RESUMEN
The purpose of this scoping review was to identify possible chondrotoxic effects caused by drugs usually used for intra-articular injections. PubMed, Scopus, Web of Science and Cochrane were searched. Inclusion criteria required randomized controlled trials written in English that evaluate the toxic effect that damages the cartilage. The literature search resulted in 185 unique articles. 133 full-text articles were screened for inclusion, of which 65 were included. Corticosteroids, with the exception of triamcinolone, along with local anaesthetics, potentially excluding ropivacaine and liposomal bupivacaine, and nonsteroidal anti-inflammatory drugs, exhibited insufficient safety profiles to warrant casual use in clinical settings. Hyaluronic acid, on the other hand, appears to demonstrate safety while also mitigating risks associated with concurrent compounds, thereby facilitating therapeutic combinations. Additionally, there remains a paucity of data regarding platelet-rich plasma, necessitating further evaluation of its potential efficacy and safety. Overall, it seems that results are significantly influenced by the dosage and frequency of injections administered, observed in both human and animal studies.
Asunto(s)
Ácido Hialurónico , Humanos , Inyecciones Intraarticulares , Animales , Ácido Hialurónico/administración & dosificación , Ácido Hialurónico/efectos adversos , Anestésicos Locales/administración & dosificación , Anestésicos Locales/efectos adversos , Anestésicos Locales/toxicidad , Cartílago Articular/efectos de los fármacos , Cartílago Articular/patología , Corticoesteroides/administración & dosificación , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/efectos adversosRESUMEN
BACKGROUND: The local anaesthetic lidocaine is widely used in the neonatal intensive unit to treat seizures in premature babies. However, other antiepileptics administered during early development in various animal models have shown negative long-term behavioural effects. Since no long-term behavioural data so far exist regarding lidocaine exposure at an early age, we decided to perform this extended follow-up study using a sensitive behavioural test. METHODS: Neonatal mice received a subcutaneous administration of saline or one dose of lidocaine (0.5, 4, or 12 mg kg-1) on postnatal day 10 (P10; peak of the Brain Growth Spurt). A well-established test to detect long-term behavioural alterations was conducted at 2 and 6 months of age, corresponding to early and late adulthood in humans. RESULTS: All animal survived to later testing. No signs of acute toxicity were observed. Lidocaine exposure did not result in any negative behavioural effects during habituation to a new home environment at any of the two studied time points, compared to saline placebo. CONCLUSIONS: Lidocaine does not by itself produce any negative long-term behavioural effects in mice exposed in early life (P10) despite long-term follow-up. This is reassuring regarding the current practice of treating seizures in premature babies with intravenous lidocaine.
Asunto(s)
Anestésicos Locales , Animales Recién Nacidos , Conducta Animal , Lidocaína , Animales , Lidocaína/toxicidad , Lidocaína/farmacología , Lidocaína/administración & dosificación , Ratones , Conducta Animal/efectos de los fármacos , Anestésicos Locales/toxicidad , Anestésicos Locales/administración & dosificación , Masculino , Femenino , Convulsiones/inducido químicamente , Relación Dosis-Respuesta a DrogaRESUMEN
Local anesthetic (LA) cardiotoxicity is one of the main health problems in anesthesiology and pain management. This study reviewed the reported LA-induced cardiac toxicity types, risk factors, management, and mechanisms, with attention to the use of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) in heart toxicity research. Important scientific databases were searched to find relevant articles. We briefly assessed the reported cardiotoxic effects of different types of LA drugs, including ester- and amide-linked LA agents. Furthermore, cardiotoxic effects and clinical manifestations, strategies for preventing and managing LA-induced cardiotoxic effects, pharmacokinetics, pharmacodynamics, and sodium channel dynamics regarding individual variability and genetic influences were discussed in this review. The applications and importance of hiPSC-CMs cellular model for evaluating the cardiotoxic effects of LA drugs were discussed in detail. This review also explored hiPSC-CMs' potential in risk assessment, drug screening, and developing targeted therapies. The main mechanisms underlying LA-induced cardiotoxicity included perturbation in sodium channels, ROS production, and disorders in the immune system response due to the presence of LA drugs. Furthermore, drug-specific characteristics including pharmacokinetics and pharmacodynamics are important determinants after LA drug injection. In addition, individual patient factors such as age, comorbidities, and genetic variability emphasize the need for a personalized approach to mitigate risks and enhance patient safety. The strategies outlined for the prevention and management of LA cardiotoxicity underscore the importance of careful dosing, continuous monitoring, and the immediate availability of resuscitation equipment. This comprehensive review can be used to guide future investigations into better understanding LA cardiac toxicities and improving patient safety.
