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Despite new concepts and strategies of basic and advanced life support, the outcome of patients with out-of-hospital cardiac arrest (OHCA) remains poor. The main reason accounting for these poor results is a low-flow phase during conventional cardiopulmonary resuscitation (CPR) with insufficient end organ perfusion. The early use of venoarterial extracorporeal membrane oxygenation (vaECMO) during CPR, i.e. extracorporeal resuscitation (ECPR) might improve OHCA survival rates as well as the neurological outcome in resuscitated patients. This article on a case series discusses the management of ECPR in three patients with OHCA. All patients suffered from a witnessed OHCA and received effective bystander CPR. After subsequent advanced cardiac life support could not achieve a return of spontaneous circulation (ROSC), vaECMO support was established as a bridge to therapy on site or after transportation to a primary or tertiary hospital. During the course of therapy two patients died and one patient was discharged after a full recovery. Early ECPR might improve the outcome in patients with prolonged cardiac arrest without ROSC. The use of ECPR should be based on the individual decision of an experienced ECPR team considering defined inclusion and exclusion criteria. As the outcome mainly depends on the duration and quality of conventional CPR, ECPR support should be requested immediately after establishing advanced life support (approximately 10-15 min).

Introduction: Airway management, mechanical ventilation and resuscitation can be performed almost everywhere--even in space--but not under water. The present study assessed the technical feasibility of resuscitation under water in a manikin model., Methods: Tracheal intubation was assessed in a hyperbaric chamber filled with water at 20 m of depth using the Pentax AWS S100 video laryngoscope, the Fastrach™ intubating laryngeal mask and the Clarus optical stylet with guidance by a laryngeal mask airway (LMA) and without guidance. A closed suction system was used to remove water from the airways. A test lung was ventilated to a maximum depth of 50 m with a modified Oxylator(®) EMX resuscitator with its expiratory port connected either to a demand valve or a diving regulator. Automated chest compressions were performed to a maximum depth of 50 m using the air-driven LUCAS™ 1., Results: The mean cumulative time span for airway management until the activation of the ventilator was 36 s for the Fastrach™, 57 s for the Pentax AWS S100, 53s for the LMA-guided stylet and 43 s for the stylet without LMA guidance. Complete suctioning of the water from the airways was not possible with the suction system used. The Oxylator(®) connected to the demand valve ventilated at 50 m depth with a mean ventilation rate of 6.5 min(-1) vs. 14.7 min(-1) and minute volume of 4.5 l min(-1) vs. 7.6 l min(-1) compared to the surface. The rate of chest compression at 50 m was 228 min(-1) vs. 106 min(-1) compared to surface. The depth of compressions decreased with increasing depth., Conclusion: Airway management under water appears to be feasible in this manikin model. The suction system requires further modification. Mechanical ventilation at depth is possible but modifications of the Oxylator(®) are required to stabilize ventilation rate and administered minute volumes. The LUCAS™ 1 cannot be recommended at major depth., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

The objective of the present investigation was to study the ability of sulfobutylether-β-cyclodextrin (SBEβCD) to form an inclusion complex with sevoflurane (SEV), a volatile anesthetic with poor water solubility. The inclusion complex was prepared, characterized and its cellular toxicity and blood-brain barrier (BBB) permeation potential of the formulated SEV have also been examined for the purpose of controlled drug delivery. The SEV-SBEβCD complex was nontoxic to the primary brain microvascular endothelial (pEND) cells at a clinically relevant concentration of sevoflurane. The inclusion complex exhibited significantly higher BBB permeation profiles as compared with the reference substance (propranolol) concerning calculated apparent permeability values (Papp). In addition, SEV binding affinity to SBEβCD was confirmed by a minimal Gibbs free energy of binding (ΔGbind) value of -1.727 ± 0.042 kcal·mol-1 and an average binding constant (Kb) of 53.66 ± 9.24 mM indicating rapid drug liberation from the cyclodextrin amphiphilic cavity.

The current report highlights the use of venoarterial extracorporeal membrane oxygenation (va-ECMO) in a case of pulmonary embolism complicated by right ventricular failure. A 38-year-old woman was admitted to a secondary care hospital with dyspnea and systemic hypotension. Diagnostic testing revealed a massive pulmonary embolism. Thrombolytic therapy was unsuccessful necessitating thromboendarterectomy in the presence of cardiogenic shock. To allow the necessary transport of the highly unstable patient to a tertiary care center a mobile ECMO team was called in. The team immediately initiated awake va-ECMO as a bridge to therapy. Extracorporeal support subsequently allowed a safe transportation and successful completion of the surgical procedure with complete recovery.

Background: In addition to specific treatment of the underlying cause, the therapy of acute respiratory distress syndrome (ARDS) consists of lung protective ventilation and a range of adjuvant and supportive measures., Aim: A survey was conducted to determine the current treatment strategies for ARDS in German ARDS centers., Material and Methods: The 39 centers listed in the German ARDS network in 2011 were asked to complete a questionnaire collecting data on the clinic, epidemiology as well as diagnostic and therapeutic measures regarding ARDS treatment., Results: Of the centers 25 completed the questionnaire. In 2010 each of these centers treated an median of 31 (25-75 percentile range 20-59) patients. Diagnostic measures at admission were computed tomography of the thorax (60 % of the centers), whole body computed tomography (56 %), chest x-ray (52 %), abdominal computed tomography (32 %) and cranial computed tomography (24 %). Transesophageal echocardiography was performed in 64 %, pulmonary artery pressure was measured in 56 % and cerebral oximetry in 12 %. Sedation was regularly interrupted in 92 % of the centers and in 68 % this was attempted at least once a day. A median minimum tidal volume of 4 ml/kg (range 2-6) and a maximum tidal volume of 6 ml/kg (4-8) were used. Methods to determine the optimal positive end-expiratory pressure (PEEP) were the best PEEP method (60 %), ARDS network table (48 %), empirical (28 %), pressure volume curve (16 %), computed tomography (8 %), electrical impedance tomography (8 %) and others (8 %). Median minimum and maximum PEEPs were 10 cmH2O (range 5-15) and 21 cmH2O (15-25), respectively. Median plateau pressure was limited to 30 cmH2O (range 26-45). The respiratory rate was set below 20/min in 20 % and below 30/min in 44 %. Controlled ventilator modes were generally preferred with 80 % using biphasic positive airway pressure (BIPAP/BiLevel), 20 % pressure controlled ventilation (PCV) and 4 % airway pressure release ventilation (APRV). Assisted modes were only utilized by 8 % of the centers. Recruitment maneuvers were used by 28 %, particularly during the early phase of the ARDS. Muscle relaxants were administered by 32 % during the early phase of the ARDS. Complete prone positioning was used by 60 % of the centers, whereas 88 % utilized incomplete (135°) prone positioning. Continuous axial rotation was utilized by 16 %. Spontaneous breathing tests were used in 88 % of the centers with 60 % performing these at least once a day. Supportive therapies were frequently applied and mainly consisted of nitrous oxide (44 %), prostacycline (48 %) and corticosteroids (52 %). A restrictive fluid therapy was used in 48 % and a special nutrition regimen in 28 % of the centers. Of the participating centers 22 were able to offer extracorporeal membrane oxygenation (ECMO). In this case, respiratory therapy was modified by further reducing tidal volumes (91 %), inspiratory pressures (96 %) as well as using lower respiratory rates (≤ 8/min in 31 %). Only 9 % reduced PEEP during ECMO. Regular recruitment maneuvers were used by 14 %. Positioning maneuvers during ECMO were used by 82 %., Conclusions: Lung protective ventilation with reduced tidal volumes as well as inspiratory pressures represents the current standard of care and was utilized in all network centers. Prone positioning was widely used. Promising adjuvant therapies such as the muscle relaxation during the early phase of the ARDS, fluid restriction and corticosteroids were used less frequently. During ECMO respirator therapy was generally continued with ultraprotective ventilator settings.

