1 Xenon is an anesthetic with minimal hemodynamic side effects, making it an ideal agent for cardiocompromised patients. We investigated if xenon induces pharmacological preconditioning (PC) of the rat heart and elucidated the underlying molecular mechanisms. 2 For infarct size measurements, anesthetized rats were subjected to 25 min of coronary artery occlusion followed by 120 min of reperfusion. Rats received either the anesthetic gas xenon, the volatile anesthetic isoflurane or as positive control ischemic preconditioning (IPC) during three 5-min periods before 25-min ischemia. Control animals remained untreated for 45 min. To investigate the involvement of protein kinase C (PKC) and p38 mitogen-activated protein kinase (MAPK), rats were pretreated with the PKC inhibitor calphostin C (0.1 mg kg À1 ) or the p38 MAPK inhibitor SB203580 (1 mg kg À1). Additional hearts were excised for Western blot and immunohistochemistry. 3 Infarct size was reduced from 50.9716.7% in controls to 28.1710.3% in xenon, 28.679.9% in isoflurane and to 28.575.4% in IPC hearts. Both, calphostin C and SB203580, abolished the observed cardioprotection after xenon and isoflurane administration but not after IPC. Immunofluorescence staining and Western blot assay revealed an increased phosphorylation and translocation of PKC-e in xenon treated hearts. This effect could be blocked by calphostin C but not by SB203580. Moreover, the phosphorylation of p38 MAPK was induced by xenon and this effect was blocked by calphostin C. 4 In summary, we demonstrate that xenon induces cardioprotection by PC and that activation of PKC-e and its downstream target p38 MAPK are central molecular mechanisms involved. Thus, the results of the present study may contribute to elucidate the beneficial cardioprotective effects of this anesthetic gas.

Obese surgical patients have impaired tissue penetration of the prophylactic antibiotic cefoxitin, and inadequate tissue concentrations despite increased clinical dose (2 g). Inadequate tissue antibiotic concentrations may be a factor in the increased risk of SSIs in obese surgical patients. Additional studies are needed to define doses achieving adequate tissue concentrations.

Summary Rotator cuff repair can be associated with significant and difficult to treat postoperative pain. We aimed to evaluate the available literature and develop recommendations for optimal pain management after rotator cuff repair. A systematic review using procedure‐specific postoperative pain management (PROSPECT) methodology was undertaken. Randomised controlled trials published in English from 1 January 2006 to 15 April 2019 assessing postoperative pain after rotator cuff repair using analgesic, anaesthetic or surgical interventions were identified from MEDLINE, Embase and Cochrane Databases. Out of 322 eligible studies identified, 59 randomised controlled trials and one systematic review met the inclusion criteria. Pre‐operative and intra‐operative interventions that improved postoperative pain were paracetamol, cyclo‐oxygenase‐2 inhibitors, intravenous dexamethasone, regional analgesia techniques including interscalene block or suprascapular nerve block (with or without axillary nerve block) and arthroscopic surgical technique. Limited evidence was found for pre‐operative gabapentin, perineural adjuncts (opioids, glucocorticoids, or α‐2‐adrenoceptor agonists added to the local anaesthetic solution) or postoperative transcutaneous electrical nerve stimulation. Inconsistent evidence was found for subacromial/intra‐articular injection, and for surgical technique‐linked interventions, such as platelet‐rich plasma. No evidence was found for stellate ganglion block, cervical epidural block, specific postoperative rehabilitation protocols or postoperative compressive cryotherapy. The analgesic regimen for rotator cuff repair should include an arthroscopic approach, paracetamol, non‐steroidal anti‐inflammatory drugs, dexamethasone and a regional analgesic technique (either interscalene block or suprascapular nerve block with or without axillary nerve block), with opioids as rescue analgesics. Further randomised controlled trials are required to confirm the influence of the recommended analgesic regimen on postoperative pain relief.

We previously demonstrated that the anesthetic gas xenon exerts cardioprotection by preconditioning in vivo via activation of protein kinase C (PKC)‐ɛ and p38 mitogen‐activated protein kinase (MAPK). P38 MAPK interacts with the actin cytoskeleton via the MAPK‐activated protein kinase‐2 (MAPKAPK‐2) and heat‐shock protein 27 (HSP27). The present study further elucidated the underlying molecular mechanism of xenon‐induced preconditioning (Xe‐PC) by focusing on a potential link of xenon to the cytoskeleton. Anesthetized rats received either xenon (Xe‐PC, n=6) or the volatile anesthetic isoflurane (Iso‐PC, n=6) during three 5‐min periods interspersed with two 5‐min and one final 10‐min washout period. Control rats (n=6) remained untreated for 45 min. Additional rats were either pretreated with the PKC inhibitor Calphostin C (0.1 mg kg−1) or with the p38 MAPK inhibitor SB203580 (1 mg kg−1) with and without anesthetic preconditioning (each, n=6). Hearts were excised for immunohistochemistry of F‐actin fibers and phosphorylated HSP27. Phosphorylation of MAPKAPK‐2 and HSP27 were assessed by Western blot. HSP27 and actin colocalization were investigated by co‐immunoprecipitation. Xe‐PC induced phosphorylation of MAPKAPK‐2 (control 1.0±0.2 vs Xe‐PC 1.6±0.1, P<0.05) and HSP27 (control 5.0±0.5 vs Xe‐PC 9.8±1.0, P<0.001). Both effects were blocked by Calphostin C and SB203580. Xe‐PC enhanced translocation of HSP27 to the particulate fraction and increased F‐actin polymerization. F‐actin and pHSP27 were colocalized after Xe‐PC. Xe‐PC activates MAPKAPK‐2 and HSP27 downstream of PKC and p38 MAPK. These data link Xe‐PC to the cytoskeleton, revealing new insights into the mechanisms of Xe‐PC in vivo. British Journal of Pharmacology (2005) 146, 445–455. doi:

Both, PKC and ERK1/2 mediate desflurane-induced preconditioning. PKC-epsilon and ERK1/2 are both activated in a time dependent manner during desflurane-induced preconditioning, but ERK1/2 activation during desflurane-induced preconditioning is not PKC dependent. Moreover, ERK1/2 blockade abolished PKC-epsilon activation, suggesting ERK-dependent activation of PKC-epsilon during desflurane-induced preconditioning.