Evaluation of the palliative symptom burden score (PSBS) in a specialised palliative care unit of a university medical centre - a longitudinal study.

BACKGROUND: The implementation of standardised, valid and reliable measurements in palliative care is subject to practical and methodological challenges. One aspect of ongoing discussion is the value of systematic proxy-based assessment of symptom burden in palliative care. In 2011, an expert-developed proxy-based instrument for the assessment of symptom burden in palliative patients, the Palliative Symptom Burden Score (PSBS), was implemented at the Specialised Palliative Care Unit of the University Medical Centre in Dusseldorf, Germany. The present study investigated its feasibility, acceptance and psychometric properties. METHODS: The PSBS was rated by nursing staff three times a day over 5 years (N = 820 patients). Feasibility and nurses' acceptance of PSBS were analysed. Structural validity was investigated by principal component analysis. Construct validity was examined via cross-validation with the Hospice and Palliative Care Evaluation checklist. Discriminative validity of the PSBS was analysed by means of Kruskal-Wallis test of patients' performance score. Reliability of the PSBS was evaluated by internal consistency analysis, test-retest and split-half-reliability. Inter-rater reliability was investigated by observer agreement of nurses' ratings of symptom burden within a day. Sensitivity to change was analysed by Wilcoxon test with repeated measures of the PSBS before and after palliative complex treatment. RESULTS: A high degree of acceptance and the feasibility of a high-frequency proxy-based symptom burden assessment approach were demonstrated. There were low rates of missing values and no indications of the adoption of prior ratings. PSBS in its present form demonstrates good structural and construct validity (rs = .27-.79, p's < .001) and high sensitivity to changes in symptom burden (p's < .01, except sweating), but unsatisfactory reliability (α = .41-.67; test-retest: rs = .30-.88; p's < .001; split-half: rs = .69; p < .001; inter-rater: n.s.). CONCLUSIONS: The study presents a framework for the post hoc validation of an already existing documentation tool in palliative care. This study supports the notion that PSBS might not be reflective of an overall construct and will therefore require further development and critical comparison to other already established symptom burden instruments in palliative care.

Animal-assisted therapy at a University Centre for Palliative Medicine - a qualitative content analysis of patient records.

BACKGROUND: Animal-assisted therapy (AAT) is a therapeutic concept, which has only recently been explored in more detail within the palliative care setting. A programme of AAT was begun in June 2014 at the Interdisciplinary Centre for Palliative Medicine of the University Hospital Dusseldorf, Germany. The AAT sessions were performed by two trained and certified dog assistant therapy teams (DATT). To date only very limited scientific data are available with regard to feasibility, therapeutic indications and efficacy of AAT in palliative care. The present qualitative study aims to describe the first year's practice and experience of AAT after implementation as an integral part of adjunctive therapy options offered within an academic palliative care centre. METHODS: This study is a qualitative content analysis of all post-encounter protocols of AAT interventions recorded by the dog handlers from June 2014 through May 2015. Qualitative content analysis was conducted according to Mayring's approach; the report followed the recommendations of the Standards for Reporting Qualitative Research (SRQR). RESULTS: Fifty-two patients received 84 AAT interventions, with only 18 patients receiving more than one intervention due to discharge or death. In 19 cases relatives also participated in the AAT session. The inductive coding process yielded four main categories. One hundred and fifty-three codes related to the content and structure of the AAT sessions, with physical contact with the dog taking considerable precedence. The AAT sessions included conversations with the dog handler, 10.5% of which related to the current health state as well as to discussions around death and dying. Eighty-nine codes related to perceived emotional responses, with pleasure being the most often observed response. Two hundred and seventeen codes related to the effects of the AAT sessions, identifying the dog as a catalyst of communication and observing patients' physical activation or relaxation. CONCLUSIONS: AAT may constitute a valuable and practicable adjunct to the interdisciplinary therapeutic repertoire of palliative care in the hospital setting. The results of this study suggest that patients may potentially benefit from AAT in terms of facilitated communication, positive emotional responses, enhanced physical relaxation or motivation for physical activation. These early stage results will need to be followed-up by more robust study designs.

Self-confidence and knowledge of German ICU physicians in palliative care - a multicentre prospective study.

