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At least 19 recordsLinked to original sources
PubMed2026

Morbidity and mortality from local anesthetics: localized and systemic toxicity.

PURPOSE OF THE REVIEW: Local anesthetics remain vital to modern medicine, yet their narrow therapeutic window continues to result in complications. This review synthesizes recent literature to define the current landscape of local anesthetic-associated adverse events. RECENT FINDINGS: Perioperative mortality attributable to local anesthetics persists despite sustained safety initiatives and professional society recommendations. Pharmacovigilance and case data identify lidocaine (oropharyngeal, topical, and via local infiltration) as the predominant contributor to adverse outcomes, including death. Local anesthetic systemic toxicity remains an issue, with a recent shift in epidemiology: an increasing proportion of toxic events originates from surgeon- and proceduralist-administered analgesia. Anesthesiologist-controlled methods also cause toxicity via catheter-based delivery and nerve blocks in highly vascular regions. Localized toxicity in the form of high neuraxial contributes to morbidity, with recent reviews reinforcing known risk factors; whereas localized neurotoxicity appears less troublesome when managed appropriately. SUMMARY: The cumulative evidence identifies shifts in the patterns of systemic and localized toxicities. Bupivacaine-based peripheral nerve blocks no longer represent the principal cause of complications because of the advent of ultrasound guidance and lipid emulsion therapy. In contrast, high neuraxial techniques persist as a cause of morbidity, accompanied by intravenous/oropharyngeal lidocaine, proceduralist-administered local infiltration analgesia, and catheter-based delivery.

Humans↗
PubMed2026

Adductor Canal Block and Local Anesthetic Versus Local Anesthetic Alone in ACL Reconstruction: A Double-Blind Randomized Controlled Trial.

BACKGROUND: Effective postoperative analgesia is crucial for early recovery after anterior cruciate ligament reconstruction (ACLR). Local infiltration analgesia (LIA) and adductor canal block (ACB) are common regional techniques, but their combined efficacy remains unclear. PURPOSE: To compare the effectiveness of LIA alone versus LIA combined with ACB in patients undergoing ACLR, with primary outcomes including postoperative opioid consumption and quadriceps function. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: A double-blind randomized controlled trial enrolled 100 patients undergoing ACLR under general anesthesia. Patients were randomized into 2 groups: LIA + sham (saline injection) (n = 50) and LIA + ACB (n = 50). The primary outcome was postoperative opioid consumption in the first 24 hours. Secondary outcomes included visual analog scale (VAS) pain score, quadriceps function assessed by straight leg raise (SLR) at 3 hours, Quality of Recovery-15 (QoR-15) score, and Knee Injury and Osteoarthritis Outcome Score (KOOS) at 1 week. Statistical analysis was performed using t tests and chi-square tests with a P value <.05 considered significant. RESULTS: There was no significant difference in 24-hour opioid consumption between the LIA + ACB and LIA-only groups (P = .109). Similarly, VAS pain scores at 24 hours postoperatively showed no significant differences between the groups (P = .0804). Early functional recovery, assessed by SLR performance at 3 hours, was equivalent between groups (P = .6711). Additionally, QoR-15 scores on postoperative day 1 and KOOS values at 1 week demonstrated no significant differences (P = .6486 and P = .9054, respectively). Intraoperative opioid consumption was not different between the groups (P = .127). CONCLUSION: These findings indicate that the addition of ACB to LIA does not yield postoperative analgesic in ACLR. Consequently, LIA alone suffices for routine ACLR, potentially enabling clinicians to optimize perioperative workflows without incurring the additional time, financial burden, and resources associated with routine ACB administration. TRIAL REGISTRATION: ClinicalTrials.gov; NCT04721119.

Humans↗
PubMed1976

Molecular mechanisms of nerve block by local anesthetics.

