Maternal and fetal catecholamines and uterine incision-to-delivery interval during elective cesarean.

The fetal sympathoadrenal system is activated during periods of intrauterine stress such as inadequate uterine perfusion. During cesarean, the period of interruption of utero-placental blood flow is extended as the time interval from uterine incision to delivery increases. An increasing uterine incision-to-delivery interval with spinal or general anesthesia has been associated with a poorer neonatal outcome. This association has not been demonstrated previously in patients undergoing cesarean delivery under epidural anesthesia. We investigated the correlation between prolonged uterine incision-to-delivery intervals, fetal catecholamine concentrations, and fetal blood gas values at delivery in 25 parturients undergoing cesarean under epidural anesthesia and in 28 under spinal anesthesia. Infants delivered after prolonged uterine incision-to-delivery intervals had significantly lower pH values in both the epidural and spinal groups. With longer uterine incision-to-delivery intervals, umbilical arterial norepinephrine concentrations were increased significantly. Umbilical arterial pH values were significantly lower in infants with higher umbilical arterial catecholamine concentrations. The importance of minimizing the uterine incision-to-delivery interval, regardless of the type of anesthetic selected, is demonstrated.

High-performance liquid chromatographic analysis of the 2-chloroprocaine metabolite, diethylaminoethanol, in blood and serum.

BACKGROUND AND OBJECTIVES: 2-Chloroprocaine is rapidly metabolized in the blood to yield 2-chloro-para-aminobenzoic acid (an inactive metabolite) and diethylaminoethanol (DEAE). DEAE possesses local anesthetic activity. The only reported assay for DEAE is a colorimetric method. METHODS: Clinical samples of whole blood and serum were obtained from patients receiving stepped intravenous infusions of 3% 2-chloroprocaine. A high pH-dependent liquid-liquid extraction step with diethyl ether was used to eliminate interfering peaks in high-pressure liquid chromatography (HPLC) analysis. Separation and quantitation were performed using HPLC on a polymeric-reversed phase column with a mobile phase consisting of 10% or 20% acetonitrile (for whole blood or serum analysis, respectively) in 50 mm aqueous sodium phosphate buffer, pH = 11.50. The elution order of DEAE and its analogues was tested to interpret the HPLC separation mechanism. RESULTS: Extraction recovery of DEAE from whole blood was 67 +/- 13.5%, from serum, 71 +/- 12.2%, and from water, 75 +/- 2.9%. The high pH value of the mobile phase resulted in sharp, well-resolved peaks with run times of approximately 8 minutes using 20% acetonitrile. The lower limit of detection was 5 ng/mL of DEAE from a 1-mL sample. The elution order of DEAE and its analogues indicated that separation was based on the hydrophobicity of the analytes rather than polar group interactions occurring with silica-based stationary phase. CONCLUSIONS: A new, simple and rapid HPLC method for extraction and measurement of DEAE in whole blood or serum samples is reported here.

The tumescent technique: the effect of high tissue pressure and dilute epinephrine on absorption of lidocaine.

