Towards Implementation of OMOP in a German University Hospital Consortium.

BACKGROUND: In 2015, the German Federal Ministry of Education and Research initiated a large data integration and data sharing research initiative to improve the reuse of data from patient care and translational research. The Observational Medical Outcomes Partnership (OMOP) common data model and the Observational Health Data Sciences and Informatics (OHDSI) tools could be used as a core element in this initiative for harmonizing the terminologies used as well as facilitating the federation of research analyses across institutions. OBJECTIVE: To realize an OMOP/OHDSI-based pilot implementation within a consortium of eight German university hospitals, evaluate the applicability to support data harmonization and sharing among them, and identify potential enhancement requirements. METHODS: The vocabularies and terminological mapping required for importing the fact data were prepared, and the process for importing the data from the source files was designed. For eight German university hospitals, a virtual machine preconfigured with the OMOP database and the OHDSI tools as well as the jobs to import the data and conduct the analysis was provided. Last, a federated/distributed query to test the approach was executed. RESULTS: While the mapping of ICD-10 German Modification succeeded with a rate of 98.8% of all terms for diagnoses, the procedures could not be mapped and hence an extension to the OMOP standard terminologies had to be made.Overall, the data of 3 million inpatients with approximately 26 million conditions, 21 million procedures, and 23 million observations have been imported.A federated query to identify a cohort of colorectal cancer patients was successfully executed and yielded 16,701 patient cases visualized in a Sunburst plot. CONCLUSION: OMOP/OHDSI is a viable open source solution for data integration in a German research consortium. Once the terminology problems can be solved, researchers can build on an active community for further development.

[Does annual simulation training influence the safety climate of a university hospital? : Prospective 5­year investigation using dimensions of the safety attitude questionnaire]. / Beeinflusst jährliches Simulationstraining das Sicherheitsklima einer universitären Klinik? : Prospektive Fünfjahresuntersuchung anhand Dimensionen des "Safety Attitudes Questionnaire".

BACKGROUND: Simulation-based training with a focus on non-technical skills can have a positive influence on safety relevant attitudes of participants. If an organization succeeds in training sufficient staff, it may experience a positive change in the safety climate. As the effects of a single training are of a transient nature, annual training sessions may lead to an incremental improvement of safety relevant attitudes of employees over time. In spring 2012 the Department of Anesthesia at the University Hospital of Erlangen established an annual simulation-based training for staff members (e.g. consultants, trainee anesthetists and nurse anesthetists). OBJECTIVE: The study aimed to test whether an annual simulation-based training would result in an incremental longitudinal improvement in attitudes towards teamwork, safety and stress recognition. METHODS: A survey comprising three domains (teamwork climate, safety climate and stress recognition) of the safety attitudes questionnaire (SAQ) and items addressing briefing and speaking up was distributed to all participants in an annual in-house simulation training. Participants filled out the questionnaire in the morning of each training day. The attitudes were measured before the first training series in 2012, 6 months after the first training and then every year (2013-2016). Participants generated a personalized identification code which allowed individuals to be anonymously tracked over time. Results of the 5­point Likert scale were transformed to a 100-point scale. Results were calculated at the group level and at the individual level. Univariable linear regression was used to calculate mean changes per year. RESULTS: Over a period of 5 years (2012-2016) a total of 255 individuals completed the questionnaire. Each year, 14-20% of all nurse anesthetists and 81-90% of all anesthetists participated in the simulation-based training. As a result of annual staff turnover 16-24% of participants were new staff members. A personalized code allowed the before and after comparison of 99 staff members who had participated twice or more. Physicians had a higher mean score for teamwork climate before the first training (+8.7 p < 0.001). Mean teamwork climate and safety climate scores before the first training increased over a period of 5 years (3.11 for teamwork climate, p < 0.001 and 2.73 for safety climate, p < 0.001). Repeat participation led to a bigger mean change of individual attitudes in nurse anesthetists: teamwork climate 5.2 (nurses) vs. 1.4 (physicians) and safety climate 5.3 (nurses) vs. 2.8 (physicians) without reaching significance. Participants acknowledged the importance of briefings but confirmed their existence in less than half of the cases. The frequency of briefings increased over the 5­year period. There were no changes in attitude towards speaking up. CONCLUSION: Over a 5-year period, small positive changes in attitudes towards teamwork and safety occurred. Low participation of nurse anesthetists as well as personnel turnover may have weakened the impact of simulation-based training on the safety climate.

