Blood Concentrations Of Lidocaine Research Articles

Ефективність і безпечність безперервного внутрішньовенного введення лідокаїну як компонента інтраопераційного знеболювання та післяопераційної інтенсивної терапії при обширних резекціях печінки

Purpose - to improve the effectiveness and determine the safety of intraoperative analgesia and postoperative intensive care for extensive liver resections with intravenous lidocaine compared with traditional analgesia and the use of epidural anesthesia. Materials and methods. 108 patients of 18 years of age and older who underwent extensive liver resection were examined and analyzed. The studied patients were stratified into three groups, depending on the choice of intra- and postoperative analgesia: the Group I (22 patients) - intravenous lidocaine administration + traditional intra- and postoperative analgesia, the Group II (73 patients) - epidural anesthesia (EDA) in the thoracic spine + traditional intra - and postoperative analgesia, the Group III (13 patients) - control, which used only traditional intra- and postoperative analgesia. Probability of differences was assessed using Student’s t-test, non-parametric Mann-Whitney U-test, Pearson’s χ2 test. Results. The blood lidocaine concentration in 2 hours after surgery was higher in the Group II (2.37±1.08 μg/ml) compared to the Group I (1.84±1.16 μg/ml). The values for 14 hours after the intervention did not differ (2.62±2.56 μg/ml - in the Group I, 2.85±1.25 μg/ml - in the Group II). In some cases, the local anesthetic content exceeded the toxic level without corresponding clinical symptoms. Intravenous lidocaine administration led to a decrease pain intensity within 4 days after surgery by almost 1.5 times, epidural administration - by 1.5-2 times compared to the standard analgesia, and was also accompanied by a lengthening of the time interval until the first injection of narcotic analgesics from 86.968.2 min to 394.3666.5 and 553.252.8.5 min, respectively. Changing the route of local anesthetic administration from epidural to intravenous led to decrease intraoperative volume of infusion therapy from 9.4±2.5 ml/kg/h to 7.4±1.3 ml/kg/h, as well as to reduction of the norepinephrine dose to eliminate hypotension by 1.3 times. Lidocaine administration attenuated the intensity of the systemic inflammatory response syndrome, which was manifested by a reduction in the concentration of IL-1, IL-4, IL-10 compared to multicomponent analgesia without a statistical difference with the epidural route of lidocaine administration. Conclusions. The use of lidocaine as an adjuvant in traditional intra- and postoperative analgesia for extensive liver resection reduces pain intensity and the degree of systemic inflammatory response syndrome. Changing the method of using lidocaine from epidural to intravenous leads to more stable intraoperative blood circulation, reduction the volume of infusion therapy and the need for sympathomimetic support without increasing blood concentration, and in the proposed method is an attractive alternative to epidural analgesia. The research was carried out in accordance with the principles of the Declaration of Helsinki. The study protocol was approved by the Local Ethics Committee of the institution mentioned in the work. Informed consent of the patients was obtained for the research. No conflict of interests was declared by the authors.

Security and efficacy of intravenous injection of lidocaine in major hepatic resection

Objective. To determine in dynamics the blood lidocaine concentration in the patients while performing major hepatic resection with its epidural and intravenous injection for intra– and postoperative anesthesia and to estimate the toxicity potential.
 Materials and methods. Into the investigation 27 patients were included, to whom hepatic resection with preservation of 30 – 60% of parenchyma was done. In all the patients multicomponent intraoperative anesthesia was applied. Depending on adjuvant used, the patients were divided into two groups: the first – 7 patients, in whom intravenous lidocaine injection was applied, and the second – 20 patients, in whom multicomponent anesthesia was added by thoracic epidural anesthesia.
 Results. In 2 h postoperatively a tendency towards enhanced blood concentration of lidocaine was observed by 28.8% after its epidural injection, comparing with intravenous injection – 2.37 and 1.84 mcg/ml (р=0.29) accordingly without principal difference in 14 h after the operation – 2.85 and 2.62 mcg/ml (р=0.76) accordingly. In no one patient toxic life–threatening reactions were registered.
 Conclusion. The adjuvant application of lidocaine for intra– and postoperative anesthesia, using intravenous and epidural introduction in major hepatic resection performance, do not lead to raising of the medicinal compound concentration in the blood higher than conventional toxic content. The blood concentration of the preparation while its epidural introduction may be higher, than in intravenous introduction, witnessing in favor of secureness of intravenous application of lidocaine and at the same time a statistically significant difference between indices of its concentration in various ways of introduction was not observed.