BACKGROUND: Little is known about ICU physicians' self-confidence and knowledge related to palliative care. Our objective was to investigate self-confidence and knowledge of German ICU physicians related to palliative care, and to assess the impact of work experience, gender, specialty and additional certifications in pain or palliative medicine. METHODS: In a multicentre prospective observational study ICU physicians of ten hospitals were asked to rate their self-confidence and to complete a multiple choice questionnaire for the assessment of knowledge. Beyond descriptive statistics and non-parametric tests for group comparisons, linear regression analysis was used to assess the impact of independent variable on self-confidence and knowledge. Spearman's rank test was calculated. RESULTS: 55% of answers in the knowledge test were correct and more than half of the participants rated themselves as "rather confident" or "confident". Linear regression analysis revealed that an additional certificate in either pain or palliative medicine significantly increased both knowledge and self-confidence, but only 15 out of 137 participants had at least one of those certificates. Relation between self-confidence and the results of the knowledge test was weak (r = 0.270 in female) and very weak (r = -0.007 in male). CONCLUSIONS: Although the questionnaire needs improvement according to the item analysis, it appears that, with respect to palliative care, ICU Physicians' self-confidence is not related to their knowledge. An additional certificate in either pain or palliative medicine was positively correlated to both self-confidence and knowledge. However, only a minority of the participants were qualified through such a certificate.

Dipyrone (metamizole) markedly interferes with platelet inhibition by aspirin in patients with acute and chronic pain: A case-control study.

BACKGROUND: Nonopioid analgesic drugs may interfere with platelet inhibition by aspirin. Recent in vitro and clinical studies in patients with cardiovascular disease have suggested that this pharmacodynamic interaction may also occur with dipyrone, a nonopioid analgesic popular in Europe, Asia and South America. OBJECTIVE: Dipyrone is used extensively in acute and chronic pain. This study was undertaken to provide clinical data, so far missing, on its interactions in this group of patients. DESIGN: A case-control study. SETTING: Primary care in one European university hospital centre. PATIENTS: In total, 27 patients with stable cardiovascular, cerebrovascular or peripheral arterial disease and acute or chronic pain were identified and given dipyrone for at least 5 days in combination with low-dose aspirin. In total, 10 comparable patients on low-dose aspirin alone served as controls. MAIN OUTCOME MEASURES: Platelet-rich plasma was prepared to determine arachidonic acid-induced aggregation (aggregometry) and thromboxane formation (immunoassay). Platelet sensitivity to aspirin was examined in vitro. The presence of dipyrone (metabolites) in plasma was confirmed by HPLC. Additional in vitro measurements examined the aspirin/dipyrone interaction in healthy donors. RESULTS: Inhibition of aggregation was observed in only six of 27 patients receiving aspirin with dipyrone, with absence of complete inhibition by antiplatelet therapy showing in 78% of patients. In contrast, aggregation was completely inhibited in nine of 10 control patients (P < 0.001). Platelet thromboxane synthesis was higher in patients receiving dipyrone + aspirin compared with controls (387 ±â€Š89 vs. 7 ±â€Š1 ng ml, P < 0.001). Aspirin added in vitro failed to inhibit aggregation and thromboxane synthesis in platelet-rich plasma from dipyrone-treated patients. In vitro measurements with blood from healthy individuals confirmed that dipyrone dramatically reduces inhibition of platelet thromboxane synthesis by aspirin. CONCLUSIONS: Dipyrone given for 5 days or longer blunts platelet inhibition by low-dose aspirin in the majority of recipients. TRIAL REGISTRATION: German Clinical Trials Register: DRKS ID DRKS00000204. Universal Trial Number (UTN): U1111-1113-3946.

Integrating Palliative Care Into Comprehensive Cancer Centers: Consensus-Based Development of Best Practice Recommendations.

BACKGROUND: International associations admit that specialized palliative care (SPC) is an obvious component of excellent cancer care. Nevertheless, gaps in integration at the international level have been identified. Recommendations for integrating SPC in clinical care, research, and education are needed, which are subject of the present study. MATERIALS AND METHODS: A Delphi study, with three written Delphi rounds, including a face-to-face-meeting with a multiprofessional expert panel (n = 52) working in SPC in 15 German Comprehensive Cancer Centers (CCCs) funded by the German Cancer Aid was initiated. Initial recommendations are built on evidence-based literature. Consensus was defined in advance with ≥80% agreement based on the question of whether each recommendation was unambiguously formulated, relevant, and realizable for a CCC. RESULTS: A total of 38 experts (73.1%) from 15 CCCs performed all three Delphi rounds. Consensus was achieved for 29 of 30 recommendations. High agreement related to having an organizationally and spatially independent palliative care unit (≥6 beds), a mobile multiprofessional SPC team, and cooperation with community-based SPC. Until round 3, an ongoing discussion was registered on hospice volunteers, a chair of palliative care, education in SPC among staff in emergency departments, and integration of SPC in decision-making processes such as tumor boards or consultation hours. Integration of SPC in decision-making processes was not consented by a low-rated feasibility (76.3%) due to staff shortage. CONCLUSION: Recommendations should be considered when developing standards for cancer center of excellence in Germany. Definition and implementation of indicators of integration of SPC in CCCs and evaluation of its effectiveness are current and future challenges. IMPLICATIONS FOR PRACTICE: General and specialized palliative care (SPC) is an integral part of comprehensive cancer care. However, significant diversity concerning the design of SPC in the German Comprehensive Cancer Center (CCC) Network led to the establishment of consensual best practice recommendations for integration of SPC into the clinical structures, processes, research, and education throughout the CCC network. The recommendations contribute to a greater awareness relating to the strategic direction and development of SPC in CCCs. The access to information about SPC and access to offers regarding SPC shall be facilitated by implementing the recommendations in the course of treatment of patients with cancer.