Septic cardiomyopathy in rat LPS-induced endotoxemia: relative contribution of cellular diastolic Ca(2+) removal pathways, myofibrillar biomechanics properties and action of the cardiotonic drug levosimendan.

Cardiac dysfunction is a common complication in sepsis and is characterized by forward pump failure. Hallmarks of septic cardiomyopathy are decreased myofibrillar contractility and reduced Ca(2+) sensitivity but it is still not clear whether reduced pump efficiency is predominantly a diastolic impairment. Moreover, a comprehensive picture of upstream Ca(2+) handling mechanisms and downstream myosin biomechanical parameters is still missing. Ca(2+)-sensitizing agents in sepsis may be promising but mechanistic insights for drugs like levosimendan are scarce. Here, we used an endotoxemic LPS rat model to study mechanisms of sepsis on in vivo hemodynamics, multicellular myofibrillar Ca(2+) sensitivity, in vitro cellular Ca(2+) homeostasis and subcellular actomyosin interaction with intracardiac catheters, force transducers, confocal Fluo-4 Ca(2+) recordings in paced cardiomyocytes, and in vitro motility assay, respectively. Left ventricular ejection fraction and myofibrillar Ca(2+) sensitivity were depressed in LPS animals but restored by levosimendan. Diastolic Ca(2+) transient kinetics was slowed down by LPS but ameliorated by levosimendan. Selectively blocking intracellular and sarcolemmal Ca(2+) extrusion pathways revealed minor contribution of sarcoplasmic reticulum Ca(2+) ATPase (SERCA) to Ca(2+) transient diastole in LPS-evoked sepsis but rather depressed Na(+)/Ca(2+) exchanger and plasmalemmal Ca(2+) ATPase. This was mostly compensated by levosimendan. Actin sliding velocities were depressed in myosin heart extracts from LPS rats. We conclude that endotoxemia specifically impairs sarcolemmal diastolic Ca(2+) extrusion pathways resulting in intracellular diastolic Ca(2+) overload. Levosimendan, apart from stabilizing Ca(2+)-troponin C complexes, potently improves cellular Ca(2+) extrusion in the septic heart.

Pharmacodynamic response modelling of arterial blood pressure in adult volunteers during propofol anaesthesia.

BACKGROUND: Concentration effect relationships are commonly described with a direct response model as for example the sigmoid E(max) model with one effect compartment as site of action. In this study we investigated whether models with more than one effect site, or indirect response, or counter-regulatory response models may be more appropriate for modelling the propofol effect on arterial blood pressure. METHODS: Nine young healthy volunteers received propofol as target controlled infusion with predefined increasing and decreasing plasma target concentrations. Propofol concentrations were determined from arterial blood samples. Arterial blood pressure was measured invasively at radial artery site. Pharmacokinetic/-pharmacodynamic modelling was performed by population analysis with MONOLIX, testing different direct, indirect and counter-regulatory response models. RESULTS: Propofol plasma concentrations were well described by a three-compartment model. The propofol effect on arterial blood pressure was best described by a direct sigmoid E(max) model with two effect site compartments. CONCLUSIONS: Two effect sites were needed to describe the propofol effect on arterial blood pressure. This may reflect different pathways of arterial blood pressure response to propofol.

Influence of intensive care treatment on the protein binding of sufentanil and hydromorphone during pain therapy in postoperative cardiac surgery patients.

