Modification of Bupivacaine-Induced Myotoxicity with Dantrolene and Caffeine In Vitro.

BACKGROUND: Local anesthetics, especially bupivacaine, have myotoxic effects in clinically used concentrations and context. Detailed mechanisms of these effects are unknown, but an increase in intracellular calcium levels is suspected to be the most important trigger. Dantrolene and caffeine modify cellular calcium release from the sarcoplasmic reticulum. The aim of our study was to investigate the effect of dantrolene and caffeine on bupivacaine-induced myotoxicity in vitro. METHODS: A cell culture model of primary muscle cells of BALB/c AnNCrl mice was established. Cells were incubated simultaneously with increasing concentrations of bupivacaine, dantrolene, and caffeine. The fraction of dead cells was calculated after staining with propidium iodide and analysis by flow cytometry. The half-maximal inhibitory concentration of bupivacaine was calculated for each concentration. Group differences were determined by using 1-way analysis of variances with subsequent post hoc 1-way Dunnett t test. RESULTS: Both dantrolene and caffeine alone had no effect on muscle cell survival. Increasing concentrations of bupivacaine caused increasing cell death. Dantrolene dose-dependently reduced the fraction of necrotic cells, whereas caffeine dose-dependently increased the fraction of dead cells. CONCLUSIONS: Dantrolene attenuated, and caffeine enhanced, bupivacaine-induced myotoxicity, presumably by modifying sarcoplasmic calcium release. This indicates that intracellular calcium release is an important factor for local anesthetic-induced cell death.

In vitro myotoxic effects of bupivacaine on rhabdomyosarcoma cells, immortalized and primary muscle cells.

BACKGROUND: Rhabdomyosarcoma is a rare malignant skeletal muscle tumor. It mainly occurs in children and young adults and has an unsatisfactory prognosis. Prior studies showed a direct myotoxic effect of bupivacaine on differentiated muscle cells in vitro and in vivo. Exact mechanisms of this myotoxicity are still not fully understood, but a myotoxic effect on malignant muscle tumor cells has not been examined so far. Thus, the aim of this study was to examine if bupivacaine has cytotoxic effects on rhabdomyosarcoma cells, immortalized muscle cells and differentiated muscle cells. METHODS: Cell lines of rhabdomyosarcoma cells, immortalized muscle cells and differentiated muscle cells were established. After microscopic identification, cells were exposed to various concentrations of bupivacaine (500, 1,000, 1,750, 2,500 and 5,000 ppm) for 1 and 2 h, respectively. 24 and 28 h after incubation the cultures were stained with propidium iodid and analyzed by flow cytometry. The fraction of dead cells was calculated for each experiment and the concentration with 50% cell survival (IC50) was computed. Cell groups as well as incubation and recovery time were compared (ANOVA/Bonferroni p < 0.01). RESULTS: The total number of cultured cells was similar for the different local anesthetics and examined concentrations. Increasing concentrations of bupivacaine led to a decrease in survival of muscle cells. IC50 was highest for immortalized cells, followed by rhabdomyosarcoma cells and differentiated cells. Exposure time, but not recovery time, had an influence on survival. CONCLUSION: Bupivacaine has clear but different cytotoxic effects on various muscle cell types in vitro. Differentiated primary cells seem to be more vulnerable than tumor cells possibly because of more differentiated intracellular structures.

The cytotoxicity of bupivacaine, ropivacaine, and mepivacaine on human chondrocytes and cartilage.