Background: Nowadays Caesarean sections are mainly undertaken using spinal anesthesia; therefore, it is important to minimize potential side effects and risks associated with this technique. Currently, many studies have been conducted to optimize the dose of local anesthetics to avoid hypotension, which often occurs during spinal anesthesia., Aim: In a retrospective study design the high-volume, low-concentration technique with up to 12 ml isobaric bupivacain 0.1% (1 mg/ml) and sufentanil (1 µg/ml), which has been used at the University Hospital Würzburg for many years was analyzed with respect to reliability and side effects. The use of this technique so far is unique among university hospitals in Germany., Material and Methods: Of the 1424 anesthesia protocols from 2001 to 2007 a total of 1368 were analyzed. Demographic data and parameters, such as location of puncture, dose and extent of anesthesia, hemodynamic stability and additional medication were recorded. A decrease of systolic blood pressure of more than 20% of the initial value was defined as hypotension., Results: The median volume used for spinal anesthesia was 9 ml, containing 9 mg bupivacaine and 9 µg sufentanil. The rate of hypotension was 48.8 %. No significant differences in hypotension between lower and higher volumes were detectable. In 0.84% (n=12) of the cases the procedure had to be changed to general anesthesia and additional analgesia was administered in 3 cases (0.22%)., Conclusion: The high-volume, low-concentration technique is an effective approach for spinal anesthesia with a small number of cases needing general anesthesia or additional analgesics. The rate of hypotension was moderate compared to other studies; however, because of the retrospective and non-randomized study design the dependence of this rate on dose and given volume should be interpreted with caution.

In-line stabilisation of the neck can increase the difficulty of tracheal intubation with direct laryngoscopy. We randomly assigned 56 patients with cervical spine pathology scheduled for elective surgery to tracheal intubation using either the C-MAC(®) (n = 26) or GlideScope(®) (n = 30), when the head and neck were stabilised in-line. There was no significant difference in the median (IQR [range]) intubation times between the C-MAC (19 (14-35 [9-90]) s and the GlideScope (23, (15-32 [8-65]) s. The first-attempt failure rate for the C-MAC was 42% (95% CI 23-63%) compared with 7% (95% CI 1-22%) for the GlideScope, p = 0.002. The laryngeal view was excellent and comparable with both devices, with the C-MAC requiring significantly more attempts and optimising manoeuvers (11 vs 5, respectively, p = 0.04). There were no significant differences in postoperative complaints e.g. sore throat, hoarseness and dysphagia. Both devices provided an excellent glottic view in patients with cervical spine immobilisation, but tracheal intubation was more often successful on the first attempt with the GlideScope., (© 2014 The Association of Anaesthetists of Great Britain and Ireland.)

A 23-year-old woman was mortally afraid of dental interventions and decided to have her four wisdom teeth removed by outpatient surgery under endotracheal anaesthesia. According to the files, the patient was categorized as ASA I and Mallampati II, and surgery was considered an elective routine intervention. Soon after initiation of anaesthesia, O2 saturation and blood pressure dropped, and the young woman died shortly afterwards in spite of immediate resuscitation measures. At first, an allergic reaction to succinylcholine, which had been administered as a muscle relaxant, was suspected. Autopsy and histological examination showed haemorrhagic pulmonary oedema and a defined lesion in the midportion of the oesophageal mucosa in spite of correct placement of the endotracheal breathing tube. Ultimately, misintubation into the oesophagus, which had not been noticed at first, was determined as cause of death.

Objective: To investigate the impact of the phophodiesterase-4 inhibition (PD-4-I) with rolipram on hepatic integrity in lipopolysaccharide (LPS) induced hyperinflammation., Materials and Methods: Liver microcirculation in rats was obtained using intravital microscopy. Macrohemodynamic parameters, blood assays, and organs were harvested to determine organ function and injury. Hyperinflammation was induced by LPS and PD-4-I rolipram was administered intravenously one hour after LPS application. Cell viability of HepG2 cells was measured by EZ4U-kit based on the dye XTT. Experiments were carried out assessing the influence of different concentrations of tumor necrosis factor alpha (TNF-α) and LPS with or without PD-4-I., Results: Untreated LPS-induced rats showed significantly decreased liver microcirculation and increased hepatic cell death, whereas LPS + PD-4-I treatment could improve hepatic volumetric flow and cell death to control level whithout influencing the inflammatory impact. In HepG2 cells TNF-α and LPS significantly reduced cell viability. Coincubation with PD-4-I increased HepG2 viability to control levels. The heme oxygenase 1 (HO-1) pathway did not induce the protective effect of PD-4-I., Conclusion: Intravenous PD-4-I treatment was effective in improving hepatic microcirculation and hepatic integrity, while it had a direct protective effect on HepG2 viability during inflammation.

Background: Up to 50% of septic patients develop acute kidney injury (AKI). The pathomechanism of septic AKI is poorly understood. Therefore, we established an innovative rodent model to characterize sepsis-induced AKI by standardized colon ascendens stent peritonitis (sCASP). The model has a standardized focus of infection, an intensive care set up with monitoring of haemodynamics and oxygenation resulting in predictable impairment of renal function, AKI parameters as well as histopathology scoring., Methods: Anaesthetized rats underwent the sCASP procedure, whereas sham animals were sham operated and control animals were just monitored invasively. Haemodynamic variables and blood gases were continuously measured. After 24 h, animals were reanesthetized; cardiac output (CO), inulin and PAH clearances were measured and later on kidneys were harvested; and creatinine, urea, cystatin C and neutrophil gelatinase-associated lipocalin (NGAL) were analysed. Additional sCASP-treated animals were investigated after 3 and 9 days., Results: All sCASP-treated animals survived, whilst ubiquitous peritonitis and significantly deteriorated clinical and macrohaemodynamic sepsis signs after 24 h (MAP, CO, heart rate) were obvious. Blood analyses showed increased lactate and IL-6 levels as well as leucopenia. Urine output, inulin and PAH clearance were significantly decreased in sCASP compared to sham and control. Additionally, significant increase in cystatin C and NGAL was detected. Standard parameters like serum creatinine and urea were elevated and sCASP-induced sepsis increased significantly in a time-dependent manner. The renal histopathological score of sCASP-treated animals deteriorated after 3 and 9 days., Conclusions: The presented sCASP method is a standardized, reliable and reproducible method to induce septic AKI. The intensive care set up, continuous macrohaemodynamic and gas exchange monitoring, low mortality rate as well as the opportunity of detailed analyses of kidney function and impairments are advantages of this setup. Thus, our described method may serve as a new standard for experimental investigations of septic AKI.

