Metabolite Monoethylglycinexylidide Research Articles

A case of a lidocaine intoxication of a 12 week old boy due to a circumcision in a domestic setting - clinical, toxicological and forensic aspects.

Lidocaine is a local anaesthetic commonly used during circumcision for dorsal penile nerve block (DPNB). We describe a case of a 12-week-old infant who presented generalized seizures due to local anesthetic systemic toxicity after Lidocaine administration for circumcision in a non-hospital setting. Serum concentrations of Lidocaine (16.4mg/L) and its main active metabolite monoethylglycinexylidide (MEGX, 1.36mg/L) were determined by HPLC-DAD, in a sample collected shortly after administration, which were higher than in comparable cases reported in literature. The reason for the overdose was assumed to be accidental systemic application. Due to suspicion of an improperly performed circumcision and bodily harm, police was involved and a clinical forensic examination was carried out. Here, we present analytical, clinical and forensic aspects of this case.

Functional assessment of CYP3A4 allelic variants on lidocaine metabolism in vitro.

AimHuman cytochrome P450 3A4 is the most abundant isoform of P450 enzyme in the liver. It plays an important role in the metabolism of wide variety of xenobiotic and endogenous substrates. So far, there are few reports about the functional characterization of CYP3A4 variants in terms of specific substrates. The aim of this study was to systematically investigate the genetic polymorphisms of 23 CYP3A4 alleles and evaluate their catalytic activities on the metabolism of lidocaine in vitro.Methods and resultsThe wild-type and 22 CYP3A4 variants were expressed in Spodoptera frugiperda 21 insect cells. Then the insect microsomes were incubated with the CYP3A4-specific substrate lidocaine. Reactions were performed with 50–3,000 µM for 60 min at 37°C. Lidocaine and its metabolite monoethylglycinexylidide were analyzed by ultra-performance liquid chromatography-tandem mass spectrometry system. Of the 23 CYP3A4 allelic variants tested, 2 variants (CYP3A4*17 and CYP3A4*30) had no detectable enzyme activity; and 5 variants (CYP3A4*2, CYP3A4*5, CYP3A4*9, CYP3A4*16 and CYP3A4*24) showed significantly decreased intrinsic clearance values compared with wild-type CYP3A4*1.ConclusionAs the first study of all these CYP3A4 alleles for lidocaine metabolism, our results in vitro assessment may provide novel insights into the allele-specific and substrate-specific activity of CYP3A4 and may also offer a reference to the personalized treatment of lidocaine in a clinical setting.

Shear wave elastography results correlate with liver fibrosis histology and liver function reserve.

To evaluate the correlation of shear wave elastography (SWE) results with liver fibrosis histology and quantitative function reserve. Weekly subcutaneous injection of 60% carbon tetrachloride (1.5 mL/kg) was given to 12 canines for 24 wk to induce experimental liver fibrosis, with olive oil given to 2 control canines. At 24 wk, liver condition was evaluated using clinical biochemistry assays, SWE imaging, lidocaine metabolite monoethylglycine-xylidide (MEGX) test, and histologic fibrosis grading. Clinical biochemistry assays were performed at the institutional central laboratory for routine liver function evaluation. Liver stiffness was measured in triplicate from three different intercostal spaces and expressed as mean liver stiffness modulus (LSM). Plasma concentrations of lidocaine and its metabolite MEGX were determined using high-performance liquid chromatography repeated in duplicate. Liver biopsy samples were fixed in 10% formaldehyde, and liver fibrosis was graded using the modified histological activity index Knodell score (F0-F4). Correlations among histologic grading, LSM, and MEGX measures were analyzed with the Pearson linear correlation coefficient. At 24 wk liver fibrosis histologic grading was as follows: F0, n = 2 (control); F1, n = 0; F2, n = 3; F3, n = 7; and F4, n = 2. SWE LSM was positively correlated with histologic grading (r = 0.835, P < 0.001). Specifically, the F4 group had a significantly higher elastic modulus than the F3, F2, and F0 groups (P = 0.002, P = 0.003, and P = 0.006, respectively), and the F3 group also had a significantly higher modulus than the control F0 group (P = 0.039). LSM was negatively associated with plasma MEGX concentrations at 30 min (r = -0.642; P = 0.013) and 60 min (r = -0.651; P = 0.012), time to ½ of the maximum concentration (r = -0.538; P = 0.047), and the area under the curve (r = -0.636; P = 0.014). Multiple comparisons showed identical differences in these three measures: significantly lower with F4 (P = 0.037) and F3 (P = 0.032) as compared to F0 and significantly lower with F4 as compared to F2 (P = 0.032). SWE LSM shows a good correlation with histologic fibrosis grading and pharmacologic quantitative liver function reserve in experimental severe fibrosis and cirrhosis.

