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Abstract: Given the international growth of physician associate/physician assistant (PA) and PA-comparable professions, it is crucial to understand the educational curricula of PA/PA-comparable professions worldwide. This article provides an overview of the process and development of the PA/PA-comparable curricula mapping design applying an international framework. It uses an innovative web-based tool, the Learning Opportunities, Objectives, and Outcomes Platform (LOOOP), to map and evaluate course content, teaching strategies, assessment formats, and learning outcomes. It highlights the project's rationale, challenges, and future implications., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 PA Education Association.)

Background: Due to the coronavirus pandemic, the medical faculties in the Federal Republic of Germany converted their curricula to digital formats on a large scale and very quickly in spring 2020 as an emergency measure. At the same time, a start was made on the nationwide exchange of digital teaching/learning materials via the online platform "LOOOP share" in order to save local resources. Among other things, virtual patient cases (VP) were shared across faculties for case-based learning, through which students can acquire clinical decision-making skills. Objectives: Within the framework of the cooperation project "National Learning Platforms for Digital Patient-Related Learning in Medical Studies" (DigiPaL), the usability of VPs for students and teachers should be improved, and the spectrum of disease patterns that are covered by VPs should be systematically expanded. Results: With the participation of many locations, a total of 150 VPs were developed by 96 case authors from 16 faculties, in addition to the existing 403 VPs. The thematic selection was made on the basis of criteria oriented to the National Competence Based Catalogue of Learning Objectives for Undergraduate Medical Education (NKLM). After completion, these VPs were also made available to all faculties for free use via "LOOOP share" and the CASUS learning platform. Discussion: Even after the pandemic, these developed VPs should be available to the faculties and thus make a lasting contribution to improve medical training in Germany - especially in light of digital teaching formats being expressly advocated on the basis of the adapted current Medical Licensure Act (ÄApprO). A possible application is interdisciplinary learning of clinical decision-making with the help of blended learning formats within the framework of a longitudinal curriculum. The large number of involved colleagues and faculties shows that the nationally coordinated development of VPs across faculties was commonly seen as useful., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2022 Jennebach et al.)

Large clinical trials testing hydrocortisone therapy in septic shock have produced conflicting results. Subgroups may benefit of hydrocortisone treatment depending on their individual immune response. We performed an exploratory analysis of the database from the international randomized controlled clinical trial Corticosteroid Therapy of Septic Shock (CORTICUS) employing machine learning to a panel of 137 variables collected from the Berlin subcohort comprising 83 patients including demographic and clinical measures, organ failure scores, leukocyte counts and levels of circulating cytokines. The identified theranostic marker was validated against data from a cohort of the Hellenic Sepsis Study Group (HSSG) ( n = 246), patients enrolled in the clinical trial of Sodium Selenite and Procalcitonin Guided Antimicrobial Therapy in Severe Sepsis (SISPCT, n = 118), and another, smaller clinical trial (Crossover study, n = 20). In addition, in vitro blood culture experiments and in vivo experiments in mouse models were performed to assess biological plausibility. A low serum IFNγ/IL10 ratio predicted increased survival in the hydrocortisone group whereas a high ratio predicted better survival in the placebo group. Using this marker for a decision rule, we applied it to three validation sets and observed the same trend. Experimental studies in vitro revealed that IFNγ/IL10 was negatively associated with the load of (heat inactivated) pathogens in spiked human blood and in septic mouse models. Accordingly, an in silico analysis of published IFNγ and IL10 values in bacteremic and non-bacteremic patients with the Systemic Inflammatory Response Syndrome supported this association between the ratio and pathogen burden. We propose IFNγ/IL10 as a molecular marker supporting the decision to administer hydrocortisone to patients in septic shock. Prospective clinical studies are necessary and standard operating procedures need to be implemented, particularly to define a generic threshold. If confirmed, IFNγ/IL10 may become a suitable theranostic marker for an urging clinical need., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 König, Kolte, Ahlers, Oswald, Krauss, Roell, Sommerfeld, Dimopoulos, Tsangaris, Antoniadou, Jaishankar, Bogatsch, Löffler, Rödel, Garcia-Moreno, Tuchscherr, Sprung, Singer, Brunkhorst, Oppert, Gerlach, Claus, Coldewey, Briegel, Giamarellos-Bourboulis, Keh and Bauer.)

