Sustained Release from Ionic-Gradient Liposomes Significantly Decreases ETIDOCAINE Cytotoxicity.

PURPOSE: Etidocaine (EDC) is a long lasting local anesthetic, which alleged toxicity has restricted its clinical use. Liposomes can prolong the analgesia time and reduce the toxicity of local anesthetics. Ionic gradient liposomes (IGL) have been proposed to increase the upload and prolong the drug release, from liposomes. METHODS: First, a HPLC method for EDC quantification was validated. Then, large unilamellar vesicles composed of hydrogenated soy phosphatidylcholine:cholesterol with 250 mM (NH4)2SO4 - inside gradient - were prepared for the encapsulation of 0.5% EDC. Dynamic light scattering, nanotracking analysis, transmission electron microscopy and electron paramagnetic resonance were used to characterize: nanoparticles size, polydispersity, zeta potential, concentration, morphology and membrane fluidity. Release kinetics and in vitro cytotoxicity tests were also performed. RESULTS: IGLEDC showed average diameters of 172.3 ± 2.6 nm, low PDI (0.12 ± 0.01), mean particle concentration of 6.3 ± 0.5 × 1012/mL and negative zeta values (-10.2 ± 0.4 mV); parameters that remain stable during storage at 4°C. The formulation, with 40% encapsulation efficiency, induced the sustained release of EDC (ca. 24 h), while reducing its toxicity to human fibroblasts. CONCLUSION: A novel formulation is proposed for etidocaine that promotes sustained release and reduces its cytotoxicity. IGLEDC can come to be a tool to reintroduce etidocaine in clinical use.

Lipid rescue resuscitation from local anaesthetic cardiac toxicity.

Systemic local anaesthetic toxicity is a rare but potentially fatal complication of regional anaesthesia. This toxicity is due to inhibition of ionotropic and metabotropic cell signal systems and possibly mitochondrial metabolism. It is associated with CNS excitation and, in the extreme, refractory cardiac dysfunction and circulatory collapse. Infusion of lipid emulsion has been shown in animal models to reliably reverse otherwise intractable cardiac toxicity and the mechanism of lipid rescue is probably a combination of reduced tissue binding by re-established equilibrium in a plasma lipid phase and a beneficial energetic-metabolic effect. Recent case reports have suggested the clinical efficacy of lipid infusion by the recovery of patients from intractable cardiac arrest. Future areas of investigation will focus on improved treatment regimes and better understanding of the mechanism of lipid rescue, which might allow superior alternative therapies, or treatment of other toxic events. An educational website has been established to help disseminate information about lipid emulsion therapy and to serve as a medium for physicians to share experiences or thoughts on the method and local anaesthetic toxicity.

Local anesthesia: advances in agents and techniques.

The improvements in agents and techniques for local anesthesia are possibly the most important advances in dental science to have occurred in the past 100 years. The agents currently available in dentistry have most of the characteristics of an ideal local anesthetic. Today's anesthetics can be administered with minimal irritation and little concern for stimulating allergic reactions. A variety of agents are available that provide rapid onset of surgical anesthesia with adequate duration. This article provides a brief review of the local anesthetic agents, formulations, and techniques used in dentistry with special emphasis on newly introduced agents and procedures.

Peribulbar anesthesia and sub-Tenon injection for vitreoretinal surgery: 300 cases.

BACKGROUND AND OBJECTIVES: We carried out a prospective study in order to evaluate the efficacy and safety of peribulbar anaesthesia supplemented by a sub-Tenon injection in case of inadequate analgesia during vitreoretinal surgery. METHODS: We performed 300 consecutive vitreoretinal procedures. Patients received a mean volume of 17+/-4.5 ml of a mixture of etidocaine 1%, bupivacaine 0.50% and hyaluronidase (25 UI/ml). Supplementation was represented by a sub-Tenon infiltration of lidocaine 2% (2 or 3 ml). This volume was not included in the mean volume. RESULTS: Analgesia was adequate throughout surgery without any supplementation in 85% of cases and with a sub-Tenon infiltration in 99%. Akinesia was complete in 82%, mild in 15% and absent in 3% of cases. The sub-Tenon injection was performed immediately before starting the procedure in 58% of cases and during the surgery with a delay of 80+/-21 min in 42%. Eleven patients (3.66%) were agitated during surgery and two of them needed a general anaesthesia to allow for the procedure. Generalised epilepsy was encountered in two patients (0.66%) immediately after the peribulbar injection in one patient and 15 min later in the other. The systolic blood pressure severely decreased between 60 to 70 mm Hg 40 min after the accomplishment of the peribulbar in 2 patients and at 90 min in 2 others. CONCLUSION: Our results demonstrate that peribulbar anaesthesia alone offers excellent analgesia in 85% of patients and supplemented by a sub-Tenon injection in 99%.

