P. Dabadie

Comparison of the Effects of Bupivacaine and Ropivacaine on Heart Cell Mitochondrial Bioenergetics

Background High lipophilic local anesthetics interfere with mitochondrial energy metabolism. These metabolic effects could in part explain some of the toxic effects of local anesthetics, such as bupivacaine‐induced myocardial depression. The aim of this study was to compare the bioenergetic effects of the local anesthetics bupivacaine and ropivacaine. Methods The effects of both local anesthetics on mitochondrial energy metabolism were studied in rat heart isolated mitochondria and in saponin‐skinned left ventricle fibers. Oxygen consumption, adenosine triphosphate synthesis, and enzymatic activities of the complexes of the respiratory chain were measured. Results Bupivacaine and ropivacaine acted, in isolated mitochondria, as uncouplers between oxygen consumption and phosphorylation of adenosine diphosphate. Further, an inhibitory effect of mitochondrial respiration was evidenced with both anesthetics during maximal respiration and was assigned to a direct inhibition of complex I of the respiratory chain. Mitochondrial adenosine triphosphate synthesis was decreased by both mechanisms. However, both in isolated mitochondria and in permeabilized heart fibers, ropivacaine was less potent than bupivacaine. Adenosine triphosphate synthesis was completely suppressed at 3 mM ([approximately] 0.1%) bupivacaine, whereas 3 mM ropivacaine induced only about a 40% inhibition. Conclusions Ropivacaine disturbs mitochondrial energy metabolism less than bupivacaine does. The lower lipid solubility of ropivacaine may be responsible for the lesser dose‐dependent effects of this drug on mitochondrial bioenergetics.

Hemodynamic effects of spinal anesthesia in the elderly: single dose versus titration through a catheter.

Sixty elderly patients (> 70 yr old) undergoing surgery for hip fracture were prospectively studied in order to compare hemodynamic tolerance of titrated doses of hyperbaric bupivacaine using continuous spinal anesthesia (CSA) versus single-dose spinal anesthesia (SDSA). Patients were randomized into two groups (CSA group: n = 30; SDSA group: n = 30). The SDSA patients received 10-15 mg of 0.5% hyperbaric bupivacaine (based on age and height), and the CSA patients received a starting dose of 5 mg of 0.5% hyperbaric bupivacaine, followed after 15 min by optional reinjection of 2.5 mg every 5 min until a T10 level sensory block was reached. Onset of anesthesia, noninvasive hemodynamic variables and the need for ephedrine were studied for 4 h after induction of anesthesia. Spinal anesthesia was successful in all patients. Decreases in mean arterial pressure were significantly less frequent and less pronounced in the CSA group (19.9% +/- 1.6% of the baseline value) than in the SDSA group (40.2% +/- 1.9%, P < 0.0001). The mean dose of ephedrine was significantly less in the CSA group (1.8 +/- 0.7 mg, administered to only 37% of patients) than in the SDSA group (19.4 +/- 3.3 mg administered to all patients, P < 0.0001). No late complications related to the spinal anesthesia technique were observed in either group. We concluded that CSA, using small titrated doses of 0.5% hyperbaric bupivacaine, is safe, efficient, and provides better hemodynamic stability than SDSA in elderly patients. (Anesth Analg 1996;82:312-6)

Uncoupling effects of local anesthetics on rat liver mitochondria.

We demonstrate in this paper that bupivacaine, a local anesthetic, can act alone as an uncoupler of rat liver mitochondria. It stimulates state 4 respiration, induces a swelling in potassium acetate (in the presence of valinomycin), and collapses the transmembrane potential. Lidocaine, another local anesthetic, requires the presence of a lipophilic anion such as TPB− to produce the same effects. TPB− can also reinforce the action of bupivacaine. These differences in action of the two local anesthetics can be explained by the difference in their liposolubility.

Generation of procoagulant microparticles in cerebrospinal fluid and peripheral blood after traumatic brain injury.