Background: In the context of the European Resuscitation Council (ERC) guidelines, modifications of the proposed treatment algorithm need to be performed in order to respond to different parameters. In this respect several factors interacting with cardiac arrest are essential and need to be included in the therapy. This case report demonstrates an example of resuscitation in the situation of hypothermia., Case Report: After a near drowning accident and approximately 30 min underwater, a patient suffering from severe hypothermia initially required resuscitation after the rescue. A return of spontaneous circulation (ROSC) was successfully achieved within a short length of time and after 15 days on the intensive care unit the patient was discharged to a rehabilitation facility without any signs of focal neurological deficits., Discussion: Section 8 of the ERC guidelines provides additional information for resuscitation under specific conditions. In this case report, hypothermia was one of the main criteria leading to an adjusted pharmacological therapy. Furthermore, selection of the appropriate hospital for an optimal advanced treatment including controlled warming of the patient and management of hypothermia-induced complications had to be evaluated.

Unlabelled: In an acute respiratory distress syndrome, venovenous extracorporeal membrane oxygenation (vvECMO) can rapidly normalize arterial hypoxemia and carbon dioxide tension (PaCO2). Considering the positive relationship between PaCO2 and cerebral blood flow, the aim of the current study was to evaluate cerebral regional tissue oxygen saturation (rSO2) during the implementation of vvECMO. Fifteen acute respiratory distress syndrome patients with recordings of cerebral rSO2 by near-infrared spectroscopy before vvECMO implementation until the optimization of the ECMO/ventilator settings were retrospectively studied., Results: median (interquartile range). The cerebral rSO2 increased significantly (p < 0.05) from 69(61-74) to 75(60-80)% after ECMO was started, concomitant to the arterial oxygenation. Until the end of the observation period after 83(44-132) minutes, cerebral rSO2 decreased significantly to 61(52-71)%. PaCO2 decreased from 70(61-87) to 43(38-54) mm Hg and the pH increased from 7.23(7.14-7.29) to 7.39(7.34-7.43). The baseline arterial oxygen saturation and tension as well as the actual bicarbonate concentration were negatively correlated with the absolute change in cerebral rSO2 (ΔrSO2). In the 11 nonhypoxemic patients (arterial oxygen saturation ≥90%) ΔPaCO2 was significantly correlated with ΔrSO2. Patients receiving vvECMO treatment are at risk for a decrease in cerebral rSO2. This decrease is more distinct in patients with normal baseline arterial oxygenation and high actual bicarbonate.

Object: The authors undertook this study to investigate whether the physiological mechanism of cerebral blood flow (CBF) regulation by alteration of the arterial partial pressure of carbon dioxide (PaCO₂) can be used to increase CBF after aneurysmal subarachnoid hemorrhage (aSAH)., Methods: In 6 mechanically ventilated patients with poor-grade aSAH, the PaCO₂ was first decreased to 30 mm Hg by modification of the respiratory rate, then gradually increased to 40, 50 and 60 mm Hg for 15 minutes each setting. Thereafter, the respirator settings were returned to baseline parameters. Intracerebral CBF measurement and brain tissue oxygen saturation (StiO₂), measured by near-infrared spectroscopy (NIRS), were the primary and secondary end points. Intracranial pressure (ICP) was controlled by external ventricular drainage., Results: A total of 60 interventions were performed in 6 patients. CBF decreased to 77% of baseline at a PaCO₂ of 30 mm Hg and increased to 98%, 124%, and 143% at PaCO₂ values of 40, 50, and 60 mm Hg, respectively. Simultaneously, StiO₂ decreased to 94%, then increased to 99%, 105%, and 111% of baseline. A slightly elevated delivery rate of cerebrospinal fluid was noticed under continuous drainage. ICP remained constant. After returning to baseline respirator settings, both CBF and StiO₂ remained elevated and only gradually returned to pre-hypercapnia values without a rebound effect. None of the patients developed secondary cerebral infarction., Conclusions: Gradual hypercapnia was well tolerated by poor-grade SAH patients. Both CBF and StiO₂ reacted with a sustained elevation upon hypercapnia; this elevation outlasted the period of hypercapnia and only slowly returned to normal without a rebound effect. Elevations of ICP were well compensated by continuous CSF drainage. Hypercapnia may yield a therapeutic potential in this state of critical brain perfusion. Clinical trial registration no.: NCT01799525 ( ClinicalTrials.gov ).

We investigated the ionization profiles for open-ring (OR) and closed-ring (CR) forms of midazolam and drug-binding modes with heptakis-(2,3,6-tri-O-methyl)-β-cyclodextrin (trimethyl-β-cyclodextrin; TRIMEB) using molecular modeling techniques and quantum mechanics methods. The results indicated that the total net charges for different molecular forms of midazolam tend to be cationic for OR and neutral for CR at physiological pH levels. The thermodynamic calculations demonstrated that CR is less water-soluble than OR, mainly due to the maximal solvation energy (ΔG(CR)(solv = -9.98 kcal·mol ⁻¹), which has a minimal ΔG(OR)(solv) of -67.01 kcal·mol⁻¹. A cell viability assay did not detect any signs of TRIMEB and OR/CR-TRIMEB complex toxicity on the cEND cells after 24 h of incubation in either Dulbecco's Modified Eagles Medium or in heat-inactivated human serum. The molecular docking studies identified the more flexible OR form of midazolam as being a better binder to TRIMEB with the fluorophenyl ring introduced inside the amphiphilic cavity of the host molecule. The OR binding affinity was confirmed by a minimal Gibbs free energy of binding (ΔG(bind)) value of -5.57 ± 0.02 kcal·mol⁻¹, an equilibrium binding constant (K(b)) of 79.89 ± 2.706 μM, and a ligand efficiency index (LE(lig)) of -0.21 ± 0.001. Our current data suggest that in order to improve the clinical applications of midazolam via its complexation with trimethyl-β-cyclodextrin to increase drug's overall aqueous solubility, it is important to concern the different forms and ionization states of this anesthetic. All mean values are indicated with their standard deviations.

Background: Recently, clinical trials revealed renal impairment induced by hydroxyethyl starch (HES) in septic patients. In prior studies, we managed to demonstrate that HES accumulated in renal proximal tubule cells (PTCs). The related pathomechanism has not yet been discovered. To validate our hypothesis that the HES molecule itself is harmful, regardless of its molecule size or origin, we conducted a comprehensive study to elucidate the influences of different HES preparations on PTC viability in vitro., Methods: Cell viability of human PTC was measured with a cytotoxicity assay, quantifying the reduction of tetrazolium salt to colored formazan. Experiments were performed by assessing the influence of different carrier solutions of HES (balanced, nonbalanced, culture medium), different average molecular weights (70, 130, 200 kDa), different origins (potato or corn derived), and various durations of incubation (2-21 hours). Furthermore, HES 130/0.4 was fractionated by ultrafiltration, and the impact on cell viability of average single-size fractions with <3, 3 to 10, 10 to 30, 30 to 50, 50 to 100, and >100 kDa was investigated. We also tested the possible synergistic effects of inflammation induced by tumor necrosis factor-α., Results: All tested HES solutions, regardless of origin or carrier matrix, decreased cell viability in an equivalent, dose-dependent manner. Coincubation with tumor necrosis factor-α did not reduce HES-induced reduction of cell viability. Minor differences were detected comparing 70, 130, and 200 kDa preparations. Analysis of fractionated HES revealed that each fraction decreased cell viability. Even small HES molecules (10-30 kDa) were significantly deleterious., Conclusions: For the first time, we were able to show that only the total mass of HES molecules applied is responsible for the harmful impact on renal PTC in vitro. Neither molecular size nor their origin showed any relevance.

