Second infant spinal anesthetic: Incidence, dose modification, and adverse events after initial failure.

INTRODUCTION: Infant spinal anesthesia is an important technique in premature and ex-premature infants undergoing lower abdominal surgery. Previous studies of infant spinal anesthesia report high failure rates, but fail to adequately identify contributing factors. The aim of this study is to retrospectively review spinal anesthetics from a quaternary anesthetic centre to determine overall spinal failure rate, incidence of second spinal attempts and adverse events associated with a second spinal anesthetic. METHODS: A retrospective review of infant spinal anesthetics performed between May 2016 and June 2023. RESULTS: Five hundred and fifty-one infants (mean postmenstrual age 42.9 weeks and weight 3873 g) were included. The overall success rate on first attempt was 86.5% with a further 5.1% requiring a successful second spinal anesthetic after initial failure. Spinal anesthetic failure requiring conversion to general anesthesia occurred in 9.4% of cases The causes of failed spinal anesthetic were inability to access the subdural space (dry tap 4.2%), inadequate motor blockade (2.9%), and repeated bloody taps (2.2%). Spinal anesthetic failure was significantly increased in cases where the anesthetist was routinely performing less than 5 spinal anesthetics per year [OR 2.21 (95% CI 1.28, 3.83, p = .004)] but only weakly associated with years of pediatric anesthetic experience. Failure rates were 21.4% with styletted spinal needles and 9.2% for non styletted [OR 2.68 (95% CI 1.23-5.86, p = .012)]. The incidence of perioperative apnoea was 6.7% with the highest rate in infants in which failed spinal anesthesia required conversion to general anesthesia (25%). There were 28 cases where initial spinal anesthetic failed to produce adequate anesthesia and a repeat spinal anesthetic was performed. Repeat spinal anesthesia was successful in 92.8% of cases with awake caudal anesthesia successful in 7.2% of cases. In three cases high spinal blockade occurred, one after a single spinal and two after a repeat spinal. Both repeat spinal high block cases required intubation and brief resuscitation. CONCLUSION: Infant spinal anesthesia is associated with high success rates if experienced anesthetists are present or performing the block. Repeat spinal anesthesia may be associated with an increased incidence of high spinal block. Greater awareness of the slow onset of high block should promote techniques aimed at minimizing cephalad spread of local anesthetic including slight head up positioning during surgery.

Safety of blood reinfusion drains after local infiltration analgesia in total joint replacement.

BACKGROUND: Local infiltration analgesia (LIA) is frequently administered to patient undergoing joint replacement surgical procedures. The aim of the present research was to verify the safety of collected shed blood to be reinfused postoperatively, by measuring levobupivacaine levels in drainage blood in patients undergoing LIA during knee replacement surgery. PATIENTS AND METHODS: 24 patients who underwent total knee arthroplasty (TKA) and 12 scheduled for total hip arthroplasty (THA) who received intraoperative LIA were considered. Blood samples were collected from shed blood which was present in drainage 2 and 5 hours after surgery and serum was analysed by liquid chromatography-tandem mass spectrometry. RESULTS: At 2 hours postoperatively, the median levobupivacaine serum concentration in the collected shed blood was 1.2 mg/L (SD: 4.2) for TKA and 17.13 mg/L (SD: 24.4) for THA. At 5 hours, levobupivacaine concentration was 1.84 mg/L (SD: 2.2) for TKA and 17.5 mg/L (SD: 25.2) for THA. Higher values of average serum levobupivacaine concentration were reported in drains collected from patients who had undergone THA compared to TKA (p<0.001). BMI significantly influenced levels of serum drug, that resulted to be higher in patients with BMI<25 (p= 0.01). CONCLUSION: Levobupivacaine from collected shed blood that would have been returned to the patient, was below toxicity level at 2 and 5 hours after LIA during total joint replacement. The average serum levobupivacaine concentration was found to be higher in drains taken from THA patients than TKA patients. Patients with lower BMI demonstrated the highest levels of levobupivacaine in shed blood and a lower blood volume needed for central nervous system toxicity. Therefore, in patients with a lower BMI undergoing THA, anaesthetic dosage should be reduced or autotransfusion should be avoided to prevent potential risks of toxicity.

Extrapleural infusion of levobupivacaine versus levobupivacaine-sufentanil-adrenaline after video-assisted thoracoscopic surgery (VATS): A randomised controlled trial.

