Bupivacaine inhibits acylcarnitine exchange in cardiac mitochondria.

BACKGROUND: The authors previously reported that secondary carnitine deficiency may sensitize the heart to bupivacaine-induced arrhythmias. In this study, the authors tested whether bupivacaine inhibits carnitine metabolism in cardiac mitochondria. METHODS: Rat cardiac interfibrillar mitochondria were prepared using a differential centrifugation technique. Rates of adenosine diphosphate-stimulated (state III) and adenosine diphosphate-limited (state IV) oxygen consumption were measured using a Clark electrode, using lipid or nonlipid substrates with varying concentrations of a local anesthetic. RESULTS: State III respiration supported by the nonlipid substrate pyruvate (plus malate) is minimally affected by bupivacaine concentrations up to 2 mM. Lower concentrations of bupivacaine inhibited respiration when the available substrates were palmitoylcarnitine or acetylcarnitine; bupivacaine concentration causing 50% reduction in respiration (IC50 +/- SD) was 0.78+/-0.17 mM and 0.37+/-0.03 mM for palmitoylcarnitine and acetylcarnitine, respectively. Respiration was equally inhibited by bupivacaine when the substrates were palmitoylcarnitine alone, or palmitoyl-CoA plus carnitine. Bupivacaine (IC50 = 0.26+/-0.06 mM) and etidocaine (IC50 = 0.30+/-0.12 mM) inhibit carnitine-stimulated pyruvate oxidation similarly, whereas the lidocaine IC50 is greater by a factor of roughly 5, (IC50 = 1.4+/-0.26 mM), and ropivacaine is intermediate, IC50 = 0.5+/-0.28 mM. CONCLUSIONS: Bupivacaine inhibits mitochondrial state III respiration when acylcarnitines are the available substrate. The substrate specificity of this effect rules out bupivacaine inhibition of carnitine palmitoyl transferases I and II, carnitine acetyltransferase, and fatty acid beta-oxidation. The authors hypothesize that differential inhibition of carnitine-stimulated pyruvate oxidation by various local anesthetics supports the clinical relevance of inhibition of carnitine-acylcarnitine translocase by local anesthetics with a cardiotoxic profile.

Pretreatment or resuscitation with a lipid infusion shifts the dose-response to bupivacaine-induced asystole in rats.

BACKGROUND: The authors sought to confirm a chance observation that intravenous lipid treatment increases the dose of bupivacaine required to produce asystole in rats. The authors also measured the partitioning of bupivacaine between the lipid and aqueous phases of a plasma-lipid emulsion mixture. METHODS: Anesthetized Sprague-Dawley rats were used in pretreatment (protocol 1) and resuscitation (protocol 2) experiments. In protocol 1, animals were pretreated with saline or 10%, 20%, or 30% Intralipid (n = 6 for all groups), then received 0.75% bupivacaine hydrochloride at a rate of 10 ml x kg x min(-1) to asystole. In protocol 2, mortality was compared over a range of bolus doses of bupivacaine after resuscitation with either saline or 30% Intralipid (n = 6 for all groups). The lipid:aqueous partitioning of bupivacaine in a mixture of plasma and Intralipid was measured using radiolabeled bupivacaine. RESULTS: Median doses of bupivacaine (in milligrams per kilogram) producing asystole in protocol 1 were for 17.7 for saline, 27.6 for 10% Intralipid, 49.7 for 20% Intralipid, and 82.0 for 30% Intralipid (P < 0.001 for differences between all groups). Differences in mean +/- SE concentrations of bupivacaine in plasma (in micrograms per milliliter) were significant (P < 0.05) for the difference between saline (93.3 +/- 7.6) and 30% Intralipid (212 +/- 45). In protocol 2, lipid infusion increased the dose of bupivacaine required to cause death in 50% of animals by 48%, from 12.5 to 18.5 mg/kg. The mean lipid:aqueous ratio of concentrations of bupivacaine in a plasma-Intralipid mixture was 11.9 +/- 1.77 (n = 3). CONCLUSIONS: Lipid infusion shifts the dose-response to bupivacaine-induced asystole in rats. Partitioning of bupivacaine into the newly created lipid phase may partially explain this effect. These results suggest a potential application for lipid infusion in treating cardiotoxicity resulting from bupivacaine.