Local anesthetics block nerve conduction by preventing the increase in membrane permeability to sodium ions that normally leads to a nerve impulse. Among anesthetics containing tertiary amine groups, the cationic, protonated form appears to be more active than the neutral form. However, the neutral forms, as well as uncharged molecules like benzocaine and the aliphatic alcohols, also depress sodium permeability. Studies of single myelinated nerves and squid axons show no direct interaction between calcium ions and local anesthetics, thus disproving theories based on competition between these two agents. Likewise, hypotheses attributing local anesthesia to changes in electrical potentials at the membrane-water interface are disproven by the demonstrated potencies of electrically uncharged anesthetics. Hypotheses that propose that local anesthetics act by expanding the nerve membrane and causing a change in protein conformation that blocks sodium permeability are vague in conception and difficult to test experimentally. Evidence from voltage-clamp studies of single nerve fibers indicates that anesthetic molecules interact with the sodium channels directly, from the inner side of the nerve membrane. Anesthetics bind within sodium channels which have opened during membrane depolarization, preventing the normal sodium ion flux. Anesthetic molecules can dissociate from open channels, but not from channels that remain closed when the nerve is kept at rest. The "gating" properties that regulate the opening and closing of sodium channels are reversibly modified during anesthesia. Specifically, the inactivation function responds more slowly and requires more negative membrane potential changes to reach the same values as in unanesthetized nerves. A second, slow inactivation is observed following external application of tertiary amine anesthetics. The selective binding of anesthetics to open sodium channels provides a simple explanation for Wedenski inhibition, in which the block increases with the frequency of nerve impulses. When impulses occur at higher frequencies more sodium channels are open over a period of time comparable to the time necessary for the anesthetic binding reaction, thus more channels are blocked. In addition the changes of the inactivation function result in a longer refractory period and, thus, a decrease of impulse height at higher frequencies. Charged anesthetic molecules may bind in the pore of the sodium channel. Their binding can be modulated by the electrical field in the membrane. The channel has a higher affinity for larger anesthetic molecules, but this may result from their greater hydrophobicity as well as from their size. The binding site favors molecules that contain more polar linkages between the amine group and the aromatic residue. Binding of amine anesthetics is weakly stereospecific and, surprisingly, shows no absolute requirement for the terminal alkyl ammonium moiety present in most local anesthetics...

Action Potentials↗
PubMed1977

Neural blockade by local anesthetics.

Local anesthetics block nerve impulse propagation by occluding transmembrane sodium channels, so preventing depolarization. First, the uncharged lipid-soluble anesthetic base pentrates the membrane; then the positively charged cation binds to anionic components of the sodium channel's internal axoplasmic mouth. Though primarily a carrier, the base contributes to blockade by causing the membrane to swell, so pinching the sodium channels. Dissolved in water, local anesthetic salt crystals dissociate into anesthetic cation and base-proportional to the drug's fixed pKa and the tissue's variable pH. The cation-base concentration ration is critical to optimal neural blockade. If there is too little base, few anesthetic molecules will penetrate to the neural target; if too little cation, few sodium channels will be plugged.

Anesthetics, Local↗
PubMed1979

Etidocaine, a new local anesthetic.

Different local anesthetics have different physicochemical properties that result in different biological effects. Etidocaine (Duranest) is said to be a long-acting anesthetic with a rapid onset of action, properties that are particularly useful in busy office practices in which lengthy operative procedures are performed. Clinical testing confirmed that this anesthetic does, indeed, work in this manner, which makes it a good addition to the varieties of local anesthetics available.

Acetanilides↗
PubMed1979

Alteration of insulin binding and cytoskeletal organization in cultured fibroblasts by tertiary amine local anesthetics.