Asunto(s)
Anestésicos Locales , Cardiotoxicidad , Células Madre Pluripotentes Inducidas , Miocitos Cardíacos , Humanos , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Células Madre Pluripotentes Inducidas/efectos de los fármacos , Células Madre Pluripotentes Inducidas/metabolismo , Anestésicos Locales/efectos adversos , Anestésicos Locales/toxicidad , Cardiotoxicidad/etiología , AnimalesRESUMEN
Local anaesthetics (LAs) can have detrimental effects on rat, bovine, canine, and human tendon tissues and cells. Currently, there has been no available data on the impact of these drugs on equine tenocytes. Even if LA injection for managing painful tendon conditions in horses is limited, it is usually used via intra-articular, intrasynovial, perineural, and intrathecal as well as for lameness examinations. In this in vitro study, the cytotoxic effects of LAs, including lidocaine, mepivacaine, and bupivacaine on equine tenocytes, in the presence and absence of platelet rich plasma (PRP), were investigated. PRP accelerates tissue healing and can exert cytoprotective effects on different cell types exposed to different stressful conditions, including drugs. Results indicated that the exposure to LAs significantly reduced tenocytes viability in dose- and time-dependent manners while PRP was able to counteract their cytotoxic effects. Furthermore, microscopy and flow cytometry analyses revealed apoptosis and necrosis in equine tenocytes exposed to these drugs, that were both reduced when PRP was in the medium. These findings highlight the importance of considering the tenocyte toxicity associated with intrathecal and intraneural LA injections, as they might affect tenocytes or reduce the efficacy of associated therapies. Moreover, this study also highlights the protective effects of PRP, which could make LA injections safer.
Asunto(s)
Anestésicos Locales , Bupivacaína , Lidocaína , Mepivacaína , Plasma Rico en Plaquetas , Tenocitos , Animales , Caballos , Tenocitos/efectos de los fármacos , Anestésicos Locales/farmacología , Anestésicos Locales/toxicidad , Bupivacaína/toxicidad , Lidocaína/farmacología , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Apoptosis/efectos de los fármacosRESUMEN
Purpose: This study was performed to evaluate the effects of intraoperative intravenous lidocaine on postoperative delirium in elderly patients with hip fracture. Patients and methods: In total, 100 elderly patients undergoing hip fracture surgery were randomized to the lidocaine group (Group L) or saline (control) group (Group C). Before anesthetic induction, Group L received lidocaine at 1 mg/kg for more than 10 minutes followed by continuous infusion at 1.5 mg/kg/h until the end of surgery. Group C received normal saline, and the injection methods were consistent with those in Group L. General anesthesia was induced with propofol, sufentanil, and cis-atracurium. Anesthesia was maintained by propofol and remifentanil. The primary outcome was the incidence of postoperative delirium in the first 7 postoperative days. The secondary outcomes included the severity of delirium, onset and duration of delirium, emergence agitation, adverse events, total propofol dose, intraoperative opioid dosage, length of post-anesthesia care unit stay, extubation time, and patient satisfaction with postoperative pain management. Results: All 100 patients completed the study. The incidence of postoperative delirium was lower in Group L than in Group C (14% vs 36%, P = 0.011). The delirium severity scores were lower in Group L (3 [3-4]) than in Group C (4 [4-5]) (P = 0.017). In addition, the incidences of hypertension, tachycardia, and emergence agitation were significantly lower in Group L than in Group C. No cases of local anesthetic toxicity occurred in either group. Conclusion: Patients received lidocaine at 1 mg/kg for more than 10 minutes followed by continuous infusion at 1.5 mg/kg/h until the end of surgery, which can reduce the incidence of postoperative delirium in elderly patients undergoing hip fracture. In addition, the used regimen of lidocaine would not increase the risk of local anesthetic toxicity.