Nitric oxide synthase inhibition modulates the ventilatory depressant and antinociceptive actions of fourth ventricular infusions of morphine in the awake dog.

BACKGROUND: The role of nitric oxide (NO) production, at the brain-stem level, in ventilatory control and pain perception is poorly understood. Furthermore, it is not clear whether NO synthase (NOS) inhibition can affect morphine-induced ventilatory depression or analgesia. The central hypothesis of this investigation was that NO, at supraspinal sites, can influence ventilation and nociception and can modulate the ventilatory depressant and antinociceptive actions of morphine. Using drug delivery via the fourth cerebral ventricle, the authors examined the ventilatory and nociceptive effects of an NOS inhibitor and an NO donor in the presence or absence of morphine sulfate (MS). METHODS: The studies were performed in awake dogs that were restrained in a stanchion using a fourth ventricle to cisterna magna perfusion system. The dogs were chronically prepared with fourth ventricle and cisterna magna guide cannulae, femoral arterial/venous catheters, and a tracheostomy. Agents were prepared in a temperature- and pH-controlled artificial cerebrospinal fluid, perfused at 1 ml/min through the fourth ventricle cannula, and permitted to flow out through the cisterna magna cannula. The authors measured PaCO2, ventilatory drive (inspiratory occlusion pressures during carbon dioxide rebreathing), and nociception (hindpaw withdrawal threshold to increasing electrical current). Study groups were organized according to the following perfusion sequences (40 min each step): (1) MS (1 microgram/ml)-->MS + the NOS inhibitor, nitro-L-arginine (L-NA; 10(-6), then 10(-5) M)-->MS + L-NA (10(-5) M) + the NO donor, S-nitroso-acetylpenicillamine (SNAP; 10(-4) M); (2) SNAP (10(-5) M)-->SNAP (10(-4) M); (3) L-NA (10(-6), then 10(-5) M)-->L-NA (10(-5) M) + MS (1 microgram/ml)-->L-NA (10(-5) M) + MS + SNAP (10(-4) M); (4) MS (1 microgram/ml)-->MS + SNAP (10(-4) M); and (5) continuous MS (1 microgram/ml) perfusion (time control). Each perfusion sequence was preceded by a 45- to 60-min perfusion with drug-free artificial cerebrospinal fluid, during which time baseline values for each measured variable were obtained. RESULTS: Nitro-L-arginine alone dose dependently and significantly reduced PaCO2 and increased the nociceptive threshold. S-nitroso-acetylpenicillamine alone did not change the ventilation or nociceptive threshold. Morphine sulfate elicited a marked increase in PaCO2, a decrease in ventilatory drive, and an increase in nociceptive threshold (P < 0.05 compared with baseline). With L-NA pretreatment (sequence 3), but not posttreatment (sequence 1), MS-induced ventilatory depression, relative to baseline, was significantly attenuated. For both the L-NA pre- and posttreatment protocols, combined MS/L-NA perfusions produced a significantly greater antinociceptive effect than seen when MS was given alone. The L-NA effects on MS-induced ventilatory depression and antinociception were reversed with SNAP coadministration. CONCLUSIONS: Endogenous NO, produced at supraspinal sites, acts as a ventilatory depressant and as a nociceptive mediator. When NOS is inhibited, the ventilatory depressant actions of morphine can be reduced and the antinociceptive actions of morphine can be potentiated. However, NOS inhibitor treatment is more effective in suppressing morphine-induced ventilatory depression when given before, rather than after, morphine administration. The specific mechanisms involved in these actions remain to be identified.

Low back pain patients unresponsive to an epidural steroid injection: identifying predictive factors.

This study examined factors that help to identify low back pain patients who do not benefit from a lumbar epidural steroid injection (LESI). Two-hundred and forty-nine chronic low back pain patients assessed their pain intensity before, 1 day after, and 2 weeks after receiving a LESI. All patients completed a comprehensive pain questionnaire and a Brief Symptom Inventory (BSI) prior to treatment. Diagnosis and extent of pathology were independently assessed by two physicians. One-hundred and thirty-one patients (52.6%) were followed 1 year after treatment. Results showed that average pain intensity ratings decreased in 62.3% of patients 2 weeks after receiving a LESI. One year after treatment, 62.6% felt that LESI was helpful. Nine patients (7%) felt that the treatment was harmful. Four factors were identified that best predicted poor outcome 2 weeks after LESI: (a) greater number of previous treatments for pain; (b) more medications taken; (c) pain not necessarily increased by activities, and (d) pain increased by coughing. Factors that predicted no benefit 1 year after treatment included (a) pain does not interfere with activities; (b) unemployment due to pain; (c) normal straight-leg raise test prior to treatment; and (d) pain not decreased by medication.