Result of the feasibility study of lidocaine (LDC) for peripheral venous pain induced by oxaliplatin (L-OHP).

e21624 Background: For the patients with colorectal cancer, CapeOx or SOX, combination of L-OHP with oral fluoropyrimidines Capecitabine or S-1, is commonly used in clinical practice. These regimens, different from FOLFOX, do not necessarily require central venous port placement and can be administered via peripheral vein. However, peripheral vascular pain induced by administration of L-OHP was discussed. Methods: LDC was concomitantly administered through the lateral duct of drip route from 30 minutes before to end of L-OHP administration, to patients with colorectal cancer who are to be administered L-OHP (100 mg/m2 or more) via the peripheral vein for the first time. LDC dose was set at two levels of 0.5 (Level 1) and 1.5 (Level 2) mg / kg / Hr. Safety, symptoms of pain and pharmacokinetics of LDC were evaluated. The DLT criteria were (1) an allergic reaction of Grade 2 or higher, (2) non-hematological toxicity of Grade 3 or more related to LDC, (3) cessation of administration of L-OHP or LDC, (4) higher than 5 mcg / mL of blood concentration of LDC. Results: A total of nine patients were enrolled (Level 1: 3, Level 2: 6). No DLTs were observed. The average Cmax of LDC was 0.4 (range: 0.3 - 0.5) mcg/ml at Level 1 and 1.3 (0.5 - 2.3) mcg / ml at Level 2. In the pain assessment (VAS score), in Level 1, 2 cases did not feel pain, 1 case was 3/10. In Level 2, there were no pain in 4 cases and 2/10 in the remaining 2 cases. Conclusions: To alleviate vascular pain caused by peripheral intravenous administration of L-OHP, concomitant administration of LDC could be safe and effective. Clinical trial information: UMIN000011393.

Efficacy and Safety of a Lidocaine and Ropivacaine Mixture for Scalp Nerve Block and Local Infiltration Anesthesia in Patients Undergoing Awake Craniotomy.

Mixtures of various local anesthetics, such as lidocaine and ropivacaine, have been widely used. However, their efficacy and safety for scalp nerve blocks and local infiltration during awake craniotomy have not been fully elucidated. We prospectively investigated 53 patients who underwent awake craniotomy. Scalp block was performed for the blockade of the supraorbital, supratrochlear, zygomaticotemporal, auriculotemporal, greater occipital, and lesser occipital nerves with a mixture containing equal volumes of 2% lidocaine and 0.75% ropivacaine, including 5 μg/mL of epinephrine. Infiltration anesthesia was applied at the site of skin incision using the same mixture. The study outcomes included changes in heart rate and blood pressure after head pinning and skin incision, and incidence of severe pain on emergence from anesthesia. Total doses and plasma concentrations of lidocaine and ropivacaine were measured at different time points after performing the block. The heart rate and blood pressure after head pinning were marginally, but significantly, increased when compared with baseline values. There were no significant differences in heart rate and blood pressure before and after the skin incision. Nineteen percent of the patients (10/53) complained of incisional pain at emergence from anesthesia. The highest observed blood concentrations of lidocaine and ropivacaine were 1.9±0.9 and 1.1±0.4 μg/mL, respectively. No acute anesthetic toxicity symptom was observed. Scalp block with a mixture of lidocaine and ropivacaine seems to provide effective and safe anesthetic management in patients undergoing awake craniotomy.

WITHDRAWN: Topical lidocaine for the treatment of postherpetic neuralgia.

