Enantiomer-specific effects of an intravenously administered arrhythmogenic dose of bupivacaine on neurons of the nucleus tractus solitarius and the cardiovascular system in the anesthetized rat.

BACKGROUND AND OBJECTIVE: This investigation was designed to determine whether the effects on the cell firing rate (CFR) at the nucleus tractus solitarius (NTS) and on the cardiovascular system, which are associated with a toxic dose of bupivacaine, have an enantiomer-specific component. METHODS: Adult Sprague-Dawley rats were anesthetized with chloral hydrate, and a femoral artery and vein were cannulated. After the cranial surface was exposed, a 3-mm hole was drilled 2 mm caudal and 1.5 mm lateral with respect to lambda for placement of a 1-microns tungsten microelectrode. Cells of the NTS were located 6-6.5 mm from the brain surface, and CFR was continuously recorded. Lead II electrocardiogram and arterial blood pressure were also recorded. Twenty-four animals received either d- or l-bupivacaine (2 mg/kg) in random order. RESULTS: Cell firing rates decreased from 21 +/- 13 to 0 +/- 0 impulses/second (p < 0.001) at 34 +/- 15 seconds after the injection of d-bupivacaine. Cell firing rates decreased from 22 +/- 17 to 2 +/- 4 impulses/second (p < 0.01) at 68 +/- 45 seconds after injection of l-bupivacaine. In addition to the decreases in blood pressure and heart rate that were found, all animals exhibited an inversion in electrical axis beginning within 2-3 seconds after bupivacaine administration. Mild bradycardia was noted in four of the animals receiving the l-bupivacaine, whereas severe bradycardia was observed in all animals receiving d-bupivacaine. Most important, this severe bradycardia was accompanied by progressive hypotension. In addition, all animals receiving d-bupivacaine became apneic and died, whereas all animals receiving l-bupivacaine continued to breathe and all but two of the animals survived. CONCLUSIONS: Data in the current report support the hypothesis that effects of bupivacaine on neurons of the NTS and on the cardiovascular system have an enantiomer-specific component.

The correlation between predicted and measured patient specific analgesic concentrations after intravenous titration: a guide for initial maintenance requirements with methadone.

The relationship between the analgesic methadone concentrations measured and those predicted using a pharmacokinetic approach were assessed in 22 patients referred for long-term management of severe pain with intravenous methadone. Five milligrams of methadone were administered IV every 10 minutes until the patient reported a visual analog scale (VAS) pain score of less than or equal to 2. Initial maintenance infusion rates were chosen based on the number of 5 mg doses required to produce satisfactory analgesia. Overall, the methadone concentrations predicted using pharmacokinetic modeling were in excellent agreement with those actually measured. Over 95% of the variance in the data was explained using this model (r2 = 0.9704). Using the rapid titration paradigm described here, one can obtain a reasonable estimate of patient specific analgesic (target) concentration as well as initial infusion requirements for methadone.

Effects of an intravenously administered arrhythmogenic dose of bupivacaine at the nucleus tractus solitarius in the conscious rat.

This study was designed to further investigate the CNS-mediated cardiovascular toxicity of local anesthetics and to determine any effect of anesthesia on the firing rate of cells in the nucleus tractus solitarius (NTS) of conscious animals. Adult Sprague-Dawley rats were anesthetized with chloral hydrate. A femoral artery and vein were cannulated. A 3-mm hole was then drilled for placement of a unidirectional microdrive. The animal was removed from the stereotactic instrument, and EKG electrodes, pressure transducer and the microdrive containing a 1-micron tungsten electrode were attached. Animals were then placed in a canvas sling for recovery from the anesthetic. Cells of the NTS were located and cell firing rate (CFR) was continuously recorded. None of the animals exhibited any sign of discomfort upon recovery from anesthesia. CFRs decreased from 19 +/- 13 to 4 +/- 4 impulses/second at 20 +/- 16 seconds after the IV injection of bupivacaine (p less than 0.01). Maximum decreases in blood pressures were 26 +/- 15% of control and occurred at 32 +/- 14 seconds after the injection of bupivacaine. The maximum decrease in heart rate was 38 +/- 16% and occurred at 13 +/- 10 seconds after the injection of bupivacaine. Maximum heart rate changes occurred significantly earlier than maximum decreases in CFR (p less than 0.01). On the other hand, maximum blood pressure changes occurred significantly later than maximum decreases in CFR (p less than 0.01). The data reported here demonstrate that conscious animals respond similarly to animals anesthetized with chloral hydrate with respect to the medullary effect of local anesthetics.

Continuous postoperative epidural analgesia in management of postoperative surgical pain.

In the last fifteen months we have used continuous postoperative epidural analgesia after open urologic surgery and herein report our experience with the first 64 patients. Incisional pain was completely eliminated in 96 percent of patients. Epidural analgesia diminished pain-related pulmonary complications without sedation. Complications were tolerable and manageable. Hypotension due to sympathetic blockade responds to intravenous fluid administration. Urinary retention is avoidable if the epidural infusion is discontinued prior to removing the urethral catheter. Itching is an undesirable consequence observed by 20 percent of patients when morphine is used.

Pharmacokinetics of hydromorphone after intravenous, peroral and rectal administration to human subjects.

