Current clinical use of intravenous fosfomycin in ICU patients in two European countries.

PURPOSE: In Europe, intravenous fosfomycin (IV) is used particularly in difficult-to-treat or complex infections, caused by both Gram-positive and Gram-negative pathogens including multidrug-resistant strains. Here, we investigated the efficacy and safety of intravenous fosfomycin under real-life conditions. METHODS: Prospective, multi-center, and non-interventional study in patients with bacterial infections from 20 intensive care units (ICU) in Germany and Austria (NCT01173575). RESULTS: Overall, 209 patients were included (77 females, 132 males, mean age: 59 ± 16 years), 194 of which were treated in intensive care (APACHE II score at the beginning of fosfomycin therapy: 23 ± 8). Main indications (± bacteremia or sepsis) were infections of the CNS (21.5%), community- (CAP) and hospital-acquired pneumonia (HAP)/ventilator-associated pneumonia (VAP, 15.3%), bone and joint infections (BJI, 11%), abdominal infections (11%), and bacteremia (10.5%). Most frequently identified pathogens were S. aureus (22.3%), S. epidermidis (14.2%), Enterococcus spp. (10.8%), E. coli (12.3%) and Klebsiella spp. (7.7%). At least one multidrug-resistant (MDR) pathogen was isolated from 51 patients (24.4%). Fosfomycin was administered with an average daily dose of 13.7 ± 3.5 g over 12.4 ± 8.6 days, almost exclusively (99%) in combination with other antibiotics. The overall clinical success was favorable in 81.3% (148/182) of cases, and in 84.8% (39/46) of patients with ≥ 1 MDR pathogen. Noteworthy, 16.3% (34/209) of patients developed at least one, in the majority of cases non-serious, adverse drug reaction during fosfomycin therapy. CONCLUSION: Our data suggest that IV fosfomycin is an effective and safe combination partner for the treatment of a broad spectrum of severe bacterial infections in critically ill patients.

Endothelial progenitor cell mobilization by preoperative exercise: a bone marrow response associated with postoperative outcome.

BACKGROUND: Preoperative anaemia is associated with increased morbidity in patients undergoing major surgery. Whether erythrocytes are the only bone-marrow-derived cell lineage that associates with increased surgical complications is unknown. This prospective observational trial studied the mobilization of endothelial progenitor cells (EPCs) in response to exercise in association with postoperative complications. METHODS: After IRB approval, 60 subjects undergoing major thoracic surgery were exercised to exhaustion (peak V̇(O2)). Peripheral blood collected before and after peak exercise was quantified for EPC lineages by fluorescence-activated cell sorter analysis. Complication analysis was based on the Clavien-Dindo classification. RESULTS: Exhaustive exercise increased EPC [CD45-133+34+ cells=150 (0.00-5230) to 220 (0.00-1270) cells µl(-1); median change (range)=20 (-4,180-860) cells µl(-1); P=0.03] but not mature endothelial cell (EC) subpopulations. Pre-exercise levels [odds ratio (OR)=0.86, 95% confidence interval (CI): 0.37-2.00, P=0.72), change after exercise as a continuous variable (OR=0.95, 95% CI: 0.41-2.22, P=0.91) and a positive response after exercise (change >0 cells µl(-1); OR=0.41, 95% CI: 0.13-1.28, P=0.12) were not statistically significantly associated with the incidence of postoperative complications. Post-hoc receiver operating characteristic curve analyses revealed that subjects with a CD45-133+34+ increase ≥60 cells µl(-1) in response to exercise suffered fewer postoperative complications [86% sensitivity, 48% specificity and AUC=0.67 (95% CI: 0.52-0.81)]. CONCLUSIONS: Preoperative exercise induces EPC into the peripheral circulation. Subjects with a poor EPC response had a pre-existing propensity for postoperative complications. This warrants further research into the role of bone marrow function as a critical component to endothelial repair mechanisms. CLINICAL TRIAL REGISTRATION: IRB 2003-0434 (University of Texas M.D. Anderson Cancer Center, Houston, TX, USA).

[Post-resuscitation syndrome. Role of inflammation after cardiac arrest]. / Postreanimationssyndrom. Rolle der Entzündung nach Herz-Kreislauf-Stillstand.

