ABSTRACT
BACKGROUND: Long-lasting local anesthetic use for perioperative pain control is limited by possible cardiotoxicity (e.g., arrhythmias and contractile depression), potentially leading to cardiac arrest. Off-target cardiac sodium channel blockade is considered the canonical mechanism behind cardiotoxicity; however, it does not fully explain the observed toxicity variability between anesthetics. The authors hypothesize that more cardiotoxic anesthetics (e.g., bupivacaine) differentially perturb other important cardiomyocyte functions (e.g., calcium dynamics), which may be exploited to mitigate drug toxicity. METHODS: The authors investigated the effects of clinically relevant concentrations of racemic bupivacaine, levobupivacaine, or ropivacaine on human stem cell-derived cardiomyocyte tissue function. Contractility, rhythm, electromechanical coupling, field potential profile, and intracellular calcium dynamics were quantified using multielectrode arrays and optical imaging. Calcium flux differences between bupivacaine and ropivacaine were probed with pharmacologic calcium supplementation or blockade. In vitro findings were correlated in vivo using an anesthetic cardiotoxicity rat model (females; n = 5 per group). RESULTS: Bupivacaine more severely dysregulated calcium dynamics than ropivacaine in vitro (e.g., contraction calcium amplitude to 52 ± 11% and calcium-mediated repolarization duration to 122 ± 7% of ropivacaine effects, model estimate ± standard error). Calcium supplementation improved tissue contractility and restored normal beating rhythm (to 101 ± 6%, and 101 ± 26% of control, respectively) for bupivacaine-treated tissues, but not ropivacaine (e.g., contractility at 80 ± 6% of control). Similarly, calcium pretreatment mitigated anesthetic-induced arrhythmias and cardiac depression in rats, improving animal survival for bupivacaine by 8.3 ± 2.4 min, but exacerbating ropivacaine adverse effects (reduced survival by 13.8 ± 3.4 min and time to first arrhythmia by 12.0 ± 2.9 min). Calcium channel blocker nifedipine coadministration with bupivacaine, but not ropivacaine, exacerbated cardiotoxicity, supporting the role of calcium flux in differentiating toxicity. CONCLUSIONS: Our data illustrate differences in calcium dynamics between anesthetics and how calcium may mitigate bupivacaine cardiotoxicity. Moreover, our findings suggest that bupivacaine cardiotoxicity risk may be higher than for ropivacaine in a calcium deficiency context.
Subject(s)
Anesthetics, Local , Calcium , Female , Rats , Humans , Animals , Anesthetics, Local/toxicity , Cardiotoxicity , Myocytes, Cardiac , Amides/pharmacology , Bupivacaine/toxicity , Ropivacaine/toxicity , Arrhythmias, Cardiac/chemically inducedABSTRACT
Purpose: Prolonged local anesthesia (PLA) of the cornea is currently assumed to cause neurotrophic keratitis and is strongly discouraged. We investigate whether PLA of the cornea per se causes neurotrophic keratitis. Methods: PLA of the cornea was induced in 12 female albino BALB/c mice by retrobulbar injection of a polymeric prodrug (PGS-TTX) where the site 1 sodium channel blocker tetrodotoxin (TTX) was slowly released from the polymer polyglycerol sebacate. The duration and depth of corneal anesthesia was monitored by the Cochet-Bonnet esthesiometer. Corneal injury from PLA was assessed by slit lamp examination with 2% sodium fluorescein dye, histology, corneal nerve density by immunohistochemistry with anti-ß III tubulin antibody and confocal microscopy, and corneal neurotrophin levels (substance P and neurokinin A) by an enzyme-linked immunosorbent assay. PLA was also induced by topical amitriptyline (80 mM), used as a positive control for local anesthetic-induced corneal injury. Frequent ocular lubrication was provided. Results: Retrobulbar PGS-TTX resulted in complete corneal anesthesia lasting 50.1 ± 3.6 hours and mean time to complete resolution of block of 55.1 ± 3.6 hours with no keratopathy provided lubrication was provided. Topical 80 mM amitriptyline induced complete corneal anesthesia for 24 hours and developed keratopathy. There was no difference in the histology, levels of corneal neurotrophins, and corneal nerve density between the retrobulbar PGS-TTX group and normal cornea. Conclusions: In the absence of topical toxicity or corneal exposure, PLA of the cornea per se does not cause keratitis. Translational Relevance: PLA of the cornea could be highly beneficial in acute and chronic painful corneal conditions.
