[Intraocular Lens as a Drug Delivery Device: State of the Art and Future Perspective]. / Die Intraokularlinse als Arzneimittelträger: Stand der Forschung und Ausblick.

Development of an intraocular lens (IOL) as a drug delivery device has been pursued for many years and is a promising concept in modern cataract surgery. Common postoperative conditions such as posterior capsule opacification (PCO), intraocular inflammation or the rare but severe complications of cataract surgery like endophthalmitis are potential therapeutic targets for a drug-eluting IOL. There are three techniques of pharmacological IOL modification: Firstly, surface modification of the IOL ("coating"); secondly, IOL optic modification ("soaking") and lastly, loading the IOL haptics with a slow release system. The last option does not interfere with the IOL optics at all. Therefore, a broad spectrum of pharmacological agents needs to be assessed in preclinical and clinical studies to determine which agent/IOL combination is safe and efficient. For pharmacological PCO prophylaxis, erufosine-loaded IOLs are of great clinical interest. Heparin-coated IOLs might become clinically relevant for attenuation of intraocular inflammation after cataract surgery and cefuroxime-loaded IOLs for endophthalmitis prophylaxis.

Anesthesia in swine : optimizing a laboratory model to optimize translational research.

In order to extrapolate novel therapies from the bench to the bedside (translational research), animal experiments are scientifically necessary. Swine are popular laboratory animals as their cardiorespiratory physiology is very similar to humans. Every study has to be approved by the local and/or national animal ethical committees. As swine are extremely sensitive to stress the primary goal is therefore to provide a calm, stress-free environment in both housing and experimental facilities. Swine should be properly sedated for transport and normothermia needs to be ensured. It is recommended to commence anesthesia by injecting ketamine and propofol followed by endotracheal intubation during spontaneous breathing. After intubation, anesthesia maintenance is performed with morphine or piritramide, propofol and rocuronium and routine monitoring is applied analogue to a clinical operating theater for humans. Normothermia (38.5 °C) needs to be ensured. While surgical procedures can be readily extrapolated from a human operating theater to swine, non-anesthesiologist scientists may lose the animal rapidly due to airway management problems. Vascular access can be secured by cut-downs or ultrasound-guided techniques in the inguinal and the neck region. For humane euthanasia of pigs, morphine, followed by propofol, rocuronium and potassium chloride are recommended. As radical animal right groups may threaten scientists, it is prudent that animal laboratories have unmarked entrance doors, are located in buildings that are not accessible to the public and strictly controlled access of laboratory staff is enforced. In conclusion, swine are an excellent laboratory animal for bench to bedside research and can be managed properly when basic knowledge and adequate skills on careful handling, anesthesia and surgical considerations are present.

EGFR-blockade with erlotinib reduces EGF and TGF-ß2 expression and the actin-cytoskeleton which influences different aspects of cellular migration in lens epithelial cells.

INTRODUCTION: After cataract surgery, residual lens epithelial cells migrate and proliferate within the capsular bag resulting in posterior capsule opacification (PCO). The up-regulation of TGF-ß2, EGF and FGF-2 has been identified as a key factor in PCO pathogenesis leading to actin fiber assembly and alterations in the migration pattern. In this in vitro study, the influence of Erlotinib as a selective EGFR inhibitor is investigated on the cellular features indicated, which might promote a future clinical application. METHODS: Expression of EGF, FGF-2 and TGF-ß2 was measured using RT-PCR and ELISA in human lens epithelial cells (HLEC). Computational data of an in vitro time lapse microscopy assay were used for statistical analysis of single cell migration with a particular focus on cell-cell interaction; cell velocity distribution; and displacement before, during and after mitosis. The effect of Erlotinib on the actin-cytoskeleton was evaluated using Alexa Fluor 488 Phalloidin and epifluorescence microscopy. RESULTS: EGF and TGF-ß2 mRNA expression and protein levels are reduced by Erlotinib, while FGF-2 expression remained stable. Overall fluidity of cell-cell interaction is less in the presence of Erlotinib compared to the control and the velocity distribution across all cells becomes less uniform within the cell cluster. After mitosis, HLEC move significantly faster without EGFR inhibition, which can be completely blocked by Erlotinib. Furthermore, Erlotinib diminishes the amount of actin stress fibers and the stress fiber diameter. CONCLUSION: As a novel effect of Erlotinib on HLEC, we describe the down-regulation of EGF and TGF-ß2 expression, both are crucial factors for PCO development. Cellular movement displays complex alterations under EGFR inhibition, which is partly explained by actin fiber depletion. These findings further underline the role of Erlotinib in pharmacologic PCO prophylaxis.