Cardiac arrest with subsequent cardiopulmonary resuscitation causes an ischemic reperfusion syndrome of the whole body resulting in localized damage of particularly sensitive organs, such as the brain and heart, together with systemic sequelae. The main factor is a generalized activation of inflammatory reactions resulting in symptoms similar in many aspects to those of sepsis. Systemic inflammation strengthens organ damage due to disorders in the macrocirculation and microcirculation due to metabolic imbalance as well as the effects of direct leukocyte transmitted tissue destruction. The current article gives an overview on the role of inflammation following cardiac arrest and presents in detail the underlying mechanisms, the clinical symptoms and possible therapeutic approaches.

[Anesthesiological management of Caesarean sections : nationwide survey in Germany]. / Anästhesiologisches Management der Sectio caesarea : Deutschlandweite Umfrage.

BACKGROUND: The rate of Caesarean sections in Germany continues to rise. The change in anesthetic technique of choice from general to spinal anesthesia began later than in other countries and at the last survey in 2002 was not widely established. The literature on the anesthetic management of Caesarean sections contains many controversies, for example fluid preload before performing spinal anesthesia and the vasopressor of choice. Other issues have received relatively little attention, such as the level of experience of anesthesiologists working autonomously on the labour ward or the timing of antibiotic prophylaxis. The aim of the current survey was to provide an updated overview of anesthetic management of Caesarean sections in Germany. MATERIAL AND METHODS: A questionnaire was sent out to 709 departments of anesthesiology serving obstetric units in Germany. The questionnaire concerned various aspects of anesthetic management of Caesarean sections. RESULTS: A total of 360 questionnaires (50.8%) were returned of which 346 were complete and could be analyzed, accounting for 330,000 births and 90,000 Caesarean sections per year. The predominant anesthetic method used for Caesarean sections was spinal anesthesia (90.8%) using hyperbaric bupivacaine and in approximately one third of the hospitals surveyed without administering intrathecal opioids. Approximately 12% of the departments surveyed used traumatic Quincke needles. In 86.2% the vasopressor of choice was caffedrine/theodrenaline. Nitrous oxide was used in only 19.2% of departments surveyed when general anesthesia is performed. An antibiotic drug was administered in only 11% of hospitals before cord clamping. In 43.1% no neonatologist was available to treat unexpected critically ill newborns. In 32.1% of departments surveyed residents with less than 2 years experience worked autonomously on the labour ward. CONCLUSIONS: Currently the predominant anesthetic technique of choice in Germany is spinal anaesthesia and at a much higher rate than in 2002. In addition 12% of departments use traumatic Quincke needles which are associated with a higher incidence of postpuncture headache. Nitrous oxide is no longer frequently used in Germany. Finally, the administration of an antibiotic before cord clamping has been shown to lead to lower rates of endometritis and postoperative wound infection without detrimental effects on the newborn. This is practiced in only a small minority of departments across Germany.

Pain, postdural puncture headache, nausea, and pruritus after cesarean delivery: a survey of prophylaxis and treatment.

BACKGROUND: The need for a cesarean delivery may interfere negatively with the overall experience of childbirth. Several factors related to anesthesiological management such as postoperative pain and discomfort, nausea and pruritus, and postdural puncture headache (PDPH), may lead to dissatisfaction and have a negative impact on early mobilization and a new mother's ability to care for her newborn baby. Optimal prophylaxis and treatment decrease these complications, increase satisfaction, and prevent chronic pain. This survey determined how prophylaxis and treatment of pain, PDPH, nausea, and pruritus after cesarean section (CS) is managed. METHODS: A questionnaire was sent to 709 departments of anesthesiology serving an obstetric unit in Germany. The questionnaire asked about different aspects of pain management, the management of accidental dural puncture (ADP), and treatment of PDPH. Further we asked about therapy and prophylaxis of nausea and pruritus in the peripartal setting. RESULTS: In all, 360 questionnaires (50.8%) were returned; 346 were complete and analyzed (accounting for 330000 births per year). Paracetamol (77.5%) and piritramide (85.6%) are the most common analgesics used. If epidural catheters were used for anesthesia for CS, 47.7% were used for postoperative pain therapy. However, 92.7% of the departments removed catheters in less than 24 hours after delivery. In case of an ADP most departments (69.9%) repeated puncture, 2.6% placed catheters intrathecally. Median blood volume for an epidural blood patch was 10ml. CONCLUSION: Apart from conservative treatment of PDPH, prophylaxis and treatment of pain after cesarean delivery, PDPH, nausea, and pruritus varied widely, indicating the need for the qualitative evaluation of overall management.

