Hemoadsorption in the critically ill-Final results of the International CytoSorb Registry.

The aim of the current paper is to summarize the results of the International CytoSorb Registry. Data were collected on patients of the intensive care unit. The primary endpoint was actual in-hospital mortality compared to the mortality predicted by APACHE II score. The main secondary endpoints were SOFA scores, inflammatory biomarkers and overall evaluation of the general condition. 1434 patients were enrolled. Indications for hemoadsorption were sepsis/septic shock (N = 936); cardiac surgery perioperatively (N = 172); cardiac surgery postoperatively (N = 67) and "other" reasons (N = 259). APACHE-II-predicted mortality was 62.0±24.8%, whereas observed hospital mortality was 50.1%. Overall SOFA scores did not change but cardiovascular and pulmonary SOFA scores decreased by 0.4 [-0.5;-0.3] and -0.2 [-0.3;-0.2] points, respectively. Serum procalcitonin and C-reactive protein levels showed significant reduction: -15.4 [-19.6;-11.17] ng/mL; -17,52 [-70;44] mg/L, respectively. In the septic cohort PCT and IL-6 also showed significant reduction: -18.2 [-23.6;-12.8] ng/mL; -2.6 [-3.0;-2.2] pg/mL, respectively. Evaluation of the overall effect: minimal improvement (22%), much improvement (22%) and very much improvement (10%), no change observed (30%) and deterioration (4%). There was no significant difference in the primary outcome of mortality, but there were improvements in cardiovascular and pulmonary SOFA scores and a reduction in PCT, CRP and IL-6 levels. Trial registration: ClinicalTrials.gov Identifier: NCT02312024 (retrospectively registered).

Hemoadsorption in 'Liver Indication'-Analysis of 109 Patients' Data from the CytoSorb International Registry.

BACKGROUND: Our aim is to report the results of the 'liver indication' subset of patients in the CytoSorb International Registry. METHODS: Structured data were recorded. Treatment characteristics and changes from T1 (start of hemoadsorption) to T2 (termination) were evaluated with a special focus on bilirubin, C-reactive protein, procalcitonin, interleukin-6, platelet levels, SOFA scores, mortality, and subjective assessment by the attending physicians. RESULTS: Until January 2021, from the total 1434 patients, 109 (age: 49.2 ± 17.1 years, 57.8% males) received treatment for hyperbilirubinemia. APACHE II-predicted mortality was 49.6 ± 26.8%. In the study, 91% of patients were alive at the termination of hemoadsorption and improvement was observed by the physicians in 75 cases. Overall, 65 (59.6%) patients died in the hospital, and 60 (55.0%) died in the ICU. Patients received a median of two treatments for a median of 43 h (interquartile range: 24-72 h) in total. Serum bilirubin levels reduced significantly to -4.6 (95% CI: -6.329 to -2.8) mg/dL. Thrombocytopenia was reported in four patients as an adverse event. CONCLUSIONS: We report the largest case series on hemoadsorption for 'liver indication' from the CytoSorb International Registry. The finding of significant bilirubin removal observed in our study could have substantial impact in designing and executing further studies on the effects of hemoadsorption in liver dysfunction, which are certainly warranted.

Tryptophan immunoadsorption during pregnancy and breastfeeding in patients with acute relapse of multiple sclerosis and neuromyelitis optica.