Patients' perception of types of errors in palliative care - results from a qualitative interview study.

BACKGROUND: Medical errors have been recognized as a relevant public health concern and research efforts to improve patient safety have increased. In palliative care, however, studies on errors are rare and mainly focus on quantitative measures. We aimed to explore how palliative care patients perceive and think about errors in palliative care and to generate an understanding of patients' perception of errors in that specialty. METHODS: A semistructured qualitative interview study was conducted with patients who had received at least 1 week of palliative care in an inpatient or outpatient setting. All interviews were transcribed verbatim and analysed according to qualitative content analysis. RESULTS: Twelve patients from two centers were interviewed (7 women, median age 63.5 years, range 22-90 years). Eleven patients suffered from a malignancy. Days in palliative care ranged from 10 to 180 days (median 28 days). 96 categories emerged which were summed up under 11 umbrella terms definition, difference, type, cause, consequence, meaning, recognition, handling, prevention, person causing and affected person. A deductive model was developed assigning umbrella terms to error-theory-based factor levels (definition, type and process-related factors). 23 categories for type of error were identified, including 12 categories that can be considered as palliative care specific. On the level of process-related factors 3 palliative care specific categories emerged (recognition, meaning and consequence of errors). CONCLUSION: From the patients' perspective, there are some aspects of errors that could be considered as specific to palliative care. As the results of our study suggest, these palliative care-specific aspects seem to be very important from the patients' point of view and should receive further investigation. Moreover, the findings of this study can serve as a guide to further assess single aspects or categories of errors in palliative care in future research.

Comparison of antibiotic prophylaxis with cotrimoxazole/colistin (COT/COL) versus ciprofloxacin (CIP) in patients with acute myeloid leukemia.

PURPOSE: Recent meta-analyses showed that antibiotic prophylaxis in patients with neutropenia after chemotherapy reduced the incidence of fever and mortality rate. Fluoroquinolones appear to be most effective and well tolerated. Thus, in April 2008, we changed our antibiotic prophylaxis regimen from cotrimoxazole/colistin (COT/COL) to the fluoroquinolone ciprofloxacin (CIP) in patients with acute myeloid leukemia (AML). The aim of this retrospective study was to compare efficacy and development of bacterial resistance with two different prophylaxis regimens over a time period of more than 4 years. METHODS: Induction chemotherapy courses given for AML during the antibiotic prophylaxis period with COT/COL (01/2006-04/2008) and CIP (04/2008-06/2010) were retrospectively analyzed with a standard questionnaire. RESULTS: Eighty-five courses in the COT/COL group and 105 in the CIP group were analyzed. The incidence of fever was not significantly different (COT/COL 80 % vs CIP 77 %; p = 0.724). Also, the rate of microbiologically documented infections was nearly the same (29 vs 26 %; p = 0.625). In addition, there was no significant difference in the incidence of clinically documented infections (11 vs 19 %; p = 0.155) or in the rates of detected gram-positive and gram-negative bacteria. Of note, there was no increase in resistance rates or cases with Clostridium difficile-associated diarrhea in the CIP group. CONCLUSION: The antibiotic prophylaxis with CIP compared to COT/COL in AML was similarly effective with no increase in bacterial resistance. COT/COL may have the advantages of providing additional prophylaxis against Pneumocystis jirovecii pneumonia and leaving fluoroquinolones as an additional option for treatment of febrile neutropenia.

The characteristics of patients who discontinue their dying process - an observational study at a single university hospital centre.

