François Sztark

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.

Coagulation parameters in patients receiving dabigatran etexilate or rivaroxaban: Two observational studies in patients undergoing total hip or total knee replacement

INTRODUCTION Dabigatran and rivaroxaban have recently been added to the armamentarium for thromboprophylaxis in orthopedic surgery. Although this is their first licensed indication, others will soon follow. Owing to their claimed predictable anticoagulant response that dispenses with the need for monitoring coagulation, their effects are poorly described in routine cases. However, interpreting blood coagulation results and evaluating whether a treatment is properly targeted in the case of untoward incidents will become a common concern for clinicians. METHODS Eighty patients undergoing total hip or knee replacement were included in two studies. Forty of them received dabigatran (study 1) and 40 rivaroxaban (study 2). Blood samples (n = 176 and 166) were taken preoperatively and twice a week from the first postoperative day. RESULTS Dabigatran increased aPTTr about two-fold and PT about 1.2-fold, and it was mostly an initiation-phase modulator of thrombin generation. Mean circulating concentrations as measured by a diluted thrombin time were 105 ± 85 ng/mL at T(max) in samples from patients receiving the full dosing. They depended significantly on renal function, body weight and gender. Rivaroxaban increased aPTTr and PTr around 1.5 fold and modified the initiation and amplification phases of thrombin generation, with a lowered and prolonged thrombin burst. Mean circulating concentrations as measured by an antiXa test were 117 ± 78 ng/mL at T(max). With both drugs, routine coagulation tests, thrombin generation curves and functionally determined concentrations exhibited high interindividual variability. CONCLUSION Routine coagulation tests are altered in patients receiving dabigatran or rivaroxaban, but their alterations poorly reflect the circulating concentrations as determined by functional approaches.

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)

High-Protein Enteral Nutrition Enriched With Immune-Modulating Nutrients vs Standard High-Protein Enteral Nutrition and Nosocomial Infections in the ICU: A Randomized Clinical Trial

IMPORTANCE Enteral administration of immune-modulating nutrients (eg, glutamine, omega-3 fatty acids, selenium, and antioxidants) has been suggested to reduce infections and improve recovery from critical illness. However, controversy exists on the use of immune-modulating enteral nutrition, reflected by lack of consensus in guidelines. OBJECTIVE To determine whether high-protein enteral nutrition enriched with immune-modulating nutrients (IMHP) reduces the incidence of infections compared with standard high-protein enteral nutrition (HP) in mechanically ventilated critically ill patients. DESIGN, SETTING, AND PARTICIPANTS The MetaPlus study, a randomized, double-blind, multicenter trial, was conducted from February 2010 through April 2012 including a 6-month follow-up period in 14 intensive care units (ICUs) in the Netherlands, Germany, France, and Belgium. A total of 301 adult patients who were expected to be ventilated for more than 72 hours and to require enteral nutrition for more than 72 hours were randomized to the IMHP (n = 152) or HP (n = 149) group and included in an intention-to-treat analysis, performed for the total population as well as predefined medical, surgical, and trauma subpopulations. INTERVENTIONS High-protein enteral nutrition enriched with immune-modulating nutrients vs standard high-protein enteral nutrition, initiated within 48 hours of ICU admission and continued during the ICU stay for a maximum of 28 days. MAIN OUTCOMES AND MEASURES The primary outcome measure was incidence of new infections according to the Centers for Disease Control and Prevention (CDC) definitions. Secondary end points included mortality, Sequential Organ Failure Assessment (SOFA) scores, mechanical ventilation duration, ICU and hospital lengths of stay, and subtypes of infections according CDC definitions. RESULTS There were no statistically significant differences in incidence of new infections between the groups: 53% (95% CI, 44%-61%) in the IMHP group vs 52% (95% CI, 44%-61%) in the HP group (P = .96). No statistically significant differences were observed in other end points, except for a higher 6-month mortality rate in the medical subgroup: 54% (95% CI, 40%-67%) in the IMHP group vs 35% (95% CI, 22%-49%) in the HP group (P = .04), with a hazard ratio of 1.57 (95% CI, 1.03-2.39; P = .04) for 6-month mortality adjusted for age and Acute Physiology and Chronic Health Evaluation II score comparing the groups. CONCLUSIONS AND RELEVANCE Among adult patients breathing with the aid of mechanical ventilation in the ICU, IMHP compared with HP did not improve infectious complications or other clinical end points and may be harmful as suggested by increased adjusted mortality at 6 months. These findings do not support the use of IMHP nutrients in these patients. TRIAL REGISTRATION trialregister.nl Identifier: NTR2181.