Background This is an update of the original Cochrane review published in Issue 2, 2007. The cause of postherpetic neuralgia is damage to peripheral neurons, dorsal root ganglia, and the dorsal horn of the spinal cord, secondary to herpes zoster infection (shingles). In postherpetic neuralgia, peripheral neurons discharge spontaneously and have lowered activation thresholds, and exhibit an exaggerated response to stimuli. Topical lidocaine dampens peripheral nociceptor sensitisation and central nervous system hyperexcitability, and may benefit patients with postherpetic neuralgia. Objectives To examine efficacy and safety of topical lidocaine in the treatment of postherpetic neuralgia. Search methods We searched the Cochrane Pain, Palliative and Supportive Care Group Trials Register, CENTRAL, MEDLINE, EMBASE, LILACS, SIGLE, Citation Index, the reference lists of all eligible trials, key textbooks, and previous systematic reviews. Last search conducted April 2011. Selection criteria Randomised or quasi‐randomised trials comparing topical applications of lidocaine in patients of all ages with postherpetic neuralgia (pain persisting at the site of shingles at least one month after the onset of the acute rash). Data collection and analysis Two review authors extracted data, and a third checked them. Main results In the original review three studies involving 182 topical lidocaine treated participants and 132 control participants were included. Two studies gave data on pain relief, and the remaining study provided data on secondary outcome measures. The largest study published as an abstract compared topical lidocaine patch to a placebo patch and accounted for 150 of the 314 participants (48%). A meta‐analysis combining two studies identified a significant difference between topical lidocaine and control groups for the primary outcome measure: a mean improvement in pain relief according to a pain relief scale. Topical lidocaine relieved pain better than placebo (P = 0.003). There was a statistical difference between the groups for the secondary outcome measure of mean VAS score reduction (P = 0.03), but this was only for a single small study. There were a similar number of adverse skin reactions in both treatment and placebo groups. The highest recorded blood lidocaine concentration varied between 59 ng/ml and 431 ng/ml between studies. The latter figure is high and the authors of the study suggest that the sample had been contaminated during the assay procedure. Authors' conclusions Since the last version of this review in Issue 2, 2007 no new studies have been found and the results therefore remain the same. There is still insufficient evidence to recommend topical lidocaine as a first‐line agent in the treatment of postherpetic neuralgia with allodynia. Further research should be undertaken on the efficacy of topical lidocaine for other chronic neuropathic pain disorders, and also to compare different classes of drugs (e.g. topical anaesthetic applications versus anti‐epileptic drugs).

8% Lidocaine Pump Spray Relieves Pain Associated With Peripheral Blood Flow Disorders

It is often difficult to reduce pain associated with peripheral blood flow disorders (PBFD) using standard analgesics. We assessed the analgesic effects of a metered-dose 8% lidocaine in patients with PBFD. Twenty-four patients with PBFD-related pain were enrolled in this double-blind placebo-controlled crossover study. Patients were randomized to receive either 8% lidocaine or saline on the painful site with a metered-dose spray. After a 3-day period, patients were crossed over to receive the alternative treatment. Pain was assessed with a visual analog scale (VAS) before and 15 minutes after the treatment. Patients were also asked to record the time at which pain appeared again. The blood concentration of lidocaine was measured at 15, 30, and 60 minutes after lidocaine application. There were no significant differences in VAS before treatment between the placebo and lidocaine treatments. However, lidocaine significantly decreased VAS at rest from 5.5+/-3.1 cm (mean+/-SD) to 0.6+/-0.9 cm and on movement from 8.4+/-2.0 cm to 1.7+/-1.7 cm, resulting in a significant difference between the 2 sprays. The median time to recurrence of pain was 3 hours. The blood concentration of lidocaine was less than 0.3 microg/mL in all patients. A metered-dose 8% lidocaine pump spray produced prompt analgesia in patients with PBFD-related pain without severe side effects.

Regional anesthesia for carotid surgery

Evidence from retrospective studies suggests that regional anesthesia reduces the risks of major complications associated with carotid endarterectomy compared with general anesthesia, namely: stroke, stroke/death, death and myocardial infarction. A superficial cervical plexus block is the regional anesthetic technique of choice. It is as efficacious as a combined (superficial and deep) cervical plexus block and carries substantially less risk of inducing a life-threatening complication from the block placement than a cervical epidural or a deep cervical plexus block. Lidocaine, mepivacaine, bupivacaine and ropivacaine are all suitable agents for this block but bupivacaine provides the longest duration of postoperative analgesia. The addition of epinephrine 1: 300,000 (3.75 microg/ml) reduces maximal blood concentrations of lidocaine and bupivacaine without inducing any adverse hemodynamic effects. The anesthesiologist should learn how to place a superficial cervical plexus block. The technique is easy to master, effective and carries a low risk of inducing a serious complication.