BACKGROUND: Our objective was to evaluate the effect of intensive care treatment on the protein binding of sufentanil and hydromorphone in cardiac surgery patients during postoperative analgesia using a target-controlled infusion (TCI) and patient-controlled analgesia (PCA). METHODS: Fifty adult patients were enrolled in this prospective randomized study; of which, 49 completed the study (age range 40-81 yr). Sufentanil was administered as an analgesic intraoperatively, and hydromorphone was dosed after operation with TCI and PCA until 8 a.m. on the first postoperative day. Arterial plasma samples were collected for drug and protein concentration measurements up to 24 h after cardiac surgery. Corresponding patient data were collected from the electronic patient data system. After explorative data analysis with principal component analysis, multivariate regression analysis and non-linear mixed effects modelling was used to study the effect of treatment on protein binding. RESULTS: Data of 35 patients were analysed. The median protein binding of sufentanil and hydromorphone was 88.4% (IQ range 85.7-90.5%) and 11.6% (IQ range 9.5-14.3%), respectively. Free fraction of sufentanil increased towards the end of the study period, whereas hydromorphone free fraction remained nearly constant. The total sufentanil concentration and volume balance were identified as significant covariates for the protein binding of sufentanil. For the protein binding of hydromorphone, no significant covariate effects were found. CONCLUSIONS: Sufentanil protein binding was significantly dependent on changes in the total drug concentration and volume balance addressing the importance of adequate dosing and fluid-guided therapy. Hydromorphone protein binding was nearly constant throughout the study period. CLINICAL TRIAL REGISTRATION: EudraCT 2011-003648-31 and ClinicalTrials.gov: NCT01490268.

["Jump in at the deep end" : simulator-based learning in acute care]. / "Sprung ins kalte Wasser" : Simulatorbasiertes Lernen in akutmedizinischen Bereichen.

BACKGROUND: With high-fidelity simulators in a modern blended learning setting, students are able to acquire knowledge and practical skills in acute medicine in realistic scenarios. However, it has not yet been clarified if the sequence of linking between knowledge and simulator-based training of practical skills plays an important role for increasing knowledge, for the self-concept and learning emotions of trainees. AIM: In a pilot study the influence of the type of knowledge acquisition under two independent conditions was investigated in which the order of presenting the learning material (firstly theory and then simulation vs. simulation elements before the theory) was reversed. In addition the influence of individual attributes of personality on the construction of situated knowledge was correlated with these conditions in two groups. MATERIAL AND METHODS: To investigate the outcome of simulator-based learning 20 students were randomly allocated to one of the two conditions and undertook two scenarios (anaphylactic shock and myocardial infarction), whereby the theoretical lessons were given either before or after the scenarios. Using standardized questionnaires and problem-centered semi-standardized interviews, the following variables of the participants were assessed: personality traits, current positive and negative feelings, professional self-concept, general self-efficacy and coping strategies for stress. Theoretical knowledge and practical skills were assessed using a knowledge test and standardized assessment questionnaires which also focused on performance and patient safety. RESULTS: All together the results showed a slight advantage for the condition of theory before simulation which was not determined by the acquisition of knowledge but by a better performance of trainees as assessed by the trainers. Regarding knowledge acquisition, no statistically significant differences could be shown. Significant differences (p < 0.05) were found for negative feelings (very intense negative emotional state) and for the professional self-concept (perception of own professional skills) in favor of the theory then simulation condition. More extrovert participants showed poorer results which could not be attributed to one of the conditions. However, the participants always assessed the allocated learning condition as the best premise for effective learning outcome. Reaction to stress has been described as "jumping in at the deep end" as well as the lasting effect on learning from errors. CONCLUSION: In the context of simulation-based teaching, the learning outcome not only depends on knowledge, practical skills and motivational variables but also on the presence of negative feelings, ability self-concepts and various personality traits. There was a trend which showed that simulation in the field of anesthesiology and emergency medicine should be set up with the theoretical basis first in order to avoid negative feelings.

[Implementation of a patient data management system. Effects on intensive care documentation]. / Einführung eines Patientendatenmanagementsystems. Auswirkungen auf die intensivmedizinische Dokumentation.

