Phillip O. Bridenbaugh

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.

Tourniquet pain: a volunteer study

The effect of inflation pressure (300 and 400 mm Hg) and method of exsanguination (gravity and Esmarch bandage) on the time of onset and the severity of tourniquet-induced pain in the lower extremity was investigated in 11 unmedicated adult volunteers. Each volunteer underwent eight experiments in a random order. A visual analog scale was used to assess pain and discomfort. Blood pressure and pulse rate were measured continuously. Experiments were concluded when the pain rose to a prefixed level. All experiments were performed using a standard orthopedic tourniquet (7 cm wide). Ten additional experiments were carried out using a Bier blockade tourniquet (5 cm wide). There were no differences in duration of tourniquet inflation between inflation pressures not between methods of exsanguination. There was a small and transient but nevertheless statistically significant increase in blood pressure caused by inflation and a significantly larger increase just before deflation. The 5-cm tourniquet experiments, otherwise identical to the 7-cm tourniquet experiments, were tolerated significantly longer due to a longer time of onset and less severe pain. The 5-cm tourniquet also needed significantly higher inflation pressures to fully occlude the arterial supply (240–450 mm Hg). In all instances, 260 mm Hg was adequate to fully occlude the arterial supply when a 7-cm tourniquet was used. Only half of the experiments were concluded due to intolerable pain at the site of the tourniquet. Most of the others were concluded due to pain mainly in the calf or pain throughout the leg. We conclude that the clinical syndrome of “tourniquet pain” consists of several components and is not due just to the pain and pressure under the tourniquet.

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.

Arterial and Venous Plasma Levels of Bupivacaine Following Epidural and Intercostal Nerve Blocks

Arterial and peripheral venous plasma levels of huptvacaine were determined in 30 patients following epidural anesthesia using 150 and 225 mg, as well as following intercostal nerve block with 400 mg. Arterial levels were consistently higher than levels in simultaneously sampled venous blood, and the highest levels occurred with bilateral intercostal nerve block. No evidence of systemic toxicity was observed. The results suggest that bupivacaine may have a wider margin of safety in man than is now stated.

Pharmacodynamics and pharmacokinetics of epidural ropivacaine in humans

The purpose of this study was to characterize the pharmacodynamics and pharmacokinetics of three concentrations of the new long-acting amide local anesthetic, ropivacaine, given epidurally in 15 physical status ASA I or II patients for elective, lower-extremity orthopedic procedures using a nonrandomized open-label design. Three groups of five patients each received either 0.57%, 0.75%, or 1.0% ropivacaine. Upper and lower levels of analgesia to pinprick were determined at frequent intervals until normal sensation had completely returned. Motor blockade ums assessed by use of a modified Bromage scale after each determination of level of analgesia. Fifteen venous blood samples were collected over 12 h after ropivacaine injection. Pharmacokinetic parameters were derived using serum concentration-time data. No significant differences were found between the three groups in terms of onset or recovery of motor and sensory blockade. Median maximum thoracic levels of analgesia achieved were 8, 6, and 5 for the 0.5%, 0.75%, and 1.0% groups, respectively, and occurred at 29 ± 11, 37 ± 23, and 30 ± 9 min. Respective times to two-segment regression were 2.8 ± 1.0, 3.0 ± 0.5, and 2.9 ± 0.6 h. Total durations of sensory blockade were 5.4 ± 0.7, 6.5 ± 0.4, and 6.8 ± 0.8 h, respectively. No statistically significant differences were noted between the three groups in term of clearance (CL). The mean residence time (MRT) was significantly longer for the 0.5% group when compared with the 1% group. The peak concentration (Cmax) for the 0.5% group was found to be significantly lower than for either the 0.75% or 1% groups. Mean (± SD) values of the pharmacokinetic parmeters for the 0.5%, 0.75%, and 1.0% groups were, respectively, MRT: 9.9 ± 3.6, 7.5 ± 2.6, and 4.5 ± 0.8 h; CL: 0.35 ± 0.21, 0.34 ± 0.24, and 0.52 ± 0.11 L·kg−1·h−1; Cmax: 0.53 ± 0.19, 1.07 ± 0.57, and 1.53 ± 0.60 μg/mL; and tmax: 1.6 ± 1.4, 0.66 ± 0.19, and 0.65 ± 0.16 h. Pharmacokinetic and pharmacodynamic characteristics of epidural ropivacaine are similar to those of epidural bupivacaine in humans.

Neural Blockade and Pharmacokinetics following Subarachnoid Lidocaine in the Rhesus Monkey I. Effects of Epinephrine

A sensitive and reliable animal model for the objective physiologic and pharmacokinetic evaluation of spinal anesthesia has been developed. Using this model, spinal anesthesia using lidocaine (30 mg) in 7.5% dextrose with and without epinephrine was compared. Epinephrine did not alter the degree or duration of time to achieve maximum motor block. However, epinephrine did significantly increase the time for complete motor recovery. A significantly higher dermatome level of sensory block was achieved in the epinephrine-containing solutions, as well as a significantly longer time for complete recovery. This reflects a latent effect of epinephrine, as the time for two-segment regression was independent of epinephrine. Pharmacokinetic analysis showed no effect of epinephrine on absorption and elimination constants. The maximum plasma concentration and time to reach maximum plasma concentration were equal with and without epinephrine.