Attenuation of human lens epithelial cell spreading, migration and contraction via downregulation of the PI3K/Akt pathway.

BACKGROUND: Posterior capsule opacification (PCO) represents a major challenge in the postoperative management of cataract patients. Spreading, migration and contraction of residual human lens epithelial cells play a pivotal role in the pathogenesis of PCO. Therefore, we analyzed the effect of the alkylphosphocholine (APC) erufosine on these cellular features as well as on PI3K/Akt, a crucial pathway in PCO pathogenesis. METHODS: Human lens epithelial cells were cultured under standard cell culture conditions. Cell spreading was analyzed on fibronectin-coated wells and chemokinetic migration was assessed by time-lapse microscopy. For evaluation of cell-mediated collagen matrix contraction, the cells were seeded into collagen gels and incubated with an APC in different non-toxic concentrations before the surface area was measured on day 6. The activity of PI3K/Akt was assessed by an ELISA kit after incubation of the cells with different APC concentrations. RESULTS: Human lens epithelial cell spreading and migration were attenuated by APCs as follows: 7 % spreading, 48 % migration (0.1 µM APC), and 32 % spreading, 68 % migration (1.0 µM APC). APC concentrations of 0.1 µM reduced collagen gel diameter by 5 %, and 1.0 µM by less than 1 %, compared to untreated, cell-populated gels that resulted in a cell diameter contraction of 36 %. PI3K was downregulated in a concentration-dependent manner. CONCLUSIONS: The crucial cellular features of PCO pathogenesis are attenuated by the APC erufosine via downregulation of the PI3K pathway. Thus, erufosine might become a valuable tool for pharmacologic PCO prophylaxis in the future.

[Out-of-hospital emergency medicine in Germany, Austria and Switzerland : randomized prospective studies from 1990 to 2012]. / Außerklinische Notfallmedizin in Deutschland, Österreich und der Schweiz : Randomisierte, prospektive Studien von 1990 bis 2012.

BACKGROUND: Only randomized clinical trials can improve the outcome of life-threatening injuries or diseases but observations from England and North America suggest that the number of such randomized clinical trials is decreasing. In this study contributions from German speaking countries with regards to randomized clinical trials in emergency medicine over the last 22 years were investigated. METHODS: The Medline database was searched from January 1990 to December 2012 for prospective randomized clinical trials in the prehospital setting using the criteria "cardiac arrest", "cardiopulmonary resuscitation", "multiple trauma", "hemorrhagic shock", "head trauma", "stroke" as well as myocardial infarction and emergency medical service. Only studies originating from Germany, Austria or Switzerland were included. RESULTS: A total of 474 studies were found and 25 studies (5.3 %) fulfilled the inclusion criteria. In the last 22 years German speaking countries have published approximately one prospective, randomized, clinical trial per year on prehospital emergency medicine. The median number of patients included in the trials was 159 (minimum 16, maximum 1,219). Most (80 %) studies originated from Germany and most (64 %) studies were conducted by anesthesiology departments. Cardiac arrest was the most frequent subject of the investigated studies. Approximately 50 % of the studies had financial support from industrial companies. CONCLUSION: A significant increase or decrease in the number of prospective randomized clinical trials in the out-of-hospital setting could not be found in German speaking countries despite the fact that the absolute numbers of studies had increased. Only about one prospective, randomized clinical trial with an emergency medicine core tracer diagnosis originated from Germany, Austria and Switzerland per year.

