Yoshihiro Kakiuchi

Lidocaine Toxicity During Frequent Viscous Lidocaine Use for Painful Tongue Ulcer

Oral viscous lidocaine is useful for the treatment of symptoms induced by oral inflamed mucosa, such as radiation- or chemotherapy-induced mucositis. The toxic reactions associated with an accidental overdose have been reported in pediatric cases. We report a case of lidocaine toxicity in a 22-year-old man during frequent viscous lidocaine use for severe painful tongue ulcer. The toxic symptoms developed when the amount of oral viscous lidocaine exceeded 240 ml per day. The serum lidocaine concentration associated with this use was 6.7 microg/ml. The toxic symptoms continued in spite of the serum lidocaine concentration below the toxic level after the start of a diluted preparation, which contained a half-dose lidocaine. It is speculated that lidocaine metabolites might have contributed to the toxic symptoms. Clinicians should consider the risk of lidocaine toxicity in cases of frequent viscous lidocaine use, and determine the serum concentrations of lidocaine and its metabolites.

Free lidocaine concentrations during continuous epidural anesthesia in geriatric patients.

Background and Objectives To evaluate the effects of aging on lidocaine pharmacokinetics, the plasma concentrations of total and free lidocaine and its metabolites were measured during continuous thoracic epidural anesthesia in middle-aged (age 41 ± 9 years, n = 7) and elderly (age 72 ± 2 years, n = 7) male patients. Methods After establishment of general anesthesia, 7 mL 1.5% lidocaine with epinephrine 1:200,000 was injected into the epidural space and subsequently infused at a rate of 5 mL/h for 5 hours. Plasma concentrations of total and free lidocaine, monoethylglycinexylidide (MEGX), and glycinexylidide (GX) were measured at 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, and 300 minutes after initial lidocaine injection using high-performance liquid chromatography (HPLC) with ultraviolet (UV) detection. Results The elderly group showed a stronger upward trend in the corrected free lidocaine concentrations and lower corrected total MEGX concentrations than the middle-aged group. Conclusions Lidocaine metabolite activity in the elderly male patients was lower than that in the middle-aged male patients. Free lidocaine concentration is prone to increase in elderly patients. Caution must be exercised during continuous thoracic epidural anesthesia combined with general anesthesia in geriatric patients.

The plasma concentration of lidocaine's principal metabolite increases during continuous epidural anesthesia in infants and children

C ontinuous epidural anesthesia is frequently used for anesthesia and analgesia during and after surgery in infants and children. Nevertheless, there are no data on the pharmacokinetics of repeatedly administered epidural lidocaine in children. We measured the concentrations of lidocaine and its principal active metabolite, monoethylglycinexylidide (MEGX), in plasma samples obtained in a group of infants and children during continuous epidural anesthesia with lidocaine.

Plasma concentrations of lidocaine and its principal metabolites during continuous epidural infusion of lidocaine with or without epinephrine.

BACKGROUND AND OBJECTIVES The purpose of this study was to evaluate the effect of epinephrine on the absorption of lidocaine and the accumulation of active metabolites of lidocaine during continuous epidural anesthesia. METHODS Lidocaine was administered as an initial bolus of 5 mg/kg of 2% lidocaine solution followed by continuous infusion at 2.5 mg/kg/h. Patients in group I (n = 10) received lidocaine alone and patients in group II (n = 10) received lidocaine + epinephrine (5 pg/mL). Concentrations of lidocaine and its active metabolites, monoethylglycinexylidide (MEGX) and glycinexylidide (GX), were measured in plasma samples obtained after 15 minutes, 30 minutes, and 1, 2, and 3 hours of infusion using high-performance liquid chromatography with ultraviolet detection. RESULTS Plasma lidocaine concentrations were higher in group I for the first 30 minutes; however, after 1 hour the levels were the same. Plasma MEGX and GX increased continuously in both groups. MEGX levels the were significantly higher in group I, but there was no significant difference in the sum of lidocaine + MEGX after 2 hours. There was no significant difference in GX levels between the two groups. CONCLUSIONS With respect to continuous epidural administration, addition of epinephrine to lidocaine solutions is ineffective after 2 hours for reducing the potential for systemic toxicity, because the sum of the plasma concentrations of lidocaine and its principal active metabolite, MEGX, are unaffected.

Plasma lidocaine concentrations during continuous thoracic epidural anesthesia after clonidine premedication in children.

