Higher Lidocaine Concentrations Research Articles

Abstract 14031: Effects of Custodiol-HTK and Del Nido Solutions in a Coronary-Perfused Rabbit Ventricular Wedge Model

Introduction: Distinct cardioplegic solutions are used in cardiac surgery for myocardial protection. Custodiol-HTK (CUS) solution consists of histidine, tryptophan, ketoglutarate and mannitol to reduce cellular edema. Del Nido (DN) is a nonglucose-based solution containing low calcium and high lidocaine concentrations, preventing intracellular Ca2+ accumulation during ischemia. Hypothesis: Using a coronary-perfused rabbit experimental model, this study compares the effects of CUS and DN on transmural electrocardiogram (ECG) and tension parameters. Methods: Twelve left ventricular (LV) wedge preparations from 12 rabbit hearts were arterially perfused with Tyrode's solution and stimulated at a cycle length of 1000 ms. Simultaneous recording of transmural ECG and tension were obtained. After exposure to normal Tyrode, the LV wedge preparation was perfused with 20 cc of CUS (n=6) or 20 cc of DN (n=6) leading to complete arrest maintained for 30 minutes. ECG and tension recordings were obtained under baseline conditions and at 5, 15, and 30 minutes after reperfusion with normal Tyrode. Differences in change from baseline ECG and tension parameters after CUS or DN were compared using a mean differences regression model. Results: Reperfusion effects of CUS and DN on ECG and tension are shown in Table 1 . After reperfusion, DN group had a significantly greater increase in QRS duration, significantly more QT shortening and more ST segment change compared to CUS group. At 5- and 15-minutes post-reperfusion, the CUS group had significantly higher tension recovery. Negative T wave were observed in 1 of 6 wedges of the CUS group and 5/6 (83.3%) wedges of the DN group. Conduction block was observed in 0/6 wedges in the CUS group and 5/6 (83.3%) wedges in the DN group. Conclusions: In a LV coronary-perfused rabbit wedge preparation, Custodiol-HTK cardioplegia led to less ischemic changes in ECG and faster tension recovery following reperfusion compared to del Nido cardioplegia.

Postmortem redistribution of lidocaine after illegal use

Lidocaine is the most common local anesthetics used for para cervical block to reduce pain associated with surgical abortion. Topical form of lidocaine and its contents have been used for illicit purposes and suicidal intentions. Analysis of lidocaine in different body organs is important for us as a toxicologist to help determine the postmortem redistribution of lidocaine and to avoid misleading of the high lidocaine concentrations. We present two case reports of lidocaine related death. All samples were extracted using solid phase extraction and lidocaine was identified and quantified by gas chromatography with mass spectrometry (GCMS). First case (Case 1) was 25-year-old pregnant women who was undergoing criminal abortion during the first trimester and she died before reaching hospital. Second case (Case 2) was 30-year-old man who ingested of solution contain 10% lidocaine from Avocaine spray 50 ml bottle resulting in seizures and subsequently died. Post-mortem investigations and autopsy show no clear finding. Lidocaine concentrations were detected all analyzed samples with lethal levels. The concentrations of lidocaine were as follows: Case 1 blood 17 mg/l, brain 19 mg/kg, liver 7 mg/kg, kidney 14 mg/kg, and stomach 3 mg/kg. Case 2 blood 63.05 mg/l, urine 21 mg/l, oral swap 9.6 mg/l, brain 29.5 mg/kg, liver 67 mg/kg, kidney 19.2 mg/kg, and stomach 110.2 mg/kg. Our results represent that blood and tissues lidocaine levels were above the lower level of lethal range, therefore, the possibility of lidocaine overdose is expected and considering lidocaine as the cause of death in both cases cannot rule out. Distribution of lidocaine was different in both cases, suggesting, the effect of route of administration. Toxicological findings and factors affecting lidocaine postmortem redistribution and results interpretation are discussed.

Effect of Lidocaine on Viability and Gene Expression of Human Adipose-derived Mesenchymal Stem Cells: An in vitro Study.

