Addition of bicarbonate to plain bupivacaine does not significantly alter the onset or duration of plexus anesthesia.

BACKGROUND AND OBJECTIVES: In an effort to elucidate further the effect of alkalinization of bupivacaine on its anesthetic effect, a study was undertaken using alkalinized and non-alkalinized bupivacaine for lumbar plexus block and comparing the results with those obtained previously with brachial plexus block. METHODS: Thirty consenting adult patients about to undergo lower extremity surgery under regional anesthesia were selected for the study. All of the patients received an inguinal paravascular lumbar plexus block ("3-in-1 block"), along with a sciatic block to allow the anticipated surgery to be carried out. The patients were divided into two groups, one receiving plain "alkalinized" 0.5% bupivacaine; the other receiving plain "non-alkalinized" 0.5% bupivacaine. After each lumbar plexus block, the onset and duration of analgesia and anesthesia of the nerves derived from the lumbar plexus were determined by an independent investigator who was unaware of which solution had been administered. RESULTS: There was no statistically significant difference between the two groups with respect to the onset or duration of anesthesia and analgesia. CONCLUSIONS: The data obtained in the present study indicate that alkalinization of non-epinephrine-containing bupivacaine does not reduce the latency or increase the duration of analgesia or anesthesia after lumbar plexus block. Since most of the studies that do show such an effect of alkalinization were carried out using epinephrine-containing bupivacaine, it is postulated that in those studies alkalinization contributed to the decrease in latency and increase in duration, not so much by providing an increased amount of local anesthetic in the free base form, but by reactivating epinephrine's vasoconstrictor activity, which is inactivated by a low pH.

Effect of progesterone on the cardiac electrophysiologic alterations produced by ropivacaine and bupivacaine.

Bupivacaine-induced cardiotoxicity is enhanced in pregnant laboratory animals and in progesterone-pretreated isolated cardiac tissues. Ropivacaine is a new local anesthetic chemically related to bupivacaine. Although clinically equipotent with bupivacaine, ropivacaine is less cardiodepressant. Progesterone levels are elevated during pregnancy, and exogenously increasing progesterone levels in rabbits has increased bupivacaine's depressive effects on excitability. In neural tissues, bupivacaine's increased onset of block and depression of compound action potentials in tissues from progesterone-treated animals was similar to its effect in nerves from pregnant animals. This study determined whether exogenously increased progesterone levels can increase myocardial sensitivity to ropivacaine. Female ovariectomized rabbits were pretreated with progesterone for 4 days. After killing, the hearts were removed and Purkinje fibers (PFs) and ventricular muscle (VM) action potential parameters recorded. Tissues from animals receiving either progesterone or placebo were exposed to either ropivacaine or bupivacaine at concentrations ranging from 3.5 to 18.7 microM. Preparations were routinely paced at 2 Hz except where rate-dependent effects on the maximal rate of depolarization of phase zero (Vmax) were determined. Progesterone increased depression of myocardial Vmax only to bupivacaine (P less than 0.05). Ropivacaine was generally 3-5 times less potent in depressing cardiac electrophysiologic parameters. Bupivacaine demonstrated rate-dependent depression of Vmax that at higher frequencies was greater than ropivacaine's effects (P less than 0.05). Ropivacaine is less cardiodepressant than bupivacaine in this isolated PF-VM preparation. Exogenously increasing progesterone levels in vivo does not increase ropivacaine's depression of myocardial Vmax in isolated PF-VM tissues as it does to bupivacaine.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of progesterone on the cardiac electrophysiologic action of bupivacaine and lidocaine.

Pregnancy is accompanied by an increased cardiac and neural sensitivity to some local anesthetic agents such as bupivacaine. The current study was initiated to investigate the relationship between increased progesterone concentrations and the electrophysiologic effects of bupivacaine, and lidocaine in isolated Purkinje fiber (PF)-ventricular muscle (VM) preparations. Twenty-four oophorectomized female white rabbits were killed after receiving 30 mg.kg-1.day-1 of progesterone intramuscularly or peanut oil alone for 4 days. PF and VM action potentials were recorded using standard electrophysiologic procedures. Plasma progesterone concentrations were 5 +/- 2.9 ng/ml in control animals compared to 59.8 +/- 11.0 ng/ml in progesterone-treated animals (P less than 0.05). Bupivacaine (3.5-17.4 microM) depressed the maximal rate of depolarization (Vmax) of PF to a significantly greater extent in tissues from progesterone-treated animals as compared to control animals. For example, at 3.5 microM bupivacaine decreased PF Vmax 52% in progesterone-treated tissues compared to 32% in controls (P less than 0.05); the Vmax of VM was also depressed to a greater extent in tissues from progesterone-treated animals (P less than 0.001). Lidocaine did not demonstrate an enhanced depressant effect in tissues from progesterone-treated animals. These results indicate that progesterone selectively increases the cardiac membrane depressant effects of bupivacaine but not lidocaine. This may contribute to the enhanced toxicity of bupivacaine in pregnant animals.

