Klaus Hahnenkamp

The effects of local anesthetics on perioperative coagulation, inflammation, and microcirculation.

M ajor surgery is associated with a hypercoagulable and proinflammatory state that persists into the postoperative period (1,2). Perioperative inflammatory responses to trauma can trigger hypercoagulability, especially in patients undergoing vascular surgery, and are associated with vasoocclusive and thromboembolic events—major causes of postoperative morbidity and mortality (3–5). The mechanisms for these effects are poorly understood, but hypercoagulability seems to originate from what is known as the “stress response” to major surgery (4,6). Postoperative changes occur in all aspects of the coagulation system, including increased plasma levels of coagulation factors (1), decreased levels and more rapid inactivation of endogenous coagulation inhibitors (7), enhanced platelet reactivity (8), and impaired fibrinolysis (9). In addition, increasing attention has been given to the close link between hemostasis and inflammation (10), which is minutely influenced by general anesthesia with parenteral opioids (3). However, recent evidence suggests that regional anesthesia has a protective effect against the perioperative stress response. The beneficial effects of the epidural administration of local anesthetic (LA) have been attributed to the changes in physiology induced by neuraxial anesthesia and better pain management (5,11). However, as discussed below, there are hints that the pharmacodynamic effects of LA itself may contribute to these effects. This review is arranged according to the different effects of LAs—first on the hypercoagulable and inflammatory responses to surgery, and second on microcirculation. Stress Response

Remifentanil Directly Activates Human N-methyl-D- aspartate Receptors Expressed in Xenopus laevis Oocytes

Background: Clinical studies suggest that intraoperative administration of the clinical remifentanil formulation Ultiva® (GlaxoWellcome GmbH & Co, Bad Oldesloe, Germany) increases postoperative pain and postoperative analgesic requirements, but mechanisms remain unclear. N-methyl-d-aspartate (NMDA) receptors are thought to play a major role in development of postoperative pain and opiate tolerance. The authors hypothesized that Ultiva® directly stimulates human NMDA receptors. Methods: To test this hypothesis, the authors expressed human NR1A/NR2A and NR1A/NR2B NMDA receptors in Xenopus laevis oocytes by injection of messenger RNA prepared in vitro. After protein expression, they used a two-electrode voltage clamp to measure currents induced by NMDA receptor agonists and opioids. Results: Noninjected cells were unresponsive to all compounds tested. Glutamate/glycine (1 nm–1 mm each) or Ultiva® (0.01 pm–0.1 mm) stimulated NMDA receptors concentration dependently. NR1A/2A EC50 values were 8.0 μM/12 μM for glutamate/glycine and 3.5 nM for Ultiva®, and NR1A/2B EC50 values were 3.9 μM/1.9 μM for glutamate/glycine and 0.82 μM for Ultiva®. Glycine in combination with Ultiva® showed no additive effect compared with Ultiva® alone. Ultiva®-induced currents were inhibited by MK-801 (pore blocker) but not by 7-CK (glycine antagonist), D-AP5 (glutamate antagonist), or naloxone. Fentanyl (10 μM) did not stimulate NMDA receptors. Conclusion: These data indicate that Ultiva® but not fentanyl stimulates NMDA receptors of different subunit combinations (NR1A/2A, NR1A/2B). The mechanism seems to be allosteric activation of the NMDA receptor.

Selective iNOS inhibition prevents hypotension in septic rats while preserving endothelium-dependent vasodilation.

