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Axel R. Heller

Klinik und Poliklinik für Anaesthesiologie und Intensivtherapie
Universitätsklinikum Carl Gustav Carus
an der Technischen Universität Dresden
Fetscherstraße 74, D-01307 Dresden
Dear Visitor

Thank you for your interest in my profile. At present I am responsible for around 100 anesthetists in our department providing services in 32 operation rooms, additional 13 interventional and emergency workstations and two Intensive Care Units. Further, one helicopter and one ground Emergency Medical Service is staffed by our department. I am engaged in several experimental and clinical research projects as well as in the teaching of our students and the staff development with a focus on family friendly corporate governance. Within this framework I understand my assignment as the senior executive physician of the department to employ co-operative strategy oriented process optimization in patient care and staff leadership. For that purpose we apply modern tools for quality and team management such as the SixSigma Method.
Again, thank you for your interest
Best regards

Axel Heller MD, PhD, MBA, DEAA

Employment history
* University Hospital Dresden/ Germany (1998-)
- Professor (2007-)
- Vice Chair (2003-)
- Senior Lecturer (2002-)
- Senior Scientist (2002-2006)
- Assistant Professor (2002-2007)
- Fellow (2001-)
- Researcher (1998-)
- Lecturer (1998-)
- Resident (1998-2001)
* University Hospital Mannheim/ Germany (1995-1998)
- Adjunct instructor (1996-1998)
- Resident (1995-1998)
- Researcher (1995-1998)
* Justus Liebig University Giessen/Gemany (1992-1994)
- Visiting scientist (1992-1994)

* ATLS- Provider 2010
* Health care management 2009-01-15 - Dresden International University
* Pain medicine 2008-11-21 - Saxonian Board of Physicians
* Critical care medicine - 2005-04-21 - Saxonian Board of Physicians
* Anesthesiology 2001-07-04 - Saxonian Board of Physicians
* Emergency Medicine 1996-11-20 - Board of Physicians Northern Badenia

Scientific titles and degrees
* MD: 1998-02-15 - Title of dissertation: "Effects of Omega 3 Fatty acids on Pulmonary Vascular Reactions" Mentor: Heinz Neuhof
* PhD: 2002-06-27 - Title of thesis: "Immunomodulation in systemic inflammation and acute lung injury" Mentor: Thea Koch
* DEAA: 2002-11 Diploma of the European Academy of Anesthesiology and Intensive Care
* MBA: 2008-12-05 - Title of thesis: "Strategy oriented Workflow Management as Critical Success Factor for Hospitals" Mentor: Michael Albrecht