Continuous infusion of interpleural bupivacaine maintains effective analgesia after cholecystectomy.

Twenty-five patients who had undergone elective cholecystectomy were prospectively randomized to receive via an interpleural catheter either a continuous infusion of 0.25% bupivacaine at 0.125 mL.kg-1.h-1 (n = 13) or repeated bolus injections (n = 12) of 0.5% bupivacaine with epinephrine 1:200,000 at 0.4 mL/kg every sixth hour. Adequacy of pain relief was measured by the amount of patient-controlled analgesia morphine required postoperatively and by patient scores on a visual analog scale obtained every sixth hour. Two venous blood samples for measurements of serum bupivacaine levels were obtained from patients in the continuous group at hours 6 and 24; four blood samples were obtained from patients in the bolus group, both immediately before and 30 min after injections at hours 6 and 24. Among the patients receiving the bolus injections, morphine was required 62 +/- 15 (SEM) times over the 24-h study period with total morphine dosage averaging 30 +/- 15 mg. Corresponding values for patients in the continuous groups were 35 +/- 10 times and 23 +/- 5 mg of morphine. The difference was not, however, statistically significant, but when activity during the 2-h time periods immediately before reinjection were examined, patients in the bolus group required and received significantly more morphine than did those in the continuous group (P less than 0.05). Patients in the continuous group had visual analog scale scores that averaged 2.9 +/- 0.6 over the 24-h study period. Patients within the bolus group had visual analog scale scores before and again 30 min after injection that averaged 5.8 +/- 0.8 and 1.8 +/- 0.5, respectively (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of two different volumes of 0.5% bupivacaine in a canine model of interpleural analgesia.

The effect of increasing interpleural injectate volume was determined in a chronic canine model. Changes in evoked potentials were used as a marker of nerve blockade. Electrodes were fastened to the right fifth, seventh and ninth ribs of adult dogs at distal (D), middle (M) and proximal (P) sites. Electrodes were also fastened to the ipsilateral laminae of the fifth (T5L), seventh (T7L) and ninth (T9L) thoracic vertebrae. Evoked potentials were recorded at each lamina after stimuli were applied to the corresponding distal, middle and proximal rib electrodes. Interpleural catheters were placed under direct vision during surgery. The effects of 10 ml and 20 ml of 0.5% bupivacaine were studied for each dog. Following 10 ml of 0.5% bupivacaine, intercostal nerve block was produced at T5 and T7, as evidenced by decreases in amplitude (range, 6-53% of control, p less than 0.05) and increases in latency (range, 108-122% of control, p less than 0.05) of evoked potentials recorded between laminae and distal or middle electrodes. No significant changes were seen in any potentials recorded over T9. After 20 ml of 0.5% bupivacaine, all T5 potentials were abolished. Significant decreases in amplitude (range, 22-36% of control, p less than 0.05) and increases in latency (range, 117-126% of control, p less than 0.05) were produced at all T7 rib sites. Except for the D-T7L comparison, all T5 and T7 changes produced by 20 ml of bupivacaine were greater (p less than 0.05) than those produced by 10 ml. Twenty milliliters of bupivacaine also produced decreases in amplitude (range, 41-51% of control at all sites, p less than 0.05) and increases in latency (115% at D-T9L, p less than 0.05) at T9 sites. Twenty milliliters of 0.5% bupivacaine produces intercostal nerve block that is more pronounced and widespread than that produced by 10 ml of bupivacaine.

Interpleural anesthetics in the dog: differential somatic neural blockade.