Transplacental Distribution of Lidocaine and Its Metabolite in Peridural Anesthesia Administered to Patients With Gestational Diabetes Mellitus

Neonatal effects of drugs administered to mothers before delivery depend on the quantity that crosses the placental barrier, which is determined by the pharmacokinetics of the drug in the mother, fetus, and placenta. Diabetes mellitus can alter the kinetic disposition and the metabolism of drugs. This study investigated the placental transfer of lidocaine and its metabolite monoethylglycinexylidide (MEGX) in pregnant women with gestational diabetes mellitus (GDM) submitted to peridural anesthesia. A total of 10 normal pregnant women (group 1) and 6 pregnant women with GDM (group 2) were studied, all at term. The patients received 200 mg 2% lidocaine hydrochloride by the peridural locoregional route. Maternal blood samples were collected at the time of delivery and, after placental expulsion, blood samples were collected from the intervillous space, umbilical artery, and vein for determination of lidocaine and MEGX concentrations and analysis of the placental transfer of the drug. The following respective lidocaine ratios between the maternal and the fetal compartments were obtained for groups 1 and 2: umbilical vein/maternal peripheral blood, 0.60 and 0.46; intervillous space/maternal blood, 1.01 and 0.88; umbilical artery/umbilical vein, 0.77 and 0.91; and umbilical vein/intervillous space, 0.53 and 0.51. The following MEGX ratios for groups 1 and 2 were, respectively, fetal/maternal, 0.43 and 0.97; intervillous space/maternal blood, 0.64 and 0.90; umbilical artery/umbilical vein, 1.09 and 0.99; and umbilical vein/intervillous space, 0.55 and 0.78. Gestational diabetes mellitus did not affect the transplacental transfer of lidocaine but interfered with the transfer of MEGX, acting as a mechanism facilitating the transport of the metabolite.

Comparison of Five Commonly-Available, Lidocaine-Containing Topical Anesthetics and Their Effect on Serum Levels of Lidocaine and Its Metabolite Monoethylglycinexylidide (MEGX)

Topical anesthetics are commonly applied for a variety of indications. Several lidocaine-containing topical anesthetics are available for purchase over the counter (OTC). Recently, the authors' group has shown that there is great interindividual discrepancy in the manner in which lidocaine is absorbed and metabolized for even a single OTC product. The authors compare five commonly-available lidocaine preparations and their levels of absorption when applied to the face. Three of the preparations are available OTC; two require prescriptions and were compounded in a pharmacy. Twenty-five subjects enrolled in this Institutional Review Board-approved study were randomly assigned to one of five groups. The five topical anesthetics were LMX-4 (4% lidocaine; Biopelle/Ferndale Laboratories, Ferndale, Michigan), Topicaine (4% lidocaine; Ebsa Laboratories, Jupiter, Florida), 2.5% lidocaine/2.5% prilocaine (generic EMLA preparation; High Tech Pharmaceuticals, Amityville, New York), LET (4% lidocaine, 1:2000 epinephrine, and 0.5% tetracaine), and BLT (20% benzoncaine, 6% lidocaine, and 4% tetracaine). After a patch test for adverse reactions, the topical anesthetic was applied to each patient's face and neck and covered with an occlusive dressing for 60 minutes. Blood was drawn at 90, 120, 150, 240, and 480 minutes to measure serum levels of lidocaine and monoethylglycinexylidide (MEGX). The average age of the 17 women and eight men included in the study was 26 years (range, 22-62 years), and the average weight was 70.9 kg (range, 46.4-96.4 kg). The OTC preparations had the highest serum lidocaine and MEGX levels. Topicaine had the greatest serum levels of individual lidocaine absorption (0.808 µg/mL), followed by generic EMLA (0.72 µg/mL), LMX-4 (0.44 µg/mL), BLT (0.17 µg/mL), and LET (0.13 µg/mL). On average, Topicaine had the highest serum lidocaine and MEGX levels: 0.438 µg/mL and 0.0678 µg/mL, respectively. There were significant interindividual differences between the serum levels of MEGX and lidocaine in all groups except LET (P<.0001). There were significant differences between the 4% lidocaine-containing preparations (P=.0439); the 2.5% preparation had a greater absorption than the 4% lidocaine-containing preparation and the 6% lidocaine preparation (P=.0016). There were three adverse reactions in patients who received OTC preparations, one of which resulted in postinflammatory hyperpigmentation. This study demonstrates that although topical anesthetics are considered safe, some individuals have unpredictably high absorption levels. This study also demonstrates that the concentration of lidocaine, the formulation of the drug, and the individual patient all have significant effects on serum levels of lidocaine. The authors recommend that even OTC topical anesthetics be used under the supervision of a healthcare professional to avoid adverse toxic effects and, in rare cases, death. 2.

