[Interprofessional symptom management at the end of life]. / Interprofessionelle Symptomkontrolle am Lebensende.

At the end of life patients often show distressful symptoms which significantly reduce their quality of life. The goal of all healthcare professionals should be to recognize the beginning of this end of life period in order to provide good symptom management. For this purpose, existing symptoms have to be recorded, suitable therapeutic goals have to be defined for the current situation and potential therapeutic strategies have to be individually formulated. Besides the identification of underlying causes with the possibility of causal treatment, a symptom-based therapy is often necessary. Therapeutic approaches of different professions should be equally considered and should additionally be used for the benefit of the patient.

[Potential of specialized outpatient palliative care]. / Möglichkeiten der spezialisierten ambulanten Palliativversorgung.

Palliative care patients with incurable advanced disease suffering from complex symptoms can receive specialized outpatient palliative care in addition to the existing ambulatory care system. Qualified physicians and nurses care for patients and their dependents in cooperation with other professionals. In addition to a 24/7 on-call service for emergencies or acute crises, patients and their dependents are offered regular visits.

[Interprofessional symptom management at the end of life]. / Interprofessionelle Symptomkontrolle am Lebensende.

At the end of life patients often show distressful symptoms which significantly reduce their quality of life. The goal of all healthcare professionals should be to recognize the beginning of this end of life period in order to provide good symptom management. For this purpose, existing symptoms have to be recorded, suitable therapeutic goals have to be defined for the current situation and potential therapeutic strategies have to be individually formulated. Besides the identification of underlying causes with the possibility of causal treatment, a symptom-based therapy is often necessary. Therapeutic approaches of different professions should be equally considered and should additionally be used for the benefit of the patient.

[Establishment of the new cross-sectional field of pain medicine : An application example at the medical faculty of Heidelberg]. / Etablierung des neuen Querschnittsbereichs Schmerzmedizin : Ein Anwendungsbeispiel der Medizinischen Fakultät Heidelberg.

Studies from recent years paint a picture of qualitatively deficient treatment in pain medicine. In order to improve the situation knowledge on targeted diagnostics and effective therapy should be imparted at an early stage during undergraduate studies. For this reason the cross-sectional field Q14 - pain medicine was newly created in the revision of the medical physician licencing regulations. The Q14 was then established in a longitudinal, multidisciplinary form at the medical faculty in Heidelberg, whereby the complete Kern cycle was run through. The present project report describes and discusses the establishment. The results of the first multiple choice examination and an online-based evaluation by the students are presented. The latter show that the students recognized the relevance of the teaching program for their future professional career; however, the presentation of the interdisciplinary aspect must still be improved. The students were critical of the longitudinal structure and this does indeed involve a great deal of organization for the faculty and students. On the other hand this corresponds to the basic conception of a cross-sectional field and gives a good depiction of the multidisciplinary character. The first evaluation results set the precedent for further fine adjustments of the cross-sectional field. A continuous further development is generally needed with respect to the Kern cycle.

[Cancer breakthrough pain. Indications for rapidly effective opioids]. / Tumordurchbruchschmerz. Indikation für schnell wirksame Opioide.

The pharmacotherapy of tumor pain has two main aims: to deliver an adequate basic analgesia using long-term retarded opioid medication and an effective treatment of tumor breakthrough pain using rapidly effective non-retarded opioids. Breakthrough pain is characterized by a sudden onset and rapid increase in the pain level and should be treated with correspondingly rapidly effective opioids. The pharmacological characteristics of previously available and routinely prescribed non-retarded opioids do not always correspond in oral galenics to the demands resulting from the definition of tumor breakthrough pain. As alternatives to these substances five different rapidly effective fentanyl preparations are now available for transmucosal administration.

[From wheelchair dependency to the ability to walk: lumbar sympathectomy as a treatment for complex regional pain syndrome]. / Vom Rollstuhl zur Gehfähigkeit: Lumbale Sympathektomie zur Therapie langjähriger chronischer Schmerzen.