Theory: Although medical students are exposed to a variety of emotions, the impact of emotions on learning has received little attention so far. Shame-provoking intimate examinations are among the most memorable events for students. Their emotions, however, are rarely addressed during training, potentially leading to withdrawal and avoidance and, consequently, performance deficits. However, emotions of negative valance such as shame may be particularly valuable for learning, as they might prompt mental rehearsal. We investigated the effect of shame on learning from the perspective of cognitive load theory., Hypotheses: We hypothesized that (a) training modality determines state shame, (b) state shame directly affects the quality of a clinical breast examination as one example of a shame-provoking exam, and (c) students who experience shame during training outperform those who just discuss the emotion during subsequent performance assessments., Method: Forty-nine advanced medical students participated in a randomized controlled, single-blinded study. After a basic, low-fidelity breast examination training, students were randomized to further practice either on a high-fidelity mannequin including a discussion of their emotions or by examining a standardized patient's real breasts. Last, all students conducted a breast examination in a simulated doctor's office. Dependent variables were measures of outcome and process quality and of situational shame., Results: Students training with a standardized patient experienced more shame during training (p < .001, d = 2.19), spent more time with the patient (p = .005, d = 0.89), and documented more breast lumps (p = .026, d = 0.65) than those training on a mannequin. Shame interacted with training modality, F(1, 45) = 21.484, p < .001, η 2 = 0.323, and differences in performance positively correlated to decline in state shame (r = .335, p = .022)., Conclusions: Students experiencing state shame during training do reenact their training and process germane load-in other words, learn. Furthermore, altering simulation modality offers a possibility for educators to adjust the affective component of training to their objectives.

Introduction: This study presents a web-based method and its interface ensuring alignment of all parts of a curriculum map including competencies, objectives, teaching and assessment methods, workload and patient availability. Needs, acceptance and effectiveness are shown through a nine-year study., Methods: After a comprehensive needs assessment, the curriculum map and a web-based interface "Learning Opportunities, Objectives and Outcome Platform" (LOOOP) were developed according to Harden's conceptual framework of 10-steps for curriculum mapping. The outcome was measured by surveys and results of interdisciplinary MCQ-assessments. The usage rates and functionalities were analysed., Results: The implementation of LOOOP was significantly associated with improved perception of the curriculum structure by teachers and students, quality of defined objectives and their alignment with teaching and assessment, usage by students to prepare examinations and their scores in interdisciplinary MCQ-assessment. Additionally, LOOOP improved the curriculum coordination by faculty, and assisted departments for identifying patient availability for clinical training., Conclusion: LOOOP is well accepted among students and teachers, has positive effect on curriculum development, facilitates effective utilisation of educational resources and improves student's outcomes. Currently, LOOOP is used in five undergraduate medical curricula including 85,000 mapped learning opportunities (lectures, seminars), 5000 registered users (students, teachers) and 380,000 yearly page-visits.

Clinical reasoning is an essential competency in medical education. This study aimed at developing and validating a test to assess diagnostic accuracy, collected information, and diagnostic decision time in clinical reasoning. A norm-referenced computer-based test for the assessment of clinical reasoning (ASCLIRE) was developed, integrating the entire clinical decision process. In a cross-sectional study participants were asked to choose as many diagnostic measures as they deemed necessary to diagnose the underlying disease of six different cases with acute or sub-acute dyspnea and provide a diagnosis. 283 students and 20 content experts participated. In addition to diagnostic accuracy, respective decision time and number of used relevant diagnostic measures were documented as distinct performance indicators. The empirical structure of the test was investigated using a structural equation modeling approach. Experts showed higher accuracy rates and lower decision times than students. In a cross-sectional comparison, the diagnostic accuracy of students improved with the year of study. Wrong diagnoses provided by our sample were comparable to wrong diagnoses in practice. We found an excellent fit for a model with three latent factors-diagnostic accuracy, decision time, and choice of relevant diagnostic information-with diagnostic accuracy showing no significant correlation with decision time. ASCLIRE considers decision time as an important performance indicator beneath diagnostic accuracy and provides evidence that clinical reasoning is a complex ability comprising diagnostic accuracy, decision time, and choice of relevant diagnostic information as three partly correlated but still distinct aspects.