Subject(s)
Corneal Dystrophies, Hereditary , Keratitis , Anesthesia, Local/adverse effects , Anesthetics, Local/toxicity , Animals , Cornea , Female , MiceABSTRACT
ABSTRACT: Local anesthetic systemic toxicity (LAST) is a life-threatening event caused by elevated local anesthetic plasma concentration. It is often unrecognized or misdiagnosed. Peripartum women are at increased risk for toxicity due to pregnancy-related physiological changes. Rising serum drug levels can cause cellular level impairment of mitochondria and voltage-gated ion channels leading to a cascade of symptoms that can end in cardiac arrest. Local anesthetic systemic toxicity can mimic other maternal pathologies but may be considered if local anesthetics have been used. Published treatment guidelines for this event include lipid emulsion which is approved for use in pregnant women. We review LAST in the maternity care setting, published treatment protocols, management of maternity patients with toxicity, and recommendations to increase awareness among maternity care clinicians for this medical emergency.
Subject(s)
Anesthesia, Local/adverse effects , Anesthetics, Local/adverse effects , Anesthetics, Local/toxicity , Drug-Related Side Effects and Adverse Reactions/diagnosis , Fat Emulsions, Intravenous/administration & dosage , Fat Emulsions, Intravenous/therapeutic use , Labor, Obstetric , Anesthesia, Local/methods , Anesthetics, Local/administration & dosage , Drug-Related Side Effects and Adverse Reactions/etiology , Female , Humans , Maternal Health Services , Postpartum Period , Practice Guidelines as Topic , PregnancyABSTRACT
Currently, the influences of free terminal groups (hydroxyl, carboxyl and ester) of PLGA on encapsulating active pharmaceutical ingredient are relatively ambiguous even though PLGA types were defined as critical quality attributes in vast majority of design of experiment process. In this study, emulsion method combined with premix membrane emulsification technique has been used to encapsulate ropivacaine (RVC), a small molecule local anesthetic in clinical. Based on the narrow particle size distribution, the influences and mechanisms of the terminal groups on properties of ropivacaine loaded microspheres have been investigated in detail. It was found that microspheres prepared by PLGA with hydroxyl or ester groups exhibited lower encapsulation efficiency but faster in vitro release rate than that of carboxyl groups. In the meanwhile, on microcosmic level analysis by quartz crystal microbalance with dissipation, atomic force microscope and confocal laser scanning microscopy, we attributed this distinction to the specific interaction between ropivacaine and different terminal groups. Subsequently, the reaction activation centers were verified by density functional simulation calculation and frontier molecular orbital theory at molecular level. Additionally, pharmacokinetics and pharmacodynamic research of infiltration anesthesia model were performed to compare sustained release ability, duration and intensity of the anesthetic effect in vivo. Finally, potential safety and toxicity were evaluated by the biochemical analysis. This study not only provides a novel mechanism of drug encapsulation process but also potential flexible selections in terms of various anesthesia indications in clinical.
Subject(s)
Anesthetics, Local/administration & dosage , Drug Carriers/chemistry , Drug Compounding/methods , Polylactic Acid-Polyglycolic Acid Copolymer/chemistry , Ropivacaine/administration & dosage , Anesthesia, Local/methods , Anesthetics, Local/adverse effects , Anesthetics, Local/pharmacokinetics , Anesthetics, Local/toxicity , Animals , Delayed-Action Preparations/administration & dosage , Delayed-Action Preparations/pharmacokinetics , Drug Liberation , Emulsions , Injections, Intradermal , Male , Microspheres , Models, Animal , Particle Size , Rats , Ropivacaine/adverse effects , Ropivacaine/pharmacokinetics , Ropivacaine/toxicity , Toxicity Tests, AcuteABSTRACT
BACKGROUND: Electroacupuncture is well known for its advantageous neuroanalgesic and therapeutic effects on myocardial ischemia-reperfusion injury. The purpose of the present research was to verify whether electroacupuncture can alleviate bupivacaine-induced myocardial injury. METHODS: Specific pathogen-free Wistar rats were used to establish the bupivacaine-induced myocardial injury model. Western blot, PCR, transmission electron microscope and enzyme-linked immunosorbent (ELISA) methods were used to evaluate bupivacaine-induced structure injury and dysfunction of the mitochondria as well as the alleviating effects of lipid emulsion, acupoint injection, and electroacupuncture pre-treatment of the oxidase stress response. RESULTS: Bupivacaine caused structural damage, degradation, and swelling of mitochondria. Furthermore, it reduced adenosine triphosphate (ATP) synthesis and impaired energy metabolism in the mitochondria. Structural and functional impairment of the mitochondria was alleviated via lipid emulsion injection, acupoint injection, and electroacupuncture pre-treatment. Electroacupuncture pre-treatment of PC6 yielded a greater alleviating effect than others approaches. Following electroacupuncture pre-treatment of PC6 point, the number of mitochondria increased; apoptosis was reduced, enzymatic activity of cytochrome C oxidase (COX) and superoxide dismutase and expression of uncoupling protein 2, voltage-dependent anion channel 1, and Bcl 2 were upregulated and SLC25A6, MDA levels were downregulated. Additionally, our findings indicated that electroacupuncture pre-treatment of PC6 point exerted an effect on the mitochondria via the mitochondrial-transcription-factor-A/nuclear-respiratory-factor-1/proliferator-activated-receptor-gamma-coactivator-1 pathway. CONCLUSION: The present study revealed that electroacupuncture pre-treatment of PC6 could effectively alleviate bupivacaine-induced myocardial mitochondrial damage, thereby providing a theoretical basis for clinical studies and applications of this treatment method.