BACKGROUND: Up to every fourth woman with multiple sclerosis (MS) or neuromyelitis optica spectrum disorder (NMOSD) suffers a clinically relevant relapse during pregnancy. High doses of steroids bear some serious risks, especially within the first trimester of pregnancy. Immunoadsorption (IA) is an effective and more selective treatment option in disabling MS relapse than plasma exchange. Data on the use of IA during pregnancy and breastfeeding are scarce. METHODS: In this retrospective multicenter study, we analyzed the safety and efficacy of IA treatment in acute relapses during pregnancy or breastfeeding. The primary outcome parameter - change of acute relapse-related disability after IA - was assessed using Expanded Disability Status Scale (EDSS) and visual acuity (VA) measurements for patients with optic neuritis (ON). RESULTS: A total of 24 patients were analyzed, 23 with relapsing-remitting MS, and 1 with NMOSD. Twenty patients were treated with IA during pregnancy. Four patients received IA postnatally during the breastfeeding period. Treatment was started at a mean 22.5 [standard deviation (SD) 13.9] days after onset of relapse. Patients were treated with a series of 5.8 (mean, SD 0.7) IA treatments within 7-10 days. Sixteen patients received IA because of steroid-refractory relapse, eight were treated without preceding steroid pulse therapy. EDSS improved clinically relevant from 3.5 [median, interquartile range (IQR) 2] before IA to 2.5 (median, IQR 1.1) after IA, p < 0.001. In patients with ON, VA improved in four out of five patients. Altogether, in 83% of patients, a rapid and marked improvement of relapse-related symptoms was observed after IA with either a decrease of ⩾1 EDSS grade or improvement in VA ⩾20%. No clinically relevant side effect was reported in 138 IA treatments. CONCLUSIONS: Tryptophan-IA was found to be effective and well tolerated in MS/NMOSD relapses, both as an escalation option after insufficient response to steroid pulse therapy and as first-line relapse treatment during pregnancy and breastfeeding.

Emergence times and airway reactions during general anaesthesia with remifentanil and a laryngeal mask airway: A multicentre randomised controlled trial.

BACKGROUND: Avoidance of airway complications and rapid emergence from anaesthesia are indispensable for the use of a laryngeal mask airway (LMA). Evidence from adequately powered randomised studies with a low risk of bias for the optimal anaesthetic in this context is limited. OBJECTIVE: We tested the hypothesis that when using remifentanil-based intra-operative analgesia, desflurane would be the most suitable anaesthetic: with noninferiority in the occurrence of upper airway complications and superiority in emergence times compared with sevoflurane or propofol. DESIGN: A randomised, multicentre, partially double-blinded, three-arm, parallel-group study. SETTING: Two university and two regional German hospitals, from February to October 2015. PATIENTS: A total of 352 patients (age 18 to 75 years, ASA physical status I to III, BMI less than 35 kg m and fluent in German) were enrolled in this study. All surgery was elective with a duration of 0.5 to 2 h, and general anaesthesia with a LMA was feasible. INTERVENTION: The patients were randomised to receive desflurane, sevoflurane or propofol anaesthesia. MAIN OUTCOME MEASURES: This study was powered for the primary outcome 'time to state date of birth' and the secondary outcome 'intra-operative cough'. Time to emergence from anaesthesia and the incidence of upper airway complications were assessed on the day of surgery. RESULTS: The primary outcome was analysed for 343 patients: desflurane (n=114), sevoflurane (n=111) and propofol (n=118). The desflurane group had the fastest emergence. The mean (± SD) times to state the date of birth following desflurane, sevoflurane and propofol were 8.1 ±â€Š3.6, 10.1 ±â€Š4.0 and 9.8 ±â€Š5.1 min, respectively (P < 0.01). There was no difference in upper airway complications (cough and laryngospasm) across the groups, but these complications were less frequent than in previous studies. CONCLUSION: When using a remifentanil infusion for intra-operative analgesia in association with a LMA, desflurane was associated with a significantly faster emergence and noninferiority in the incidence of intra-operative cough than either sevoflurane or Propofol. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02322502; EudraCT identifier: 2014-003810-96.

The inventory as a core element in the further development of the science curriculum in the Mannheim Reformed Curriculum of Medicine.