To assess the biologic effects of lidocaine on the viability, proliferation, and function of human adipose tissue-derived mesenchymal stromal/stem cells (MSCs) in vitro. Adipose-derived MSCs from three donors were exposed to lidocaine at various dilutions (2 mg/mL to 8 mg/mL) and exposure times (0.5 to 4 hours). Cell number and viability, mitochondrial activity, and real-time reverse-transcriptase quantitative polymerase chain reaction (RT-qPCR) were analyzed at 0 (immediate effects) or 24 and 48 hours (recovery effects) after treatment with lidocaine. Trypan blue staining showed that increasing concentrations of lidocaine decreased the number of observable viable cells. 3-[4,5,dimethylthiazol-2-yl]-5-[3-carboxymethoxy-phenyl]-2-[4-sulfophenyl]-2H-tetrazolium (MTS) assays revealed a concentration- and time- dependent decline of mitochondrial activity and proliferative ability. Gene expression analysis by RT-qPCR revealed that adipose-derived MSCs exposed to lidocaine express robust levels of stress response/cytoprotective genes. However, higher concentrations of lidocaine caused a significant downregulation of these genes. No significant differences were observed in expression of extracellular matrix (ECM) markers COL1A1 and DCN except for COL3A1 (P < .05). Levels of messenger RNA (mRNA) for proliferation markers (CCNB2, HIST2H4A, P < .001) and MKI67 (P < .001) increased at 24 and 48 hours. Expression levels of several transcription factors- including SP1, PRRX1, and ATF1-were modulated in the same manner. MSC surface markers CD44 and CD105 demonstrated decreased expression immediately after treatment, but at 24 and 48 hours postexposure, the MSC markers showed no significant difference among groups. Lidocaine is toxic to MSCs in a dose- and time- dependent manner. MSC exposure to high (4-8 mg/mL) concentrations of lidocaine for prolonged periods can affect their biologic functions. Although the exposure time in vivo is short, it is essential to choose safe concentrations when applying lidocaine along with MSCs to avoid compromising the viability and potency of the stem cell therapy.

Absence of cytotoxic and inflammatory effects following in vitro exposure of chondrogenically-differentiated human mesenchymal stem cells to adenosine, lidocaine and Mg2+ solution

BackgroundALM solution, a combination of adenosine, lidocaine and Mg2+, is an emerging small volume therapy that has been shown to prevent and correct coagulopathy and surgery-related inflammation in preclinical models, though its application in orthopaedic surgery is yet to be demonstrated. The effect of ALM solution on chondrocytes is unknown. The aim of this preliminary study was to investigate the effect of ALM solution on viability and inflammatory responses of chondrogenically-differentiated human bone marrow-derived mesenchymal stem cells (chondro-MSC), in vitro.MethodsChondro-MSC were exposed to media only, saline (0.9% NaCl or 1.3% NaCl) only, or saline containing ALM (1 mM adenosine, 3 mM lidocaine, 2.5 mM Mg2+) or tranexamic acid (TXA, 100 mg/ml) for 1 or 4 h. Responses to ALM solutions containing higher lidocaine concentrations were also compared. Chondrocyte viability was determined using WST-8 colorimetric assays and inflammatory cytokine (TNF-α, IL-1β, IL-8) and matrix metalloproteinases (MMP-3, MMP-12, MMP-13) concentrations using multiplex bead arrays.ResultsThe viability of chondro-MSC was significantly greater after 1 h treatment with ALM compared to saline (96.2 ± 7.9 versus 75.6 ± 7.3%). Extension of exposure times to 4 h had no significant adverse effect on cell viability after treatment with ALM (1 h, 85.4 ± 5.6 v 4 h, 74.0 ± 15.2%). Cytotoxicity was evident following exposure to solutions containing lidocaine concentrations greater than 30 mM. There were no significant differences in viability (80 ± 5.4 v 57.3 ± 16.2%) or secretion of IL-8 (60 ± 20 v 160 ± 50 pg/ml), MMP-3 (0.95 ± 0.6 v 3.4 ± 1.6 ng/ml), and MMP-13 (4.2 ± 2.4 v 9.2 ± 4.3 ng/ml) in chondro-MSC exposed to saline, ALM or TXA.ConclusionsShort-term, in vitro exposure to clinically-relevant concentrations of ALM solution had no adverse inflammatory or chondrotoxic effects on human chondro-MSC, with responses comparable to saline and TXA. These findings provide support for continued evaluation of ALM solution as a possible therapeutic to improve outcomes following orthopaedic procedures.

Extended pain relief achieved by analgesic-eluting biodegradable nanofibers in the Nuss procedure: in vitro and in vivo studies.

BackgroundThe most common complaint after the Nuss procedure is severe postoperative chest pain. The aim of this study was to evaluate the effectiveness of analgesic-eluting biodegradable nanofibers in pain relief after the Nuss procedure.Materials and methodsPoly(d,l)-lactide-co-glycolide, lidocaine, and ketorolac were dissolved in 1,1,1,3,3,3-hexafluoro-2-propanol. This solution was electrospun into a nanofibrous membrane. The elution method and high-performance chromatography were used to characterize the in vitro drug release. Stainless steel bars with and without coating of the analgesic-eluting nanofibrous membrane were implanted underneath the sternums of New Zealand white rabbits. The in vivo characteristics were further investigated.ResultsThe in vitro study showed that the biodegradable nanofibers released high doses of lidocaine and ketorolac within 10 days. The in vivo study demonstrated high local and systemic concentrations of lidocaine and ketorolac. The serum creatinine level was unaffected. Animals that received implants of the analgesic-eluting nanofiber-coated stainless steel bar exhibited significantly greater food and water ingestion and physical activity than the control group did, indicating effective pain relief.ConclusionThe proposed analgesic-eluting biodegradable nanofibers contribute to the achievement of extended pain relief after the Nuss procedure, without obvious adverse effects, in an animal model.