Subject(s)
Bupivacaine/toxicity , Electroacupuncture/methods , Mitochondria, Heart/physiology , Mitochondrial Proteins/metabolism , Myocardial Reperfusion Injury/prevention & control , Anesthetics, Local/toxicity , Animals , Apoptosis , Male , Mitochondrial Proteins/genetics , Myocardial Reperfusion Injury/chemically induced , Myocardial Reperfusion Injury/metabolism , Myocardial Reperfusion Injury/pathology , Oxidative Stress , Rats , Rats, WistarABSTRACT
INTRODUCTION: Systemic reactions from local tetracaine use are often an anomaly - not only is tetracaine short-acting and quickly metabolized by the pseudocholinesterase system leading to very limited systemic uptake, but most adverse reactions are usually associated with dental or spinal anesthesia. Furthermore, reactions to local anesthetics manifest in standard allergy-type reactions. When local anesthetics lead to nervous or cardiac system abnormalities, it is termed a local anesthetic systemic toxicity - an event with an incidence currently estimated to be 0.03%. CASE PRESENTATION: We present a case of a 56-year-old female who experienced a systemic reaction to tetracaine 1% while undergoing a fine needle biopsy of a thyroid nodule. The patient had previous allergic reactions to lidocaine. Upon conclusion of the procedure, the patient began convulsing and became rigid and non-verbal. She was able to move all extremities, had no respiratory distress, no swelling, hives, or redness, and was swallowing without difficulty. After about 5 min, the patient began to improve and experienced reversal of all previous symptoms. Her physical exam and labs were otherwise normal, she returned to her baseline functioning, and was discharged without any medical interventions. DISCUSSION: This case illustrates a case of LAST in a patient with previous Lidocaine allergy without any other obvious risk factors. There have been no cases of cross-reaction between lidocaine and tetracaine so it explores the possibility of patients having cross reaction to those two different kinds of local anesthetic.
Subject(s)
Anesthetics, Local/toxicity , Seizures/chemically induced , Tetracaine/toxicity , Anesthesia, Local/adverse effects , Anesthesia, Local/methods , Biopsy, Needle/adverse effects , Female , Humans , Middle Aged , Thyroid Nodule/pathologyABSTRACT
OBJECTIVES: The purpose of this study was to perform an updated analysis of complications associated with upper and lower extremity peripheral nerve blocks (PNBs) performed with ultrasound (US) guidance versus the landmark approach. METHODS: We conducted a single-center retrospective cohort analysis to compare the incidence of PNB complications between the techniques. The primary outcome was local anesthetic systemic toxicity (LAST), whereas the secondary outcomes included short- and long-term nerve injuries. The current query included cases performed between 2012 and 2015. A combined analysis included data extending to 2006. The Statistical examination relied on the χ2 test. RESULTS: During this 4-year period, we performed 7789 US-guided and 498 landmark-guided blocks with no statistically significant difference in the incidence of nerve injury or LAST between the groups. Our 10-year analysis, however, revealed a significant increase (P < .01) in the rate of LAST with the landmark technique: 7 of 5932 versus 0 of 16,858 cases. The combined data also revealed a significant increase (P < .01) in short-term injuries associated with the landmark approach (30 of 5932 versus 33 of 16,858) but no significant difference in the incidence of long-term injuries. CONCLUSIONS: Our analysis supports a conclusion that the use of US guidance during PNBs leads to a significant reduction in the incidence of LAST, adding to growing evidence from similar investigations. The impact of US on the incidence of nerve injuries remains unclear, considering that the nature of transient deficits is thought to be multifactorial, and the frequency of lasting injuries did not differ significantly in this study.