BACKGROUND: End-of-life integrated care plans are used as structuring tools for the care of the dying. A widely adopted example is the Liverpool Care Pathway for the Dying Patient (LCP). Recently, several concerns were raised about LCP care, such as a worry that diagnosis of dying might be leading to a self-fulfilling trajectory, including hastening of death. However, data on rates of discontinuation of LCP care are lacking. In an observational study, we therefore investigated the incidence, features and trajectory of patients who were discontinued from the LCP. We hypothesised that (1) it is common to discontinue patients from the LCP, (2) quality of life does not decrease for discontinued LCP patients, and (3) discontinued patients live longer than patients who remain within LCP care. METHODS: All adult patients who were diagnosed as dying in a German university hospital specialized palliative care unit were included in 2013 and 2014. Actuarial estimation of survival prognostication tools and a number of quality of life indicators were used for data collection. Survival time was analysed using Kaplan-Meier estimates. Group differences in quality of life were tested using multivariate analysis of variance. RESULTS: 159 patients were included in a digital version of the LCP. 15 patients (9.4 %) were discontinued later. Quality of life did not decrease for discontinued patients during LCP care (p = 0.16). LCP discontinued patients lived significantly longer than the remaining LCP subgroup (difference of means 296 hours, 95 % confidence interval 105.5 to 451.5 hours; difference of survival function estimates p < 0.0001). CONCLUSIONS: When patients are diagnosed as dying, death is not the inevitable outcome of an end-of-life integrated care plan such as the LCP. Instead, it is common to discontinue the LCP care. Regular careful interprofessional assessments are important for identifying those patients who need to be discontinued from their end-of-life care plan. In this study, we found no evidence for harm by the LCP. We conclude that a correctly applied integrated care plan can be useful to provide good and safe care for the dying. TRIAL REGISTRATION: Internal Clinical Trial Register of the Medical Faculty, Heinrich Heine University Düsseldorf, No. 2015053680 (22 May 2015).

Digital breast tomosynthesis: observer performance of clustered microcalcification detection on breast phantom images acquired with an experimental system using variable scan angles, angular increments, and number of projection views.

PURPOSE: To investigate the dependence of microcalcification cluster detectability on tomographic scan angle, angular increment, and number of projection views acquired at digital breast tomosynthesis ( DBT digital breast tomosynthesis ). MATERIALS AND METHODS: A prototype DBT digital breast tomosynthesis system operated in step-and-shoot mode was used to image breast phantoms. Four 5-cm-thick phantoms embedded with 81 simulated microcalcification clusters of three speck sizes (subtle, medium, and obvious) were imaged by using a rhodium target and rhodium filter with 29 kV, 50 mAs, and seven acquisition protocols. Fixed angular increments were used in four protocols (denoted as scan angle, angular increment, and number of projection views, respectively: 16°, 1°, and 17; 24°, 3°, and nine; 30°, 3°, and 11; and 60°, 3°, and 21), and variable increments were used in three (40°, variable, and 13; 40°, variable, and 15; and 60°, variable, and 21). The reconstructed DBT digital breast tomosynthesis images were interpreted by six radiologists who located the microcalcification clusters and rated their conspicuity. RESULTS: The mean sensitivity for detection of subtle clusters ranged from 80% (22.5 of 28) to 96% (26.8 of 28) for the seven DBT digital breast tomosynthesis protocols; the highest sensitivity was achieved with the 16°, 1°, and 17 protocol (96%), but the difference was significant only for the 60°, 3°, and 21 protocol (80%, P < .002) and did not reach significance for the other five protocols (P = .01-.15). The mean sensitivity for detection of medium and obvious clusters ranged from 97% (28.2 of 29) to 100% (24 of 24), but the differences fell short of significance (P = .08 to >.99). The conspicuity of subtle and medium clusters with the 16°, 1°, and 17 protocol was rated higher than those with other protocols; the differences were significant for subtle clusters with the 24°, 3°, and nine protocol and for medium clusters with 24°, 3°, and nine; 30°, 3°, and 11; 60°, 3° and 21; and 60°, variable, and 21 protocols (P < .002). CONCLUSION: With imaging that did not include x-ray source motion or patient motion during acquisition of the projection views, narrow-angle DBT digital breast tomosynthesis provided higher sensitivity and conspicuity than wide-angle DBT digital breast tomosynthesis for subtle microcalcification clusters.

Tunneling and suture of thoracic epidural catheters decrease the incidence of catheter dislodgement.