In vitro effects of lidocaine on contractility of circular and longitudinal equine intestinal smooth muscle

The purpose of the study was to compare the contractility-enhancing effects of lidocaine in equine jejunal circular (CSM) and longitudinal smooth muscle (LSM) in vitro. In previous studies, more pronounced effects of lidocaine were observed in ischaemia–reperfusion (IR) injured smooth muscle. Therefore in this study, effects were examined in both non-injured control tissues and tissues challenged by a defined, artificial IR injury. Isometric contractile performance of CSM and LSM, assessed by frequency (F), amplitude (A) and mean active force (MAF) of contractions, was defined as contractility.LSM featured lower basic contractility compared to CSM. Lidocaine provoked contractility-enhancing effects in both smooth muscle layers, but except for F at high lidocaine concentrations, contractility of LSM remained lower throughout the trial. Additionally, higher lidocaine concentrations were required to cause significant effects in LSM. No differences were observed in contractility of control and IR injured smooth muscle, but higher lidocaine concentrations were needed to provoke effects in IR injured smooth muscle. In contrast to CSM, contractility of LSM did not decrease at comparably high lidocaine concentrations.Differences in basic contractility of CSM and LSM might be explained by physiologically lower activity of LSM per se or by a thinner LSM layer with fewer smooth muscle cells taking part in contractions. The smaller thickness of the LSM layer may also contribute to persisting discrepancies in contractility following lidocaine application. Additionally, variations in lidocaine concentrations necessary for inducing significant effects could result from differences in the molecular structure of CSM and LSM cells.

Commentary on an article by Brett P. Wiater, MD, et al.: “Risk Factors for Chondrolysis of the Glenohumeral Joint. A Study of Three Hundred and Seventy-five Shoulder Arthroscopic Procedures in the Practice of an Individual Community Surgeon”

Chondrolysis remains a catastrophic and devastating condition of the shoulder that has had many associated but not well-proven causes. Numerous published case reports and small case series have led to difficulty in extrapolating any meaningful data with respect to the true etiology of this condition1-6. Wiater et al. were presented with a unique opportunity to review a specific cohort of patients from a single community orthopaedic surgeon as a result of a medicolegal action related to chondrolysis. They were provided complete access to the medical records on 375 intra-articular shoulder arthroscopic procedures performed by the surgeon from 1999 to 2008. A number of factors were assessed, including patient age at the time of surgery, side of surgery, date of surgery, preoperative diagnosis, type of anesthesia, procedure performed, use and type of suture anchors, use of radiofrequency, and use and location of a postoperative local anesthetic infusion catheter. They also were able to ascertain the type and concentration of local anesthetic used for postoperative analgesia and whether epinephrine was used in the infusate. Forty-nine surgical procedures (13%) were complicated by chondrolysis. Each of these forty-nine procedures was associated with intra-articular infusion of either Marcaine (bupivacaine) or lidocaine. Furthermore, none of the patients who had an arthroscopic procedure without infusion of anesthetics developed postoperative chondrolysis. Additional significant factors associated with the development of chondrolysis were arthroscopic Bankart repair, arthroscopic debridement, one or more suture anchors in the glenoid, and surgery duration. Only six shoulders had 0.25% Marcaine, but none had chondrolysis in that group. A recent systematic review of studies from peer-reviewed journals identified 100 cases of chondrolysis7. Fifty-nine percent of the cases involved post-arthroscopic use of anesthetic infusate (usually bupivacaine, with lidocaine used in only two cases). Finally, the authors of a recent study reported eighteen cases of chondrolysis related to the intra-articular infusion of bupivacaine with epinephrine through an intra-articular pain pump catheter8. Forty-five pain pumps were used in the 113 arthroscopic procedures during the same time period. Chondrolysis developed in sixteen of thirty-two patients with a high-flow intra-articular pain pump catheter and in just two of twelve patients with a low-flow intra-articular pain pump catheter. (The pump type was not determined for the forty-fifth patient.) This information, in conjunction with the finding by Wiater et al. that the duration of surgery was correlated with the development of chondrolysis, provides a possible link between the newer, higher-flow pain pumps and the development of this condition. Given the literature to date, in conjunction with this unique article by Wiater et al., it appears reasonable to caution against the use of intra-articular infusion of anesthetics, specifically bupivacaine or higher concentrations of lidocaine. Basic science studies by Chu et al.9 and Gomoll et al.10 further highlight the potential chondrotoxic effects of bupivacaine, and these negative correlations far outweigh any possible analgesic benefits. Furthermore, the issue of the association of high-flow intra-articular pain pumps with higher rates of chondrolysis and their continued use should be carefully examined as well. The authors did not specifically analyze or hypothesize about the association between chondrolysis and suture anchors in the glenoid, and it is not intuitively clear why this association would exist, given that hundreds of thousands of these implants have been placed since their introduction in the early 1990s. In summary, Wiater et al. were provided with a unique opportunity to explore the possible causes of chondrolysis, a rare but devastating condition in the shoulder. While many unanswered questions remain, their paper, combined with the recent peer-reviewed literature, has further illuminated the role of local anesthetics and high-flow pain pumps in causing chondrolysis, and the intra-articular use of these techniques in association with shoulder arthroscopy should be avoided.