Subject(s)
Nerve Block/adverse effects , Nerve Block/methods , Peripheral Nerve Injuries/etiology , Peripheral Nerves/drug effects , Transcutaneous Electric Nerve Stimulation/methods , Ultrasonography, Interventional/methods , Adult , Aged , Anesthetics, Local/toxicity , Cohort Studies , Female , Humans , Male , Middle Aged , Peripheral Nerves/diagnostic imaging , Retrospective StudiesABSTRACT
BACKGROUND: The relatively short duration of effect of local anesthetics has been addressed by encapsulation in drug delivery systems. Codelivery with a single compound that produces an adjuvant effect on nerve block but without intrinsic local anesthetic properties can further prolong the nerve block effect. Here, we investigated whether codelivery of more than 1 encapsulated adjuvant compound can further enhance nerve blockade. METHODS: Liposomes loaded with bupivacaine (Bup), dexamethasone phosphate (DexP), or dexmedetomidine (DMED) were synthesized and its in vitro drug release profiles were determined. Animals (Sprague-Dawley rats) were injected with liposomal Bup (Lipo-Bup) and adjuvants at the sciatic nerve and underwent a modified hot plate test to assess the degree of nerve block. The duration of block was monitored and the tissue reaction was assessed. RESULTS: Coinjection of Lipo-Bup with liposomal DexP (Lipo-DexP) and liposomal DMED (Lipo-DMED) prolonged the duration of sciatic nerve block 2.9-fold compared to Lipo-Bup alone (95% confidence interval, 1.9- to 3.9-fold). The duration of the block using this combination was significantly increased to 16.2 ± 3.5 hours compared to Lipo-Bup with a single liposomal adjuvant (8.7 ± 2.4 hours with Lipo-DMED, P = .006 and 9.9 ± 5.9 hours with Lipo-DexP, P = .008). The coinjection of Lipo-Bup with liposomal adjuvants decreased tissue inflammation (P = .014) but did not have a significant effect on myotoxicity when compared to Lipo-Bup alone. Coinjection of Lipo-Bup with unencapsulated adjuvants prolonged the duration of nerve block as well (25.0 ± 6.3 hours; P < .001) however was accompanied by systemic side effects. CONCLUSIONS: Codelivery of Lipo-DexP and Lipo-DMED enhanced the efficacy of Lipo-Bup. This benefit was also seen with codelivery of both adjuvant molecules in the unencapsulated state, but with marked systemic toxicity.
Subject(s)
Adjuvants, Anesthesia/administration & dosage , Anesthesia, Local/methods , Anesthetics, Combined/administration & dosage , Anesthetics, Local/administration & dosage , Bupivacaine/administration & dosage , Dexamethasone/administration & dosage , Dexmedetomidine/administration & dosage , Nerve Block/methods , Sciatic Nerve/drug effects , Adjuvants, Anesthesia/toxicity , Anesthesia, Local/adverse effects , Anesthetics, Combined/toxicity , Anesthetics, Local/toxicity , Animals , Bupivacaine/toxicity , Dexamethasone/toxicity , Dexmedetomidine/toxicity , Drug Liberation , Kinetics , Liposomes , Male , Nerve Block/adverse effects , Pain Threshold/drug effects , Rats, Sprague-Dawley , Time FactorsABSTRACT
Cell therapy based on the trophic, mitogenic, and immunomodulatory capacity of mesenchymal stem cells is a promising treatment modality for degenerative musculoskeletal conditions. Local anesthetics have been commonly used in interventional procedures for alleviating pain, but local anesthetics may have negative impact on MSC dosing because of cytotoxicity or other biological effects. Because previous studies have not reached consensus yet on the potential complications of local anesthetics in cell therapy, we reviewed 11 studies that involve in vitro experimentation with MSCs using aminoamide-type anesthetics including lidocaine, ropivacaine, mepivacaine, bupivacaine, articaine, and prilocaine. Three studies that compare the effects of different types of local anesthetic agents showed that ropivacaine has the least detrimental effects on mesenchymal stem cell populations, whereas lidocaine seems to have the most significant effects on stem cell viability. Concentration- and time-dependent effects on cell viability were reported with bupivacaine, ropivacaine, lidocaine, and mepivacaine. We conclude that local anesthetic agents have time- and concentration-dependent detrimental effects on MSCs. However, in vivo studies will be required to understand the interactions of these agents with MSCs, because in vitro studies cannot replicate the pharmacokinetics of anesthetics in vivo or the recovery of MSCs in a more physiological environment.