Anesthetic efficacy and heart rate effects of the intraosseous injection of 1.5% etidocaine (1:200,000 epinephrine) after an inferior alveolar nerve block.

OBJECTIVE: The purpose of this study was to determine the anesthetic efficacy and heart rate effects of an intraosseous (IO) injection of 1.5% etidocaine with 1:200,000 epinephrine after an inferior alveolar nerve block. STUDY DESIGN: In a repeated-measures designed study, 48 subjects randomly received 2 combinations of injections at 2 separate appointments. The combinations were an inferior alveolar nerve (IAN) block (with 3% mepivacaine) + IO injection with 1.8 mL of 1.5% etidocaine hydrochloride containing 1:200,000 epinephrine, and an IAN + mock IO injection. The first molar was blindly tested with a pulp tester at 2-minute cycles for 60 minutes after the injection. Anesthesia was considered successful when 2 consecutive 80 readings (no subject response) were obtained. Heart rate (pulse rate) was measured with a pulse oximeter. RESULTS: Lip numbness occurred in 100% of the subjects with both the techniques. For the first molar, anesthetic success for the IAN + mock IO and the IAN + IO etidocaine hydrochloride groups, respectively, were 81% and 100%. The differences were significant (P <.05) when the IAN + IO etidocaine hydrochloride technique was compared with the IAN + mock IO. A mean increase in heart rate of 32 beats/min occurred in 90% of the subjects with the IO injection of the etidocaine hydrochloride solution. In 89% of these subjects, the heart rate returned to within 5 beats of baseline values 4 minutes or less after solution deposition. CONCLUSIONS: The IO injection of 1.8 mL of 1.5% etidocaine hydrochloride with 1:200,000 epinephrine, when used to augment an inferior alveolar nerve block, significantly increased anesthetic success in the first molar. The majority of subjects receiving the IO injection of the etidocaine hydrochloride solution had a transient increase in heart rate.

Compound motor action potential recording distinguishes differential onset of motor block of the obturator nerve in response to etidocaine or bupivacaine.

The purpose of this investigation was to establish an objective (quantitative) method for determining onset time of motor block induced by different local anesthetics. Twenty-four consenting patients undergoing transurethral surgery during spinal anesthesia were randomized to receive direct obturator nerve block with 10 mL of plain bupivacaine 0.5% (n = 12) or 10 mL of plain etidocaine 1% (n = 12). Another 14 patients (control group) received obturator nerve "block" with saline. After identification of the obturator nerve, patients underwent testing of nerve conduction by recording compound motor action potentials (CMAPs) of thigh adductor muscles in response to stimulation provided by a nerve stimulator at 0.2 to 0.5-mA currents. Testing ended when CMAP amplitudes had returned to their baseline values (control group) or when motor blockade was 90% complete (local anesthetic groups). In all 38 patients, the amplitude of the thigh CMAPs decreased immediately after injection of saline or local anesthetic. While CMAP amplitudes in the control group returned to their initial (baseline) values after 3-6 min, the patients receiving etidocaine or bupivacaine achieved > or = 90% motor blockade after 6 and 13 min, respectively. In the present report, the time to > or = 90% block was significantly faster in patients given etidocaine compared with those given bupivacaine. We conclude that electromyographic recording of CMAPs can be used to compare the ability of different local anesthetics to induce motor block.

Pain of injection and duration of anesthesia for intradermal infiltration of lidocaine, bupivacaine, and etidocaine.

