Anterior Quadratus Lumborum block area comparison in the three different volumes of Ropivacaine: a double-blind, randomized controlled trial in healthy volunteers.

BACKGROUND: In abdominal surgery, ultrasound-guided anterior quadratus lumborum blocks (QLB) are performed to induce analgesia. However, no study reported suitable volumes of the anterior QLB for the different postoperative analgesia regions. Therefore, this prospective randomized controlled study assessed the dermatomal spread and analgesic effects of the three different volumes of a local anesthetic for anterior QLB. METHODS: Ultrasound-guided anterior QLB was performed at the L2 level on 30 healthy volunteers. The volunteers were randomized to receive 20 ml (n = 10), 30 ml (n = 10), and 40 mL (n = 10) of 0.375% ropivacaine. The cutaneous sensory blocked area (CSBA), the number of block dermatomes, and the block duration time were measured by determining the extent of the cold sensation. RESULTS: The CSBA was significantly larger in the 40 ml group than in the 30 (P = 0.001; 1350.6 ± 234.4 vs. 1009.5 ± 151.6 cm2) and 20 ml groups (P < 0.001; 1350.6 ± 234.4 vs. 808.1 ± 120.5 cm2). Similarly, the number of blocked dermatomes was significantly higher in the 40 ml group than in the 30- and 20-ml groups. However, no significant difference was observed in block duration among the groups. CONCLUSIONS: No difference was observed in block duration with the various volumes of 0.375% ropivacaine. However, the larger volume for anterior QLB contributed to a larger area of cutaneous sensory blockade. Appropriate volumes in anterior QLB can create suitable postoperative analgesia levels for the different operative sites. TRIAL REGISTRATION: The study was registered in the Chinese Clinical Trial Registration Center on www.chictr.org.cn on 27th April 2018 (registration number: ChiCTR-IOR-17010853).

Apelin-13 Reverses Bupivacaine-Induced Cardiotoxicity via the Adenosine Monophosphate-Activated Protein Kinase Pathway.

BACKGROUND: Cardiotoxicity can be induced by the commonly used amide local anesthetic, bupivacaine. Bupivacaine can inhibit protein kinase B (AKT) phosphorylation and activated adenosine monophosphate-activated protein kinase alpha (AMPKα). It can decouple mitochondrial oxidative phosphorylation and enhance reactive oxygen species (ROS) production. Apelin enhances the phosphatidylinositol 3-kinase (PI3K)/AKT and AMPK/acetyl-CoA carboxylase (ACC) pathways, promotes the complete fatty acid oxidation in the heart, and reduces the release of ROS. In this study, we examined whether exogenous (Pyr1) apelin-13 could reverse bupivacaine-induced cardiotoxicity. METHODS: We used the bupivacaine-induced inhibition model in adult male Sprague Dawley (SD) rats (n = 48) and H9c2 cardiomyocyte cell cultures to explore the role of apelin-13 in the reversal of bupivacaine cardiotoxicity, and its possible mechanism of action. AMPKα, ACC, carnitine palmitoyl transferase (CPT), PI3K, AKT, superoxide dismutase 1 (SOD1), and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (p47-phox) were quantified. Changes in mitochondrial ultrastructure were examined, and mitochondrial DNA, cell viability, ROS release, oxygen consumption rate (OCR) were determined. RESULTS: Apelin-13 reduced bupivacaine-induced mitochondrial DNA lesions in SD rats (P < .001), while increasing the expression of AMPKα (P = .007) and PI3K (P = .002). Furthermore, apelin-13 blocked bupivacaine-induced depolarization of the mitochondrial membrane potential (P = .019) and the bupivacaine-induced increases in ROS (P = .001). Also, the AMPK pathway was activated by bupivacaine as well as apelin-13 (P = .002) in H9c2 cardiomyocytes. Additionally, the reduction in the PI3K expression by bupivacaine was mitigated by apelin-13 in H9c2 cardiomyocytes (P = .001). While the aforementioned changes induced by bupivacaine were not abated by apelin-13 after pretreatment with AMPK inhibitor compound C; the bupivacaine-induced changes were still mitigated by apelin-13, even when pretreated with PI3K inhibitor-LY294002. CONCLUSIONS: Apelin-13 treatment reduced bupivacaine-induced oxidative stress, attenuated mitochondrial morphological changes and mitochondrial DNA damage, enhanced mitochondrial energy metabolism, and ultimately reversed bupivacaine-induced cardiotoxicity. Our results suggest a role for the AMPK in apelin-13 reversal of bupivacaine-induced cardiotoxicity.

Single and Repeated Intrapleural Ropivacaine Administration: A Plasma Concentration and Pharmacodynamics Study.