Introduction: The German Council of Science and Humanities as well as a number of medical professional associations support the strengthening of scientific competences by developing longitudinal curricula for teaching scientific competences in the undergraduate medical education. The National Competence Based Catalogue of Learning Objectives for Undergraduate Medical Education (NKLM) has also defined medical scientific skills as learning objectives in addition to the role of the scholar. The development of the Mannheim science curriculum started with a systematic inventory of the teaching of scientific competences in the Mannheim Reformed Curriculum of Medicine (MaReCuM). Methods: The inventory is based on the analysis of module profiles, teaching materials, surveys among experts, and verbatims from memory. Furthermore, science learning objectives were defined and prioritized, thus enabling the contents of the various courses to be assigned to the top three learning objectives. Results: The learning objectives systematic collection of information regarding the current state of research, critical assessment of scientific information and data sources, as well as presentation and discussion of the results of scientific studies are facilitated by various teaching courses from the first to the fifth year of undergraduate training. The review reveals a longitudinal science curriculum that has emerged implicitly. Future efforts must aim at eliminating redundancies and closing gaps; in addition, courses must be more closely aligned with each other, regarding both their contents and their timing, by means of a central coordination unit. Conclusion: The teaching of scientific thinking and working is a central component in the MaReCuM. The inventory and prioritization of science learning objectives form the basis for a structured ongoing development of the curriculum. An essential aspect here is the establishment of a central project team responsible for the planning, coordination, and review of these measures.

Comprehension through cooperation: Medical students and physiotherapy apprentices learn in teams - Introducing interprofessional learning at the University Medical Centre Mannheim, Germany.

AIM: In order to better prepare future health care professionals for interprofessional cooperation, interprofessional learning sessions for medical students and physiotherapy apprentices were developed at the University Medical Centre Mannheim, Germany. The experience gained from designing, implementing and evaluating these learning sessions is presented and discussed. METHOD: A total of 265 medical students and 43 physiotherapy apprentices attended five interprofessional learning sessions. Of these, 87-100% responded to closed and open-ended questions on a self-developed questionnaire (24 items). The responses regarding self-reported learning gains, benefit, motivation and satisfaction with the sessions were analyzed separately by professions. RESULTS: The learning sessions were well received by both groups. More than 75% of all participants were of the opinion that they could not have learned the new material in a better way. Significant differences between the medical students and the physiotherapy apprentices were mainly found with regard to perceived learning gains, which physiotherapy apprentices reported as being lower. Positive aspects of interprofessionalism were most often emphasized in the responses to the open-ended questions. Most frequently criticized were organizational aspects and a lack of perceived learning gains. CONCLUSION: The introduction of interprofessional learning entails great effort in terms of organizational and administrative challenges. However, the project is considered worthwhile because the interprofessional aspects of the learning sessions were indeed valued by the participants. Permanently including and expanding interprofessional learning in the curricula of both professions longitudinally is therefore something to strive for.

Emergence times and airway reactions in general laryngeal mask airway anesthesia: study protocol for a randomized controlled trial.

BACKGROUND: The use of a laryngeal mask airway (LMA) in appropriate patients supports fast-track anesthesia with a lower incidence of postoperative airway-connected adverse events. Data on the most favorable anesthetic in this context, with the lowest rate of upper airway complications and fast emergence times, are controversial and limited. Desflurane seems to match these criteria best, but large randomized controlled trials (RCTs) with a standardized study protocol are lacking. Therefore, we aim to compare desflurane with other commonly used anesthetics, sevoflurane and propofol, in a sufficiently powered RCT. We hypothesize that desflurane is noninferior regarding the frequency of upper airway events and superior regarding the emergence times to sevoflurane and propofol. METHODS/DESIGN: A total of 351 patients undergoing surgery with an LMA will be included in this prospective, randomized, double-blind controlled, multicenter clinical trial. The patients will be randomly assigned to the three treatment arms: desflurane (n = 117), sevoflurane (n = 117), and propofol (n = 117). The emergence time (time to state the date of birth) will be the primary endpoint of this study. The secondary endpoints include further emergence times, such as time to open eyes, to remove LMA, to respond to command and to state name. Additionally, we will determine the frequency of cough and laryngospasm, measured intraoperatively and at emergence. We will assess the postoperative recovery on the first postoperative day via the Postoperative Quality Recovery Scale. DISCUSSION: Despite increasing importance of cost-effective and safe anesthesia application, we lack proof for the most advantageous anesthetic agent, when an LMA is used. There are only a few RCTs comparing desflurane to other commonly used anesthetics (sevoflurane, propofol and isoflurane) in patients with LMA. These RCTs were conducted with small sample sizes, huge interstudy variability, and some also showed strong biases. The present multicenter RCT will provide results from a large sample size with a standardized study protocol and minimized bias, which is feasible in the clinical routine. Furthermore, we will expand our knowledge regarding the most favorable recovery on the first postoperative day, which impacts patients' comfort after surgery. TRIAL REGISTRATION: EudraCT Identifier: 2014-003810-96, 5 September 2014 ClinicalTrials.gov: NCT02322502, December 2014.