BACKGROUND: Bupivacaine and etidocaine are local anesthetics said to be long acting based on nerve block data. There are insufficient data on pain of infiltration and duration of anesthesia when either is used for dermal infiltration to assess suitability for skin surgery. OBJECTIVE: We conducted a randomized, placebo-controlled, double-blinded comparison of intradermal 1% etidocaine, 0.5% bupivacaine, and 2% lidocaine for pain of injection and duration of anesthesia. METHODS: Twenty subjects received the above three agents plus normal saline, each with and without epinephrine 1:200,000, with all solutions adjusted to pH 5.95 +/- 0.15. RESULTS: Lidocaine hurt least and etidocaine hurt most. Adrenalized solutions were more painful than plain. For plain solutions bupivacaine lasted longest and lidocaine lasted shortest by far. For adrenalized solutions bupivacaine lasted 27% longer than lidocaine and 45% longer than etidocaine. CONCLUSION: Where epinephrine is contraindicated and long anesthesia matters, use plain bupivacaine. When epinephrine can be used, lidocaine lasts almost as long as bupivacaine and hurts less.

Etidocaine and extradural somatosensory evoked potentials after posterior tibial nerve stimulation.

We have examined the effects of lumbar extradural administration of 1% etidocaine 10 ml on somatosensory evoked potentials to posterior tibial nerve stimulation measured in the cervical extradural space. Eight patients, anaesthetized with propofol and nitrous oxide, were studied before hysterectomy and a control group received a similar anaesthetic and 0.9% sodium chloride solution 10 ml in the lumbar extradural space. Etidocaine decreased significantly overall amplitude of the evoked potentials and the amplitudes of all peaks, between 30 and 50 min after extradural injection. The effects of etidocaine on spinal cord conduction were greater than those found previously for lignocaine and bupivacaine, suggesting that it is the local analgesic of choice for inhibiting afferent conduction.

Regression of sensory anesthesia during continuous epidural infusions of bupivacaine and opioid for total knee replacement.

The epidural administration of morphine and fentanyl delay the regression of sensory anesthesia in postoperative patients receiving epidural bupivacaine. This study was performed to determine any differential effects of two lipid-soluble opioids upon regression of sensory anesthesia during coadministration with epidural bupivacaine. Forty-eight patients scheduled for total knee replacement underwent lumbar epidural catheterization and received 1.5% etidocaine with 1:200,000 epinephrine to establish sensory anesthesia to approximately T6 bilaterally. Patients were randomized by the investigational pharmacy to receive either: (a) bupivacaine without opioid (control) (n = 16), or (b) bupivacaine with 1 mg/mL of meperidine (n = 16), or (c) bupivacaine with 3 micrograms/mL of fentanyl (n = 16) in a double-blind fashion. Intraoperatively, 0.5% bupivacaine +/- opioid was administered by epidural infusion at a rate of 10 mL/h. Postoperatively, the bupivacaine concentration was decreased to 0.25% (+/- the same opioid), and the infusion rate was decreased to 4 mL/h. Pinprick sensory anesthesia and verbal numerical pain score were recorded each hour after surgery by a blinded investigator. For each patient, the study was considered terminated when the cephalad level of sensory anesthesia bilaterally decreased five dermatomal segments or the pain score reached "5" (moderate pain). Patients receiving epidural infusions of bupivacaine and meperidine had a significantly slower regression of sensory anesthesia and slower development of pain. There was no difference in the rate of regression of sensory anesthesia or the development of pain among patients receiving bupivacaine alone or bupivacaine with fentanyl.

Complications related to thoracic epidural analgesia: a prospective study in 1071 surgical patients.

In a prospective study, the complications of 1071 patients scheduled for thoracic epidural catheterization for postoperative analgesia (TEA) were studied. All catheters were inserted preoperatively between segment Th 2/3 and Th 11/12 under local anesthesia. Balanced anesthesia with endotracheal intubation and TEA were combined. Postoperatively 389 patients (36.9%) were monitored on a normal surgical ward. Buprenorphine, 0.15 to 0.3 mg, and if needed bupivacaine 0.375% 3-5 ml h-1 were given epidurally. Primary perforation of the dura occurred in 13 patients (1.23%). Radicular pain syndromes were observed in six patients (0.56%). In one patient (0.09%) respiratory depression was seen in close connection with the epidural administration of 0.3 mg buprenorphine. Although 116 patients (10.83%) showed one abnormal clotting parameter but no clinical signs of hemorrhage, there was no complication related to this group. No persisting neurological sequelae caused by the thoracic epidural catheters were found. In conclusion, continuous TEA with buprenorphine for postoperative pain relief after major abdominal surgery is a safe method without too high a risk of catheter-related or drug-induced complications, even on a normal surgical ward and when one clotting parameter is abnormal.