Distribution of Bupivacaine Enantiomers and Lidocaine and Its Metabolite in the Placental Intervillous Space and in the Different Maternal and Fetal Compartments in Term Pregnant Women

The aim of this study is to determine the concentrations of lidocaine and its metabolite, monoethylglycine xylidide (MEGX), and of the enantiomers of bupivacaine in maternal and fetal compartments. Ten healthy pregnant women were submitted to epidural anesthesia. Drug concentrations were determined in the maternal vein, fetal umbilical artery and vein, and the placental intervillous space. The highest concentrations of the bupivacaine enantiomers lidocaine and of lidocaine and of its MEGX metabolite were detected in maternal plasma and in the placental intervillous space. The placental transfer was 33% for the (+)-(R)-bupivacaine enantiomer and 31% for the (-)-(S)-bupivacaine enantiomer. For lidocaine and its MEGX metabolite, respective placental transfers were 60% and 43%. Lidocaine concentration in the fetal umbilical vein was 1.46 times higher than in the fetal umbilical artery. The highest concentrations of lidocaine and its metabolite and of the enantiomers of bupivacaine were detected in the placental intervillous space. The higher lidocaine concentrations in the fetal umbilical vein than in the fetal umbilical artery suggest that there was tissue uptake of the drug or drug metabolization by the fetus.

Sustained delivery of lidocaine into the cochlea using poly lactic/glycolic acid microparticles

Lidocaine is a local anesthetic that is known to suppress tinnitus via systemic or local application; however, this effect has only limited duration. The current study aimed to establish a method for the sustained delivery of lidocaine into the cochlea using poly lactic/glycolic acid (PLGA) microparticles. Experimental study. Lidocaine-loaded PLGA microparticles were produced and their in vitro-release profiles were examined. The lidocaine concentrations in the perilymph were measured at different time points following the application of the lidocaine-loaded PLGA microparticles to the round-window membranes of guinea pigs. The possible adverse effects of the local application of lidocaine-loaded PLGA microparticles were also examined. The in vitro analyses revealed that the microparticles were capable of the sustained delivery of lidocaine. The in vivo experiments demonstrated the sustained delivery of lidocaine into the cochlear fluid, and the maintenance of high lidocaine concentrations in the perilymph for up to 3 days after application. Nystagmus and inflammation in the middle ear mucosa were not detected after the local application of lidocaine-loaded PLGA microparticles, although temporary hearing loss was observed. Lidocaine-loaded PLGA microparticles were shown to be capable of the sustained delivery of lidocaine into the cochlea, suggesting that they could be used for the attenuation of peripheral tinnitus.

Viscoanaesthesia in cataract surgery: a prospective, randomized clinical trial

We aimed to compare viscoanaesthesia (VisThesia) with intracameral lidocaine in cataract surgery carried out under topical anaesthesia. In this prospective study 98 patients were randomly assigned to receive VisThesia (group 1, n = 49) or 0.5 cc of 1% unpreserved lidocaine (group 2, n = 49). All surgery was carried out by one surgeon using clear corneal technique. Pachymetry, the status of the cornea and anterior chamber, and intraocular pressure (IOP) were checked pre- and postoperatively. Mean pain scores were 0.12 (maximum: 3) in group 1 and 0.37 in group 2; the difference between the groups was not statistically significant (95% confidence interval [CI] 0.003-0.487; p = 0.05). A total of 48 patients in group 1 (98%) and 49 in group 2 (100%) reported no discomfort or only mild discomfort. No significant differences in flare and cells in the anterior chamber or IOP were found between the two study groups. There was a significantly greater frequency of corneal oedema in group 1 (p = 0.001). Postoperative central corneal thickness values were also significantly higher in group 1 (95% CI 11.64-57.24; p = 0.003). Results suggest that viscoanaesthesia provides a level of comfort during cataract surgery under topical anaesthesia similar to that facilitated by intracameral lidocaine. However, patients who are given viscoanaesthesia may have increased risk for postoperative corneal oedema.

