Systemic lidocaine does not attenuate hepatic dysfunction after liver surgery in rats.

BACKGROUND: Lidocaine has been shown to attenuate ischemia-reperfusion (I/R) injury in the heart, lung, and brain, potentially due to modulation of inflammatory responses and apoptotic signaling pathways. Because hepatic I/R injury after liver surgery still poses a significant risk for postoperative liver dysfunction or even failure, we investigated whether systemic lidocaine would also positively affect hepatocellular damage and overall liver function after hepatic I/R injury. In addition the potential underlying mechanisms of action were studied. METHODS: A standardized rat model of 70% I/R injury was used to assess the effects of systemic lidocaine on hepatocellular damage after 60 minutes of ischemia and subsequent reperfusion. To better mimic the clinical situation, we combined 45 minutes of ischemia with partial hepatectomy in a second model. Systemic lidocaine was administered continuously, starting 30 minutes before the ischemic insult until 20 minutes of reperfusion. Hepatocellular function was assessed using different variables of liver synthesis, cellular integrity, and metabolism. Inflammation was evaluated by measuring leukocyte influx and apoptosis detected using TUNEL staining and a caspase-3 assay. RESULTS: In both models, I/R injury resulted in a significant increase in biochemical and histological hepatocellular damage with comparable values in control and lidocaine-treated animals. Postoperative liver function was significantly impaired secondary to ischemia, yet no significant differences between control and lidocaine groups could be observed. Likewise, there was no significant difference between control and lidocaine-treated animals with respect to I/R injury-induced leukocyte influx, as a marker for inflammatory response. CONCLUSION: Systemic lidocaine in therapeutic concentrations neither attenuated hepatocellular damage nor improved postoperative liver function after hepatic I/R injury.

Magnesium--essentials for anesthesiologists.

Magnesium plays a fundamental role in many cellular functions, and thus there is increasing interest in its role in clinical medicine. Although numerous experimental studies indicate positive effects of magnesium in a variety of disease states, large clinical trials often give conflicting results. However, there is clear evidence for magnesium to benefit patients with eclampsia or torsades de pointes arrhythmias. In addition, magnesium seems to have antinociceptive and anesthetic as well as neuroprotective effects, yet well-designed large clinical trials are required to determine its actual efficacy in pain management or in the state of stroke or subarachnoid hemorrhage. The current review aims to provide an overview of current knowledge and available evidence with respect to physiologic aspects of magnesium and proposed indications and recommendations for its use in the clinical setting.

Guanine nucleotide-binding proteins of the G12 family shape immune functions by controlling CD4+ T cell adhesiveness and motility.

Integrin-mediated adhesion plays a central role in T cell trafficking and activation. Genetic inactivation of the guanine nucleotide-binding (G) protein alpha-subunits Galpha(12) and Galpha(13) resulted in an increased activity of integrin leukocyte-function-antigen-1 in murine CD4(+) T cells. The interaction with allogeneic dendritic cells was enhanced, leading to an abnormal proliferative response in vitro. In vivo, T cell-specific inactivation of Galpha(12) and Galpha(13) caused lymphadenopathy due to increased lymph node entry and enhanced T cell proliferation, and the susceptibility toward T cell-mediated diseases was enhanced. Mechanistically, we show that in the absence of Galpha(12) and Galpha(13) the activity of the small GTPases Rac1 and Rap1 was increased, whereas signaling of the small GTPase RhoA was strongly reduced. Our data indicate that locally produced mediators signal through Galpha(12)- and Galpha(13)-coupled receptors to negatively regulate cell polarization and adhesiveness, thereby fine-tuning T cell trafficking, proliferation, and susceptibility toward T cell-mediated diseases.

Systemic lidocaine shortens length of hospital stay after colorectal surgery: a double-blinded, randomized, placebo-controlled trial.

OBJECTIVE: To characterize the beneficial effects of perioperative systemic lidocaine on length of hospital stay, gastrointestinal motility, and the inflammatory response after colorectal surgery. SUMMARY BACKGROUND DATA: Surgery-induced stimulation of the inflammatory response plays a major role in the development of several postoperative disorders. Local anesthetics possess anti-inflammatory activity and are thought to positively affect patients' outcome after surgery. This double-blinded, randomized, and placebo-controlled trial aimed to evaluate beneficial effects of systemic lidocaine and to provide insights into underlying mechanisms. METHODS: Sixty patients undergoing colorectal surgery, not willing or unable to receive an epidural catheter, were randomly assigned to lidocaine or placebo treatment. Before induction of general anesthesia, an intravenous lidocaine bolus (1.5 mg/kg) was administered followed by a continuous lidocaine infusion (2 mg/min) until 4 hours postoperatively. Length of hospital stay, gastrointestinal motility, and pain scores were recorded and plasma levels or expression of pro- and anti-inflammatory mediators determined. RESULTS: Lidocaine significantly accelerated return of bowel function and shortened length of hospital stay by one day. No difference could be observed in daily pain ratings. Elevated plasma levels of IL-6, IL-8, complement C3a, and IL-1ra as well as expression of CD11b, L- and P-selectin, and platelet-leukocyte aggregates were significantly attenuated by systemic lidocaine. CONCLUSIONS: Perioperative intravenous lidocaine not only improved gastrointestinal motility but also shortened length of hospital stay significantly. Anti-inflammatory activity modulating the surgery-induced stress response may be one potential mechanism. Systemic lidocaine may thus provide a convenient and inexpensive approach to improve outcome for patients not suitable for epidural anesthesia.