Airway reactions and emergence times in general laryngeal mask airway anaesthesia: a meta-analysis.

BACKGROUND: Desflurane's short emergence time supports fast track anaesthesia. Data on the rate of upper airway complications and emergence time when desflurane is used with laryngeal mask airway (LMA) are controversial and limited. OBJECTIVES: To compare recovery time variables and the rates of upper airway adverse events in patients with an LMA undergoing general surgery with desflurane, sevoflurane, isoflurane or propofol anaesthesia. DESIGN: A systematic review and meta-analysis of randomised controlled trials (RCTs). DATA SOURCES: A systematic search for eligible RCTs in Embase (Elsevier) and in PubMed (National Library of Medicine) databases up to September 2013. ELIGIBILITY CRITERIA: RCTs investigating the rates of cough overall, cough at emergence, laryngospasm, time to eye opening, time to removal of the LMA, time to respond to command and time to state date of birth in patients with an LMA, during emergence from desflurane, sevoflurane, isoflurane or propofol anaesthesia. RESULTS: Thirteen RCTs were included and analysed. We found a strong interstudy variability. There was no difference in the rates of upper airway events between desflurane and sevoflurane or between desflurane and a control group consisting of all the other anaesthetics combined. Comparing desflurane (n = 284) with all other anaesthetic groups (n = 313), the risk ratio [95% confidence interval (95% CI)] was 1.12 (0.63 to 2.02, P = 0.70). Cough at emergence was only measured in patients receiving desflurane (n = 148) and sevoflurane (n = 146): the risk ratio (95% CI) was 1.49 (0.55 to 4.02, P = 0.43). Laryngospasm was rare and there was no significant difference in its incidence when desflurane (n = 262) was compared with all other anaesthetics combined (n = 289; risk ratio 1.03; 95% CI 0.33 to 3.20, P = 0.96). The times of all emergence variables were significantly faster in the desflurane group than in all other groups. CONCLUSION: When using an LMA, upper airway adverse reactions in association with desflurane anaesthesia were no different from those noted with sevoflurane, isoflurane or propofol anaesthesia. Emergence from general anaesthesia with desflurane is significantly faster than all the other anaesthetics. Due to interstudy variations and the small size of the trials, further large-scale, multicentre studies are required to confirm or refute the results of this meta-analysis.

Effect of empirical treatment with moxifloxacin and meropenem vs meropenem on sepsis-related organ dysfunction in patients with severe sepsis: a randomized trial.

CONTEXT: Early appropriate antimicrobial therapy leads to lower mortality rates associated with severe sepsis. The role of empirical combination therapy comprising at least 2 antibiotics of different mechanisms remains controversial. OBJECTIVE: To compare the effect of moxifloxacin and meropenem with the effect of meropenem alone on sepsis-related organ dysfunction. DESIGN, SETTING, AND PATIENTS: A randomized, open-label, parallel-group trial of 600 patients who fulfilled criteria for severe sepsis or septic shock (n = 298 for monotherapy and n = 302 for combination therapy). The trial was performed at 44 intensive care units in Germany from October 16, 2007, to March 23, 2010. The number of evaluable patients was 273 in the monotherapy group and 278 in the combination therapy group. INTERVENTIONS: Intravenous meropenem (1 g every 8 hours) and moxifloxacin (400 mg every 24 hours) or meropenem alone. The intervention was recommended for 7 days and up to a maximum of 14 days after randomization or until discharge from the intensive care unit or death, whichever occurred first. MAIN OUTCOME MEASURE: Degree of organ failure (mean of daily total Sequential Organ Failure Assessment [SOFA] scores over 14 days; score range: 0-24 points with higher scores indicating worse organ failure); secondary outcome: 28-day and 90-day all-cause mortality. Survivors were followed up for 90 days. RESULTS: Among 551 evaluable patients, there was no statistically significant difference in mean SOFA score between the meropenem and moxifloxacin group (8.3 points; 95% CI, 7.8-8.8 points) and the meropenem alone group (7.9 points; 95% CI, 7.5-8.4 points) (P = .36). The rates for 28-day and 90-day mortality also were not statistically significantly different. By day 28, there were 66 deaths (23.9%; 95% CI, 19.0%-29.4%) in the combination therapy group compared with 59 deaths (21.9%; 95% CI, 17.1%-27.4%) in the monotherapy group (P = .58). By day 90, there were 96 deaths (35.3%; 95% CI, 29.6%-41.3%) in the combination therapy group compared with 84 deaths (32.1%; 95% CI, 26.5%-38.1%) in the monotherapy group (P = .43). CONCLUSION: Among adult patients with severe sepsis, treatment with combined meropenem and moxifloxacin compared with meropenem alone did not result in less organ failure. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00534287.