BACKGROUND: Intraarticular injections of local anesthetics are frequently used as part of multimodal pain regimens. However, recent data suggest that local anesthetics affect chondrocyte viability. In this study, we assessed the chondrotoxic effects of mepivacaine, ropivacaine, and bupivacaine. We hypothesized that specific cytotoxic potencies directly correlate with analgesic potencies, and that cytotoxic effects in intact cartilage are different than in osteoarthritic tissue. METHODS: Human articular chondrocytes were exposed to equal and equipotent concentrations of bupivacaine, ropivacaine, and mepivacaine for 1 hour. Cell viability, apoptosis, and necrosis were determined at predefined time points using flow cytometry, live-dead staining, and caspase detection. Intact and osteoarthritic human cartilage explants were treated with equipotent concentrations of named drugs to determine cell viability applying fluorescence microscopy. RESULTS: Chondrotoxic effects increased from ropivacaine to mepivacaine to bupivacaine in a time-dependent and concentration-dependent manner. Compared with control, bupivacaine 0.5% decreased chondrocyte viability to 78% ± 9% (P = 0.0183) 1 hour and 16% ± 10% (P < 0.0001) 24 hours later, as determined by live-dead staining in monolayer cultures. Viability rates were reduced to 80% ± 7% (P = 0.0475) 1 hour and 80% ± 10% (P = 0.0095) 24 hours after treatment with ropivacaine 0.75%. After exposure to mepivacaine 2%, viable cells were scored 36% ± 6% (P < 0.0001) after 1 hour and 30% ± 11% (P < 0.0001) after 24 hours. Ropivacaine treatment was less chondrotoxic than bupivacaine (P = 0.0006) and mepivacaine exposure (P = 0.0059). Exposure to concentrations up to 0.25% of bupivacaine, 0.5% of ropivacaine, and 0.5% of mepivacaine did not reveal significant chondrotoxicity in flow cytometry. However, chondrotoxicity did not correlate with potency of local anesthetics. Immediate cell death was mainly due to necrosis followed by apoptosis. Cellular death rates were clearly higher in osteoarthritic compared with intact cartilage after bupivacaine, mepivacaine, and ropivacaine treatment in a decreasing order. CONCLUSION: Bupivacaine, ropivacaine, and mepivacaine are chondrotoxic in a time-dependent, concentration-dependent, and drug-dependent manner. Chondrotoxic and analgesic potencies do not directly correlate. Cellular death rates were higher in osteoarthritic compared with intact cartilage after local anesthetic treatment.

The myotoxic effect of bupivacaine and ropivacaine on myotubes in primary mouse cell culture and an immortalized cell line.

BACKGROUND: The 2 local anesthetics (LAs) bupivacaine and ropivacaine have acute cytotoxic effects on different tissues. In this respect, LA-induced myotoxicity has been subject to various studies; however, the exact mechanisms are still not fully understood. Most in vitro studies use immortalized cell lines because of feasibility. Thus, establishing a primary cell line might result in more accurate results. In this study, we examined the effects of immortalization on bupivacaine- and ropivacaine-induced myotoxicity in vitro. METHODS: An immortalized (N = 6) and a primary cell line (N = 8) of the same tissue and species were established, and differentiation in myotubes was induced. Cells were exposed to increasing concentrations of bupivacaine and ropivacaine for 1 or 2 hours, respectively. Twenty-four and 48 hours after treatment, the fractions of dead and vital cells were measured using flow cytometry. Significance was tested through 1-way analysis of variance with post hoc Dunnett T3 test. Medians of dataset pairs were compared by T test. RESULTS: In both cell lines, increasing concentrations of both LAs resulted in decreased cell survival (e.g., P < 0.001 for 5000 ppm bupivacaine, 1 or 2 hours of incubation, and 24 hours recovery in both cell lines). For the same LA concentrations, survival was significantly higher in the immortalized cell culture (e.g., P < 0.001 for 2500 ppm ropivacaine, 1 hour of incubation, and 24 hours recovery). In addition, equal concentrations of bupivacaine resulted in significantly fewer vital cells compared with ropivacaine (e.g., P = 0.032 for 2500 ppm ropivacaine, 1 hour of incubation, and 24 hours recovery). Two hours of incubation resulted in a significantly higher rate of dead cells compared with 1 hour of incubation (e.g., P = 0.004 for C2C12 cells, 2500 ppm bupivacaine, and 24 hours recovery). CONCLUSIONS: Primary skeletal muscle cells are more vulnerable to LAs than immortalized cells. The higher myotoxic potential of bupivacaine compared with ropivacaine in vivo can be reproduced in vitro. Incubation time has an influence on cell survival.

Cytotoxicity of local anesthetics on human mesenchymal stem cells in vitro.