UNLABELLED Nitric oxide (NO) derived from inducible nitric oxide synthase (iNOS) mediates hypotension and metabolic derangements in sepsis. We hypothesized that selective iNOS-inhibition would prevent hypotension in septic rats without inhibiting endothelium-dependent vasodilation caused by the physiologically important endothelial NOS. Rats were exposed to lipopolysaccharide (LPS) for 6 h and the selective iNOS-inhibitor L-N6-(1-iminoethyl)-lysine (L-NIL), the nonselective NOS-inhibitor N:(G)-nitro-L-arginine methyl ester (L-NAME), or control. Mean arterial pressure (MAP) and vasodilation to acetylcholine (ACh, endothelium-dependent), sodium nitroprusside (SNP, endothelium-independent), and isoproterenol (ISO, endothelium-independent beta agonist) were determined. Exhaled NO, nitrate/nitrite-(NOx) levels, metabolic data, and immunohistochemical staining for nitrotyrosine, a tracer of peroxynitrite-formation were also determined. In control rats, L-NAME increased MAP, decreased the response to ACh, and increased the response to SNP, whereas L-NIL did not alter these variables. LPS decreased MAP by 18% +/- 1%, decreased vasodilation (ACh, SNP, and ISO), increased exhaled NO, NOx, nitrotyrosine staining, and caused acidosis and hypoglycemia. L-NIL restored MAP and vasodilation (ACh, SNP, and ISO) to baseline and prevented the changes in exhaled NO, NOx, pH, and glucose levels. In contrast, L-NAME restored MAP and SNP vasodilation, but did not alter the decreased response to ACh and ISO or prevent the changes in exhaled NO and glucose levels. Finally, L-NIL but not L-NAME decreased nitrotyrosine staining in LPS rats. In conclusion, L-NIL prevents hypotension and metabolic derangements in septic rats without affecting endothelium-dependent vasodilation whereas L-NAME does not. IMPLICATIONS Sepsis causes hypotension and metabolic derangements partly because of increased nitric oxide. Selective inhibition of nitric oxide produced by the inducible nitric oxide synthase enzyme prevents hypotension and attenuates metabolic derangements while preserving the important vascular function associated with endothelium-dependent vasodilation in septic rats.

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

BackgroundSeveral 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. MethodsMeasurement 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&agr;q protein and inhibition of various proteins within the signaling pathway served for defining mechanisms and sites of action more specifically. ResultsLAs 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&agr;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. ConclusionInhibition of G protein–coupled receptor signaling by LAs was found to be time dependent and reversible. Critically requiring G&agr;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.

Effect of different anaesthetic regimes on the oculocardiac reflex during paediatric strabismus surgery.

The oculocardiac reflex (OCR) is induced by mechanical stimulation and therefore is frequently encountered during strabismus surgery. This study was designed to determine how various anaesthetic regimes modulate the haemodynamic effects of the OCR during paediatric strabismus surgery. Thirty‐nine patients (4–14 years, ASA I) were randomized to one of four anaesthetic regimes: group P: propofol (12 mg·kg–1·h–1) and alfentanil (0.04 mg·kg–1·h–1); group S: sevoflurane 1–1.2 MAC in 30% O2/70% N2O; group K: ketamine racemate (10–12 mg·kg–1·h–1) and midazolam (0.3–0.6 mg·kg–1·h–1; group H: halothane 1–1.2 MAC in 30% O2/70% N2O. Electrocardiogram (ECG), beat‐to‐beat heart rate (HR) and blood pressure (BP) changes were measured during and after a standardized traction was applied to an external eye muscle (4–6 Newton, 90 s). OCR was defined as a 10% change in HR induced by traction. OCR occurred in 77% of patients. Whereas virtually all patients in the P, H and S groups developed OCR, only 22% developed it in group K. Median HR change in group P (–37 bpm) was significantly greater (P < 0.05) than in group H (–17 bpm) or group K (–7 bpm). Median BP change in group K (+10 mmHg) was significantly different (P < 0.05) from group H (–5 mmHg), group S (–3 mmHg) and group P (–8 mmHg). Atrioventricular rhythm disorders were significantly more frequent in group P compared with group K (P < 0.02). Respiration‐induced sinus dysrhythmia was significantly less frequent (P < 0.001) in group K (0%), compared with group P (100%), group H (56%) and group S (55%). Of the anaesthetic techniques studied, ketamine anaesthesia is associated with the least haemodynamic changes induced by OCR during strabismus surgery in paediatric patients.

Selective iNOS Inhibition Attenuates Acetylcholine- and Bradykinin-induced Vasoconstriction in Lipopolysaccharide-exposed Rat Lungs