Tertiary amine local anesthetics cause a time- and dose-dependent, reversible increase in insulin binding sites in cultured chick embryo fibroblasts. Incubation of fibroblasts with 0.2 mM dibucaine for 3 h at 37 degrees C results in a twofold to threefold increase in insulin binding, with an increase in average number of binding sites (Ka = 3.0 X 10(7) M-1) from 9 X 10(3) per cell. Trypsin or ethyleneglycoltetraacetic acid (EGTA) alone increases insulin binding twofold to threefold, but fails to further increase 125I-insulin binding in cells pretreated with dibucaine. Transformation of chick embryo fibroblasts with Rous sarcoma virus causes a threefold to fivefold increase in insulin binding, which is not further increased by incubation with dibucaine. As demonstrated by transmission electron microscopy, dibucaine and trypsin also induce changes in the cytoskeleton of chick embryo fibroblasts, characterized by disorganization and disappearance of microfilament and microtubule bundles. These alterations are accompanied by gross morphologic changes, including rounding of cells and appearance of numerous ruffles and blebs on the cell surface. These observations are consistent with the hypothesis that expression of surface receptors in cultured chick embryo fibroblasts is related to the organization and disorganization of cytoskeletal structures.

Anesthetics, Local↗
PubMed1977

Central-nervous-system toxicity of local anesthetic mixtures in monkeys.

The central-nervous-system toxicities of local anesthetic mixtures consisting of lidocaine and etidocaine or lidocaine and tetracaine, administered intravenously to four healthy, non-medicated rhesus monkeys, were evaluated. Toxicities were compared by determining seizure dosages for each drug alone and then in a lidocaine-etidocaine-tetracaine mixture. Arterial plasma levels of lidocaine and etidocaine at which electrical seizure activity occurred also were measured when the drugs were administered alone and in combination. The seizure dosages and arterial plasma levels for the drug mixtures studied were equal to the sums of the dosages and thresholds for individual constituents of the mixtures. Under the conditions of this investigation local anesthetic toxicity was additive. (Key words: Anesthetics, local, lidocaine; Anesthetics, local, etidocaine; Anesthetics, local, tetracaine; Brain, seizure thresholds; Toxicity, convulsions.)

Acid-Base Equilibrium↗
PubMed1976

Molecular mechanism of inhibition of firefly luminescence by local anesthetics.

The kinetics of the action of local anesthetics upon firefly luciferin and luciferase systems is presented. Clinical concentrations of local anesthetics inhibited this ATP-induced luminescence in a dose-dependent manner. From the effects of temperature and pH upon the inhibitory action of the local anesthetics, it is concluded that hydrophobic ligand-enzyme interaction is the predominant cause of the inhibition, but hydrophilic interaction also contributes to the inhibition to a lesser degree. A molecular theory of anesthesia is outlined which postulates that release of electrostricted water molecules from the hydrophilic parts of the enzyme due to the protein conformational changes induced by anesthetics is the cause of the decreased luminescence. A similar mechanism is expected to occur at the cell membrane, which probably dehydrates the sodium channel and suppresses the conductance of this ion across the membrane. These events lead to a volume expansion of the total system, and the system becomes reactive to a pressure which reverses the anesthesia by shifting the equilibrium to the nonanesthetized original volume. The pressure antagonism of anesthesia can be explained by this overall volume expansion and not by a mere swelling of the cell membrane.

Anesthetics, Local↗
PubMed1979

The local anesthetic effect of cyproheptadine on mammalian nerve fibres.

The local anesthetic effect of cyproheptadine on nerve fibres in the rabbit's cervical vagus and sciatic nerve was studied by the single sucrose-gap technique. Local anesthetics such as procaine and tetracaine, and an antihistaminic with local anesthetic activity, diphenhydramine, were studied for comparison. Increasing concentrations of cypropheptadine, starting from 5 x 10(-5) M, produced a dose-related fall in the amplitude of the compound action potential of the vagus nerve without significant change in the resting membrane potential. A complete reversibility of the local anesthetic effect was difficult or impossible to obtain when doses greater than 1 x 10(-4) M were used. Cyproheptadine was more potent than procaine and diphenhydramine, and less potent than tetracaine in producing nerve conduction block. Frequency-dependent block was observed with cyproheptadine and the other agents at frequencies that can be considered low (1--5 Hz). Myelinated fibres of the sciatic nerves were also blocked by cyproheptadine within the same range of concentrations (1 x 10(-4) to 1 x 10(-3) M). Our results provide an additional explanation for the mechanism underlying the actions of cyproheptadine as an antiarrhythmic and an antipruritic agent.