Lack of Impact of Intravenous Lidocaine on Analgesia, Functional Recovery, and Nociceptive Pain Threshold after Total Hip Arthroplasty

The analgesic effect of perioperative low doses of intravenous lidocaine has been demonstrated after abdominal surgery. This study aimed to evaluate whether a continuous intravenous low-dose lidocaine infusion reduced postoperative pain and modified nociceptive pain threshold after total hip arthroplasty. Sixty patients participated in this randomized double-blinded study. Patients received lidocaine 1% (lidocaine group) with a 1.5 mg/kg intravenous bolus in 10 min followed by a 1.5 mg . kg . h intravenous infusion or saline (control group). These regimens were started 30 min before surgical incision and stopped 1h after skin closure. Lidocaine blood concentrations were measured at the end of administration. In both groups, postoperative analgesia was provided exclusively by patient-controlled intravenous morphine. Pain scores, morphine consumption, and operative hip flexion were recorded over 48 h. In addition, pressure pain thresholds and the extent of hyperalgesia around surgical incision were systematically measured at 24 and 48 h. In comparison with the placebo, lidocaine did not induce any opioid-sparing effect during the first 24 h (median [25-75% interquartile range]; 17 mg [9-28] vs. 15 mg [8-23]; P = 0.54). There was no significant difference regarding the effects of lidocaine and placebo on pain score, pressure pain thresholds, extent in the area of hyperalgesia, and maximal degree of active hip flexion tolerated. Mean plasma lidocaine concentration was 2.1 +/- 0.4 mug/ml. Low dose perioperative intravenous lidocaine after total hip arthroplasty offers no beneficial effect on postoperative analgesia and does not modify pressure and tactile pain thresholds.

Serum concentrations of lidocaine and its metabolites after prolonged infusion in healthy horses

Continuous-rate infusions (CRI) of lidocaine are often used for prolonged duration but, to date, only limited time/concentration relationships administered as a short term (24 h) CRI have been reported. To determine the time/concentration profile of lidocaine and its active metabolites glycinexylidide (GX) and monoethylglycinexylidide (MEGX) during a 96 h lidocaine infusion. Lidocaine was administered to 8 mature healthy horses as a continuous rate infusion (0.05 mg/kg bwt/min) for 96 h. Blood concentrations of lidocaine, GX and MEGX were determined using high performance liquid chromatography during and after discontinuation of the infusion. Serum lidocaine concentrations reached steady state by 3 h and did not accumulate thereafter. Concentrations were above the target therapeutic concentration (980 ng/ml) only at 6 and 48 h, and did not reach the range described as potentially causing toxicity (>1850 ng/ml) at any time. MEGX did not accumulate over time, while the GX accumulated significantly up to 48 h and then remained constant. The serum concentrations of lidocaine, MEGX and GX were below the limit of detection within 24 h of discontinuation of the infusion. None of the horses developed any signs of lidocaine toxicity during the study. The metabolism of lidocaine was not significantly impaired by prolonged infusion and no adverse effects were observed. Prolonged infusions appear to be safe in normal horses but the accumulation of GX, a potentially toxic active metabolite, is cause for concern.