BACKGROUND: Patient data management systems (PDMS) enable digital documentation on intensive care units (ICU). A commercial PDMS was implemented in a 25-bed ICU replacing paper-based patient charting. The ICU electronic patient record is completely managed inside the PDMS. It compiles data from vital signs monitors, ventilators and further medical devices and facilitates some drug dose and fluid balance calculations as well as data reuse for administrative purposes. Ventilation time and patient severity scoring as well as coding of diagnoses and procedures is supported. Billing data transferred via interface to the central billing system of the hospital. Such benefits should show in measurable parameters, such as documented ventilator time, number of coded diagnoses and procedures and others. These parameters influence reimbursement in the German DRG system. Therefore, measurable changes in cost and reimbursement data of the ICU were expected. MATERIAL AND METHODS: A retrospective analysis of documentation quality parameters, cost data and mortality rate of a 25-bed surgical ICU within a German university hospital 3 years before (2004-2006) and 5 years after (2007-2011) PDMS implementation. Selected parameters were documented electronically, consistently and reproducibly for the complete time span of 8 years including those years where no electronic patient recording was available. The following parameters were included: number of cleared DRG, cleared ventilator time, case mix (CM), case mix index (CMI), length of stay, number of coded diagnoses and procedures, detailed overview of a specific procedure code based on daily Apache II and TISS Core 10 scores, mortality, total ICU costs and revenues and partial profits for specific ICU procedures, such as renal replacement therapy and blood products. RESULTS: Systematic shifts were detected over the study period, such as increasing case numbers and decreasing length of stay as well as annual fluctuations in severity of disease seen in the CM and CMI. After PDMS introduction, the total number of coded diagnoses increased but the proportion of DRG relevant diagnoses dropped significantly. The number of procedures increased (not significantly) and the number of procedures per case did not rise significantly. The procedure 8-980 showed a significant increase after PDMS introduction whereas the DRG-relevant proportion of those procedures dropped insignificantly. The number of ventilator-associated DRG cases as well as the total ventilator time increased but not significantly. Costs and revenues increased slightly but profit varied considerably from year to year in the 5 years after system implementation. A small increase was observed per case, per nursing day and per case mix point. Additional revenues for specific ICU procedures increased in the years before and dropped after PDMS implementation. There was an insignificant increase in ICU mortality rate from 7.4 % in the year 2006 (before) to 8.5 % in 2007 (after PDMS implementation). In the following years mortality dropped below the base level. CONCLUSION: The implementation of the PDMS showed only small effects on documentation of reimbursement-relevant parameters which were too small to set off against the total investment. The method itself, a long-term follow-up of different parameters proved successful and can be adapted by other organizations. The quality of results depends on the availability of long-term parameters in good quality. No significant influence of PDMS on mortality was found.

The impact of intra-operative sufentanil dosing on post-operative pain, hyperalgesia and morphine consumption after cardiac surgery.

BACKGROUND: There is an ongoing debate whether opioids when used for intra-operative analgesia may enhance post-operative pain. We studied the effect of two different intra-operative dosings of sufentanil on post-operative morphine consumption, pain and hyperalgesia after cardiac anaesthesia. METHODS: Forty-two male patients (age: 48-74 years) undergoing first-time coronary artery bypass graft surgery were randomized to one of two groups receiving total intravenous anaesthesia with propofol and a target controlled infusion of sufentanil with a target of 0.4 ng/mL (group SL, n = 20) or 0.8 ng/mL (group SH, n = 22) plasma concentration. Post-operative morphine requirement in the first 48 h was assessed using patient-controlled analgesia (PCA). Pain rating during deep inspiration, and the extent of primary and secondary hyperalgesia near the sternotomy wound were assessed. RESULTS: The post-operative morphine requirements in the first 48 h were 0.68 ± 0.21 mg/kg in group SL and 0.96 ± 0.44 mg/kg in group SH (p < 0.05). In group SL, pain during deep inspiration was significantly lower on the first post-operative day (p < 0.05). Primary hyperalgesia had its maximum on the second and third post-operative day, without a difference between the two groups. The extent of secondary mechanical pinprick hyperalgesia was not different between the groups. DISCUSSION: Intra-operative dosing of sufentanil significantly influenced post-operative morphine consumption, pain and hyperalgesia. For cardiac anaesthesia in combination with propofol, a sufentanil target concentration of 0.4 ng/mL may be preferable.

Changes in total and unbound concentrations of sufentanil during target controlled infusion for cardiac surgery with cardiopulmonary bypass.