Comparison of two needle lengths in regional ophthalmic anesthesia with etidocaine and hyaluronidase.

The effect of needle length on the efficacy of regional ophthalmic anesthesia in conjunction with cataract surgery was studied in 97 patients using a two-site injection technique. The local anesthetic used was etidocaine 1.5% with hyaluronidase. In 48 patients, the anesthetic was administered inferolaterally with a 22-millimeter needle, and in the other 49 patients, with a 31-millimeter needle. Every patient had a medial injection with a 12-millimeter needle to achieve lid akinesia and to complete the globe akinesia. At 5 minutes, lid akinesia was considered better in the 22-millimeter needle group (P < .005). After one supplemental dose, when necessary, complete globe akinesia was achieved at 15 minutes significantly more often (94% vs 79%) in the 31-millimeter needle group (P < .05). Lid akinesia in the two groups was identical at that time. Eight patients in the short-needle group and three in the long-needle group experienced some pain during surgery. Throughout the study, the required intraorbital anesthetic volumes were smaller in the 31-millimeter needle group. We recommend the use of a 31-millimeter needle inferolaterally in combination with a 12-millimeter needle medially to achieve satisfactory regional anesthesia for cataract surgery.

Hyaluronidase improves regional ophthalmic anaesthesia with etidocaine.

The effect of adding hyaluronidase to regional ophthalmic anaesthesia with etidocaine 1.5% was examined. Two studies were performed in a double-blind fashion. In Study #1, 70 patients were given peribulbar anaesthesia with etidocaine either with or without hyaluronidase (7.5 IU.ml-1) using a standard intraorbital injection and separate lid injections. The block was supplemented as needed. Lower intraorbital volumes (6.4 +/- 2.2 ml vs 8.2 +/- 2.3 ml, P < 0.01) and improved scores for globe akinesia (P < 0.01), lid akinesia (P < 0.01) and analgesia (P < 0.05) were recorded in the hyaluronidase group than in the plain etidocaine group. In Study #2, 80 patients were randomized to receive etidocaine and hyaluronidase either at a concentration of 7.5 IU.ml-1 or 15 IU.ml-1 using a two-injection-site technique. No differences were noted in the volumes of local anaesthetics required or in the success rates between the two groups. It was concluded that the addition of hyaluronidase to etidocaine decreases the volume needed and improves the quality of block compared with plain etidocaine. Doubling the dose of hyaluronidase does not improve the effectiveness of block.

Orbicular muscle akinesia: a comparison, using electromyography, of three techniques.

Ninety patients scheduled for elective cataract extraction under local anesthesia received an inferolateral intraconal injection of 4 mL of etidocaine mixed with hyaluronidase. They were divided into three groups of 30 patients each according to the method used to provide orbicular akinesia. Those in group I had a nasal, intraorbital injection; those in group II underwent electrostimulation to locate branches of the facial nerve in the eyelids; and those in group III had the anesthetic agent injected subcutaneously into the lids. Ten minutes after the regional blockade, orbicular muscle activity of the upper eyelid, as measured by electromyography, was found to be higher in group I than in the other two groups. The muscular activity of the lower lid at 10 minutes, or of either of the lids at 20 minutes, was similar in all three groups. The use of electrostimulation did not yield better orbicular akinesia than the infiltration technique alone. Nasal injection improved globe akinesia.

Effect of thoracic epidural etidocaine 1.5% on somatosensory evoked potentials, cortisol and glucose during cholecystectomy.