Subject(s)
Amides/toxicity , Anesthetics, Local/toxicity , Bupivacaine/toxicity , Lidocaine/toxicity , Mepivacaine/toxicity , Mesenchymal Stem Cells/drug effects , Anesthesia, Local/statistics & numerical data , Humans , RopivacaineSubject(s)
Anesthesia, Dental , Anesthesia, General , Anesthesia, Local/statistics & numerical data , Anesthetics, Local/therapeutic use , Dental Care for Children/methods , Adolescent , Anesthesia, Dental/methods , Anesthesia, Dental/statistics & numerical data , Anesthesia, General/statistics & numerical data , Anesthesia, Inhalation/statistics & numerical data , Anesthesia, Local/adverse effects , Anesthetics, Local/administration & dosage , Anesthetics, Local/toxicity , Child , Child, Preschool , Conscious Sedation/statistics & numerical data , Dental Anxiety , Documentation , Humans , Hypersensitivity , Infant , Infant, Newborn , Nitrous Oxide/administration & dosage , Pain/prevention & control , Pain Measurement , Paresthesia , Pediatric Dentistry , United StatesABSTRACT
QX-314 has been shown to produce long-acting local anesthesia in vivo in animals; however, translation to humans has been impeded by concerns about toxicity. We investigated whether the newly emerged QX-OH molecule could confer long-lasting anesthesia with a low local toxicity in rats. In rat sciatic nerve block model, QX-OH 25mM produced a longer sensory block than QX-314 25mM (median [25th, 75th percentiles], 5.5 [4.25, 6] h vs. 3 [3, 4] h; P=0.03). QX-OH 35mM produced a longer sensory block than QX-314 35mM (8 [6, 12] h vs. 6 [4, 6.5] h, P=0.038). QX-OH at 35 and 45mM generated longer motor blocks than QX-314, with tissue toxicity less than that of QX-314 at the same concentration. In contrast with bupivacaine, QX-OH was clearly superior in terms of sensory and motor blockade durations after a single bolus injection. There was no significant difference in tissue toxicity between QX-OH (25 and 35mM) and bupivacaine. In rat cutaneous trunci pinprick model, the QX-OH-induced pain threshold remained significantly different from baseline at 6h (25mM, P<0.0001), 10h (35mM, P<0.0001), and 12h (45mM, P<0.0001). The time required for full recovery from the subcutaneous anesthetic effect was significantly longer for QX-OH than for QX-314 and bupivacaine. So QX-OH produced concentration-dependent, reversible, and long-acting local anesthesia in animal models with a moderate local toxicity.
Subject(s)
Anesthetics, Local/pharmacology , Lidocaine/analogs & derivatives , Anesthesia, Local , Anesthetics, Local/toxicity , Animals , Bupivacaine/pharmacology , Bupivacaine/toxicity , Lidocaine/pharmacology , Lidocaine/toxicity , Male , Muscle, Skeletal/drug effects , Muscle, Skeletal/physiology , Nerve Block , Rats, Sprague-Dawley , Reflex/drug effects , Sciatic Nerve/drug effectsABSTRACT
Local anesthetic toxicity is thought to be mediated partly by inhibition of cardiac mitochondrial function. Intravenous (i.v.) lipid emulsion may overcome this energy depletion, but doses larger than currently recommended may be needed for rescue effect. In this randomized study with anesthetized pigs, we compared the effect of a large dose, 4 mL/kg, of i.v. 20% Intralipid® ( n = 7) with Ringer's acetate ( n = 6) on cardiovascular recovery after a cardiotoxic dose of bupivacaine. We also examined mitochondrial respiratory function in myocardial cell homogenates analyzed promptly after needle biopsies from the animals. Bupivacaine plasma concentrations were quantified from plasma samples. Arterial blood pressure recovered faster and systemic vascular resistance rose more rapidly after Intralipid than Ringer's acetate administration ( p < 0.0001), but Intralipid did not increase cardiac index or left ventricular ejection fraction. The lipid-based mitochondrial respiration was stimulated by approximately 30% after Intralipid ( p < 0.05) but unaffected by Ringer's acetate. The mean (standard deviation) area under the concentration-time curve (AUC) of total bupivacaine was greater after Intralipid (105.2 (13.6) mg·min/L) than after Ringer's acetate (88.1 (7.1) mg·min/L) ( p = 0.019). After Intralipid, the AUC of the lipid-un-entrapped bupivacaine portion (97.0 (14.5) mg·min/L) was 8% lower than that of total bupivacaine ( p < 0.0001). To conclude, 4 mL/kg of Intralipid expedited cardiovascular recovery from bupivacaine cardiotoxicity mainly by increasing systemic vascular resistance. The increased myocardial mitochondrial respiration and bupivacaine entrapment after Intralipid did not improve cardiac function.
