Cardiac Electrophysiologic Effects of Different Local Anesthetics in Langendorff-Perfused Rabbit Hearts.

Topical anesthesia: To use or not to use—that is the question

The impact of drugs used in anaesthesia on bacteria

We thank Drs. Harmon and Lan for their interest in our review and for their thoughts concerning the effects of local anesthetics besides their ability to block Na+ channels. We had to restrict our manuscript on local anesthetic effects on perioperative coagulation, inflammation, and microcirculation (1) because of the restricted information and therefore were not able to cover influences of local anesthetic on all perioperative aspects. We agree completely that the role of local anesthetics in ischemia reperfusion is unclear and has not yet been elucidated in detail. Some studies report local anesthetic effects on myocardial infarction and reperfusion of the ischemic heart. Although the discussion is still controversial (2), experiments of myocardial ischemia in a porcine (3) and a dog model (4) have shown that lidocaine preserved the ischemic myocardium and was able to reduce infarct size. This effect may be a result of antiinflammatory effects of lidocaine in areas of myocardial infarction or stunned myocardium. We thank Drs. Harmon and Lan for their most interesting comment on our review and fully support their view that these effects of systemic local anesthetics on perioperative ischemia reperfusion should be studied in more detail, especially as local anesthetics are probably the most commonly used compounds in anesthesia. They are safe, have an infrequent rate of side effects, and are easy to use. K. Hahnenkamp C. W. Hoenemann

It has been demonstrated that local anesthetics have several effects on the immune system. Monocytes and macrophages are essential components of the host response to microbial infection; however, the effect of local anesthetics on monocyte surface receptor expression remains unclear. We designed this study to investigate the effects of local anesthetics on monocyte mCD14 and human leukocyte antigen (HLA)-DR expression and lipopolysaccharide (LPS)-induced or staphylococcal enterotoxin B (SEB)-induced tumor necrosis factor (TNF)-alpha production. Blood samples were obtained from 10 healthy volunteers. The effects of local anesthetics on LPS- or SEB-induced TNF-alpha production were determined by using an enzyme-linked immunosorbent assay. After different doses of local anesthetics were added, the blood was stimulated with LPS (10 ng/mL) or SEB (10 micro g/mL) for 4 h. The effects of local anesthetics on monocyte mCD14 and HLA-DR expression were measured by dual monoclonal antibody staining and flow cytometry. Local anesthetics showed no effect on LPS- or SEB-induced TNF-alpha production in human whole blood. Local anesthetics suppressed monocyte HLA-DR expression in a dose-dependent manner (P < 0.05) but had no effect on monocyte mCD14 expression. This study demonstrated that local anesthetics suppress HLA-DR expression on the surface of human monocytes. Monocyte surface receptors have a crucial role in the host response to microbial infection. We investigated the effects of local anesthetics on monocyte mCD14 and human leukocyte antigen (HLA)-DR expression. Our results show that local anesthetics suppress HLA-DR expression on the surface of human monocytes.