The effect of thoracic (T7-8) epidural etidocaine 1.5%, 9 ml, and continuous per- and postoperative epidural infusion of etidocaine 1.5%, 4 ml/h, on early (less than 500 ms) somatosensory evoked potentials (SEPs), and cortisol and glucose in plasma during cholecystectomy, was examined in ten patients. Spread of analgesia (pin-prick) was T3 (T1-T3) to L2 (T11-L3) 35 min after injection of etidocaine, and T3 (T2-T4) to T12 (T8-L4) 3 h after surgical incision (median (range)). Before operation, epidural etidocaine had no significant effects on peak-to-peak amplitude of SEPs to electrical stimulation at the L1, T10 or T6 dermatomal level (P greater than 0.09). SEPs were abolished in only two patients at T6, and no patient had SEPs abolished at T10 or L1. The plasma concentrations of cortisol and glucose were significantly increased 20 min after surgical incision and remained increased throughout the study. No correlation was found between the block-induced decrease in the peak-to-peak amplitude at T6 or T10 and increase in plasma cortisol, except for a negative correlation at T10 and the initial increase in cortisol (Rs = 0.72, P = 0.03). In conclusion, thoracic epidural administration of 9 ml of etidocaine 1.5% does not provide total afferent somatic blockade assessed by SEP and the stress response to cholecystectomy.

[Dose limits for local anesthetics. Recommendations based on toxicologic and pharmacokinetic data]. / Grenzdosis für Lokalanaesthetika. Empfehlungen nach toxikologischen und pharmakokinetischen Daten.

Since Heinrich Braun added adrenaline to cocaine (and later also to procaine) in 1903 to allow clinical use of this local anesthetic, "limiting dosages" for local anesthetics have been "recommended" with no reference to the technique of administration, on the assumption that adrenaline will lower the toxicity of the local anesthetic used. However, the limiting dosages determined up to now do not take account of important pharmacokinetic and toxicological data: (1) The dependence of blood levels measured on the technique of regional anesthesia and (2) the raised toxicity of a local anesthetic solution containing adrenaline following inadvertent intravascular (intravenous) injection. A maximum dose recommendation that differs according to the technique of local anesthesia is suggested for (A) subcutaneous injection, (B) injection in regions of high absorption, (C) single injection (perineural, e.g. plexus), (D) protracted injection (catheter, combined techniques), (E) injection into vasoactive regions (near to the spinal cord, spinal, epidural, sympathetic). This sequential categorization also underscores the need for selection of appropriate techniques as well as for concomitant monitoring referred to the technique of administration and to the expected and the possible plasma level curve.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of etidocaine administered epidurally on changes in somatosensory evoked potentials after dermatomal stimulation.

The effect of lumbar epidural anesthesia with similar volumes (approximately 20 ml) of 1% and 1.5% etidocaine on early (less than 0.5 seconds) somatosensory evoked potentials (SEPs) to electrical stimulation of the S1, L1, and T10 dermatomes was examined in two groups of ten patients in a randomized, double-blind study. Level of analgesia to pinprick was T7.7 +/- 0.9 in the 1% group and T6.6 +/- 0.6 in the 1.5% group and all patients had total motor block. Despite similar analgesia to pinprick, SEP amplitude was more reduced in the 1.5% group, in which SEPs were abolished in all patients at the L1 level.

Periocular anaesthesia: technique, effectiveness and complications with special reference to postoperative ptosis.

The effectiveness of periocular anaesthesia and its complications were examined in 100 successive cataract operations. The patients were divided into 3 groups according to the duration of ocular compression with an Autopressor device after administration of periocular anaesthesia. In the control group, no compression was used (C-O, n = 36 patients). In the other two groups, compression was used for 10 (C-10, n = 32) and for 20 (C-20, n = 32) min. No differences in globe or orbicular akinesia were found between the groups. At 10 min, immobilisation of the globe in different directions was attained in 60.1-84.5% of the patients. Compression for an additional 10 min did not significantly improve the akinesia. In contrast, the hitherto undescribed loss of light perception increased with time: 15 patients at 10 min and 22 at 20 min were unable to see light. Chemosis and haematomas in the upper eyelid occurred more often in C-0 than in the other 2 groups. One day postoperatively the average palpebral aperture was smaller in C-0 than in the other two groups. The frequent postoperative ptosis (74.3% on the 1st day) decreased rapidly, but on postoperative day 7, 9 patients still had ptosis. In only one patient was ptosis still recognizable at 6 weeks postoperatively. No serious complications occurred. This study demonstrates that periocular anaesthesia with ocular compression is a suitable method for cataract surgery.

Influence of intravenous local anaesthetics upon quadriceps muscle function.