Cyclooxygenase (COX)-2 mediates ischemic pre- and postconditioning as well as anesthetic-induced preconditioning. However, the role of COX-1 and -2 in anesthetic-induced postconditioning has not been investigated. We evaluated the role of COX-1 and -2 in sevoflurane-induced postconditioning in vivo. Pentobarbital-anaesthetized male C57BL/6 mice were subjected to 45 minutes of coronary artery occlusion and 3 hours of reperfusion. Animals received either no intervention, the vehicle dimethyl sulfoxide (DMSO, 10 µL/g intraperitoneally), acetylsalicylic acid (ASA, 5 µg/g intraperitoneally), the selective COX-1 inhibitor SC-560 (10 µg/g intraperitoneally), or the selective COX-2 inhibitor NS-398 (5 µg/g intraperitoneally). 1.0 MAC (minimum alveolar concentration) sevoflurane was administered for 18 minutes during early reperfusion either alone or in combination with ASA, SC-560, and NS-398. Infarct size was determined with triphenyltetrazolium chloride. Statistical analysis was performed using 1-way and 2-way analyses of variance with post hoc Duncan testing. The infarct size in the control group was 44% ± 9%. DMSO (42% ± 7%), ASA (36% ± 6%), and NS-398 (44% ± 18%) had no effect on infarct size. Sevoflurane (17% ± 4%; P < .05) and SC-560 (26% ± 10%; P < .05) significantly reduced the infarct size compared with control condition. Sevoflurane-induced postconditioning was not abolished by ASA (16% ± 5%) and SC-560 (22% ± 4%). NS-398 abolished sevoflurane-induced postconditioning (33% ± 14%). It was concluded that sevoflurane induces postconditioning in mice. Inhibition of COX-1 elicits a myocardial infarct size reduction and does not abolish sevoflurane-induced postconditioning. Blockade of COX-2 abolishes sevoflurane-induced postconditioning. These results indicate that sevoflurane-induced postconditioning is mediated by COX-2., (© The Author(s) 2014.)

Background Information: Glucocorticoids (GCs), including the synthetic GC derivate dexamethasone, are widely used as immunomodulators. One of the numerous side effects of dexamethasone therapy is hypertension arising from reduced release of the endothelium-derived vasodilator nitric oxide (NO)., Results: Herein, we described the role of dexamethasone and its glucocorticoid receptor (GR) in the regulation of NO synthesis in vitro using the mouse myocardial microvascular endothelial cell line, MyEND. GC treatment caused a firm decrease of extracellular NO levels, whereas the expression of endothelial NO synthase (eNOS) was not affected. However, GC application induced an impairment of tetrahydrobiopterin (BH4 ) concentrations as well as GTP cyclohydrolase-1 (GTPCH-1) expression, both essential factors for NO production upstream of eNOS. Moreover, dexamethasone stimulation resulted in a substantially decreased GR gene and protein expression in MyEND cells. Importantly, inhibition of proteasome-mediated proteolysis of the GR or overexpression of an ubiquitination-defective GR construct improved the bioavailability of BH4 and strengthened GTPCH-1 expression and eNOS activity., Conclusions: Summarising our results, we propose a new mechanism involved in the regulation of NO signalling by GCs in myocardial endothelial cells. We suggest that a sufficient GR protein expression plays a crucial role for the management of GC-induced harmful adverse effects, including deregulations of vasorelaxation arising from disturbed NO biosynthesis., (© 2014 Société Française des Microscopies and Société de Biologie Cellulaire de France. Published by John Wiley & Sons Ltd.)

Background: Ultrasound guidance is still a young method in regional anesthesia when compared to nerve stimulation and only a few studies exist comparing these two techniques in an axillary multiple injection approach., Aim: This prospective, randomized, observer-blinded study compared an ultrasound-guided (SONO) quadruple injection axillary block (out of plane, perineural) with a nerve stimulation-guided (STIM) triple injection axillary block for upper limb surgery., Material and Methods: A total of 60 patients were randomized to either the SONO (n = 30) or STIM (n = 30) group. For the block 40-50 ml mepivacaine 1.5 % (plexus) and 5-10 ml mepivacaine 0.5 % (subcutaneous in the medial skin of the arm) was used. Anesthesia time was recorded as the primary end point. After evaluation of block-related pain using a visual analog scale (VAS) a blinded observer tested sensory and motor function of the median nerve (MED), ulnar nerve (ULN), radial nerve (RAD), musculocutaneous nerve of the upper limb (MUC) and medial cutaneous nerve of the forearm (CAM) at defined times. The main outcome variable was onset time (defined loss of sensory/motor function)., Results: No differences were observed between the groups in terms of onset time (single nerves 10-20 min, plexus 20-25 min) and success rate (SONO 90 %, STIM 89 %). Patient satisfaction as measured by block-related pain score (VAS 2 cm), complications (vascular puncture SONO 7 %, STIM 11 %; paresthesia SONO 21 %, STIM 22 %) and patient acceptance (SONO 92 %, STIM 91 %) showed no differences. Performance time was shorter in the SONO group (6.68 ± 1.72 min vs. 8.05 ± 2.58, p = 0.02)., Conclusion: Nerve stimulation-guided axillary plexus blocks performed by trained anesthesiologists may result in similar onset times and success rates compared to ultrasound-guided blocks.

Background: Breakdown of microvascular endothelial barrier functions contributes to disturbed microcirculation, organ failure, and death in sepsis. Increased endothelial cAMP levels by systemic application of phosphodiesterase 4 inhibitors (PD-4-I) have previously been demonstrated to protect microvascular barrier properties in a model of systemic inflammation (systemic inflammatory response syndrome) suggesting a novel therapeutic option to overcome this problem. However, in a clinically relevant model of polymicrobial sepsis long-term effects, immunomodulatory effects and effectivity of PD-4-I to stabilize microvascular barrier functions and microcirculation remained unexplored., Methods: We induced polymicrobial sepsis using the colon ascendens stent peritonitis (CASP) model in which we performed macrohemodynamic and microhemodynamic monitoring with and without systemic intravenous application of different doses of PD-4-I rolipram in Sprague-Dawley rats over 26 h., Results: All animals with CASP showed clinical and laboratory signs of sepsis and peritonitis. Whereas macrohemodynamic adverse effects were not evident, application of PD-4-I led to stabilization of endothelial barrier properties as revealed by reduced extravasation of fluorescein isothiocyanate-albumin. However, only low-dose application of 1 mg/kg body weight per hour of PD-4-I improved microcirculatory flow in the CASP model, whereas high-dose therapy of 3 mg/kg BW per hour PDI-4-I had adverse effects. Accordingly, sepsis-induced acute kidney injury and lung edema were prevented by PD-4-I treatment. Furthermore, PD-4-I showed immunomodulatory effects as revealed by decreased interleukin 1α (IL-1α), IL-1β, IL-12, and tumor necrosis factor α levels following PD-4-I treatment, which appeared not to correlate with barrier-stabilizing effects of rolipram., Conclusions: These data provide further evidence that systemic application of PD-4-I could be suitable for therapeutic microvascular barrier stabilization and improvement of microcirculatory flow in sepsis.