Journal articles

M Carl, A Alms, J Braun, A Dongas, J Erb, A Goetz, M Goepfert, W Gogarten, J Grosse, A R Heller, M Heringlake, M Kastrup, A Kroener, S A Loer, G Marggraf, A Markewitz, D Reuter, D V Schmitt, U Schirmer, C Wiesenack, B Zwissler, C Spies (2010)  S3 guidelines for intensive care in cardiac surgery patients: hemodynamic monitoring and cardiocirculary system.   Ger Med Sci 8: 06  
Abstract: Hemodynamic monitoring and adequate volume-therapy, as well as the treatment with positive inotropic drugs and vasopressors are the basic principles of the postoperative intensive care treatment of patient after cardiothoracic surgery. The goal of these S3 guidelines is to evaluate the recommendations in regard to evidence based medicine and to define therapy goals for monitoring and therapy. In context with the clinical situation the evaluation of the different hemodynamic parameters allows the development of a therapeutic concept and the definition of goal criteria to evaluate the effect of treatment. Up to now there are only guidelines for subareas of postoperative treatment of cardiothoracic surgical patients, like the use of a pulmonary artery catheter or the transesophageal echocardiography. The German Society for Thoracic and Cardiovascular Surgery (Deutsche Gesellschaft für Thorax-, Herz- und Gefässchirurgie, DGTHG) and the German Society for Anaesthesiology and Intensive Care Medicine (Deutsche Gesellschaft für Anästhesiologie und lntensivmedizin, DGAI) made an approach to ensure and improve the quality of the postoperative intensive care medicine after cardiothoracic surgery by the development of S3 consensus-based treatment guidelines. Goal of this guideline is to assess the available monitoring methods with regard to indication, procedures, predication, limits, contraindications and risks for use. The differentiated therapy of volume-replacement, positive inotropic support and vasoactive drugs, the therapy with vasodilatators, inodilatators and calcium sensitizers and the use of intra-aortic balloon pumps will also be addressed. The guideline has been developed following the recommendations for the development of guidelines by the Association of the Scientific Medical Societies in Germany (AWMF). The presented key messages of the guidelines were approved after two consensus meetings under the moderation of the Association of the Scientific Medical Societies in Germany (AWMF).
Martina Wendel, Axel R Heller (2010)  Mitochondrial function and dysfunction in sepsis.   Wien Med Wochenschr 160: 5-6. 118-123 Mar  
Abstract: Mitochondria are the key source of cellular ATP and their structure and function are markedly affected by pathophysiologic processes associated with the host's response to invading pathogens. In particular, the highly reactive compound peroxynitrite, generated by the reaction of nitric oxide and superoxide anions, inhibits mitochondrial enzymes and damages lipids, proteins, and nucleic acids. Enhanced oxidative stress induces DNA strand breaks that are repaired by activation of poly(ADP-ribose)polymerase (PARP). This process consumes large amounts of nicotinamide adenine dinucleotide (NAD(+)) leading to cellular NAD(+) depletion that impairs flux of reducing equivalents into the respiratory chain and also further promotes inflammation. In experimental studies, novel therapeutic strategies that aim to ameliorate the host's pathogen response or to modulate intracellular signaling events related to oxidative stress protected mitochondrial function and preserved cellular respiration ultimately leading to improved organ function.
Jörg U Bleyl, Axel R Heller, Antonia Fehrenbach, Manuel Heintz, Heinz Fehrenbach, Gesa Klenz, Marcelo Gama de Abreu, Matthias Hübler, Peter M Spieth, Thea Koch (2010)  Pretreatment with perfluorohexane vapor attenuates fMLP-induced lung injury in isolated perfused rabbit lungs.   Exp Lung Res 36: 6. 342-351 Aug  
Abstract: The authors investigated the protective effects and dose dependency of perfluorohexane (PFH) vapor on leukocyte-mediated lung injury in isolated, perfused, and ventilated rabbit lungs. Lungs received either 18 vol.% (n = 7), 9 vol.% (n = 7), or 4.5 vol.% (n = 7) PFH. Fifteen minutes after beginning of PFH application, lung injury was induced with formyl-Met-Leu-Phe (fMLP). Control lungs (n = 7) received fMLP only. In addition 5 lungs (PFH-sham) remained uninjured receiving 18 vol.% PFH only. Pulmonary artery pressure (mPAP), peak inspiratory pressure (P(max)), and lung weight were monitored for 90 minutes. Perfusate samples were taken at regular intervals for analysis and representative lungs were fixed for histological analysis. In the control, fMLP application led to a significant increase of mPAP, P(max), lung weight, and lipid mediators. Pretreatment with PFH attenuated the rise in these parameters. This was accompanied by preservation of the structural integrity of the alveolar architecture and air-blood barrier. In uninjured lungs, mPAP, P(max), lung weight, and lipid mediator formation remained uneffected in the presence of PFH. The authors concluded that pretreatment with PFH vapor leads to an attenuation of leukocyte-mediated lung injury. Vaporization of perfluorocarbons (PFCs) offers new therapeutic options, making use of their protective and anti-inflammatory properties in prophylaxis or in early treatment of acute lung injury.
K E Clemens, I Quednau, A R Heller, E Klaschik (2010)  Impact of cafedrine/theodrenaline (Akrinor) on therapy of maternal hypotension during spinal anesthesia for Cesarean delivery: a retrospective study.   Minerva Ginecol 62: 6. 515-524 Dec  