Acute progesterone treatment has no effect on bupivacaine-induced conduction blockade in the isolated rabbit vagus nerve.

Pregnancy decreases anesthetic requirements during regional anesthesia. Using an in vitro animal model, this study attempts to elucidate the mechanism of hormonal effects on nerve conduction in desheathed rabbit vagus nerve. The acute effects of progesterone administration on neural blockade induced by bupivacaine were investigated in terms of changes in compound action potentials of A, B, and C fibers. No change in baseline compound action potential was found after 30 min of perfusion of the nerve with progesterone. Exposure of the nerve to progesterone before exposure to bupivacaine did not significantly increase the degree of conduction blockade produced by bupivacaine, and a radioactive assay demonstrated that progesterone was taken up acutely by neural tissue over a 45-min measurement period. These results indicate that although progesterone was taken up in significant amounts by neural tissue, an acute exposure does not increase the sensitivity of the nerves to bupivacaine. Hence, the increased sensitivity of nerves to local anesthetics seen with pregnancy or with chronic progesterone treatment requires some period of time to occur. The mechanism is therefore unlikely to be a direct effect of progesterone on the cell membrane but may involve hormonal effects on protein synthesis.

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.

Does pregnancy alter the systemic toxicity of local anesthetics?

The toxicity of mepivacaine in chronically instrumented nonpregnant and pregnant sheep was evaluated, and compared with data from previous studies of the toxicity of other local anesthetics. Thirteen preparations were studied, seven nonpregnant (NP) and six pregnant (P). Mepivacaine 2 mg.kg-1.min-1 was infused at a constant rate into the femoral vein until toxic manifestations occurred, in the following sequence: convulsions, hypotension, respiratory arrest, and circulatory collapse. The doses and plasma concentrations of mepivacaine necessary to produce toxic symptoms were similar in NP and P animals, whereas, in a previous study, pregnancy enhanced the cardiotoxicity of bupivacaine. No malignant ventricular arrhythmias were observed throughout the study. Protein binding of mepivacaine was also determined in sera from nonpregnant and pregnant ewes and compared with that for bupivacaine. Serum protein binding of mepivacaine was not reduced in pregnancy at the drug concentrations associated with toxic symptoms; at circulatory collapse, it was approximately 22% in NP and P. In contrast, the proportion of bound bupivacaine was 73% in NP and 51% in P, a significant difference. These protein binding data suggest that, although lethal concentrations of bupivacaine, determined in the previous study, were higher in NP than in P animals, concentrations of free drug were similar. Thus, the difference between the two drugs may be related to gestational increases in the availability of free drug in the case of bupivacaine.

Rationale for spinal anesthesia.

Spinal anesthesia is probably the most widely used form of regional anesthesia today. A number of clinical studies suggest that spinal anesthesia may be superior to general or epidural anesthesia for certain patients and for certain surgical procedures. The endocrine-metabolic response to surgery appears to be blunted when spinal anesthesia is employed compared to the response during general anesthesia. Blood loss and thromboembolic complications are also reduced when spinal anesthesia is used, particularly for major lower limb orthopedic procedures. Although long-term survival is not affected by the anesthetic technique employed, short-term mortality may be decreased in elderly patients having major orthopedic surgery under spinal anesthesia. Compared to epidural blockade, spinal anesthesia provides a more rapid onset, a more predictable level of analgesia, and a more profound degree of surgical anesthesia. On the other hand, spinal anesthesia is associated with a greater degree of hypotension compared to epidural anesthesia. The results of these various investigations show that a scientific rationale exists for the continued use of spinal anesthesia.