BACKGROUND: Target controlled infusion (TCI) with sufentanil is usually performed using the Gepts model, which was derived from patients undergoing general surgery. It is, however, known that pharmacokinetics of sufentanil can be changed during cardiopulmonary bypass (CPB). We tested whether TCI during coronary artery bypass surgery with CPB produces constant total, unbound sufentanil concentration-time course or both. METHODS: After IRB approval, written informed consent was obtained from 38 male patients (48-74 yr) undergoing coronary artery bypass surgery. Anaesthesia was managed with propofol and TCI of sufentanil, using the Gepts model, targeting plasma concentrations of 0.4 (n=18) or 0.8 ng ml(-1) (n=20). Arterial blood samples were taken before, during, and after CPB. Total and unbound sufentanil concentrations were measured by HPLC with tandem mass spectrometry. The accuracy of the TCI model was assessed by the prediction error, and a pharmacokinetic model was determined by population analysis. RESULTS: The median prediction error of the TCI with the Gepts model before, during, and after CPB was 59.6, 3.9, and -10.4%, respectively. The unbound sufentanil concentrations increased significantly during CPB. Pharmacokinetic modelling showed an increase in elimination and intercompartmental clearance after initiation of CPB. CONCLUSIONS: Neither total nor unbound sufentanil concentrations remained constant when performing a TCI with the Gepts model in coronary artery bypass surgery with CPB. A pharmacokinetic model derived from patients undergoing cardiac surgery with CPB might improve the performance of TCI in this population.

[Undergraduate teaching of anaesthesiology : a nationwide survey in Germany]. / Universitäre Lehre der Anästhesiologie : Bestandsaufnahme in Deutschland.

BACKGROUND: In 2003 anaesthesiology was implemented as a compulsory speciality of undergraduate teaching in Germany due to the revised regulations of medical education. Besides the preexisting subject of emergency medicine an obligatory course in anaesthesiology was introduced. Thus anaesthesiology has gained considerable importance in all medical faculties. To gain insight into the current status of undergraduate medical education in the university departments of anaesthesiology a nationwide survey at all university departments in Germany was initiated. METHODS: In cooperation with the German Society of Anaesthesiology and Intensive Care Medicine (DGAI) a standardized questionnaire was developed and sent to 36 departments of anaesthesiology of all German medical faculties. Questions concerned the structure of the respective curriculum, learning goals, teaching, assessment and evaluation methods as well as facultative courses. RESULTS: Of the 36 university departments of anaesthesiology, 35 returned the questionnaire. In 66% undergraduate education in anaesthesiology is part of the fourth or fifth year of medical training. In 91% of the faculties lectures were accompanied by teaching in small student groups. A simulator-based training is integrated either in anaesthesiology and/or in emergency medicine in 91% of the departments of anaesthesiology. In 69% of the departments contents of anaesthesia, critical care medicine, emergency medicine and pain management are an integral part of undergraduate teaching in anaesthesiology. The primary learning goals are directed towards general anaesthesia and there is less focus on topics of preoperative or postoperative care, such as preoperative risk evaluation, postoperative pain management and regional anaesthesia. Besides a multiple choice test (91%) oral (63%) and/or practical examinations (71%) are used as assessment tools. In 71% of the medical faculties the respective departments of anaesthesiology are leading and organising skills laboratories. In student evaluations anaesthesiology achieved best ranking in 66% of the medical faculties compared to other specialties. The possibility to take an elective course in anaesthesiology exists in 74% of the faculties. Half of these faculties organize this elective as a longitudinal course for one complete semester, the other half as a full time course over mostly 1 or 2 weeks. At present E-learning plays a minor role. CONCLUSIONS: This survey provides detailed information about the current status of undergraduate teaching of the university departments of anaesthesiology in Germany. The study shows a remarkable consistency of structure, contents and methods of education in anaesthesiology throughout all university departments of anaesthesiology. This information is the basis for triggering synergistic effects, for improving educational standards in anaesthesiology and for introducing a platform for developing modern learning media, e.g. through the scientific society DGAI.

Population pharmacokinetics of dexmedetomidine during long-term sedation in intensive care patients.