Injection of lidocaine into the subcutaneous tissues by the tumescent technique results in a delayed absorption of the local anesthetic and has allowed clinicians to exceed the maximum recommended dose of lidocaine without reported complications. However, little knowledge exists about the mechanisms that permit such high doses of lidocaine to be used safely with this technique. The presence of low concentration epinephrine and the increased tissue pressure resulting from the tumescent injection have both been implicated as important factors, but neither has been studied in patients whose results were not altered by the variability of the suction procedure. The purpose of this work was to determine the effect of tissue pressure during tumescent injection and presence of low concentration epinephrine on the absorption of lidocaine from subcutaneous tissues in human volunteers. Twenty healthy female human volunteers were randomized into four study groups. After body fat measurements, all subjects received an injection of 7 mg/kg of lidocaine into the subcutaneous tissues of both lateral thighs. The injected solution consisted of 0.1% lidocaine and 12.5 meq/liter sodium bicarbonate in normal saline with or without 1:1,000,000 epinephrine. Tissue pressure was recorded during injection using a specially designed double-barreled needle. The time required for injection was also recorded. Subjects in group 1 received lidocaine with epinephrine injected by a high-pressure technique. Group 2 subjects received lidocaine with epinephrine injected by a low-pressure technique. Group 3 subjects received lidocaine without epinephrine injected under high pressure. Group 4 subjects received lidocaine without epinephrine injected under low pressure. Following injection, sequential blood samples were drawn over a 14-hour period, and plasma lidocaine concentrations were determined by gas chromatography. No suction lipectomy was performed. Maximum tissue pressure during injection was 339 +/- 63 mmHg and 27 +/- 9 mmHg using high- and low-pressure techniques, respectively. Addition of 1:1,000,000 epinephrine, regardless of the pressure of injected fluid, significantly delayed the time to peak plasma concentration by over 7 hours. There was no significant difference in the peak plasma concentration of lidocaine among the four groups. Peak plasma concentrations greater than 1 mcg/ml were seen in 11 subjects. Epinephrine (1:1,000,000) significantly delays the absorption of lidocaine administered by the tumescent technique. High pressure generated in the subcutaneous tissues during injection of the solution does not affect lidocaine absorption. The delay in absorption may allow time for some lidocaine to be removed from the tissues by suction lipectomy. In addition, the slow rise to peak lidocaine concentration in the epinephrine groups may allow the development of systemic tolerance to high lidocaine plasma levels.

Efficacy and long term effects of antenatal prophylaxis with anti-D immunoglobulin.

OBJECTIVE: To measure the safety and efficacy of antenatal treatment with anti-D immunoglobulin. DESIGN: Open study with historical controls. SETTING: Multicentre study in 17 hospitals in West Yorkshire. PATIENTS: 1238 Rh negative women who delivered Rh positive infants after 34 weeks in their first pregnancy in 1980-1 (group 1) and 2000 similar primigravidas from 1978-9 (group 2). Obstetric data were collected for 616 women in group 1 who had a subsequent pregnancy, 536 similar women in group 2, and 410 Rh positive but otherwise similar primigravidas who delivered in the same hospitals in 1978-81 (group C). INTERVENTIONS: Anti-D immunoglobulin 100 micrograms intramuscularly was given at 28 and 34 weeks to the mothers in their first pregnancy who delivered in 1980-1. END POINTS: Detection of anti-D antibody in the first or any subsequent pregnancy in groups 1 and 2. For all three groups having subsequent pregnancies gestation at delivery, birth weight, fetal survival at one month, pre-eclampsia defined as blood pressure greater than 140/90 on two occasions more than 12 hours apart, and proteinuria greater than 0.25 milligram. MEASUREMENTS AND MAIN RESULTS: Antenatal immunisation to Rh(D) occurred in six mothers in group 1 and 32 group 2. Most immunisations occurred in the first or second pregnancy. The rates of abortion, gestation at delivery, birth weight, and fetal survival were not significantly different among the three groups. The incidence of pre-eclampsia was lower in mothers given antenatal anti-D immunoglobulin, but the difference was not significant. CONCLUSIONS: Antenatal prophylaxis with anti-D immunoglobulin is effective, and the effect of giving it in the first pregnancy persists into at least the second pregnancy. It seems to be safe for the fetus in the index and subsequent pregnancies.

Haemodynamic changes following buprenorphine and morphine.

Twenty-five women were investigated on the day after lower abdominal surgery in a single-blind non-cross-over trial to assess and compare the haemodynamic effects of intravenous injections of buprenorphine 0.3 mg and morphine 7.5 mg. Arterial blood pressure was measured by sphygmomanometry and cardiac output by thoracic impedance cardiography. Arterial blood pressure was significantly reduced following both drugs (p < 0.05), although the mean decrease in systolic arterial pressure was less than 8 mmHg. However, in one patient in each group the decrease was more than 20 mmHg. Cardiac output decreased but the mean reduction was less than 5%. The greatest individual decreases were 21% after buprenorphine and 30% after morphine. Myocardial contractility, assessed by systolic time indices, did not appear to change. There were no consistent differences in the haemodynamic effects of the two drugs.

Fundamental properties of local anesthetics. I. The dependence of lidocaine's ionization and octanol:buffer partitioning on solvent and temperature.