Malignant hyperthermia is a potentially lethal inherited disorder characterized by disturbance of calcium homeostasis in skeletal muscle. Volatile anesthetics and/or the depolarizing muscle relaxant succinylcholine may induce this hypermetabolic muscular syndrome due to uncontrolled sarcoplasmic calcium release via functionally altered calcium release receptors, resulting in hypoxemia, hypercapnia, tachycardia, muscular rigidity, acidosis, hyperkalemia, and hyperthermia in susceptible individuals. Since the clinical presentation of malignant hyperthermia is highly variable, survival of affected patients depends largely on early recognition of the symptoms characteristic of malignant hyperthermia, and immediate action on the part of the attending anesthesiologist. Clinical symptoms of malignant hyperthermia, diagnostic criteria, and current therapeutic guidelines, as well as adequate management of anesthesia in patients susceptible to malignant hyperthermia, are discussed in this review.

Background: Protective tidal volumes such as 6 mL/kg can still result in tidal hyperinflation and expose the lung to mechanical stress. Further reduction of tidal volume and apneic oxygenation might mitigate lung injury. We aimed to assess the influence of minimal tidal volumes and apneic oxygenation in combination with arterio-venous extracorporeal lung assist (av-ECLA) on ventilator-associated lung injury., Methods: Acute respiratory distress syndrome was induced in swine (N.=24) by saline lavage. The animals were randomized into three groups, ventilated in a pressure-controlled mode with a tidal volume (VT) of 6 mL/kg, 3 mL/kg and 0 mL/kg body weight, respectively. The latter two groups were instrumented with an av-ECLA device. Lung injury was assessed by histological examination of lung tissue at the end of the 24 hour experiment and by gas exchange parameters., Results: Oxygenation was significantly lower in the 3 and 0 mL/kg groups, whereas CO2 remained in the targeted range in all groups. Histological examination revealed a reduction of tidal hyperinflation in the apical lung regions in the 3 and 0 mL/kg groups. In lower lung regions an increase of inflammation, intra-alveolar exudation and formation of atelectasis was shown in the animals ventilated with lower VTs., Conclusion: In combination with highly effective CO2-removal, the reduction of tidal volumes up to 0 mL was feasible. Tidal hyperinflation could be reduced in the upper lung areas, yet inflammation in the lower lung was higher with low tidal volumes. This stresses the differing mechanical properties of inhomogeneous injured lungs.

Bilayered oromucosal film preparations (buccal films) offer a promising way to enable drug administration via the oral cavity. Adding a non-soluble or slowly eroding/dissolving backing layer to a mucoadhesive drug-loaded layer enables unidirectional drug delivery. The aim of this study was to investigate different approaches to the manufacture of bilayered films and to examine their properties by applying different characterization methods including an optimized experimental setup for the study of drug release from bilayered films. A solvent suitability study was performed screening over 15 polymers with respect to their feasibility for viscous film formation for film preparation by solvent casting method. Two methods (double-casting and pasting) were found as suitable methods for bilayered film manufacturing. Results from drug release experiments indicated that slowly eroding hypromellose backing layer films revealed the best shielding of the drug-loaded layer to enable unidirectional drug release. In summary, manufacturing of bilayered films using the described methods was feasible. Furthermore, the use of an optimized experimental setup for drug dissolution studies enabled monitoring of drug release without delays in sampling., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The cytochrome P450 (CYP)3A4 enzyme affects the metabolism of most drug-like substances, and its inhibition may influence drug safety. Modulation of CYP3A4 by flavonoids, such as anthocyanins, has been shown to inhibit the mutagenic activity of mammalian cells. Considering the previous investigations addressing CYP3A4 inhibition by these substances, we studied the three-dimensional quantitative structure-activity relationship (3D-QSAR) in a series of anthocyanin derivatives as CYP3A4 inhibitors. For the training dataset (n=12), comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) yielded crossvalidated and non-crossvalidated models with a q (2) of 0.795 (0.687) and r (2) of 0.962 (0.948), respectively. The models were also validated by an external test set of four compounds with r (2) of 0.821 (CoMFA) and r (2) of 0.812 (CoMSIA). The binding affinity modes associated with experimentally derived IC50 (half maximal inhibitory concentration) values were confirmed by molecular docking into the CYP3A4 active site with r (2) of 0.66. The results obtained from this study are useful for a better understanding of the effects of anthocyanin derivatives on inhibition of carcinogen activation and cellular DNA damage.

Background: While the impact of volatile anaesthetics to induce malignant hyperthermia (MH) is abundantly clear, the role of succinylcholine still remains controversial. To evaluate the influence of succinylcholine on porcine MH events, the authors investigated the hemodynamic and metabolic responses in MH susceptible (MHS) and non-susceptible (MHN) swine following either succinylcholine or halothane application alone or a combination of both substances., Methods: With approval of the local animal care committee 27 MHS and 30 MHN pigs were anaesthetized and mechanically ventilated. Fiberoptic probes for continuous PCO2 measurement were inserted into the femoral vein and the triceps muscle. Group A received succinylcholine 4 mg/kg, group B incremental doses of halothane (0.5, 1.0 vol%) and group C succinylcholine and halothane simultaneously. Vital signs were recorded continuously., Results: Prior to drug application measured values did not differ between MHS and MHN. While MHN pigs did not show relevant alterations, succinylcholine, halothane and the combination of both lead to significant hemodynamic and metabolic changes in MHS swine., Conclusions: Hemodynamic and metabolic alterations following succinylcholine were similar to halothane in MHS pigs. The combination of both pharmacological agents potentiated the observed effects. According to these results succinylcholine acted as an independent and supportive factor during onset of an MH episode.

Positioning therapy may improve lung recruitment and oxygenation and is part of the standard care in severe acute respiratory distress syndrome (ARDS). Venovenous extracorporeal membrane oxygenation (vvECMO) is a rescue strategy that may ensure sufficient gas exchange in ARDS patients failing conventional therapy. The aim of this case series was to describe the feasibility and pitfalls of combining positioning therapy and vvECMO in patients with severe ARDS. A retrospective cohort of nine patients is described. The patients received 20 (15-86) hours (median, 25(th) and 75(th) percentile) of positioning therapy while being treated with vvECMO. The initial PaO2/FiO2 index was 64 (51-67) mmHg and the arterial carbon dioxide tension was 60 (50-71) mmHg. Positioning therapy included 135 degrees prone, prone positioning and continuous lateral rotational therapy. During the first three days, the oxygenation index improved from 47 (41-47) to 12 (11-14) cmH2O/mmHg. The lung compliance improved from 20 (17-28) to 42 (27-43) ml/cmH2O. Complications related to positioning therapy were facial oedema (n=9); complications related to vvECMO were entrance of air (n=1) and pump failure (n=1). However, investigation of root causes revealed no association with the positioning therapy and had no documented effect on the outcome. The reported cases suggest that positioning therapy can be performed safely in ARDS patients treated with vvECMO, providing appropriate precautions are in place and a very experienced team is present.