BACKGROUND: Dexmedetomidine is a highly selective and potent α(2)-adrenoceptor agonist registered for sedation of patients in intensive care units. There is little information on factors possibly affecting its pharmacokinetics during long drug infusions in critically ill patients. We characterized the pharmacokinetics of dexmedetomidine in critically ill patients during long-term sedation using a population pharmacokinetic approach. METHODS: Twenty-one intensive care patients requiring sedation and mechanical ventilation received dexmedetomidine with a loading dose of 3-6 µg kg(-1) h(-1) in 10 min and a maintenance dose of 0.1-2.5 µg kg(-1) h(-1) for a median duration of 96 h (range, 20-571 h). Cardiac output (CO), laboratory and respiratory parameters, and dexmedetomidine concentrations in arterial plasma were measured. The pharmacokinetics was determined by population analysis using linear multicompartment models. RESULTS: The pharmacokinetics of dexmedetomidine was best described by a two-compartment model. The population values (95% confidence interval) for elimination clearance, inter-compartmental clearance, central volume of distribution, and volume of distribution at steady state were 57.0 (42.1, 65.6), 183 (157, 212) litre h(-1), 12.3 (7.6, 17.0), and 132 (96, 189) litre. Dexmedetomidine clearance decreased with decreasing CO and with increasing age, whereas its volume of distribution at steady state was increased in patients with low plasma albumin concentration. CONCLUSIONS: The population pharmacokinetics of dexmedetomidine was generally in line with results from previous studies. In elderly patients and in patients with hypoalbuminaemia, the elimination half-life and the context-sensitive half-time of dexmedetomidine were prolonged.

Equipment for pre-hospital airway management on Helicopter Emergency Medical System helicopters in central Europe.

BACKGROUND: For advanced out-of-hospital airway management, skilled personnel and adequate equipment are key prerequisites. There are little data on the current availability of airway management equipment and standards of medical staff on Helicopter Emergency Medical System (HEMS) helicopters in central Europe. METHODS: An internet search identified all HEMS helicopters in Austria, Switzerland and Luxembourg. We identified 15 HEMS helicopter bases in Switzerland, 28 in Austria and three in Luxembourg. A questionnaire was sent to all bases, asking both for the details of the clinical background and experience of participating staff, and details of airway management equipment carried routinely on board. RESULTS: Replies were received from 14 helicopter bases in Switzerland (93%), 25 bases in Austria (89%) and all three bases in Luxembourg. Anaesthesiologists were by far the most frequent attending physicians (68-85%). All except one bases reported to have at least one alternative supraglottic airway device. All bases had capnometry and succinylcholine. All bases in the study except two in Austria had commercial pre-packed sets for a surgical airway. All helicopters were equipped with automatic ventilators, although not all were suitable for non-invasive ventilation (NIV; Switzerland: 43%, Austria: 12%, Luxembourg: 100%). Masks for NIV were rarely available in Switzerland (two bases; 14%) and in Austria (three bases; 12%), whereas all three bases in Luxembourg carried those masks. CONCLUSION: Most HEMS helicopters carry appropriate equipment to meet the demands of modern advanced airway management in the pre-hospital setting. Further work is needed to ensure that appropriate airway equipment is carried on all HEMS helicopters.

Precision and accuracy of a new device (CNAPTM) for continuous non-invasive arterial pressure monitoring: assessment during general anaesthesia.

BACKGROUND: Continuous non-invasive arterial pressure measured with CNAP (CNAP) has been shown to be superior to intermittent oscillometric measurements during procedural sedation and spinal anaesthesia. We assessed the performance of CNAP during general anaesthesia by analysis of agreement with invasive measurements of arterial pressure (AP). METHODS: Eighty-eight patients undergoing elective abdominal surgery, cardio-, or neurosurgery were included in the study. Systolic, diastolic, and mean AP measured by an intra-arterial catheter in the radial artery (IAP) were compared with those obtained by CNAP from the same arm. Data were analysed to determine the precision (i.e. measurement error) and accuracy (i.e. systematic error) of beat-to-beat CNAP values with respect to IAP. Also, we compared the frequency of fast changes in AP (FCAP) and hypotension (IOH) by both methods. RESULTS: CNAP precision of 4.5, 3.1, and 3.2 mm Hg (systolic, diastolic, and mean AP, respectively) was not significantly different from IAP precision, and CNAP accuracy was +6.7, -5.6, and -1.6 mm Hg. The frequency of AP pairs having a difference within the calculated limits of agreement was 81%, 64%, and 76% for systolic, diastolic, and mean AP, respectively. The calculated limits of agreement were +/-17.6, +/-11.4, and +/-12.0 mm, Hg, respectively. CNAP and IAP detected simultaneously to 82.1% FCAP and to 84.6% IOH. CONCLUSIONS: CNAP provides real-time estimates of arterial pressure comparable with those generated by an invasive intra-arterial catheter system during general anaesthesia.

Interaction of physostigmine and alfentanil in a human pain model.