There is no report concerning oral clonidine’s effects on epidural lidocaine in children. Therefore, we performed a study to assess the concentrations of plasma lidocaine and its major metabolite (monoethylglycinexylidide [MEGX]) in children receiving continuous thoracic epidural anesthesia after oral clonidine premedication. Ten pediatric patients, aged 1–9 yr, were randomly allocated to the Control or Clonidine 4 &mgr;g/kg group (n = 5 each). Anesthesia was induced and maintained with sevoflurane in oxygen and air (Fio2 40%). Epidural puncture and tubing were carefully performed at the Th11–12 intervertebral space. An initial dose of 1% lidocaine (5 mg/kg) was injected through a catheter into the epidural space, followed by 2.5 mg · kg−1 · h−1. Plasma concentrations of lidocaine and MEGX were measured at 15 min, 30 min, and every 60 min for 4 h after the initiation of continuous epidural injection. The concentrations of lidocaine and MEGX were measured using high-pressure liquid chromatography with ultraviolet detection. Hemodynamic variables were similar between members of the Control and Clonidine groups during anesthesia. The Clonidine group showed significantly smaller lidocaine concentrations (p < 0.05) and the concentration of MEGX tended to be smaller in the plasma of the Clonidine group for the initial 4 h after the initiation of epidural infusion. In conclusion, oral clonidine preanesthetic medication at a dose of 4 &mgr;g/kg decreases plasma lidocaine concentration in children.

Propofol does not inhibit lidocaine metabolism during epidural anesthesia.

Propofol is sometimes used in combination with epidural anesthesia with lidocaine. In this study, we investigated the effect of propofol on the plasma concentration of lidocaine and its principal metabolites during epidural anesthesia with lidocaine. Thirty-two patients were randomly allocated to receive either propofol or sevoflurane anesthesia (n = 16 each). In the propofol group, anesthesia was maintained with a target concentration of propofol of 4 &mgr;g/mL. In the sevoflurane group, anesthesia was maintained with 1.5% sevoflurane. Lidocaine was administered epidurally in an initial dose of 5 mg/kg, followed by a continuous infusion at 2.5 mg · kg−1 · h−1. Free components of plasma lidocaine and its metabolites—monoethylglycinexylidide (MEGX) and glycinexylidide (GX)—were measured 30, 60, 120, and 180 min after the initiation of continuous epidural injection by using high-performance liquid chromatography. Free lidocaine, MEGX, and GX were separated from 2 mL of plasma by ultrafiltration filter units. Hemodynamic data were similar between groups. The plasma concentrations of free lidocaine were not significantly different between groups. The ratios of free MEGX to free lidocaine and free GX to free MEGX were not different between groups. In conclusion, propofol does not alter the metabolism of epidural lidocaine compared with sevoflurane.

Plasma lidocaine, monoethylglycinexylidide, and glycinexylidide concentrations after epidural administration in geriatric patients.

Background and Objectives: The purpose of this study was to evaluate the effect of age on the pharmacokinetics of lidocaine after epidural administration. Methods: Two percent lidocaine with epinephrine (5 μg/mL) was administered in two different age groups: an adult group (age 42 ± 6 years, n = 10) and an elderly group (age 77 ± 4 years, n = 10). Concentrations of lidocaine and its active metabolites, monoethylglycinexylidide (MEGX) and glycinexylidide (GX), were measured in plasma samples obtained after 15, 30, 45, 60, 90, 120, 150, and 180 minutes of administration using high‐performance liquid chromatography with ultraviolet detection. Results: No significant differences in plasma concentrations of lidocaine and its metabolites were observed between the two groups during the 3 hours of study. However, the elderly group showed significantly longer mean residence times (MRTs) and lower plasma clearance of lidocaine during the period compared with the adult group (P < .05). Plasma concentration ratios of MEGX/lidocaine were significantly lower in the elderly group after 2 hours of lidocaine administration (P < .05). Conclusions: The increase in plasma lidocaine concentration after epidural anesthesia in elderly patients was not as high as anticipated. However, the elderly patients showed longer MRTs, lower clearance, and lower ratios of MEGX/lidocaine than did the adult (middle‐age) patients.

Epinephrine does not reduce the plasma concentration of lidocaine during continuous epidural infusion in children