The protonation equilibrium and hydrophobic character of lidocaine were characterized by its pKa and the octanol:buffer partition coefficients of the charged (P+) and neutral (Po) drug species. These measurements were accomplished by ultraviolet spectrophotometry of pure lidocaine HCl solutions at different temperatures, ionic strengths, and buffer concentrations. Corroboration of the pKa determination by the potentiometric method and of the partition coefficients by gas chromatography validated the general application of the spectrophotometric technique. The pKa increased with decreasing temperature (7.61 +/- 0.06 at 36 degrees C; 7.94 +/- 0.04 at 26 degrees C, in water; mean +/- SD), increasing ionic strength (8.06 +/- 0.02 at 26 degrees C in 0.165 M NaCl) and increasing buffer capacity (8.28 +/- 0.06 at 25 degrees C in 0.15 M NaCl + 20 mM buffer). Octanol:buffer partition coefficients for both the protonated and the neutral species (expressed as mole fractions) increased upon warning: 0.55 +/- 0.04 and 2666 +/- 202, respectively, at 25 degrees C, and 0.75 +/- 0.09 and 3210 +/- 272, respectively, at 36 degrees C. Ionic strength and buffer concentration had no significant effect on either P value. The increase in pKa at lower temperatures coupled with the decreased partition coefficients resulted in a nearly constant concentration of the protonated species in octanol as the system was cooled, whereas the concentration of the neutral species fell by more than 80%. This finding may explain the large increase in the impulse blocking potency of lidocaine observed upon nerve cooling, if the protonated anesthetic species is the more active form of the drug competing with the neutral species for a common binding site.

Comparative pharmacokinetics of bupivacaine and ropivacaine, a new amide local anesthetic.

The pharmacokinetics of ropivacaine, a new amide local anesthetic, and bupivacaine were determined in dogs after IV and epidural administration. After 15-minute IV infusions of 3.0 mg/kg ropivacaine (n = 6) and 3.4 mg/kg bupivacaine (n = 4), the maximum arterial concentrations (Cmax) of ropivacaine averaged 2.41 +/- 0.52 micrograms/ml compared with 3.35 +/- 0.16 micrograms/ml of bupivacaine. The elimination half life (t 1/2 beta) of ropivacaine (25.9 +/- 1.7 min) was significantly shorter than for bupivacaine (39.1 +/- 13.3 min) after IV infusion. This was reflected by mean clearance values (Cl) for ropivacaine of 41.1 +/- 8.2 ml.min-1.kg-1 compared with 32.3 +/- 4.8 ml.min-1.kg-1 for bupivacaine, although the difference was not statistically significant. After epidural injections (ropivacaine n = 6; bupivacaine n = 5), a dose-related increase in Cmax was observed with both drugs. Although Cmax tended to be higher for ropivacaine, a significant difference was only attained when comparing Cmax after administration of 0.25% plain solutions of both agents. The addition of epinephrine did not consistently decrease the Cmax of either agent. The apparent t 1/2 beta of both agents was significantly longer after epidural administration than after IV infusion. No differences existed between t 1/2 beta values for ropivacaine and bupivacaine after epidural administration. Total body clearance of both agents tended to be lower after epidural administration, particularly when epinephrine-containing solutions were employed. Little difference existed between the two drugs when equivalent solutions were administered.(ABSTRACT TRUNCATED AT 250 WORDS)

Alterations in the pharmacokinetic properties of amide local anaesthetics following local anaesthetic induced convulsions.

The comparative pharmacokinetic properties of lidocaine, bupivacaine, etidocaine and mepivacaine were investigated in convulsing and non-convulsing dogs. The same dose of a given local anaesthetic was administered as either a 30-s intravenous (IV) bolus to produce convulsions or as a 15-min IV infusion producing no convulsions. Derived pharmacokinetic data were found to be different in convulsing and non-convulsing animals. Total body clearance was found to be significantly reduced for lidocaine (29%, P less than 0.05), bupivacaine (31%, P less than 0.05), etidocaine (60%, P less than 0.01) and mepivacaine (68%, P less than 0.01) in convulsing animals. Increases in elimination half-life only achieved statistical significance in mepivacaine-treated animals (non-convulsing 45.2 min, convulsing 105.4 min, P less than 0.01). Overall, the most profound effects of convulsions on pharmacokinetic data were seen with mepivacaine. Convulsions were associated with increases in heart rate ranging from 117% (lidocaine, P less than 0.05) to 129% (mepivacaine, P less than 0.05), increases in cardiac output ranging from 78% (mepivacaine) to 232% (bupivacaine, P less than 0.05) and increases in mean arterial pressure ranging from 45% (lidocaine, P less than 0.05) to 80% (bupivacaine, P less than 0.05). The results suggest that when local anaesthetic-induced seizures occur in man, it cannot be assumed that these drugs will be distributed and eliminated as predicted by intravenous infusion of non-toxic doses.