[Intraocular lens as a drug delivery device]. / Intraokularlinse als Medikamententräger.

The development of an intraocular lens (IOL) as a drug delivery device has been the purpose of numerous preclinical studies and might become a future technology in cataract surgery. There are three techniques of pharmacological IOL modification: surface modification (coating), optic modification (soaking) or haptic modification with a slow-release-system. The therapeutic goals are endophthalmitis, postoperative inflammation and posterior capsule opacification.

EGF receptor inhibitor erlotinib as a potential pharmacological prophylaxis for posterior capsule opacification.

BACKGROUND: Posterior capsule opacification (PCO) is the most frequent complication after cataract surgery, leading to a loss of sight if untreated. Erlotinib might be of therapeutic interest as an effective target agent (selective EGF-tyrosin-kinase-1 inhibitor). In this in-vitro study, erlotinib was evaluated for ocular biocompatibility and its effect on cell proliferation, migration, 3D matrix contraction and spreading of human lens epithelial cells. METHODS: To exclude toxic concentrations, erlotinib was assessed for its biocompatibility on five different human ocular cell types in vitro by the tetrazolium dye-reduction assay (MTT) and the Live-Dead assay. To determine its effect on human lens epithelial cell (HLE-B3) proliferation, the MTT test was performed after incubation with different concentrations of erlotinib. Chemotactic migration was analyzed with the Boyden chamber assay and chemokinetic migration was assessed by time lapse microscopy. Contraction was measured by a 3D collagen type 1 matrix contraction assay, and cell spreading was determined by measuring the cell diameter on a fibronectin coated surface. RESULTS: The maximum non-toxic concentration of erlotinib was determined to be 100 µM in cell culture. Erlotinib potently inhibits human lens epithelial cell proliferation, with an IC50 of about 10 µM (8.8 µM ± 0.9 µM SD; r (2) =0.94). Chemotactic migration (p=0.004) and chemokinetic migration (p=0.001) were reduced significantly in a concentration-based manner. Erlotinib prevented human lens epithelial cells from matrix contraction (p=0.001) and cell-spreading (p=0.001). CONCLUSIONS: Erlotinib might become of clinical relevance for PCO prophylaxis in the future since it displayed good biocompatibility on ocular cells and mitigated human lens epithelial cell proliferation, migration, contraction, and spreading in vitro. Further studies are warranted to evaluate its potential for clinical application.

[Alkylphosphocholines inhibit lens epithelial cell proliferation and attachment]. / Alkylphosphocholine hemmen die Proliferation und Anhaftung von Linsenepithelzellen.

BACKGROUND: Posterior capsule opacification (PCO) is one of the major concerns in modern cataract surgery. Ten years after successful surgery, Nd:YAG capsulotomy is required in up to 42% of patients with an acrylic sharp-edged intraocular lens (IOL). Some accommodative and multifocal IOLs display even higher capsulotomy rates. Pharmacologic prophylaxis with alkylphosphocholines (APCs) could be a novel option in PCO prevention. METHODS: The human lens epithelial cell line HLE-B3 served as an in-vitro model. After incubation with APCs in different concentrations (0.01, 0.1, and 1 mM), the trypan blue exclusion assay and the live/dead test were performed at serum concentrations of only 5%. Cell proliferation was assessed with the MTT test. Evaluation of cell attachment was done with fibronectin- and laminin-coated wells. RESULTS: APCs can inhibit the proliferation of human lens epithelial cells in the presence of only 5% serum in a dose-dependent manner. Proliferation inhibition of 60% and attachment inhibition of about 50% were reached at concentrations of 0.1 µM. CONCLUSION: APCs inhibit proliferation and attachment of human lens epithelial cells in nontoxic concentrations in vitro. The substance can be applied topically, and an intraoperative application for pharmacologic PCO prophylaxis is feasible.