Septal surgery is a well-established procedure used to treat nasal obstruction due to deviation of the nasal septum, which is carried out under local or general anaesthesia. Local anaesthesia is used for postoperative pain control, but its effectiveness and safety are unclear. To assess the effectiveness of perioperative local anaesthesia for reducing pain in septal surgery and to evaluate the risk of associated complications. The Cochrane ENT Information Specialist searched the Cochrane ENT Trial Register; Central Register of Controlled Trials; Ovid MEDLINE; Ovid Embase; CINAHL; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 9 January 2018. Randomised controlled trials and cluster-randomised controlled trials involving adults or children (or both) who underwent septal surgery. We included studies comparing local anaesthesia versus no treatment/placebo. We also included studies comparing different types of local anaesthesia to each other (i.e. local injection, the addition of an anaesthetic agent to nasal packing, where used, and sphenopalatine ganglion block). We used the standard methodological procedures expected by Cochrane. The primary outcome was postoperative pain intensity at 12, 24 and 48 hours measured by visual analogue scale (VAS) or another pain outcome tool including numerical or verbal rating scales. Secondary outcomes were requirement for additional analgesia, duration of hospitalisation and adverse effects (postoperative bleeding and postoperative vomiting). We used GRADE to assess the quality of the evidence for each outcome; this is indicated in italics. We included seven randomised controlled trials involving 493 participants. In all studies the participants were adults undergoing septoplasty. These studies were heterogeneous and the quality of the body of evidence ranged from low to very low. Few of the studies provided reliable data for the primary outcome in this review.Local anaesthetic injection versus no treatment/placeboTwo studies (142 participants) compared local anaesthetic injection versus placebo but these studies did not report postoperative pain at 12, 24 or 48 hours. It is unclear whether local anaesthetic injection changed the risk of vomiting (odds ratio (OR) 3.10, 95% confidence interval (CI) 0.12 to 79.23; 60 participants; one study) (low-quality evidence). Neither study reported the requirement for additional analgesia, duration of hospitalisation or uncontrollable postoperative bleeding.Local anaesthetic application via nasal packing versus no packing/packing with placeboFour studies (301 participants) used nasal packing postoperatively and compared the addition of local anaesthetic to the pack versus packing with a placebo added. Compared with packing with placebo, the addition of local anaesthetic to nasal packing reduced the pain score on a VAS (ranging from 0 to 100) at 12 hours (mean difference (MD) -16.95, 95% CI -22.27 to -11.62; 151 participants; two studies; I2 = 49%) (low-quality evidence) and at 24 hours postoperatively (MD -7.53, 95% CI -9.76 to -5.29; 268 participants; four studies; I2 = 83%) (very low-quality evidence). These studies did not report postoperative pain at 48 hours. The addition of local anaesthetic to nasal packing decreased the requirement for additional analgesia (OR 0.15, 95% CI 0.07 to 0.34; 151 participants; two studies; I2 = 15%) (moderate-quality evidence). No studies reported duration of hospitalisation, postoperative vomiting or uncontrollable postoperative bleeding.No studies compared the addition of local anaesthetic to nasal packing versus no packing.Sphenopalatine ganglion block versus no treatment/placeboOne study (50 participants) compared sphenopalatine ganglion block versus no treatment but this study did not report postoperative pain, requirement for additional analgesia, duration of hospitalisation, vomiting or uncontrollable postoperative bleeding. The addition of local anaesthesia to nasal packs (if these are being used) following septal surgery may reduce postoperative pain within the first 12 hours, compared to nasal packing with a placebo added. The effect is uncertain at 24 hours because the quality of the evidence is very low. Evidence was lacking for other outcomes, including adverse effects. There is a lack of evidence about the effects of local anaesthesia added to nasal packing compared to no nasal packing. There is also a lack of evidence about the effects of local anaesthesia given by injection and the effects of sphenopalatine ganglion block.

Local anesthetics are not free from potentially fatal complications. Therefore every new local anesthetic should be tested to demonstrate a lower, or at least similar, degree of toxicity over clinically used analogs. Most toxic effects from local anesthetics affect the cardiac electrophysiologic function, so the aim of this study was to characterize the electrophysiologic effects of a new long-acting local anesthetic (IQB-9302, Ciprocaine), and compare them with those of bupivacaine in the anesthetized dog. Eight Beagle dogs received three increasing infusion doses of either IQB-9302 or bupivacaine. Under isoflurane anesthesia, dogs were instrumented to monitor cardiovascular (cardiac output, arterial and venous blood pressures) and cardiac electrophysiologic data (sinus and atrioventricular (AV) node function, atrial, nodal and ventricular conduction times, and refractoriness). Only the highest dose of both drugs induced hemodynamic or electrophysiologic alterations: cardiac output and heart rate were reduced while blood pressures remained unchanged. Atrial and intranodal conduction times and atrial refractoriness increased similarly with both anesthetics, but to a slightly lesser extent with IQB-9302. Significant increases in His-Purkinje and intraventricular conduction times were the most severe noxious effects and occurred only with large doses of either drug. IQB-9302 was slightly less toxic than bupivacaine and, unlike this latter drug, potentially fatal arrhythmias were not induced. IQB-9302 has hemodynamic and cardiac electrophysiologic effects similar to those caused by bupivacaine. Nevertheless, slightly less toxic effects were derived from IQB-9302 administration than with bupivacaine, and, unlike the latter, the former might be less proarrhytmogenic. The new long-acting local anesthetic IQB-9302 may offer clinical advantages compared with bupivacaine.