Changes in stroke volume induced by passive leg raising in spontaneously breathing patients: comparison between echocardiography and Vigileo™/FloTrac™ device

IntroductionPassive leg raising (PLR) is a simple reversible maneuver that mimics rapid fluid loading and increases cardiac preload. The effects of this endogenous volume expansion on stroke volume enable the testing of fluid responsiveness with accuracy in spontaneously breathing patients. However, this maneuver requires the determination of stroke volume with a fast-response device, because the hemodynamic changes may be transient. The Vigileo™ monitor (Vigileo™; Flotrac™; Edwards Lifesciences, Irvine, CA, USA) analyzes systemic arterial pressure wave and allows continuous stroke volume monitoring. The aims of this study were (i) to compare changes in stroke volume induced by passive leg raising measured with the Vigileo™ device and with transthoracic echocardiography and (ii) to compare their ability to predict fluid responsiveness.MethodsThirty-four patients with spontaneous breathing activity and considered for volume expansion were included. Measurements of stroke volume were obtained with transthoracic echocardiography (SV-TTE) and with the Vigileo™ (SV-Flotrac) in a semi-recumbent position, during PLR and after volume expansion (500 ml saline). Patients were responders to volume expansion if SV-TTE increased ≥ 15%.ResultsFour patients were excluded. No patients received vasoactive drugs. Seven patients presented septic hypovolemia. PLR-induced changes in SV-TTE and in SV-Flotrac were correlated (r2 = 0.56, P < 0.0001). An increase in SV-TTE ≥ 13% during PLR was predictive of response to volume expansion with a sensitivity of 100% and a specificity of 80%. An increase in SV-Flotrac ≥16% during PLR was predictive of response to volume expansion with a sensitivity of 85% and a specificity of 90%. There was no difference between the area under the ROC curve for PLR-induced changes in SV-TTE (AUC = 0.96 ± 0.03) or SV-Flotrac (AUC = 0.92 ± 0.05). Volume expansion-induced changes in SV-TTE correlated with volume expansion-induced changes in SV-Flotrac (r2 = 0.77, P < 0.0001). In all patients, the highest plateau value of SV-TTE recorded during PLR was obtained within the first 90 s following leg elevation, whereas it was 120 s for SV-Flotrac.ConclusionsPLR-induced changes in SV-Flotrac are able to predict the response to volume expansion in spontaneously breathing patients without vasoactive support.

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.

Effects of intermittent femoral nerve injections of bupivacaine, levobupivacaine, and ropivacaine on mitochondrial energy metabolism and intracellular calcium homeostasis in rat psoas muscle.

Background:Long-acting local anesthetics cause muscle damage. Moreover, long-acting local anesthetics act as uncoupler of oxidative phosphorylation in isolated mitochondria and enhance sarcoplasmic reticulum Ca2+ release. The aim of the study was to evaluate effects of perineural injections of local anesthetics on mitochondrial energetic metabolism and intracellular calcium homeostasis in vivo. Methods:Femoral nerve block catheters were inserted in adult male Wistar rats. Rats were randomized and received seven injections (1 ml/kg) of bupivacaine, levobupivacaine, ropivacaine, or isotonic saline at 8-h intervals. Rats were killed 8 h after the last injection. Psoas muscle was quickly dissected from next to the femoral nerve. Local anesthetic concentrations in muscle were determined. Oxidative capacity was measured in saponin-skinned fibers. Oxygen consumption rates were measured, and mitochondrial adenosine triphosphate synthesis rate was determined. Enzymatic activities of mitochondrial respiratory chain complexes were evaluated. Local calcium release events (calcium sparks) were analyzed as well as sarcoplasmic reticulum calcium content in saponin-skinned fibers. Results:Eight hours after the last injection, psoas muscle concentration of local anesthetics was less than 0.3 &mgr;g/g tissue. Adenosine triphosphate synthesis and adenosine triphosphate–to–oxygen ratio were significantly decreased in the muscle of rats treated with local anesthetics. A global decrease (around 50%) in all of the enzyme activities of the respiratory chain was observed. Levobupivacaine increased the amplitude and frequency of the calcium sparks, whereas lower sarcoplasmic reticulum calcium content was shown. Conclusion:Bupivacaine, levobupivacaine, and ropivacaine injected via femoral nerve block catheters induce a deleterious effect in mitochondrial energy, whereas only levobupivacaine disturbs calcium homeostasis.

Comparison of Effects of Equiosmolar Doses of Mannitol and Hypertonic Saline on Cerebral Blood Flow and Metabolism in Traumatic Brain Injury

The potential superiority of hypertonic saline (HTS) over mannitol (MTL) for control of intracranial pressure (ICP) following traumatic brain injury (TBI) is still debated. Forty-seven severe TBI patients with increased ICP were prospectively recruited in two university hospitals and randomly treated with equiosmolar infusions of either MTL 20% (4 mL/kg; n=25 patients) or HTS 7.5% (2 mL/kg; n=22 patients). Serum sodium, hematocrit, ICP, arterial blood pressure, cerebral perfusion pressure (CPP), shear rate, global indices of cerebral blood flow (CBF) and metabolism were measured before, and 30 and 120 min following each infusion during the course of illness. Outcome was assessed at 6 months. Both HTS and MTL effectively and equally reduced ICP levels with subsequent elevation of CPP and CBF, although this effect was significantly stronger and of longer duration after HTS and correlated with improved rheological blood properties induced by HTS. Further, effect of HTS on ICP appeared to be more robust in patients with diffuse brain injury. In contrast, oxygen and glucose metabolic rates were left equally unaffected by both solutions. Accordingly, there was no significant difference in neurological outcome between the two groups. In conclusion, MTL was as effective as HTS in decreasing ICP in TBI patients although both solutions failed to improved cerebral metabolism. HTS showed an additional and stronger effect on cerebral perfusion of potential benefit in the presence of cerebral ischemia. Treatment selection should therefore be individually based on sodium level and cerebral hemodynamics.