Access to patients is a crucial factor for student-centred medical education. However, increasing numbers of students, teacher shortage, a patient spectrum consisting of rarer diseases, and quicker discharges limit this necessary access, and therefore pose a challenge for curriculum designers. The herein presented algorithm improves access to patients in four steps by using routinely available electronic patient data already during curriculum development. Step I: Learning objectives are mapped to appropriate ICD-10 (International Statistical Classification of Diseases) codes. Step II: It is determined which learning opportunities need to be considered first for patient allocation in order to maximise overall benefit. Step III: Hospital's departments with the highest expertise on respective learning objectives are assessed and selected for teaching. Step IV: Patients of the chosen department that present the best match for a given learning opportunity are assigned to participation. This integrated analysis of learning objectives and existing clinical data during curriculum development is a well-structured method to maximise access to patients. Furthermore, this algorithm identifies learning objectives of a curriculum that do not correspond well to the spectrum of patients of the respective teaching hospital and which should therefore be taught in learning formats without patient contact.

Introduction: Both for curricular development and mapping, as well as for orientation within the mounting supply of learning resources in medical education, the Semantic Web ("Web 3.0") poses a low-threshold, effective tool that enables identification of content related items across system boundaries. Replacement of the currently required manual with an automatically generated link, which is based on content and semantics, requires the use of a suitably structured vocabulary for a machine-readable description of object content. Aim of this study is to compile the existing taxonomies and ontologies used for the annotation of medical content and learning resources, to compare those using selected criteria, and to verify their suitability in the context described above., Methods: Based on a systematic literature search, existing taxonomies and ontologies for the description of medical learning resources were identified. Through web searches and/or direct contact with the respective editors, each of the structured vocabularies thus identified were examined in regards to topic, structure, language, scope, maintenance, and technology of the taxonomy/ontology. In addition, suitability for use in the Semantic Web was verified., Results: Among 20 identified publications, 14 structured vocabularies were identified, which differed rather strongly in regards to language, scope, currency, and maintenance. None of the identified vocabularies fulfilled the necessary criteria for content description of medical curricula and learning resources in the German-speaking world., Discussion: While moving towards Web 3.0, a significant problem lies in the selection and use of an appropriate German vocabulary for the machine-readable description of object content. Possible solutions include development, translation and/or combination of existing vocabularies, possibly including partial translations of English vocabularies.

Objective: The importance of the acquisition of practical medical skills during medical school is increasing. With the consensus statement "Practical Skills," developed by the GMA as part of the National Competency-Based Learning Objective Catalogue for Medicine (NKLM), a reference frame was created for the procurement of such skills. This frame consists of 290 learning objectives divided by "organ system," type (core or elective learning objective), current stage of medical education and level of instruction. By comparing a large and well evaluated range of student tutorials with the consensus statement, one can analyze the practical benefit of the statement, as well as evaluate the tutorial program for completeness., Methods: In the first stage, four evaluators in two groups independently classified all consensus statement's learning objectives by each of the 48 tutorials currently offered. The inter-rater reliability among the evaluators of each group was calculated both collectively, and according to each organ system. In the second stage, disagreements in the classification were resolved through discussion and consensus decision-making. The coverage of the learning objectives by the tutorials, in the required level of instruction, was then analyzed separately by learning objective type and organ system. Reasons for any initial dissent were recorded and grouped thematically., Results: The correlation between the classifications of the two evaluators was moderately significant. The strength of this correlation, and thus the precision of individual learning goals wording, varied according to organ system. After a consensus was reached, the results show that the offered tutorials covered 66% of all learning objectives, as well as 74% of the core objectives. The degree of coverage differed according to organ system and stage of medical education., Conclusion: The consensus statement is suitable to systematically analyze and develop teaching units. The comparison with established curricula also offers possibilities for further development of the consensus statement, and therefore also of the NKLM.

Aim: To evaluate the use of prehospital non-invasive ventilation (NIV) in patients with acute exacerbation of chronic obstructive pulmonary disease., Methods: 36 adult patients were treated by prehospital NIV or standard oxygen therapy., Results: Prehospital NIV was described as feasible by the paramedics. Prehospital improvement of respiratory rate and dyspnoea was significantly better and the length of intensive care was significantly lower in NIV patients., Conclusion: Prehospital NIV can be managed by a trained emergency team with high but sustainable workload. Dyspnoea and length of intensive care may be significantly reduced., Clinical Trial Registration Number: ISRCTN47620321.