Subject(s)
Anesthetics, Local/toxicity , Bupivacaine/toxicity , Fat Emulsions, Intravenous/pharmacology , Phospholipids/pharmacology , Soybean Oil/pharmacology , Anesthetics, Local/blood , Animals , Bupivacaine/blood , Cell Respiration/drug effects , Emulsions/pharmacology , Heart/drug effects , Heart/physiology , Hemodynamics/drug effects , Mitochondria/drug effects , Mitochondria/metabolism , Myocardium/metabolism , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/metabolism , SwineABSTRACT
BACKGROUND: Lidocaine and epinephrine could potentially decrease adipocyte viability, but these effects have not been substantiated. The phosphorylation status of perilipin in adipocytes may be predictive of cell viability. Perilipin coats lipid droplets and restricts access of lipases; phospho-perilipin lacks this protective function. OBJECTIVES: The authors investigated the effects of tumescent solution containing lidocaine and epinephrine on the phosphorylation status of perilipin in adipocytes. METHODS: In this in vitro study, lipoaspirates were collected before and after tumescence from 15 women who underwent abdominoplasty. Fat samples were fixed, sectioned, and stained for histologic and immunohistochemical analyses. Relative phosphorylation of perilipin was inferred from pixel intensities of immunostained adipocytes observed with confocal microscopy. RESULTS: For adipocytes collected before tumescent infiltration, 10.08% of total perilipin was phosphorylated. In contrast, 30.62% of total perilipin was phosphorylated for adipocytes collected from tumescent tissue (P < .01). CONCLUSIONS: The tumescent technique increases the relative phosphorylation of perilipin in adipocytes, making these cells more vulnerable to lipolysis. Tumescent solution applied for analgesia or hemostasis of the donor site should contain the lowest possible concentrations of lidocaine and epinephrine. LEVEL OF EVIDENCE 5.
Subject(s)
Adipocytes/drug effects , Anesthesia, Local , Anesthetics, Local/pharmacology , Lidocaine/pharmacology , Norepinephrine/pharmacology , Perilipin-1/metabolism , Adipocytes/metabolism , Adult , Anesthesia, Local/adverse effects , Anesthetics, Local/toxicity , Female , Fluorescent Antibody Technique , Humans , Lidocaine/toxicity , Lipolysis/drug effects , Microscopy, Confocal , Middle Aged , Norepinephrine/toxicity , PhosphorylationABSTRACT
Cannabidiol (CBD), a major non-psychotomimetic constituent of Cannabis sativa, has therapeutic potential for certain psychiatric and neurological disorders. Studies in laboratory animals and limited human trials indicate that CBD has anticonvulsant and neuroprotective properties. Its effects against cocaine neurotoxicity, however, have remained unclear. Thus, the present study tested the hypothesis that CBD protects against cocaine-induced seizures and investigated the underlying mechanisms. CBD (30 mg/kg) pre-treatment increased the latency and reduced the duration of cocaine (75 mg/kg)-induced seizures in mice. The CB1 receptor antagonist, AM251 (1 and 3mg/kg), and the CB2 receptor antagonist, AM630 (2 and 4 mg/kg), failed to reverse this protective effect, suggesting that alternative mechanisms are involved. Synaptosome studies with the hippocampus of drug-treated animals revealed that cocaine increases glutamate release, whereas CBD induces the opposite effect. Finally, the protective effect of this cannabinoid against cocaine-induced seizure was reversed by rapamycin (1 and 5mg/kg), an inhibitor of the mammalian target of rapamycin (mTOR) intracellular pathway. In conclusion, CBD protects against seizures in a model of cocaine intoxication. These effects possibly occur through activation of mTOR with subsequent reduction in glutamate release. CBD should be further investigated as a strategy for alleviating psychostimulant toxicity.