The Effects of the Local Anesthetics Lidocaine and Procaine on Glycine and γ-Aminobutyric Acid Receptors Expressed in Xenopus Oocytes

The voltage-dependent sodium channel is the primary site of action for local anesthetics (LAs). Although systemically administered low-dose LAs have been shown to exert antihyperalgesic effects, the molecular targets responsible for these effects are not fully known and their functional effects on inhibitory neurotransmitter receptors associated with antinociception have not been sufficiently studied. We examined the effects of lidocaine and procaine (0.1 microM to 3 or 10 mM) on recombinant human alpha1 glycine, alpha1beta2gamma2S gamma-aminobutyric acid type A (GABA(A)), and rho1 GABA(C) receptors expressed in Xenopus laevis oocytes, using a two-electrode voltage-clamp system. We also evaluated the effects of LAs on two mutant glycine receptors, alpha1(S267C) and alpha1(S267Q), in an effort to clarify the interaction between LAs and glycine receptors. Low concentrations of both lidocaine and procaine enhanced glycine receptor function, whereas high concentrations of lidocaine and procaine inhibited glycine receptor function. Lidocaine (10 microM) produced a significant leftward shift in the glycine concentration-response curve, indicating an increase in the apparent affinity for glycine. This enhancement was not altered in the mutant receptors. Both lidocaine and procaine at high concentrations inhibited GABA(A) receptor currents, whereas neither lidocaine nor procaine affected GABA(C) receptor function. Lidocaine and procaine enhanced glycine receptor function at low concentrations and inhibited the functions of glycine and GABA(A) receptors at high concentrations. The mechanism of the LA-induced enhancement of glycine receptor function probably differs from that of general anesthetics. These findings may explain the pharmacological effects of LAs, such as antinociception and convulsion.

Two cases of idiopathic superior laryngeal neuralgia treated by superior laryngeal nerve block with a high concentration of lidocaine

Carbamazepine therapy is among the most effective drug regimens to treat patients who have superior laryngeal neuralgia similar to trigeminal neuralgia. However, some patients are resistant to carbamazepine. We report two patients with superior laryngeal neuralgia who were successfully treated with superior laryngeal block using high concentrations of lidocaine, after treatment with carbamazepine failed.

The critical role of concentration for lidocaine block of peripheral nerve in vivo: studies of function and drug uptake in the rat.

The adjustment of local anesthetic dosage for peripheral nerve block must meet two basic requirements: a drug concentration sufficient to inhibit Na+ channels to the point of impulse failure and a volume of drug sufficient to expose a length of nerve longer than the "critical length" for propagation failure. This study examines the lidocaine dosage requirement, in milligrams, for functionally assayed sciatic nerve block in the rat using a fourfold range of volume corresponding to concentrations from 2 to 7 mg/ml and compares these blocks with the intraneural lidocaine content after injection of equipotent doses. Lidocaine was injected percutaneously at the sciatic nerve in volumes of 0.05 ml, 0.1 ml, and 0.2 ml (all at pH 6.8), and quantitative neurobehavioral assays were conducted on male Sprague-Dawley rats weighing from 200 to 250 g. The dose requirements for 50% maximum possible effect (ED50) and for just achieving complete block (i.e., minimal blocking dose for 90% effect), the fraction of completely blocked animals, and the duration of complete block at all doses were assessed for the inhibition of three different functions: proprioception, motor, and nocifensive activities. Radiolabeled (14C) lidocaine was injected in separate experiments, and the total drug content and its longitudinal distribution were determined in nerves dissected from animals (sevoflurane anesthetized) at 10 min, the time of peak block, after injection of the E50 and minimal blocking dose for 100% effect for the three different volumes. For all functions, the smaller the volume, the lower was the E50, resulting in a nearly constant concentration to achieve an equivalent degree of block. Durations of block were longer, and the dose to full block was lower for the smaller injected volumes. Intraneural lidocaine, at the equipotent doses for analgesia, was not related to concentration but rather increased with increasing volume, being almost proportional to the given dose. The longitudinal spread of lidocaine was also greater with increasing volume of lidocaine solution. Blocks of greater depth and longer duration result from injection of smaller volumes and, correspondingly, higher lidocaine concentrations containing the same dose. The corollary is that lower lidocaine doses are required to achieve the same effect when smaller volumes are injected. Curiously, when the equivalent E50 is injected, total drug taken into the nerve is less from the smaller volumes than from the larger volumes, even though the peak functional effects are equal. Total intraneural local anesthetic may not represent the effective drug in the compartment that contains nerve axons, the actual location of neural blockade.