The diving accident is a rare incident for an emergency physician which requires special physical and patho-physiological knowledge. With increasing recreational activities and the fascination of diving also for older persons diving accidents are expected to occur more often. There can be several reasons for diving accidents such as the ignorance of the physics of diving, a trauma under water as well as internistical illnesses like heart attach, stroke or hypoglycaemia. The therapy of the underlying illness should not be left aside while dealing with the patient. The careful rescue and the immobilisation are most important for the initial therapy. The patient should receive oxygen, if possible via a demand valve, until a hyperbaric chamber is reached. There is no specific medical therapy for decompression illness. It is very important that a pre-information is sent to the closest hyperbaric chamber as soon as possible since often the chamber needs some time to be properly prepared for usage. In order to receive information regarding the depth where the diving incident occured, the duration of the diving trip and the decompression stops, it is important to secure the diving computer of the victim for the hyperbaric chamber. Also outside diving, decompression illness can occur, for example working in a tunnel under hyperbaric conditions. These accidents have to be treated according to the same guidelines., (Georg Thieme Verlag Stuttgart * New York.)

Purpose: Changes in blood flow distribution are important for heat dispersion and for supportive therapeutic strategies such as simultaneous whole body hyperthermia (WBH) and administration of chemotherapy. The aim of this clinical study was to determine changes in hepatic blood flow during WBH for the treatment of metastatic cancer., Materials and Methods: This observational clinical study was part of a phase I/II feasibility study of WBH. WBH was induced using a radiant heat device. Hepatic blood flow was estimated using indocyanine green clearance measurements. The plasma disappearance rate of indocyanine green (PDR-ICG) was recorded in percent/min. We used an invasive thermo-dye-dilution technique to estimate hepatic blood flow, cardiac output, and volume status. Mean arterial blood pressure was also measured invasively. To determine the effects of hyperthermia the measurements were performed at defined temperature points., Results: In 10 of 22 treatments the PDR-ICG fell below normal values during hyperthermia, which represented a significant fall in hepatic blood flow. Cardiac output, volume status, and mean arterial blood pressure did not differ between patients whose liver blood flow was reduced and those whose liver blood flow remained unchanged., Conclusions: We observed distinct reductions in hepatic blood flow during WBH, which suggested a significant redistribution of blood flow away from the core during WBH. This was not mirrored by global circulatory parameters.

Background: Combination of epidural and general anesthesia (combined anesthesia) avoids the intraoperative use of intravenous analgesics and may reduce the surgical stress response during major abdominal surgery. This study examines the differences in intraoperative hemodynamic stability, cortisol levels and activity of cardiovascular hormones between combined anesthesia and isoflurane/fentanyl anesthesia., Material/methods: Sixty ASA I-II patients were prospectively randomized to receive either combined anesthesia, i.e, isoflurane anesthesia combined with thoracic epidural analgesia (bolus of 12 ml 0.2% ropivacaine containing 1 microg/ml sufentanil 30 min before incision, followed by continuous infusion at 6 ml/h) or isoflurane/fentanyl anesthesia (IV fentanyl as required) for major abdominal surgery. Depth of anesthesia was monitored using Bispectral Index. Administration of fluids and of vasopressors was directed by a standardized protocol. Blood samples for angiotensin II, vasopressin, catecholamines, and cortisol were drawn before anesthesia, after induction (but before using the epidural catheter), and 40 min after skin incision., Results: After induction of anesthesia, mean arterial pressure decreased by 12-20 mmHg in both groups and angiotensin-II concentrations increased. Vasopressin increased predominantly after opening the abdomen in both groups. Under combined anesthesia, intraoperative epinephrine and cortisol concentrations were considerably lower. Intraoperative crystalloid fluid substitution, blood loss and urine output did not differ between groups. There were more hypotensive periods and the demand for colloids and low-dose continuous norepinephrine was greater under combined anesthesia., Conclusions: Combined anesthesia reduces the intraoperative stress response, but moderate hemodynamic instability is relatively common and has to be compensated for by adequate volume replacement and vasopressor support.