Comparative systemic toxicity of convulsant and supraconvulsant doses of intravenous ropivacaine, bupivacaine, and lidocaine in the conscious dog.

This study evaluated the systemic toxicity, arrhythmogenicity, and mode of death of convulsant and supraconvulsant doses of lidocaine, bupivacaine, and ropivacaine. Experiments in awake dogs were designed to mimic the clinical situation of an accidental intravenous (IV) injection of local anesthetics. On the first experimental day, lidocaine (8 mg.kg-1.min-1), bupivacaine (2 mg.kg-1.min-1), and ropivacaine (2 mg.kg-1.min-1) were infused intravenously until seizures occurred (n = 6 for each group). The average dose and arterial plasma concentration at seizure onset was 20.8 +/- 4.0 mg/kg and 47.2 +/- 5.4 micrograms/mL for lidocaine, 4.31 +/- 0.36 mg/kg and 18.0 +/- 2.7 micrograms/mL for bupivacaine, and 4.88 +/- 0.47 mg/kg and 11.4 +/- 0.9 micrograms/mL for ropivacaine. The margin of safety between the convulsive and lethal doses was determined by administering two times the convulsive dose 24 h later. Two dogs given lidocaine died because of progressive hypotension, respiratory arrest, and finally cardiovascular collapse with an average peak plasma concentration (Cmax) of 469 micrograms/mL. No ventricular arrhythmias were observed in this group. Ventricular arrhythmias occurred in five of six dogs receiving bupivacaine. Four animals died because of hypotension, respiratory arrest, and cardiovascular collapse. One additional animal died because of ventricular fibrillation. The Cmax for bupivacaine was 70.1 +/- 14.6 micrograms/mL in nonsurvivors. In the ropivacaine group one animal died because of hypotension, respiratory arrest, and cardiovascular collapse (Cmax = 72.4 micrograms/mL). A surviving dog had transient premature ventricular contractions. Twenty-four hours later three times the convulsive dose was administered to the survivors.(ABSTRACT TRUNCATED AT 250 WORDS)

Phenylephrine in treating maternal hypotension due to spinal anaesthesia for caesarean delivery: effects on neonatal catecholamine concentrations, acid base status and Apgar scores.

Maternal and neonatal catecholamine concentrations, following the use of either phenylephrine or ephedrine to treat a drop in maternal blood pressure after spinal anaesthesia for caesarean delivery, were compared. Patients were randomly assigned to one of two groups: Group 1 patients (n = 20) were treated with ephedrine given as 5 mg intravenous bolus injections; Group 2 patients (n = 20) were treated with phenylephrine given as 40 micrograms intravenous bolus injections, for decreases in maternal systolic blood pressure to maintain maternal systolic blood pressure above 100 mmHg. Maternal vein (MV), umbilical vein (UV), and umbilical artery (UA) blood samples were taken at the time of delivery. Samples were analyzed for catecholamine concentrations and blood gas values. Noradrenaline concentrations in UA, UV and MV (at delivery) samples were significantly higher in group 1 compared to group 2; they were 6858 +/- 3689 vs 1674 +/- 944 pg.ml-1 (P < 0.0001), 1265 +/- 758 vs 395 +/- 470 pg.ml-1 (P < 0.001) and 239 +/- 165 vs 103 +/- 93 pg.ml-1 (P < 0.01), respectively. Comparing blood gas values between groups 1 and 2, statistically significant differences were observed in UA pH (7.28 +/- 0.01 and 7.32 +/- 0.01 pH units, P = 0.01), UA pCO2 (7.32 +/- 0.24 and 6.68 +/- 0.21 kPa, P = 0.03), UA base excess (2.2 +/- 0.4 and 0.9 +/- 0.4 mmol.1-1, P = 0.04) and UV base excess (2.0 +/- 0.3 and 0.7 +/- 0.3 mmol.1-1, P = 0.004). No significant differences in maternal characteristics, acid base values, incidence of nausea and vomiting, and Apgar scores were observed between groups. Phenylephrine appears to be as safe and effective as ephedrine in treatment of drop in blood pressure in healthy non-labouring parturients undergoing caesarean delivery. The use of phenylephrine was also associated with significantly lower noradrenaline concentrations in both mother and neonate.