Lysophospholipids control integrin-dependent adhesion in splenic B cells through G(i) and G(12)/G(13) family G-proteins but not through G(q)/G(11).

Integrin-mediated adhesion is a crucial step in lymphocyte extravasation and homing. We show here that not only the chemokines CXCL12 and CXCL13 but also the lysophospholipids sphingosine 1-phosphate (S1P) and lysophosphatidic acid (LPA) enhance adhesion of murine follicular and marginal zone B cells to ICAM-1 in vitro. This process involves clustering of integrin LFA-1 and is blocked by pertussis toxin, suggesting that G(i) family G-proteins are involved. In addition, lysophospholipid-induced adhesion on ICAM-1 depends on Rho and Rhokinase, indicative of an involvement of G(12)/G(13), possibly also G(q)/G(11) family G-proteins. We used G(12)/G(13)- or G(q)/G(11)-deficient B cells to study the role of these G-protein families in lysophospholipid-induced adhesion and found that the pro-adhesive effects of LPA and S1P are completely abrogated in G(12)/G(13)-deficient marginal zone B cells, reduced in G(12)/G(13)-deficient follicular B cells, and normal in G(q)/G(11)-deficient B cells. We also show that loss of lysophospholipid-induced adhesion results in disinhibition of migration in response to the follicular chemokine CXCL13, which might contribute to the abnormal localization of splenic B cell populations observed in B cell-specific G(12)/G(13)-deficient mice in vivo. Taken together, this study shows that lysophospholipids regulate integrin-mediated adhesion of splenic B cells to ICAM-1 through G(i) and G(12)/G(13) family G-proteins but not through G(q)/G(11).

G12/G13 family G proteins regulate marginal zone B cell maturation, migration, and polarization.

G protein-coupled receptors play an important role in the regulation of lymphocyte functions such as migration, adhesion, proliferation, and differentiation. Although the role of G(i) family G proteins has been intensively studied, no in vivo data exist with respect to G12/G13 family G proteins. We show in this study that mice that lack the G protein alpha-subunits G alpha12 and G alpha13 selectively in B cells show significantly reduced numbers of splenic marginal zone B (MZB) cells, resulting in a delay of Ab production in response to thymus-independent Ags. Basal and chemokine-induced adhesion to ICAM-1 and VCAM-1, two adhesion molecules critically involved in MZB localization, is normal in mutant B cells, and the same is true for chemokine-induced migration. However, migration in response to serum and sphingosine 1-phosphate is strongly increased in mutant MZB cells, but not in mutant follicular B cells. Live-cell imaging studies revealed that G alpha12/G alpha13-deficient MZB cells assumed more frequently an ameboid form than wild-type cells, and pseudopod formation was enhanced. In addition to their regulatory role in serum- and sphingosine 1-phosphate-induced migration, G12/G13 family G proteins seem to be involved in peripheral MZB cell maturation, because also splenic MZB cell precursors are reduced in mutant mice, although less prominently than mature MZB cells. These data suggest that G12/G13 family G proteins contribute to the formation of the mature MZB cell compartment both by controlling MZB cell migration and by regulating MZB cell precursor maturation.

Receptors, G proteins, and their interactions.

Membrane receptors coupling to intracellular G proteins (G protein-coupled receptors) form one of the major classes of membrane signaling proteins. They are of great importance to the practice of anesthesiology because they are involved in many systems of relevance to the specialty (cardiovascular and respiratory control, pain transmission, and others) and many drugs target these systems. In recent years, understanding of these signaling systems has grown. The structure of receptors and G proteins has been elucidated in more detail, their regulation is better understood, and the complexity of interactions between the various parts of the system (receptors, G proteins, effectors, and regulatory molecules) has become clear. These findings may help explain both actions and side effects of drugs. In addition, these newly discovered targets are likely to play important roles in disease states of relevance to anesthesiologists.