The pharmacokinetic properties of hydromorphone in healthy young male subjects were studied after i.v., peroral, and rectal administration. After i.v. administration the following pharmacokinetic parameters were found: elimination half-life 2.36 +/- 0.5 h, hepatic extraction ratio 0.51, apparent volume of distribution 2.9 +/- 1.3 L kg-1 and volume of central compartment 0.23 +/- 0.2 L kg-1. The absolute bioavailability after peroral administration was 50.7 +/- 29.8 per cent, and that after rectal administration was 33 +/- 22 per cent.

Does diazepam really reduce the cardiotoxic effects of intravenous bupivacaine?

The effect of diazepam on the cardiovascular toxicity of bupivacaine was investigated in a rat model. Under chloral hydrate (400 mg/kg intraperitoneal) anesthesia, unilateral femoral venous and bilateral femoral arterial cannulae were placed for administration of drugs, for blood sampling, and for continuous qualitative monitoring of arterial blood pressure. Lead II ECG was continuously recorded and a tracheostomy performed to increase FIO2 by use of a "T-piece." Four groups of 24 to 36 rats each were studied. All rats received IV bupivacaine 2 mg/kg, within 10 seconds. Group I, the control group, received only bupivacaine. Groups II and III received IV diazepam 0.2 mg/kg, or diazepam vehicle in an equivalent volume, respectively. Five minutes after this pretreatment, groups II and III received IV bupivacaine 2 mg/kg. Group IV was given diazepam, 0.2 mg/kg, 30 seconds after injection of 2 mg/kg bupivacaine. A marked respiratory and metabolic acidosis occurred in all rats but was significantly worse in groups II and III. No rat in the study became hypoxemic. Serious arrhythmias (ventricular or supraventricular tachycardia) were noted in all groups, but the incidence was significantly higher in the group of rats given diazepam pretreatment than in the other three groups. It is concluded that IV diazepam 0.2 mg/kg given 5 minutes before administration of IV bupivacaine 2 mg/kg increases the incidence of serious cardiac arrhythmias. Second, this increase is not solely due to increased acidosis, because the rats receiving the vehicle (group III) developed equivalent acidosis but did not develop increased arrhythmias.

Absolute bioavailability of hydromorphone after peroral and rectal administration in humans: saliva/plasma ratio and clinical effects.

The absolute bioavailability of hydromorphone was investigated in eight healthy male subjects by a cross-over design (with washout period of two weeks) after intravenous (2 mg), peroral (4 mg) and rectal (3 mg) administration of hydromorphone. The use of saliva hydromorphone concentrations as a noninvasive technique in pharmacokinetic evaluation was investigated, and the clinical effects after the three routes of administration were determined. Hydromorphone has an absolute bioavailability of 51.35 +/- 29.29% and 36.33 +/- 29.60% after peroral and rectal administration, respectively. More side effects were observed after intravenous administration of hydromorphone than after rectal or peroral dosing. The saliva sampling for the hydromorphone concentration was found to be a useful noninvasive technique for the estimation of the elimination half-life of hydromorphone.

A self-instructional approach to gross anatomy: evaluation of five years experience.

A largely self-instructional teaching method in gross anatomy for dental students, developed and tested over five years at the University of Louisville, is presented and evaluated. The merits of the method include reduced faculty teaching load, the potential to accommodate increased numbers of students without comparable increases in faculty or physical plant, apparent improvement in the quality of instruction, student satisfaction, early identification of marginal students, and conservation of cadavers.

The influence of body temperature on the production of ulcers of restraint in the rat.

It has been observed that gastric ulceration after restraint in rats is accompanied by a marked drop in body temperature. This investigation seeks to determine whether hypothermia is causally related to the restraint ulcer. Experimental animals were restrained for 18 hr while rectal temperatures were monitored with a telethermometer probe. Body temperatures of rats restrained at room temperature fell 5.0 degrees C in the first 5 hr. Gastric ulceration in this group was 100%. When body temperatures were mainatined at 38 degrees C, only 26% developed ulcers. Ulcer induction is not only accompanied by a marked temperature drop, but prevention of this phenomenon reduces the incidence of ulcers.

Tannic acid-iron alum reactions: stain of choice for macroscopic sections of brain to be embedded in plastic.

As a macroscopic stain for gross brain sections to be embedded in plastic, tannic acid-iron alum is superior to the generally recommended LeMasurier's variation of the Berlin blue technique because of its greater permanency in plastic. However, as originally adopted for use with brain tissue by Mulligan, the intense black staining of gray matter is too dark for plastic embedded specimens. A modification of this method designed to overcome this difficulty is described. Staining procedure: Wash formalin-fixed brain slices overnight in running water. Wash in distilled water, 2 changes, 30 minutes each. Place slices individually in Mulligan's solution at a temperature of 60-65 C for 4 minutes. Rinse in ice water for 10 seconds. Mordant in 0.4% tannic acid in distilled water for 1 minute. Wash in running tap water for 1 minute. Develop in 0.08% ferric ammonium sulfate in distilled water until gray matter is light gray, about 10-15 seconds. Wash in lukewarm running water for 1 hour, then gently hand-rub whitish film from myelinated surfaces. Store briefly in 3% formalin or 25% glycerine if necessary depending on plastic embedding procedure to be followed.