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

QXOH-LB, a fixed-dose combination (35 mM QXOH and 10 mM levobupivacaine) has been shown to induce a long duration of local anesthesia in animal efficacy testing, which indicates potential for postoperative pain management. In this study, we evaluated the potential toxicity of QXOH-LB in NIH mice under the Guidance on the repeated-dose toxicity published by the China Food and Drug Administration. Mice (n = 30 per sex per group) were subcutaneously injected 5, 10, 20 mg/kg QXOH-LB, 5, 10, 20 mg/kg QXOH, and 5 mg/kg levobupivacaine (LB) once a day for 14 days with sacrifice of main study animals; remaining mice (n = 10 per sex per group) were monitored for an additional 4-week recovery period. Mice in the 10 and 20 mg/kg QXOH, and 20 mg/kg QXOH-LB died, which was considered due to excessive respiratory inhibition. The doses of 10 mg/kg QXOH-LB and 5 mg/kg QXOH were well tolerated without any clinical signs of toxicity. Therefore, the no-observed-adverse-effect level (NOAEL) of QXOH-LB and QXOH was considered to be 10 and 5 mg/kg/day, respectively. In the dose range from 5 to 20 mg/kg, the exposure of QXOH and LB in QXOH-LB was equal to each agent used alone at the same dose in NIH mice. There was no gender difference on exposure and no evidence of accumulation.

Influence of Levobupivacaine Regional Scalp Block on Hemodynamic Stability, Intra- and Postoperative Opioid Consumption in Supratentorial Craniotomies: A Randomized Controlled Trial.

BACKGROUND: The anesthetic management of supratentorial craniotomy (CR) necessitates tight intraoperative hemodynamic control. This type of surgery may also be associated with substantial postoperative pain. We aimed at evaluating the influence of regional scalp block (SB) on hemodynamic stability during the noxious events of supratentorial craniotomies and total intravenous anesthesia, its influence on intraoperative anesthetic agents' consumption, and its effect on postoperative pain control. METHODS: Sixty patients scheduled for elective CR were prospectively enrolled. Patient, anesthesiologist, and neurosurgeon were blind to the random performance of SB with either levobupivacaine 0.33% (intervention group [group SB], n = 30) or the same volume of saline (control group [group CO], placebo group, n = 30). General anesthesia was induced and maintained using target-controlled infusions of remifentanil and propofol that were adjusted according to hemodynamic parameters and state entropy of the electroencephalogram (SE), respectively. Mean arterial blood pressure (MAP), heart rate (HR), SE, and propofol and remifentanil effect-site concentrations (Ce) were recorded at the time of scalp block performance (Baseline), and 0, 1, 3, and 5 minutes after skull-pin fixation (SP), skin incision (SI), CR, and dura-mater incision (DM). Morphine consumption and postoperative pain intensity (0-10 visual analog scale [VAS]) were recorded 1, 3, 6, 24, and 48 hours after surgery. Propofol and remifentanil overall infusion rates were also recorded. Data were analyzed using 2-tailed Student unpaired t tests, 2-way mixed-design analysis of variance (ANOVA), and Tukey's honestly significant difference (HSD) tests for post hoc comparisons as appropriate. RESULTS: Demographics and length of anesthetic procedure of group CO and SB were comparable. SP, SI, and CR were associated with a significantly higher MAP in group CO than in group SB, at least at one of the time points of recording surrounding those noxious events. This was not the case at DM. Similarly, HR was significantly higher in group CO than in group SB during SP and SI, at least at 1 of the points of recording, but not during CR and DM. Propofol and remifentanil Ce and overall infusion rates were significantly higher in group CO than in group SB, except for propofol Ce during SP. Postoperative pain VAS and cumulative morphine consumption were significantly higher in group CO than in group SB. CONCLUSIONS: In supratentorial craniotomies, SB improves hemodynamic control during noxious events and provides adequate and prolonged postoperative pain control as compared to placebo.

Is it safe for patients to drive after intra-articular knee injection?

BACKGROUND: Intra-articular knee injection is a central component in the current management of knee pain. While this is a routinely performed outpatient procedure, institutional policies for driving post injection differ. This study examines brake response times (BRTs) before and after intra-articular knee injection. Our hypothesis is that BRTs would not significantly differ and thus patients driving ability/safety is unaffected. METHODS: Forty-five patients previously listed for right intra-articular knee injection were prospectively evaluated. Patients underwent baseline assessment of BRT prior to injection. All patients received 10 ml of fluid consisting of one milliliter of 10 mg/ml triamcinolone mixed with nine milliliters of 0.5% levobupivacaine. BRT was re-examined on the same day prior to discharge home. Pre- and post-injection BRTs were examined using the same machine and assessor. RESULTS: The mean age of the cohort was 64.0 ± 12.4 and compromised of 37.8% males. There was no significant difference in the mean pre- and post-injection braking time (0.83 ± 0.29 vs 0.78 ± 0.30 s, p = .42), or in the rate of failed braking time (11.1% vs 6.7%, p = .46). CONCLUSION: This study found that BRT did not significantly differ before and after the intra-articular injection, nor did it cause an increased number of patients failing their BRTs. These findings suggest patients should not be prevented from driving after intra-articular knee injection.

