[Systemic effects of amide-linked local anesthetics : Old drugs, new magic bullets?] / Systemische Effekte der Amid-Lokalanästhetika : Alte Substanzen, neue Wunderwaffen?

Besides the well-known analgesic effects of amide-linked local anesthetics exerted via the inhibition of the voltage-gated sodium channel, these substances also possess a certain number of properties, which bear the potential to positively influence the outcome after surgery. The results of several experimental as well as clinical studies suggest the possibility of an enhanced recovery after surgery, reduction in the incidence of chronic pain, preservation of endothelial barrier function during acute lung injury and the prevention of metastasis of solid tumors by systemic effects of local anesthetic administration. Mechanistic studies were able to identify several "new targets", such as the inhibition of spinal glycine transporters or of inflammatory signaling as induced by tumor necrosis factor alpha. Further elucidation of these mechanistic pathways as well as the translation of these promising experimental results into clinical practice is a crucial component of research activities in the field of anesthesia.

Effectiveness of tip rotation in fibreoptic bronchoscopy under different experimental conditions: an in vitro crossover study.

Background: Proper manipulation of fibreoptic bronchoscopes is essential for successful tracheal intubation or diagnostic bronchoscopy. Failure of proper navigation and rotation of the fibrescope may lead to difficulties in advancing the fibrescope and might also be responsible for (unnecessary) difficulties and delays in fibreoptic tracheal intubation, with subsequent hypoxaemia. The present study, therefore, aimed to assess the effectiveness of tip rotation in flexible bronchoscopes in different experimental conditions. Methods: Five differently sized pairs of fibrescopes (outer diameters of 2.2, 2.4, 3.5, 4.2, and 5.2 mm) were inserted into paediatric airway manikins via an appropriately sized laryngeal mask and were turned clockwise or anticlockwise at the fibrescope body or cord to 45, 90, and 180°, with the cord held either straight or bent. The primary outcome measure was the ratio of rotation measured at the tip over the rotation performed with the fibrescope body or cord. Results: Overall, the 'body' turn was significantly less effective when a bent cord was present (mean difference ranging from 29.8% (95% confidence interval 8.8-50.9) to 117.4% (93.6-141.2). This difference was diminished when the 'cord' turn was performed. Smaller fibrescopes, with outer diameters of 2.2 and 2.4 mm, were inferior with respect to the transmission of 'body' rotation to the tip. Conclusions: 'Cord' turning of the fibrescope appears to be more effective in rotating the tip than a turn of the fibrescope 'body' only. Straightening the fibrescope cord and combined 'body' and 'cord' turning are recommended.

Clinically relevant concentrations of lidocaine and ropivacaine inhibit TNFα-induced invasion of lung adenocarcinoma cells in vitro by blocking the activation of Akt and focal adhesion kinase.

BACKGROUND: Matrix-metalloproteinases (MMP) and cancer cell invasion are crucial for solid tumour metastasis. Important signalling events triggered by inflammatory cytokines, such as tumour necrosis factor α (TNFα), include Src-kinase-dependent activation of Akt and focal adhesion kinase (FAK) and phosphorylation of caveolin-1. Based on previous studies where we demonstrated amide-type local anaesthetics block TNFα-induced Src activation in malignant cells, we hypothesized that local anaesthetics might also inhibit the activation and/or phosphorylation of Akt, FAK and caveolin-1, thus attenuating MMP release and invasion of malignant cells. METHODS: NCI-H838 lung adenocarcinoma cells were incubated with ropivacaine or lidocaine (1 nM-100 µM) in absence/presence of TNFα (20 ng ml(-1)) for 20 min or 4 h, respectively. Activation/phosphorylation of Akt, FAK and caveolin-1 were evaluated by Western blot, and MMP-9 secretion was determined by enzyme-linked immunosorbent assay. Tumour cell migration (electrical wound-healing assay) and invasion were also assessed. RESULTS: Ropivacaine (1 nM-100 µM) and lidocaine (1-100 µM) significantly reduced TNFα-induced activation/phosphorylation of Akt, FAK and caveolin-1 in NCI-H838 cells. MMP-9 secretion triggered by TNFα was significantly attenuated by both lidocaine and ropivacaine (half-maximal inhibitory concentration [IC50]=3.29×10(-6) M for lidocaine; IC50=1.52×10(-10) M for ropivacaine). The TNFα-induced increase in invasion was completely blocked by both lidocaine (10 µM) and ropivacaine (1 µM). CONCLUSIONS: At clinically relevant concentrations both ropivacaine and lidocaine blocked tumour cell invasion and MMP-9 secretion by attenuating Src-dependent inflammatory signalling events. Although determined entirely in vitro, these findings provide significant insight into the potential mechanism by which local anaesthetics might diminish metastasis.

Volatile anaesthetics reduce neutrophil inflammatory response by interfering with CXC receptor-2 signalling.