Compatibility of studies and family: approaches at the Medical Faculty Mannheim.

The compatibility of studies or a career with children is becoming increasingly important. This is partly attributable to the fact that it is important for people of either gender to spend time with their families, their children. Not too long ago, raising children was almost exclusively the domain of the mother. On the other hand, more and more women study medicine. More than half of first year students are now female. Many of these young women, like their male counterparts, would like to start families. The possibility to both study and have children is particularly important during the "training" life phase. The Medical Faculty Mannheim realises the need for action and wants to actively tackle the associated challenges in terms of advice, study design and infrastructure. This article represents the steps which the faculty - in close cooperation with the Equality Office, the Dean of Studies and the University Hospital - has taken so far or is currently putting in place to enable students to successfully combine the challenge of studying with that of having children. These include individual advice services on study organisation, information about support services, changes to the infrastructure and more intensive cooperation between the various departments.

Isoflurane/nitrous oxide anesthesia and stress-induced procedures enhance neuroapoptosis in intrauterine growth-restricted piglets.

PURPOSE: There is compelling evidence that interference of various anesthetics with synaptic functions and stress-provoking procedures during critical periods of brain maturation results in increased neuroapoptotic cell death. The hypothesis is that adverse intrauterine environmental conditions leading to intrauterine growth restriction (IUGR) with altered brain development may result in enhanced susceptibility to developmental anesthetic neurotoxicity. METHODS: This was a prospective, randomized, blinded animal study performed in a university laboratory involving 20 normal-weight (NW) and 19 IUGR newborn piglets. General inhalation anesthesia with isoflurane and nitrous oxide at clinically comparable dosages were administered for about 10 h. Surgical and monitoring procedures were accompanied by appropriate stage of general anesthesia. Resulting effects on developmental anesthetic and stress-induced neurotoxicity were assessed by estimation of apoptotic rates in untreated piglets and piglets after 10-h general anesthesia with MAC 1.0 isoflurane in 70 % nitrous oxide and 30 % oxygen. RESULTS: IUGR piglets exposed to different levels of isoflurane inhalation exhibited a significant increased apoptosis rate (TUNEL-positive neuronal cells) compared to NW animals of similar condition (P < 0.05). Cardiovascular and metabolic monitorings revealed similar effects of general anesthesia together with similar effects on brain electrical activity and broadly a similar dose-dependent gradual restriction in brain oxidative metabolism in NW and IUGR piglets. CONCLUSIONS: There is no indication that the increased rate in neuroapoptosis in IUGR piglets is confounded by additional adverse systemic or organ-specific impairments resulting from administered mixed inhalation anesthesia. Developmental anesthetic and stress-induced neuroapoptosis presumably originated in response to fetal adaptations to adverse conditions during prenatal life and should be considered in clinical interventions on infants having suffered from fetal growth restriction.

Correlations of cave levels, stream terraces and planation surfaces along the River Mur-Timing of landscape evolution along the eastern margin of the Alps.