The Sedative Effect of High Dose Lidocaine

To the Editor: In their case report Gaughen and Durieux (1) report hypotension, and a BIS value of zero in a 75-yr-old woman who received an unintended infusion of 800 mg of lidocaine over 8 min while also anesthetized with sevoflurane. Following recovery, weakness persisted for more than an hour. We would like to support their findings with our experience. A few years ago one of us (PS) together with eight other anesthesiologists took part as volunteers in a clinical study of the effects of IV lidocaine on pain perception (unpublished data). We received 1 mg/kg IV lidocaine as a bolus, followed by an infusion of 5 mg/kg over 2 hr. Even though the blood lidocaine concentrations were less than that associated with toxicity (5 μg/mL) (2), all subjects reported deep sedation, and muscle weakness. Some had speech disturbances and diplopia but none reported tinnitus or metallic taste. The presence of sedation as an early sign of lidocaine toxicity is not well documented in the anesthetic literature even though it has been described elsewhere (3). We suggest monitoring for sedation during lidocaine (and possible other local anesthetics) administration as an early sign of a high blood concentration. Using BIS in these cases might provide an objective measurement of the level of sedation. Peter Szmuk, MD Department of Anesthesiology University of Texas Medical School Dallas, TX Children’s Medical Center at Dallas Dallas, TX Outcome Research Institute Louisville, KY [email protected] Alan Farrow-Gillespie, MD Paul Sheeran, MD Department of Anesthesiology University of Texas Medical School Dallas, TX Children’s Medical Center at Dallas Dallas, TX Tiberiu Ezri, MD Department of Anesthesia The Edith Wolfson Medical Center, Holon Affiliated to Sackler Medical School Tel Aviv University, Israel Outcome Research Institute Louisville, KY

Simultaneous determination of nikethamide and lidocaine in human blood and cerebrospinal fluid by high performance liquid chromatography

Nikethamide and lidocaine are often requested to be quantified simultaneously in forensic toxicological analysis. A simple reversed-phase high performance liquid chromatography (RP-HPLC) method has been developed for their simultaneous determination in human blood and cerebrospinal fluid. The method involves simple protein precipitation sample treatment followed by quantification of analytes using HPLC at 263 nm. Analytes were separated on a 5 μm Zorbax Dikema C 18 column (150 mm × 4.60 mm, i.d.) with a mobile phase of 22:78 (v/v) mixture of methanol and a diethylamine–acetic acid buffer, pH 4.0. The mean recoveries were between 69.8 and 94.4% for nikethamide and between 78.9 and 97.2% for lidocaine. Limits of detection (LODs) for nikethamide and lidocaine were 0.008 and 0.16 μg/ml in plasma and 0.007 and 0.14 μg/ml in cerebrospinal fluid, respectively. The mean intra-assay and inter-assay coefficients of variation (CVs) for both analytes were less than 9.2 and 10.8%, respectively. The developed method was applied to blood sample analyses in eight forensic cases, where blood concentrations of lidocaine ranged from 0.68 to 34.4 μg/ml and nikethamide ranged from 1.25 to 106.8 μg/ml. In six cases cerebrospinal fluid analysis was requested. The values ranged from 20.3 to 185.6 μg/ml of lidocaine and 8.0 to 72.4 μg/ml of nikethamide. The method is simple and sensitive enough to be used in toxicological analysis for simultaneous determination of nikethamide and lidocaine in blood and cerebrospinal fluid.

Continuous low-dose intravenous lidocaine is effective for visceral pain secondary to peritoneal carcinomatosis in terminal cancer patients

8533 Background: Lidocaine, a local anesthetic, is often used as an anti-arrhythmic and as an analgesic of best support care (BSC) for patients with neuropathic pain. However, little is known about the effect of low-dose lidocaine on the abdominal pain of terminally-ill patients with peritoneal carcinomatosis. Aim: To evaluate whether visceral pain is controlled and activities of daily life (ADL) are improved during continuous lidocaine infusion. Methods: 28 terminally ill patients with peritoneal carcinomatosis due to the gastrointestinal (26) and gynecologic (2) cancers were studied. Despite aggressive pain management with opiates, non-steroidal anti-inflammatory drugs and other adjuvants, debilitating pain persisted. After a test dose of 2mg/kg intravenously, lidocaine was administered at low-doses (0.4 and/or 0.8mg/kg-h) through a vein and continued for more than 24 hours. Pain was quantitated on a faces rating scale from the level 0 (no pain) to 5 (severe pain); doses of opiates, amounts of oral intake, side effects, and ADL were measured before and after lidocaine. Results: Age (mean±SE) was 62±2, and percentage of males was 54%. Patients were not hypercalcemia but were slightly malnutrished (albumin 2.9±0.1g/dl) and anemic (hemoglobin 10.3±0.4g/dl). The duration of lidocaine administration in hospital was 18±3days. Abdominal symptoms improved within 1.2±0.1days after beginning lidocaine, and pain scale decreased from 2.7±0.2 to 0.6±0.2; p<0.001. In 68% of patients, the pain level became zero. Blood concentration of lidocaine at 0.8mg/kg-h was 3.0±0.4μg/ml 1 week later. 68% of patients needed no increase in opiate dosage during lidocaine administration. Waist size did not decrease, however, oral intake increased (p=0.002) during lidocaine administration. No obvious side effects, such as perioral numbness, were seen except for emotional lability noted in 4 patients. 43% patients were able to be discharged for continued end-of-life comfort care with home parenteral nutrition and continuation of lidocaine administration. Conclusions: We suggest that continuous, low-dose intravenous lidocaine is BSC and is a very effective approach for analgesia and improvement of ADL in patients with peritoneal carcinomatosis. No significant financial relationships to disclose.