[Thrombolysis during cardio-pulmonary resuscitation]. / Thrombolyse während der kardiopulmonalen Reanimation.

Sudden cardiac death is a leading cause of death in Europe. In the vast majority, myocardial infarction or pulmonary embolism is the underlying cause. Lethality is still high, especially if the arrest occurs out of hospital. For these two severe conditions, thrombolysis has proven to be an established therapy. Coronary perfusion is restored or the occlusion in the pulmonary arteries is removed, restoring normal circulation and normalising right-ventricular afterload. Nevertheless, thrombolysis was contraindicated during cardio-pulmonary resuscitation (CPR) for many years due to the fear of severe bleeding complications. Case reports and series using thrombolysis as successful ultima ratio therapy during prolonged CPR were soon followed by retrospective and interventional studies. These trials showed significantly improved survival for patients after thrombolysis during CPR. Nevertheless, none of these trials was randomised. Other trials showed that bleeding complications do not occur more frequently after thrombolysis during CPR. Experimental investigations demonstrated that thrombolysis during CPR improves cerebral microcirculation. The results of the randomised, multicenter trial TROICA show that tenecteplase alone, does not significantly improve survival. Further studies on thrombolysis during CPR with additional administration of heparin and acetylsalicylic acid must follow to ascertain the role of thrombolysis during CPR. Although thrombolysis during CPR is not a standard therapy, it should not be withheld from patients in whom pulmonary embolism is the suspected cause of cardiac arrest, as well as in selected other patients on the physician's individual decision according to recent guidelines.

Survey on the use of oxytocin for cesarean section.

BACKGROUND: The administration of oxytocin at high doses during cesarean section may cause severe cardiovascular complications. However, a dosage as low as 1 IU has been proven to suffice. Bolus administration is not superior to infusion and causes more severe side effects. The purpose of this survey was therefore to determine dosages and routes of administration of oxytocin during cesarean section in Germany. METHODS: A questionnaire was sent to 709 departments of anesthesiology. The questionnaire asked about the standard dosage of oxytocin and route of administration (bolus and/or slow infusion) used for cesarean section. RESULTS: A total of 360 questionnaires (50.8%) were returned; 346 of these were filled out and therefore analyzed (accounting for approximately 329,000 births). It was found that 295 (85.3%) departments administer oxytocin as a bolus, and 48 (13.9%) give it only as a slow infusion. A bolus of 1-3 IU is administered at 176 departments (51.8%), 5-9 IU at 71 (20.9%), 10 IU at 39 (11.6%), and 12-40 IU at 6 (1.8%). Additionally, 3-9 IU were slowly infused at 56 departments (16.7%), 10 IU at 174 (50.3%), 12-20 IU at 51 (14.7%), and 23-40 IU at 22 (6.4%). The median cumulative oxytocin dose is 13 IU, ranging from 1 to 80 IU. CONCLUSION: Most of the responding departments give oxytocin as a bolus at a relatively low dose. However, despite the potentially fatal side effects, one out of eight departments administers 10 IU or more as a bolus.

[New aspects of perioperative statin therapy]. / Neue Aspekte der perioperativen Statintherapie.

Statins are effective drugs for treatment and prevention of cardiovascular diseases. Besides their lipid-lowering properties, statins act through multiple pleiotropic effects including vasoprotective mechanisms, effects on coagulation, anti-inflammatory properties and stabilization of atherosclerotic plaques. In recent years many studies have investigated the effects of statins administered to patients in the perioperative period. Results indicate that the perioperative use of statins is beneficial, most of all for patients with a high cardiovascular risk profile. However, most study designs are retrospective and vulnerable to systematic bias. The number of randomized controlled trials is very limited and include only low numbers of patients. Currently it is not known when perioperative treatment with statin should be started and how long it should be continued postoperatively to reach optimal protective effects. A pre-existing statin therapy should be continued perioperatively because discontinuation leads to a higher rate of complications in the perioperative period. Larger randomized controlled trials are therefore necessary to evaluate the efficiency and the safety of perioperative statin use, especially for patients with a low or intermediate cardiovascular risk profile.