Asunto(s)
Delirio del Despertar , Lidocaína , Anciano , Humanos , Anestésicos Locales/toxicidad , Delirio del Despertar/prevención & control , Lidocaína/farmacología , Propofol , Estudios Prospectivos , Fracturas de Cadera/cirugíaRESUMEN
The development of local anesthetics revolutionized the performance of painful interventions. Local anesthetics have an effect on voltage-gated sodium channels in nerve fibers and modulate the conduction of impulses. With respect to the chemical structure, local anesthetics can be divided into amide and ester types. The structural differences of local anesthetics have an influence on the duration of action, the degradation pathways and specific side effects. Severe adverse events include cardiotoxicity and neurotoxicity. In addition to basic measures, such as the monitoring and securing of vital parameters, lipid infusion represents a treatment option in cases of intoxication. The recent developments of local anesthetics are particularly concerned with the reduction of toxicity and prolonging the duration of action.
Asunto(s)
Amidas , Anestésicos Locales , Humanos , Anestésicos Locales/toxicidad , Ésteres , DolorRESUMEN
This study was aimed at examining the anesthetic effects and spinal cord injuries in the rats by intrathecal injection of levobupivacaine at different concentrations. Rats with successful intrathecal cannulation were selected and randomly divided into six groups (n = 72), and administered 0.1 mL of 0.125%, 0.25%, 0.5%, or 0.75% levobupivacaine, saline or 5% lidocaine via intrathecal catheters. The potency of levobupivacaine was evaluated by walking behavior. To identify the motor and sensory function, walking behavior and paw withdrawal thresholds (PWTs) were measured once a day. After 7 days, the L4-5 spinal cord segments were removed for histological examination. The onset time of 0.125% levobupivacaine intrathecal injection was 70.0 ± 8.9 s, and the maintenance time was 9.5 ± 1.8 min. The onset time of 0.75% levobupivacaine intrathecal injection was significantly shortened to 31.0 ± 5.5 s, and the maintenance time was significantly extended to 31.3 ± 5.4 min. The severe injury was observed in the 5% lidocaine group, while milder injury was observed in the 0.75% levobupivacaine group. The damage in the 0.5% levobupivacaine group was mild, and there were no histological abnormalities in the 0.125%, 0.25% levobupivacaine and saline groups. The neurotoxicity of intrathecally administered levobupivacaine was concentration dependent. In addition, higher concentrations of levobupivacaine were associated with shorter onset and longer maintenance times. The clinical concentration of levobupivacaine should not exceed 0.5% to avoid potential damage.
Asunto(s)
Anestésicos Locales , Bupivacaína , Animales , Ratas , Anestésicos Locales/toxicidad , Bupivacaína/toxicidad , Inyecciones Espinales , Levobupivacaína , Lidocaína/toxicidadRESUMEN
THE AIM OF THE STUDY: Was to assess the lidocaine and bupivacaine systemic toxicity in forensic medical practice. The number of patients' clinical observations equal three with local anesthetic systemic toxicity (LAST) from the practice of forensic medical experts were studied, and a search of scientific publications for the last 5 years in PubMed database was conducted. The amount of publications, describing cases with LAST, equal four were selected. Differential diagnostic features between LAST and anaphylaxis were considered. The literature data about relationship between lidocaine's concentration in the blood serum and clinical features are shown. The forensic medical assessment of LAST is proposed.
