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.

The effects of bupivacaine, L-nitro-L-arginine-methyl ester, and phenylephrine on cardiovascular adaptations to asphyxia in the preterm fetal lamb.

UNLABELLED: The preterm fetal lamb that is exposed to clinically relevant plasma concentrations of lidocaine loses its cardiovascular adaptations to asphyxia, and its condition deteriorates further. Nitric oxide (NO) is an important regulator of vascular tone, and local anesthetics are known to inhibit endothelium-dependent vasodilation. The purpose of the present study was to determine whether the adverse effects of lidocaine noted in the preterm fetal lamb also occur with bupivacaine and whether the inhibition of NO results in effects similar to those of bupivacaine. Thirty-two chronically prepared pregnant sheep were studied at 117-119 days' gestation. Maternal and fetal blood pressure, heart rate, and acid-base state were evaluated. Fetal organ blood flows were determined using 15-microM diameter dye-labeled microspheres. After a control period, mild to moderate asphyxia (fetal PaO2 15 mm Hg) was induced by partial umbilical cord occlusion and maintained throughout the experiment. Ewes in Group I (n = 13) were given a two-step intravenous infusion of bupivacaine for 180 min. Fetuses in Group II (n = 12) received an intravenous injection of L-nitro-L-arginine-methyl ester (L-NAME) (25 mg/kg), and measurements were taken 10 and 30 min after the injection. A third group (Group III) of fetuses (n = 7) were given an intravenous infusion of phenylephrine to mimic the blood pressure increases noted in L-NAME-treated fetuses. At 90 min of stable asphyxia, there was a significant decrease in fetal PaO2 and pHa and an increase in PaCO2 and mean arterial blood pressure. There was also an increase in blood flow to the adrenals, myocardium, and cerebral cortex, whereas blood flow to the placenta decreased. Administration of bupivacaine during asphyxia did not affect the changes in mean arterial blood pressure and acid-base state but did abolish the increases in blood flows to the myocardium and cerebral cortex. Injection of L-NAME to the asphyxiated fetus resulted in an increase in mean arterial blood pressure above the level noted at 90 min of cord occlusion, and an increase in fetal PaO2 toward control levels. This was accompanied by a reduction in organ blood flows to preasphyxia levels. In asphyxiated Group III fetuses, titration of the phenylephrine infusion to achieve blood pressure increases similar to those noted with L-NAME were also associated with an increase in fetal PaO2. These data indicate that bupivacaine abolishes some of the circulatory adaptations to mild to moderate asphyxia induced by partial cord occlusion in the preterm fetal lamb. It is not clear whether these effects of bupivacaine are due to inhibition of NO. IMPLICATIONS: In the preterm fetal lamb, clinically relevant plasma concentrations of bupivacaine achieved by intravenous infusion to the pregnant ewe (80% gestation) abolished some of the fetal cardiovascular adaptations to asphyxia induced by partial umbilical cord occlusion.

Estrogen-induced changes in protein binding of bupivacaine during in vitro fertilization.

BACKGROUND: Patients having in vitro fertilization (IVF) procedures that use gonadotropin-releasing hormone agonist down-regulation undergo hormonal manipulation of estrogen concentrations to induce oocyte maturation. After achieving minimal estrogen concentrations (baseline), stimulation increases estrogen concentrations to supraphysiologic levels, leading to egg retrieval. The isolated effect of estrogen on protein binding has not previously been reported. This study was conducted to measure the effect of estrogen concentrations on protein binding of two concentrations of bupivacaine, 1 microg/ml and 5 microg/ml, corresponding, respectively, to systemic concentrations expected after administration of epidural anesthesia and associated with bupivacaine toxicity. Serum proteins were measured to address the mechanism. METHODS: Twenty-nine healthy women undergoing IVF procedures were enrolled and venous samples were drawn at times of minimal and maximal estrogen concentrations. The percentage of free bupivacaine was determined at fixed concentrations of 1 and 5 microg/ml. Serum albumin and alpha1-acid glycoprotein concentrations were measured at baseline and at retrieval in a group of 24 women. RESULTS: The percentage of free bupivacaine increased between times of minimal and maximal serum estrogen concentrations, corresponding to decreased protein binding. Concentrations of serum albumin and alpha1-acid glycoprotein decreased between baseline and retrieval times. CONCLUSIONS: Patients undergoing IVF procedures demonstrate a decrease in protein binding of bupivacaine from baseline concentrations. These changes may be explained by a decrease in albumin and alpha1-acid glycoprotein. During anesthesia for egg retrieval, clinicians should consider the implications of increased free fraction of drug, especially for highly protein-bound agents.