Regional anaesthesia, local anaesthetics and the surgical stress response.

Epidural anaesthesia has the potential to improve patients' outcome after major surgical procedures by reducing postoperative morbidity and duration of recovery. Possible benefits include the attenuation of cardiac complications, an earlier return of gastrointestinal function associated with an increase in patients' comfort overall, decreased incidence of pulmonary dysfunction, beneficial effects on the coagulation system and a reduction in the inflammatory response. The underlying mechanisms, however, remain unclear. Since local anaesthetics (LAs), reabsorbed from the epidural space, seem to contribute to these effects, it is not easy to differentiate between the systemic effects of LAs and the effects of neuraxial blockade by epidural anaesthesia. Thus, in patients not able or willing to receive intra- and/or postoperative epidural analgesia, systemic administration of LAs may be considered to be a new therapeutic approach for the prevention of postoperative disorders by modulation of the peri- and postoperative inflammatory.

Time-dependent inhibition of G protein-coupled receptor signaling by local anesthetics.

BACKGROUND: Several beneficial effects of local anesthetics (LAs) were shown to be due to inhibition of G protein-coupled receptor signaling. Differences in exposure time might explain discrepancies in concentrations of LAs required to achieve these protective effects in vivo and in vitro (approximately 100-fold higher). Using Xenopus oocytes and human neutrophils, the authors studied time-dependent effects of LAs on G protein-coupled receptor signaling and characterized possible mechanisms and sites of action. METHODS: Measurement of agonist-induced Ca2+-activated Cl currents, using a two-electrode voltage clamp technique, and determination of superoxide anion production by cytochrome c assay were used to assess the effects of LAs on G protein-coupled receptor signaling in oocytes and primed and activated human neutrophils, respectively. Antisense knockdown of G alpha q protein and inhibition of various proteins within the signaling pathway served for defining mechanisms and sites of action more specifically. RESULTS: LAs attenuated G protein-coupled receptor signaling in both models in a time-dependent and reversible manner (lidocaine reduced lysophosphatidic acid signaling to 19 +/- 3% after 48 h and 25 +/- 2% after 6 h of control response in oocytes and human neutrophils, respectively). Whereas no effect was observed after extracellularly applied or intracellularly injected QX314, a lidocaine analog, using G alpha q-depleted oocytes, time-dependent inhibition also occurred after intracellular injection of QX314 into undepleted oocytes. Inhibition of phosphatases or protein kinases and agonist-independent G-protein stimulation, using guanosine 5'-O-3-thiotriphosphate or aluminum fluoride, did not affect time-dependent inhibition by LAs. CONCLUSION: Inhibition of G protein-coupled receptor signaling by LAs was found to be time dependent and reversible. Critically requiring G alpha q-protein function, this effect is located downstream of guanosine diphosphate-guanosine triphosphate exchange and is not dependent on increased guanosine triphosphatase activity, phosphatases, or protein kinases.

The effects of S(-)-, R(+)-, and racemic bupivacaine on lysophosphatidate-induced priming of human neutrophils.

UNLABELLED: Local anesthetics modulate inflammatory responses and may therefore be potentially useful in mitigating perioperative inflammatory injury. The inflammatory modulating effects of S(-)-bupivacaine are not known. Therefore, we compared the effects of S(-)-bupivacaine, R(+)-bupivacaine, and racemic bupivacaine on neutrophil function and receptor signaling. Priming (by lysophosphatidic acid [LPA]) and activation (by N-formylmethionine-leucyl-phenylalanine) of superoxide release by isolated human neutrophils was studied by using a cytochrome c-reduction assay. LPA receptor signaling in Xenopus oocytes was studied by using voltage clamp. All three local anesthetics were without effect on activation. S(-)-Bupivacaine inhibited priming more than did racemic bupivacaine; R(+)-bupivacaine was without effect. At 10(-4) M, S(-)-bupivacaine inhibited approximately 50%. Comparable results were obtained in our recombinant model, where S(-)-bupivacaine most effectively inhibited LPA signaling. Compared with racemic bupivacaine and other anesthetics, S(-)-bupivacaine appears particularly effective in suppressing neutrophil priming, a process responsible in part for the overactive neutrophil response. IMPLICATIONS: Overactive inflammatory responses underlie several perioperative disorders. Compared with racemic bupivacaine and other anesthetics, S(-)-bupivacaine appears particularly effective in suppressing neutrophil priming, a process responsible in part for the overactive neutrophil response.

Inflammatory responses after surgery.

The inflammatory response after major surgery is of great importance for patients, physicians and perioperative medicine in general. This article, although not intended to be comprehensive, provides an overview of present knowledge about inflammatory mechanisms, predictive parameters and therapeutic approaches.