Morphologic Assessment of Plasma Membrane Blebbing Provides a Sensitive, Early Indicator of Low Dose Lidocaine Neurotoxicity

Background: Lidocaine is a local anesthetic that is frequently used for spinal anesthesia. in clinical and animal studies, lidocaine is associated with an increased risk of spinal neurotoxicity following spinal anesthesia. The mechanism of lidocaine neurotoxicity has not been fully elucidated, but it does not involve blockade of sodium channels, the mechanism by which lidocaine causes local anesthesia. Previous in vitro studies assessing cytoplasmic calcium, nerve conduction and action potential generation, and cell death, have demonstrated overt neurotoxicity at higher concentrations of lidocaine (≥ 2% [74 mM] of the hydrochloride formulation), but equivocal results at lower concentrations. Clinically available preparations of lidocaine for spinal anesthesia contain 5% or 2.5% lidocaine hydrochloride. in most cases, lidocaine mixes rapidly with cerebrospinal fluid after injection for spinal anesthesia, so that lower concentrations are more clinically relevant. We have therefore evaluated morphologic assessment of plasma membrane blebbing as a more sensitive assay of neuronal injury by lidocaine.

Aesthetic surgery: Coming of age

lation has resulted in a growing demand for such interventions to ameliorate the visible signs of ageing. Particular concerns are imperfections in the appearance of the skin, including unevenness in colour and texture, raised or depressed scars, wrinkles, sagging accumulations of subcutaneous fat, and hair loss. Fine wrinkling, photodamage caused by lifelong sun exposure, and scars caused by acne, chickenpox, surgery, or trauma can now be treated by laser resurfacing. High-energy shortpulsed or scanned carbondioxide lasers and pulsed erbium yttrium-aluminiumgarnet (YAG) lasers precisely remove skin tissue of uniform depth with little bleeding, while limiting the heat-related damage to surrounding tissues and so minimising the risk of scars and pigmentary changes. With proper selection of patients and wound care, the results of laser resurfacing are dramatic. Wrinkles round the eyes and mouth, typically unresponsive to face-lifting, can be successfully treated. Vascular lesions, such as superficial blood vessels, %elangiectasias, port-wine stains, haemangiomas, and leg veins, as well as scars, striae, and diffuse skin redness, can be treated quickly and effectively with several lasers, including the potassium-titanylphosphate laser and the newestgeneration pulsed-dye lasers, which can eliminate vascular patches with little or no bruising. Pigmented lesions, including tattoos and dark brown birthmarks, can be lightened with lasers that selectively destroy the pigment while sparing the adjacent tissue by emitting very short intense bursts of laser energy called Q-switched pulses. Qswitched lasers of specific wavelengths (Q-switched ruby, alexandrite, or neodymium YAG lasers) are best suited for removing tattoos of particular colours. Unwanted hair can also be treated quickly with lasers adapted for this purpose. Best results are seen in dark-haired, light-skinned patients, in whom a few treatments can result in a sharp permanent reduction in hair growth. Injectable or implantable filler substances are available for correction of soft-tissue losses from ageing, scarring, or skin disease. These materials can help reduce grooves between the cheeks and the nose as well as wrinkles, improve the contour of thinning lips, and fill deep acne scars. Bovine dermal collagen implants were approved in the USA by the Food and Drug Administration (FDA) in the early 1980s. Since then, autologous collagen products that may offer longer duration of correction and lower risk of allergic reactions have been developed, as have various Lower face before (top) and I month after C02 laser resurfacing other injectable substances, none of which are yet approved for use in the USA. Alternatively, fat can be taken from a non-facial site and implanted into facial sites in the same individual, thus eliminating the risk of immune reaction. Synthetic implantable agents--eg, expanded polytetrafluoroethylene--are available in various shapes and sizes and offer a permanent filling effect while being immunologically inert. Frown lines of the forehead and around the eyes respond well to treatment with botulinum A exotoxin. This substance, which is not yet approved for this indication by the FDA, is injected into the relevant muscle groups to provide relaxation of dynamic skin creases for 3-6 months. Age-related fat redistribution can occur in the cheeks and below the chin and jaw. Cervicofacial liposuction effectively removes fat from these regions and improves the contour of the neck and face. Liposuction also removes larger volumes of fat from other body areas that are resistant to diet and exercise, such as the upper arms, abdomen, hips, and thighs. Liposuction is safest and most effective with the tumescent anaesthetic technique--ie, injection of several litres of dilute lidocaine, epinephrine, and sodium bicarbonate into the subcutaneous fat before liposuction. The effects of fluid compression and epinephrine on the subcutaneous compartment allow use of high concentrations of lidocaine and decrease the need for sedation. Liposuction can now be done with little blood loss and with mild postoperative pain, swelling, and bruising. Improved techniques for hair transplantation have enabled a more natural appearance. Dermatological surgeons have learned to transplant hair singly or in groups of two or three into the balding scalp in the same configurations as on normal scalps. The technology is available to transplant even large bald patches within only one or two sessions. Given the demand for aesthetic procedures and the improvements that are increasing their efficacy, cosmetic dermatological surgery can be expected to remain a growing area within dermatology.