This study was undertaken to assess the effects of intravenous administration of mepivacaine and etidocaine on muscle function. Seven male volunteers were given mepivacaine (5 mg/kg) and etidocaine (50 mg) intravenously, on separate occasions. A reference group of 11 male volunteers received 0.9% saline solution intravenously. Muscle function was tested by measurements of isometric muscle force of knee extension and by quantitative electromyographic (EMG) recordings from the quadriceps muscle during knee extension at different degrees of isometric muscle force. At the end of the mepivacaine and etidocaine infusions, the mean venous plasma concentrations of the two anaesthetic agents were 2.9 and 1.2 micrograms/ml, respectively. The muscle strength remained unchanged during infusion of the two local anaesthetics. Mepivacaine had a minor effect on the mean rectified EMG amplitudes at the end of the infusion at maximal voluntary muscle contraction, but no such effect was observed at submaximal knee extension force. However, at the plasma concentrations mentioned above, the clinical influence of intravenous infusion of the local anaesthetics on muscle function was negligible.

Intraoperative topical etidocaine for reducing postoperative pain after laparoscopic tubal ligation.

Self-reported postoperative pain was reduced significantly (P less than .05) for up to six hours in a group of ambulatory surgical patients with the application of 5 mL of 1% etidocaine to the banded portion of each fallopian tube after laparoscopic tubal ligation with Falope Rings in comparison to a control group receiving normal saline. The etidocaine group had less nausea and vomiting and smaller antiemetic and analgesic requirements than did the control group, though those results were not statistically significant.

PIP: The results of a randomized, double-blind, clinical trial suggest that topical etidocaine can significantly reduce postoperative pain when applied to the fallopian tubes after tubal banding. The 97 study subjects were woman admitted to a New York clinic in 1985-87 for same- day laparoscopic tubal ligation with Falope rings. All patients received general anesthesia and underwent the standard 2-puncture laparoscopic technique. In the 46 cases, 5 mL of 1% etidocaine was applied to the banded portion of each fallopian tube after ligation. In the 41 controls, normal saline was administered to the tubes. Patients were asked to rate their postoperative pain on a scale from 0 (no pain)- 10 (worse pain ever experienced) at 3 intervals: 2 hours after return from the recovery room, at the time of hospital discharge, and 24 hours after discharge. Mean analog pain scores were significantly lower in the etidocaine group than the placebo group after return from the recovery room and the time of discharge (p0.05); there was no significant differences between the 2 groups 24 hours after discharge in terms of pain level. Women who received etidocaine also required less medication for postoperative nausea and vomiting (24%) than controls (37%), but this difference was not significant. Finally, a smaller percentage of women from the etidocaine group required parenteral or oral analgesics postoperatively (74% compared with 95% of the controls). Application of etidocaine to the banded tubes took only 2-3 minutes and was easily learned by the operating gynecologists.

Motor and sensory blockade after epidural injection of mepivacaine, bupivacaine, and etidocaine--a double-blind study.

In a double-blind study of epidural anesthesia, 30 young volunteers were given either 2% mepivacaine (400 mg), 0.5% bupivacaine (100 mg), or 1.5% etidocaine (300 mg), all solutions containing epinephrine (1:200,000). The spread of analgesia was equal in the groups, whereas the longest duration was noted in the etidocaine and bupivacaine groups. With use of a method for determining muscle force, motor blockade during anesthesia was recorded quantitatively for hip flexion, knee extension, and plantar flexion of the big toe. Onset of motor blockade was significantly more rapid with etidocaine than with bupivacaine and mepivacaine. All subjects given etidocaine developed complete motor blockade, but with the other local anesthetics 5%-33% of the initial muscle force remained. The least motor blockade was found in the L5-S2 segment (plantar flexion of the big toe). The duration of maximal motor blockade varied between 60 min (mepivacaine) and 360 min (etidocaine). With each of the three local anesthetics, motor function returned simultaneously in the three muscle groups tested. Complete restoration of muscle function occurred significantly later for etidocaine (600 min) than for bupivacaine (360 min) and mepivacaine (180 min). With etidocaine, the motor blockade outlasted the sensory blockade by 150 min. The Bromage scale corresponded to the motor blockade only during the first half of the regression phase. Not until 1-3 h after attainment of Bromage grade 0 was the muscle force of all movements restored (90% of control values).