PURPOSE: The purpose of this study was to investigate the cytotoxic potency of local anesthetics on human mesenchymal stem cells (MSCs) before and after chondrogenic differentiation. METHODS: MSCs were exposed to equal and equipotent concentrations of bupivacaine, ropivacaine, and mepivacaine for 1 hour. Cell viability, apoptosis, and necrosis were determined using flow cytometry and live/dead staining. After chondrogenic differentiation, MSC viability was determined in aggregates exposed to equipotent concentrations of the named agents, applying fluorescence microscopy. RESULTS: All local anesthetics showed detrimental cytotoxic effects on MSC monolayer cultures in a concentration- and time-specific manner. Minimum viability rates were found 96 hours after a 1-hour exposure. Bupivacaine 0.5% caused a reduction of vital MSCs to 5% ± 1%. Sixteen percent ± 2% viable cells were detected after treatment with 0.75% ropivacaine. Exposure to 2% mepivacaine decreased vitality rates to 1% ± 0%. Ropivacaine was significantly less cytotoxic than were bupivacaine and mepivacaine. Immediate cell death was mainly caused by necrosis followed by apoptosis afterward. Viability rates of MSCs embedded in cartilaginous tissue after chondrogenic differentiation were not reduced by local anesthetic treatment. CONCLUSIONS: Local anesthetics are cytotoxic to MSCs in a concentration-, time-, and agent-dependent manner in monolayer cultures but not in whole-tissue probes. CLINICAL RELEVANCE: MSCs are applied for treatment of cartilage defects. Intra-articular application of local anesthesia is a common procedure in pain management and has shown chondrotoxic effects. Therefore, it is crucial to evaluate the impact of local anesthetics on human MSCs and regenerative cartilage tissue engineering.

Airway Management of Orofacial Infections Originating in the Mandible.

The primary aim of this study was to assess the incidence of a difficult airway and emergency tracheostomy in patients with orofacial infections originating in the mandible, and a secondary aim was to determine the potential predictors of difficult intubation. This retrospective single-center study included all patients who were referred between 2015 and 2022 with an orofacial infection originating in the mandible and who were surgically drained under intubation anesthesia. The incidence of a difficult airway regarding ventilation, laryngoscopy, and intubation was analyzed descriptively. Associations between potential influencing factors and difficult intubation were examined via multivariable analysis. A total of 361 patients (mean age: 47.7 years) were included in the analysis. A difficult airway was present in 121/361 (33.5%) patients. Difficult intubation was most common in patients with infections of the massetericomandibular space (42.6%), followed by infections of the mouth floor (40%) and pterygomandibular space (23.5%). Dyspnea and stridor were not associated with the localization of infection (p = 0.6486/p = 0.4418). Multivariable analysis revealed increased age, restricted mouth opening, higher Mallampati scores, and higher Cormack-Lehane classification grades as significant predictors of difficult intubation. Higher BMI, dysphagia, dyspnea, stridor and a non-palpable mandibular rim did not influence the airway management. Patients with a difficult airway were more likely to be admitted to the ICU after surgery than patients with regular airway were (p = 0.0001). To conclude, the incidence of a difficult airway was high in patients with orofacial infections originating in the mandible. Older age, limited mouth opening, a higher Mallampati score, and a higher Cormack-Lehane grade were reliable predictors of difficult intubation.

3,4-Methylenedioxymethamphetamine (Ecstasy) increases the sensitivity of the contractile apparatus to calcium ions in both malignant hyperthermia-susceptible and normal skeletal muscle fibres.

CONTEXT AND OBJECTIVES: The present study was designed to investigate whether 3,4-methylenedioxymethamphetamine (MDMA, 'Ecstasy') increases the sensitivity of the contractile apparatus to calcium in muscle fibres from malignant hyperthermia-susceptible and malignant hyperthermia-negative pigs, whether it causes calcium ion release from the sarcoplasmic reticulum and whether it inhibits calcium reuptake into the sarcoplasmic reticulum. DESIGN: Experimental study, using a model of porcine saponin-skinned fibres. RESULTS: Administration of MDMA in concentrations of 1, 2 and 4 mmol l(-1)l did not result in relevant force transients in skinned muscle fibres of malignant hyperthermia-susceptible or malignant hyperthermia-negative pigs. Furthermore, MDMA in these concentrations did not alter calcium ion loading of the sarcoplasmic reticulum in either group. With regard to changes in the calcium ion sensitivity of the contractile proteins, however, MDMA dose-dependently increased (pCa50) values (negative decadic logarithm of [Ca2+] at which isometric force is half-maximal) in both groups. CONCLUSION: In the present study, we were able to demonstrate that MDMA dose-dependently increases the sensitivity of the contractile apparatus to calcium in both malignant hyperthermia-susceptible and malignant hyperthermia-negative fibres. Consequently, the malignant hyperthermia status should not affect the calcium sensitivity of the contractile apparatus. However, the increased calcium sensitivity is an important finding that must be appreciated, particularly in relation to the agonistic effect of MDMA at the nicotinic acetylcholine receptor, which increases intracellular calcium ion concentrations.