Automated analysis of lidocaine and its metabolite in plasma by in‐tube solid‐phase microextraction coupled with LC‐UV for pharmacokinetic study

A sensitive, selective, and reproducible in-tube solid-phase microextraction and liquid chromatographic (in-tube SPME/LC-UV) method for determination of lidocaine and its metabolite monoethylglycinexylidide (MEGX) in human plasma has been developed, validated, and further applied to pharmacokinetic study in pregnant women with gestational diabetes mellitus (GDM) subjected to epidural anesthesia. Important factors in the optimization of in-tube SPME performance are discussed, including the draw/eject sample volume, draw/eject cycle number, draw/eject flow rate, sample pH, and influence of plasma proteins. The limits of quantification of the in-tube SPME/LC method were 50 ng/mL for both metabolite and lidocaine. The interday and intraday precision had coefficients of variation lower than 8%, and accuracy ranged from 95 to 117%. The response of the in-tube SPME/LC method for analytes was linear over a dynamic range from 50 to 5000 ng/mL, with correlation coefficients higher than 0.9976. The developed in-tube SPME/LC method was successfully used to analyze lidocaine and its metabolite in plasma samples from pregnant women with GDM subjected to epidural anesthesia for pharmacokinetic study.

Can fractional lasers enhance transdermal absorption of topical lidocaine in an in vivo animal model?

It has been shown in vitro that pretreatment of skin with fractional lasers enhances transdermal delivery of drugs. The aim of this study is to demonstrate in vivo firstly that laser enhances transdermal drug absorption and secondly that this can be manipulated by altering laser settings. Four pigs were used in the IACUC approved animal study. On day 0, 5 g of 4% topical lidocaine was applied under occlusion for 60 minutes to a 400 cm(2) area on the abdomen. Blood was drawn at 0, 60, 90, 120, 180, and 240 minutes. On day 7, the Er:YAG laser was used at 500, 250, 50, and 25 µm ablative depth, respectively, over a 400 cm(2) area on the abdomen. Five grams of 4% topical lidocaine was applied immediately with occlusion for 60 minutes, and then removed. Blood was drawn at 0, 60, 90, 120, 180, and 240 minutes. The serum was extracted and analyzed for lidocaine and its metabolite monoethylglycinexylidide (MEGX). Serum levels of lidocaine and MEGX were undetectable in untreated skin. Following laser treatment both lidocaine and MEGX were detectable. Peak levels of lidocaine were significantly higher (P = 0.0002) at 250 µm (0.62 mg/L), compared to 500 µm (0.45 mg/L), 50 µm (0.48 mg/L), and 25 µm (0.3 mg/L). Peak levels of MEGX were significantly higher (P ≤ 0.0001) at 250 µm (0.048 mg/L), compared to 500 µm (0.018 mg/L), 50 µm (0.036 mg/L), and 25 µm (0.0144 mg/L). This study demonstrates that laser pretreatment significantly increases absorption of topical lidocaine so that it is detectable in the blood and that manipulating laser settings can affect drug absorption. Future work will look at translating this effect into clinical benefit.