Differential somatic neural effects of interpleural bupivacaine were determined in dogs. Alterations in evoked responses were used as a marker of neural blockade. Electrode pairs were fastened to the external surface of the right seventh ribs of five male mongrel dogs (25-30 kg) at distal (D), middle (M), and proximal (P) locations. Electrodes were similarly fastened to the ipsilateral laminae of the fifth (T5L), seventh (T7L), and ninth (T9L) thoracic vertebrae, and the contralateral cranium over the sensorimotor cortex (SMC). Pediatric feeding tubes were used as interpleural catheters. Following interpleural bupivacaine (10 ml, 0.5%) intercostal nerve block was produced, as manifested by decreases in amplitude (range 12-32% of control, P less than 0.05), and increases in latency (range 108-126% of control, P less than 0.05), of evoked potentials recorded between T7L and rib electrodes. The block was found to localize over dependent portions of the rib with changes in animal position, indicating a strong influence of gravity. No significant changes were seen in potentials recorded between T9L and T5L, and T9L and SMC, regardless of position. T9L-T5L and T9L-SMC potentials were abolished or severely attenuated following direct subarachnoid or epidural injection of bupivacaine at T7. Thus, there are no spinal, epidural, or gross CNS effects of interpleural bupivacaine.

A randomized, double-blind comparison of the effects of interpleural bupivacaine and saline on morphine requirements and pulmonary function after cholecystectomy.

The effect of interpleural bupivacaine and saline placebo on morphine requirements and pulmonary function after cholecystectomy was investigated. Twenty-six patients were randomly assigned on postoperative day 1 to receive either 20 ml preservative-free saline (group 1) or 20 ml 0.5% bupivacaine with epinephrine, 5 micrograms/ml (group 2) through an interpleural catheter. Adequacy of pain relief was determined by the amount of morphine used by the patient following interpleural injection. Morphine use via a patient-controlled analgesia (PCA) system was recorded for several hours before and after interpleural injection. All patients had a forced vital capacity (FVC) and FEV1 measurement immediately before and 1 h after interpleural injection. Mean hourly PCA morphine use ranged from 1.6 to 2.8 mg for the 6 h prior to interpleural treatment for groups 1 and 2. There was no difference in PCA use between the groups during this time. Group 1 patients did not reduce PCA morphine use after interpleural saline. Patients in group 2, however, significantly reduced PCA morphine use after interpleural bupivacaine. Mean PCA morphine use for group 2 was 0.38 +/- 0.15 mg/h (mean +/- SE) (81% reduction vs. control) for the first 2 h after bupivacaine (P less than 0.05). Mean PCA use in group 2 was 0.52 +/- 0.2 mg/h (73% reduction vs. control) for the third hour after bupivacaine (P less than 0.05). At the fourth and fifth hours after bupivacaine injection, mean PCA morphine use was not significantly different from that in group 1. FVC and FEV1 did not improve after interpleural saline.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of aerosolized and/or intravenous lidocaine on hemodynamic responses to laryngoscopy and intubation in outpatients.

A randomized, double-blind study was carried out on 40 unpremedicated, ASA I-II adult surgical outpatients to assess the effects of aerosolized lidocaine, intravenous lidocaine, both, or neither, on circulatory responses to laryngoscopy and intubation. Lidocaine (4 mg/kg) or saline was given by nebulizer in the holding area beginning at -15 minutes. The patient underwent a standardized induction of anesthesia that included IV curare (3 mg) and O2 by facemask at minute 2, followed by IV thiopental (5 mg/kg) and succinylcholine (1.5 mg/kg) at minute 5. Lidocaine (2 mg/kg) or saline was given by IV push at minute 4. Laryngoscopy was begun at 5 minutes and continued for 45 seconds before intubation. Heart rate and systolic, diastolic, and mean blood pressures were automatically recorded at 1-minute intervals from 0 to 11 minutes. The four treatment groups included: group 1, aerosolized and IV saline; group 2, aerosolized saline, IV lidocaine; group 3, aerosolized lidocaine, IV saline; and group 4, aerosolized and IV lidocaine. There were no differences among the four treatment groups (n = ten per group) in any of the four hemodynamic variables before laryngoscopy and intubation. Within each group, after intubation all four hemodynamic variables increased significantly over the corresponding baseline values for that group. However, the maximum values attained after intubation did not differ significantly among the four treatment groups for any of the four hemodynamic variables, whether those maxima were expressed as absolute values or as a percentage of baseline.(ABSTRACT TRUNCATED AT 250 WORDS)