Machine learning for the prediction of preclinical airway management in injured patients: a registry-based trial.

OBJECTIVE: The aim of this study was to determine the feasibility of using machine learning to establish the need for preclinical airway management for injured patients based on a standardized emergency dataset. METHODS: A registry-based, retrospective analysis was conducted of adult trauma patients who were treated by physician-staffed emergency medical services in southwestern Germany between 2018 and 2020. The primary outcome was to assess the feasibility of using the random forest (RF) and Naive Bayes (NB) machine learning algorithms to predict the need for preclinical airway management. The secondary outcome was to use a principal component analysis to determine the attributes that can be used and advanced for future model development. RESULTS: In total, 25,556 adults with multiple injuries were identified, including 1,451 patients (5.7%) who required airway management. Key attributes were auscultation, injury pattern, oxygen therapy, thoracic drainage, noninvasive ventilation, catecholamines, pelvic sling, colloid infusion, initial vital signs, preemergency status, and shock index. The area under the receiver operating characteristics curve was between 0.96 (RF; 95% confidence interval [CI], 0.96-0.97) and 0.93 (NB; 95% CI, 0.92-0.93; P<0.01). For the prediction of airway management, RF yielded a higher precision-recall area than NB (0.83 [95% CI, 0.8-0.85] vs. 0.66 [95% CI, 0.61-0.72], respectively; P<0.01). CONCLUSION: To predict the need for preclinical airway management in injured patients, attributes that are commonly recorded in standardized datasets can be used with machine learning. In future models, the RF algorithm could be used because it has robust prediction accuracy.

[Liposomal bupivacaine-No breakthrough in postoperative pain management]. / Liposomales Bupivacain ­ kein Durchbruch in der postoperativen Schmerztherapie.

One of the main limitations concerning the use of local anesthetics is due to their restricted duration of action. In recent years, liposomal formulations with prolonged release kinetics have been developed to extend the pharmacological duration of action of the 1­stage peripheral regional anesthesia (single-shot procedure) and thus bring about a longer duration of action. The focus here is particularly on achieving postoperative freedom from pain for at least 24 h (or even better 48 h) and thus early mobilization of patients using on-demand medication causing (at most) minor local sensory blockade without causing motor impairments (at least that is the ideal). Therefore, methods of utilizing slow-release drugs as seen in liposomal carrier systems have experienced increasing scientific attention in the last few years. A common modern pharmacological example with a theoretically significantly longer duration of action is liposomal bupivacaine, an amide local anesthetic. Due to a multivesicular liposome structure, the retarded release of the active component bupivacaine HCl leads to a theoretical pharmacological effectiveness of up to 72 h. Previous studies consistently showed a safety profile comparable to conventional bupivacaine HCl. Liposomal bupivacaine has been approved by the U.S. Food and Drug Administration (FDA) under the trade name Exparel© (Pacira Pharmaceuticals, Parsippany, NJ, USA) since 2011; however, its use is currently limited to local wound infiltration, transverse abdominis plane (TAP) blocks, and interscalene nerve blocks of the brachial plexus. In 2020, the European Medicines Agency (EMA) also approved the use of liposomal bupivacaine for blockade of the brachial plexus or the femoral nerve and as a field block or for wound infiltration to treat postoperative pain. So far, studies on the clinical effectiveness of liposomal bupivacaine have been very heterogeneous and there have been no conclusive meta-analyses with sufficient rigor or significance. Recent systematic reviews and meta-analyses, combining the results of clinical studies regarding the analgesic efficiency of liposomal bupivacaine in different fields of application, consistently refuted any benefit of clinical relevance provided by the liposomal formulation. There is currently sufficient evidence to now end the ongoing debate around liposomal bupivacaine. The aim of this work is to give the reader a current, evidence-based overview of this substance.

The toxic effects of s(+)-ketamine on differentiating neurons in vitro as a consequence of suppressed neuronal Ca2+ oscillations.