BACKGROUND: Dislocation of epidural catheters (EC) is associated with early termination of regional analgesia and rare complications like epidural bleeding. We tested the hypothesis that maximum effort in fixation by tunneling and suture decreases the incidence of catheter dislocation. METHODS: Patients scheduled for major surgery (n = 121) were prospectively randomized in 2 groups. Thoracic EC were subcutaneously tunneled and sutured (tunneled) or fixed with adhesive tape (taped). The difference of EC length at skin surface level immediately after insertion and before removal was determined and the absolute values were averaged. Postoperative pain was evaluated by numeric rating scale twice daily and EC tips were screened microbiologically after removal. RESULTS: Both groups did not differ with respect to treatment duration (tunneled: 109 hours ± 46, taped: 97 ± 37) and postoperative pain scores. Tunneling significantly reduced average extent (tunneled: 3 mm ± 7, taped: 10 ± 18) and incidence of clinically relevant EC dislocation (>20 mm, tunneled: 1/60, taped: 9/61). Bacterial contamination showed a tendency to be lower in patients with tunneled catheters (8/59, taped: 14/54, P = 0.08). CONCLUSION: Thorough fixation of EC by tunneling and suturing decreases the incidence and extent of dislocation and potentially even that of bacterial contamination.

Evidence for the use of Levomepromazine for symptom control in the palliative care setting: a systematic review.

BACKGROUND: Levomepromazine is an antipsychotic drug that is used clinically for a variety of distressing symptoms in palliative and end-of-life care. We undertook a systematic review based on the question "What is the published evidence for the use of levomepromazine in palliative symptom control?". METHODS: To determine the level of evidence for the use of levomepromazine in palliative symptom control, and to discover gaps in evidence, relevant studies were identified using a detailed, multi-step search strategy. Emerging data was then scrutinized using appropriate assessment tools, and the strength of evidence systematically graded in accordance with the Oxford Centre for Evidence-Based Medicine's 'levels of evidence' tool. The electronic databases Medline, Embase, Cochrane, PsychInfo and Ovid Nursing, together with hand-searching and cross-referencing provided the full research platform on which the review is based. RESULTS: 33 articles including 9 systematic reviews met the inclusion criteria: 15 on palliative sedation, 8 regarding nausea and three on delirium and restlessness, one on pain and six with other foci. The studies varied greatly in both design and sample size. Levels of evidence ranged from level 2b to level 5, with the majority being level 3 (non-randomized, non-consecutive or cohort studies n = 22), with the quality of reporting for the included studies being only low to medium. CONCLUSION: Levomepromazine is widely used in palliative care as antipsychotic, anxiolytic, antiemetic and sedative drug. However, the supporting evidence is limited to open series and case reports. Thus prospective randomized trials are needed to support evidence-based guidelines.

Structural differences between the bladder dome and trigone revealed by mRNA expression analysis of cold-cut biopsies.

OBJECTIVE: To establish the mRNA expression profiles of selected genes involved in bladder contractility and epithelial permeability in the bladder dome and trigone in order to evaluate the use of cold-cut biopsies for comparative quantitative studies into the anatomical differences between these two bladder regions. PATIENTS AND METHODS: After informed consent, cold-cut biopsies from the bladder dome and trigone were obtained from eight asymptomatic subjects. RNA was extracted from muscle biopsies, and the expression levels of selected genes were analysed using TaqMan real-time PCR-based gene expression assays. Protein levels and localization were investigated by immunofluorescence. RESULTS: mRNA levels of NK2 receptor, P2X1, ASIC1a and muscarinic cholinergic receptors M(2), and M(3) were significantly higher in the dome than in the trigone (P < 0.05). In contrast, the mRNA levels of cellular adhesion and tight junction proteins were up-regulated in the trigone. There were no significant differences in expression levels of NK1R, and TRPV1 between the dome and trigone. Although the mRNA levels of uroplakin UP2 were similar in both sample groups, the smooth muscle (SM) markers were up-regulated in the dome biopsies, indicating the higher SM content of these biopsies. Consistent with these observations, when normalizing for the SM content, there were no significant differences in the levels of SM-specific markers between the two sample groups. In contrast, occludin, junctional adhesion molecule 1, claudins 1 and 4, γ-catenin and E-cadherin were up-regulated in the trigone. These observations were confirmed by immunofluorescence labelling, showing differences in the amount of SM and in the structure of urothelium of the dome and trigone. CONCLUSIONS: Our mRNA and immunofluorescence data show that cold-cut biopsies from the bladder dome have a higher relative SM content compared with the trigone, reflecting a well-developed network of suburothelial myofibroblasts and muscularis mucosae present in the bladder dome. An up-regulation of the genes encoding the tight junction proteins in the bladder trigone is independent of the urothelium content, and might imply further discrepancy between these regions.