The effects of epinephrine on the anesthetic and hemodynamic properties of ropivacaine and bupivacaine after epidural administration in the dog.

Ropivacaine is a new local anesthetic that is chemically related to mepivacaine and bupivacaine. Previous laboratory studies have demonstrated that ropivacaine possesses an anesthetic profile similar to that of bupivacaine and has less arrhythmogenic potential. The current study was initiated to compare the hemodynamic and anesthetic effects of epidurally administered 0.75% bupivacaine and 1% ropivacaine, with and without epinephrine (1:200,000), in the dog. Two groups of six dogs were randomly assigned to the ropivacaine or bupivacaine treatment groups. Administration of 0.75% bupivacaine and 1% ropivacaine with and without epinephrine was randomized. Volumes of 3 ml of each solution were injected in a blinded manner via an indwelling lumbar epidural catheter with 48 hours between injections. No statistically significant difference existed between the four treatment groups with regard to onset and duration of sensory or motor block. Hemodynamic changes were, for the most part, not different between drugs. Significant decreases were seen in mean arterial blood pressure and cardiac output in all test groups. No difference in the degree of cardiovascular depression was observed. The addition of epinephrine did not alter onset or duration of sensory or motor block in this animal model. Epinephrine reduced the average anesthetic blood concentration observed in both treatment groups at the various time intervals, but not the time to achieve the mean maximum blood level. No residual adverse effects were observed in any animal.

Bupivacaine with and without epinephrine for intercostal nerve block.

In a double-blinded study, 15 American Society of Anesthesiologists class I or II patients, following lateral thoracotomy with general anesthesia, were randomized into two groups for intercostal nerve block with either bupivacaine, 0.5%, and epinephrine, 1:200,000, or plain bupivacaine, 0.5%. Blood concentrations of bupivacaine, epinephrine, and norepinephrine were serially measured. Blood pressure, heart rate, respiratory rate, temperature, and electrocardiogram were monitored. Peak blood bupivacaine concentrations were significantly lower in patients receiving bupivacaine with epinephrine. Peak epinephrine concentrations were significantly greater in patients receiving bupivacaine with epinephrine, but still within a safe range. No significant differences were seen in heart rate, blood pressure, respiratory rate, or temperature between the two groups, and/no dysrhythmias occurred. Peak norepinephrine concentrations were not significantly different between the two groups. The potential risk of toxic bupivacaine blood concentrations associated with intercostal nerve blocks can be reduced by the addition of epinephrine at a concentration of 1:200,000.

Reversal of bupivacaine epidural anesthesia by intermittent epidural injections of crystalloid solutions.

This study was designed to determine whether epidural motor blockade could be reversed by postoperative injections of crystalloid solutions via the epidural catheter. Twenty-seven patients (ASA physical status I, nonlaboring) had epidural anesthesia with 0.75% bupivacaine for elective cesarean delivery. Postoperatively, patients were randomized to receive three 15-mL injections (over 30 min) of crystalloid solutions (normal saline or Ringer's lactate) or no treatment (control) via the epidural catheter. Degree of motor and sensory blockade was evaluated with an investigator blinded to treatment group. Rate of resolution of sensory blockade was not different among groups. However, time for resolution of motor blockade was more than twice as long in the control group than in either treatment group (control = 178 +/- 70 min vs Ringer's lactate = 84 +/- 44 min, normal saline = 70 +/- 38 min, P = 0.001). The data suggest that unwanted motor blockade due to epidural anesthesia can be reversed by epidural injections of crystalloid solutions.

