Geoffrey T. Tucker

Pharmacokinetic Aspects of Intravenous Regional Anesthesia

The kinetics of disposition of lidocaine after intravenous regional anesthesia of the arm and direct intravenous infusion were studied in volunteers. Plasma levels of the drug in blood samples from a contralateral artery and in some cases also from the pulmonary artery and a contralateral vein were determined by gas chromatography. Peak plasma levels of lidocaine after cuff release (iv regional anesthesia) were 20 to 80 per cent lower than those found when the same dose was given directly into a vein over three minutes. Peak levels after cuff release were inversely proportional to tourniquet-application time; they also tended to be lower (by about 40 per cent) when the same dose was given in 0.5 per cent instead of 1.0 per cent solution. During the first few minutes after cuff release, distribution of lidocaine within the pulmonary system buffers the vital organs against high blood levels of the drug. Computer analysis of the data afforded estimates of the amount of drug remaining in the arm as a function of time after cuff release. Release of drug into the systemic circulation was found to be biphasic, an initial fast release of about 30 per cent of the dose, followed by a gradual washout of the remainder. Calculations indicated that even 30 minutes after cuff release about 50 per cent of the dose still remained in the arm. If anesthesia is to be re-established following cuff release this may be possible 10 to 30 minutes after initial release by injection of about half of the original dose following reinflation of the cuff.

Binding of anilide-type local anesthetics in human plasma. I. Relationships between binding, physicochemical properties, and anesthetic activity.

The rank-order of binding in human plasma for a series of anilide-type local anesthetics, determined by ultrafiltration and gas chromatography, was: bupivacaine > mepivacaine > lidocaine > the N-dimethyl analog of lidocaine. Drugs were added to plasma in citro, pH maintained at 7.4±0.1 and temperature, 26±2 C. Attempts to identify the plasma-binding factor proved unsuccessful. However, binding to plasma lipoproteins was not entirely ruled out owing to difficulty in dispersing corresponding Cohn fractions in buffer. Extensive plasma-binding of bupivacaine was confirmed by equilibrium-dialysis and gel-filtration experiments. Good correlation between extent of binding and distribution of the drugs between plasma and erythrocytes was found. The distribution between buffer and erythrocytes indicated that binding to erythrocytic components had the same rank-order as binding to plasma. Relationships between the binding properties, physicochemical characteristics and anesthetic activity are discussed. Durations of anesthesia, determined in isolated nerve preparations correlated with the binding characteristics.

Systemic Absorption of Mepivacaine in Commonly Used Regional Block Procedures

Arterial plasma level-versus-time profiles of mepivacaine were determined for 70 surgical patients undergoing epidural, caudal, intercostalnerve, brachial-plexus, and sciatic/femoral-nerve blocks. A single dose of 500 mg of mepivacaine HCl was used. The conditions studied were route of injection, concentration of drug solution (1 and 2 per cent), and presence or absence of epinephrine, 1:200,000, in the injected solution. Each condition tested resulted in significant changes in maximum plasma levels (Cpmax), time to occurrence of Cpmax (tmax), and areas under plasma level-versus-time curves (∫Cp.dt). The highest plasma concentrations (5–10 µg base/ml) were seen after intercostal-nerve blocks using plain solutions, but addition of epinephrine caused these to become comparable to peak levels after the other blocks (2–5 µg base/ml). For those blocks studied at both concentrations, use of the 2 per cent solution was always associated with the higher Cpmax and ∫Cp.dt values. Mean values of tmax using plain solutions ranged from 9 min (intercostal block) to 30 min (sciatic/femoral) and were increased two-to-threefold by the addition of epinephrine. No systemic toxic reactions were encountered, indicating the safety of the dosage used under the conditions of the study. Addition of epinephrine, 1:200,000, to mepivacaine solutions is recommended for the nerve blocks investigated, especially for intercostal-nerve block.

Binding of anilide-type local anesthetics in human plasma. II. Implications in vivo, with special reference to transplacental distribution.

Using an ultrafiltration technique, significantly less bupivacaine and lidocaine have been shown to bind, in citro, in human umbilical plasma than in corresponding maternal plasma. Competitive binding of the agents and the absence of significant binding in cerebrospinal fluid have also been demonstrated. Umbilical/maternal bupivacaine concentration ratios at delivery in blood samples from women receiving the drug for caudal or epidural block were significantly lower than corresponding ratios reported in the literature for lidocaine and mepivacaine (0.2–0.4 cs. 0.5–0.7). Differences between the plasma binding of bupivacaine, lidocaine and mepivacaine may explain, in part, observed differences between their placental passage.

Role of Epinephrine in Regional Block Anesthesia With Etidocaine: A Double-blind Study

Fifty healthy females scheduled for abdominal hysterectomy were administered 1 percent etidocaine (20 ml.) for lumbar epidural block anesthesia. Use of a plain solution or a solution containing 1:200,000 epinephrine was pre-selected randomly and administered in a double-blind fashion. Measurements of onset and duration of sensory anesthesia did not vary significantly between the two groups. Motor anesthesia did have a faster onset in patients receiving solutions containing epinephrine but the duration or quality of motor anesthesia did not vary significantly.An additional five patients were given bilateral intercostal nerve block anesthesia with plain solutions of 0.5 percent etidocaine (60 ml.) for clinical comparison with previously studied patients who received similar blocks with solutions containing epinephrine. No apparent clinically significant difference was noted.Plasma levels of etidocaine were measured for both techniques. Although the plain solutions produced higher blood levels than the epinephrine containing solutions for both techniques, they were not significantly different. The conclusion of this study is that the addition of 1:200,000 epinephrine to solutions of etidocaine for lumbar epidural and intercostal nerve block may provide some protection against systemic toxicity but has little if any benefit on the clinical effects of the drug.

CAUDAL AND EPIDURAL BLOCKS WITH BUPIVACAINE FOR CHILDBIRTH: REPORT OF 657 PARTURIENTS

Single-and intermittent-dose caudal or epidural blocks were administered to 657 parturients along with 0.25, 0.5 and 0.75% bupivacaine hydrochloride, a long-acting local anesthetic agent. Onset occurred in 4 to 10 minutes and maximum anesthesia in 15 to 30 minutes. Duration was 3½ to 7 hours. In an intermittent technic, the need for refill doses with 0.25%. solutions of bupivacaine hydrochloride occurred in only 34% of the patients and with 0.5% in 13%, as compared with 72% of the patients who received 1.0% mepivacaine hydrochloride. Two inadvertent intravenous injections of 100 and 120 mg of bupivacaine hydrochloride caused mild systemic toxic reactions but no untoward sequelae. One inadvertent subarachnoid injection of 110 mg resulted in total spinal block with uneventful recovery. No evidence of fetal depression occurred from bupivacaine hydrochloride.