BACKGROUND: Preclinical and clinical studies suggest an important role for cholinesterase inhibitors in pain therapy. The aim of this study was to examine the analgesic and antihyperalgesic properties of the cholinesterase inhibitor physostigmine and the opioid alfentanil, alone and in combination, in an experimental pain model in humans. METHODS: Twenty healthy volunteers were enrolled in this double-blind and placebo-controlled cross-over study. Transcutaneous electrical stimulation at high current densities induced spontaneous acute pain and stable areas of hyperalgesia for painful mechanical stimuli (pinprick-hyperalgesia). Pain intensities, measured on a numeric rating scale (NRS) from 0 to 10, and the extent of the hyperalgesic areas were assessed before, during, and 145 min after i.v. infusions of physostigmine (30 microg kg(-1) in 15 min), alfentanil (20 microg kg(-1) in 2 min), the combination of the same doses of both drugs, or saline 0.9%. The type of interaction was determined by fitting an interaction model to the data. RESULTS: Starting from a baseline value of NRS=6, the maximum reduction of pain intensity was 50.4 (sd 22.3) % after alfentanil, 35.4 (20.0) % after physostigmine, and 60.4 (17.1) % after the combination. The hyperalgesic areas were reduced by 53.8 (33.2) %, 47.0 (26.3) %, and 54.8 (33.2) %, respectively. The data were best described by a model assuming an infra-additive interaction for analgesic and antihyperalgesic effects. CONCLUSIONS: Physostigmine and alfentanil showed distinct effects on pain and hyperalgesia in a human pain model. The interaction of both drugs was found to be infra-additive.

[Airway management in the German air rescue service]. / Atemwegsmanagement im deutschen Luftrettungsdienst.

BACKGROUND: The equipment carried in rescue helicopters concerning airway management is not standardized in Germany. The current DIN/EN equipment regulations are not detailed for every single item resulting in differences between the various rescue bases. The aim of this survey was to show existing differences in airway management equipment. METHODS: All 72 German air rescue helicopters listed in the ADAC air rescue stations atlas 2006/2007 received a questionnaire. RESULTS: A total of 64 bases returned the questionnaire (88.9%). The most frequent types of supraglottic airway equipment were laryngeal masks (67.2%), Combitubes (32.8%) and laryngeal tubes (29.7%). Cricothyrotomy sets were more frequent (68.8%) than tracheostomy sets (35.9%). Of the bases 18.8% had masks suitable for non-invasive ventilation (NIV). All helicopters were equipped to carry out capnometry. CONCLUSIONS: The rescue helicopters were found to have differences with respect to the equipment carried for airway management. Medical treatment according to current guidelines is possible on almost all bases.

Prehospital airway management on rescue helicopters in the United Kingdom.

Adequate equipment is one prerequisite for advanced, out of hospital, airway management. There are no data on current availability of airway equipment on UK rescue helicopters. An internet search revealed all UK rescue helicopters, and a questionnaire was sent to the bases asking for available airway management items. We identified 27 helicopter bases and 26 (96%) sent the questionnaire back. Twenty-four bases (92%) had at least one supraglottic airway device; 16 (62%) helicopters had material for establishing a surgical airway (e.g. a cricothyroidotomy set); 88% of the helicopters had CO(2) detection; 25 (96%) helicopters carried automatic ventilators; among these, four (15%) had sophisticated ventilators and seven (27%) helicopters carried special face masks suitable for non-invasive ventilation. We found a wide variation in the advanced airway management equipment that was carried routinely on air ambulances. Current guidelines for airway management are not met by all UK air ambulances.

Pharmacodynamic modelling of the bispectral index response to propofol-based anaesthesia during general surgery in children.