BACKGROUND Nonselective nitric oxide synthase (NOS) inhibition has detrimental effects in sepsis because of inhibition of the physiologically important endothelial NOS (eNOS). The authors hypothesized that selective inducible NOS (iNOS) inhibition would maintain eNOS vasodilation but prevent acetylcholine- and bradykinin-mediated vasoconstriction caused by lipopolysaccharide-induced endothelial dysfunction. METHODS Rats were administered intraperitoneal lipopolysaccharide (15 mg/kg) with and without the selective iNOS inhibitors L-N6-(1-iminoethyl)-lysine (L-NIL, 3 mg/kg), dexamethasone (1 mg/kg), or the nonselective NOS inhibitor Nomega-nitro-L-arginine methylester (L-NAME, 5 mg/kg). Six hours later, the lungs were isolated and pulmonary vasoreactivity was assessed with hypoxic vasoconstrictions (3% O2), acetylcholine (1 microg), Biochemical Engineering, and bradykinin (3 microg). In additional lipopolysaccharide experiments, L-NIL (10 microM) or 4-Diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP, 100 microM), a selective muscarinic M3 antagonist, was added into the perfusate. RESULTS Exhaled nitric oxide was higher in the lipopolysaccharide group (37.7+/-17.8 ppb) compared with the control group (0.4+/-0.7 ppb). L-NIL and dexamethasone decreased exhaled nitric oxide in lipopolysaccharide rats by 83 and 79%, respectively, whereas L-NAME had no effect. In control lungs, L-NAME significantly decreased acetylcholine- and bradykinin-induced vasodilation by 75% and increased hypoxic vasoconstrictions, whereas L-NIL and dexamethasone had no effect. In lipopolysaccharide lungs, acetylcholine and bradykinin both transiently increased the pulmonary artery pressure by 8.4+/-2.0 mmHg and 35.3+/-11.7 mmHg, respectively, immediately after vasodilation. L-NIL and dexamethasone both attenuated this vasoconstriction by 70%, whereas L-NAME did not. The acetylcholine vasoconstriction was dose-dependent (0.01-1.0 microg), unaffected by L-NIL added to the perfusate, and abolished by 4-DAMP. CONCLUSIONS In isolated perfused lungs, acetylcholine and bradykinin caused vasoconstriction in lipopolysaccharide-treated rats. This vasoconstriction was attenuated by administration of the iNOS inhibitor L-NIL but not with L-NAME. Furthermore, L-NIL administered with lipopolysaccharide preserved endothelium nitric oxide-dependent vasodilation, whereas L-NAME did not.

Efficacy and safety of intravenous lidocaine for postoperative analgesia and recovery after surgery: a systematic review with trial sequential analysis

BACKGROUND Improvement of postoperative pain and other perioperative outcomes remain a significant challenge and a matter of debate among perioperative clinicians. This systematic review aims to evaluate the effects of perioperative i.v. lidocaine infusion on postoperative pain and recovery in patients undergoing various surgical procedures. METHODS CENTRAL, MEDLINE, EMBASE, and CINAHL databases and ClinicalTrials.gov, and congress proceedings were searched for randomized controlled trials until May 2014, that compared patients who did or did not receive continuous perioperative i.v. lidocaine infusion. RESULTS Forty-five trials (2802 participants) were included. Meta-analysis suggested that lidocaine reduced postoperative pain (visual analogue scale, 0 to 10 cm) at 1-4 h (MD -0.84, 95% CI -1.10 to -0.59) and at 24 h (MD -0.34, 95% CI -0.57 to -0.11) after surgery, but not at 48 h (MD -0.22, 95% CI -0.47 to 0.03). Subgroup analysis and trial sequential analysis suggested pain reduction for patients undergoing laparoscopic abdominal surgery or open abdominal surgery, but not for patients undergoing other surgeries. There was limited evidence of positive effects of lidocaine on postoperative gastrointestinal recovery, opioid requirements, postoperative nausea and vomiting, and length of hospital stay. There were limited data available on the effect of systemic lidocaine on adverse effects or surgical complications. Quality of evidence was limited as a result of inconsistency (heterogeneity) and indirectness (small studies). CONCLUSIONS There is limited evidence suggesting that i.v. lidocaine may be a useful adjuvant during general anaesthesia because of its beneficial impact on several outcomes after surgery.

Efficacy of intravenous paracetamol compared to dipyrone and parecoxib for postoperative pain management after minor-to-intermediate surgery: a randomised, double-blind trial.