BACKGROUND: Growing evidence suggests a protective effect of volatile anaesthetics in ischaemia-reperfusion (I/R)-injury, and the accumulation of neutrophils is a crucial event. Pro-inflammatory cytokines carrying the C-X-C-motif including interleukin-8 (IL-8) and CXC-ligand 1 (CXCL1) activate CXC receptor-1 (CXCR1; stimulated by IL-8), CXC receptor-2 (CXCR2; stimulated by IL-8 and CXCL1), or both to induce CD11b-dependent neutrophil transmigration. Inhibition of CXCR1, CXCR2, or both reduces I/R-injury by preventing neutrophil accumulation. We hypothesized that interference with CXCR1/CXCR2 signalling contributes to the well-established beneficial effect of volatile anaesthetics in I/R-injury. METHODS: Isolated human neutrophils were stimulated with IL-8 or CXCL1 and exposed to volatile anaesthetics (sevoflurane/desflurane). Neutrophil migration was assessed using an adapted Boyden chamber. Expression of CD11b, CXCR1, and CXCR2 was measured by flow cytometry. Blocking antibodies against CXCR1/CXCR2/CD11b and phorbol myristate acetate were used to investigate specific pathways. RESULTS: Volatile anaesthetics reduced CD11b-dependent neutrophil transmigration induced by IL-8 by >30% and CD11b expression by 18 and 27% with sevoflurane/desflurane, respectively. This effect was independent of CXCR1/CXCR2 expression and CXCR1/CXCR2 endocytosis. Inhibition of CXCR1 signalling did not affect downregulation of CD11b with volatile anaesthetics. Blocking of CXCR2-signalling neutralized effects by volatile anaesthetics on CD11b expression. Specific stimulation of CXCR2 with CXCL1 was sufficient to induce upregulation of CD11b, which was impaired with volatile anaesthetics. No effect of volatile anaesthetics was observed with direct stimulation of protein kinase C located downstream of CXCR1/CXCR2. CONCLUSION: Volatile anaesthetics attenuate neutrophil inflammatory responses elicited by CXC cytokines through interference with CXCR2 signalling. This might contribute to the beneficial effect of volatile anaesthetics in I/R-injury.

Regional anaesthesia and cancer metastases: the implication of local anaesthetics.

Clinical and basic science studies have demonstrated the anti-inflammatory properties of local anaesthetics. Recent studies have begun to unravel molecular pathways linking inflammation and cancer. Regional anaesthesia is associated in some retrospective clinical studies with reduced risk of metastasis and increased long-term survival. The potential beneficial effects of regional anaesthesia have been attributed mainly to the inhibition of the neuroendocrine stress response to surgery and to the reduction in the requirements of volatile anaesthetics and opioids. Because cancer is linked to inflammation and local anaesthetics have anti-inflammatory effects, these agents may participate in reducing the risk of metastasis, but their mechanism of action is unknown. We demonstrated in vitro that amide local anaesthetics attenuate tumour cell migration as well as signalling pathways enhancing tumour growth and metastasis. This has provided the first evidence of a molecular mechanism by which regional anaesthesia might inhibit or reduce cancer metastases.

[Special situations of preconditioning and prehabilitation in oncological visceral surgery]. / Spezialsituationen der Präkonditionierung und Prähabilitation in der onkologischen Viszeralchirurgie.

BACKGROUND: Prehabilitation prior to complex visceral oncological surgery is playing an increasingly important role. OBJECTIVE: The aim of this review article is to present special situations of preconditioning in visceral oncological patient cohorts. The following conditions were defined as special situations with subsequently increased risk profile: cardiopulmonary comorbidities, geriatric patients, neoadjuvant therapy and simultaneous fatigue. MATERIAL AND METHODS: A selective literature review based on a search in the electronic databases MEDLINE, PubMed, Cochrane Library and the International Standard Randomization Controlled Trial Number (ISRCTN) was performed. RESULTS: The identification of high-risk patients is an essential part of the preoperative evaluation conducted by the anesthesiologist prior to surgery. The cardiovascular and the pulmonary risk profile are determined by means of prediction indices evaluating patient-specific and surgery-related risk factors. The increased use of new oral anticoagulants and dual platelet aggregation inhibition requires individualized treatment strategies. Numerous studies have shown clinically relevant effects of exercise therapy interventions throughout all phases of oncological treatment. In addition to positive effects on therapy-associated side effects, sport can also counteract the effects of sedentary behavior in cancer patients and improve the health-related quality of life. The effectiveness of sport and exercise therapies as well as psychological interventions in oncological patients with fatigue (CRF) is broad, with important components being motivation and compliance. DISCUSSION: In high-risk patients an interdisciplinary approach to planning and conduction of prehabilitation is essential for the early detection and optimization of perioperative risk factors and potential complications. The aim is faster recovery, reduced morbidity and mortality and the possibility to improve long-term survival and quality of life.

Anesthesia and colorectal cancer - The perioperative period as a window of opportunity?

Gastrointestinal malignancies largely contribute to cancer related deaths in the United States, with colorectal cancer representing the 3rd place of the ten leading entities of mortality due to cancer for both females and males. The majority of patients with GI tumors has to undergo surgery (either as a curative or palliative intervention) and are therefore also in need for a proper general and/or regional anesthesia. Recent findings have suggested that the type of anesthesia administered might have an impact on cancer recurrence and metastasis and thus this new field in the anesthesia world has become a largely studied topic. This review highlights current concepts and summarizes the evidence for an impact of the type of anesthesia on patient outcome after cancer surgery, suggesting the perioperative period might be a "window of opportunity" which should not be missed.