Comparative pharmacokinetics of ropivacaine and bupivacaine in nonpregnant and pregnant ewes.

We determined the pharmacokinetics and protein binding of ropivacaine and bupivacaine after intravenous administration to nonpregnant and pregnant sheep. All animals were in good condition throughout the study. The highest mean total serum drug concentrations were found at the end of infusion. For both drugs, pregnancy was associated with lower volumes of distribution during the terminal phase of drug elimination (V(d)beta) and steady state (V(d)ss), as well as with a lower total body clearance (CL). The relationship between V(d)beta and CL was such that the elimination half-life (T(1/2)beta) was not altered. There were also differences between the two drugs. In all animals, the distribution half-life (T(1/2)alpha), T(1/2)beta, volume of central compartment (V(c)), V(d)beta, V(d)ss, and mean residence times (MRT) were greater and CL lower for bupivacaine than ropivacaine. For both drugs, protein binding was concentration-dependent and greater in pregnant ewes. In conclusion, the pharmacokinetics of ropivacaine and bupivacaine are altered by ovine pregnancy in a similar way. If these data are applicable to humans, an unintended intravascular injection of either drug could be expected to result in higher total serum concentrations in the pregnant than in the nonpregnant patient, but drug levels would decline at similar rates in both groups of individuals. However, differences between the two drugs, particularly in T(1/2)beta and MRT, may make ropivacaine preferable for use in obstetric anesthesia.

Effect of midazolam on development of acute tolerance to alfentanil: the role of pharmacokinetic interactions.

This study in rats was performed to explore whether the inhibitory effect of midazolam on the development of acute tolerance to the analgesic effect of alfentanil is due to pharmacokinetic mechanisms. Analgesia was determined with tail-compression and hot-plate tests. Alfentanil and midazolam concentrations in plasma and the brain were measured using a radioimmunoassay and chromatographic technique, respectively. After the 4-h period of alfentanil administration (155 microg x kg(-1) x h(-1) after a 50-microg/kg bolus), when acute tolerance had already developed, midazolam (2-mg/kg bolus) enhanced the alfentanil-induced analgesia by 120% (P < 0.001) with the tail-compression test and 76% (P < 0.01) with the hot-plate test. At the height of midazolam-induced enhancement of the analgesic effect of alfentanil, the measurements of the alfentanil and midazolam plasma and brain concentrations did not demonstrate any significant changes in the drugs' concentrations. The results confirm that midazolam attenuates the development of acute tolerance to the analgesic effect of alfentanil and indicate that this interaction is not pharmacokinetic.

Time course characteristics of acute tolerance development to continuously infused alfentanil in rats.

The time course of the development of acute tolerance to alfentanil was characterized in rat experiments using various algorithms of continuous infusion of the drug. To maintain analgesia at a constant level (tail compression test), alfentanil use was steadily increased: Time to 50% increase in alfentanil use was 255 +/- 98 min with analgesia maintained at a level of 50% increase in the pressure threshold, and 203 +/- 116 min with analgesia maintained at a level of 200% increase. With the use of the alfentanil infusion regimen designed to rapidly achieve and maintain the constant alfentanil plasma concentration (120 ng/mL), the rate of development of acute tolerance, measured in terms of time to 50% recovery during continuing infusion, was 81 +/- 26 min with the compression test and 88 +/- 38 min with the hot-plate test, but 374 +/- 46 min with the rotarod test (P < 0.0001). Thus we demonstrated rapid development of acute tolerance to continuously infused alfentanil with different methods of tolerance assessment. The results also indicate that the time course of tolerance development does not depend on the type of noxious stimulation (mechanical versus thermal) if the response is organized predominantly supraspinally, and that acute tolerance to the direct effect of alfentanil on motor functions does not mask the rapid development of tolerance to its analgesic effect.

Antinociceptive and motor-blocking efficacy of ropivacaine and bupivacaine after epidural administration in the dog.