Effects of lidocaine and bupivacaine on isolated rabbit mesenteric capacitance veins

Background and Objectives. The direct effects of circulating lidocaine and bupivacaine on splanchnic capacitance veins have not been examined previously. This article reports on the effects of clinically relevant concentrations of lidocaine and bupivacaine on adrenergic responsiveness of isolated rabbit mesenteric veins and examines the mechanism of changes. Methods. Rings of ileal mesenteric capacitance veins were suspended in tissue baths for isometric tension measurements. Effects of lidocaine and bupivacaine on contractile responses to adrenergic nerve stimulation, exogenous norepinephrine (10 −6 M NE), and potassium chloride (80 mM KCl) were examined in endothelium-intact, L-NAME (10 −4 M) treated or denuded veins. Results. Constriction in response to adrenergic nerve stimulation was attenuated by lidocaine and bupivacaine in a dose-dependent manner, with the potency of bupivacaine being higher than lidocaine. Unstimulated or potassium-constricted veins with and without endothelium were unaffected by lidocaine (0.25–100 μg/mL) and bupivacaine (0.1–100 μg/mL). In veins preconstricted by exogenously administered NE, a cumulative increase of both anesthetics produced no effect at low doses, an augmentation of constriction to NE at 5–20 μg/mL bupivacaine and 20–100 μg/mL lidocaine, and minimal effect at 50–100 μg/mL bupivacaine. These actions persisted in denuded or L-NAME treated veins. Nonincremental delivery of high concentrations of lidocaine or bupivacaine produced relaxation of NE and potassium-constricted rings in the absence and presence of L-NAME. Conclusions. Lidocaine and bupivacaine in concentrations typical during uncomplicated regional anesthesia inhibit adrenergic neurotransmission in rabbit mesenteric capacitance veins and produce modest venodilatation. Higher doses, resembling concentrations during accidental intravascular injection, result in substantial loss in vasomotor control of these capacitance vessels, which may contribute to hemodynamic effects.

Absorption of Intubation-Related Lidocaine from the Trachea during Prolonged Cardiopulmonary Resuscitation

The purpose of this study was to determine whether lidocaine is absorbed from the trachea during the artificial circulation of cardiopulmonary resuscitation. The tissue distribution of lidocaine was investigated in eight individuals (Cases 1-8) who underwent cardiopulmonary resuscitation before being pronounced dead. In Cases 1-4, there was no restoration of heart beat during cardiopulmonary resuscitation. Heart massage had been continued for 5 min in Cases 1 and 2, and for 60 min in Cases 3 and 4. Relatively high concentrations of lidocaine (more than 0.1 mg/L) were detected in the blood left in the heart and/or in the large thoracic vessels in the four cases. In Cases 1-3, a large proportion of the lidocaine detected in these blood samples may have diffused from the trachea after cessation of cardiopulmonary resuscitation since no lidocaine was detected in the cerebrospinal fluid, cerebrum, liver, right kidney, and/or right femoral muscle. In Case 4, however, tracheal lidocaine was thought to have been absorbed during cardiopulmonary resuscitation because 0.167-0.340 mg/L or mg/kg lidocaine was detected in the cerebrospinal fluid, liver, right kidney, and right femoral muscle. This was substantiated in experiments performed in rabbit carcasses given 50 microL/kg Xylocaine jelly (a 2% lidocaine hydrochloride preparation) intratracheally, followed by rhythmical thoracic compressions (100-150 times per minute) for 60 min. A possible reason for lack of absorption of lidocaine from the trachea of Case 3 during a 60-min cardiopulmonary resuscitation procedure may have been that effective blood circulation was not obtained during cardiopulmonary resuscitation because of bleeding and pulmonary collapse. Cases 5-8 survived for 3 h to 10 days after successful cardiopulmonary resuscitation; it was obvious that lidocaine was distributed to the tissues under the influence of the natural circulation. The kidney to liver lidocaine ratio in Case 4 (0.8) was much lower than that in Cases 5-8 (1.3-4.6), although the lidocaine ratio in the blood in the left ventricle when compared to blood in the right ventricle was similar in the five cases. The kidney to liver lidocaine ratio may be helpful in judging whether the lidocaine detected was absorbed during the artificial circulation of cardiopulmonary resuscitation or naturally. Additionally, postmortem diffusion of tracheal lidocaine into the blood in the left ventricle was much greater than into the blood in the right ventricle due to their anatomical location during a supine position. The pattern of tissue distribution of lidocaine gives useful information on the state of decedents during cardiopulmonary resuscitation.

Graded, irreversible changes in crayfish giant axon as manifestations of lidocaine neurotoxicity in vitro.