Pharmacokinetics of lidocaine and its active metabolite monoethylglycinexylidide after a single intravenous administration in chickens (Gallus domesticus) anesthetized with isoflurane

Pharmacokinetics of lidocaine and its active metabolite monoethylglycinexylidide after a single intravenous administration in chickens (<i>Gallus domesticus</i>) anesthetized with isoflurane

Lidocaïne test for easier and less time consuming assessment of liver function in several hepatic injury models

In this study, we developed an ex vivo functional assay to assess liver metabolic capacity adapted from the lidocaïne test in rats. Animals used were subjected to different models of liver injury: hypothermic ischemia (H/I, n=8), ischemia-reperfusion (I/R, n=8) and CCl4 induced liver cirrhosis (n=11), and compared with sham operated rats (n=5). Livers were then extracted and a fragment of whole tissue was incubated with lidocaïne for 15, 30, 60, 120, 240, 360, and 720min at which both lidocaïne and its major metabolite monoethylglycinexylidide (MEGX) were measured by high performance liquid chromatography (HPLC). A histological study and biochemical assays (transaminase levels) were also performed to further evaluate and confirm our data. Pharmacokinetic profile of lidocaïne metabolism in sham-operated animals revealed that the maximum concentration of MEGX is achieved at 120min. Both lidocaïne metabolism and MEGX formation levels were significantly altered in all three models of hepatic injury. The extent of hepatic damage was confirmed by increased levels of transaminase levels and alteration of hepatocyte's structure with areas of necrosis. Our method provides reliable and reproducible results using only a small portion of liver which allows for a fast and easy assessment of liver metabolic capacity. Moreover, our method presents an alternative to the in vivo technique and seems more feasible in a clinical setting.

A Simple Method for Quantification of Lidocaine and Its Metabolite Monoethylglycine Xylidide in Plasma

We developed a simple and fast LC method quantifying lidocaine and its metabolite monoethylglycinexylidide (MEGX) in plasma. An extraction of liquid–liquid with dichloromethane and sodium hydroxide, was done using 500 μL of plasma or serum, with a UV detection at 210 nm. The results showed linearity of r = 0.996 for lidocaine and 0.998 for MEGX. Precision and accuracy showed coefficient of variation within an acceptable range. Stability test was acceptable for a period of 90 days. Levels were assayed for two patients, in the first, 1,256.14 ng mL−1 of lidocaine and 17.79 ng mL−1 of MEGX were obtained while in the second the levels for the substances were 1,194.33 and 10.47 ng mL−1. This simple and fast method is reliable and can be recommended for the quantification of lidocaine and MEGX in plasma.

Pharmacokinetics of lidocaine and its metabolite in peridural anesthesia administered to pregnant women with gestational diabetes mellitus

Peridural blockade with lidocaine, bupivacaine, and fentanyl is an anesthetic procedure extensively used in obstetrics, justifying the pharmacokinetic study of these drugs during labor. To investigate the influence of the physiopathological changes of gestational diabetes mellitus (GDM) on the pharmacokinetics of lidocaine and its metabolite monoethylglycinexylidide (MEGX) in pregnant women subjected to peridural anesthesia. Ten normal pregnant women (group 1) and six pregnant women with GDM (group 2) were studied, all of them at term. The patients received 200 mg 2% lidocaine hydrochloride without a vasoconstrictor by the peridural locoregional route. Maternal blood samples were collected at predetermined times for the analysis of lidocaine and MEGX by chromatography and pharmacokinetic analysis. The median pharmacokinetic parameters of lidocaine for groups 1 and 2 (P </= 0.05), respectively, were as follows: for Cmax 879.11 and 1,145.58 ng/ml, AUC(0-infinity) 256.01 and 455.95 mug min(-1) ml(-1), Cl/f/kg 10.61 and 5.64 ml min(-1) kg(-1), and Vd/f/kg 3.26 and 2.19 L/kg. The median pharmacokinetic parameters of MEGX for groups 1 and 2 (P </= 0.05), respectively, were as follows: for Cmax 82.71 and 141.38 ng/ml, Tmax 44.71 and 193.14 min, t(1/2)alpha 7.64 and 59.77 min, alpha 0.097 and 0.012/min, and AUC(0-infinity) 29.91 and 108.23 mug min(-1) ml(-1). The present data permit us to conclude that the apparent clearance of lidocaine and MEGX was reduced in diabetic patients compared to normal women, suggesting that GDM inhibits the CYP1A2/CYP3A4 isoforms responsible for the metabolism of this drug and its metabolite.