Action Potentials↗
PubMed1977

The pH-dependent rate of action of local anesthetics on the node of Ranvier.

Local anesthetic solutions were applied suddenly to the outside of single myelinated nerve fibers to measure the time course of development of block of sodium channels. Sodium currents were measured under voltage clamp with test pulses applied several times per second during the solution change. The rate of block was studied by using drugs of different lipid solubility and of different charge type, and the external pH was varied from pH 8.3 to pH 6 to change the degree of ionization of the amine compounds. At pH 8.3 the half-time of action of amine anesthetics such as lidocaine, procaine, tetracaine, and others was always less than 2 s and usually less than 1 s. Lowering the pH to 6.0 decreased the apparent potency and slowed the rate of action of these drugs. The rate of action of neutral benzocaine was fast (1 s) and pH independent. The rate of action of cationic quaternary QX-572 was slow (greater than 200 s) and also pH independent. Other quaternary anesthetic derivatives showed no action when applied outside. The result is that neutral drug forms act much more rapidly than charged ones, suggesting that externally applied local anesthetics must cross a hydrophobic barrier to reach their receptor. A model representing diffusion of drug into the nerve fiber gives reasonable time courses of action and reasonable membrane permeability coefficients on the assumption that the hydrophobic barrier is the nodal membrane. Arguments are given that there may be a need for reinterpretation of many published experiments on the location of the anesthetic receptor and on which charge form of the drug is active to take into account the effects of unstirred layers, high membrane permeability, and high lipid solubility.

Anesthetics, Local↗
PubMed1978

[Choice of a local anesthetic in obstetrical analgesia].

A local anaesthetic may be selected from amongst the two major groups of drugs of this type: amino-alcoyl-esters and amino-acylamides. In practice, three substances are available or will shortly be available in France: lignocaine, etidocaine and bupivacaine, thus limiting the choice. This choice is guided by the toxicity of the substance, its clinical effects and 1st side effects. 1-Toxicity depends upon the nature of the substance, the dose necessary to obtain analgesia and to prolong it for a sufficient time. 2-Amongst the clinical effects which should be noted in the choice of a local anaesthetic are the latent period before analgesia is obtained, the degree of sensory block, the degree of motor block and the duration of action. The three substances available are compared in relations to these parameters and in the light of the specific requirements of obstetric analgesia. The value of the addiction of adrenalin is discussed. 3-The side effects are those of the local anesthetic itself and of its possible association with adrenalin. On the basis of the various criteria mentioned, it would seem that the analgesic of choice for obstetric analgesia is bupivacaine used with or without adrenalin.

Anesthesia, Obstetrical↗
PubMed1979

Fast kinetic studies on the allosteric interactions between acetylcholine receptor and local anesthetic binding sites.

Preincubation of receptor-rich membrane fragments from Torpedo marmorata with tertiary amine local anesthetics and several toxins such as histrionicotoxin, crotoxin and cerulotoxin, modifies the amplitude and time course of the relaxation processes monitored upon rapid mixing of the membrane fragments with the fluorescent agonist, Dns-C6-Cho. In particular, the amplitude of the rapid relaxation process, which is proportional to the fraction of acetylcholine receptor sites in a high-affinity state, increases; accordingly, the rate constant of the 'slow' and 'intermediate' relaxation processes also increases up to ten times (except with histrionicotoxin) whereas in a higher range of local anesthetic concentrations the rate constant of the 'rapid' relaxation process decreases. The data are accounted for by a two-state model of the acetylcholine regulator, assuming distinct binding sites for cholinergic agonists and local anesthetics and allosteric interactions between these two classes of sites; local anesthetics stabilize the regulator in a high-affinity state for agonists even in the absence of agonist, and modify the rate constants for th interconversions between the low-affinity and high-affinity states. The model accounts for the 'slow' fluorescence increase monitored upon addition of local anesthetics to a suspension of receptor-rich membranes supplemented with trace amounts of Dns-C6-Cho. The effect of local anesthetics on the apparent rate constant of the 'rapid' relaxation process can be accounted for on the basis of an additional low-affinity binding of local anesthetics to the acetylcholine receptor site. Finally the increase of the apparent rate constant of the 'intermediate' relaxation process can be simply accounted for by assuming the existence of a third state, corresponding to the 'active' state, to which local anesthetics bind and block ionic transport.