Hypertonic saline reverses bupivacaine-induced depression of rabbit Purkinje fiber depolarization Vmax

The present study describes the effect of a hypertonic increase in sodium chloride concentration on electrophysiological parameters. Membrane depolarization was recorded from rabbit Purkinje fibers superfused with warm, aerated Tyrode solution. An amount of 5% NaCl above that in normal Tyrode solution (HyNaCl, 344 mOsm) was added to the bathing medium for 30 min, significantly increasing the maximal rate of depolarization (Vmax + 15% vs - 7% for control), with minor effects on other parameters. When bupivacaine was superfused over the preparation for 30 min either in normal Tyrode or in HyNaCl, Vmax was significantly deveased (33% and 15%, respectively). HyNaCl protected the cardiac tissues from the depressive effect of 05micron/ml bupivacaine. We suggest that the infusion of hypertonic saline in intact animals may prove effective in preventing or reversing the cardiodepressant effect of bupivacaine

Tourniquet pain during spinal anesthesia: a comparison of plain solutions of tetracaine and bupivacaine.

The incidence of tourniquet pain was evaluated in 40 patients having orthopedic surgery of the lower extremities during spinal anesthesia using 15 mg of a plain solution of either 0.5% tetracaine or 0.5% bupivacaine. The drugs were administered in a randomized fashion, and measurement of the levels of sensory anesthesia to pinprick and motor blockade as well as the occurrence of tourniquet pain were made by an independent blinded observer. The onset and maximum cephalad spread of sensory anesthesia and the onset and degree of motor block were similar in both groups of patients. However, the duration of sensory anesthesia was significantly longer in patients in whom tetracaine was used. The incidence of tourniquet pain was significantly greater in patients given tetracaine (60%) than in patients given bupivacaine (25%). The occurrence of tourniquet pain was not related to the level of sensory anesthesia, because patients in the tetracaine group had a higher level of sensory anesthesia (mean T6) than did patients in the bupivacaine group (mean T10) at the onset of tourniquet pain. It is speculated that during spinal anesthesia both A and C fibers (mediating fast and slow pain, respectively) are initially equally inhibited. However, as the concentration of local anesthetic in the cerebrospinal fluid declines, C fibers may become unblocked earlier with tetracaine than A fibers, resulting in tourniquet pain in the presence of an otherwise satisfactory spinal anesthetic.

Effect of pregnancy on bupivacaine-induced conduction blockade in the isolated rabbit vagus nerve.

Bupivacaine-induced conduction blockade of A, B, and C fibers of the isolated vagus nerve was compared in fourteen pregnant and fourteen nonpregnant rabbits. After a control period in HEPES-Liley solution, the isolated nerves were exposed to bupivacaine concentrations of 0.1 mM to 1.0 mM. After 30 min exposure, the nerves were stimulated supramaximally and the percent reduction in amplitude of A, B, and C fiber compound action potentials was recorded. Linear regressions were fitted by the least squares method. The A fiber conduction blockade was consistently greater in the nerves from pregnant rabbits (P less than 0.001). The slope of the C fiber dose-response curves was also significantly greater in nerves from pregnant rabbits (P less than 0.01). The results indicate that the response of isolated nerves from pregnant animals to local anesthetic-induced conduction blockade differs from that of nerves from nonpregnant animals. However, it is not certain whether the difference is related simply to a more rapid diffusion and shorter onset of block or an enhanced sensitivity of the nerve membrane during pregnancy.

Esmolol for control of increases in heart rate and blood pressure during tracheal intubation after thiopentone and succinylcholine.

Esmolol, an ultra-short-acting cardioselective beta-adrenergic blocker, was investigated in a double-blind prospective protocol for its ability to control haemodynamic responses associated with tracheal intubation after thiopentone and succinylcholine. Thirty ASA physical status I patients received a 12-minute infusion of esmolol (500 micrograms X kg-1 X min-1 for four minutes, then 300 micrograms X kg-1 X min-1 for 8 minutes) or saline. Five minutes after the start of the drug/placebo infusion, anaesthesia was induced with 4 mg X kg-1 thiopentone followed by succinylcholine for tracheal intubation. Prior to induction esmolol produced significant decreases in heart rate (HR) (9.3 +/- 1.8 per cent) and rate-pressure product (RPP) (13.1 +/- 1.8 per cent), systolic blood pressure (SAP) (4.3 +/- 1.5 per cent) and mean arterial blood pressure (MAP) (1.7 +/- 2.0 per cent). Increases in HR, SAP and RPP after intubation were approximately 50 per cent less in patients given esmolol compared to patients given placebo. There were highly significant differences in HR (p less than 0.0001), and RPP (p less than 0.0005) and significant differences in SAP (p less than 0.05) when the maximal esmolol post-intubation response was compared to the maximal placebo response. Infusion of esmolol in the dose utilized in this study significantly attenuated but did not completely eliminate cardiovascular responses to intubation.