For more than five decades, the use of corticosteroids as an adjunctive therapy to treat severe sepsis and septic shock has incited consistent debate. Negative results of the Corticosteroid Therapy of Septic Shock (CORTICUS) study evoked a revision of Surviving Sepsis Campaign guidelines suggesting a more restricted use of low-dose hydrocortisone only in patients with severe septic shock. Hemodynamic improvement by low-dose steroids was evident and independent from adrenal insufficiency, but did not improve survival. The roles of cortisol measurement and adrenal function tests for treatment decisions have been questioned. An international task force introduced the concept of critical illness-related corticosteroid insufficiency, which challenges the predominant role of adrenal dysfunction and underscores sustained inflammation due to tissue steroid resistance. Whether moderate steroid doses induce superinfections and muscle weakness is unclear. This article reviews recent publications, actual recommendations, ongoing discussions, and future perspectives.

The transfusion of fresh-frozen plasma (FFP) is suggested to minimize dilution coagulopathy when applied instead of colloids during paediatric craniofacial surgery (pCFS). We prospectively compared plasmatic haemostaseologic function between volume replacement with FFPs versus human albumin (HA) in a pilot study. Thirty infants with primary craniosynostosis were scheduled for pCFS. In 15 of those, FFPs were available from the identical donor as for packed red blood cells (pRBC), and were thus employed for intraoperative volume replacement. The remaining 15 infants were infused with HA-5% instead. Haemoglobin(Hb)-values, global coagulation parameters (activated partial thromboplastin time-aPTT; prothrombin time-PT), selected clotting factors (F) (VIII, XI, XIII), antithrombin-AT, fibrinolytic factors (fibrinogen; plasminogen; alpha2-antiplasmin-alpha2A), and activation parameters (thrombin-antithrombin-complex-TAT; plasmin-antiplasmin-complex-PAP; D-dimers) were assessed and compared between both groups after induction of anaesthesia, before transfusion of pRBC, and at the end of surgery. Patients and treatment characteristics were balanced between both groups. Prolongation of aPTT and decreases of PT, FXI, FXIII, AT3, and fibrinolytic factors were more pronounced in the HA-group. Increases in F VIII activity, activation parameters, and the course of Hb-values were similar among both groups. There was no difference regarding clinical endpoints (peri-/postoperative pRBC-transfusions, postoperative blood loss). In conclusion, the application of HA was associated with a more distinct dilution of procoagulant factors, AT3, and fibrinolytic factors than the use of FFPs. However, the course of activation markers suggested a similar extent of clotting and fibrinolytic activation with the use of both transfusion regimens, and there were no differences with regard to clinical endpoints.

Objective: To determine whether glycemic control is less feasible when hydrocortisone is given as a bolus compared with continuous application in septic shock patients., Design: Observational prospective pilot study., Setting: Fourteen-bed surgical university hospital ICU., Patients: Sixteen consecutive patients with septic shock receiving a continuous infusion of 200 mg hydrocortisone/day and an infusion regime of insulin keeping blood glucose below 150 mg/dl., Intervention: Blood glucose and insulin infusion were adjusted to steady state before intervention. At baseline, the continuous hydrocortisone infusion was replaced with a single bolus of 50 mg hydrocortisone. During a subsequent 6-h period, blood glucose was monitored hourly and insulin infusion was kept constant. Afterwards, hydrocortisone application and adjustment of blood glucose was resumed according to standard treatment., Results: Mean blood glucose in steady state at baseline immediately prior to intervention was 128 mg/dl (range 114-141 mg/dl; 95% confidence interval). After bolus injection of hydrocortisone, blood glucose increased significantly within 6 h with peak levels of 154 mg/dl (range 132-178 mg/dl; p<0.01). Blood glucose returned to baseline with restoration of continuous hydrocortisone infusion. There were marked inter-individual variations with peak glucose values up to 254 mg/dl, but no significant difference in intra-individual glucose variability before and after bolus injection of hydrocortisone., Conclusions: Bolus injections of hydrocortisone may induce significant increases of blood glucose in patients with septic shock. The individual response is highly variable and we speculate that repetitive boluses would induce marked undulation of blood glucose. In terms of glycemic-control strategies, a continuous infusion of hydrocortisone seems to be preferable.

Therapeutical hyperthermia has been considered for cancer therapy since William Coley observed tumour remission after induction of fever by bacterial toxins at the end of the 19th century. Because fever is associated with a variety of immunological reactions, it has been suspected, that therapeutical hyperthermia might also activate the immune system in a reproducible manner and thereby positively influence the course of the disease. During the last decade, new insight has been gained regarding the immunological changes taking place during therapeutic hyperthermia. In this chapter, we review the most relevant data known about the effect of hyperthermia on the immune system with special focus on alterations induced by therapeutical whole-body hyperthermia (WBH) in cancer patients.