BACKGROUND: Peripheral blocks are increasingly used for analgesia after video-assisted thoracic surgery (VATS). We hypothesised that addition of sufentanil and adrenaline to levobupivacaine would improve the analgesic effect of a continuous extrapleural block. METHODS: We randomised 60 patients undergoing VATS to a 5-mL h-1 extrapleural infusion of levobupivacaine at 2.7 mg mL-1 (LB group) or levobupivacaine at 1.25 mg mL-1 , sufentanil at 0.5 µg mL-1 , and adrenaline at 2 µg mL-1 (LBSA group). The primary outcome was the cumulative morphine dose administered as patient-controlled analgesia (PCA-morphine) at 48 and 72 h. The secondary outcomes were pain according to numerical rating scale (NRS) at rest and after two deep breaths twice daily, peak expiratory flow (PEF) daily, quality of recovery (QoR)-15 score at 1 day and 3 weeks postoperatively, serum levobupivacaine concentrations at 1 h after the start and at the end of the intervention, and adverse events. RESULTS: At 48 h, the median cumulative PCA-morphine dose for the LB group was 6 mg (IQR, 2-10 mg) and for the LBSA group 7 mg (IQR, 3-13.5 mg; p = .378). At 72 h, morphine doses were 10 mg (IQR, 3-22 mg) and 12.5 mg (IQR, 4-21 mg; p = .738), respectively. Median NRS score at rest and after two deep breaths was 3 or lower at all time points for both treatment groups. PEF did not differ between groups. Three weeks postoperatively, only the LB group returned to baseline QoR-15 score. The LB group had higher, but well below toxic, levobupivacaine concentrations at 48 and 72 h. The incidence of nausea, dizziness, pruritus and headache was equally low overall. CONCLUSION: For a continuous extrapleural block, and compared to plain levobupivacaine at 13.5 mg h-1 , levobupivacaine at 6.25 mg h-1 with addition of sufentanil and adrenaline did not decrease postoperative morphine consumption. The levobupivacaine serum concentrations after 48 and 72 h of infusion were well below toxic levels, therefore our findings support the use of the maximally recommended dose of levobupivacaine for a 2- to 3-day continuous extrapleural block.

'Walking epidural': comparison of the analgesic efficacy of levobupivacaine 0.0625% + fentanyl 2mcg/mL versus ropivacaine 0.075% + fentanyl 2mcg/mL.

INTRODUCTION: Epidural infusion with low local anesthetic concentrations with opiates decrease the severity of the motor blockade associated. The present study aims to compare the analgesic efficacy and the motor blockade between two local anesthetic epidural infusions: levobupivacaine 0.0625% + fentanyl 2mcg/mL versus ropivacaine 0.075% + fentanyl 2mcg/mL. MATERIALS AND METHODS: In a single-blind prospective randomized study, 60 laboring parturient had continuous epidural analgesia as follows: 30 of them received levobupivacaine 0.0625% + fentanyl 2mcg/mL and 30 of them received ropivacaine 0.075% + fentanyl 2mcg/mL and rates of infusion were adjusted to the height. Analgesic, motor blockade and satisfaction records were collected as well as maternal and neonate adverse events. RESULTS: After 2 h of the catheter placement, patients who received levobupivacaine showed a mean VAS of 3.2 [1.8-4.6] versus 1.8 [1.2-2.5] (p = 0.05) in patients who received ropivacaine. In addition, patients who received levobupivacaine showed a punctuation in Bromage scale of 0.0 [0.0-1.0] versus 0.0 [0.0-0.0] (p = 0.04) in patients who received ropivacaine. Finally, the parturient who received levobupivacaine scored a mean satisfaction index of 8.1 [7.3-8.9] versus 9.3 [8.7-9.8] (p = 0.02) in those who received ropivacaine. We did not register maternal nor neonate adverse events. CONCLUSION: Both infusions (levobupivacaine 0.0625% + fentanyl 2mcg/mL and ropivacaine 0.075% + fentanyl 2mcg/mL) are effective for labor analgesia. However, ropivacaine would present a better pharmacodynamic profile with less motor blockade and decreased need for analgesic rescue hence improving patient's satisfaction.

Hemodynamic Safety and Effect of Dexmedetomidine on Superficial Cervical Block Quality for Carotid Endarterectomy: A Prospective Study.