The Effect of Erythromycin and Fluvoxamine on the Pharmacokinetics of Intravenous Lidocaine

Inhibitors of CYP3A4 (cytochrome P450 3A4) have a minor effect on lidocaine pharmacokinetics. We studied the effect of coadministration of the antidepressant fluvoxamine (CYP1A2 inhibitor) and antimicrobial drug erythromycin (CYP3A4 inhibitor) on lidocaine pharmacokinetics in a double-blind, randomized, three-way crossover study. Nine volunteers ingested daily 100 mg fluvoxamine and placebo, 100 mg fluvoxamine and 1500 mg erythromycin, or their corresponding placebos for 5 days. On day 6, 1.5 mg/kg lidocaine was administered IV over 60 min. Concentrations of lidocaine and its major metabolite monoethylglycinexylidide were measured for 10 h. Fluvoxamine alone decreased the clearance of lidocaine by 41% (P < 0.001) and prolonged its elimination half-life from 2.6 to 3.5 h (P < 0.01). During the combination of fluvoxamine and erythromycin, lidocaine clearance was 53% smaller than during placebo (P < 0.001) and 21% smaller than during fluvoxamine alone (P < 0.05). During the combination phase the half-life of lidocaine (4.3 h) was longer than during the placebo (2.6 h; P < 0.001) or fluvoxamine (3.5 h; P < 0.01). We conclude that inhibition of CYP1A2 by fluvoxamine considerably reduces elimination of lidocaine and may increase the risk of lidocaine toxicity. Concomitant use of both fluvoxamine and a CYP3A4 inhibitor such as erythromycin can further increase plasma lidocaine concentrations by decreasing its clearance.

Liquid chromatographic method for the determination of lidocaine and monoethylglycine xylidide in human serum containing various concentrations of bilirubin for the assessment of liver function

A high-performance liquid chromatographic method is described for determination of lidocaine (2-(dietyloamino)- N-(2,6-dimetylofenylo) acetamid) and its metabolite, monoethylglycine xylidide (MEGX), in human serum containing various concentration of bilirubin. Lidocaine and its metabolite were extracted from human serum using dichloromethane. After separation of the layers and freezing at −32 °C, the organic layer was decanted and evaporated under a stream of nitrogen. The sample was dissolved in the mobile phase (12% acetonitrile in 15 mM potassium dihydrogen orthophosphate, pH 3.0), and after separation on a Supelcosil LC-8-DB column, the analytes were measured by ultraviolet detection at 205 nm. Trimethoprim (TMP) was used as the internal standard. The recovery of the examined analytes ranged from 95.7 to 97.9% for lidocaine and from 98.0 to 99.9% for MEGX. The lower limit of quantification (LLOQ) was established at 200 μg/l for lidocaine and at 10 μg/l for MEGX. The choice of suitable conditions for chromatographic separation of lidocaine and its metabolite MEGX allowed the elimination of the influence of endogenous bilirubin on the result of analysis.