BACKGROUND Traumatic brain injury (TBI) can induce cell damage. Procoagulant microparticles (MPs) are reliable markers of cell stimulation. The aim of this study was to investigate the generation of procoagulant MPs in the cerebrospinal fluid (CSF) and plasma of patients with severe TBI. MATERIAL CSF and plasma MPs of 16 patients with severe TBI were quantified by functional prothrombinase assay (i) on the day of the trauma, (ii) during a 10-day follow-up and compared with control samples. The cellular origin of MP was determined after capture with specific antibodies. RESULTS The CSF and plasma of patients with severe TBI revealed a significantly increased generation of MP compared with control samples on the day of the trauma (CSF: 4.5 +/- 1.8 vs. 0.83 +/- 0.28 nanomolar PhtdSer equivalent; p = 0.01 and plasma 4.1 +/- 3.7 vs. 2.3 +/- 0.19 nanomolar PhtdSer equivalent; p = 0.02). Procoagulant MPs were mainly of platelet and endothelial origin in CSF. MPs decreased significantly in the CSF 10 days after TBI. In CSF, a sustained generation of procoagulant MP was evidenced in two patients presenting a poor clinical outcome. In the blood flow, elevated amounts of procoagulant MPs were detected in three patients presenting disseminated intravascular coagulopathy during the follow-up. CONCLUSION Procoagulant MP testifying to platelet and endothelial activation are produced in the CSF and in the plasma after severe TBI. A sustained generation of procoagulant MP in the CSF could contribute to a poor clinical outcome.

Absence of Stereospecific Effects of Bupivacaine Isomers on Heart Mitochondrial Bioenergetics

Background Highly lipophilic local anesthetics interfere with mitochondrial energy metabolism. These metabolic effects could, in part, explain some toxic effects of local anesthetics, such as bupivacaine-induced myocardial depression. The purpose of this study was to compare the optically pure isomers of bupivacaine on heart mitochondrial bioenergetics. Methods Both bupivacaine enantiomers were tested on rat heart isolated mitochondria. Oxygen consumption, adenosine triphosphate synthesis, and enzymatic activities of the four complexes of the respiratory chain were measured. Results No significant differences were found between R(+)- and S (−)-bupivacaine on mitochondrial oxidative phosphorylation with a similar dose-dependent decrease in adenosine triphosphate synthesis. Complex I (nicotinamide adenine dinucleotide ubiquinone reductase) was the enzymatic complex of the respiratory chain most sensitive to the bupivacaine isomers. Half-inhibitory concentrations for R (+)- and S (−)-bupivacaine were not statistically different (3.3 ± 0.4 mm and 2.8 ± 0.6 mm, respectively). Conclusions No stereospecific effects of bupivacaine enantiomers were shown in the inhibition of complex I activity and uncoupling of oxidative phosphorylation. This can be correlated with the lack of stereospecific effects of bupivacaine on myocardial depression. The lipid solubility of local anesthetics appears to be the principal physicochemical factor affecting the potency of these tertiary amines on mitochondrial bioenergetics.

EFFECTS OF THE ANAESTHETIC PROPOFOL ON THE CALCIUM-INDUCED PERMEABILITY TRANSITION OF RAT HEART MITOCHONDRIA : DIRECT PORE INHIBITION AND SHIFT OF THE GATING POTENTIAL

Mitochondrial calcium exchanges are involved in intracellular calcium homeostasis and in the contraction‐relaxation process in myocytes. The calcium‐induced permeability transition of the heart mitochondria inner membrane appears to be an important calcium efflux mechanism involved in some physiological and pathological situations. The negative inotropic effect of the anaesthetic propofol results in part from a decrease in intracellular calcium availability. Thus, this study evaluates the effects of propofol on calcium transport and permeability transition of heart mitochondria. The propofol‐inhibition of the permeability transition of liver mitochondria was previously investigated [Eriksson, O. (1991) FEBS Lett. 279, 45–48] in such conditions that its uncoupling effect was not taken into account. We show here that propofol uncoupling results in a decrease in calcium uptake rate which could in part explain the decreased permeability transition rate. However, comparison of equipotent uncoupling concentrations of propofol and carbonylcyanide m‐chlorophenylhydrazone reveals that beyond this uncoupling effect, propofol has a direct inhibitory action on the permeability transition pore, concomittant with a shift of its gating potential.