The Influence of Lactic Acid on the Serum Protein Binding of Bupivacaine: Species Differences

: Various animal models have been used for studies of bupivacaine cardiovascular toxicity. These studies are difficult to relate to the clinical situation, since the disposition of bupivacaine in the various species is unknown. The serum protein binding of bupivacaine, therefore, was determined in human, sheep, monkey, dog, and rat at physiologic pH using ultrafiltration. Since a mixed acidosis results during a systemic toxicity reaction to bupivacaine, the influences of an acidic pH, resulting from the addition of lactic acid, also was examined. All sera exhibited two classes of binding sites, a high-affinity, low-capacity class (class 1) and a low-affinity, high-capacity class (class 2). When compared to human serum at physiologic pH, a significantly higher (P less than 0.05) affinity constant for the class 1 sites was observed for all species studied, with the exception of the rat. All species studied exhibited a significantly lower (P less than 0.05) capacity for the class 1 sites. The binding parameters of the class 2 sites displayed no significant difference. An acid pH resulted in a decrease in bupivacaine protein binding over the entire concentration range studied for all species, with the exception of the monkey. Monkey serum exhibited no change in bupivacaine binding with a decrease in pH. Since protein binding explains only a portion of the total disposition of bupivacaine, further delineation of each animal model under both acidotic and physiologic conditions needs to be accomplished before the animal studies currently under investigation can be extrapolated to the clinical situation.

Comparison of Neural Blockade and Pharmacokinetics after Subarachnoid Lidocaine in the Rhesus Monkey. Ii: Effects of Volume, Osmolality, and Baricity

The effects of volume, osmolality, and baricity on lidocaine spinal anesthesia in the rhesus monkey were studied. Changes in neural blockade, physical properties of cerebrospinal fluid, and arterial pharmacokinetics associated with variations in injectate composition were assessed. Wide ranges of volume, baricity, and osmolality were studied using 1, 2, and 5% lidocaine prepared in either sterile water or 7.5% dextrose. Minimal changes in neural blockade were found in the ranges of osmolality and baricity studied, although 5% lidocaine in sterile water resulted in significantly shorter complete recovery times for both sensory and motor block when compared to other solutions. Samples of cerebrospinal fluid obtained after injection of lidocaine showed increases or decreases in specific gravity and osmolality depending on the physical properties of the solution injected. No differences in elimination phase pharmacokinetics were found with any of the lidocaine solutions. Rates of systemic absorption increased with decreasing osmolality. Osmotic potentiation of lidocaine spinal anesthesia could not be demonstrated.

Hypotension in spinal anesthesia: a comparison of isobaric tetracaine with epinephrine and isobaric bupivacaine without epinephrine

Two isobaric spinal anesthetic solutions (bupivacaine 0.5%/20 mg without epinephrine and tetracaine 0.5%/15 ing with 0.2 mg epinephrine) were compared in a double-blind study of 60 patients. Patients were injected while in the lateral recumbent position and were immediately turned supine and horizontal. Up to 30 min after injection, no differences were found between the groups regarding segmental level of analgesia, changes in heart rate, and onset to or maximum decrease in mean arterial pressure (MAP). No correlation was found between maximum decrease in MAP and level of analgesia. At time of maximum decrease in MAP (tetracaine group − 16.7 ± 12.8% (mean + SEM), bupivacaine group − 19 A + 14.8%) the level of analgesia was significantly higher in the tetracaine group (T5–6) than in the bupivacaine group (T7–8). Hypotension occurred in five patients in the bupivacaine group and in six in the tetracaine group. Two patients in the tetracaine group (but none in the bupivacaine group) had bradycardia. Hypotension together with bradycardia was observed in one patient in the tetracaine group but in no patient in the bupivacaine group. Two patients in each group developed postlumbar puncture headache. The authors conclude that the choice of local anesthetic agent, by itself, is not the sole cause of hypotension seen with spinal anesthesia.

Pharmacokinetics and Neural Blockade after Subarachnoid Lidocaine in the Rhesus Monkey III. Effects of Phenylephrine

Using a rhesus monkey model, lidocaine (30 mg) in 7.5% dextrose was compared with lidocaine (30 mg) in 7.5% dextrose containing 1.5 mg of phenylephrine (Neosynephrine). Phenylephrine increased both duration of maximum motor block and time for complete motor recovery. A significantly higher sensory dermatome level and significantly longer time for complete sensory recovery was found when the lidocaine solution contained phenylephrine. Time for two-segment regression of sensory blockade was unaffected by phenylephrine. The slope of the regression phase for motor block was parallel for both treatments, suggesting differences in neural blockade were caused by a more profound initial block when phenylephrine was added. Pharmacokinetic analysis revealed identical absorption and elimination constants. Maximum plasma concentrations of lidocaine and time to reach maximum plasma concentrations were identical with and without phenylephrine. The systemic absorption (fraction of drug absorbed from the subarachnoid space) was complete with and without phenylephrine. No lag times for systemic absorption were found for either treatment. Our data demonstrate that there are no clinically significant differences between phenylephrine and epinephrine when added to lidocaine solutions for spinal anesthesia.