BACKGROUND AND OBJECTIVES: This study was initiated to evaluate the antinociceptive and motor blocking capabilities of epidurally administered 0.5% and 0.75% ropivacaine and bupivacaine using a blinded, random crossover design in the dog. Additionally, serum drug concentrations and serum protein binding were determined. METHODS: Twelve male beagles were prepared with chronic epidural and arterial catheters under sterile conditions. The epidural space was identified by a loss-of-resistance technique using an 18-gauge thin-wall Crawford needle via the midline approach. The catheter was attached to a Schraeder-type Teflon valve sutured subcutaneously. Local anesthetic drugs were administered into the lumbar epidural space in a constant volume of 3.0 mL. Evaluation of antinociceptive and motor blocking qualities were evaluated at regular intervals. Arterial blood samples were drawn during the 15 minutes following local anesthetic injection for drug concentration and pharmacokinetic analysis. RESULTS: Onset time of motor block in the ropivacaine 0.5% group was longer than in other groups but not significantly different. Duration of motor and sensory block demonstrated a dose-dependent relationship of both drugs. Bupivacaine 0.5% and 0.75% produced motor block (81 +/- 42 minutes and 198 +/- 44 minutes [mean +/- SD], respectively) of significantly longer duration than corresponding concentrations of ropivacaine (69 +/- 35 minutes and 133 +/- 32 minutes, respectively). The onset times for sensory block of the vertebral dermatomes were not different between groups. No difference was found in duration of dermatomal sensory block between the 0.5% solutions. However, the duration of dermatomal sensory block was significantly longer in the bupivacaine 0.75% group than in any other group. Peak arterial serum drug concentrations were not different between drugs at equal concentrations and were reached between 2 and 6 minutes in all animals. Both drugs were highly bound to serum proteins (> 98%). No severe adverse effects or sequelae were observed. CONCLUSIONS: The 0.5% solutions produced similar sensory block of the vertebral dermatomes. Duration of dermatomal block with 0.75% bupivacaine was longer than with the corresponding ropivacaine concentration. Ropivacaine produced motor block of shorter duration as compared with bupivacaine. Serum concentrations of the two drugs were similar after injection of the same doses. In this animal model, ropivacaine produced shorter durations of sensory and motor block than corresponding concentrations of bupivacaine. These data are consistent with previously published data in animals and humans.

The analgesic response to intravenous lidocaine in the treatment of neuropathic pain.

This study was performed in order to determine concentration-effect, and graded and quantal dose-response relationships for the clinical administration of intravenous (IV) lidocaine to patients with neuropathic pain. Thirteen patients were administered 500 mg of IV lidocaine at a rate of 8.35 mg/min over 60 min. Visual analog pain scores and venous blood samples were obtained concomitantly at 10 min intervals for 60 min. Blood samples were also obtained for determination of serum and serum water lidocaine concentrations at the onset of analgesia and at the time complete pain relief was attained. Lidocaine concentrations were determined by gas chromatography. Graded dose-response curves were prepared individually and for the group as a whole, and a quantal dose-response curve was prepared for the entire group. The dose-response relationship for IV lidocaine was characterized by large increases in pain relief for concomitant minimal increases in dosage. The difference between the ED50 (372.0 mg) and the ED90 (416.5 mg) was 44.5 mg of lidocaine (5.3 min of infusion). The concentration-effect relationship was also steep with pain scores abruptly decreasing over a range of 0.62 microgram/mL of lidocaine. Interestingly, the free concentration of lidocaine had no better correlation with the onset of analgesia or the attainment of complete analgesia than the serum concentration of lidocaine. This suggests that the mechanism of analgesia to IV lidocaine may not be based upon a conventional concentration-effect relationship. In conclusion, the results of this study suggest that the analgesic response to IV lidocaine is best characterized by a precipitous "break in pain" over a narrow dosage and concentration range.

Maternal and neonatal fentanyl and bupivacaine concentrations after epidural infusion during labor.

Labor analgesia using continuous epidural infusions of low-dose bupivacaine and fentanyl may be maintained for many hours. We examined the potential for drug accumulation in both mother and neonate after these long-term infusions. Pregnant women receiving a 10-mL/h continuous infusion of labor analgesia with 0.125% bupivacaine and 2 micrograms/mL of fentanyl were evaluated. Maternal venous and umbilical venous drug concentrations were measured at delivery. Umbilical artery blood gases were obtained. Scanlon neurobehavioral testing was performed on all infants. Length of infusion times varied from 1 to 15 h. Maternal and neonatal drug concentrations remained relatively constant throughout the infusion period. All umbilical blood gas values and neurobehavioral scores were within normal limits. In conclusion, even when maintained for many hours, continuous infusion labor analgesia does not appear to result in significant fetal drug accumulation. No adverse neonatal effects were seen.

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.

Comparative systemic toxicity of ropivacaine and bupivacaine in nonpregnant and pregnant ewes.