INTOXICATION MORTELLE APRÈS INGESTION ACCIDENTELLE DE XYLOCAINE VISQUEUSE À 2% CHEZ UNE JEUNE ENFANT

We report a case of fatal intoxication with 2% viscous lidocaine. A 18 month old infant was admitted after malaise and cardiorespiratory arrest at home. He was resuscitated, then seizures appeared before arrival at the hospital. Treatment was symptomatic, including cardiorespiratory resuscitation and administration of anticonvulsants. Identification of lidocaine and its metabolite monoethylglycinexylidide (MEGX) MEGX was performed after organic extraction by High Performance Liquid Chromatography (HPLC) with Diode Array Detection (DAD); the serum concentrations, determined by Fluorescence Polarisation Immuno Assay (FPIA), were : 1,1 μg / ml for lidocaine and 0,94 μg / ml for MEGX (H+7) and 0,30 μg / ml for the lidocaine (Day+1). Neurotoxic manifestations appear at lower concentrations than cardiotoxic symptoms which are correlated with plasma levels of lidocaine. The toxic symptoms begin with headache, hallucinations, seizure, coma, respiratory arrest and circulatory collapse. The toxic symptoms can persist even after the decrease of lidocaine concentration under therapeutic levels. There is no antidote and acute lidocaine toxicity is managed with supportive therapy (diazepam for seizures, intubation, chronotropic agents). Considering the gravity of these poisonings which remain rare, the 2% viscous lidocaine prescription is forbidden for children under 6 years old.

Rapid and Sensitive Liquid Chromatography–Tandem Mass Spectrometry Method for Determination of Monoethylglycinexylidide

A large body of evidence currently documents the utility of the MEGX test for real-time assessment of liver function in transplantation, critical care medicine, and various experimental models (1). The test is based on the conversion of lidocaine to its deethylated metabolite monoethylglycinexylidide (MEGX), primarily through the hepatic cytochrome P450 system. In the standard MEGX test, an intravenous bolus of a small lidocaine dose (1 mg/kg) is administered over 2 min. Blood specimens are collected for serum MEGX determination both before and at 15 and/or 30 min after lidocaine administration. The most commonly used method to measure serum MEGX has been an automated fluorescence polarization immunoassay (Abbott Laboratories) with a detection limit of 3 μg/L. This test, however, is no longer commercially available. HPLC methods with ultraviolet detection (2)(3) and gas chromatographic (GC) procedures with ionization or nitrogen-phosphorous detection (4)(5) were originally reported, but all of these techniques had a limit of quantification >10 μg/L. Several studies have shown that transplant candidates with MEGX test results <10 μg/L have a particularly poor 1-year survival rate (6)(7)(8). An improved HPLC method with fluorescence detection (9) and a capillary GC method with nitrogen-phosphorus detection (10) were therefore developed that achieved an adequate analytical sensitivity with limits of detection of ∼1–2 μg/L. The disadvantage of the HPLC method with fluorescence detection is the necessity to derivatize MEGX. Because of its flexibility and high specificity, liquid chromatography–tandem mass spectrometry (LC-MS-MS) is finding increasing application for the quantification of numerous analytes. We now describe a reliable, simple, sensitive, and rapid procedure for determining MEGX in serum by LC-MS-MS. This procedure also allows the simultaneous measurement of serum lidocaine concentrations in the same sample. MEGX hydrochloride and lidocaine hydrochloride were kind gifts from Astra (Stockholm, Sweden). The internal …

Could local anesthesia while breast-feeding be harmful to infants?

Few studies have been carried out on the levels and possible toxicity of local anesthetics in breast milk after parenteral administration. The purpose of this study is to determine the amount of lidocaine and its metabolite monoethyl-glycinexylidide (MEGX) in breast milk after local anesthesia during dental procedures. The study population consisted of seven nursing mothers (age, 23-39 years) who received 3.6 to 7.2 mL 2% lidocaine without adrenaline. Blood and milk concentrations of lidocaine and its metabolite MEGX were assayed using high-performance liquid chromatography. The milk-to-plasma ratio and the possible daily doses in infants for both lidocaine and MEGX were calculated. The lidocaine concentration in maternal plasma 2 hours after injection was 347.6 +/- 221.8 microg/L, the lidocaine concentration in maternal milk ranged from 120.5 +/- 54.1 microg/L (3 hours after injection) to 58.3 +/- 22.8 microg/L (6 hours after injection), the MEGX concentration in maternal plasma 2 hours after injection was 58.9 +/- 30.3 microg/L, and the MEGX concentration in maternal milk ranged from 97.5 +/- 39.6 microg/L (3 hours after injection) to 52.7 +/- 23.8 microg/L (6 hours after injection). According to these data and considering an intake of 90 mL breast milk every 3 hours, the daily infant dosages of lidocaine and MEGX were 73.41 +/- 38.94 microg/L/day and 66.1 +/- 28.5 microg/L/day respectively. This study suggests that even if a nursing mother undergoes dental treatment with local anesthesia using lidocaine without adrenaline, she can safely continue breastfeeding.