OBJECTIVE: Dexmedetomidine as an adjuvant to local anesthetics (LAs) in regional anesthesia has demonstrated a positive effect on the quality of regional blocks, but there are no studies on usage in superficial cervical block (SCB) for carotid endarterectomy (CEA), in which the management of mean arterial pressure is essential. The authors designed a prospective, randomized, double-blinded study to investigate the effects of the addition of dexmedetomidine on the hemodynamic management and quality of SCB. DESIGN: A prospective, randomized, double-blinded study. SETTING: A single-center study at a university hospital center. PARTICIPANTS: Ultrasound-guided SCB was performed on 60 patients classified as American Society of Anesthesiologists Grades II and III undergoing elective CEA surgery who were assigned into 2 groups randomly. INTERVENTION(S): Both groups received 2 mg/kg of 0.5% levobupivacaine with 2 mg/kg of 2% lidocaine. The intervention group additionally received 50 µg of dexmedetomidine. MEASUREMENTS AND MAIN RESULTS: The onset and duration of sensory block and analgesia, hemodynamic parameters, and adverse effects were recorded. There were minimum effects on hemodynamic parameters and no differences in the incidence of adverse effects. The time to first analgesia was longer in the intervention group than in the control group (N = 30). There was no difference in the duration of the sensory block between groups. The log-rank test indicated a significant difference in the probability of the Numeric Pain Rating Scale <3. CONCLUSION: The addition of 50 µg of dexmedetomidine to 0.5% levobupivacaine and 2% lidocaine for SCB did not influence the hemodynamics and frequency of adverse effects. The median sensory block duration time showed no statistical difference between the groups, but the quality of analgesia postoperatively was much improved in the study group.

The Optimization of the Synthesis Process and the Identification of Levobupivacaine Hydrochloride.

In this study, we not only optimized and improved the synthesis process of levobupivacaine hydrochloride (21) but also conducted a comprehensive exploration of critical industrial-scale production details, and a novel high-performance liquid chromatography (HPLC) analysis method was developed. Starting with the readily available and cost-effective (R,S)-N-(2,6-dimethylphenyl)piperidine-2-carboxamide (28) as the initial material and utilizing l-(-)-dibenzoyl tartaric acid (29) for chiral separation, and then through substitution and a salting reaction, levobupivacaine hydrochloride (21) was obtained with high purity (chemical purity of 99.90% and enantiomeric excess (ee) values of 99.30%). The total yield of the three steps was 45%. Structures of intermediates and the final product were confirmed using nuclear magnetic resonance (NMR) (1H NMR, 13C NMR), mass spectrometry (MS), and elemental analysis. The crystal structure of the final product was determined through differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and X-ray diffraction (XRD). Furthermore, we evaluated the risk of the substitution reaction using a reaction calorimeter and accelerating rate calorimetry (ARC). This process offers the advantages of simple operation, greenness, safety, controllable quality, and cost-effectiveness. It provides reliable technical support for the industrial-scale production of levobupivacaine hydrochloride (21), which is of significant importance in meeting clinical demands. Pilot-scale production has already been successfully completed by China National Medicines Guorui Pharmaceutical Co., Ltd., with a production scale of 20 kg.

0.125% 8 ml/h v.s. 0.25% 8 ml/h of levobupivacaine in continuous paravertebral block for postoperative analgesia in video-assisted thoracoscopic surgery: a randomized, controlled, double-blind study.

PURPOSE: Research has shown that a higher dose of bupivacaine administered in continuous paravertebral block (CPVB) provides a greater analgesic effect after video-assisted thoracoscopic surgery (VATS). In this randomized, controlled, double-blind study, we hypothesized that 0.25% 8 ml/h of levobupivacaine administered in CPVB after VATS provides a greater analgesic effect than 0.125% 8 ml/h. METHODS: Fifty patients who underwent unilateral VATS were randomized to receive a postoperative continuous infusion of 0.125% (low group, n = 25) or 0.25% (high group, n = 25) levobupivacaine at 8 mL/h for CPVB. The primary outcome was the visual analog scale (VAS) score during coughing on the morning of postoperative day (POD) 1. The secondary outcomes were the VAS scores at rest and during coughing on POD 2, the number of anesthetized dermatomes, the frequency of rescue analgesics, postoperative nausea and vomiting, patient satisfaction, and adverse events and complications. RESULTS: There was no significant difference in the VAS score during coughing on the morning of POD 1 between the low and high groups [median, 37.5 (interquartile range 21-50) vs. 40.0 (interquartile range 21-50), respectively; p = 0.79]. Similarly, there were no significant differences in any secondary outcomes between the two groups. CONCLUSIONS: Levobupivacaine at 0.25% 8 ml/h in CPVB did not provide better analgesia after VATS over 0.125% 8 ml/h. CLINICAL TRIAL REGISTRATION NUMBER: UMIN000037930.

Chronological changes in plasma levobupivacaine concentrations after bilateral modified thoracoabdominal nerve block through perichondrial approach.