BACKGROUND: Ropivacaine is a new amide local anesthetic, having therapeutic properties similar to those of bupivacaine but with a wider margin of safety. Bupivacaine is probably the most commonly used drug in obstetric epidural analgesia, even though laboratory studies have suggested that pregnancy increases the cardiotoxicity of bupivacaine but not of other local anesthetics. The current study was designed to reevaluate, in a random and blinded fashion, the systemic toxicity of bupivacaine and ropivacaine in nonpregnant and pregnant sheep. METHODS: Chronically prepared nonpregnant and pregnant ewes were randomized to receive an intravenous infusion of ropivacaine or bupivacaine at a constant rate of 0.5 mg.kg-1.min-1 until circulatory collapse. The investigators were blinded to the identity of local anesthetic. Heart rate, arterial blood pressure, and cardiac rhythm were monitored throughout the study. Arterial blood samples were obtained before infusion and at the onset of toxic manifestations, which appeared in the following sequence: convulsions, hypotension, apnea, and circulatory collapse. Serum drug concentrations and protein binding were determined. Blood pH and gas tensions were measured. RESULTS: There were no significant differences between non-pregnant and pregnant animals in the doses or serum concentrations of either drug required to elicit toxic manifestations. In nonpregnant animals, similar doses and serum concentrations of ropivacaine and bupivacaine were associated with the onset of convulsions and circulatory collapse. In pregnant ewes, greater doses of ropivacaine as compared to bupivacaine were required to produce convulsions (7.5 +/- 0.5 vs. 5.0 +/- 0.6 mg.kg-1) and circulatory collapse (12.9 +/- 0.8 vs. 8.5 +/- 1.2 mg.kg-1). The corresponding serum concentrations of ropivacaine were similar to those of bupivacaine. Pregnancy did not affect the serum protein binding of either drug. The proportion of animals manifesting a malignant ventricular arrhythmia as the terminal event was similar among all groups. CONCLUSIONS: The systemic toxicity of ropivacaine or bupivacaine is not enhanced by gestation in sheep. This is in contrast to an earlier study in which the cardiotoxicity of bupivacaine was enhanced during ovine pregnancy. Greater doses of ropivacaine, as compared to bupivacaine, are needed to produce toxic manifestations in pregnant animals.

Relationship between body surface area and arterial concentrations of bupivacaine following lumbar epidural anesthesia.

BACKGROUND AND OBJECTIVES: Most prior studies have shown no relationship between body mass or body surface area (BSA) and maximum plasma concentration of local anesthetic agent (Cmax) following neural block. METHODS: Forty-nine patients, aged 55 or older, undergoing elective total hip arthroplasty, had arterial plasma bupivacaine concentrations measured (gas chromatography) at 10-minute intervals for the first 60 minutes following lumbar epidural injection of 25 mL 0.75% bupivacaine plain. Hemodynamic stability was maintained with either low-dose epinephrine (EPI) or phenylephrine (PHE) intravenous infusions. RESULTS: A significant relationship between arterial bupivacaine concentration and BSA was noted for both EPI and PHE groups at each observation point (P < .05). In addition, Cmax for each group was correlated to both BSA and body mass (P < .05). Arterial plasma bupivacaine concentrations were significantly higher in patients at 10, 20, 30, and 40 minutes following epidural injection in patients receiving PHE than EPI (P < .05). CONCLUSIONS: Between 20% and 40% of the variability in the arterial concentrations of bupivacaine following lumbar epidural injection in elderly patients can be accounted for by differences in BSA.

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.

Single versus staged epidural injections of 0.75% bupivacaine: pharmacokinetic and pharmacodynamic effects.

Epidural anesthesia may be performed as a single injection or by staged doses. Thirty patients undergoing primary total hip replacement were randomly assigned to have epidural anesthesia using a single injection or a staged technique with 25 mL of 0.75% bupivacaine. Arterial plasma bupivacaine concentrations were significantly higher in the single injection group for the first 15 min but were not significantly different thereafter. Peak bupivacaine concentrations did not differ significantly between groups, but the time to achieve the peak concentration was delayed by staging injections (P = 0.001). Hemodynamic effects were similar between groups. Resolution of thoracic sensory block through T12 and duration of motor block measured by Bromage scale were both significantly longer in the staged injection group (P < 0.01). The method of epidural injection may affect resolution of neural block and the time to reach peak arterial plasma concentration of local anesthetic.

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.

Effect of ropivacaine and bupivacaine on uterine blood flow in pregnant ewes.