BACKGROUND: Intrapleural analgesia has been increasingly recommended for postoperative analgesia after thoracic surgery. However, the analgesic effect provided by a single intrapleural administration is time limited. This study reports the efficacy and safety of repeated intrapleural 0.75% ropivacaine administration after thoracoscopic surgery. METHODS: Twenty patients were randomly divided into two groups: a single administration group receiving a single intrapleural injection of 0.75% ropivacaine 15 mL (single administration group, SA group), and a repeated administration group with an intrapleural injection of 0.75% ropivacaine 15 mL every 4h for 4 doses (repeated administration group, RA group). The primary outcomes of this study were the peak plasma concentration of ropivacaine and 24h morphine consumption. The secondary outcomes were pain score, patient satisfaction, extubation time, hospital length of stay, and adverse reactions. RESULTS: In SA group, the highest plasma concentration after intrapleural administration of 0.75% ropivacaine 15 mL was 1345±364 µg/L. The highest plasma concentration in RA group after the fourth administration was 1864±492 µg/L. The 24h morphine consumption in RA group was significantly less than that in SA group (9.0±5.66 vs 15.9±3.48 mg, P=0.004). The NRS scores at rest and while coughing of patients in RA group were significantly lower than those in SA group at 5, 9, 13, 17 and 24h after operation. The patients in RA group had higher satisfaction than those in SA group. There was no significant difference in postoperative adverse events, drainage tube placement days and hospital length of stay between the two groups. CONCLUSION: Repeated intrapleural administration with 0.75% ropivacaine, 15 mL every 4h for 4 doses after video-assisted thoracoscopic lobectomies, can provide a more durable and more effective analgesic effect than single intrapleural administration. Repeated intrapleural administration of ropivacaine is an effective postoperative method of analgesia resulting in higher patient satisfaction. Moreover, it was also able to keep the plasma concentration of ropivacaine within a possible safe range. CLINICAL TRIAL REGISTRATION NUMBER: ChiCTR-IOR-17010560.

Evaluation of Recombinant CYP3A4 Variants on the Metabolism of Oxycodone In Vitro.

Cytochrome P450 3A4 is a highly polymorphic enzyme and metabolizes approximately 40%-60% of therapeutic drugs. Its genetic polymorphism may significantly affect the expression and function of CYP3A4 resulting in alterations of the pharmacokinetics and pharmacodynamics of the CYP3A4-mediated drugs. The purpose of this study was to evaluate the catalytic activities of 30 CYP3A4 nonsynonymous variants and wild type toward oxycodone in vitro. CYP3A4 proteins were incubated with oxycodone for 30 min at 37 °C and the reaction was terminated by cooling to -80 °C immediately. Ultraperformance liquid chromatography tandem mass-spectrometry was used to analyze noroxycodone, and kinetic parameters Km, Vmax, and intrinsic clearance (Vmax/Km) of noroxycodone were also determined. Compared with CYP3A4.1, 24 CYP3A4 variants (CYP3A4.2-.5, -.7-.16, -.18 and -.19, -.23 and -.24, -.28 and -.29, and -.31-.34) exhibited significantly decreased relative clearance values (from 4.82% ± 0.31% to 80.98% ± 5.08%), whereas CYP3A4.6, -.17, -.20, -.21, -.26, and -.30 displayed no detectable enzyme activity. As the first study of these alleles for oxycodone metabolism in vitro, results of this study may provide insight into establishing the genotype-phenotype relationship for oxycodone and serve as a reference for clinical administrators and advance the provision of personalized precision medicine.

Ganoderic acid A alleviates myocardial ischemia-reperfusion injury in rats by regulating JAK2/STAT3/NF-κB pathway.

This study aimed to investigate the protective effect of GanodericacidA (GA) on myocardial ischemia-reperfusion (MIR) injury. The myocardial injury model in rats was established by ligating left anterior descending coronary artery. We measured cardiac hemodynamic, antioxidant enzyme activity, and various biochemical indexes of myocardial tissue, and evaluated myocardial infarction and damage. Further, the expression of JAK2/STAT3/NF-κB signaling pathway-related proteins in myocardial tissue was measured by western blot. The results showed that the myocardial infarction extention was obviously reduced upon GA treatment. Compared with the control group, ischemia-reperfusion rats showed significant increase in lactate dehydrogenase (LDH) and creatine Kinase (CK), which were significantly decreased in GA group. Besides, GA pretreatment effectively decreased the levels of inflammatory cytokines in serum. The phosphorylation of Janus Kinase 2 (JAK2), signal transducer and activator of transcription (STAT3)and Nuclear factor-κB (NF-κB) in reperfusion group were significantly higher than that in control group, which were reversed upon GA treatment. In conclusion, GA may reduce myocardial injury by regulating JAK2/STAT3/NF-κB pathway.