A new local anesthetic, ropivacaine. Its epidural effects in humans.

The current study was initiated to evaluate the epidural anesthetic properties of 0.5%, 0.75%, and 1.0% ropivacaine, a new local anesthetic agent structurally similar to bupivacaine. Fifteen patients scheduled for lower limb orthopedic surgery were enrolled in the study. As the concentration of ropivacaine increased from 0.5% to 1.0%, the time to onset of sensory anesthesia decreased from 6.4 +/- 1.7 (SD) min to 2.4 +/- 0.6 min and the maximum level of sensory anesthesia increased from T6 to T1. These changes were not statistically significant. Time to regression of anesthesia to T12 increased from 255 +/- 73 min with the 0.5% solution to 356 +/- 75 min with 1.0% ropivacaine (P less than 0.05). The degree of motor blockade using the Bromage scale varied with the concentration. When the 0.5% concentration was used, only one patient (20%) had greater than 1+ motor blockade. However, all of the patients receiving the 0.75% or 1.0% solution had at least 2+ motor blockade. Sensory anesthesia was adequate for surgery in 14 of the 15 patients. The mean peak plasma concentration of ropivacaine (Cmax) increased from 0.65 +/- 0.15 micrograms/mL with the 100-mg dose to 1.30 +/- 0.43 microgram/mL with the 200-mg dose. No adverse effects were noted in any patient in the study. These initial studies in humans suggest that ropivacaine provides satisfactory sensory anesthesia with minimal motor blockade at a concentration of 0.5%. An increase in concentration resulted in a more profound motor blockade. The Cmax of ropivacaine in this study was below levels associated with toxicity in animal studies.

Fundamental properties of local anesthetics. II. Measured octanol:buffer partition coefficients and pKa values of clinically used drugs.

Because local anesthetic molecules interact with ion channel proteins embedded in membranes to effect impulse blockade, and because their clinical potency often depends on both vascular absorption and distribution into the tissue surrounding the site of deposition, the ability to partition into these various compartments is an important determinant of local anesthetic action. Therefore, the hydrophobic nature of local anesthetics used clinically was characterized by the octanol:buffer partition coefficients of their charged (P+) and neutral (Po) species. This was accomplished by previously described optical methods in which direct spectrophotometric measurement of both the pH-dependent distribution coefficient (Q) and of the ionization permit calculation of the pKa and partition coefficients. The rates of alkaline hydrolysis of ester-linked molecules also were measured to assess potential interference of such hydrolysis with the physicochemical assays. Results indicate that the hydrophobicity of a local anesthetic is increased by manipulation of the molecular structure at three sites: (a) the aromatic ring; (b) the intermediate linking group; and (c) the tertiary amine. Po for the agents studied was 10(3)-10(5) times greater than P+. Although there is no systematic relationship between hydrophobicity and pKa, the latter is greater with ester-linked (pKa = 8.59-9.30) than with amide-linked (pKa = 7.92-8.21) local anesthetics. All of the charged species, with the exception of bupivacaine, selectively partition into the aqueous environment (P+ less than 1.0). The temperature dependence of partitioning of the local anesthetics, measured at 25 and 36 degrees C, indicates an entropy-driven hydrophobic uptake. Solutions buffered with bicarbonate and including 5% CO2 showed the same local anesthetic partitioning as that of CO2-free solutions, suggesting that potentiation of impulse blockade by CO2 is not due to increased membrane uptake. Correlations of physicochemical properties of local anesthetics with potencies on isolated nerve confirm that the more potent local anesthetics have greater octanol:buffer partition coefficients, and that the ester-linked local anesthetics are more potent than their amide-linked counterparts having the same hydrophobicities. The correlations of structure with potency also suggest that the extracellular protonated species may contribute to impulse blockade.

Pregnancy does not alter lidocaine toxicity.