Comparison of Intraosseous and Infiltration Injections For Venous Lidocaine Blood Concentrations and Heart Rate Changes after Injection of 2% Lidocaine with 1:100,000 Epinephrine

The purpose of this prospective, randomized study was to compare the venous blood levels of lidocaine and heart rate changes after intraosseous and infiltration injections of 1.8 ml of 2% lidocaine with 1:100,000 epinephrine. Using a crossover design, 20 subjects randomly received an intraosseous and infiltration injection at two separate appointments. The heart rate was measured using a pulse oximeter. Venous blood samples were collected before the injections and at 2, 5, 10, 15, 20, 25, 30, 45, and 60 min after the injections. The blinded plasma samples were analyzed for lidocaine concentrations using high-performance liquid chromatography (HPLC). The intraosseous injection resulted in a statistically significant increase in heart rate, when compared to the infiltration injection, during solution deposition and for 2 min after the injection. The plasma levels of lidocaine were not statistically different for maxillary anterior intraosseous and infiltration injections when using 1.8 ml of 2% lidocaine with 1:100,000 epinephrine.

The anticonvulsant effects of volatile anesthetics on lidocaine-induced seizures in cats.

Large concentrations of sevoflurane and isoflurane, but not halothane, induce spikes in the electroencephalogram. To elucidate whether these proconvulsant effects affect lidocaine-induced seizures, we compared the effects of sevoflurane, isoflurane, and halothane in cats. Fifty animals were allocated to 1 of 10 groups: 70% nitrous oxide (N2O), 0.6 minimum alveolar anesthetic concentration (MAC) + 70% N2O, 1.5 MAC + 70% N2O, and 1.5 MAC of each volatile agent in oxygen. Lidocaine 4 mg x kg(-1) x min(-1) was infused IV under mechanical ventilation with muscle relaxation. Electroencephalogram in the cortex, amygdala, and hippocampus and multiunit activities in the midbrain reticular formation (R-MUA) were recorded. Lidocaine induced spikes first from the amygdala or hippocampus in the 70% N2O and halothane groups and from the cortex in the sevoflurane and isoflurane groups. Lidocaine induced seizures in all cats in the 70% N2O and 0.6 MAC + N2O groups. Seizure occurrence was reduced in the 1.5 MAC + N2O group (P < 0.05 versus 70% N2O). The onset of seizure was delayed in the 0.6 MAC + N2O and 1.5 MAC groups for sevoflurane and isoflurane, but not for halothane, compared with the 70% N2O group (P < 0.05). Lidocaine increased R-MUA with seizure by 130%+/-56% in the 70% N2O group. The increase of R-MUA with seizure was more suppressed in the volatile anesthetic groups than in the 70% N2O group (P < 0.05). In the present study, sevoflurane and isoflurane attenuated seizure when the blood lidocaine concentration was accidentally increased. Increasingly, epidural blockade is combined with general anesthesia to achieve stress-free anesthesia and continuous pain relief in the postoperative period. In the present study, sevoflurane and isoflurane attenuated seizure when the blood lidocaine concentration was accidentally increased.