Effect of decreased inspiratory times on tidal volume. Bench model simulating cardiopulmonary resuscitation.

BACKGROUND: During cardiopulmonary resuscitation (CPR) with a chest compression rate of 60-100/min the time for secure undisturbed ventilation in the chest decompression phase is only 0.3-0.5 s and it is unclear which tidal volumes could be delivered in such a short time. OBJECTIVES: Attempts were made to assess the tidal volumes that can be insufflated in such a short time window. METHODS: In a bench model tidal volumes were compared in simulated non-intubated and intubated patients employing an adult self-inflating bag-valve with inspiratory times of 0.25, 0.3, and 0.5 s. Respiratory system compliance values were 60 mL/cmH(2)O being representative for respiratory system conditions shortly after onset of cardiac arrest and 20 mL/cmH(2)O being representative for conditions after prolonged cardiac arrest. RESULTS: With a respiratory system compliance of 60 mL/cmH(2)O, tidal volumes (mean+/-SD) in non-intubated versus intubated patients were 144+/-13 mL versus 196+/-23 mL in 0.25 s (p<0.01), 178+/-10 versus 270+/-14 mL in 0.3 s (p<0.01), and 310+/-12 mL versus 466+/-20 mL in 0.5 s (p<0.01). With a respiratory system compliance of 20 mL/cmH(2)O, tidal volumes in non-intubated patient versus intubated patients were 128+/-10 mL versus 186+/-20 mL in 0.25 s (p<0.01), 158+/-17 versus 250+/-14 mL in 0.3 s (p<0.01) and 230+/-21 mL versus 395+/-20 mL in 0.5 s (p<0.01). CONCLUSIONS: Ventilation windows of 0.25, 0.3, and 0.5 s were too short to provide adequate tidal volumes in a simulated non-intubated cardiac arrest patient. In a simulated intubated cardiac arrest patient, ventilation windows of at least 0.5 s were necessary to provide adequate tidal volumes.

[Fatalities due to nitrous oxide. Complications from mistakes in nitrous oxide supply]. / Lachgasbedingte Todesfälle. Komplikationen durch Verwechslungen in der Lachgaszufuhr.

Despite inspiratory oxygen fraction measurement being regulated by law in the European norm EN 740, fatal errors in nitrous oxide delivery still occur more frequently than expected, especially after construction or repair of gas connection tubes. Therefore, if nitrous oxide is to be used further in a hospital, all technical measures and system procedures should be employed to avoid future catastrophes. Among these are measurement of the inspiratory oxygen fraction (F(I)O(2)) and an automatic limitation of nitrous oxide. Also all anaesthetists involved should be informed about repair or construction of central gas supply tubes. Additionally, more awareness of this problem in daily routine is necessary. Furthermore, a system of detecting and analysing errors in anaesthesia has to be improved in each hospital as well as in the anaesthesia community as a whole. Measures for a better "error culture" could include data exchange between different critical incident reporting systems, analysis of closed claims, and integration of medical experts in examination of recent catastrophes.

Fatal errors in nitrous oxide delivery.

Nitrous oxide continues to be used frequently and the possibility of inadvertent fatal hypoxaemia resulting from technical errors with its administration still exists. A Medline analysis revealed only a few case reports over the last 30 years, and a closed claim analysis only reported 'claims involving oxygen supply lines' predating 1990. The aim of this study was to assess the frequency of nitrous oxide-related catastrophes during general anaesthesia in Germany, Austria, and Switzerland. As nitrous oxide-related anaesthesia casualties are rare but generally prosecuted, they almost invariably attract significant media attention. We scanned mass media archives from April 2004 until October 2006 for nitrous oxide-related disasters during general anaesthesia. This approach detected six incidents which were almost certainly nitrous oxide ventilation-related deaths. Searching non-scientific data bases demonstrates that severe incidents involving oxygen supply lines occurred after 1990, and may be much more frequent than previously thought.