BACKGROUND: In the immature brain, neuronal Ca2+ oscillations are present during a time period of high plasticity and regulate neuronal differentiation and synaptogenesis. In this study we examined the long-term blockade of hippocampal Ca2+ oscillations, the role of the N-methyl-D-aspartate (NMDA) receptors and the effects of S(+)-ketamine on neuronal synapsin expression. METHODS: Hippocampal neurons were incubated at day 15 in culture with the specific NMDA receptor antagonists dizocilpine (MK 801, 100 µM) or S(+)-ketamine (3 µM to 25 µM) for 24 hours. Terminal-deoxynucleotidyl-transferase (TUNEL) and activated caspase3 were used to detect apoptotic neurons. Ca2+ oscillations were detected after loading the neurons with the Ca2+-sensitive dye fura-2AM, and dual wavelength excitation fluorescence microscopy was performed. Ca2+/calmodulin kinase II (CaMKII) was measured using Western blots. Synapsin was identified with confocal antisynapsin immunofluorescence. RESULTS: Blocking the NMDA receptor with MK 801 or 25 µM S(+)-ketamine resulted in a significant increase in apoptotic neurons. MK 801 led to a significant increase in cytosolic Ca2+ concentration and reduction of the amplitude and frequency of the Ca2+ oscillations. Similar to MK 801, the long-term application of S(+)-ketamine resulted in a significant increase in cytosolic Ca2+ concentration 24 hours after washout. This was associated with a down-regulation of the CaMKII and a reduction of the synapsin 24 hours after washout. CONCLUSION: Neuronal Ca2+ oscillations mediate neuronal differentiation and synaptogenesis via activating CaMKII. By acting via the NMDA receptor, S(+)-ketamine exerts its toxic effect through the suppression of neuronal Ca2+ oscillations, down-regulation of the CaMKII, and consecutively reduced synaptic integrity.

[Strategic planning: an important economic action for German hospitals]. / Strategische Planung - Eine wichtige ökonomische Handlungsweise für deutsche Krankenhäuser.

In medical systems, economic issues and means of action are in the course of dwindling human (physicians and nurses) and financial resources are more important. For this reason, physicians must understand basic economic principles. Only in this way, there may be medical autonomy from social systems and hospital administrators. The current work is an approach to present a model for strategic planning of an anesthesia department. For this, a "strengths", "weaknesses", "opportunities", and "threats" (SWOT) analysis is used. This display is an example of an exemplary anaesthetic department.

Collateral damages in the SARS-CoV-2 pandemia- two cases.

BACKGROUND AND AIMS: At present, "severe acute respiratory syndrome new coronavirus" (SARS-CoV-2) affects the whole world and has led to a pandemia with almost 2.000.000 infected patients in the mid of April 2020 (WHO). Thus, health care specialists primarily focus on therapy of corona disease 2019 (COVID-19) and a lot of effort has been undertaken to get more manpower on intensive care units. However, the number of patients with life threatening diseases other than COVID-19 like heart attacks or strokes has not changed at all. With a strong focus on COVID-19, there is a marked risk of diagnostic and therapeutic delays or misdiagnoses, potentially harming those patients. In this respect, we present two of those cases with the intent to improve the medical management of "traditional" diseases in times of corona pandemia. METHODS: We present two patients with diseases others than SARS-CoV-2. Both cases were treated in our institution, a tertiary care hospital in the Southwest of Germany. RESULTS: One patient had a prolonged treatment on intensive care unit (ICU) because of heart failure following voluntary isolation because of fearing COVID-19 and subsequent shortage of medication. Another patient with hypothesis of COVID-19 of primary care physician because of fever and a history of skiing in a high risk region for SARS-CoV-2 was sent home for isolation. After disease progression, the patient presented in an external hospital with fever, pain in the right ear and tachypnea. Immediately, antibiotics were started at same day, but nevertheless, he developed a septic shock, leading to multi organ failure. In blood samples, bacteria Streptococcus pyogenes was found, without any signs of SARS-CoV-2-infection. Despite adequate antibiosis, the patient developed fixed pupils, brain edema and died because of massive brain edema. CONCLUSION: Focusing only on COVID-19 may lead to delayed diagnosis and therapy in patients with "traditional diseases". These two cases impressively clarify medical challenges in times of SARS-CoV-2 pandemia. It is important to emphasize that physicians and health care professionals have not only to focus on COVID-19 and virus associated diseases, but also on adequate drug supply, intake and monitoring and differential diagnoses, respectively.