Subject(s)
Antiemetics/therapeutic use , Cannabidiol/therapeutic use , Glutamic Acid/metabolism , Seizures/drug therapy , Signal Transduction/drug effects , TOR Serine-Threonine Kinases/metabolism , Anesthetics, Local/toxicity , Animals , Cocaine/toxicity , Disease Models, Animal , Dose-Response Relationship, Drug , Immunosuppressive Agents/therapeutic use , Indoles/pharmacology , Male , Mice , Seizures/chemically induced , Sirolimus/therapeutic useABSTRACT
Accidental intravascular or high-dose injection of local anesthetics (LA) can result in serious, potentially life-threatening complications. Indeed, adequate supportive measures and the administration of lipid emulsions are required in such complications. The study's objectives were threefold: (i) evaluate the myocardial toxicity of levobupivacaine when administered intravenously; (ii) investigate levobupivacaine toxicity on cardiomyocytes mitochondrial functions and cellular structure; (iii) assess the protective effects of a lipid emulsion in the presence or absence of myocardial ischemia. Domestic pigs randomized into two groups of 24 animals each, with either preserved coronary circulation or experimental myocardial ischemia. Six animals from each group received either: (i) single IV injection of saline, (ii) lipid emulsion (Intralipid(®) ), (iii) levobupivacaine, (iv) combination levobupivacaine-Intralipid(®) . Serially measured endpoints included: heart rate, duration of the monophasic action potentials (dMAP), mean arterial pressure, and peak of the time derivative of left ventricular pressure (LV dP/dtmax ). In addition, the following cardiomyocytes mitochondrial functions were measured: reactive oxygen species (ROS) production, oxidative phosphorylation, and calcium retention capacity (CRC) as well as the consequences of ROS production on lipids, proteins, and DNA. IV injection of levobupivacaine induced sinus bradycardia and reduced dMAP and LV dP/dtmax . At the mitochondrial level, oxygen consumption and CRC were decreased. In contrast, ROS production was increased leading to enhanced lipid peroxidation and structural alterations of proteins and DNA. Myocardial ischemia was associated with global worsening of all changes. Intralipid(®) quickly improved haemodynamics. However, beneficial effects of Intralipid(®) were less clear after myocardial ischemia.
Subject(s)
Anesthetics, Local/toxicity , Bupivacaine/analogs & derivatives , Heart Conduction System/drug effects , Hemodynamics/drug effects , Mitochondria, Heart/drug effects , Myocardial Ischemia/complications , Myocytes, Cardiac/drug effects , Phospholipids/pharmacology , Soybean Oil/pharmacology , Action Potentials , Anesthetics, Local/administration & dosage , Animals , Arterial Pressure/drug effects , Bradycardia/chemically induced , Bradycardia/physiopathology , Bradycardia/prevention & control , Bupivacaine/administration & dosage , Bupivacaine/toxicity , Calcium/metabolism , Cytoprotection , Disease Models, Animal , Emulsions/pharmacology , Heart Conduction System/physiopathology , Heart Rate/drug effects , Injections, Intravenous , Levobupivacaine , Lipid Peroxidation/drug effects , Mitochondria, Heart/metabolism , Mitochondria, Heart/pathology , Myocardial Ischemia/metabolism , Myocardial Ischemia/pathology , Myocardial Ischemia/physiopathology , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/pathology , Oxidative Phosphorylation/drug effects , Oxidative Stress/drug effects , Oxygen Consumption/drug effects , Sus scrofa , Time Factors , Ventricular Dysfunction, Left/chemically induced , Ventricular Dysfunction, Left/physiopathology , Ventricular Dysfunction, Left/prevention & control , Ventricular Function, Left/drug effectsABSTRACT
BACKGROUND: Although the incidence of severe local anaesthetic systemic toxicity (LAST) has been declining, the risk of LAST still remains. There are no national treatment guidelines for LAST in Finland. We performed a national survey of the occurrence of LAST and its treatment in 2011-2013. METHODS: A structured electronic questionnaire was sent to the anaesthesia department chiefs of all Finnish public hospitals (n = 45) in spring 2014. We collected information about the occurrence and outcome of LASTs and existence of treatment protocols. RESULTS: The questionnaire response rate was 100% covering approximately 95% of all regional anaesthesias managed by anaesthesiologists in Finnish hospitals. The total number of regional anaesthesias, excluding spinal anaesthesia, performed by anaesthesiologists was approximately 211,700 during the survey period. Fifteen cases of LAST were reported (0.7 : 10,000); all patients recovered without negative sequelae. Fourteen patients, in five of whom ultrasound guidance had been applied, developed central nervous system toxicity symptoms and only one cardiac symptoms. Lipid emulsion was given to this latter patient, and to four of the other 14. The relative risk (95% confidence intervals) for occurrence of LAST in non-academic hospital vs. university hospitals was 3.3 (1.0-10.3; P = 0.04). Treatment protocols for LAST included lipid emulsion in 47% of the departments. CONCLUSIONS: The incidence of LAST in Finland is very low. Several departments have adopted lipid emulsion treatment for LAST despite lack of national recommendations and knowledge of the possible mechanism of action.