[How do I write an original article? An introduction for beginners]. / Wie schreibe ich eine Originalarbeit? Eine Anleitung für Einsteiger.

Less than 50% of abstracts presented on scientific conferences get published as full articles. This manuscript is a hands-on instruction on how to collate a scientific investigation into an article. Criteria for authorship should be decided based on the Vancouver statement. The first step is a description of materials and methods including the statistical analysis (approximately 1,000 words), which should already be done during the study itself. The second step is describing the results without interpretation (approximately 350 words); graphs are better than tables. The discussion (approximately 1,000-1,350 words) is initiated with a short description of the most important results, followed by a defence of the model employed. Subsequently, the mechanisms of the results are discussed and put into context with the results of comparable studies; the clinical implication of the most important aspects should be discussed. This is followed by the limitations of the investigation to allow a realistic classification; the conclusions should be low-key rather than exaggerated. The last step is the introduction (approximately 350 words), which has to "hit the nail on the head" in order to attract the reader; this is followed by the abstract and references. Issues that are absolutely to be avoided are insufficient preparation of the study, no answers to the hypothesis of the study, contradictions within the manuscript, superficial discussion, changing terms, reflexive sentences, and a conclusion that is not supported by the data. The first author and mentor should write the first draft of the manuscript; subsequently, the co-authors have to contribute with constructive critique to improve the article until a final draft has been achieved after several rounds of revision and further critique. A journal should be targeted where the manuscript has a realistic chance of publication. If the reviewer's comments can be answered, a careful revision is always warranted and should be performed even if the editor rejected the manuscript. All parties involved should be informed about each step of the project by the first author in order to ensure enduring success.

Head position for opening the upper airway.

Inexperienced rescuers may encounter severe problems in an unconscious patient with opening and maintaining a patent upper airway. Designing a ventilating device that could indicate how to open an upper airway correctly may be beneficial. The heads of 102 volunteers were randomly placed in different head positions by one investigator. A pocket mask was then pressed gently on the volunteer's face followed by measurement of the head position angles. Mean (SD) flexion was - 4 degrees (8 degrees) (95% CI - 5.9 to - 2.9); the mean neutral position was 21 degrees (6 degrees) (95% CI, 19.9 to 22.3); extension was 42 degrees (6 degrees) (95% CI 40.8 to 43.0 degrees) and differed significantly between each position (p < 0.001). The flexion and neutral position angles were significantly greater in men than in women: - 2 (7 degrees) vs. -8 (7 degrees) and 22 (7 degrees) vs 20 (5 degrees); p < 0.001 and p = 0.03, respectively. Maximum extension of the head in both supine men and women was 42 degrees, which could be utilised to optimise assisted ventilation of an unprotected upper airway.

[Ventilation of an unprotected airway: evaluation of a new peak-inspiratory-flow and airway-pressure-limiting bag-valve-mask]. / Beatmung eines ungeschützten Atemwegs: Evaluation eines neuen spitzenfluss- und druckbegrenzenden Beatmungsbeutels.

BACKGROUND: Currently 30 chest compressions and 2 ventilations with an inspiratory time of 1 s are recommended during cardiopulmonary resuscitation with an unprotected airway, thus spending about 15% instead of 40% of resuscitation time on ventilation. Time could be gained for chest compressions when reducing inspiratory time from 2 s to 1 s, however, stomach inflation may increase as well. METHODS: In an established bench model we evaluated the effect of reducing inspiratory time from 2 s to 1 s at different lower oesophageal sphincter pressure (LOSP) levels using a novel peak inspiratory-flow and peak airway-pressure-limiting bag-valve-mask device (Smart-Bag). RESULTS: A reduction of inspiratory time from 2 s to 1 s resulted in significantly lower peak airway pressure with LOSP of 0.49 kPa (5 cm H2O), 0.98 kPa (10 cm H2O) and 1.47 kPa (15 cm H2O) and an increase with 1.96 kPa (20 cm H2O). Lung tidal volume was reduced with 1 s compared to 2 s. When reducing inspiratory time from 2 s to 1 s, stomach inflation occurred only at a LOSP of 0.49 kPa (5 cm H2O). CONCLUSIONS: In this model of a simulated unprotected airway, a reduction of inspiratory time from 2 s to 1 s using the Smart-Bag resulted in comparable inspiratory peak airway pressure and lower, but clinically comparable, lung tidal volume. Stomach inflation occurred only at a LOSP of 0.49 kPa (5 cm H2O), and was higher with an inspiratory time of 2 s vs 1 s.