Asunto(s)
Bupivacaína , Lidocaína , Humanos , Bupivacaína/toxicidad , Anestésicos Locales/toxicidadRESUMEN
Prolonged exposure to local anesthetics (LAs) or intrathecal administration of high doses of LAs can cause spinal cord damage. Intraspinal administration of LAs is increasingly being used in children and neonates. Therefore, it is important to study LA-related spinal cord damage and the underlying mechanism in developmental models. First, neonatal Sprague-Dawley rats received three intrathecal injections of 0.5% ropivacaine, 1% ropivacaine, 2% ropivacaine or saline (90-min interval) on postnatal day 7. Electron microscopy, luxol fast blue staining and behavioral tests were performed to evaluate the spinal neurotoxicity caused by ropivacaine at different concentrations. Western blot analysis and immunostaining was performed to detect the expression changes of p-Akt, Akt, myelin gene regulatory factor (MYRF) and myelin basic protein (MBP) in the spinal cord treated with different concentrations of ropivacaine. Our results showed that 1% or 2% ropivacaine impaired myelination in the spinal cord and induced sensory dysfunction, but 0.5% ropivacaine did not. Moreover, 1% or 2% ropivacaine decreased the expression of p-Akt, MYRF and MBP in the spinal cord. Then, in order to further explore the role of these proteins in this model, the Akt-specific activator (SC79) was intraperitoneally injected 30 min before 2% ropivacaine treatment. Interestingly, SC79-mediated activation of Akt partly rescued ropivacaine-induced myelination impairments and sensory dysfunction. Overall, the results showed that ropivacaine caused spinal neurotoxicity in a dose-dependent manner in neonatal rats and that activation of the Akt partly rescued ropivacaine-induced these changes. These data provide insight into the neurotoxicity to the developing spinal cord caused by LAs.
Asunto(s)
Amidas , Proteínas Proto-Oncogénicas c-akt , Humanos , Niño , Ratas , Animales , Ropivacaína/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Animales Recién Nacidos , Ratas Sprague-Dawley , Amidas/farmacología , Anestésicos Locales/farmacología , Anestésicos Locales/toxicidad , Médula Espinal/metabolismo , Factores de Transcripción/metabolismoRESUMEN
Peripheral neurotoxicity injury caused by local anesthetics is a common complication of clinical anesthesia. The study of its mechanism is helpful to prevent and treat the neurotoxic injury of local anesthetics. Previous studies on peripheral neurotoxicity injury caused by local anesthetics have mainly focused on in vitro cell experiments. Due to the lack of an animal model of peripheral neurotoxicity damage caused by local anesthetics, there are few in vivo experimental studies regarding this topic. Herein, 1% ropivacaine hydrochloride was injected into the sciatic nerve by direct incision and exposure of the sciatic nerve to create a local anesthetic neurotoxic injury model. The results showed that 1% ropivacaine hydrochloride could reduce the lower limb motor score and mechanical paw withdrawal threshold in mice 48 hours after injection. Pathological sections showed that 48 hours after treatment with 1% ropivacaine hydrochloride, the sciatic nerve showed increased axonal edema and degeneration, edema between nerve fiber bundles, increased degeneration of axon and myelin sheath vacuoles, edema of nerve bundle membrane and local degeneration and necrosis, and a large number of inflammatory cells around the nerve adventitia were soaked. The above results show that under open vision, 1% ropivacaine hydrochloride can cause injury to the sciatic nerve after 48 h of treatment, which can simulate the neurotoxic damage of local anesthetics. This animal model provides a research tool for studying the mechanism of neurotoxic injury caused by local anesthetics.