The local anesthetic (LA) systemic toxicity of trunk blocks is a major concern. Recently, modified thoracoabdominal nerve block through perichondrial approach (M-TAPA) has attracted attention; however, plasma LA level is unknown. We tested whether the peak plasma LA concentration following M-TAPA, using 25 mL of 0.25% levobupivacaine mixed with epinephrine on each side, would be below the toxic level (2.6 µg/mL). We recruited 10 patients undergoing abdominal surgery with planned M-TAPA between November 2021 and February 2022. In all patients, 25 mL of 0.25% levobupivacaine mixed with 1:200,000 epinephrine was administered on each side. Blood samples were obtained at 10, 20, 30, 45, 60, and 120 min after the block. The highest individual peak and the mean peak plasma LA concentrations were 1.03 and 0.73 µg/mL, respectively. We could not capture the peak in five patients; however, the highest concentrations in all patients were significantly lower than the toxic level. A negative correlation between the peak level and body weight was observed. Our results indicated that the plasma LA concentration following M-TAPA using total of 50 mL of 0.25% levobupivacaine with epinephrine remains below the toxic level. Further research is required due to the small sample size of this study.Trial registry number: UMIN000045406.

Comparison of the efficacy of two doses of dexmedetomidine as an adjunct to levobupivacaine in infraclavicular brachial plexus block: prospective double-blinded randomized controlled trial.

BACKGROUND: This prospective, double-blind, randomized, controlled trial compared the efficacy of two dexmedetomidine doses (50 and 100-µg) combined with levobupivacaine on sensory block duration in infraclavicular brachial plexus block. We hypothesized that perineural dexmedetomidine would extend sensory block duration dose-dependently. METHODS: The study included 60 patients aged 20 to 60 years of both sex with an ASA I/II undergoing forearm and hand surgery. The patients were randomly assigned into three equal groups (n = 20) for ultrasound-guided infraclavicular brachial plexus block. The L group received 35-mL 0.5% levobupivacaine plus normal saline, the LD50 group received 35-mL 0.5% levobupivacaine plus 50-µg dexmedetomidine, and the LD100 group received 35-mL 0.5% levobupivacaine plus 100-µg dexmedetomidine. Patients were investigated for onset and duration of sensory blockade, time to first postoperative rescue analgesia, and the total 24-h postoperative morphine requirement. RESULTS: The LD100 group had a longer sensory block duration (15.55 ± 1.1 h; 95% confidence interval (CI), 15.04-16.06) than the LD50 group (12.8 ± 1.2 h; 95% CI, 12.24-13.36 h) (p < 0.001) or the L group (9.95 ± 1.05 h; 95% CI, 9.46-10.44 h) (p < 0.001). The LD100 group took longer to request postoperative rescue analgesia and required fewer postoperative morphine doses than the LD50 and L groups (P < 0.001). CONCLUSIONS: Sensory block duration was longer with perineural 100-µg dexmedetomidine as an adjunct to levobupivacaine than with 50-µg dexmedetomidine. TRIAL REGISTRATION: This study was approved by the Ethics Committee of Aswan University Hospital (approval number: aswu/125/4/17) (date of registration: 04/04/2017). Furthermore, the trial was retrospectively registered at ClinicalTrial.gov (NCT04729868) with a verification date of January 2021.

Comparison of plasma levobupivacaine concentrations with and without epinephrine following erector spinae plane block for breast cancer surgery: a randomized controlled trial.

BACKGROUND: The erector spinae plane (ESP) block requires a large volume of local anesthetic to provide effective analgesia, which has the potential to cause local anesthetic systemic toxicity (LAST). Adjunctive epinephrine slows the entry of local anesthetic into the plasma and decreases its toxic effect on vulnerable tissues. We compared plasma levobupivacaine concentrations with and without epinephrine after ESP blocks for breast cancer surgery. METHODS: In this prospective, double-blinded, randomized controlled trial, 35 patients who underwent elective unilateral partial mastectomy with sentinel lymph node biopsy were enrolled. The patients were randomized to group L (ESP block with 2 mg/kg levobupivacaine) or LE (ESP block with 2 mg/kg levobupivacaine and 5 µg/mL epinephrine). Blood samples were obtained at 2.5, 5, 7.5, 10, 12.5, 15, 30, 60, and 120 min after the ESP block, and plasma concentrations of levobupivacaine were compared. RESULTS: Twenty-nine patients were included in the analysis. The maximum plasma concentration (Cmax) and the time to maximum concentration (Tmax) were, respectively, 1.24 µg/mL and 6.0 min in group L and 0.62 µg/mL and 7.2 min in group LE. The two groups showed no significant differences in the numerical rating scale scores immediately after extubation and 5 and 9 h after the ESP block, or in the interval from the ESP block to the first rescue analgesia. No patient developed symptoms suggestive of LAST. CONCLUSIONS: A single bolus of 2 mg/kg levobupivacaine in the ESP block resulted in a short Tmax with high Cmax. Adding epinephrine to levobupivacaine decreased the Cmax and delayed the Tmax after ESP blocks but had no effect on postoperative analgesia. TRIAL REGISTRATION: UMIN Clinical Trials Registry, UMIN000034479 . The trial was retrospectively registered on October 13, 2018.