Extracorporeal membrane oxygenation (ECMO) is increasingly used in ARDS patients with hypoxemia and/or severe hypercapnia refractory to conventional treatment strategies. However, it is associated with severe intracranial complications, e.g. ischemic or hemorrhagic stroke. The arterial carbon dioxide partial pressure (PaCO2) is one of the main determinants influencing cerebral blood flow and oxygenation. Since CO2 removal is highly effective during ECMO, reduction of CO2 may lead to alterations in cerebral perfusion. We report on the variations of cerebral oxygenation during the initiation period of ECMO treatment in a patient with hypercapnic ARDS, which may partly explain the findings of ischemic and/or hemorrhagic complications in conjunction with ECMO.

Background: During early in-hospital management of the arriving trauma patient the timing of the trauma team alert is an important organisational step. To evaluate the accordance of the estimated and the real arriving time we performed a retrospective data analysis at a level I German trauma centre., Methods: Retrospective data analysis. Trauma team alerts from September 2010 until March 2011 were analysed. According to the hospitals pre-alert algorithm, trauma team alert took place 10 min before the estimated time of arrival., Results: There were 165 trauma team alerts included in the analysis. The estimated arrival time coincided with the real arrival time in less than 10 % of cases. In 76 % of the cases, the patient arrived in an acceptable time frame with the trauma team waiting less than 14 min. In 3 % of the cases, the patient arrived prior to the trauma team., Conclusion: An exact estimation of the arrival time is rare. With a trauma team alert 10 min prior to the estimated time of arrival, an acceptable waiting time can be achieved. Arrival of the patient prior to the trauma team can be avoided.

Background: Leukocytes containing opioid peptides locally control inflammatory pain. In the early phase of complete Freund's adjuvant (CFA)-induced hind paw inflammation, formyl peptides (derived e.g. from Mycobacterium butyricum) trigger the release of opioid peptides from neutrophils contributing to tonic basal antinociception. In the later phase we hypothesized that toll-like-receptor-(TLR)-4 activation of monocytes/macrophages triggers opioid peptide release and thereby stimulates peripheral opioid-dependent antinociception., Results: In Wistar rats with CFA hind paw inflammation in the later inflammatory phase (48-96 h) systemic leukocyte depletion by cyclophosphamide (CTX) or locally injected naloxone (NLX) further decreased mechanical and thermal nociceptive thresholds. In vitro β-endorphin (β-END) content increased during human monocyte differentiation as well as in anti-inflammatory CD14+CD16- or non-classical M2 macrophages. Monocytes expressing TLR4 dose-dependently released β-END after stimulation with lipopolysaccharide (LPS) dependent on intracellular calcium. Despite TLR4 expression proinflammatory M1 and anti-inflammatory M2 macrophages only secreted opioid peptides in response to ionomycin, a calcium ionophore. Intraplantar injection of LPS as a TLR4 agonist into the inflamed paw elicited an immediate opioid- and dose-dependent antinociception, which was blocked by TAK-242, a small-molecule inhibitor of TLR4, or by peripheral applied NLX. In the later phase LPS lowered mechanical and thermal nociceptive thresholds. Furthermore, local peripheral TLR4 blockade worsened thermal and mechanical nociceptive pain thresholds in CFA inflammation., Conclusion: Endogenous opioids from monocytes/macrophages mediate endogenous antinociception in the late phase of inflammation. Peripheral TLR4 stimulation acts as a transient counter-regulatory mechanism for inflammatory pain in vivo, and increases the release of opioid peptides from monocytes in vitro. TLR4 antagonists as new treatments for sepsis and neuropathic pain might unexpectedly transiently enhance pain by impairing peripheral opioid analgesia.

Background: Missed or delayed detection of progressive neuronal damage after traumatic brain injury (TBI) may have negative impact on the outcome. We investigated whether routine follow-up CT is beneficial in sedated and mechanically ventilated trauma patients., Methods: The study design is a retrospective chart review. A routine follow-up cCT was performed 6 hours after the admission scan. We defined 2 groups of patients, group I: patients with equal or recurrent pathologies and group II: patients with new findings or progression of known pathologies., Results: A progression of intracranial injury was found in 63 patients (42%) and 18 patients (12%) had new findings in cCT 2 (group II). In group II a change in therapy was found in 44 out of 81 patients (54%). 55 patients with progression or new findings on the second cCT had no clinical signs of neurological deterioration. Of those 24 patients (44%) had therapeutic consequences due to the results of the follow-up cCT., Conclusion: We found new diagnosis or progression of intracranial pathology in 54% of the patients. In 54% of patients with new findings and progression of pathology, therapy was changed due to the results of follow-up cCT. In trauma patients who are sedated and ventilated for different reasons a routine follow-up CT is beneficial.

Intra- and postoperative bleeding disorders are common in cardiac surgery. The etiology of perioperative coagulopathy frequently becomes apparent as a combination of several acquired and inherited disorders. Differential diagnosis of microvascular bleeding include altered homeostasis (e.g. anemia, hypothermia, acidosis, hypocalcemia), impaired primary hemostasis, antithrombotic medication, dilutive and consumptive coagulopathy, fibrinolysis and the absence or deficiency of coagulation factors. Timely detection of underlying pathology and subsequent rigorous treatment has the potential to minimize perioperative transfusion requirements, prevent resternotomy and improve patient outcome remarkably. Point-of-care-systems can provide fast bed-sided analysis, which contribute to early diagnosis and intervention. Individual and regularly revised algorithms, adapted to the individualized institutional infrastructure, may facilitate resource-saving treatment of perioperative coagulopathy., (© Georg Thieme Verlag Stuttgart · New York.)

Cardiac surgery requires cardiopulmonary bypass (CPB) with extracorporeal circulation (ECC) for intracardiac procedures. The surgical strategy determines access for monitoring and insertion sites with high-flow cannulas. The perioperative care of cardiac surgical patients requires adequate hemodynamic monitoring for reasonable catecholamine therapy and fluid management. Therefore, the knowledge of the vascular anatomy is essential to provide professional care to patients undergoing ECC during thoracic vascular and cardiac surgery. This article is a review of hemodynamic monitoring and access for ECC in patients for adult cardiac surgery for anaesthesiologists and intensivists., (© Georg Thieme Verlag Stuttgart · New York.)