Asunto(s)
Anestésicos Locales , Modelos Animales , Síndromes de Neurotoxicidad , Animales , Ratones , Anestésicos Locales/efectos adversos , Anestésicos Locales/toxicidad , Edema , Síndromes de Neurotoxicidad/etiología , Síndromes de Neurotoxicidad/patología , Ropivacaína/toxicidad , Nervio Ciático/patologíaRESUMEN
OBJECTIVE: Severe neurologic complications after spinal anesthesia are rare but highly distressing, especially in pregnant women. Bupivacaine is widely used in spinal anesthesia, but its neurotoxic effects have gained attention. METHODS: Furthermore, the etiology of bupivacaine-mediated neurotoxicity in obstetric patients remains unclear. Female C57BL/6 mice were intrathecally injected with 0.75% bupivacaine on the 18th day of pregnancy. We used immunohistochemistry to examine DNA damage after bupivacaine treatment in pregnant mice and measured γ-H2AX (Ser139) and 8-OHdG in the spinal cord. A PARP-1 inhibitor (PJ34) and autophagy inhibitor (3-MA) were administered with bupivacaine in pregnant mice. Parp-1flox/flox mice were crossed with Nes-Cre transgenic mice to obtain neuronal conditional knockdown mice. Then, LC3B and P62 staining were performed to evaluate autophagic flux in the spinal cords of pregnant wild-type (WT) and Parp-1-/- mice. We performed transmission electron microscopy (TEM) to evaluate autophagosomes. RESULTS: The present study showed that oxidative stress-mediated DNA damage and neuronal injury were increased after bupivacaine treatment in the spinal cords of pregnant mice. Moreover, PARP-1 was significantly activated, and autophagic flux was disrupted. Further studies revealed that PARP-1 knockdown and autophagy inhibitors could alleviate bupivacaine-mediated neurotoxicity in pregnant mice. CONCLUSION: Bupivacaine may cause neuronal DNA damage and PARP-1 activation in pregnant mice. PARP-1 further obstructed autophagic flux and ultimately led to neurotoxicity.
Asunto(s)
Anestésicos Locales , Bupivacaína , Animales , Femenino , Humanos , Ratones , Embarazo , Anestésicos Locales/toxicidad , Apoptosis , Autofagia , Bupivacaína/toxicidad , Ratones Endogámicos C57BL , Estrés Oxidativo , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacologíaRESUMEN
INTRODUCTION: Benzonatate is an FDA-approved antitussive agent that resembles tetracaine, procaine, and cocaine in its chemical structure. Based on structural similarities to known local anesthetics and recent findings of benzonatate exerting local anesthetic-like effects on voltage-gated sodium channels in vitro, we hypothesized that benzonatate will act as a local anesthetic to yield peripheral nerve blockade. METHODS: Benzonatate was injected at the sciatic nerve of Sprague-Dawley rats. Sensory and motor blockade were assessed using a modified hot plate test and a weight-bearing test, respectively. Additionally, the effect of co-injection with tetrodotoxin and Tween 80 (a chemical permeation enhancer) was examined. Myotoxicity of benzonatate was assessed in vivo by histological analysis. RESULTS: Benzonatate produced a concentration-dependent sensory and motor nerve blockade with no appreciable systemic effects. Co-injection with tetrodotoxin or Tween 80 produced prolongation of sensory nerve blockade. Histologic assessment showed significant inflammation and myotoxicity from benzonatate injection, even at low concentrations. CONCLUSION: This study demonstrates that benzonatate does act as a local anesthetic at the peripheral nerve, with sensory and motor nerve blockade. Benzonatate interacts with tetrodotoxin and Tween 80 to prolong nerve blockade. However, benzonatate causes significant myotoxicity, even at subtherapeutic concentrations.
Asunto(s)
Anestésicos Locales , Polisorbatos , Ratas , Animales , Anestésicos Locales/toxicidad , Tetrodotoxina/toxicidad , Polisorbatos/farmacología , Miotoxicidad/patología , Ratas Sprague-Dawley , Nervio Ciático/patologíaRESUMEN
Currently, lipid emulsion (LE) is widely used to treat local anesthetic systemic toxicity (LAST). LE also ameliorates intractable cardiovascular collapse caused by lipid-soluble non-local anesthetic drug toxicity. This review aims to provide the underlying mechanism of LE resuscitation in drug toxicity (including LAST) and a detailed description of LE treatment and to discuss further research directions. We searched for relevant articles using the following keywords: "local anesthetic systemic toxicity or LAST or toxicity or intoxication or poisoning" and "Intralipid or lipid emulsion". The underlying mechanisms of LE treatment can be classified into indirect and direct effects. One indirect effect known as the lipid shuttle is a commonly accepted mechanism of LE treatment. The lipid shuttle involves the absorption of highly lipid-soluble drugs (e.g., bupivacaine) from the heart and brain through the lipid phase, which are then delivered to the muscle, adipose tissue, and liver for storage and detoxification. The direct effects include inotropic effects, fatty acid supply, attenuation of mitochondrial dysfunction, glycogen synthase kinase-3ß phosphorylation, and inhibition of nitric oxide. These mechanisms appear to act synergistically to treat drug toxicity. The recommended protocol for LE treatment of LAST is as follows: a bolus administration of 20% LE at 1.5 ml/kg over 2-3 min followed by 20% LE at 0.25 ml/kg/min. LAST most commonly occurs after intravenous administration of local anesthetics. However, non-local anesthetic drugs that cause drug toxicity are orally administered. Further studies are needed to determine the optimal dosing schedule of LE treatment for non-local anesthetic drug toxicity.