High concentrations of lidocaine induce irreversible conduction block with little effect on resting membrane potential (Em). We assumed the mechanism of persistent neurologic deficit caused by local anesthetics may result from neural death, as represented by the loss of Em. We investigated the effects of lidocaine on Em and action potential (AP) in single crayfish giant axons in vitro. Axons were perfused with two doses of lidocaine for either 15 or 30 min, and they were continuously washed. No axons exposed to 80 mM lidocaine for 30 min showed recovery of AP and Em. Those exposed to 40 mM for 30 min and 80 mM for 15 min showed a return to baseline for Em, but no recovery of AP. Those exposed to 40 mM lidocaine for 15 min showed full recovery of Em and AP immediately after washing. The membrane depolarization was significantly greater during exposure to 80 mM lidocaine for 30 min than in other groups. We conclude that lidocaine has a direct neurotoxic effect on crayfish giant axons and that the generation of AP is more vulnerable than the maintenance of Em. The irreversibility of AP and Em is dose- and time-dependent. Highly concentrated lidocaine induced an irreversible conduction block and a complete loss of resting membrane potential in crayfish giant axons in vitro. Our results may represent a possible explanation for various grades of local anesthetic-induced neurotoxicity in clinical cases if the same toxicity occurs in mammalian nerves in vivo.

Graded, Irreversible Changes in Crayfish Giant Axon as Manifestations of Lidocaine Neurotoxicity In Vitro

High concentrations of lidocaine induce irreversible conduction block with little effect on resting membrane potential (Em).We assumed the mechanism of persistent neurologic deficit caused by local anesthetics may result from neural death, as represented by the loss of Em. We investigated the effects of lidocaine on Em and action potential (AP) in single crayfish giant axons in vitro. Axons were perfused with two doses of lidocaine for either 15 or 30 min, and they were continuously washed. No axons exposed to 80 mM lidocaine for 30 min showed recovery of AP and Em. Those exposed to 40 mM for 30 min and 80 mM for 15 min showed a return to baseline for Em, but no recovery of AP. Those exposed to 40 mM lidocaine for 15 min showed full recovery of Em and AP immediately after washing. The membrane depolarization was significantly greater during exposure to 80 mM lidocaine for 30 min than in other groups. We conclude that lidocaine has a direct neurotoxic effect on crayfish giant axons and that the generation of AP is more vulnerable than the maintenance of Em. The irreversibility of AP and Em is dose- and time-dependent. Implications: Highly concentrated lidocaine induced an irreversible conduction block and a complete loss of resting membrane potential in crayfish giant axons in vitro. Our results may represent a possible explanation for various grades of local anesthetic-induced neurotoxicity in clinical cases if the same toxicity occurs in mammalian nerves in vivo. (Anesth Analg 1998;86:569-73)

Adverse effects and drug interactions associated with local and regional anaesthesia.

Systemic and localised adverse effects of local anaesthetic drugs usually occur because of excessive dosage, rapid absorption or inadvertent intravascular injection. Small children are more prone than adults to methaemoglobinaemia, and the combination of sulfonamides and prilocaine, even when correctly administered, should be avoided in this age group. The incidence of true allergy to local anaesthetics is rare. All local anaesthetics can cause CNS toxicity and cardiovascular toxicity if their plasma concentrations are increased by accidental intravenous injection or an absolute overdose. Excitation of the CNS may be manifested by numbness of the tongue and perioral area, and restlessness, which may progress to seizures, respiratory failure and coma. Bupivacaine is the local anaesthetic most frequently associated with seizures. Treatment of CNS toxicity includes maintaining adequate ventilation and oxygenation, and controlling seizures with the administration of thiopental sodium or benzodiazepines. Cardiovascular toxicity generally begins after signs of CNS toxicity have occurred. Bupivacaine and etidocaine appear to be more cardiotoxic than most other commonly used local anaesthetics. Sudden onset of profound bradycardia and asystole during neuraxial blockade is of great concern and the mechanism(s) remains largely unknown. Treatment of cardiovascular toxicity depends on the severity of effects. Cardiac arrest caused by local anaesthetics should be treated with cardiopulmonary resuscitation procedures, but bupivacaine-induced dysrhythmias may be refractory to treatment. Many recent reports of permanent neurological complications involved patients who had received continuous spinal anaesthesia through a microcatheter. Injection of local anaesthetic through microcatheters and possibly small-gauge spinal needles results in poor CSF mixing and accumulation of high concentrations of local anaesthetic in the areas of the lumbosacral nerve roots. In contrast to bupivacaine, the hyperbaric lidocaine (lignocaine) formulation carries a substantial risk of neurotoxicity when given intrathecally. Drugs altering plasma cholinesterase activity have the potential to decrease hydrolysis of ester-type local anaesthetics. Drugs inhibiting hepatic microsomal enzymes, such as cimetidine, may allow the accumulation of unexpectedly high (possibly toxic) blood concentrations of lidocaine. Reduction of hepatic blood flow by drugs or hypotension will decrease the hepatic clearance of amide local anaesthetics. Special caution must be exercised in patients taking digoxin, calcium antagonists and/or beta-blockers.