Background: Sevoflurane is a known triggering agent of malignant hyperthermia (MH). The present study analyzed different effects of sevoflurane on skeletal muscle of MH susceptible and nonsusceptible individuals in vitro and compared the results to the standardized test protocol with halothane and caffeine. A potential influence of a present ryanodine receptor type 1 (RyR1) mutation was investigated., Methods: Muscle bundles of 24 MH-susceptible patients with or without an RyR1 mutation, 35 MH-nonsusceptible and 10 MH-equivocal patients were exposed either to sevoflurane 8 vol% bolus or increasing doses of 2, 4, 6, and 8 vol%. In MH-positive patients, a screening for mutations in the RyR1 gene was performed., Results: The in vitro parameters initial length, weight, predrug resting tension, and predrug twitch height did not differ between the groups. Sevoflurane caused significant contractures in MH-susceptible but not in MH-nonsusceptible muscle after increasing doses [1.4 (0.3-6.0) vs. 0 (0-0) mN] and after bolus application [6.9 (2.4-21.4) vs. 0 (0-0) mN]. However, only 50% of the susceptible patients developed contractures ≥ 2 mN after increasing concentrations while 83% did so after rapid bolus administration. Presence of an RyR1 mutation was detected in 36% of the examined MH-positive patients but had no influence on developing contractures., Conclusion: Sevoflurane-induced contractures do not reliably detect MH susceptibility on an individual level. Therefore, sevoflurane is no suitable alternative for diagnostic use. Mutation-specific effects regarding contracture sizes after incubation with sevoflurane, halothane, or caffeine were not found., (© 2013 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Background: Malignant hyperthermia (MH), a metabolic myopathy triggered by volatile anesthetics and depolarizing muscle relaxants, is a potentially lethal complication of general anesthesia in susceptible patients. The implementation of modern inhalation anesthetics that research indicates as less potent trigger substances and the recommended limitations of succinylcholine use, suggests there may be considerable decline of fulminant MH cases. In the presented study, the authors analyzed suspected MH episodes during general anesthesia of patients that were referred to the Wuerzburg MH unit between 2007 and 2011, assuming that MH is still a relevant anesthetic problem in our days., Methods: With approval of the local ethics committee data of patients that underwent muscle biopsy and in vitro contracture test (IVCT) between 2007 and 2011 were analyzed. Only patients with a history of suspected MH crisis were included in the study. The incidents were evaluated retrospectively using anesthetic documentation and medical records., Results: Between 2007 and 2011 a total of 124 patients were tested. 19 of them were referred because of suspected MH events; 7 patients were diagnosed MH-susceptible, 4 MH-equivocal and 8 MH-non-susceptible by IVCT. In a majority of cases masseter spasm after succinylcholine had been the primary symptom. Cardiac arrhythmias and hypercapnia frequently occurred early in the course of events. Interestingly, dantrolene treatment was initiated in a few cases only., Conclusions: MH is still an important anesthetic complication. Every anesthetist must be aware of this life-threatening syndrome at any time. The rapid onset of adequate therapy is crucial to avoid major harm and possibly lethal outcome. Dantrolene must be readily available wherever MH triggering agents are used for anesthesia.

In 2010 the Helsinki Declaration on Patient Safety in Anaesthesiology was launched. In this joined statement under the auspice of the European Society of Anaesthesiology the need for protocols for different aspects of perioperative procedures that could affect patient safety was stated. All participating institutions should have--among others--protocols for checking equipment and drugs required for the delivery of safe anaesthesia. The background for this being the fact that the lack of carefully checking equipment and drugs--or not adhering to existing checklists--is a latent threat to patient safety and thus may increase morbidity and mortality.In this part of a series the authors present protocols existing in their clinic for checking anaesthesia equipment and drugs., (© Georg Thieme Verlag Stuttgart · New York.)

A 30-year-old patient was admitted to hospital with fever and respiratory insufficiency due to community acquired pneumonia. Within a few days the patient developed septic cardiomyopathy and severe acute respiratory distress syndrome (ARDS) which deteriorated under conventional mechanical ventilation. Peripheral venoarterial extracorporeal membrane oxygenation (va-ECMO) was initiated by the retrieval team of an ARDS/ECMO centre at a paO2/FIO2 ratio of 73 mmHg and a left ventricular ejection fraction (EF) of 10 %. After 12 h va-ECMO was converted to veno-venoarterial ECMO (vva-ECMO) for improvement of pulmonary and systemic oxygenation. Left ventricular function improved (EF 45 %) 36 h after starting ECMO and the patient was weaned from vva-ECMO and converted to vv-ECMO. The patient was weaned successfully from vv-ECMO after 5 additional days and transferred back to the referring hospital for weaning from the ventilator.

The spinal anaesthesia, epidural anaesthesia or combinations of these techniques (combined spinal epidural anaesthesia) so far remain the gold standard to facilitate caesarean section. For some reasons such as refusal by the patients, medical reasons or emergency caesarean section, a general anaesthesia can be necessary. In patients with preeclampsia hypertension during endotracheal intubation has to be avoided. Here the application of an opioid is possible or even necessary to lessen increases of the heart rate and blood pressure. To lessen cardiovascular response, short acting Remifentanil has advantages, e.g. the fast clearance rate in newborns. However, the risk for the newborn from respiratory depression has to be considered and experienced staff to care for the newborn should be present after childbirth. Therefore, an interdisciplinary approach seems to be vital to cope with adverse effects that may arise due to the more frequent use of opioids in conjunction with general anaesthesia for caesarean section., (© Georg Thieme Verlag Stuttgart · New York.)

Objectives: Nitric oxide synthases (NOSs) mediate the first window of anesthetic-induced preconditioning (APC). The authors tested the hypothesis that endothelial NOS (eNOS) mediates the first window and inducible NOS (iNOS) mediates the second window of APC., Design: Randomized, prospective, blinded laboratory investigation., Setting: Experimental laboratory., Participants: Mice., Interventions: Mice were subjected to a 45-minute coronary artery occlusion (CAO) and a 180-minute reperfusion. C57BL/6 mice received desflurane, 1.0 minimum alveolar concentration, for 30 minutes or 12, 24, 48, or 96 hours before CAO. In eNOS(-/-) and iNOS(-/-) mice, desflurane was given 30 minutes and 48 hours before CAO. In the control groups, no desflurane was administered. Myocardial infarct size (IS) was determined after staining with Evans blue and triphenyltetrazolium chloride., Measurements and Main Results: The second window of APC was detectable at 48 hours but not at 12, 24, and 96 hours after preconditioning. In the control groups, IS was not different among the wild-type (50 ± 10%), eNOS(-/-) (52 ± 14%), and iNOS(-/-) (46 ± 10%) mice. The IS decreased significantly (p < 0.05) when desflurane was administered 30 minutes (10 ± 6%) or 48 hours (16 ± 7%) before CAO in wild-type mice, 48 hours (21 ± 13%) before CAO in eNOS(-/-) mice, and 30 minutes (13 ± 6%) before CAO in iNOS(-/-) mice. Desflurane given 30 minutes before CAO in eNOS(-/-) mice (60 ± 10%) and 48 hours before CAO in iNOS(-/-) mice (48 ± 21%) did not decrease the IS significantly compared with controls., Conclusions: Endothelial NOS and iNOS work independently to mediate the first and second windows of APC, respectively. Endothelial NOS is not necessary to trigger the second window of APC., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The interplay of specific leukocyte subpopulations, resident cells and proalgesic mediators results in pain in inflammation. Proalgesic mediators like reactive oxygen species (ROS) and downstream products elicit pain by stimulation of transient receptor potential (TRP) channels. The contribution of leukocyte subpopulations however is less clear. Local injection of neutrophilic chemokines elicits neutrophil recruitment but no hyperalgesia in rats. In meta-analyses the monocytic chemoattractant, CCL2 (monocyte chemoattractant protein-1; MCP-1), was identified as an important factor in the pathophysiology of human and animal pain. In this study, intraplantar injection of CCL2 elicited thermal and mechanical pain in Wistar but not in Dark Agouti (DA) rats, which lack p47(phox), a part of the NADPH oxidase complex. Inflammatory hyperalgesia after complete Freund's adjuvant (CFA) as well as capsaicin-induced hyperalgesia and capsaicin-induced current flow in dorsal root ganglion neurons in DA were comparable to Wistar rats. Macrophages from DA expressed lower levels of CCR2 and thereby migrated less towards CCL2 and formed limited amounts of ROS in vitro and 4-hydroxynonenal (4-HNE) in the tissue in response to CCL2 compared to Wistar rats. Local adoptive transfer of peritoneal macrophages from Wistar but not from DA rats reconstituted CCL2-triggered hyperalgesia in leukocyte-depleted DA and Wistar rats. A pharmacological stimulator of ROS production (phytol) restored CCL2-induced hyperalgesia in vivo in DA rats. In Wistar rats, CCL2-induced hyperalgesia was completely blocked by superoxide dismutase (SOD), catalase or tempol. Likewise, inhibition of NADPH oxidase by apocynin reduced CCL2-elicited hyperalgesia but not CFA-induced inflammatory hyperalgesia. In summary, we provide a link between CCL2, CCR2 expression on macrophages, NADPH oxidase, ROS and the development CCL2-triggered hyperalgesia, which is different from CFA-induced hyperalgesia. The study further supports the impact of CCL2 and ROS as potential targets in pain therapy.