Image quality of microcalcifications in digital breast tomosynthesis: effects of projection-view distributions.

PURPOSE: To analyze the effects of projection-view (PV) distribution on the contrast and spatial blurring of microcalcifications on the tomosynthesized slices (X-Y plane) and along the depth (Z) direction for the same radiation dose in digital breast tomosynthesis (DBT). METHODS: A GE GEN2 prototype DBT system was used for acquisition of DBT scans. The system acquires PV images from 21 angles in 3° increments over a ±30° range. From these acquired PV images, the authors selected six subsets of PV images to simulate DBT of different angular ranges and angular increments. The number of PV images in each subset was fixed at 11 to simulate a constant total dose. These different PV distributions were subjectively divided into three categories: uniform group, nonuniform central group, and nonuniform extreme group with different angular ranges and angular increments. The simultaneous algebraic reconstruction technique (SART) was applied to each subset to reconstruct the DBT slices. A selective diffusion regularization method was employed to suppress noise. The image quality of microcalcifications in the reconstructed DBTs with different PV distributions was compared using the DBT scans of an American College of Radiology phantom and three human subjects. The contrast-to-noise ratio (CNR) and the full width at half maximum (FWHM) of the line profiles of microcalcifications within their in-focus DBT slices (parallel to detector plane) and the FWHMs of the interplane artifact spread function (ASF) in the Z-direction (perpendicular to detector plane) were used as image quality measures. RESULTS: The results indicate that DBT acquired with a large angular range or, for an equal angular range,with a large fraction of PVs at large angles yielded superior ASF with smaller FWHM in the Z-direction. PV distributions with a narrow angular range or a large fraction of PVs at small angles had stronger interplane artifacts. In the X-Y focal planes, the effect of PV distributions on spatial blurring depended on the directions. In the X-direction (perpendicular to the chestwall), the normalized line profiles of the calcifications reconstructed with the different PV distributions were similar in terms of FWHM; the differences in the FWHMs between the different PV distributions were less than half a pixel. In the Y-direction (x-ray source motion), the normalized line profiles of the calcifications reconstructed with PVs acquired with a narrow angular range or a large fraction of PVs at small angles had smaller FWHMs and thus less blurring of the line profiles. In addition, PV distributions with a narrow angular range or a large fraction of PVs at small angles yielded slightly higher CNR than those with a wide angular range for small, subtle microcalcifications; however, PV distributions had no obvious effect on CNR for relatively large microcalcifications. CONCLUSIONS: PV distributions affect the image quality of DBT. The relative importance of the impact depends on the characteristics of the signal and the direction (perpendicular or parallel) relative to the direction of x-ray source motion. For a given number of PVs, the angular range and the distribution of the PVs affect the degree of in-plane and interplane blurring in opposite ways. The design of the scan parameters of tomosynthesis systems would require proper consideration of the characteristics of the signals of interest and the potential trade-off of the image quality of different types of signals.

Overall survival and fungal infection-related mortality in patients with invasive fungal infection and neutropenia after myelosuppressive chemotherapy in a tertiary care centre from 1995 to 2006.

OBJECTIVES: Invasive fungal infections (IFIs) contribute significantly to mortality and morbidity in patients receiving myelosuppressive chemotherapy for haematological malignancies. The present study investigates the overall survival (OS), infection-related mortality and changes in treatment of IFIs in our department from 1995 until 2006. METHODS: Outcomes of all chemotherapy courses were retrospectively evaluated using a standard questionnaire. Modified EORTC/MSG criteria for IFIs were applied: a positive PCR result for Aspergillus spp. in bronchoalveolar lavage was also defined as probable IFI. RESULTS: In total, 1693 chemotherapy courses in 592 patients were evaluated. Sixty-three percent of chemotherapy courses were given to treat acute myeloid leukaemia, with the rest for acute lymphoblastic leukaemia or aggressive lymphoma. IFIs were observed in 139/592 patients [23.5%, 95% confidence interval (CI) 20%-27%] and in 149/1693 courses (8.8%, 95% CI 8%-10%). IFI-related mortality was 56.9% in 1995-2001 and 28.6% in 2002-06, P < 0.001. Accordingly, median OS in patients with IFI increased: 54 days (95% CI 26-82 days) in 1995-2001 versus 229 days (95% CI 35-423 days) in 2002-06, P = 0.001. By multivariate analysis, factors predictive for better OS were controlled disease after chemotherapy [hazard ratio (HR) 0.228, P < 0.001], possible IFI (in contrast to proven/probable IFI, HR 0.537, P = 0.005), age <60 years (HR 0.583, P = 0.008), time period 2002-06 (HR 0.612, P = 0.021) and use of novel antifungals (HR 0.589, P = 0.033). CONCLUSIONS: Compared with 1995-2001, IFI-related mortality decreased and OS in patients with IFI increased significantly in recent years. Improved OS was associated with controlled haematological disease, certainty of IFI diagnosis (possible), younger age, time period 2002-06 and the use of novel antifungals.