The Plasma Concentration of Lidocaine's Principal Metabolite Increases During Continuous Epidural Anesthesia in Infants and Children

Continuous 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. Methods After obtaining approval from the local ethics committee and parental consent, we studied 10 infants and children, aged 3 mo to 4 yr and weighing 5-19 kg, who underwent abdominal or thoracic surgeries lasting >5 h. After induction of general anesthesia, the epidural spaces were entered via the caudal route or via the lumbar or thoracic interspaces using Tuohy 19-gauge needles (Portex Minipak[registered sign]; Hythe, Kent, England) and 22-gauge epidural catheters. The loss of resistance technique with saline was used to identify lumbar and thoracic epidural spaces. An initial dose of 1% lidocaine (5 mg/kg) without epinephrine was injected into the epidural space, followed by an infusion of the same solution (2.5 mg [center dot] kg-1 [center dot] h-1) using a motor-driven syringe pump. Anesthesia was maintained with epidural anesthesia and oxygen (33%), nitrous oxide (67%), and isoflurane (0%-1%) or sevoflurane (0%-1.5%). Blood samples were drawn at 30 min and every hour after the epidural injection for 5 h. Plasma samples were separated by centrifugation at 4[degree sign]C and stored at -20[degree sign]C until analyzed. The total plasma concentrations of lidocaine and MEGX were simultaneously measured by using high-performance liquid chromatography with ultraviolet detection; a variable wavelength ultraviolet detector (Model UV-8020; Tosoh, Tokyo, Japan) set for 210 nm was used. Analytic recoveries of lidocaine and MEGX were 97% and 90%, respectively; coefficients of variation were <5%, and compounds at concentrations as low as 0.01 [micro sign]g/mL could be detected in 250-[micro sign]L plasma samples. Results The time-dependent changes in the concentrations of plasma lidocaine, MEGX, or the sum of lidocaine and MEGX that occurred during lidocaine infusion were assessed using linear regression, and the statistical significance of the changes were determined by using multiple regression analysis. We observed that increases in plasma lidocaine were minimal during surgery, whereas MEGX levels and the sum of lidocaine and MEGX both increased significantly as a function of time (Figure 1).Figure 1: Time-dependent changes in plasma lidocaine ([large circle]), monoethylglycinexylidide (MEGX; [up triangle, open]), and the sum of lidocaine and MEGX ([square]) during continuous epidural lidocaine infusion. Data are expressed as mean +/- SD. Regression lines are defined by the equations Y = 2.6 + 0.4 h (r = 0.82, P = 0.0001) for the sum of lidocaine and MEGX; Y = 2.5 + 0.12 h (r = 0.42, P = 0.0008) for lidocaine; and Y = 0.1 + 0.28 h (r = 0.88, P = 0.0001) for MEGX, where Y is plasma concentration and h is time after the initial epidural injection. Increases in plasma lidocaine concentration were minimal; MEGX and the sum of lidocaine and MEGX were each significantly increased as a function of time.Discussion Analysis of lidocaine pharmacokinetics during epidural anesthesia for surgery in infants and children has been limited to single-dose caudal administration [1]. In their study, Ecoffey et al. [1] observed that plasma lidocaine levels peaked 28 min after the caudal administration of 5 mg/kg lidocaine; the average plasma level was 2 [micro sign]g/mL, and the average half-life was 155 min. Based on these findings, they recommended that initial doses of epidural lidocaine in infants and children should be reduced by one-third to one-half [2]. In our study, we administered epidural lidocaine as a 5-mg/kg bolus followed by infusion of 2.5 mg [center dot] kg-1 [center dot] h-1. Using this protocol, plasma lidocaine concentrations were maintained well below 5.3 [micro sign]g/mL, which is considered toxic in adults [3]. Other authors have suggested that the accumulation of lidocaine metabolites during prolonged IV administration may account for the development of toxicity even when blood lidocaine concentrations are within the therapeutic range [4-6]. Indeed, the convulsant potency of MEGX is approximately equal to that of lidocaine itself [7]. MEGX levels also increased with repeated administration of lidocaine during epidural anesthesia. The additive effects of MEGX and lidocaine have been suggested to play an important role in the development of toxic side effects associated with lidocaine administration [8]. Our findings indicate that MEGX continuously increases with time during lidocaine infusion in children and infants. Therefore, plasma MEGX accumulation must be considered when repeated or continuous administration of epidural lidocaine is used for anesthesia in pediatric patients. In conclusion, during continuous epidural anesthesia, local anesthetic accumulation may occur even when plasma lidocaine is maintained within the normal range. We observed that plasma MEGX, an active metabolite of lidocaine, increases continuously.