Amphibian Venoms↗
PubMed1979

[Density of cerebrospinal fluid and local anesthetics (author's transl)].

The densities of cerebrospinal fluid and of local anesthetics, applicable to isobaric spinal anesthesia, were determined by using the Digital Density Meter DMA 02. The density of CSF showed little variation and at 37 degrees C was 1.00021 +/- 0.00024 g/cm3 (mean +/- SD, n = 22). The density of the local anesthetics bupivacaine 0.5%, carticaine 2%, lidocaine 2%, mepivacaine 2% and prilocaine 2% varied at 25 degrees C between 1.001 and 1.005 g/cm3, at 37 degrees C between 0.997 and 1.001 g/cm3. Tetracaine 0.5% in CBF increased its density by 0.00046 g/cm3. The addition of the vasoconstrictors adrenaline and ornipressine (POR 8) increased the density of the local anesthetic solutions insignificantly. On the basis of the narrow range of variation of CSF density, reliable statements may be made on the density dependent spread of local anesthetics in spinal anesthesia.

Anesthesia, Spinal↗
PubMed1979

Reinforcing properties of some local anesthetics in rhesus monkeys.

The reinforcing properties of several local anesthetics were determined in rhesus monkeys experienced in the intravenous self-injection of cocaine. Intravenous procaine and, occasionally, tetracaine maintained response rates higher than did vehicle injections in most monkeys. In contrast, lidocaine, procainamide and diethylaminoethanol (a metabolite of procaine) failed to maintain responding resulting in their intravenous delivery. These results demonstrate that not all local anesthetics are positive reinforcers in the rhesus monkey when delivered intravenously. Furthermore, the reinforcing properties of procaine probably cannot be attributed to its metabolite diethylaminoethanol. The data suggest that short-acting, esteratic local anesthetics are most likely to have reinforcing properties in the rhesus monkey.

Anesthetics, Local↗
PubMedDate not supplied

Interaction of muscle relaxants and local anesthetics at the neuromuscular junction.

The effects on neuromuscular (NM) function of combinations of relaxants (d-tubocurarine, pancuronium, and succinylcholine) and local anesthetics (cocaine, procaine, lidocaine, etidocaine, and a quaternized derivative of procaine, procaine methobromide) were investigated using the rat's phrenic nerve--hemidiaphragm preparation. Combinations of ineffective concentrations of NM blocking agents with ineffective concentrations of local anesthetics caused a greater than 90% NM block. Preliminary administration of ineffective concentrations of local anesthetics significantly ( p less than 0.001) decreased the ED50 of NM blocking agents. The administration of ineffective concentrations of NM blocking agents caused a similar decrease of the ED50 of local anesthetics. Concentrations of d-tubocurarine and pancuronium which alone produced partial NM block had additive effects. These findings suggest that the interaction of NM blocking agents and local anesthetics consists of true potentiation caused by the different sites of action of the two types of compounds at the NM junction. The degree of potentiation may be enough to cause clinically significant NM block in patients who at the same time receive high enough doses of both agents. In vitro the NM block caused by the combinations of local anesthetics and NM blocking agents can be reversed by 4-aminopyridine.

Anesthetics, Local↗