Levobupivacaine plasma concentrations following repeat caudal anesthetics.

AIM: A single caudal anesthetic at the start of lower abdominal surgery is unlikely to provide prolonged analgesia. A second caudal at the end of the procedure extends the analgesia duration but total plasma concentrations may be associated with toxicity. Our aim was to measure total plasma levobupivacaine concentrations after repeat caudal anesthesia in infants and to generate a pharmacokinetic model for prediction of plasma concentrations after repeat caudal anesthesia in neonates, infants and children. METHODS: Infants undergoing definitive repair of anorectal malformations or Hirschsprung's disease received a second caudal anesthesia at the end of the procedure. Total levobupivacaine concentrations were assayed 3-4 times in the first 6 h after the initial caudal. These data were pooled with data from four studies describing plasma concentrations after levobupivacaine caudal or spinal anesthesia. Population pharmacokinetic parameters were estimated using nonlinear mixed-effects models. Covariates included postmenstrual age and body weight. Parameter estimates were used to simulate concentrations after a repeat levobupivacaine 2.5 mg kg-1 caudal at 3 or 4 h following an initial levobupivacaine 2.5 mg kg-1 caudal. RESULTS: Twenty-one infants (postnatal age 11-32 weeks, gestation 37-39 weeks, weight 5.2-8.6 kg) were included. The measured peak plasma concentration after repeat caudal levobupivacaine 2.5 mg kg-1 4 h after initial caudal was 1.38 mg L-1 (95% prediction interval 0.60-2.6 mg L-1 ) and 3 h after initial caudal was 1.46 mg L-1 (0.60-2.80) mg L-1 . Simulation of total plasma concentrations in neonates (7 kg, 57 weeks postmenstrual age) given caudal levobupivacaine 4 h after the initial caudal were 1.76 mg L-1 (0.68-3.50) mg L-1 if 2.5 mg kg-1 levobupivacaine was used and 0.88 mg L-1 (0.34-1.73) mg L-1 if 1.25 mg kg-1 of 0.125% levobupivacaine was used. In simulated older children (20 kg, 6 years), the mean maximum concentration was 1.43 mg L-1 (0.60-2.70) mg L-1 if 2.5 mg kg-1 levobupivacaine was repeated at 3 h. CONCLUSION: Repeat caudal levobupivacaine 2.5 mg kg-1 at 3 h after an initial 2.5 mg kg-1 dose does not exceed the concentration associated with systemic local anesthetic toxicity. In 2.5% of simulated neonates (weight 3.8 kg, PMA 40 weeks), repeat caudal anesthesia demonstrates broaching of the lower concentration limit associated with toxicity at both 3 and 4 h after initial caudal.

The Potential Effect of Lidocaine, Ropivacaine, Levobupivacaine and Morphine on Breast Cancer Pre-Clinical Models: A Systematic Review.

Breast cancer (BC) is one of the most common types of cancer and the second leading cause of death in women. Local anaesthetics (LAs) and opioids have been shown to influence cancer progression and metastasis formation in several pre-clinical studies. However, their effects do not seem to promote consensus. A systematic review was conducted using the databases Medline (via PubMed), Scopus, and Web of Science (2010 to December 2021). Search terms included "lidocaine", "ropivacaine", "levobupivacaine", "morphine", "methadone", "breast cancer", "breast carcinoma" and "breast neoplasms" in diverse combinations. The search yielded a total of 784 abstracts for initial review, 23 of which met the inclusion criteria. Here we summarise recent studies on the effect of analgesics and LAs on BC cell lines and animal models and in combination with other treatment regimens. The results suggest that local anaesthetics have anti-tumorigenic properties, hence their clinical application holds therapeutic potential. Regarding morphine, the findings are conflicting, but this opioid appears to be a tumour-promoting agent. Methadone-related results are scarce. Additional research is clearly required to further study the mechanisms underlying the controversial effects of each analgesic or LA to establish the implications upon the outcome and prognosis of BC patients' treatment.

Segmental thoracic spinal anesthesia versus general anesthesia for breast cancer surgery: A prospective randomized-controlled open-label trial.