Extreme acute physical stress leads to transient impairment of T-lymphocytes, which are essential for tumor defence and prevention of infectious diseases. Radiant whole body hyperthermia (WBH) at 41.8-42.2 degrees C may enhance the efficacy of systemic chemotherapy in patients with advanced malignancies, but is associated with marked physical stress. Aim of this study was to demonstrate stress induced short-time effects on lymphocyte subpopulations and associated cytokines during WBH. Total leukocyte count, white blood cell differential blood count, lymphocyte subpopulations (T-helper-/T4-cells, T-suppressor-/T8-cells, natural-killer-/NK-cells, gammadelta-T-cells) as well as plasma levels of Interleukin(IL)-10, IL-12 and Interferon-gamma (IFN-gamma) were measured in ten patients treated with WBH and additional cytostatic chemotherapy. Blood samples were drawn before treatment, at three temperature points during WBH, and 24 h after start of treatment. Results were compared with those obtained from a control group consisting of six patients receiving chemotherapy alone. Numbers of T4-cells decreased significantly during WBH, while numbers of NK-cells and gammadelta-T-cells increased, resulting in transient impairments of total lymphocyte counts and T4/T8-ratio. IL-12 plasma levels as well as IFN-gamma/IL-10-ratio also decreased during WBH. No significant changes were found in T8-cells of WBH patients. Changes were reversible within 24 h and could not been found in control patients. Our results support the hypothesis that WBH combined with chemo therapy induces a strong but reversible anti-inflammatory stress response in cancer patients during therapy. Further studies are necessary to examine the pathophysiological details and to evaluate the meaning of these transient immunological changes for patient's outcome.

Objectives: To optimize volume therapy during induced whole-body hyperthermia (WBH) < or = 42.2 degrees C, pulmonary capillary wedge pressure (PCWP) and intrathoracic blood volume index (ITBVI) were compared as goal parameters., Design: Prospective clinical study., Setting: ICU at university hospital., Patients: Twenty-three patients with metastatic cancers., Interventions: Radiant WBH in combination with induced hyperglycemia, hyperoxemia, and chemotherapy was applied. Volume therapy was directed to the PCWP (group A, 8 to 12 mm Hg [20 treatments]), or to ITBVI (group B, 800 to 1,100 mL/m2 [19 treatments]) following a standardized protocol. Goals other than PCWP and ITBVI were cardiac index of > 3.5 L/min/m2 and mean arterial pressure of > 55 mm Hg., Measurements and Results: In addition to the primary goals PCWP and ITBVI, at defined temperatures, central venous pressure (CVP), extravascular lung water index, the number of infusions, and packed RBCs, as well as serum lactate level, norepinephrine dosage, and levels of liver enzymes, bilirubin, creatinine, and urea were measured. Patients in group A received a significantly greater mean (+/- SD) amount of crystalloids compared to those in group B (6,175 +/- 656 vs 3,947 +/- 375 mL, respectively) and required significantly lower dosages of vasoconstrictors compared with patients in group B. Except for the lower values of CVP in patients in group A during hyperthermia, all of the other hemodynamic and laboratory parameters showed no significant differences between the groups or stayed in a normal range., Conclusion: PCWP and ITBVI are useful parameters to assess preload in induced WBH. Differences in crystalloids and vasopressor dosages may suggest an appropriate ITBVI of > 1,100 mL/m2 for patients with good cardiopulmonary health under such extremely hypercirculatory conditions.

Objective: A major cause of death in patients with severe hemorrhagic shock following trauma is the subsequent occurrence of multiple organ failure due to tissue hypoxia. Early administration of an oxygen carrier may reduce the occurrence of organ failures and improve survival. It may also reduce the need of blood products., Design and Setting: Prospective multicenter study in a university clinic., Patients: 121 patients with severe hemorrhagic shock., Interventions: Patients were randomly assigned "on-scene" to receive either up to 1000 ml of a 10% diaspirin cross-linked hemoglobin (DCLHb) solution or the study center's standard therapy., Measurements and Results: Demographic and physiological characteristics of the two treatment groups at baseline were comparable. Organ failures and survival rates until day 5 and day 28 showed no significant differences. The sponsor therefore terminated this trial prematurely after an interim evaluation of the data indicated no evidence of efficacy to offset concerns raised about the safety of DCLHb. Median volumes of cumulative blood products administered on 1 (1595 vs. 3716 ml) and 7 days (3139 vs. 4746 ml) after admission were lower in the DCLHb group., Conclusions: The early application of an oxygen carrier (DCLHb) to patients with severe hemorrhagic shock following trauma had no significant effect on the occurrence of organ failure or on 5- and 28-day survival in this abbreviated trial. However, early infusion of up to 1000 ml DCLHb reduces the need for blood products without changing morbidity or survival.