Cardiac effects of induction agents in the septic rat heart.

INTRODUCTION: The current debate about the side effects of induction agents, e.g. possible adrenal suppression through etomidate, emphasizes the relevance of choosing the correct induction agent in septic patients. However, cardiovascular depression is still the most prominent adverse effect of these agents, and might be especially hazardous in septic patients presenting with a biventricular cardiac dysfunction--or so-called septic cardiomyopathy. Therefore, we tested the dose-response direct cardiac effects of clinically available induction agents in an isolated septic rat heart model. METHODS: A polymicrobial sepsis was induced via cecal ligation and single puncture. Hearts (n = 50) were isolated and randomly assigned to five groups, each receiving etomidate, s(+)-ketamine, midazolam, propofol, or methohexitone at concentrations of 1 x 10-8 to 1 x 10-4 M. Left ventricular pressure, contractility and lusitropy, and coronary flow were measured. Cardiac work, myocardial oxygen delivery, oxygen consumption, and percentage of oxygen extraction were calculated. RESULTS: All of the induction agents tested showed a dose-dependent depression of cardiac work. Maximal cardiac work dysfunction occurred in the rank order of s(+)-ketamine (-6%)

What determines the efficacy of forced-air warming systems? A manikin evaluation with upper body blankets.

BACKGROUND: Forced-air warming has gained acceptance as an effective means to prevent perioperative hypothermia. However, little is known about the influence of air flow and air temperature at the nozzle and the influence of heat distribution in the blankets on the efficacy of these systems. METHODS: We conducted a manikin study with heat flux transducers using five forced-air warming systems to determine the factors that are responsible for heat transfer from the blanket to the manikin. RESULTS: There was no relation between air temperature at the nozzle of the power unit and the resulting heat transfer. There was also no relation between the air flow at the nozzle of the power unit and the resulting heat transfer. However, all blankets performed best at high air flows above 19 L/s. The heat exchange coefficient, the mean temperature gradient between the blanket and the manikin correlated positively with the resulting heat transfer and the difference between the minimal and maximal blanket temperature correlated negatively with the resulting heat transfer. CONCLUSIONS: The efficacy of forced-air warming systems is primarily determined by the blanket. Modern power units provide sufficient heat energy to maximize the ability of the blanket to warm the patient. Optimizing blanket design by optimizing the mean temperature gradient between the blanket and the manikin (or any other surface) with a very homogeneous temperature distribution in the blanket will enable the manufacturers to develop better forced-air warming systems.

Lipid emulsion improves recovery from bupivacaine-induced cardiac arrest, but not from ropivacaine- or mepivacaine-induced cardiac arrest.

BACKGROUND: Cardiac toxicity significantly correlates with the lipophilicity of local anesthetics (LAs). Recently, the infusion of lipid emulsions has been shown to be a promising approach to treat LA-induced cardiac arrest. As the postulated mechanism of action, the so-called "lipid sink" effect may depend on the lipophilicity of LAs. In this study, we investigated whether lipid effects differ with regard to the administered LAs. METHODS: In the isolated rat heart, cardiac arrest was induced by administration of equipotent doses of bupivacaine, ropivacaine, and mepivacaine, respectively, followed by cardiac perfusion with or without lipid emulsion (0.25 mL x kg(-1) x min(-1)). Subsequently, the times from the start of perfusion to return of first heart activity and to recovery of heart rate and rate-pressure product (to 90% of baseline values) were assessed. RESULTS: In all groups, lipid infusion had no effects on the time to the return of any cardiac activity. However, recovery times of heart rate and rate-pressure product (to 90% of baseline values) were significantly shorter with the administration of lipids in bupivacaine-induced cardiac toxicity, but not in ropivacaine- or mepivacaine-induced cardiac toxicity. CONCLUSIONS: These data show that the effects of lipid infusion on LA-induced cardiac arrest are strongly dependent on the administered LAs itself. We conclude that lipophilicity of LAs has a marked impact on the efficacy of lipid infusions to treat cardiac arrest induced by these drugs.

Alterations in intracellular Ca2+-homeostasis of skeletal muscle fibers during sepsis.