BACKGROUND: This study describes a pharmacodynamic model during general anaesthesia in children relating the bispectral index (BIS) response to the anaesthetic dosing of propofol, fentanyl, and remifentanil. METHODS: BIS, heart rate, mean arterial pressure, sedation scores, and anaesthetic protocols from 59 children aged 1-16 yr undergoing general surgery were considered for the study. Anaesthesia was performed with propofol, fentanyl, and remifentanil. A sigmoid model assuming additive interaction of propofol, fentanyl, and remifentanil was fitted to individual BIS as effect variable. The pharmacodynamic parameters were estimated by non-linear regression analysis. The ability of BIS to predict anaesthetic drug effect was quantified by the prediction probability Pk. RESULTS: BIS started at a baseline of 90 (9), decreased during induction to 30 (14) and remained at 57 (10) during anaesthesia. BIS predicted the anaesthetic drug effect with a Pk of 0.79 (0.08). The EC(50 Propofol) and the k(e0 Propofol) were 5.2 (2.7) microg ml(-1) and 0.60 (0.45) min(-1), respectively. The k(e0 Propofol) decreased from approximately 0.91 min(-1) at 1 yr to 0.15 min(-1) at 16 yr. The EC(50 Remifentanil), k(e0 Remifentanil), EC(50 Fentanyl), and the k(e0 Fentanyl) were 24.1 (13.0) ng ml(-1), 0.71 (0.32) min(-1), 8.6 (7.4) ng ml(-1), and 0.28 (0.46) min(-1), respectively. CONCLUSIONS: The effect equilibration half-time of propofol in children was age dependent. The pharmacodynamics of fentanyl and remifentanil in children were similar to those reported in adults. The BIS showed a close relationship to the modelled effect-site concentration, and therefore, it may serve as a measure of anaesthetic drug effect in children older than 1 yr.

Pharmacokinetics and pharmacodynamics of GPI 15715 or fospropofol (Aquavan injection) - a water-soluble propofol prodrug.

Propofol (2,6-diisopropylphenol) is inadequably soluble in water and is therefore formulated as a lipid emulsion. This may have disadvantages when propofol is used to provide total intravenous anaesthesia or especially during long-term sedation. There has been considerable interest in the development of new propofol formulations or propofol prodrugs. GPI 15715 or fospropofol (Aquavan injection; Guilford Pharmaceutical, Baltimore, MD) is the first water-soluble prodrug that has been thoroughly studied in human volunteers and patients. GPI 15751 or fospropofol is cleaved by alkaline phosphatase to phosphate, formaldehyde and propofol. Formaldehyde is rapidly metabolised to formate. Although a formate accumulation is the principal pathomechanism responsible for the toxicity of methanol ingestion, so far there has been no report of toxicity due to the administration of fospropofol or other phosphate ester prodrugs, such as fosphenytoin. Fosphenytoin has been successfully introduced into the market for the treatment of status epilepticus in 1996. The main side-effects were a feeling of paraesthesia after rapid i.v. administration of GPI 15715 or fospropofol, which has also been described for fosphenytoin. The pharmacokinetics of GPI 15715 or fospropofol could be described by a combined pharmacokinetic model with a submodel of two compartments for GPI 15715 and of three compartments for propofol(G). The liberated propofol(G) compared to lipid-formulated propofol showed unexpected pharmacokinetic and pharmacodynamic differences. We found a significantly greater V(c), V(dss), significantly shorter alpha- and beta-half-life and a longer MRT (mean residence time) for propofol(G). The pharmacodynamic potency of propofol(G) appears to be higher than propofol when measured by EEG and clinical signs of hypnosis. In summary, GPI 15715 or fospropofol was well suited to provide anaesthesia or conscious sedation.

Target controlled anaesthetic drug dosing.

It belongs to the particularities of anaesthesia that the conscious response of the patient to drug therapy is not available for the adjustment of drug therapy and that the side-effects of anaesthetic drug therapy would be in general lethal if no special measures were taken such as artificial ventilation. Both conditions do not allow for a slow, time-consuming titration of drug effect towards the therapeutically effective window, but measures have to be taken to reach a therapeutic target fast (within seconds to a few minutes), reliably, and with precision. Integrated pharmacokinetic-pharmacodynamic models have proved to be a useful mathematical framework to institute such drug delivery to patients. The theory of model-based interactive drug dosing on the basis of common pharmacokinetic-pharmacodynamic (pk-pd) models is outlined and the target-controlled infusion system (TCI) is presented as a new anaesthetic dosing technique that has developed during the last decade. Whereas TCI presents an open-loop dosing strategy (the past output does not influence the future input), current research deals with the model-based adaptive closed-loop administration of anaesthetics. In these systems the past output is used to adapt and individualize the initial pk-pd model to the patients and thus has an influence on future drug dosing which is based on the adapted model.