Pregnant sheep are more vulnerable to the toxic effects of bupivacaine, a potent local anesthetic, than are nonpregnant sheep. In contrast, ovine pregnancy does not enhance the toxicity of mepivacaine, a drug with properties similar to lidocaine. We studied the central nervous and cardiovascular toxicity of lidocaine in pregnant sheep receiving a continuous intravenous drug infusion at the rate of 2 mg/kg/min and compared our results with data previously obtained in nonpregnant ewes. In all animals, toxic manifestations occurred in the following sequence: convulsions, hypotension, respiratory arrest, and circulatory collapse. The doses of lidocaine required to produce these symptoms in pregnant and nonpregnant ewes were similar. Convulsions occurred at 5.9 +/- 0.6 mg/kg (mean +/- SE) in the pregnant ewe and 5.8 +/- 1.8 mg/kg in the nonpregnant ewe, whereas circulatory collapse occurred at 40.7 +/- 2.6 and 36.7 +/- 3.3 mg/kg in the pregnant and nonpregnant animals, respectively. Lidocaine plasma concentrations associated with the onset of convulsions in both pregnant and nonpregnant ewes were almost identical (12.1 +/- 0.7 and 11.7 +/- 2.0 micrograms/ml, respectively). At circulatory collapse, these concentrations were 35.1 +/- 3.2 and 41.2 +/- 6.7 micrograms/ml, respectively. It appears that pregnancy does not enhance the toxic effects of lidocaine. These findings are similar to those for mepivacaine but not for bupivacaine, and may be related in part to differences in the way pregnancy affects serum protein binding of these drugs.

Measurements of protein binding of lidocaine throughout pregnancy.

Pregnancy-related anatomic and physiologic changes result in altered pharmacologic and toxicologic responses to local anesthetics. Reductions in serum protein binding have been implicated in enhanced toxic effects. Previous studies have demonstrated these reductions in protein binding only in the term parturient. The present study defines the pattern of protein binding changes of lidocaine throughout gestation. Venous samples were obtained from pregnant patients of varying gestational age, as well as from nonpregnant control patients. The percent free drug at a fixed concentration (2 micrograms/mL) was determined for each sample using an ultrafiltration technique. The free concentration of lidocaine increased significantly throughout gestation, reflecting a corresponding decrease in protein binding. However, these changes were small compared to those in the nonparturient, which suggests that toxicity to lidocaine should not vary during pregnancy.

Bupivacaine for intercostal nerve blocks in children: blood concentrations and pharmacokinetics.

A pharmacokinetic evaluation of bupivacaine was carried out after intercostal nerve blocks performed on 28 occasions in 27 children varying in age from 3 months to 16 yr. Bupivacaine HCl, 0.5%, with epinephrine 1:200,000 was employed. Doses of 2 mg/kg, 3 mg/kg, and 4 mg/kg resulted in peak whole blood arterial bupivacaine (base) concentrations (mean +/- SD) of 0.77 +/- 0.25 microgram/ml, 1.37 +/- 0.23 microgram/ml, and 1.87 +/- 0.53 microgram/ml, respectively. Calculated pharmacokinetic parameters (mean +/- SD) were the following: apparent volume of distribution (VD beta), 2.8 +/- 0.8 L/kg; steady-state volume of distribution (VDss), 2.7 +/- 0.7 L/kg; elimination half-life (t1/2 beta), 147 +/- 80 min; and total body clearance (Cl), 16.0 +/- 7.4 ml X min-1 X kg-1, or 382 +/- 201 ml X min-1 X m-2. Compared with data reported for adult patients, our data indicate that the volume of distribution is greater and clearance is more rapid in children than in adults. The absorption of local anesthetic from the intercostal space appears to be more rapid in children than adults. In an additional group of 11 children, the relationship of the bupivacaine blood:plasma concentration ratio (lambda) to hematocrit was investigated. Hematocrit in this group ranged from 30 to 59, and lambda varied from 0.47 to 0.82. There was a significant relationship between lambda and hematocrit defined by the equation lambda = -0.0079 Hct + 1.028 (r = 0.72, P less than 0.05). Reporting bupivacaine concentration in terms of plasma concentration may introduce an artifact that is dependent on the hematocrit, and we therefore suggest that whole blood concentration values be reported by investigators in the future.

Chronotropic and inotropic effects of ropivacaine, bupivacaine, and lidocaine in the spontaneously beating and electrically paced isolated, perfused rabbit heart.