[Topical anesthesia before vascular access in children. Comparison of a warmth-producing lidocaine-tetracaine patch with a lidocaine-prilocaine patch]. / Topische Anästhesie vor Venenpunktion bei Kindern. Vergleich eines wärmenden Lidocain-Tetracain- mit einem Lidocain-Prilocain-Pflaster.

BACKGROUND: Venepuncture is one of the most stressful situations for children during induction of general anesthesia. Therefore, many clinicians use a local anesthesia patch (EMLA) containing a mixture of lidocaine and prilocaine in order to reduce the stress for pediatric patients. This study compared the effect of a new heated topical anesthesia delivery system containing lidocaine and tetracaine (Rapydan) with the lidocaine/prilocaine patch EMLA. METHODS: The study design was prospective, randomized, single-blinded and monocenter. A total of 200 children aged from 3 to 13 years were randomized into group E (EMLA) or group R (Rapydan). The primary endpoint of the study was the overall incidence of pain. Additionally, the intensity of pain during venous puncture was evaluated by means of an investigator-based 4 point pain score: 0 no reaction, 1 gentle movement/grimacing, 2 moderate withdrawal of the arm/crying and 3 strong withdrawal/screaming. Furthermore, erythema of the skin, visibility of the veins and success rate of the punctures were assessed. RESULTS: Mean contact time of the patch with the skin was 35 min in both groups. The overall incidence of pain was 46% in group E and 12% in group R (p<0.001). The intensity of pain also differed significantly between the groups. A pain score of 1 was observed in 24% (group E) versus 10% (group R), a score of 2 was documented in 13% (group E) versus 1% (group R) and a score of 3 was observed in 9% (group E) versus 1% (group R; p<0.001). Erythema of the skin was observed more frequently in group R (p<0.001). Visibility of the veins and success rate of venous puncture did not differ significantly. CONCLUSIONS: After a contact time of 35 min the Rapydan patch led to superior analgesia during venous puncture than the EMLA patch. With regard to visibility of the veins and success rate of the punctures, differences between the two patches were not observed.

Selective inhibition of guanylate cyclase prevents impairment of hypoxic pulmonary vasoconstriction in endotoxemic mice.

Nitric oxide (NO) may cause sepsis-induced impairment of hypoxic pulmonary vasoconstriction (HPV). Although NO exerts many of its actions by activating soluble guanylate cyclase (sGC), there are several cGC-independent mechanisms that may lead to NO-induced vasodilation during endotoxemia. We investigated the role of sGC for the regulation of HPV during lipopolysaccharide (LPS) induced endotoxemia using 1H-(1,2,4)oxadiazole(4,3-alpha)quinoxaline-1-one (ODQ), a specific inhibitor of sGC, in isolated, perfused, and ventilated mouse lungs. Without ODQ, lungs from LPS-challenged mice constricted significantly less in response to hypoxia as compared to lungs from mice not treated with LPS (26 +/- 27% vs. 134 +/- 37%, respectively, p < 0.05). 20 mg/kg ODQ, but not 2 mg/kg or 10 mg/kg, restored the blunted HPV response in LPS-challenged mice as compared to mice not challenged with LPS (80+/-14 % vs. 98+/-21 %). ODQ had no effect on baseline perfusion pressures under normoxic conditions. Analysis of pulmonary vascular P-Q relationships suggested that the restoration of pulmonary vascular response to hypoxia by ODQ is associated with a restoration of pulmonary vascular properties during normoxia. Our data show in a murine model that specific inhibition of sGC may be a new approach to restore HPV during endotoxemia.

[Perioperative myocardial damage in non-cardiac surgery patients]. / Perioperative Myokardschäden bei nichtkardiochirurgischen Patienten.