Asunto(s)
Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Emulsiones Grasas Intravenosas , Humanos , Preparaciones Farmacéuticas , Emulsiones Grasas Intravenosas/farmacología , Emulsiones Grasas Intravenosas/uso terapéutico , Anestésicos Locales/toxicidad , Bupivacaína/toxicidad , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/tratamiento farmacológicoRESUMEN
Ropivacaine has been described as a safer local anaesthetic (LA); however, serious cardiotoxic accidents have been reported. Intravenous-lipid-emulsion (ILE) therapy during LA intoxication seems to act as an antidote. Sodium bicarbonate is the standard treatment for sodium channel blocker drug toxicity. We compared both antidotes on the reversion of electrophysiologic toxicity induced by ropivacaine. Ropivacaine 5 mg kg-1 was administered in 24 pigs, and 3 min later, the animals received ILE: 1.5 ml kg-1 + 0.25 ml kg-1 min-1 (ILE group); sodium bicarbonate: 2 mEq kg-1 + 1 mEq kg-1 h-1 (NaHCO3 group); saline solution (CTL group). Electrophysiological parameters were evaluated for 30 min. The area under the curve (AUC) for the first 5 or 30 min was compared between groups. Ropivacaine induced a lengthening of the PR interval by 17% (P = 0.0001), His-ventricle-interval by 58% (P = 0.001), sinus QRS complex by 56% (P = 0.0001), paced QRS at 150 bpm by 257% (P = 0.0001), and at 120 bpm by 143% (P = 0.0001) in all groups. At 5 min after treatment, sinus QRS in the NaHCO3 group was shorter than that in the CTL group (AUCQRS5 , P = 0.003) or ILE group (AUCQRS5 , P = 0.045). During the first minute, seven of the animals in the NaHCO3 group vs. two in the ILE or 0 in the CTL group recovered more than 30% of the sinus QRS previously lengthened by ropivacaine (P = 0.003). Sodium bicarbonate reversed the electrophysiological toxicity of ropivacaine faster than ILE and control groups.
Asunto(s)
Cardiotoxicidad , Bicarbonato de Sodio , Porcinos , Animales , Bicarbonato de Sodio/farmacología , Ropivacaína/farmacología , Cardiotoxicidad/etiología , Frecuencia Cardíaca , Emulsiones Grasas Intravenosas/farmacología , Emulsiones Grasas Intravenosas/uso terapéutico , Antídotos/farmacología , Lípidos , Anestésicos Locales/toxicidadRESUMEN
Due to the increasing use of local anesthetic techniques in various healthcare settings, local anesthetic toxicity still occurs. Seizures are the most common symptom of local anesthetic toxicity. The relationship between local anesthetic-induced seizures and the sensation of pain has not been established till now. Here, we assessed the development of pain hypersensitivity after ropivacaine-induced seizures (RIS) and the influence of RIS on incision-induced postsurgical pain and formalin-induced acute inflammatory pain. In addition, the involvement of spinal 5-HT/5-HT3R in RIS-induced pain sensitization was investigated. According to a sequential exploratory experimental strategy, we first calculated the 50% seizure dosage of ropivacaine to be 42.66 mg/kg (95% confidence interval: 40.19-45.28 mg/kg). We showed that RIS induced significant bilateral mechanical pain hypersensitivity that lasted around 5 days, accompanied by an increase in spinal 5-HT. Moreover, RIS considerably protracted postsurgical pain and enhanced formalin-induced spontaneous flinching in the second phase. Depletion of spinal 5-HT with intrathecal injection of 5,7-dihydroxytryptamine (5,7-DHT) reduced RIS-induced pain hypersensitivity and prevented the prolonging of postsurgical pain following RIS. Likewise, blocking spinal 5-HT3R by intrathecal administration of ondansetron reversed RIS-induced pain hypersensitivity and attenuated the pronociception of RIS in the formalin test. Our findings revealed that acute RIS led to pain hypersensitivity and had pronociceptive effects on incision-induced postsurgical pain and formalin-induced acute inflammatory pain. Moreover, our data implied that RIS-induced pain sensitization depends on spinal 5-HT/5-HT3R signaling. Thus, targeting the descending serotonergic facilitation system should be an important element of the precise treatment for local anesthetic toxicity.