Background and Aims: Breast surgery is associated with moderate-to-severe postoperative pain, nausea, and vomiting. For this, neuraxial anesthesia might be a better alternative to general anesthesia (GA), providing superior analgesia, with higher patient satisfaction and lesser incidence of nausea vomiting. This randomized-controlled open-label trial was done to compare segmental spinal and GA for breast cancer surgery. Material and Methods: The present study enrolled 56 female patients scheduled to undergo breast cancer surgery. They were randomly divided into two groups, group G (received standard GA) and group TS (received segmental thoracic spinal anesthesia with 0.5% isobaric levobupi vacaine at T5-T6 inter spaces). The primary objective of this study was patient satisfaction with the anesthetic technique, while secondary objectives were hemodynamic changes, perioperative complications, time of first rescue analgesic, total opioid consumption in first 24 h, and surgeon satisfaction score. Data were expressed as mean (SD) or number (%) as indicated and were compared using Chi-square, Fisher's exact, or Student's ttest as appropriate. Results: Patient in group TS had significantly higher satisfaction score median 5 (IQR 1) compared to patients in group G median 4 (IQR 3.5) (P = 0.0001). Nausea and vomiting were significantly higher in group G compared to group TS (P = 0.01). Mean time to rescue analgesia was 33.21 ± 7.48 min in group G as compared to 338.57 ± 40.70 in group TS and opioid consumption was also significantly lower in group TS (70.00 ± 27.38) as compared to group G (366.07 ± 59.40). There was no significant difference in hemodynamic parameters (except significantly lower heart rate at 15 min in group TS (P = 0.001) and surgeon satisfaction score between groups. Quality of postoperative analgesia was better in group TS. Conclusion: Segmental thoracic spinal anesthesia technique provides better satisfaction with superior postoperative analgesia and fewer complications in patients undergoing breast cancer surgery compared to GA.

Pruritus after continuous administration of epidural morphine for post-cesarean delivery analgesia: a case control study.

BACKGROUND: Pruritus is one of the most common side effects of epidural morphine administered for post-surgery analgesia, and pregnant women tend to be highly susceptible. The relative contributions of morphine concentration, local anesthetics, and level of pain to pruritus after epidural morphine for post-cesarean delivery analgesia remain unclear. Accordingly, the present study aimed to identify risk factors for pruritus after continuous administration of epidural morphine for post-cesarean delivery analgesia. METHODS: This case control study was based on routinely collected clinical data. Participants included women who had undergone cesarean section and adopted a patient-controlled analgesia pump for postoperative analgesia. A series of logistic regression analyses were performed. Interaction terms were added to explore the moderation effects of combined local anesthetics and pain level on associations between morphine concentration and pruritus. Robustness of the results was checked through sensitivity analysis using propensity scores matching approach. RESULTS: Higher morphine concentration, assisted reproductive treatment, and multipara and cesarean section history were significantly more prevalent in the pruritus group than in the control group. The probabilities of pruritus at morphine concentrations of 10, 15, 20, 25, 30 and 40 µg/mL increased sequentially from 0.05, 0.1, 0.2, 0.35, 0.54 to 0.84, respectively. The trend remained steep in the ropivacaine stratum and became flatter when combined with levobupivacaine. At mild pain combined with levobupivacaine, the incidence of pruritus increased from 0.33 (95% confidence interval [CI] 0.1-0.68) in the 10 µg/mL morphine group to 0.48 (95% CI 0.1-0.88) in the 40 µg/mL morphine group. In the stratum of moderate pain combined with levobupivacaine, the incidence increased from 0.4 (95% CI 0.04-0.92) to 0.56 (95% CI 0.03-0.98). The results in the sensitivity analysis were in consistent with above findings. CONCLUSIONS: Higher concentrations of morphine, multipara, and assisted reproductive treatment were factors associated with a higher probability of pruritus. Pain level or combined local anesthetics could moderate the association between morphine concentration and pruritus.

The 14-day repeated-dose toxicity study of a fixed-dose combination, QXOH/levobupivacaine, via subcutaneous injection in beagle dogs.

QXOH-Levobupivacaine (LB) is a fixed-dose combination of 35-mM QXOH and 10-mM LB. It was developed for perioperative analgesia because of its long-acting analgesic effect. The purpose of this study was to evaluate the potential toxicity of QXOH-LB in beagle dogs in accordance with the Guidance on the repeated-dose toxicity published by the China Food and Drug Administration. Groups of five male and five female beagle dogs received normal saline, QXOH-LB (2, 4, and 8 mg/kg, calculated as QXOH), QXOH (2, 4, and 8 mg/kg), or LB (2 mg/kg, equals the concentration of LB in 8-mg/kg QXOH-LB group) at the volume of 1 mL/kg once per day for 14 days through subcutaneous injection. No mortality was observed. Dogs in the control group as well as animals treated with 2-mg/kg QXOH or QXOH-LB exhibited normal behaviors. Clinical signs of toxicity in dogs treated with 4 and 8 mg/kg of QXOH or QXOH-LB included decreased activity, unsteady gait, jerks, tremors, vocalization, emesis, ataxia, lateral/sternal recumbency, deep/rapid respiration, and gasping. Additionally, neurological function was found to be affected by QXOH and QXOH-LB at the doses of 4 and 8 mg/kg. All clinical signs were recovered within 24 h. The no-observed-adverse-effect level of QXOH and QXOH-LB was considered to be 2 mg/kg. Toxicokinetic data showed that exposure to QXOH and LB increased as QXOH-LB doses were increased from 4 to 8 mg/kg. There was no evidence of drug accumulation or any effect of gender.