Subject(s)
Anesthesia Department, Hospital/statistics & numerical data , Anesthesia, Local/adverse effects , Anesthetics, Local/toxicity , Fat Emulsions, Intravenous/therapeutic use , Finland , Hospitals, Public/statistics & numerical data , Humans , Incidence , Surveys and QuestionnairesABSTRACT
PURPOSE: To compare the hemodynamic changes following two different lipid emulsion therapies after bupivacaine intoxication in swines. METHODS: Large White pigs were anesthetized with thiopental, tracheal intubation performed and mechanical ventilation instituted. Hemodynamic variables were recorded with invasive pressure monitoring and pulmonary artery catheterization (Swan-Ganz catheter). After a 30-minute resting period, 5 mg.kg-1 of bupivacaine by intravenous injection was administered and new hemodynamic measures were performed 1 minute later; the animals were than randomly divided into three groups and received 4 ml.kg-1 of one of the two different lipid emulsion with standard long-chaim triglyceride, or mixture of long and medium-chain triglyceride, or saline solution. Hemodynamic changes were then re-evaluated at 5, 10, 15, 20 and 30 minutes. RESULTS: Bupivacaine intoxication caused fall in arterial blood pressure, cardiac index, ventricular systolic work index mainly and no important changes in vascular resistances. Both emulsion improved arterial blood pressure mainly increasing vascular resistance since the cardiac index had no significant improvement. On the systemic circulation the hemodynamic results were similar with both lipid emulsions. CONCLUSION: Both lipid emulsions were efficient and similar options to reverse hypotension in cases of bupivacaine toxicity.
Subject(s)
Anesthetics, Local/toxicity , Bupivacaine/toxicity , Fat Emulsions, Intravenous/therapeutic use , Hemodynamics/drug effects , Animals , Blood Pressure/drug effects , Coconut Oil , Plant Oils/therapeutic use , Random Allocation , Reproducibility of Results , Soybean Oil/therapeutic use , Swine , Time Factors , Treatment Outcome , Triglycerides/therapeutic use , Vascular Resistance/drug effectsABSTRACT
PURPOSE: To compare the hemodynamic changes following two different lipid emulsion therapies after bupivacaine intoxication in swines. METHODS: Large White pigs were anesthetized with thiopental, tracheal intubation performed and mechanical ventilation instituted. Hemodynamic variables were recorded with invasive pressure monitoring and pulmonary artery catheterization (Swan-Ganz catheter). After a 30-minute resting period, 5 mg.kg-1 of bupivacaine by intravenous injection was administered and new hemodynamic measures were performed 1 minute later; the animals were than randomly divided into three groups and received 4 ml.kg-1 of one of the two different lipid emulsion with standard long-chaim triglyceride, or mixture of long and medium-chain triglyceride, or saline solution. Hemodynamic changes were then re-evaluated at 5, 10, 15, 20 and 30 minutes. RESULTS: Bupivacaine intoxication caused fall in arterial blood pressure, cardiac index, ventricular systolic work index mainly and no important changes in vascular resistances. Both emulsion improved arterial blood pressure mainly increasing vascular resistance since the cardiac index had no significant improvement. On the systemic circulation the hemodynamic results were similar with both lipid emulsions. CONCLUSION: Both lipid emulsions were efficient and similar options to reverse hypotension in cases of bupivacaine toxicity. .