Could Local Anesthesia While Breast‐Feeding Be Harmful to Infants?

ABSTRACTBackgroundFew studies have been carried out on the levels and possible toxicity of local anesthetics in breast milk after parenteral administration. The purpose of this study is to determine the amount of lidocaine and its metabolite monoethylglycinexylidide (MEGX) in breast milk after local anesthesia during dental procedures.MethodsThe study population consisted of seven nursing mothers (age, 23–39 years) who received 3.6 to 7.2 mL 2% lidocaine without adrenaline. Blood and milk concentrations of lidocaine and its metabolite MEGX were assayed using high‐performance liquid chromatography. The milk‐to‐plasma ratio and the possible daily doses in infants for both lidocaine and MEGX were calculated.ResultsThe lidocaine concentration in maternal plasma 2 hours after injection was 347.6 ± 221.8 μg/L, the lidocaine concentration in maternal milk ranged from 120.5 ± 54.1 μg/L (3 hours after injection) to 58.3 ± 22.8 μg/L (6 hours after injection), the MEGX concentration in maternal plasma 2 hours after injection was 58.9 ± 30.3 μg/L, and the MEGX concentration in maternal milk ranged from 97.5 ± 39.6 μg/L (3 hours after injection) to 52.7 ± 23.8 μg/L (6 hours after injection). According to these data and considering an intake of 90 mL breast milk every 3 hours, the daily infant dosages of lidocaine and MEGX were 73.41± 38.94 μg/L/day and 66.1 ± 28.5 μg/L/day respectively.ConclusionsThis study suggests that even if a nursing mother undergoes dental treatment with local anesthesia using lidocaine without adrenaline, she can safely continue breast‐feeding.

Serum concentrations of lignocaine and its metabolite monoethylglycinexylidide during fibre-optic bronchoscopy in local anaesthesia

Fibre-optic bronchoscopy was performed in local anaesthesia using lignocaine. Serum concentrations of lignocaine and its active metabolite monoethylglycinexylidide (MEGX) were measured in 16 patients at regular intervals up to 120 min after administration. Lignocaine was administered as an aerosol in the upper respiratory tract and as a solution in the bronchial tree. The total dose of lignocaine ranged from 243 to 608 mg (2·4–8·0 mg kg −1 body weight). The dose of lignocaine given as an aerosol ranged from 163 to 508 mg (1·6–6·6 mg kg −1) and the dose given as a solution ranged from 60 to 180 mg (0·8–2·5 mg kg −1). The highest median serum lignocaine concentration, 10·5 μmol 1 −1, was measured 20 min after administration. None of the patients had toxic serum lignocaine levels (>26 μmol 1 −1) or adverse effects. The highest median serum MEGX concentration, 1·7 μmol 1 −1, was measured 120 min after administration. The dose of lignocaine, expressed in mg per kg body weight correlated with serum lignocaine and serum MEGX ( r s =0·47 and r s =0·39, respectively). Lignocaine is a clinically safe, local anaesthetic agent provided the total dose does not exceed 6–7 mg kg −1 body weight.