Asunto(s)
Anestésicos Locales , Serotonina , Ratas , Animales , Serotonina/farmacología , Ropivacaína/farmacología , Anestésicos Locales/toxicidad , Médula Espinal , Formaldehído/toxicidad , Dolor Postoperatorio/tratamiento farmacológico , Convulsiones/inducido químicamenteRESUMEN
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.
Asunto(s)
Anestésicos Locales , Calcio , Femenino , Ratas , Humanos , Animales , Anestésicos Locales/toxicidad , Cardiotoxicidad , Miocitos Cardíacos , Amidas/farmacología , Bupivacaína/toxicidad , Ropivacaína/toxicidad , Arritmias Cardíacas/inducido químicamenteRESUMEN
INTRODUCTION: Ropivacaine is considered to have a wider margin of cardiovascular safety. However, several reports of ventricular arrhythmias (VA) due to ropivacaine toxicity have been documented. Intravenous lipid emulsions (ILEs) have recently been used successfully in the treatment of local anesthetic intoxication. The main objective of the present study was to evaluate the efficacy of the ILEs in the prevention of pacing-induced-VA and electrophysiological alterations in an animal model of ropivacaine toxicity. METHODS: Nineteen pigs were anesthetized and instrumentalized. A baseline programmed electrical ventricular stimulation protocol (PEVSP) to induce VA was performed. Ropivacaine (5 mg·kg-1 + 100 µg·kg-1·min-1) followed by normal saline infusion (control group n = 8) or intralipid 20% (1.5 mL·kg-1 + 0.25 mL·kg-1·min-1) for the ILE group (n = 8), were administered three minutes after the ropivacaine bolus. PEVSP was repeated 25 min after the onset of ropivacaine infusion. Pacing-induced VA and electrophysiological abnormalities were assessed in both groups. A sham-control group (n = 3) without ropivacaine infusion was included. RESULTS: Most of the electrophysiological parameters evaluated were affected by ropivacaine: PR interval by 28% (p = 0.001), AV interval by 40% (p = 0.001), sinus QRS by 101% (p = 0.001), paced QRS at a rate of 150 bpm by 258% (p = 0.001), and at 120 bpm by 241% (p = 0.001). Seven animals (87.5%) in the control group and eight animals (100%) in the ILE group developed sustained-VA (p = 0.30). Successful resuscitation occurred in 100% of animals in the ILE group vs. 57% of animals in the control group, p = 0.038. Pacing-induced-VA terminated at the first defibrillation attempt in 75% of the animals in the ILE group vs. 0% in the control group, p = 0.01. CONCLUSION: Ropivacaine strongly altered the parameters of ventricular conduction, thus facilitating the induction of VA. ILEs did not prevent pacing-induced VA. However, facilitated resuscitation and termination of VA were delivered at the first defibrillation attempt compared to the control group.