BACKGROUND AND OBJECTIVES: The purpose of this study was to compare the inotropic and chronotropic effects of ropivacaine, bupivacaine, and lidocaine in an isolated, spontaneously beating rabbit heart preparation. The ability to electrically pace the heart in the presence of local anesthetic also was examined. METHODS: Hearts were perfused with Krebs-Henseleit solution, then exposed to ropivacaine or bupivacaine at 1, 6, or 13 micrograms/ml or lidocaine at 6, 20, or 40 micrograms/ml (n = 6, each concentration). Left ventricular pressure, left ventricular dP/dt (rate of change derivation from analog waveform of the left ventricular pressure wave), pulmonary artery flow, oxygen consumption, and electrocardiogram were monitored throughout the studies. Drug exposure was for 30 minutes or until a 75% decrease in left ventricular pressure occurred. RESULTS: All preparations were exposed to 1 microgram/ml bupivacaine or ropivacaine and 6 micrograms/ml lidocaine for the full 30 minutes. At the intermediate concentrations, only one of six bupivacaine preparations (6 micrograms/ml) survived the full 30-minute exposure period, compared to six of six preparations for both ropivacaine (6 micrograms/ml) and lidocaine (20 micrograms/ml; p less than 0.05). Similar results were found with exposure to the highest concentrations of these local anesthetics. No electrocardiogram changes were observed with any of the three lidocaine concentrations or with the lowest ropivacaine and bupivacaine concentration. At the intermediate concentration, atrioventricular conduction changes were seen with bupivacaine in five of six preparations, compared to one of six ropivacaine preparations (p less than 0.05). With the high concentration, ventricular tachycardia occurred in four of six bupivacaine preparations, compared to zero of six with ropivacaine (p less than 0.05). In general, left ventricular systolic pressure, dP/dt, heart rate, and oxygen consumption were reduced during exposure to all concentrations of the three local anesthetics. The most profound effects (greater than 75% reduction) were seen with 13 micrograms/ml bupivacaine. All local anesthetics caused an increase in the voltage required to pace the hearts via the atria. With 6 micrograms/ml bupivacaine and 13 micrograms/ml ropivacaine, 50% of the preparations could not be paced via the atria; and with 13 micrograms/ml bupivacaine, none of the preparations could be paced via the atria. The depressant effects of 6 micrograms/ml bupivacaine approximated those seen with 13 micrograms/ml ropivacaine. The reductions in oxygen consumption and pulmonary artery flow were not significantly different between treatment groups. CONCLUSION: The results of this study indicate that bupivacaine is more cardiodepressant and arrhythmogenic than either ropivacaine or lidocaine.

Interpleural analgesia after thoracotomy.

We examined the effects of the following variables on interpleural analgesia after thoracotomy: addition of epinephrine to local anesthetic, thoracostomy drainage, two-catheter placement, and location of catheter tips. Twenty patients were randomized to have one catheter (paravertebral tip location) or two catheters (paravertebral and lateral thoracic wall tip locations). Interpleural catheters were sutured to the parietal pleura by the surgeon at time of wound closure. Patients were then randomly assigned to receive 20 mL of 0.5% bupivacaine with 1:200,000 epinephrine through the single catheter or 10 mL of 0.5% bupivacaine with or without 1:200,000 epinephrine through each of the two catheters while supine. Bupivacaine concentrations in whole blood and in thoracostomy drainage fluid were assayed by gas chromatography. Actual content of bupivacaine in the drainage fluid was calculated. Degree of analgesia was assessed by verbal numerical pain scores over the first 4 h and opioid demand thereafter. Addition of epinephrine to bupivacaine did not influence the degree of analgesia. Approximately 30%-40% of any administered dose of bupivacaine was lost via the thoracostomy tube over a 4-h period. There was no correlation between the true initial dose (100 mg minus thoracostomy drainage) and Cmax. Use of two catheters resulted in significantly less opioid requirements after an initial 8-h period. Failure to achieve adequate interpleural analgesia in postthoracotomy patients may be related to loss of anesthetic via thoracostomy drainage, presence of extravasated blood and tissue fluid in the pleural space, and possibly sequestration and channeling of flow of local anesthetic by restricted motion of an operated lung.(ABSTRACT TRUNCATED AT 250 WORDS)