Perioperative myocardial damage occurs with a high incidence depending on the operative procedure and the patients examined and is considered to be among the most relevant risk factors for increased perioperative morbidity and mortality in patients undergoing non-cardiac surgery. The pathophysiology of myocardial damage in the perioperative period is still not well understood. Both ischemia with and without acute coronary occlusion and non-ischemic stimuli can put a substantial strain on the heart in the perioperative period. However, in many cases the clinical presentation does not allow a clear differentiation between ischemic and non-ischemic myocardial damage. In the majority of cases perioperative myocardial infarctions occur with only mild or even without any clinical symptoms. This is probably due to a considerable difference in phenotype and pathophysiology between perioperative and non-perioperative myocardial infarctions. As a result of this unexplained etiology of perioperative myocardial infarction it remains an open question whether the contemporary diagnostic and therapeutic recommendations for the acute coronary syndrome can be extrapolated to the perioperative situation. The present review reflects the current state of knowledge and presents an optional approach to the diagnosis and therapy of perioperative myocardial injury.

[Amiodaron for treatment of perioperative cardiac arrythmia: a broad spectrum antiarrythmetic agent?]. / Amiodaron zur Therapie perioperativer kardialer Rhythmusstörungen : Ein Breitspektrumantiarrhythmikum?

Cardiac arrhythmias are a common problem in the perioperative period. The incidence found in the current literature varies depending on the population studied and the definition of arrhythmia used. Overall supraventricular arrhythmias, namely atrial fibrillation, are the most common form. Because of its broad spectrum amiodarone is often used to suppress supraventricular and ventricular arrhythmias. It is believed to be safe for treating patients with severe cardiac disease and it has less proarrhyhmogenic potential than many other antiarrhythmic drugs. However, the use of amiodarone is limited by its cardiac and non-cardiac adverse effects, such as life-threatening bradycardia, pulmonary fibrosis or thyrotoxicosis. According to the guidelines of the American Heart Association, amiodarone can be used to treat atrial fibrillation. Because spontaneous conversion rates in the perioperative setting are high and the advantage of a rhythm control strategy over rate control is questionable, a rate control strategy using less toxic drugs like beta blockers or calcium channel blockers should be preferred in hemodynamically stable patients. The current guidelines of the European Resuscitation Council (ERC) recommend amiodarone to treat hemodynamically stable ventricular tachycardia and in this setting ajmaline is also highly effective. Amiodarone should be administered to patients with cardiac arrest if ventricular tachycardia or ventricular fibrillation persists after three attempts at defibrillation. Dronedarone is a derivate of amiodarone with a similar mechanism of action but with less non-cardiac side effects and is currently being tested in clinical trials. The use of the atrial-specific potassium channel blockers AZD7009 and vernakalant are also being investigated. Furthermore, the role of statins, ACE inhibitors and angiotensin receptor blockers in the prevention of atrial fibrillation has to be evaluated.

[Therapeutic hypothermia]. / Therapeutische Hypothermie.

The use of therapeutic hypothermia has been shown to improve survival and neurological outcome following cardiac arrest. Patients with traumatic brain injury or ischemic stroke also responded positively to therapeutic hypothermia, which may be induced by various procedures including surface cooling, endovascular cooling catheter and cold infusion. Possible side effects include infection and hemorrhage, as well as changes in water and electrolyte levels. It is the aim of this article to provide an overview of studies to date, as well as practical guidance for the application of therapeutic hypothermia.

[Perioperative cardioprotection. Golden standard beta-blockade?]. / Perioperative Kardioprotektion. Goldstandard beta-Blockade?

Myocardial ischemia is a major cause of perioperative morbidity and mortality. Because of a growing expectancy of lives, the prevalence of cardiovascular diseases is increasing, and thus the number of surgical patients presenting with a cardiovascular risk profile. Based upon pathophysiological considerations, different interventions to lower perioperative cardiovascular risk have been evaluated. The mostly discussed intervention believed to prevent cardiovascular complications in the perioperative period is the use of beta-blockers. Although many authors agree that perioperative beta-blockade is effective in high-risk patients, less is known about the optimal timing, dosage and the identification of patients in whom the intervention would be beneficial. Based upon the available data we try to answer questions about timing and dosage, and we discuss possible side effects and economic questions. Another cardioprotective option is the use of statins. Besides their lipid-lowering properties, so called pleiotropic effects are believed to decrease cardiac risk. Furthermore, different interventions can be used in addition to or as an alternative to perioperative beta-blocker therapy, such as alpha-2 agonists, thoracic epidural analgesia or coronary revascularization.