PurposeDuring continuous epidural anesthesia with lidocaine, plasma monoethylglycinexylidide (MEGX), an active metabolite of lidocaine, increases continuously. We assessed the effect of epinephrine on the absorption of lidocaine and the accumulation of MEGX during continuous epidural anesthesia in children. Methods: Anesthesia was administered as an initial bolus of 5 mg· kg−1 of 1 % lidocaine solution followed by continuous infusion at 2.5 mg· kg−1· hr−1. Patients in the control group (n = 8) received lidocaine alone, while patients in the epinephrine group (n = 8) received lidocaine + epinephrine (5 μg· mL−1). Concentrations of lidocaine and its active metabolite, MEGX, were measured in plasma samples obtained after 15 min, 30 min, and one, two, three, four, and five hours of infusion using high-performance liquid chromatography with ultraviolet detection.ResultsPlasma lidocaine concentrations were higher in samples from the control group for the first hour; however, after two hours the levels were the same in all samples. Plasma MEGX levels increased continuously in both groups and were significantly higher in the control group samples. The sum of lidocaine + MEGX was higher in the control group for the first two hours but there was no significant difference between groups after three hours.ConclusionsReduction of the potential for systemic toxicity by the addition of epinephrine to lidocaine is limited, because the reduction of the sum of the plasma concentrations of lidocaine and its active metabolite MEGX is small and limited to the initial phase of infusion.RésuméObjectifPendant l’anesthésie péridurale continue avec de la lidocaïne, le monoéthylglycinexylidide plasmatique (MEGX), un métabolite actif de la lidocaïne, augmente constamment. Nous avons évalué l’effet de l’épinéphrine sur l’absorption de la lidocaïne et l’accumulation de MEGX pendant l’anesthésie péridurale continue chez des enfants.MéthodeL’anesthésie a été administrée par un bolus initial de 5 mg· kg−1 d’une solution de lidocaïne à 1 % suivi d’une perfusion continue à 2,5 mg· kg−1· h−1. Les patients témoins (n = 8) ont reçu de la lidocaïne seule tandis que les autres (n = 8) ont reçu de la lidocaïne et de l’épinéphrine (5 μg· mL−1). Les concentrations de lidocaïne et de son métabolite actif, le MEGX, ont été mesurées dans des échantillons de plasma prélevés après 15 et 30 min, puis une, deux, trois, quatre et cinq heures de perfusion en utilisant la chromatographie liquide haute performance avec détection ultraviolette.RésultatsLes concentrations de lidocaïne étaient plus élevées chez les patients témoins pour la première heure; cependant, après deux heures, les niveaux étaient les mêmes dans tous les échantillons. Les niveaux de MEGX ont augmenté constamment chez les patients des deux groupes et ont été significativement plus hauts chez les témoins. La somme des concentrations de lidocaïne et de MEGX a été plus élevée dans le groupe témoin pour les deux premières heures, mais il n’y a pas eu de différence intergroupe significative après trois heures. Conclusion: La réduction des possibilités de toxicité générale, par l’ajout d’épinéphrine à la lidocaïne, est limitée, car la réduction de la somme des concentrations plasmatiques de lidocaïne et de son métabolite actif, le MEGX, est faible et n’apparaît qu’à la phase initiale de la perfusion.

Effect of ascites on tacrolimus disposition in a liver transplant recipient

To examine the effects of ascites on tacrolimus disposition, the authors measured tacrolimus concentration in blood and ascitic fluid from a patient with a living related liver transplant recipient who required removal of 500 to 2400 mL ascitic fluid daily. Tacrolimus levels in ascitic fluid ranged from 0.07 to 0.29 ng/mL and in whole blood from 7.5 to 20.3 ng/mL. The tacrolimus concentration in ascitic fluid positively correlated with that in whole blood ( r = 0.878, P <0.0001). Because the amounts of tacrolimus excreted into the ascitic fluid corresponded to only 0.01% to 0.09% of the dose administered, the authors concluded that the effects of ascites on tacrolimus disposition were negligible even though large amounts of ascitic fluid were drained regularly.

Liquid chromatographic determination of plasma ropivacaine for assessing pharmacokinetics of the viscous preparation.

We developed assay method for determination of plasma ropivacaine by using reversed-phase high performance liquid chromatography (HPLC) equipped with ordinary octadecylsilyl silica-gel (ODS) column. Plasma samples spiked with internal standard (bupivacaine) were treated by ethylacetate to extract ropivacaine and internal standard. The ropivacaine and internal standard separated on ODS column were detected by an ultra violet (UV) detector set at 215 nm. The mobile phase solvent consisted of acetonitrile, methanol and 0.05 M phosphate buffer adjusted to pH 4.0 (10 : 30 : 60, v/v) was pumped at a flow rate of 0.8 ml/min. The calibration curve of ropivacaine was linear at the concentration of 25-1,000 ng/ml (r=0.9998). The recoveries of ropivacaine from plasma were greater than 87.9% with the coefficient of variations (CVs) less than 6.1%. The CVs for intra- and inter-day assay of ropivacaine were 2.0-12.0% and 1.7-14.8%, respectively. This HPLC method was applied to determining plasma ropivacaine in two healthy subjects after receiving 0.5% ropivacaine viscous preparation, which was prepared in our hospital. Our preliminary pharmacokinetic data showed that ropivacaine viscous could be used safely based on the plasma ropivacaine concentrations (C(max): 89-125 ng/ml) for pain relief in oral mucosa.