Asunto(s)
Anestésicos Locales , Emulsiones Grasas Intravenosas , Anestésicos Locales/toxicidad , Animales , Arritmias Cardíacas/inducido químicamente , Arritmias Cardíacas/tratamiento farmacológico , Bupivacaína/toxicidad , Modelos Animales de Enfermedad , Emulsiones Grasas Intravenosas/farmacología , Emulsiones Grasas Intravenosas/uso terapéutico , Ropivacaína/toxicidad , Solución Salina , PorcinosRESUMEN
When combined with nalbuphine, local anesthetics show a longer duration of nerve block without increasing complications. However, no evidence is available concerning the effect of nalbuphine on the cardiotoxicity of local anesthetics. The objective of this work is to investigate whether nalbuphine pretreatment can increase the lethal dose threshold of ropivacaine in rats. Anesthetized Sprague Dawley rats were pretreated with different doses of nalbuphine (0.4, 0.8, 1.5, 3.0, 5.0 mg/kg) or NS (normal saline, negative control) or 30% LE (lipid emulsion, positive control) 2 ml/kg/min for 5 min (n = 6). Then 0.5% ropivacaine was infused at a rate of 2.5 mg/kg/min until asystole occurs. Time of arrhythmia, 50% mean arterial pressure- and 50% heart rate-reduction, and asystole were recorded, and ropivacaine doses were calculated. Nalbuphine (0.4-5.0 mg/kg) did not affect ropivacaine-induced arrhythmia, 50% mean arterial pressure-reduction and 50% heart rate-reduction, and asystole in rats compared with NS pre-treatment. The asystole dose threshold (in milligrams per kilogram) of group LE was higher than that of group NS (NS 28.25(6.32) vs. LE, 41.58(10.65); P = 0.04; 95% confidence interval 0.23 to 26.45), while thresholds of arrhythmia, 50% mean arterial pressure-reduction, and 50% heart rate-reduction were not affected by LE. Nalbuphine doses of 0.4-5.0 mg/kg pretreatment did not increase the threshold of ropivacaine cardiotoxicity compared with NS control; 30% LE increases the lethal dose threshold of ropivacaine in rats.
Asunto(s)
Paro Cardíaco , Nalbufina , Amidas/toxicidad , Anestésicos Locales/toxicidad , Animales , Arritmias Cardíacas/inducido químicamente , Bupivacaína , Cardiotoxicidad/etiología , Paro Cardíaco/inducido químicamente , Nalbufina/toxicidad , Ratas , Ratas Sprague-Dawley , Ropivacaína/toxicidadRESUMEN
BACKGROUND: Ropivacaine oil delivery depot (RODD) can be used to treat postoperative incision pain. The aim was to study pharmacodynamics, toxicity and toxicokinetics of RODD. METHODS: The base research of RODD were conducted. Thirty rabbits were randomly divided into saline, solvent, ropivacaine aqueous injection (RAI) 0.9 mg, RODD 0.9 mg and RODD 3 mg groups. The sciatic nerve of rabbits were isolated, dripped with RODD and the effect of nerve block were observed. In toxicity study, the rats were divided into saline, solvent and RODD 75, 150 and 300 mg/kg groups, 30 rats per group. In toxicokinetics, rats were divided into RODD 75, 150 and 300 mg/kg groups, 18 rats per group. The rats were subcutaneously injected drugs. RESULTS: The analgesic duration of RODD 3 mg and RAI 0.9 mg blocking ischiadic nerve lasted about 20 h and 2 h, respectively, and their blocking intensity was similar. The rats in RODD 75 mg/kg did not show any toxicity. Compared with saline group, in RODD 150 mg/kg group neutrophils and mononuclear cells increased, lymphocytes decreased and albumin decreased(P < 0.05), and pathological examination showed some abnormals. In RODD 300 mg/kg group, 10 rats died and showed some abnormalities in central nerve system, hematologic indexes, part of biochemical indexes, and the weights of spleen, liver, and thymus. However, these abnormal was largely recovered on 14 days after the dosing. The results of toxicokinetics of RODD 75 mg/kg group showed that the Cmax was 1.24 ± 0.59 µg/mL and the AUC(0-24 h) was 11.65 ± 1.58 h·µg/mL. CONCLUSIONS: Subcutaneous injection RODD releases ropivacaine slowly, and shows a stable and longer analgesic effect with a large safety range.