Epidural morphine provides postoperative pain relief in peripheral vascular and orthopedic surgical patients: a dose-response study.

A randomized double-blind study compared the dose-response relationship of epidural morphine for postoperative pain relief in two groups of patients whose surgical procedures would result in either moderate (femoral-popliteal bypass) or severe (total knee replacement) postoperative pain. Preservative-free morphine sulphate in doses of 0, 2, 5, or 10 mg in a volume of 10 ml saline were administered via lumbar epidural catheters. The epidural morphine was administered 1 hr after the last dose of intraoperative local epidural anesthetic in an effort to achieve a pain-free postoperative course. A significant relationship existed between the dose of epidural morphine and both time to first required pain medication and 24-hr weighted pain score. Five mg epidural morphine provided significant improvement in postoperative analgesia compared with the control in both groups. Further enhancement of analgesia occurred with 10 mg; however, late respiratory depression, demonstrated by an increased resting PaCO2 10 hr after administration, was seen only with the 10-mg dose in both surgical groups. Minor complications such as nausea, vomiting, pruritus, and urinary retention were uncommon and did not appear to be related to dose. We found that 5 mg epidural morphine provided long-lasting postoperative analgesia without serious adverse effects after peripheral vascular and orthopedic surgery.

A dose-response study of bupivacaine for spinal anesthesia.

A randomized double-blind study was performed to elucidate the interrelationships among volume, concentration, and dosage of bupivacaine administered intrathecally. Sixty male patients between the ages of 40 and 80 years having transurethral surgery in the lithotomy position were studied using 10-, 15-, and 20-mg doses of glucose-free bupivacaine as either a 0.5 or a 0.75% solution. Success rate, time of onset and duration of anaglesia and motor block, and cardiovascular responses were assessed. It was found that both 15 and 20 mg of either concentration of bupivacaine provide satisfactory spinal anesthesia for transurethral urologic procedures. However, three of 20 patients receiving the 10-mg dose required supplementation with general anesthesia. Comparison of various volumes and concentrations of bupivacaine indicates that total dosage of bupivacaine is more important than volume or concentration. In several patients with sensory block involving cervical dermatomes, there was no significant hypotension or bradycardia, which suggests that cardiac output and venous return were maintained, perhaps because of the use of lithotomy position.

Effects of concentration of local anaesthetic drugs in extradural block.

An increase in the concentration of bupivacaine from 0.5% to 0.75% and etidocaine from 1.0% to 1.5% for extradural block resulted in a more rapid onset of sensory analgesia and motor blockade, a greater frequency of adequate analgesia,a greater depth of motor block and a longer duration of sensory analgesia and motor blockade. An increase in the concentration of prilocaine from 2% to 3% failed to reveal any significant advantage. The use of the more concentrated solutions of bupivacaine and etidocaine would appear to afford significant clinical advantages in extradural anaesthesia for surgery.

Effects of adrenaline and the concentration of solution on extradural block with etidocaine.

Forty patients allocated to four groups received extradural injections of etidocaine for the performance of lower abdominal surgery. Twenty millilitre of the 1% or 1.5% solutions with or without adrenaline (1:200 000) was given in a double-blind manner. The addition of adrenaline to etidocaine did not significantly prolong the duration of analgesia, but it produced significant more motor block. Etidocaine 1.5% caused significantly longer durations of analgesia and more motor block than the 1% solution. The spread of sensory analgesia was similar with all four solutions of local anaesthetic agent.

Clinical evaluation of local anaesthetic agents.

The precise evaluation of local anaesthetic drugs in clinical practice has many difficulties. The factors which may modify the clinical profile of these drugs are: (1) procedural in nature; (2) patient related; (3) drug related; and (4) investigator related. All these factors are discussed in relation to the proper design of clinical trials.