Background and objective Paracetamol has a well established pharmacological profile, but its postoperative efficacy is in question. This double-blind, placebo-controlled study was designed to compare the efficacy of intravenous paracetamol with other intravenous non-opioids as part of a multimodal concept for perioperative pain therapy. Methods Patients undergoing minor-to-intermediate surgery under general anaesthesia were randomly assigned to receive infusions of paracetamol (1 g every 6 h), dipyrone (1 g every 6 h), parecoxib (40 mg every 12 h) separated by infusions of physiological saline 0.9%, or placebo (0.9% saline every 6 h), respectively, for at least 48 h as part of a multimodal pain concept. Patient-controlled piritramide was administered as rescue medication. Dependent variables were recorded 1, 6, 18, 30 and 42 h after extubation and 1 week after surgery. Surgical and associated pain was scored as the primary outcome on a visual analogue scale. Additionally, time to first dose and total piritramide dosage, satisfaction, respiratory depression, nausea, vomiting, sedation, itching and sweating were recorded. Results A total of 196 patients were recruited. The efficacy of paracetamol was similar to that of the other non-opioid analgesics. Surgical pain was reduced with all non-opioids compared to placebo; there was no effect on associated pain. Piritramide dosage and incidence of side effects were not reduced. Conclusion Intravenous paracetamol has equivalent efficacy to non-opioids dipyrone and parecoxib that improves postoperative pain therapy when used as part of a multimodal concept after minor-to-intermediate surgery.

The Inhibitory Effect of Bupivacaine on Prostaglandin E 2 (EP 1 ) Receptor Functioning: Mechanism of Action

Prostaglandin E2 receptors, subtype EP1 (PGE2EP1) have been linked to several physiologic responses, such as fever, inflammation, and mechanical hyperalgesia. Local anesthetics modulate these responses, which may be due to direct interaction of local anesthetics with PGE2EP1 receptor signaling. We sought to characterize the local anesthetic effects on PGE2EP1 signaling and elucidate mechanisms of anesthetic action. In Xenopus laevis oocytes, recombinant expressed PGE2EP1 receptors were functional (half maximal effect concentration, 2.09 ± 0.98 × 10−6 M). Bupivacaine, after incubation for 10 min, inhibited concentration-dependent PGE2EP1 receptor functioning (half-maximal inhibitory effect concentration, 3.06 ± 1.26 × 10−6 M). Prolonged incubation in bupivacaine (24 h) inhibited PGE2-induced calcium-dependent chloride currrents (ICl(Ca)) even more. Intracellular pathways were not significantly inhibited after 10 min of incubation in bupivacaine. But ICl(Ca) activated by intracellular injection of GTP&ggr;S (a nonhydrolyzable guanosine triphosphate [GTP] analog that activates G proteins, irreversible because it cannot be dephosphorylated by the intrinsic GTPase activity of the &agr; subunit of the G protein) was reduced after 24 h of incubation in bupivacaine, indicating a G protein-dependent effect. However, inositol 1,4,5-trisphosphate- and CaCl2- induced ICl(Ca) were unaffected by bupivacaine at any time points tested. Therefore, bupivacaine’s effect is at phospholipase C or at the G protein or the PGE2EP1 receptor. All inhibitory effects were reversible. We conclude that bupivacaine inhibited PGE2EP1 receptor signaling at clinically relevant concentrations. These effects could, at least in part, explain how local anesthetics affect physiologic responses such as fever, inflammation, and hyperalgesia during the perioperative period.

Lidocaine Reduces Neutrophil Recruitment by Abolishing Chemokine-Induced Arrest and Transendothelial Migration in Septic Patients

The inappropriate activation, positioning, and recruitment of leukocytes are implicated in the pathogenesis of multiple organ failure in sepsis. Although the local anesthetic lidocaine modulates inflammatory processes, the effects of lidocaine in sepsis are still unknown. This double-blinded, prospective, randomized clinical trial was conducted to investigate the effect of lidocaine on leukocyte recruitment in septic patients. Fourteen septic patients were randomized to receive either a placebo (n = 7) or a lidocaine (n = 7) bolus (1.5 mg/kg), followed by continuous infusion (100 mg/h for patients >70 kg or 70 mg/h for patients <70 kg) over a period of 48 h. Selectin-mediated slow rolling, chemokine-induced arrest, and transmigration were investigated by using flow chamber and transmigration assays. Lidocaine treatment abrogated chemokine-induced neutrophil arrest and significantly impaired neutrophil transmigration through endothelial cells by inhibition of the protein kinase C-θ while not affecting the selectin-mediated slow leukocyte rolling. The observed results were not attributable to changes in surface expression of adhesion molecules or selectin-mediated capturing capacity, indicating a direct effect of lidocaine on signal transduction in neutrophils. These data suggest that lidocaine selectively inhibits chemokine-induced arrest and transmigration of neutrophils by inhibition of protein kinase C-θ while not affecting selectin-mediated slow rolling. These findings may implicate a possible therapeutic role for lidocaine in decreasing the inappropriate activation, positioning, and recruitment of leukocytes during sepsis.