A 34-year-old woman developed walking disability with wheelchair dependency for more than 2 years due to chronic regional pain syndrome type II (CRPS II) in the feet. After excluding neurological and vascular disease, lumbar sympathectomy was performed on both sides. Surgical treatment was uneventful, and the patient's symptoms dramatically improved after 2 months. She is now able to walk some 500 m. This case illustrates the fact that surgical lumbar sympathectomy is an effective alternative or adjunct treatment even in fixed CRPS II.

EEG changes and serum anticholinergic activity measured in patients with delirium in the intensive care unit.

The aim of this study was to examine whether serum anticholinergic activity (SAA) is a reliable indicator of delirium in the ICU, and whether there is a significant correlation between SAA and quantitative electroencephalographic (EEG) data in delirious patients. In a prospective cohort study, we assessed ICU patients diagnosed with delirium (n = 37). EEG measurements and blood analysis including SAA were performed 48 h following ICU admission. The presence of delirium was evaluated using the Confusion Assessment Method for critically ill patients in ICU (CAM-ICU). The SAA level was measured using a competitive radioreceptor binding assay for muscarinergic receptors and quantitative EEG was measured using the CATEEM system. We found that, under comparable conditions, patients in the delirium group showed a higher relative EEG theta power and a reduced alpha power (n = 17) than did the non-delirious patients (n = 20). No difference in measured SAA levels were seen; therefore, there was no correlation between SAA and EEG measurements in delirious patients. We conclude that, in contrast to the EEG, the SAA level cannot be proposed as a tool for diagnosing delirium in ICU patients.

Adenosine A1 and A2 receptor agonists reduce endotoxin-induced cellular energy depletion and oedema formation in the lung.

BACKGROUND AND OBJECTIVE: Tissue depletion of adenosine during endotoxaemia has previously been described in the lung. Therapeutic approaches to prevent adenosine depletion and the role of A1 and A2 receptor agonists, however, have not been investigated until now. METHODS: In isolated and ventilated rabbit lungs, it was tested whether pretreatment with adenosine A1 agonist 2-chloro-N6-cyclopentyladenosine (CCPA; 10(-7) mol, n = 6) or A2 receptor agonist 5'-(N-cyclopropyl)-carboxyamido adenosine (CPCA; 10(-7) mol, n = 6) prior to injection of lipopolysaccharide (LPS) (500 pg mL-1) influenced pulmonary artery pressure (PAP), pulmonary energy content and oedema formation as compared with controls, solely infused with LPS (n = 6). Release rates of adenosine and uric acid were determined by high-performance liquid chromatography. Pulmonary tissue concentrations of high-energy phosphates were measured and the adenine nucleotide pool, adenosine 5'-triphosphate (ATP)/adenosine 5'-diphosphate (ADP) ratio and adenylate energy charge of the pulmonary tissue were calculated. RESULTS: Administration of LPS induced increases in PAP within 2 h up to 20.8 +/- 2.9 mmHg (P < 0.01). While pretreatment with the A1 agonist merely decelerated pressure increase (13.8 +/- 1.1 mmHg, P < 0.05), the A2 agonist completely suppressed the pulmonary pressure reaction (9.6 +/- 1.0 mmHg, P < 0.01). Emergence of lung oedema after exclusive injection of LPS up to 12.0 +/- 2.9 g was absent after A1 (0.6 +/- 0.5 g) and A2 (-0.3 +/- 0.2 g) agonists. These observations were paralleled by increased adenosine release rates compared with LPS controls (P < 0.05). Moreover, tissue concentrations of ADP, ATP, guanosine 5'-diphosphate, guanosine 5'-triphosphate, nicotinamide-adenine-dinucleotide and creatine phosphate were significantly reduced after LPS. Consequently, the calculated tissue adenine nucleotide pool and the adenylate energy charge increased after adenosine receptor stimulation (P = 0.001). CONCLUSIONS: Adenosine A1- and A2-receptor agonists reduced LPS-induced vasoconstriction and oedema formation by maintenance of tissue energy content. Thus, adenosine receptor stimulation, in particular of the A2 receptor, might be beneficial during acute lung injury.