Introduction: Persistently elevated serum creatine kinase (CK) is frequently associated with predisposition to malignant hyperthermia (MH). We investigated whether a minimally invasive metabolic test is suitable to diagnose MH susceptibility among patients with hyperCKemia., Methods: Thirty-nine participants were included: 10 were MH susceptible (MHS); 21 MH were non-susceptible (MHN); and 8 had MHN with persistent hyperCKemia >500 U/L. Microdialysis probes were inserted into the vastus lateralis muscle, and halothane or caffeine was injected via an attached microtubing catheter. Lactate concentrations in dialysis samples were measured spectrophotometrically., Results: Baseline lactate did not differ between the groups. After local application of halothane or caffeine, a significant lactate increase was detected only in the MHS group., Conclusions: Test results were not influenced by hyperCKemia. To avoid risks and complications of a surgical muscle biopsy this microdialysis test might be a useful screening tool for MH susceptibility among patients with persistent CK elevation., (Copyright © 2012 Wiley Periodicals, Inc.)

Oxygenation during high-frequency oscillatory ventilation is secured by a high level of mean airway pressure. Our objective was to identify a pressure difference between the airway opening of the respiratory circuit and the trachea during application of different oscillatory frequencies. Six female Pietrain pigs (57.1 ± 3.6 kg) were first ventilated in a conventional mechanical ventilation mode. Subsequently, the animals were switched to high-frequency oscillatory ventilation by setting mean airway opening pressure 5 cmH(2)O above the one measured during controlled mechanical ventilation. Measurements at the airway opening and at tracheal levels were performed in healthy lungs and after induction of acute lung injury by surfactant depletion. During high-frequency oscillatory ventilation, the airway opening pressure was set at a constant level. The pressure amplitude was fixed at 90 cmH(2)O. Starting from an oscillatory frequency of 3 Hz, the frequency was increased in steps of 3 Hz to 15 Hz and then decreased accordingly. At each frequency, measurements were performed in the trachea through a side-lumen of the endotracheal tube and the airway opening pressure was recorded. The pressure difference was calculated. At every oscillatory frequency, a pressure loss towards the trachea could be shown. This pressure difference increased with higher oscillatory frequencies (3 Hz 2.2 ± 2.1 cmH(2)O vs. 15 Hz 7.5 ± 1.8 cmH(2)O). The results for healthy and injured lungs were similar. Tracheal pressures decreased with higher oscillatory frequencies. This may lead to pulmonary derecruitment. This has to be taken into consideration when increasing oscillatory frequencies and differentiated pressure settings are mandatory.

Objectives: We hypothesized that the phosphodiesterase-III-inhibitor milrinone and the non-specific G-protein activator sodium fluoride increase the skeletal muscular lactate levels as a sign of a hypermetabolic response., Methods: With approval of the local animal care committee Sprague-Dawley rats were killed and artificially perfused either with Ringer's solution or sodium fluoride 110 mM, while milrinone 1.32 mM or Ringer's solution at 1 μl/min was applied via microdialysis probes in both hind limbs. Lactate was measured spectrophotometrically in the dialysate., Key Findings: Baseline lactate levels before drug application did not differ between hind limbs. Local infusion of milrinone via microdialysis did not significantly increase intramuscular lactate concentrations compared with the Ringer control group. Muscular perfusion with sodium fluoride resulted in a significant increase of lactate and was potentiated by combination with local milrinone., Conclusions: Phosphodiesterase-III-inhibition alone does not significantly influence the lactate levels in skeletal muscle of sacrificed rats. Sodium fluoride infusion leads to an intramuscular lactate increase, which was further potentiated by local inhibition of phosphodiesterase-III. The fluoride-mediated hypermetabolic response following sodium fluoride could be a possible explanation for the observed myotoxic adverse effects in individuals treated by fluoride-containing agents., (© 2012 The Authors. JPP © 2012. Royal Pharmaceutical Society.)

Context: The Airtraq is a disposable optical laryngoscope that is available in a double-lumen tube version. Inserting a double-lumen tube is generally more difficult compared to conventional endotracheal intubation, mainly due to its configuration., Objective: The aim of this study was to compare the Airtraq with the Macintosh laryngoscope for intubation with a double-lumen tube in patients undergoing elective thoracic surgery. The main outcome was time needed for successful intubation., Design: Prospective, randomised clinical trial., Setting: A single centre, University Hospital of Würzburg, Germany, between July 2009 and June 2011., Patients: After a scout laryngoscopy with a Macintosh laryngoscope, 60 adult patients were intubated by an anaesthesiologist with either an Airtraq (n = 30) or a Macintosh laryngoscope (n = 30)., Main Outcome Measures: The time needed for correct intubation, checked by flexible bronchoscopy, was recorded. The intubation difficulty scale (IDS) and Cormack and Lehane grade were noted. Haemodynamic variables and any evidence of oropharyngeal trauma were documented as well as postoperative sore throat, hoarseness and dysphagia., Results: The mean time needed for correct intubation was 20.1 ± 16.5 s in the Airtraq group and 17.5 ± 10 s in the Macintosh group (P = 0.86). All intubations in both groups had an IDS less than 4. The Cormack and Lehane grade was I in all 30 patients in the Airtraq group; in the Macintosh group, it was I and II in 17 and 13 patients, respectively. The incidence of hoarseness was significantly higher in the Airtraq group 24 h postoperatively (P = 0.01)., Conclusion: There was no significant difference between the Airtraq and the Macintosh laryngoscopes regarding the time needed to insert a double-lumen tube during elective thoracic surgery. Only subtle enhancement of visualisation and a higher incidence of hoarseness were observed in the Airtraq group. The Airtraq device did not result in superior patient safety in this setting.

Malignant hyperthermia is a rare but life-threatening complication of general anesthesia in predisposed patients usually triggered by potent inhalation anesthetics and/or the depolarizing muscle relaxant succinylcholine. The authors present a case of delayed sevoflurane-induced malignant hyperthermia in a 21-year-old male patient that was sufficiently treated by discontinuation of trigger agent application and dantrolene infusion. After surviving an MH episode diagnostic procedures are indicated to increase patient safety. In the presented case, the use of a novel minimal-invasive metabolic test with intramuscular injection of halothane and caffeine successfully confirmed MH susceptibility and hence might be an alternative for invasive in vitro contracture testing in selected cases.