The effects of ropivacaine, a new amide local anesthetic, on uterine blood flow and fetal well-being were compared with those of bupivacaine in 10 chronically instrumented pregnant ewes. In random sequence, animals received two intravenous infusions of each drug. The low infusion rate regimens were chosen to result in clinically relevant maternal plasma concentrations of local anesthetics, whereas the more rapid rates of infusions were given to assess the safety of higher maternal drug concentrations. An epinephrine infusion was given to demonstrate the appropriateness of the animal model for the measurement of uterine blood flow. Maternal and fetal heart rates, arterial blood pressure, and the ewe's central venous pressure, intraamniotic pressure, and uterine blood flow were recorded continuously. Arterial blood samples were taken from mother and fetus at frequent intervals to determine acid-base status and local anesthetic concentrations. A total of 39 studies were performed. None of the infusions of either local anesthetic resulted in a significant decrease in uterine blood flow or deterioration in fetal condition. The mean maternal plasma concentrations at the end of infusions were as follows: ropivacaine low dose, 1.60 +/- 0.35 micrograms/mL; bupivacaine low dose, 1.55 +/- 0.15 micrograms/mL; ropivacaine high dose, 2.50 +/- 0.37 micrograms/mL; and bupivacaine high dose, 1.83 +/- 0.19 micrograms/mL. Epinephrine infusion resulted in a 25% decrease in uterine blood flow without adverse fetal effects. We conclude that neither ropivacaine nor bupivacaine, as administered in this study, led to any ill effects on uterine artery blood flow or fetal well-being.

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.

Treatment of acute systemic toxicity after the rapid intravenous injection of ropivacaine and bupivacaine in the conscious dog.

Two groups of six beagle dogs received rapid intravenous (IV) injections of ropivacaine or bupivacaine on two occasions in a blinded random fashion. Initially, a dose sufficient to cause convulsions (CD) was given followed by twice the CD (2 x CD), which was administered 48 h later. The CD of bupivacaine (4.3 mg/kg) and ropivacaine (4.9 mg/kg) caused significant (P less than 0.05) increases in heart rate and mean arterial blood pressure. There was no difference between drug groups. Seizures were abolished by 10 mg/kg of intravenous thiamylal. Endotracheal intubation and controlled respiration with O2-enriched air with no other treatment resulted in rapid and complete recovery in all dogs. All dogs receiving 2 x CD of bupivacaine (8.6 mg/kg) or ropivacaine (9.8 mg/kg) were initially treated with thiamylal and mechanical ventilation. Two dogs in the bupivacaine group developed hypotension, respiratory arrest, ventricular tachycardia, and ventricular fibrillation, which were resistant to closed chest cardiac massage, treatment with epinephrine, bretylium, and atropine, and direct current cardioversion. The four remaining dogs in the infusion group were successfully resuscitated. All of the animals in the ropivacaine-treated group survived the administration of the 2 x CD dose. Mild hypotension developed in one dog and was treated with intravenous epinephrine (0.75 mg). This resulted in nodal tachycardia, which was abolished after treatment with bretylium. Another dog had two 1-s bursts of premature ventricular contractions requiring no treatment. The rapid treatment of convulsions and cardiovascular toxicity resulted in a decreased number of deaths in both groups when compared with dogs from a previously published study in which no therapy was instituted. Thus, early aggressive treatment of central nervous system and cardiovascular system toxicity is capable of reducing the incidence of mortality associated with the rapid intravenous administration of excessive doses of local anesthetics.

Systemic toxicity of ropivacaine during ovine pregnancy.

Ropivacaine is a new amide local anesthetic structurally related to bupivacaine and mepivacaine. Its potency and duration of action are similar to those of bupivacaine but its therapeutic index may be greater. Since pregnancy enhances the cardiotoxicity of bupivacaine, the current study was devised to compare the toxicity of ropivacaine in chronically instrumented nonpregnant and pregnant ewes during continuous intravenous infusion of the drug at the rate of 0.5 mg.kg-1.min-1. In all animals, symptoms of local anesthetic toxicity occurred in the usual order--convulsions, hypotension, apnea, and circulatory collapse. There were no significant differences between the two groups of animals in the doses and plasma concentrations of ropivacaine associated with each toxic manifestations. For example, circulatory collapse occurred at a mean dose of 11.3 +/- 1.1 mg.kg-1 in nonpregnant and 12.4 +/- 0.9 mg.kg-1 in pregnant animals, with corresponding plasma concentrations of 7.3 +/- 0.3 and 9.6 +/- 2.1 micrograms.ml-1 (P = not significant). Protein binding of ropivacaine in the concentration range associated with toxic manifestations was similar in sera obtained from nonpregnant and pregnant ewes. In conclusion, ovine pregnancy does not enhance the systemic toxicity of ropivacaine, possibly because of an absence of gestation-related increase in the availability of free drug.