[Drug application forms in chronic pain therapy]. / Arzneimittelanwendung in der Therapie chronischer Schmerzen.

The choice of the appropriate application form is a critical prerequisite to ensure therapeutic success in pain therapy. Tablets, capsules, and oral liquids are the classical application forms. Slow release formulas have optimized the therapy of chronic pain and offer the possibility of an oral basic medication with only two applications a day. Transdermal delivery systems of highly effective opioids offer particular advantages in chronic and stable pain conditions. Oromucosal delivery systems are an option for a rapidly effective rescue medication, while suppositories are not an application form of first choice because of their low acceptance by the patients and poorly reproducible bioavailability. PCA (patient controlled analgesia) needs to be reserved for patients lacking other therapeutic options. For many of those application forms specific information about prescription and application is needed to ensure good therapeutic results.

[Postoperative pulmonary complications: prophylaxis after noncardiac surgery]. / Postoperative pulmonale Komplikationen : Prophylaxe nach nichtkardiochirurgischen Eingriffen.

Postoperative pulmonary complications are a major problem after upper abdominal or thoracoabdominal surgery. They lead to a prolonged ICU stay as well as increased costs and are one of the main causes of early postoperative mortality. Even after uncomplicated operations, postoperative hypoxemia occurs in 30-50% of patients. Acute respiratory failure involves a disturbance in gas exchange. The mortality ranges from 10 to 60% according to the severity of respiratory failure. The most important complications are interstitial and alveolar pulmonary edema, atelectasis, postoperative pneumonia, hypoventilation, and aspiration. Preoperative optimization, postoperative prophylaxis according to a stepwise approach, and early mobilization decrease the rate of complications.

Adenosine-induced cardiac arrest and EEG changes in patients with thoracic aorta endovascular repair.

BACKGROUND: We studied haemodynamic and metabolic variables, and cerebral function after cardiac arrest induced by high dose of adenosine in patients undergoing thoracic aorta endovascular repair. METHODS: Arterial blood pressure, blood gas values and EEG were recorded continuously in 15 patients undergoing anaesthesia (isoflurane) for endovascular thoracic aorta repair. Cardiac arrest was induced by different doses of adenosine (Adrekar, Sanofi-Synthelabo, Berlin, Germany; 0.4-1.8 mg kg(-1) body weight). Serum concentrations of neurone-specific enolase (NSE) were determined before and after stent graft implantation. Neurological function was assessed before and after surgery. RESULTS: After adenosine, the heart beat stopped immediately for 18-58 s in close relation to the adenosine dose. EEG power was significantly reduced to -57%, but reached normal values within 5 min after cardiac arrest. In particular, the fast alpha- and beta-EEG-frequencies sensitively reflected patients' EEG activity during the procedure. No intraoperative increases in NSE concentrations, and no neurological dysfunctions after surgery, were observed. CONCLUSION: After adenosine-induced cardiac arrest, changes in haemodynamic variables and EEG power spectra reversed completely within 1 and 5 min, respectively, without persistent brain dysfunction after stent graft implantation.

Amyloid precursor protein (APP) and its derivatives change after cellular energy depletion. An in vitro-study.