Enantioselective CE analysis of hepatic ketamine metabolism in different species in vitro.

Ketamine, an injectable anesthetic and analgesic consisting of a racemic mixture of S-and R-ketamine, is routinely used in veterinary and human medicine. Nevertheless, metabolism and pharmacokinetics of ketamine have not been characterized sufficiently in most animal species. An enantioselective CE assay for ketamine and its metabolites in microsomal preparations is described. Racemic ketamine was incubated with pooled microsomes from humans, horses and dogs over a 3 h time interval with frequent sample collection. CE data revealed that ketamine is metabolized enantioselectively to norketamine (NK), dehydronorketamine and three hydroxylated NK metabolites in all three species. The metabolic patterns formed differ in production rates of the metabolites and in stereoselectivity of the hydroxylated NK metabolites. In vitro pharmacokinetics of ketamine N-demethylation were established by incubating ten different concentrations of racemic ketamine and the single enantiomers of ketamine for 8 min and data modeling was based on Michaelis-Menten kinetics. These data revealed a reduced intrinsic clearance of the S-enantiomer in the racemic mixture compared with the single S-enantiomer in human microsomes, no difference in equine microsomes and the opposite effect in canine microsomes. The findings indicate species differences with possible relevance for the use of single S-ketamine versus racemic ketamine in the clinic.

CE provides evidence of the stereoselective hydroxylation of norketamine in equines.

CE with multiple isomer sulfated-CD as selector was used for the simultaneous analysis of the stereoisomers of ketamine, norketamine, 5,6-dehydronorketamine and hydroxylated metabolites of norketamine in liquid/liquid extracts of (i) in vitro incubations with ketamine or norketamine and equine liver microsomes and (ii) plasma and urine of ponies receiving a target-controlled infusion of ketamine under isoflurane anesthesia. Hydroxynorketamine metabolites with the hydroxy group at the cyclohexanone ring could be shown to be formed stereoselectively both in vitro and in vivo. Due to the lack of standard compounds, urinary extracts were fractionated by HPLC followed by characterization of the collected fractions with CE and LC-MS(n) with 0.7 mmu mass discrimination. Comparison of LC-MS(n) data obtained with the fractions, an in vitro microsomal sample, and both pony urine and hydrolyzed pony urine led to the identification of four hydroxylated norketamine metabolites with hydroxylation at the cyclohexanone ring, two with hydroxylation at the aromatic ring and four hydroxylated metabolites of ketamine. Due to the lower detection sensitivity, only the four hydroxynorketamine metabolites with hydroxylation at the cyclohexanone ring were observed by CE. The data suggest that demethylation of ketamine followed by hydroxylation of norketamine at the cyclohexanone ring is the major metabolic pathway in equine species and that the ketamine metabolism is highly stereoselective.

In vitro evaluation of differences in phase 1 metabolism of ketamine and other analgesics among humans, horses, and dogs.

OBJECTIVE: To investigate cytochrome P450 (CYP) enzymes involved in metabolism of racemic and S-ketamine in various species and to evaluate metabolic interactions of other analgesics with ketamine. SAMPLE POPULATION: Human, equine, and canine liver microsomes. PROCEDURES: An analgesic was concurrently incubated with luminogenic substrates specific for CYP 3A4 or CYP 2C9 and liver microsomes. The luminescence signal was detected and compared with the signal for negative control samples. Ketamine and norketamine enantiomers were determined by use of capillary electrophoresis. RESULTS: A concentration-dependent decrease in luminescence signal was detected for ibuprofen and diclofenac in the assay for CYP 2C9 in human and equine liver microsomes but not in the assay for CYP 3A4 and methadone or xylazine in any of the species. Coincubation of methadone or xylazine with ketamine resulted in a decrease in norketamine formation in equine and canine liver microsomes but not in human liver microsomes. In all species, norketamine formation was not affected by ibuprofen, but diclofenac reduced norketamine formation in human liver microsomes. A higher rate of metabolism was detected for S-ketamine in equine liver microsomes, compared with the rate for the S-enantiomer in the racemic mixture when incubated with any of the analgesics investigated. CONCLUSIONS AND CLINICAL RELEVANCE: Enzymes of the CYP 3A4 family and orthologs of CYP 2C9 were involved in ketamine metabolism in horses, dogs, and humans. Methadone and xylazine inhibited in vitro metabolism of ketamine. Therefore, higher concentrations and diminished clearance of ketamine may cause adverse effects when administered concurrently with other analgesics.