Prediction of levobupivacaine concentrations in neonates and infants following neuraxial rescue blocks.

AIM: Pharmacokinetic simulation was used to characterize levobupivacaine disposition after regional anesthetic rescue for failed spinal anesthesia in neonates and infants. METHODS: Population pharmacokinetics of levobupivacaine were estimated after spinal blockade in a cohort of neonates and infants (n = 25, postnatal age 5-18 weeks, gestation 21-41 weeks, weight 2.4-6 kg). Total levobupivacaine concentrations were assayed 3-4 times in the first hour after spinal levobupivacaine 1 mg kg-1 administration. Parameters were estimated using nonlinear mixed-effects models and supported by priors. Covariates included postnatal age and total body weight. Parameter estimates were used to simulate total levobupivacaine concentrations after a primary spinal levobupivacaine 1 mg kg-1 with rescue caudal levobupivacaine 1.5-2.5 mg kg-1 . RESULTS: A one-compartment model with a mature clearance 21.5 L h-1  70 kg-1 (CV 47.3%) and central volume 189 L 70 kg-1 (CV 37%) adequately described time-concentration profiles. Clearance maturation was described using a maturation half-time of 11.5 weeks postnatal age. The absorption half-time for spinal levobupivacaine was 2.6 min (CV 56.8%). The upper (97.5% prediction) for peak concentrations after rescue caudal levobupivacaine were 1.5 mg kg-1 , 2 mg kg-1 , and 2.5 mg kg-1 was 2.05 mg L-1 , 2.5 mg L-1 , and 2.9 mg L-1 respectively. CONCLUSION: Total bupivacaine concentrations greater than 2.5 mg L-1 are associated with neurotoxicity in adults. Predicted concentrations after either a repeat spinal or a caudal rescue dose of levobupivacaine 1.5 mg kg-1 1 h after spinal levobupivacaine administration are below the neurotoxic concentration threshold.

Pharmacokinetics of intraperitoneal and subcutaneous levobupivacaine in anesthetized rats.

BACKGROUND: We compared the pharmacokinetics of levobupivacaine when administered intraperitoneally, subcutaneously, and intravenously in an anesthetized rat model, to estimate the toxicity risk of a local anesthetic when absorbed from the peritoneum. METHODS: Thirty-two rats were anesthetized with sevoflurane. In Experiment 1, we administered 5.0 mg/kg of levobupivacaine intraperitoneally (IP) (n = 7), subcutaneously (SC) (n = 6), or intravenously (IV) (n = 6). In Experiment 2, we administered 2.5 mg/kg of levobupivacaine IP (n = 7) or SC (n = 6). Data are shown as median [range] of Experiment 1. RESULTS: In either of experiments, the time to reach maximum plasma concentration of levobupivacaine was shorter in the IP group than in the SC group (IP: 2 [2-5] min; SC: 5 [2-10] min; P = 0.04), and the maximum concentration of levobupivacaine did not differ between the IP and SC groups (IP: 0.45 [0.05-0.67] µg/mL; SC: 0.47 [0.21-0.62] µg/mL; P = 0.90). The area under the curve from time 0 to 120 min after levobupivacaine administration was significantly higher in the SC group than in the IP group in both experiments (IP: 0.29 [0.10-0.54] mg h/L; SC: 0.78 [0.39-0.98] mg h/L; P = 0.04). CONCLUSION: Levobupivacaine is rapidly absorbed following IP administration, but its maximum plasma concentration within 2 h following IP administration is no statistical difference as that following SC administration. On the other hand, when levobupivacaine is given subcutaneously, Tmax can exceed 1 h, so we need to be aware of local anesthetic toxicity during this period.

Levobupivacaine-Loaded Liposome Associated with Thermogel for Prolonged Analgesia.