To study the relationship between the metabolism of amyloid precursor protein (APP) and cellular energy failure, HEK 293 cells stably transfected with betaAPP 695 underwent graded energy failure induced either by i) hypoxia (pO(2) 25 mm Hg), ii) inhibition of the respiratory chain by sodium azide (NaN(3)), or iii) by combined glucose deprivation/hypoxia of different duration and severity. Secreted APP (APPs) and the derivative betaA4 were quantified autoradiographically by immunoprecipitation, and [(35)S] methionine labeling. APP holoprotein (APPh) was determined by Western blot analysis. The concentrations of the energy-rich metabolites ATP, ADP, creatine phosphate (CrP), and adenosine were measured by high performance liquid chromatography. Mild to moderate energy failure after NaN(3) treatment (2h, 4h) and hypoxia (2h, 8h) was characterized by normal ATP concentration but also by a high reduction in CrP. A stress condition indicated by an increased ATP turnover and adenosine increase was obtained. Intracellular APPh increased but its metabolites APPs and betaA4 as measured in the extracellular compartment decreased. These changes may point to a compensatory response of APP but also to a initial disturbance in intracellular APP metabolism. Severe abnormalities in both energy formation and utilization after 8h NaN(3) and hypoxia glucose deprivation were found to be accompanied by a drastic fall in intracellular APPh concentration by at least 50%, paralleled by an accelerating reduction in the extracellular concentrations of both APPs and betaA4.A significant linear correlation between APPh and ATP and between CrP and betaA4 became obvious. The data of the present study indicate that abnormalities in APP metabolism were generated in an energy-dependent manner. The obvious similarities to sporadic Alzheimer s disease are discussed.

[Role of the innate immune response in sepsis]. / Bedeutung der angeborenen Immunantwort in der Sepsis.

The innate immune system succeeds against the majority of infections before the adaptive immune system is activated. New findings contribute to a better understanding of the pathophysiology of sepsis and lead to the development of new therapeutic strategies. The innate immune system, being responsible for the first response to infections, can trigger adaptive immune responses in case the initial response is ineffective. Both arms of the immune system interact with each other, mainly via cell-cell-interactions but also by soluble factors, such as cytokines and chemokines. Two sub-populations of helper T-cells direct both balanced activation and inhibition of the two arms of the immune systems using specific patterns of cytokine release. Results obtained in new animal models of sepsis, taking a progressive growth of bacteria into account, have implied that existing knowledge has to be reanalyzed. The idea of sepsis as a mere "over-reaction to inflammation" has to be abandoned. Various so-called pattern recognition receptors (e.g. toll-like receptors, TLRs, NOD proteins) are located intracellularly or in the plasma membrane of innate immune cells and recognize certain patterns expressed exclusively by extracellular pathogens. Upon receptor engagement, intracellular signaling pathways lead to cellular activation, followed by release of various cytokines and anti-microbial substances. During the course of sepsis a cytokine shift towards increasing immune suppression occurs. The innate immune system also contributes to the migration of leukocytes in inflammed tissue, involving chemokines and adhesion molecules. Leukocytes also secrete the tissue factor leading to formation of thrombin. The environment in sepsis can cause disseminated intravascular coagulation (DIC), but at the same time thrombin triggers the release of chemokines and adhesion molecules through endothelial cells, which represents a positive feedback mechanism for innate immune responses. New therapeutic strategies for sepsis try to establish a well-balanced immune response. Intervention is accomplished through inhibition of inflammatory cytokines, their receptors or through activation of immunostimulatory responses.

Pronounced arterial collateralization was induced after permanent rat cerebral four-vessel occlusion. Relation to neuropathology and capillary ultrastructure.

The present study investigates chronic changes in cerebral arterial vessel system, microvasculature, and brain histopathology using an adult rat model based on permanent and stepwise occlusion of four cerebral vessels. Digital subtraction angiography (DSA) was performed to study chronic changes in arterial cerebral vessel system after permanent vessel occlusion. Long-lasting functional changes such as NMDA-, AMPA- and GABA(A)-receptor binding were detected in hippocampus and dentate gyrus using autoradiography. Structural changes in cerebral capillaries were investigated using light- and electron microscopy. Chronic cerebral oligemia did not cause any significant changes in the densities of excitatory glutamate and inhibitory GABA(A) receptors. By electron microscopy we could document, however, that most capillaries in vessel-occluded animals shrank, the endothelial cells were prominent with enlarged nuclei and increased cytoplasm, and the basal membrane was thickened. In contrast to the degenerative changes in brain capillaries, pronounced arterial collateralization was disclosed by DSA after chronic brain vessel occlusion. The model of chronic occlusion of four cerebral vessels is characterized by capillary degeneration and arterial collateralization proceeding in parallel. Thus, this rat model may be useful in investigations of long-lasting compensatory mechanisms contributing to cerebrovascular or neurodegenerative disorders.