[Analgesia with remifentanil in spontaneously breathing patients undergoing brief but painful radiological procedures]. / Analgosedierung mit Remifentanil bei spontan atmenden Patienten für Eingriffe in der interventionellen Radiologie.

INTRODUCTION: Percutaneous transhepatic biliary drainage (PTBD) and stenting are very painful procedures in interventional radiology and require potent analgesia; employing remifentanil in spontaneously breathing patients may be one possible strategy. PATIENTS AND METHODS: The study group was composed of 18 men and 2 women with a mean age of 63+/-10 (mean+/-SD) years. Pain intensity was measured with a VAS score before the procedure, after local anesthesia on the rib cage, after stenting and after the radiology procedure. RESULTS: Remifentanil infusion (dosage: 0.12-0.30 microg/kg body weight/min) was infused throughout the entire radiology procedure according to physical status, past medical history, individual pain, and clinical assessment. During insufflation of 10l O(2)/min via a venturi mask, oxygen saturation did not fall below 96% at any time-point during the procedure. In the VAS score, we noted a decrease after starting the remifentanil infusion towards the end of procedure. All patients were able to move into bed without help. Postoperatively, no analgesics and no antiemetics were needed. CONCLUSIONS: Employing a remifentanil infusion for brief interventional radiology procedures in palliative treatment of patients resulted in high patient and radiologist comfort.

Employing vasopressin as an adjunct vasopressor in uncontrolled traumatic hemorrhagic shock. Three cases and a brief analysis of the literature.

Resuscitation of patients in hemorrhagic shock remains one of the most challenging aspects of trauma care. We showed in experimental studies that vasopressin, but not fluid resuscitation, enabled short-term and long-term survival in a porcine model of uncontrolled hemorrhagic shock after penetrating liver trauma. In this case report, we present two cases with temporarily successful cardiopulmonary resuscitation (CPR) using vasopressin and catecholamines in uncontrolled hemorrhagic shock with subsequent cardiac arrest that was refractory to catecholamines and fluid replacement. In a third patient, an infusion of vasopressin was started before cardiac arrest occurred; in this case, we were able to stabilize blood pressure thus allowing further therapy. The patient underwent multiple surgical procedures, developed multi-organ failure, but was finally discharged from the critical care unit without neurological damage.

[Treatment of hemorrhagic shock. New therapy options]. / Die Behandlung des hämorrhagischen Schocks. Neue Therapieoptionen.

The future of shock treatment depends on the importance of scientific results, and the willingness of physicians to optimize, and to reconsider established treatment protocols. There are four major potentially promising approaches to advanced trauma life support. First, control of hemorrhage by administration of local hemostatic agents, and a better, target-controlled management of the coagulation system. Second, improving intravascular volume by recruiting blood from the venous vasculature by preventing mistakes during mechanical ventilation, and by employing alternative spontaneous (i.e. use of the inspiratory threshold valve) or artificial ventilation strategies. In addition, artificial oxygen carriers may improve intravascular volume and oxygen delivery. Third, pharmacologic support of physiologic, endogenous mechanisms involved in the compensation phase of shock, and blockade of pathomechanisms that are known to cause irreversible vasoplegia (arginine vasopressin and K(ATP) channel blockers for hemodynamic stabilization). Fourth, employing potentially protective strategies such as mild or moderate hypothermia. Finally, the ultimate vision of trauma resuscitation is the concept of "suspended animation" as a form of delayed resuscitation after protection of vital organ systems.