Within the last few years, increasing evidence of relative adrenal insufficiency in septic shock evoked a reassessment of hydrocortisone therapy. To evaluate the effects of hydrocortisone on the balance between proinflammatory and antiinflammation, 40 patients with septic shock were randomized in a double-blind crossover study to receive either the first 100 mg of hydrocortisone as a loading dose and 10 mg per hour until Day 3 (n = 20) or placebo (n = 20), followed by the opposite medication until Day 6. Hydrocortisone infusion induced an increase of mean arterial pressure, systemic vascular resistance, and a decline of heart rate, cardiac index, and norepinephrine requirement. A reduction of plasma nitrite/nitrate indicated inhibition of nitric oxide formation and correlated with a reduction of vasopressor support. The inflammatory response (interleukin-6 and interleukin-8), endothelial (soluble E-selectin) and neutrophil activation (expression of CD11b, CD64), and antiinflammatory response (soluble tumor necrosis factor receptors I and II and interleukin-10) were attenuated. In peripheral blood monocytes, human leukocyte antigen-DR expression was only slightly depressed, whereas in vitro phagocytosis and the monocyte-activating cytokine interleukin-12 increased. Hydrocortisone withdrawal induced hemodynamic and immunologic rebound effects. In conclusion, hydrocortisone therapy restored hemodynamic stability and differentially modulated the immunologic response to stress in a way of antiinflammation rather than immunosuppression.

Whole Body Hyperthermia (WBH) has been shown to induce alterations of lymphocyte subpopulations in peripheral blood: T-cells decrease and NK-cells increase in number in the course of this therapy. As elevated temperature induces programmed cell death in healthy lymphocytes in vitro, we intended to determine the role of lymphocyte apoptosis in WBH by measuring the rate of apoptosis in blood lymphocytes in the course of this treatment. Blood was taken from cancer patients, treated with whole body hyperthermia and chemotherapy, before, during and the day after treatment. Apoptosis rates of the whole lymphocyte population, as well as, of B-, T-, CD4 + -T-, CD8 + -T-, and Natural-Killer (NK)-cell-subpopulations were determined by staining with AnnexinV-FITC and FACS flow analysis. A significant rise of apoptosis in the whole lymphocyte population, in CD4 + -T- and in CD8 + -T-cells occurred during treatment. In contrast, an elevated rate of apoptosis in NK-cells was observed 20 hours after termination of WBH. These differences were similar when the cells were incubated at 37 degrees C for 24 hours. Our results suggest, that apoptosis is one reason for the previously described decrease of T-cells during WBH and of NK-cells after WBH, and that the hyperthermia-related apoptosis-inducing mechanism is different in T-cells and NK-cells.

In oncology, the term 'hyperthermia' refers to the treatment of malignant diseases by administering heat in various ways. Hyperthermia is usually applied as an adjunct to an already established treatment modality (especially radiotherapy and chemotherapy), where tumor temperatures in the range of 40-43 degrees C are aspired. In several clinical phase-III trials, an improvement of both local control and survival rates have been demonstrated by adding local/regional hyperthermia to radiotherapy in patients with locally advanced or recurrent superficial and pelvic tumors. In addition, interstitial hyperthermia, hyperthermic chemoperfusion, and whole-body hyperthermia (WBH) are under clinical investigation, and some positive comparative trials have already been completed. In parallel to clinical research, several aspects of heat action have been examined in numerous pre-clinical studies since the 1970s. However, an unequivocal identification of the mechanisms leading to favorable clinical results of hyperthermia have not yet been identified for various reasons. This manuscript deals with discussions concerning the direct cytotoxic effect of heat, heat-induced alterations of the tumor microenvironment, synergism of heat in conjunction with radiation and drugs, as well as, the presumed cellular effects of hyperthermia including the expression of heat-shock proteins (HSP), induction and regulation of apoptosis, signal transduction, and modulation of drug resistance by hyperthermia.