[Clinical management of patients with sepsis]. / Klinisches Management bei Patienten mit Sepsis.

Sepsis and septic shock are the leading causes of death in non-cardiological intensive care units in developed countries despite recent advances in critical care medicine. Sepsis is the systemic inflammatory response to infection, often associated with hypoperfusion followed by tissue injury and organ failure. Activation of monocytes/macrophages and neutrophils with consecutive release of proinflammatory mediators and activation of the coagulation cascade, seem to play a key role in the pathogenesis of sepsis. Elimination of the septic focus,antimicrobial therapy and supportive treatment are the cornerstones of sepsis therapy. Adequate and rapid volume replacement and if necessary application of catecholamines are of highest priority to optimize tissue perfusion. Norepinephrine is the vasopressor of choice and dobutamine the preferred inotropic agent. Most experts recommend hemoglobin levels of 8-10 g/dl in severe sepsis. In addition,lung protective ventilatory strategies as well as enteral and parenteral nutrition are part of the clinical management of septic patients. In mechanically ventilated patients intensive insulin therapy to maintain blood glucose at a level between 80 and 110 mg/dl has significantly reduced mortality.Furthermore,prophylaxis of deep vein thrombosis and of stress ulcer bleeding are individually applied to septic patients. Treatment of septic patients with anti-mediator strategies or high dose AT III were not successful so far. In contrast,now two new promising treatment options may be emerging: application of small doses hydrocortisone and activated protein C [drotrecogin alfa (activated)]. Large and in part multicentric studies especially in the last 2 years now allow the practicing clinician to perform a partially evidence-based management of patients with sepsis. In addition, for the first time two options for specific therapy of sepsis,application of small doses hydrocortisone and activated protein C [drotrecogin alfa (activated)],are available which may further improve prognosis for septic patients.

N-acetylcysteine attenuates the increase in alpha-glutathione S-transferase and circulating ICAM-1 and VCAM-1 after reperfusion in humans undergoing liver transplantation.

BACKGROUND: Oxidative stress and leukocyte-endothelial interactions contribute significantly to the reperfusion injury of the transplanted liver. Therefore, we investigated the effect of N-acetylcysteine (NAC) on reperfusion injury and circulating adhesion molecules during human liver transplantation. METHODS: In a prospective study, 10 orthotopic liver transplantation patients were treated with high-dose NAC and 10 patients were treated with 5% glucose (placebo group) immediately before and during reperfusion of the donor liver. Parameters of hepatocellular injury, cellular oxygenation, plasma cytokines, and circulating adhesion molecules were determined at various time points during the liver transplantation. RESULTS: NAC had no significant effect on the arterial lactate/pyruvate or hydroxybutyrate/acetoacetate ratio during the liver transplantation. At baseline, liver transplantation patients exhibited elevated levels of cytokines and circulating adhesion molecules compared with healthy volunteers (n=7). While no significant effect of NAC on circulating L- and P-selectin was observed, it significantly inhibited the increase in circulating ICAM-1 and VCAM-1 24 hr after reperfusion. There were no significant differences in maximal postoperative values of serum aspartate transaminase (peak AST) or alanine transaminase (peak ALT) between both groups. However, NAC significantly reduced the rise in alpha-glutathione S-transferase after reperfusion of the donor liver. CONCLUSIONS: NAC attenuated the increase in alpha-glutathione S-transferase and circulating ICAM-1 and VCAM-1 after reperfusion of the donor liver, indicating possible cytoprotective effects of NAC.