The transition zone of the Eastern Alps to the Pannonian Basin provides one of the best sources of information on landscape evolution of the Eastern Alpine mountain range. The region was non-glaciated during the entire Pleistocene. Thus, direct influence of glacial carving as a landscape forming process can be excluded and relics of landforms are preserved that date back to at least the Late Neogene. In this study, we provide a correlation between various planation surfaces across the orogen-basin transition. In particular, we use stream terraces, planation surfaces and cave levels that cover a vertical spread of some 700 m. Our correlation is used to show that both sides of the transition zone uplifted together starting at least about 5 Ma ago. For our correlation we use recently published terrestrial cosmogenic nuclide (TCN) burial ages from cave sediments, new optically stimulated luminescence (OSL) ages of a stream terrace and U-Th ages from speleothems. Minimum age constraints of cave levels from burial ages of cave sediments covering the last ~ 4 Ma are used to place age constraints on surface features by parallelizing cave levels with planation surfaces. The OSL results for the top section of the type locality of the Helfbrunn terrace suggest an Early Würm development (80.5 ± 3.7 to 68.7 ± 4.0 ka). The terrace origin as a penultimate gravel deposit (in classical Alpine terminology Riss) is therefore questioned. U-series speleothem ages from caves nearby indicate formation during Marine Isotope Stages (MIS) 5c and 5a which are both interstadial warm periods. As OSL ages from the terrace also show a time of deposition during MIS 5a ending at the MIS 5/4 transition, this supports the idea of temperate climatic conditions at the time of deposition. In general, tectonic activity is interpreted to be the main driving force for the formation and evolution of these landforms, whilst climate change is suggested to be of minor importance. Obvious hiatuses in Miocene to Pleistocene sediments are related to ongoing erosion and re-excavation of an uplifting and rejuvenating landscape.

Intra-arrest transnasal evaporative cooling: a randomized, prehospital, multicenter study (PRINCE: Pre-ROSC IntraNasal Cooling Effectiveness).

BACKGROUND: Transnasal evaporative cooling has sufficient heat transfer capacity for effective intra-arrest cooling and improves survival in swine. The aim of this study was to determine the safety, feasibility, and cooling efficacy of prehospital transnasal cooling in humans and to explore its effects on neurologically intact survival to hospital discharge. METHODS AND RESULTS: Witnessed cardiac arrest patients with a treatment interval

Age-dependent effects of gradual decreases in cerebral perfusion pressure on the neurochemical response in swine.

OBJECTIVE: There is still a lack of knowledge on the age-dependent relation between a reduction in cerebral perfusion pressure (CPP) and compromised brain perfusion leading to excessive transmitter release and brain damage cascades. The hypothesis is that an age-dependent lower threshold of cerebral blood flow (CBF) autoregulation determines the amount and time course of transmitter accumulation. DESIGN AND SETTING: This was a prospective randomized, blinded animal study performed in a university laboratory involving eight newborn and 11 juvenile anesthetized pigs. INTERVENTION: Striatal dopamine, glutamate, glucose, and lactate were monitored by microdialysis. For CPP manipulation, the cisterna magna was infused with artificial cerebrospinal fluid to control intracranial pressure at the maintained arterial blood pressure (stepwise CPP decrease in 15-min stages to 50, 40, 30, and finally 0 mmHg). MEASUREMENTS AND MAIN RESULTS: Juvenile pigs showed a gradual decrease in CBF between 50 mmHg CPP (CPP-50) and 30 mmHg CPP (CPP-30), but a significant CBF reduction did not occur in newborn piglets until CPP-30 (P < 0.05). At CPP-30, brain oxidative metabolism was reduced only in juveniles, concomitantly with elevations in dopamine and glutamate levels (P < 0.05). In contrast, newborn piglets exhibited a delayed and blunted accumulated of transmitters and metabolites (P < 0.05). CONCLUSIONS: The lower limit of CBF autoregulation was associated with modifications in neurochemical parameters that clearly occurred before brain oxidative metabolism was compromised. Early indicators for mild to moderate hypoperfusion are elevated levels of lactate and dopamine, but elevated levels of glutamate appear to be an indicator of brain ischemia. The shift to the left of the lower autoregulatory threshold is mainly responsible for the postponed neurochemical response to decrements in the CPP in the immature brain.