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.

The Plasma Concentrations of Lidocaine After Slow Versus Rapid Administration of an Initial Dose of Epidural Anesthesia

We measured venous blood concentrations of lidocaine in 15 patients undergoing lower abdominal or extremity surgery after epidural injection of lidocaine.Patients were divided into either an infusion group (Group I, n = 6) or a bolus injection group (Group II, n = 9). We administered 15 ml of 2% lidocaine into the epidural space at 1 mL/min in Group I and at 1 mL/3 in Group II. Venous blood was drawn at 3, 6, 9, 12, 15, 18, 21, 30, 60, and 90 min after injection for measurement of plasma lidocaine concentrations. The peak plasma concentration (Cmax) of lidocaine in Group I was significantly less than that in Group II (P < 0.0005). We conclude that slow epidural infusion can produce a lower Cmax of lidocaine compared with that of a bolus administration and thereby decrease the potential for systemic toxicity of the local anesthetic. (Anesth Analg 1997;84:570-3)

The Plasma Concentrations of Lidocaine After Slow Versus Rapid Administration of an Initial Dose of Epidural Anesthesia

We measured venous blood concentrations of lidocaine in 15 patients undergoing lower abdominal or extremity surgery after epidural injection of lidocaine. Patients were divided into either an infusion group (Group I, n = 6) or a bolus injection group (Group II, n = 9). We administered 15 ml of 2% lidocaine into the epidural space at 1 mL/min in Group I and at 1 mL/3 in Group II. Venous blood was drawn at 3, 6, 9, 12, 15, 18, 21, 30, 60, and 90 min after injection for measurement of plasma lidocaine concentrations. The peak plasma concentration (Cmax) of lidocaine in Group I was significantly less than that in Group II (P < 0.0005). We conclude that slow epidural infusion can produce a lower Cmax of lidocaine compared with that of a bolus administration and thereby decrease the potential for systemic toxicity of the local anesthetic.

Drug management in skin surgery.

Lidocaine (lignocaine) 1% with epinephrine (adrenaline) 1:200,000 (maximum dose 40mL) is the agent of choice in skin surgery. It can be used at all sites except the fingers, toes and penis, where epinephrine should be avoided. Epinephrine-induced vasoconstriction delays local anaesthetic clearance, thus prolonging its effect and, by reducing peak blood lidocaine concentrations, enables a higher maximum dose to be used. Adding epinephrine, however, introduces the possibility of a drug interaction with tricyclic antidepressants and nonselective beta-blockers. Also, injection pain is greater because of the acidic sodium metabisulphite that has to be added to prevent epinephrine oxidation. Injection pain can be reduced by buffering the solution using sodium bicarbonate. There are no drug interactions that prevent the use of plain lidocaine: injection pain is least with 0.5% solutions. Injection of large volumes of very dilute lidocaine solutions (tumescent anaesthesia) enables higher maximum doses of lidocaine to be tolerated and large areas to be anaesthetised by infiltration. Amethocaine gel is a faster acting and more effective topical anaesthetic compared with eutectic lidocaine-prilocaine cream, but is a topical sensitiser. In high risk patients, prophylactic antibiotics should be given to prevent bacterial endocarditis when operating on infected lesions and on potentially colonised crusted lesions in high-risk patients (i.e. those with prosthetic heart valves). Wound infections following surgery on infected skin lesions can be prevented by the prophylactic use of mupirocin ointment. Aspirin-induced inhibition of platelet adhesion results in bleeding complications in approximately 15% of skin surgery patients receiving aspirin. Patients whose bleeding time is > 8 minutes are particularly at risk, and aspirin should be stopped at least 7 days prior to surgery in these patients. Aspirin can be continued in other patients without serious bleeding complications.

Large Doses of Topical Lidocaine during Microvascular Surgery Are Not Associated with Toxic Blood Concentrations

Large Doses of Topical Lidocaine during Microvascular Surgery Are Not Associated with Toxic Blood Concentrations