Comparison of programmed intermittent bolus infusion and continuous infusion for postoperative patient-controlled analgesia with thoracic paravertebral block catheter: a randomized, double-blind, controlled trial.

BACKGROUND AND OBJECTIVES: In this randomized, double-blind, controlled study, we hypothesized that programmed intermittent bolus infusion (PIBI) of local anesthetic for continuous paravertebral block (PVB), combined with patient-controlled analgesia (PCA), provided better pain control, better patient satisfaction, and decreased in local anesthetic consumption when compared with a continuous infusion (CI) combined with PCA, after video-assisted thoracoscopic unilateral lung resection surgery. METHODS: Preoperatively, patients undergoing video-assisted thoracoscopic unilateral lung resection surgery received ipsilateral paravertebral catheters inserted at the level of thoracic vertebrae 4 and 5. All the subjects received an initial bolus of 15 mL 0.375% ropivacaine via the catheters. Subjects were randomized to receive 0.2 % ropivacaine 8 mL/h as either PIBI (n=17) or CI (n=17) combined with a PCA pump. The pain scores, frequency of PCA, local anesthetic consumption, patient satisfaction, and the need for rescue analgesia with tramadol were recorded until 48 hours postoperative. RESULTS: The numeric rating scale scores in the PIBI group were significantly lower than the CI group at 4, 8, 12 hours and 4, 8, 12, 24 hours postoperatively, at rest, and during coughing, respectively. PCA local anesthetic consumption (30 mg (20-60 mg) vs 120 mg (70-155 mg), p=0.000) and frequency of PCA use over 48 hours (3 (2-6) vs 12 (7-15.5), p=0.000) was lower in the PIBI group as compared with the CI group. Additionally, the PIBI group showed greater patient satisfaction. The need for tramadol rescue was similar in the two groups. CONCLUSIONS: In PVBs, local anesthetic administered as a PIBI in conjunction with PCA provided superior postoperative analgesia to a CI combined with PCA in patients undergoing video-assisted thoracoscopic unilateral lung resection surgery. CLINICAL TRIAL REGISTRATION: ChiCTR-IOR-17011253.

Levosimendan combined with epinephrine improves rescue outcomes in a rat model of lipid-based resuscitation from bupivacaine-induced cardiac arrest.

BACKGROUND: The effectiveness of a combination of a lipid emulsion with epinephrine in reversing local anesthetic-induced cardiac arrest has been confirmed. The combination of a lipid emulsion with levosimendan, was shown to be superior to administration of a lipid emulsion alone with regard to successful resuscitation. In this study, we compared the reversal effects of levosimendan, epinephrine, and a combination of the two agents in lipid-based resuscitation in a rat model of bupivacaine-induced cardiac arrest. METHODS: Fifty-four adult male Sprague-Dawley rats were subjected to bupivacaine (15 mg·kg-1) -induced asystole and were then randomly divided into 3 groups. A lipid emulsion was used as the basic treatment, and administration of drug combinations varied in each group as follows: (1) levosimendan combined with epinephrine (LiEL); (2) epinephrine (LiE); and (3) levosimendan (LiL). The resuscitation outcomes were recorded and included the rate of return of spontaneous circulation (ROSC) and survival at 40 min, time to first heartbeat, time to ROSC, and cumulative dose of epinephrine. We calculated the wet-to-dry ratio of the lung, blood gas values at 40 min and bupivacaine concentration of cardiac tissue and plasma. RESULTS: The rates of ROSC in LiEL and LiE groups were higher than LiL group (P < 0.001; LiEL vs LiL, P = 0.001; LiE vs LiL, P = 0.007). The survival rate in LiEL group was higher than LiE group (P = 0.003; LiEL vs LiE, P = 0.008; LiEL vs LiL, P = 0.001). The time to first heart beat in LiEL group was shorter than LiE, LiL groups. (P < 0.001; LiE vs LiEL, P = 0.001; LiL vs LiEL, P < 0.001). The time to ROSC in LiEL group was shorter than LiE, LiL groups (P < 0.001; LiEL vs LiE, P < 0.001; LiEL vs LiL, P < 0.001). The result was similar for the bupivacaine concentration of cardiac tissue and plasma (cardiac tissue: P = 0.002; plasma: P = 0.011). Furthermore, there were significant differences in the blood-gas values at 40 min, wet-to-dry lung weight ratio, and ratio of damaged alveoli among groups. The LiEL group had the best result for all parameters (P < 0.01, P = 0.008, P < 0.001, respectively). Additionally, significantly less epinephrine was used in the LiEL group (P < 0.001). CONCLUSIONS: Levosimendan combined with epinephrine may be superior to either drug alone for lipid-based resuscitation in a rat model of bupivacaine-induced cardiac arrest. The drug combination was associated with a higher survival rate as well as decreased epinephrine consumption and lung damage.