388); first submitted 18 December 2018.

RéSUMé: OBJECTIF: Notre objectif était de déterminer la dose efficace à 90 % (DE90) de bupivacaïne hyperbare intrathécale pour l'accouchement par césarienne sous péri-rachianesthésie combinée (PRC) chez les personnes parturientes atteintes de super obésité (indice de masse corporelle [IMC] ≥ 50 kg·m−2). MéTHODE: Nous avons recruté des personnes parturientes ayant un IMC ≥ 50 kg·m−2 présentant des grossesses uniques à terme, en présentation céphalique et bénéficiant d'un accouchement par césarienne programmée sous PRC. Un·e statisticien·ne indépendant·e a généré le schéma posologique de bupivacaïne hyperbare à 0,75 % par incréments de 0,75 mg à l'aide d'une technique d'allocation séquentielle en escalier. La bupivacaïne a été combinée à 15 µg de fentanyl, 150 µg de morphine et à une solution physiologique salée jusqu'à un volume de 2,05 mL. Les doses initiale et maximale étaient respectivement de 9,75 mg et 12 mg. Les participant·es, l'équipe clinique et les personnes évaluant les résultats n'avaient pas connaissance de la dose. Le critère d'évaluation principal était la réussite du bloc, définie comme un bloc à T6 à la piqûre dans les dix minutes et aucune supplémentation analgésique peropératoire dans les 90 minutes suivant l'injection rachidienne. Nous avons déterminé la DE90 à l'aide d'une méthode de régression logistique. RéSULTATS: Nous avons recruté 45 personnes parturientes et en avons inclus 42 dans l'analyse. Toutes les doses ont atteint le niveau T6 en dix minutes, et le critère d'évaluation principal a été obtenu pour 0/1 (0 %) des doses de 9,75 mg, 2/3 (67 %) des doses de 10,5 mg, 21/27 (78 %) des doses de 11,25 mg et 11/11 (100 %) des doses de 12 mg. La DE90 de bupivacaïne hyperbare était de 11,56 mg (intervalle de confiance à 95 %, 11,16 à 11,99). Quatre personnes parturientes (9,5 %) ont affiché un niveau sensoriel supérieur à T2, mais aucune n'était symptomatique ni n'a nécessité d'anesthésie générale. CONCLUSION: La DE90 estimée de bupivacaïne hyperbare avec fentanyl et morphine chez les personnes parturientes hyperobèses bénéficiant d'une césarienne sous PRC était d'environ 11,5 mg. ENREGISTREMENT DE L'éTUDE: ClinicalTrials.gov (NCT03781388); soumis pour la première fois le 18 décembre 2018.

Population pharmacokinetic-pharmacodynamic model of subcutaneous bupivacaine in a novel extended-release microparticle formulation.

The objective of this study was to develop a population pharmacokinetic-pharmacodynamic model of subcutaneously administered bupivacaine in a novel extended-release microparticle formulation for postoperative pain management. Bupivacaine was administered subcutaneously in the lower leg to 28 healthy male subjects in doses from 150 to 600 mg in a phase 1 randomized, placebo-controlled, double-blind, dose-ascending study with two different microparticle formulations, LIQ865A and LIQ865B. Warmth detection threshold was used as a surrogate pharmacodynamic endpoint. Population pharmacokinetic-pharmacodynamic models were fitted to plasma concentration-effect-time data using non-linear mixed-effects modelling. The pharmacokinetics were best described by a two-compartment model with biphasic absorption as two parallel absorption processes: a fast, zero-order process and a slower, first-order process with two transit compartments. The slow absorption process was found to be dose-dependent and rate-limiting for elimination at higher doses. Apparent bupivacaine clearance and the transit rate constant describing the slow absorption process both appeared to decrease with increasing doses following a power function with a shared covariate effect. The pharmacokinetic-pharmacodynamic relationship between plasma concentrations and effect was best described by a linear function. This model gives new insight into the pharmacokinetics and pharmacodynamics of microparticle formulations of bupivacaine and the biphasic absorption seen for several local anaesthetics.