Wide Awake Open Carpal Tunnel Release: The Effect of Local Anesthetics in the Postoperative Outcome

The effects of various local anesthetics on rat brain and liver monoamine oxidase (MAO) and their antihemolytic and local anesthetic effects were studied. All local anesthetics tested at 1 x 10(-7) M to 1 x 10(-3) M inhibited MAO activity in rat liver mitochondria with 5-hydroxytryptamine (5-HT) as substrate. The order of potency was tetracaine>procaine>dibucaine>lidocaine>prilocaine. Tetracaine and procaine inhibited 5-HT oxidation much more than beta-phenylethylamine (PEA) oxidation. Dibucaine inhibited PEA oxidation as much as 5-HT oxidation. Inhibition of MAO by local anesthetics other than dibucaine was reversible. Tetracaine and procaine inhibited 5-HT oxidation competitively, whereas dibucaine inhibited it non-competitively. Antihemolytic effects were observed with dibucaine and tetracaine at concentrations of 6 x 10(-5) M and 1 x 10(-4), respectively. The order of surface anesthetic potencies was dibucaine>tetracaine>prilocaine>lidocaine>procaine. These results suggest that the inhibition of MAO activities by local anesthetics depends on both electrostatic and hydrophobic interactions between these drugs and enzyme-associated phospholipids or the hydrophobic regions of proteins.

Background: Studies have been conducted to evaluate changes in hemodynamics, postoperative bleeding, and pain in pediatric dental patients receiving general anesthesia (GA). However, a limited number of studies have evaluated the effects of local anesthetics (LA) on tooth extraction procedures during GA. There is no consensus in the literature regarding LA application in the perioperative period for dental treatments performed within the scope of GA. Aim: This study aimed to determine the retrospective physiologic effects of fluctuations in vital signs and postoperative bleeding in children who did or did not receive LA for tooth extraction under GA. Methods: A retrospective evaluation of 77 patients aged 5.16 ± 1.85 years who had the extraction of primary posterior teeth with or without LA under GA were reviewed in the post-anaesthesia care unit (PACU) for postoperative bleeding and the effects of intraoperative LA on fluctuations in postoperative parameters such as mean arterial pressure (MAP), heart rate (HR), peripheral oxygen saturation (SpO2), respiratory rate (RR), and the end-tidal carbon dioxide (EtCO2). These were compiled from the patient records of the procedures. Results: Significant differences between the baseline and peak MAP (P &lt; 0.001), HR (P = 0.011), and EtCO2 (P = 0.002) were noted in children without LA compared to those who had LA. In addition, substantial variations were observed between the baseline and peak values for MAP (P &lt; 0.001) and HR (P = 0.037) in children who had tooth extraction in the mandibular region. Statistically significant differences were noted between the baseline and peak values for patients who did not receive LA before the extraction of the first primary molar in terms of MAP (P &lt; 0.02) and EtCO2 (P = 0.032). Similarly, significant differences in MAP (P &lt; 0.02) and EtCO2 (P = 0.034) were noted in the extraction of the second primary molar. In addition, there was a significant difference in bleeding based on the number of tooth extractions in those who did not receive LA (P = 0.020). Conclusion: This study showed that in children who underwent tooth extraction under GA, additional LA application minimized changes in HR, MAP, and EtCO2, whereas a lack of LA application produced significant fluctuations from baseline to peak values of HR, MAP, and EtCO2. In addition, LA application reduced postoperative bleeding.