Postoperative 12-lead ECG predicts peri-operative myocardial ischaemia associated with myocardial cell damage.

Peri-operative myocardial ischaemia is the single most important risk factor for an adverse cardiac outcome after non-cardiac surgery. The present study examines whether intermittent 12-lead ECG recordings can be used as an early warning tool to identify patients suffering from peri-operative myocardial ischaemia and subsequent myocardial cell damage. Fifty-five vascular surgery patients at risk for or with a history of coronary artery disease were monitored for peri-operative myocardial ischaemia using intermittent 12-lead ECG recordings taken pre-operatively and at 15 min, 20 h, 48 h, 72 h and 84 h postoperatively. The effectiveness of the 12-lead ECG was gauged by examining concordance with continuous 3-channel Holter monitoring and capturing peri-operative myocardial ischaemia by serial analyses of creatine kinase myocardial band isoenzyme and cardiac troponin T and I. The incidence of peri-operative myocardial ischaemia detected by 12-lead ECG was 44% and was identifiable in most patients (88%) 15 min after surgery. The incidence of peri-operative myocardial ischaemia detected by continuous monitoring was 53%, with the most severe episodes occurring intra-operatively and during emergence from anaesthesia. The concordance of the 12-lead method with continuous monitoring was 72%. The concordance of creatine kinase myocardial band isoenzyme activity with the 12-lead method was 71% and with Holter monitoring 57%. The concordance of mass concentration of creatine kinase myocardial band with 12-lead ECG recordings was 75%, and the corresponding value for Holter monitoring was 68%. The concordance of cardiac troponin T and I levels with the 12-lead method was 85% and 87%, respectively, and concordance with Holter monitoring was 72% and 66%, respectively. The postoperative 12-lead ECG identified peri-operative myocardial ischaemia associated with subsequent myocardial cell damage in most patients undergoing vascular surgery.

Global cerebral ischemia due to cardiocirculatory arrest in mice causes neuronal degeneration and early induction of transcription factor genes in the hippocampus.

To analyze the role of specific genes and proteins in neuronal signaling cascades following global cerebral ischemia, it would be useful to have a reproducible model of global cerebral ischemia in mice that potentially allows the investigation of mice with specific genomic mutations. We first report on the development of a model of reversible cardiocirculatory arrest in mice and the consequences of such an insult to neuronal degeneration and expression of immediate early genes (IEG) in the hippocampus. Cardiocirculatory arrest of 5 min duration was induced via ventricular fibrillation in mechanically ventilated NMRI mice. After successful cardiopulmonary resuscitation (CPR), animals were allowed to reperfuse spontaneously for 3 h (n=7) and 7 days (n=7). TUNEL staining revealed a selective degeneration of a subset of neurons in the hippocampal CA1 sector at 7 days. About 30% of all TUNEL-positive nuclei showed condensed chromatin and apoptotic bodies. Immunohistochemical studies of IEG expression performed at 3 h exhibited a marked induction of c-Fos, c-Jun, and Krox-24 protein in all sectors of the hippocampus, peaking in vulnerable CA1 pyramidal neurons and in dentate gyrus. In contrast, sham-operated animals (n=3) did not reveal neuronal degeneration or increased IEG expression in the hippocampus when compared with untreated control animals (n=3). In conclusion, we present a new model of global cerebral ischemia and reperfusion in mice with the use of complete cardiocirculatory arrest and subsequent CPR. Following 5 min of ischemia, a subset of CA1 pyramidal neurons was TUNEL-positive at 7 days. The expression of IEG was observed in all sectors of the hippocampus, including selectively vulnerable CA1 pyramidal neurons. This appears to be a good model which should be useful in evaluating the role of various genes in transgenic and knockout mice following global ischemia.