Epidemiology of traumatic comas: a prospective population-based study.

Objective : Most studies on patients with severe brain injury (SBI) are based on data from specialized centres. This prospective epidemiologic study included all patients in a defined region with a coma lasting more than 24 hours or leading to a death. Methods : All patients with a SBI admitted to an emergency department in the region were included during a 1-year period. A data form was completed with initial neurological state, CT scan lesions and associated injuries. Outcome at the end of acute hospitalization was assessed from medical notes. Results : Two hundred and forty-eight patients were registered. Annual incidence was 8.5/100 000 population. Median age was 41 years. Traffic crashes were the most frequent cause (59%). Falls occurred in 30% (16% from a high level, 14% from one level). Initial GCS was above 8 in 31%, and patients with a neurological deterioration were older (52 vs 32 years). Death occurred in 52% of the cohort. Outcome was related to CT scan diagnosis, delay before eye opening and delay before obeying commands. Conclusion. This population-based cohort of patients with SBI was different from patients selected in trauma centres. The patients were older, more often injured in falls and their mortality rate remained very high.

Effects of the local anesthetic bupivacaine on mitochondrial energy metabolism: change from uncoupling to decoupling depending on the respiration state

The local anesthetic bupivacaine has been found to uncouple oxidative phosphorylation. However, the precise mechanisms of bupivacaine uncoupling have not been elucidated. In the present paper, we demonstrate that the uncoupling effect of the local anesthetic depends on the respiration state. In state 4‐respiration (no ADP phosphorylation), bupivacaine acts as a true protonophoretic uncoupler. On the other hand, in state 3‐respiration (ADP phosphorylation), bupivacaine induces a change in proton pump stoichiometry and appears to be a decoupler (slip inducer). Moreover, at high concentration, the local anesthetic inhibits the respiratory chain itself. Thus, the divergent reports in the literature on the action of bupivacaine show in fact the various mechanisms by which the local anesthetic may alter mitochondrial energy metabolism

The use of 0.25% lidocaine with fentanyl and pancuronium for intravenous regional anesthesia

The present study was designed to assess the efficacy of fentanyl and pancuronium combined with dilute lidocaine solution for intravenous regional anesthesia of the arm.Forty adult patients undergoing upper limb surgery were randomly allocated to receive either 0.6 mL/kg of 0.5% lidocaine (3 mg/kg) or 0.6 mL/kg of 0.25% lidocaine (1.5 mg/kg) with 1 micro g/kg of fentanyl and 0.5 mg of pancuronium. The onset of sensory and motor blocks was significantly shorter in the 0.5% lidocaine group (P < 0.05). However, no differences in analgesia or motor blockade were found between the two groups at 20 min tourniquet time. Regional anesthesia was considered successful in more than 85% of patients. One patient in the 0.25% lidocaine group experienced a transient diplopia after tourniquet release. Postoperative analgesia time was similar in the two groups. We conclude that the addition of fentanyl plus pancuronium to the lidocaine solution reduces the dose of the local anesthetic and possibly systemic toxicity. (Anesth Analg 1997;84:777-9)

Effects of bupivacaine on cellular oxygen consumption and adenine nucleotide metabolism.

Previous studies on isolated mitochondria have shown an alteration of mitochondrial metabolism by local anesthetics, with an inhibition of adenosine triphosphate synthesis. To show that the same is true for mitochondria intracellularly the effects of the local anesthetic bupivacaine on cellular energy metabolism were studied on cultured fibroblasts. Cells in suspension were analyzed for oxygen consumption using a polarographic method with a Clark electrode, and for cytosol and mitochondrial adenine nucleotides by high performance liquid chromatography, Bupivacaine produced a dose‐dependent inhibition of oxygen consumption (50% inhibition at 1.5 mM). After incubation in the presence of bupivacaine, adenosine triphosphate and total adenine nucleotides decreased in the cells, as did the adenylate energy charge. These results demonstrate that bupivacaine interacts with cellular energy metabolism and leads to a depletion of high‐energy phosphates. Such intracellular mechanisms could explain in part bupivacaine‐induced myocardial depression.