The α and γ subunit-dependent effects of local anesthetics on recombinant GABA A receptors

Stereostructure-based differences in the interactions of cardiotoxic local anesthetics with cholesterol-containing biomimetic membranes

Near-infrared spectroscopy (NIRS) can be used to measure tissue oxygen saturation (StO2) in different sites and in a wide range of clinical scenarios. Peripheral regional anaesthesia induces vascular changes causing increased arterial blood flow and venodilatation, but its effect on StO2 is still under debate. This is especially so for patients undergoing arteriovenous fistula surgery, wherein latest data suggest an improved outcome under brachial plexus block (BPB) compared with local anaesthesia, but no data are available. The aim of this study was to investigate changes in StO2 following BPB prior to arteriovenous fistula surgery using NIRS. A prospective observational study. A secondary teaching hospital from August 2016 to March 2017. Fifteen patients undergoing arteriovenous fistula surgery. Ultrasound-guided BPB in 15 patients undergoing arteriovenous fistula surgery. StO2 at baseline and compared with baseline and the contralateral arm following BPB measured using NIRS of the thenar eminence (NIRSth). Baseline values of StO2 assessed by NIRSth were 42.6 ± 7.7% in the arteriovenous fistula arm and 42.7 ± 9.7% in the contralateral arm. There was no significant difference between the two. Five minutes after BPB, there was a significant increase in StO2 of the blocked arm, compared with the control arm expressed as difference of absolute values (7.1 ± 9.7%). At 60 min, an absolute difference of 21.0 ± 13.5% was reached. The absolute increase in StO2 of the blocked arm compared with baseline reached significance after 5 min (8.8 ± 4.6%) and increased up to 23.2 ± 8.2% after 60 min. NIRSth indicates that BPB significantly increases StO2 of the arteriovenous fistula arm in patients undergoing haemodialysis. Clinicaltrials.gov: NCT03044496.

Anti-fibrotic and tissue regenerative mesenchymal stromal cell (MSC) properties are largely mediated by secreted cytokines and growth factors. MSCs are implanted to augment joint cartilage replacement and to treat diabetic ulcers and burn injuries simultaneously with local anesthetics, which reduce pain. However, the effect of anesthetics on therapeutic human MSC secretory function has not been evaluated. In order to assess the effect of local anesthetics on the MSC secretome, a panel of four anesthetics with different potencies - lidocaine, procaine, ropivacaine and bupivacaine - was evaluated. Since injured tissues secrete inflammatory cytokines, the effects of anesthetics on MSCs stimulated with tumor necrosis factor (TNF)-α and interferon (IFN)-γ were also measured. Dose dependent and anesthesia specific effects on cell viability, post exposure proliferation and secretory function were quantified using alamar blue reduction and immunoassays, respectively. Computational pathway analysis was performed to identify upstream regulators and molecular pathways likely associated with the effects of these chemicals on the MSC secretome. Our results indicated while neither lidocaine nor procaine greatly reduced unstimulated cell viability, ropivacaine and bupivacaine induced dose dependent viability decreases. This pattern was exaggerated in the simulated inflammatory environment. The reversibility of these effects after withdrawal of the anesthetics was attenuated for TNF-α/IFN-γ-stimulated MSCs exposed to ropivacaine and bupivacaine. In addition, secretome analysis indicated that constitutive secretion changes were clearly affected by both anesthetic alone and anesthetic plus TNFα/IFNγ cell stimulation, but the secretory pattern was drug specific and did not necessarily coincide with viability changes. Pathway analysis identified different intracellular regulators for stimulated and unstimulated MSCs. Within these groups, ropivacaine and bupivacaine appeared to act on MSCs similarly via the same regulatory mechanisms. Given the variable effect of local anesthetics on MSC viability and function, these studies underscore the need to evaluate MSC in the presence of medications, such as anesthetics, that are likely to accompany cell implantation.