[The evaluation of teaching at medical schools in Baden-Wuerttemberg]. / Lehrevaluation an den Medizinischen Fakultäten Baden-Württembergs.

This article offers an overview of options for the evaluation of medical education. After discussing theoretical and methodological issues we describe how medical education is currently being evaluated by medical faculties in Baden-Wuerttemberg, Germany.

A pig model with secondary increase of intracranial pressure after severe traumatic brain injury and temporary blood loss.

There is a lack of animal models of traumatic brain injury (TBI) that adequately simulate the longterm changes in intracranial pressure (ICP) increase following clinical TBI. We therefore reproduced the clinical scenario in an animal model of TBI and studied long-term postinjury changes in ICP and indices of brain injury. After induction of anesthesia, juvenile piglets were randomly traumatized using fluid-percussion injury (FPI) to induce either moderate (mTBI = 6 pigs: 3.2 +/- 0.6 atm) or severe (sTBI = 7 pigs: 4.1 +/- 1.0 atm) TBI. Injury was followed by a 30% withdrawal of blood volume. ICP and systemic hemodynamic were monitored continuously. Repeated measurements of global cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO2) were performed at baseline, at the end of blood withdrawal, after volume replacement, and at 8 and 24 h postinjury. Histological and immunocytochemical studies have also performed. ICP peaked immediately following FPI (mTBI: 33 +/- 16 mm Hg; sTBI: 47 +/- 14 mm Hg, p < 0.05) in both groups. In the sTBI group, we noted a second peak at 5 +/- 1.5 h postinjury. This second ICP peak was accompanied by a 50% reduction in CBF (44 +/- 31 mL . min . 100 g(-1)) and CMRO(2) (2.5 +/- 2.0 mL . min . 100 g(1)). Moderate TBI typically resulted in focal pathological change whereas sTBI caused more diffuse change, particularly in terms of the ensuing axonal damage. We thus describe an animal model of severe TBI with a reproducible secondary ICP increase accompanied by patterns of diffuse brain damage. This model may be helpful in the study of pathogenetic relevance of concomitant affections and verify new therapeutic approaches in severe TBI.

The effect of mild hypothermia on plasma fentanyl concentration and biotransformation in juvenile pigs.

Therapeutic hypothermia may alter the required dosage of analgesics and sedatives, but no data are available on the effects of mild hypothermia on plasma fentanyl concentration during continuous, long-term administration. We therefore assessed in a porcine model the effect of prolonged hypothermia on plasma fentanyl concentration during 33 h of continuous fentanyl administration. Seven female piglets (weight: 11.8 +/- 1.1 kg) were anesthetized by IV fentanyl (15 microg . kg(-1) . h(-1)) and midazolam (1.0 mg . kg(-1) . h(-1)). After preparation and stabilization (12 h), the animals were cooled to a core temperature of 31.6 degrees +/- 0.2 degrees C for 6 h and were then rewarmed and kept normothermic at 37.7 degrees +/- 0.3 degrees C for 6 more hours. Plasma fentanyl concentrations were measured by radioimmunoassay, cardiac index by thermodilution, and blood flows of the kidney, spleen, pancreas, stomach, gut, and hepatic artery by a colored microspheres technique. Furthermore, in an additional 4 pigs, temperature dependency of hepatic microsomal cytochrome P450 3A4 (CYP3A4) was determined in vitro by ethylmorphine N-demethylation. Plasma fentanyl concentration increased by 25% +/- 11% (P < 0.05) during hypothermia and remained increased for at least 6 h after rewarming. Hypothermia reduced the cardiac index (41% +/- 15%, P < 0.05), as well as all organ blood flows except the hepatic artery. A strong temperature dependency of CYP3A4 was found (P < 0.01). Mild hypothermia induced a distribution and/or elimination-dependent increase in plasma fentanyl concentration which remained increased for several hours after rewarming. Consequently, a prolonged increase of the plasma fentanyl concentration should be anticipated for appropriate control of the analgesia/sedatives during and early after therapeutic hypothermia.