OBJECTIVE: To investigate changes in intracellular Ca2+-regulation and Ca2+-sensitivity of the contractile apparatus in murine skeletal muscle fibers during sepsis. DESIGN AND SETTING: Animal study in a university-based research laboratory. SUBJECTS: Isolated muscle fibers (M. extensor digitorum longus) of septic mice. INTERVENTIONS: In one group, sepsis was induced in "black six" mice using cecal ligation and puncture (CLP). In a second group, laparotomy (SHAM), and in a third group, general anesthesia (GA) was performed. Saponin-skinned skeletal muscle fibers were examined 2, 3, 5, and 7 days after treatment, and caffeine-induced Ca2+-release from the sarcoplasmic reticulum (SR) as well as Ca2+-sensitivity of the contractile apparatus were assessed. MEASUREMENTS AND RESULTS: In the CLP group, Ca2+-release significantly decreased over 5 days and increased again after 7 days. In the SHAM group, Ca2+-release decreased at days 2 and 3, whereas no changes were observed in the GA group. Ca2+-sensitivity significantly increased over 5 days in the CLP group and decreased again at day 7. In the SHAM group, Ca2+-sensitivity increased at days 2 and 3, and no changes were seen in the GA group. CONCLUSIONS: In murine skeletal muscle fibers, Ca2+-release from the SR decreases during sepsis, with effects being most pronounced 2-3 days after CLP. In parallel, Ca2+-sensitivity of the contractile apparatus is increased, and all changes are reversible. Thus, these effects might be involved in skeletal muscle dysfunction during sepsis as corresponding changes are less pronounced or absent in control groups.

The toxicity of local anesthetics: the place of ropivacaine and levobupivacaine.

PURPOSE OF REVIEW: Ropivacaine and levobupivacaine were developed after evidence of bupivacaine-related severe toxicity. Despite a comparable analgesic profile, quantitative differences become evident with regard to their specific rate of systemic toxicity. The present article provides a concise review of the toxic potencies of levobupivacaine and ropivacaine. RECENT FINDINGS: As lipophilicity is known to be a major determinant in local anesthetic toxicity, the clinical safety profile of ropivacaine seems to be more favorable than that of levobupivacaine. Experimental studies and case reports confirm this hypothesis, showing that ropivacaine is characterized by fewer (cardio) toxic effects and, most probably, a greater margin of safety. Both agents also may dose dependently damage neurons and skeletal muscle tissue at the injection site. Although their specific rate of neurotoxicity appears to be rather low, levobupivacaine is characterized by an outstanding myotoxic potential. SUMMARY: Compared with bupivacaine, both agents may be considered as 'more well tolerated' but not as 'totally well tolerated', as they are still capable of inducing systemic and local toxicity. However, ropivacaine seems to have the greatest margin of safety of all long-acting local anesthetics at present.

A comparison of three phosphodiesterase type III inhibitors on mechanical and metabolic function in guinea pig isolated hearts.

Little is known about of the comparative cardiac lusitropic and coronary vasoactive effects of type III phosphodiesterase inhibitors independent of their systemic circulatory effects. We hypothesized that phosphodiesterase inhibitors have dissimilar concentration-dependent effects on cardiac function and metabolism and that their coronary vasodilatory effects are solely dependent on flow autoregulation secondary to positive inotropic effects. Our aim was to compare the dose-response electrophysiologic, mechanical, vasodilatory, and metabolic properties of three clinically available phosphodiesterase inhibitors in isolated Langendorff perfused guinea pig hearts. We found that, over a range from 10(-7) to 10(-4) M, amrinone, enoximone, and milrinone each produced maximal concentration-dependent positive chronotropic (12%, 18%, 26%), inotropic (16%, 26%, 26%), and lusitropic (14%, 21%, 19%) effects. At clinical concentrations, all phosphodiesterase inhibitors increased heart rate, but only milrinone significantly enhanced contractility and relaxation (11%). Each phosphodiesterase inhibitor similarly increased contractility at its highest concentration; this was accompanied by an increase in oxygen consumption, which was matched by comparable increases in coronary flow and oxygen delivery. Coronary flow reserve was preserved at the highest concentration of each drug, indicating that an increased metabolic rate was responsible for the increase in coronary flow by each drug at each concentration. Over the concentrations examined, we conclude that each of the phosphodiesterase inhibitors does not directly promote coronary vasodilation and that milrinone has the most prominent effects on contractility and relaxation at clinically relevant concentrations.