German version of the Death Attitudes Profile- Revised (DAP-GR) - translation and validation of a multidimensional measurement of attitudes towards death.

BACKGROUND: In Germany, only limited data are available on attitudes towards death. Existing measurements are complex and time consuming, and data on psychometric properties are limited. The Death Attitude Profile- Revised (DAP-R) captures attitudes towards dying and death. The measure consists of 32 items, which are assigned to 5 dimensions (Fear of Death, Death Avoidance, Neutral Acceptance, Approach Acceptance, Escape Acceptance). It has been translated and tested in several countries, but no German version exists to date. This study reports the translation of the Death Attitudes Profile-Revised (DAP-R) into German (DAP-GR) using a cross-cultural adaption process methodology and its psychometric assessment. METHODS: The DAP-R was translated following guidelines for cultural adaption. A total of 216 medical students of the Heinrich Heine University Duesseldorf participated in this study. Interrater reliability was investigated by means of Kendall's W concordance coefficient. The internal consistency of the DAP-GR Scales was assessed with Cronbach's alpha coefficients. Split-half reliability was estimated using Spearman-Brown coefficients. Convergent validity was measured by Spearman's correlation coefficient. Content validity was assessed by means of confirmatory factor analysis (CFA). All statistical analyses were performed using SPSS 24 and AMOS 22. RESULTS: The items showed fair to good interrater reliability, with W-values ranging from .30 to .79. Internal consistency of the five subscales ranged from .61 (Neutral Acceptance) to .94 (Approach Acceptance). Split-half reliability was good, with a Spearman-Brown-coefficient of .83. The results of CFA slightly diverged from the original scale. CONCLUSION: Our results suggest overall good reliability of the German version of the DAP-R. The DAP-GR promises to be a robust instrument to establish normative data on death attitudes for use in German-speaking countries.

Electronic Implementation of Integrated End-of-life Care: A Local Approach.

INTRODUCTION: The Liverpool Care Pathway for the Dying Patient is an instrument to deliver integrated care for patients in their last hours of life. Originally a paper-based system, this study investigates the feasibility of an electronic version. METHODS: An electronic Liverpool Care Pathway was implemented in a specialized palliative care unit of a German university hospital. Its use is exemplified by means of auditing and analysis of the proportion of recorded items. RESULTS: In the years 2013 and 2014 the electronic Liverpool Care Pathway was used for the care of 159 patients. The uptake of the instrument was high (67%). Most items were recorded. Apart from a high usability, the fast data retrieval allows fast analysis for auditing and research. CONCLUSIONS AND DISCUSSION: The electronic instrument is feasible in a computerized ward and has strong advantages for retrospective analysis. TRIAL REGISTRATION: Internal Clinical Trial Register of the Medical Faculty, Heinrich Heine University Düsseldorf, No. 2015124683 (7 December 2015).

"I just realized that something happened to me today" - An innovative educational approach to support students in dealing with the dissection course, death and dying.

BACKGROUND AND AIM: The dissection course is an essential part of preclinical medical education. At the Medical Faculty of Duesseldorf, a required elective course has been developed over three semesters with the aim of encouraging students to reflect on their experiences in the dissection course and offering them support in dealing with aspects of death and dying. The aim of this paper is to present this educational approach and the student evaluations. METHODS AND RESULTS: The educational concept follows a peer group approach and is comprised of several components spanning three semesters: introductory lectures, tours of the dissection hall and clinical wards, an online diary, and reflection groups. Quantitative and qualitative evaluation has shown that students rate the course positively as to its benefits and workload. While all of the components should be retained, students do wish more time to visit sites and engage with professionals in connection with death and dying. DISCUSSION: This strategy could serve as a cornerstone for longitudinal training to promote adequate coverage of topics such as death and dying. The course has a reasonable cost-benefit ratio. When transferring it to another setting, a gratification system should be considered.