A prospective randomized double-blind trial of the efficacy of a bilateral lumbar erector spinae block on the 24h morphine consumption after posterior lumbar inter-body fusion surgery.

BACKGROUND: Spine surgery is associated with considerable postoperative pain and can be challenging to treat. A loco-regional technique suitable for spine surgery should cover the dorsal root of the spinal nerves at the levels where surgery is performed. The erector spinae block is a loco-regional technique with promising results and was recently described at the thoracic level. There are no randomized trials of this technique on a lumbar level. This study tests the hypothesis that the 24-h postoperative morphine consumption is significantly lower in patients undergoing posterior lumbar inter-body fusion surgery with a lumbar erector spinae (LUMBES) block when compared with a sham block. METHODS: This prospective randomized double-blind multicenter study will randomly allocate 80 adult patients undergoing elective posterior lumbar inter-body fusion surgery during general anesthesia to one of two groups as follows: (1) bilateral erector spinae block (20 mL 0.25% levobupivacaine) or (2) bilateral sham block (20 mL NaCl 0.9%). Our primary endpoint is 24-h postoperative morphine consumption. Secondary endpoints include 72-h morphine consumption, intraoperative sufentanil dosage, postoperative pain scores at regular time intervals both at rest and during movement, time to first postoperative mobilization, and the Quality of Recovery 40 survey score. DISCUSSION: The LUMBES trial is a pragmatic clinical study that will provide evidence of whether a bilateral lumbar erector spinae block is effective in reducing 24-h postoperative morphine consumption in patients undergoing lumbar inter-body fusion surgery. If this hypothesis is confirmed, this finding could contribute to more widespread implementation of this technique. TRIAL REGISTRATION: Local ethics committee B300201837508, ClinicalTrials.gov identifier: NCT03825198 . Registered on 31 Jan 2019.

An Unusual Delayed Onset of Systemic Toxicity After Fluoroscopy-Guided Cervical Epidural Steroid Injection With Levobupivacaine: A Case Report.

BACKGROUND: Cervical epidural steroid injection (CESI) with local anesthetics is commonly used to treat neck pain and radicular pain of the upper extremity. Local anesthetic systemic toxicity (LAST) occurs shortly after injection as a complication; however, delayed onset is a very rare event, especially in central nervous system (CNS) block. CASE REPORT: We present a case in which delayed onset of LAST occurred in a patient who received CESI for cervical and arm radiating pain due to a cervical disc protrusion. We performed the interlaminar approach for CESI using fluoroscopic guidance. After confirming the location of the epidural space using the loss of resistance technique and spreading of contrast agent (Telebrix® 30), a mixture of 0.25% levobupivacaine 12.5 mg (5 mL in volume), hyaluronidase 1,500 IU (1 mL), dexamethasone 5 mg (1 mL), and normal saline 3 mL was administrated. After 50 minutes of injection, the patient showed CNS toxicity (unconsciousness, seizure) with normal blood pressure and tachycardia; therefore, she was immediately sedated with intravenous midazolam (3 mg), and 15 L/min of oxygen was administered. The patient fully recovered after 30 minutes of sedation without any sequelae. CONCLUSION: Delayed onset of LAST is a rare complication of a common procedure in CESI, so it is important to be aware of this complication and the presentation of toxicity.

Safety and Pharmacokinetics of Levobupivacaine Following Fascia Iliaca Compartment Block in Elderly Patients.

BACKGROUND: Fascia iliaca compartment block (FICB) is an increasingly popular analgesic technique in elderly patients with hip fracture. Despite requiring large volumes of local anaesthetic, there are no plasma pharmacokinetic data on FICB in elderly patients. OBJECTIVES: The objective of this study was to determine the pharmacokinetic profile of a levobupivacaine 75 mg (30 mL 0.25%) FICB dose in patients aged ≥ 80 years with fractured femur. METHODS: This was a single-arm descriptive pilot study. Twelve adults aged ≥ 80 years with hip fracture received FICB performed under ultrasound guidance. Venous blood was sampled at 10, 20, 30, 45, 60, 75, 90, 105, 120 and 240 min after injection. Total plasma levobupivacaine concentration was measured by mass spectrometry. The main outcome measures were pharmacokinetic parameters, including maximum observed plasma concentration (Cmax), time to reach Cmax (tmax) and area under the plasma concentration-time curve. RESULTS: The median (interquartile range [IQR]) Cmax was 0.82 µg/mL (0.47-1.03). tmax was 45 min (41:20-60:00). No evidence of toxicity was identified. Plasma levobupivacaine concentrations were below the threshold associated with toxicity in younger, healthy patients (2.6 µg/mL). No association was found between individual patient Cmax and α1-acid glycoprotein, weight or body mass index, although the study was not powered for these outcomes. CONCLUSIONS: Absorption of levobupivacaine was slow and all patients had plasma concentrations below the toxic threshold. This pharmacokinetic analysis concludes that the technique appears to be well-tolerated and efficacious at reducing pain and is associated with systemic plasma concentrations unlikely to be associated with major adverse effects in elderly patients. CLINICAL TRIAL REGISTRATION: ISRCTN27364035 (UK Clinical Trials Gateway).