Pain is a phenomenon present in the majority of the population, affecting, among others, the elderly, overweight people, and especially recently operated patients, analgesia being necessary. In the specific case of relief of postoperative pain, different kinds of anesthetics are being used, among them bupivacaine, a widely used drug which promotes long-lasting analgesic effects. However, cardiotoxicity and neurotoxicity are related to its repetitive use. To overcome these shortcomings, Novabupi® (a racemic mixture) was developed and is marketed as an injectable solution. This formulation contains an enantiomeric excess of the levogyre isomer, which has reduced toxicity effects. Seeking to rationalize its use by extending the duration of effect and reducing the number of applications, the objectives of this work were to develop and evaluate liposomes containing Novabupi (LBPV), followed by incorporation into thermogel. Liposomes were prepared using the lipid hydration method, followed by size reduction using sonication, and the developed formulations were characterized by hydrodynamic diameter, polydispersity index (PDI), surface zeta potential, and encapsulation efficiency. The selected optimal liposomal formulation was successfully incorporated into a thermogel without loss of thermoresponsive properties, being suitable for administration as a subcutaneous injection. In the ex vivo permeation studies with fresh rodent skin, the thermogel with liposomes loaded with 0.5% LBPV (T-gel formulation 3) showed higher permeation rates compared to the starting formulation, thermogel with 0.5% LBPV (T-Gel 1), which will probably translate into better therapeutic benefits for treatment of postoperative analgesia, especially with regard to the number of doses applied.

Effect of dexmedetomidine on characteristics of ultrasound-guided supraclavicular brachial plexus block with levobupivacaine-A prospective double-blind randomized controlled trial.

BACKGROUND AND AIMS: Levobupivacaine, a less cardiotoxic s-isomer of bupivacaine, is proved to be similar to bupivacaine, hence, proposed as a safer alternative for nerve blocks. We aimed to evaluate the effect of perineural and intravenous dexmedetomidine on characteristics of ultrasound-guided supraclavicular brachial plexus block (BPB) performed with levobupivacaine. The aim of this study is to evaluate the effect of perineural and intravenous dexmedetomidine on characteristics of ultrasound-guided supraclavicular BPB performed with levobupivacaine. MATERIAL AND METHODS: A prospective, randomized double-blind control trial done on 120 patients undergoing elective upper limb surgical procedures under supraclavicular BPB. The enrolled patients were allocated to one of the three groups: Group L - 0.5% levobupivacaine +0.9% normal saline (NS) IV infusion; Group LDI - 0.5% levobupivacaine + dexmedetomidine (1 mcg/kg) in NS IV infusion; and Group LDP - 0.5% levobupivacaine +1 mcg/kg of dexmedetomidine perineural + NS IV infusion. The onset and duration of sensory and motor blockade were recorded in minutes. One-way ANOVA was used to observe any differences between the groups, and post hoc comparisons were conducted after Bonferroni correction for multiple comparisons. RESULTS: The onset of sensory and motor blockade in Group LDP was significantly shorter than Group L and Group LDI. The duration of sensory blockade in Group LDP was significantly longer than Group LDI and Group L. The duration of motor blockade in Group LDP was prolonged compared to Group LDI and Group L. CONCLUSIONS: When dexmedetomidine is added as adjunct to levobupivacaine in supraclavicular BPB, onset of sensory and motor blockade is faster in perineural group, whereas duration of sensory and motor blockade and duration of analgesia are more prolonged when used perineurally than intravenously.

Effect of addition of intrathecal magnesium sulphate to 0.5% hyperbaric bupivacaine and 0.5% isobaric levobupivacaine on duration of analgesia in parturients undergoing elective caesarean section: A prospective randomised study.

Background and Aims: Addition of magnesium sulfate to local anesthetics improves the quality of spinal anesthesia for caesarean section. The aim of this study was to compare the effects of intrathecal 0.5% hyperbaric bupivacaine with 75-mg magnesium sulfate (MgSO4) and 0.5% isobaric levobupivacaine with 75-mg MgSO4 on the duration of analgesia in parturients undergoing elective caesarean section. Material and Methods: This prospective randomized double-blind parallel-group study was conducted in 60 parturients undergoing elective caesarean section who were randomly allocated to Group I or Group II to receive either 2 ml of 0.5% levobupivacaine with 75-mg MgSO4 or 2 ml of 0.5% hyperbaric bupivacaine with 75-mg MgSO4 intrathecally. The duration of postoperative analgesia along with sensory and motor block characteristics and hemodynamics were studied. Results: The duration of analgesia did not show a significant difference in the two groups (P = 0.175). The sensory onset time was faster in Group I (3.5 ± 1.3 min) as compared to that in Group II (4.8 ± 2 min; P = 0.004). The onset of motor blockade was not different in the two groups (P = 0.265), but there was a significant delay (P = 0.002) in motor recovery in Group II (267 ± 130.6 min) as compared to Group I (225 ± 85.4 min). Hemodynamics were comparable in the two groups. Conclusion: Intrathecal levobupivacaine with MgSO4 produces a similar duration of postoperative analgesia as compared to hyperbaric bupivacaine with MgSO4. Early motor recovery allowing early ambulation postoperatively makes isobaric levobupivacaine with MgSO4 a good alternative for caesarean sections.