Lidocaine and bupivacaine impair wound healing, but the mechanism of this side effect has not been determined. The phospholipid messenger lysophosphatidate is released from activated platelets and induces fibroblast and smooth muscle proliferation. Because it may play a role in wound healing, the authors studied the effects of local anesthetics on lysophosphatidate signaling in Xenopus oocytes. Defolliculated Xenopus oocytes expressing endogenous G protein-coupled lysophosphatidate receptors were voltage clamped and studied in the presence or absence of lidocaine or bupivacaine. Lysophosphatidate-induced Ca(2+)-activated Cl- currents (IC1(Ca)) were measured. To determine the site of action of the local anesthetics on the signaling pathway, the authors studied 1) the effects of local anesthetics on signaling induced by intracellular injection of the second messenger inositoltrisphosphate, and 2) the effects of local anesthetics on functioning of recombinantly expressed angiotensin II receptor signaling through the same pathways as the lysophosphatidate receptor. Lysophosphatidate signaling was inhibited in the presence of local anesthetics. The half maximal inhibitory concentration (IC50S) for lidocaine and bupivacaine were 29.6 mM and 4.7 mM, respectively. Neither responses induced by inositoltrisphosphate injection nor angiotensin signaling were influenced by local anesthetics. Lysophosphatidate signaling is inhibited by the extracellular application of lidocaine or bupivacaine. In contrast, inositoltrisphosphate or angiotensin signaling was not affected by local anesthetics. Therefore local anesthetics have a specific, extracellular effect on lysophosphatidate receptor functioning. As the local anesthetic concentrations used were similar to those observed after injection around surgical wounds, LP inhibition may play a role in the observed detrimental effects of local anesthetics on wound healing.

The transient receptor potential vanilloid subtype 3 (TRPV3) channel is activated by innocuous temperature and several chemical stimuli. It is proposed to be involved in pathological pain development and is therefore considered a potential target for treating pain. Local anesthetics have been used for patients with both acute and chronic pain. Although blockage of the voltage-gated sodium channel is the primary mechanism by which local anesthetics exert their effects, they cannot be explained by this mechanism alone, especially in pathologic states such as chronic pain. Indeed, the effects of local anesthetics on multiple targets involved in the pain pathway have been reported. It has also been suggested that modulating the function of transient receptor potential (TRP) channels (eg, TRPV1 and transient receptor potential ankyrin 1 [TRPA1]) is one of the mechanisms of action of local anesthetics. However, the effects of local anesthetics on TRPV3 have not been reported. We expressed TRPV3 in Xenopus oocytes and investigated the effects of local anesthetics on 2-aminoethoxydiphenyl borate (2APB)-induced currents using 2-electrode voltage-clamp techniques. Clinically used local anesthetics inhibited the 2APB-activated currents from the TRPV3 channel in a concentration-dependent manner at pharmacologically relevant concentrations with half maximal inhibitory concentration (IC50) values of 2.5 (lidocaine), 1.4 (mepivacaine), 0.28 (ropivacaine), and 0.17 (bupivacaine) mmol/L, respectively. Conversely, these local anesthetics also directly induced currents at higher concentrations, although these currents were quite small compared to the 2APB-induced currents. We found that the inhibition of TRPV3 by lidocaine is noncompetitive and independent of intracellular signaling cascades. 2APB-induced TRPV3 currents were reduced by extracellular N-(2,6-dimethylphenylcarbamoylmethyl) triethylammonium bromide (QX-314) but not by intracellular QX-314 nor benzocaine. Moreover, lidocaine showed a use-dependent block in TRPV3 inhibition. Finally, QX-314 appeared to slightly permeate the activated TRPV3 channel pore based on examination of oocytes coexpressing TRPV3 and a sodium channel. These results suggest that local anesthetics could inhibit TRPV3 channel function by extracellular interactions of their charged forms with the channel pore. Local anesthetics inhibited TRPV3 2APB-induced currents at pharmacologically relevant concentrations when TRPV3 was expressed in Xenopus oocytes. These effects seem to occur via an extracellular interaction between the charged form of the anesthetic with the TRPV3 channel pore. These results help to elucidate the mechanisms of action of local anesthetics.