Usefulness of diaphragmatic ultrasound in the early diagnosis of phrenic nerve palsy after shoulder surgery in the prevention of post-operative respiratory complications. / Utilidad de la ecografía diafragmática en el diagnóstico precoz de parálisis frénica tras cirugía de hombro para prevenir complicaciones respiratorias postoperatorias.

Phrenic nerve block is a complication that can occur after brachial plexus anaesthesia above the clavicle. The main consequence of this blockage is ipsolateral diaphragmatic paralysis, which can sometimes lead to the appearance of post-operative respiratory complications. A case is presented on a woman, who after having undergone a total shoulder prosthesis, presented with dyspnoea in the post-operative recovery unit. A diaphragmatic ultrasound was performed that enabled a rapid diagnosis to be made of a complete paralysis of the ipsolateral hemi-diaphragm. Given the suspicion of phrenic nerve block, ultrasound has proven to be a rapid diagnostic tool with high sensitivity and specificity. Its use can anticipate the possible development of immediate complications, and act as a guide in choosing the appropriate therapeutic strategy for each case in an early manner. In this case it enabled us to treat early with oxygen therapy, interscalene catheter removal, and intensive surveillance.

Myotoxicity of local anesthetics is equivalent in individuals with and without predisposition to malignant hyperthermia.

PURPOSE: Malignant hyperthermia (MH) is an inherited muscle disorder caused by abnormal elevations of intracellular calcium (Ca2+) in skeletal muscle. There are several reports of myotoxicity caused by local anesthetics, and the increased intracellular Ca2+ is considered to be an important cause. However, there is insufficient evidence regarding myotoxicity in MH-susceptible individuals when large doses of local anesthetics are administered. This study investigated the effect of MH predisposition on myotoxicity. METHODS: Human skeletal muscle samples were obtained from 22 individuals to determine susceptibility to MH, and were evaluated according to whether their Ca2+-induced Ca2+ release (CICR) rates were accelerated or not. This study was performed using surplus muscle that remained after the CICR rate test. We calculated the 50% effective concentration (EC50) values of three local anesthetics, namely lidocaine, levobupivacaine, and ropivacaine using the ratiometric dye Fura-2 AM. Significance was tested using the unpaired t test. RESULTS: In the accelerated and unaccelerated groups, respectively, the mean ± SD of the EC50 values were 1.52 ± 0.72 and 1.75 ± 0.37 mM for lidocaine (p = 0.42), 0.72 ± 0.36 and 0.79 ± 0.46 mM for levobupivacaine (p = 0.68), and 1.21 ± 0.35 and 1.62 ± 0.57 mM for ropivacaine (p = 0.06). These values were similar in individuals with and without MH predisposition. CONCLUSION: The myotoxicity of local anesthetics was equivalent in individuals with and without predisposition to MH.

Epidural Dexmedetomidine Reduces the Requirement of Propofol during Total Intravenous Anaesthesia and Improves Analgesia after Surgery in Patients undergoing Open Thoracic Surgery.

The aim of this study was to assess the systemic and analgesic effects of epidural dexmedetomidine in thoracic epidural anaesthesia (TEA) combined with total intravenous anaesthesia during thoracic surgery. Seventy-one patients undergoing open thoracotomy were included in this study and randomly divided into three groups: Control group (Group C): patients received TEA with levobupivacaine alone and were intravenously infused with saline; Epidural group (Group E): patients received TEA with levobupivacaine and dexmedetomidine, and were intravenously infused with saline; Intravenous group (group V): patients received TEA with levobupivacaine alone and were intravenously infused with dexmedetomidine. The doses of propofol used in the induction and maintenance of general anaesthesia, cardiovascular response, dose and first time of postoperative analgesia and verbal rating scale were recorded. The induction and maintenance were significantly lower in the Groups E and V. Verbal rating scale and postoperative analgesic requirements were significantly lower in Group E than in Groups C and V. Patients in Group C had more severe cardiovascular responses, as compared with Groups E and V. Epidural administration of dexmedetomidine reduced the induction and maintenance of propofol, and inhibited the cardiovascular response after intubation and extubation. Moreover, epidural dexmedetomidine provided better analgesia after open thoracotomy.