Determination of MEGX by HPLC with Fluorescence Detection

The hepatic conversion of lidocaine to its metabolite monoethylglycinexylidide (MEGX) is catalyzed by the cytochrome P450 enzyme CYP3A4 in humans. This metabolic capacity of the liver led to the development of the MEGX test, in which serum MEGX concentrations are determined, as a relatively simple real-time test of liver function [1] . A large body of evidence currently documents the clinical utility of this test [2] , demonstrating that MEGX concentrations <20 μg/L reflect a compromised hepatic function. Furthermore, several studies have shown that test results <10 μg/L are associated with an extremely high risk for pretransplant nonsurvival (3)(4). The assessment of serum MEGX concentrations <5 μg/L might be particularly relevant in pediatric patients with end-stage liver disease [4] . The automated fluorescence polarization immunoassay (FPIA; Abbott Diagnostics, N. Chicago, IL) of MEGX in serum is almost universally available and widely used. It is sensitive (detection limit: 3 μg/L) and easy to perform. However, the test is subject to interferences, most importantly from high bilirubin concentrations (5)(6). One approach to deal with this interference was proposed by Zoppi and Fumagalli, who precipitated the protein-bound bilirubin with the precipitation reagent from the Digoxin II assay supplied by Abbott (6). Given the lack of sensitive HPLC methods capable of covering the low MEGX values usually observed in patients with severe hyperbilirubinemia, this modification of the FPIA procedure has been neither compared with more-definitive methods, nor validated with patients’ samples. In addition, lidocaine concentrations >10 mg/L cross-react in the FPIA (1), which can present problems in experiments with cell cultures or microsomal preparations and in assaying samples from patients whose blood still contains lidocaine from the test dose. Furthermore, OH-MEGX, which is formed from lidocaine in rats, also cross-reacts in the FPIA, thus precluding investigations with this species (7 …

Monoethylglycinexylidide (MEGX) as an early predictor of liver dysfunction in severe sepsis

The development of demonstrable liver dysfunction in severe sepsis is associated with high rates of mortality. Lidocaine metabolite MEGX has proven to be a highly sensitive indicator of hepatic dysfunction, especially in the field of liver transplantation. The present study aimed to assess the prognostic value of MEGX formation kinetics in predicting liver dysfunction in patients with severe sepsis, and compared it with other oxygenation indices as well as gastric mucosal pH (pHi). Twenty-seven patients meeting the criteria for severe sepsis as defined by Bone et al were prospectively evaluated. Patients with hemodynamic instability, high liver enzymes (> 2 × normal) and bilirubin levels (> 3 mg/dl), coagulation disorders, and gastrointestinal bleeding were not included. A gastric tonometer (TRIP, Tonometrics, Worchester, MA) was introduced in all patients in place of a standard nasogastric tube. Gastric pHi was calculated as previously described. Oxygen delivery (DO2) was calculated by the simplified formula DO2 = CI × CaO2, and oxygen consumption (VO2) was determined by indirect calculation of the product of CI and arteriovenous oxygen content difference. Plasma aspartate aminotransferase, alanine aminotransferase, bilirubin and arterial lactate levels were determined by using enzymatic method. The serum MEGX concentrations were determined using an automated fluorescence polarization immunoassay (TDX, Abbott, Chicago) before and 15 min after an iv injection of 1 mg/kg lidocaine. Liver dysfunction indices (bilirubin > 3 mg/dl, liver enzymes > 2 × normal) were recorded until discharge or death. Effectiveness in predicting liver dysfunction was compared by calculating the sensitivity and specificity for each variable (lactate, pHi, MEGX). To evaluate the accuracy with which of these variables were able to discriminate between those %. In ROC curves constructed to compare the ability of the variables to discriminate two patient groups, MEGX displayed the greatest predictability of liver failure development in regard to lactate and pHi. Relating these variables to survival patients who developed clinically demonstrable liver dysfunction (LD+) and those who did not (LD-), receiver operating characteristics (ROC) curves were constructed. Values of the measurements given as median (25th per cent, 75th per cent) were compared by the Mann-Whitney U test. MEGX values were the only parameter that showed a significant difference when comparing the two groups (LD+, LD-), Sixty-three per cent of the patients had MEGX values below 90 μg/1 which is a limit indicated as an impaired liver function. MEGX cut-off at 60 μg/l had a prognostic sensitivity of 84% and a specificity of 100, no significancy was determined in any of the parameters. No correlation was found between MEGX or pHi and oxygen derived variables, and there was also no significant difference in hemodynamics and oxygen derived variables either between LD+ and LD- groups, or in survivors and non-survivors. Our data demonstrated that MEGX formation kinetics is an early bedside procedure to dynamically assess hepatic functions. This test might be an early sign showing the hepatic insult in severe sepsis when the global circulatory and splanchnic circulation indices are in normal range. More research is essential in order to see whether this parameter can guide therapeutic strategies for preventing liver hypoxia or metabolic impairment in the very early phase of sepsis.