Abstract: AIM: Maternal hypotension is the most frequent complication in spinal anesthesia for Cesarean delivery. Malperfusion of the foetus and nausea and vomiting of the mother are hallmarks of maternal hypotension. In this retrospective data analysis and anesthesia protocols we have investigated to explore the effects of therapeutic interventions for hypotension with cafedrine/theodrenaline (Akrinor®) during spinal anesthesia for elective Cesarean section. METHODS: In a retrospective study anesthesia charts of 173 parturients undergoing spinal anesthesia for Cesarean delivery with 10mg hyperbaric bupivacaine + 5 µg sufentanil were reviewed for 30 min after onset of hypotension with respect to blood pressure, heart rate, respiration rate, as well as APGAR scores and umbilical arterial pH. Maternal data were compared to baseline values recorded and documented immediately before placing the spinal anesthesia in the operating room. The cohort was divided into two groups according to their hemodynamic response to spinal anesthesia: 117 parturients had a drop of systolic blood pressure to <120 mmHg or <80% of baseline blood pressure and were therefore treated with Akrinor® (cafedrine/theodrenaline; treatment group); 56 patients remained within the specified limits (non-treatment group). Maternal cardiovascular parameters and newborn outcome between the groups were compared. RESULTS: Both groups were comparable with regard to baseline characteristics. In the treatment group one minute after the first application of cafedrine (43 mg)/theodrenaline (2.2 mg) mean systolic blood pressure raised from 108.6 mmHg to 117.2 mmHg (P=0.0004), mean of maximal changes of systolic blood pressure after the first application of Akrinor® was 21.3 mmHg. Blood pressure levels of the non-treatment group were regained in the treatment group 8 min after hypotension onset and remained at that level until the end of 30 min observation. No clinically relevant changes of heart rate were detectable. While mean APGAR score one minute post partum was significantly higher in the treatment group (8.9±1.2 vs. 8.4±1.1 P=0.043), mean umbilical arterial cord pH was 7.3±0.1 and APGAR scores 5 and 10 minutes postpartum did not differ significantly. CONCLUSION: The results of this study confirm a rapid and sustained increase in blood pressure after application of Akrinor® for treatment of sympathicolysis induced hypotension. No negative impact of Akrinor® on umbilical arterial cord pH and APGAR scores was observed.
Periklis Panousis, Axel R Heller, Thea Koch, Rainer J Litz (2009)  Epidural ropivacaine concentrations for intraoperative analgesia during major upper abdominal surgery: a prospective, randomized, double-blinded, placebo-controlled study.   Anesth Analg 108: 6. 1971-1976 Jun  
Abstract: BACKGROUND: The postoperative beneficial effects of thoracic epidural analgesia (TEA) within various clinical pathways are well documented. However, intraoperative data are lacking on the effect of different epidurally administered concentrations of local anesthetics on inhaled anesthetic, fluid and vasopressor requirement, and hemodynamic changes. We performed this study among patients undergoing major upper abdominal surgery under combined TEA and general anesthesia. METHODS: Forty-five patients undergoing major upper abdominal surgery were randomly assigned to one of three treatment groups receiving intraoperative TEA with either 10 mL of 0.5% (Group 1) or 0.2% (Group 2) ropivacaine (both with 0.5 microg/mL sufentanil supplement), or 10 mL saline (Group 3) every 60 min. Anesthesia was maintained with desflurane in nitrous oxide (60%) initiated at an age-adapted 1 minimum alveolar concentration (MAC) until incision. Desflurane administration was then titrated to maintain an anesthetic level between 50 and 55, as assessed by continuous Bispectral Index monitoring and the common clinical signs (PRST score). Lack of intraoperative analgesia, as defined by an increase in pulse rate, sweating, and tearing (PRST) score >2 or an increase of mean arterial blood pressure (MAP) >20% of baseline, was treated by readjusting the end-tidal concentration of desflurane toward 1 MAC, and above this level by additional rescue i.v. remifentanil infusion. Hypotension, as defined as a decrease in MAP >20% of baseline, was treated by reducing the end-tidal desflurane concentration to a Bispectral Index level of 50-55 and below that with crystalloid or norepinephrine infusion, depending on central venous pressure. RESULTS: End-tidal desflurane concentration could be significantly reduced in Group 1 to 0.7 +/- 0.1 MAC (P < 0.001) and to 0.8 +/- 0.1 MAC (P < 0.001) in Group 2, but not in Group 3. Significant hypotension occurred within 20 min in all patients of Groups 1 and 2 (MAP from 80 +/- 10 to 56 +/- 5) (Group 1), 78 +/- 18 to 58 +/- 7 mm Hg (Group 2), P < 0.01, whereas MAP remained unchanged in Group 3 (74 +/- 12 to 83 +/- 15 mm Hg, P = 0.42). Heart rate did not change significantly over time within any of the groups. Furthermore, groups did not differ significantly regarding i.v. fluid and norepinephrine requirement. Patients in Group 3 received more remifentanil throughout the surgical procedure (7.2 +/- 4.9 mg x kg(-1) x h(-1)) when compared with Group 2 (1.6 +/- 2.2 mg x kg(-1) x h(-1)), P < 0.01. Remifentanil infusion among patients receiving ropivacaine 0.5% was not necessary at any time. CONCLUSION: Epidural administration of 0.5% ropivacaine leads to a more pronounced sparing effect on desflurane concentration for an adequate anesthetic depth when compared with a 0.2% concentration of ropivacaine at comparable levels of vasopressor support and i.v. fluid requirement.
A R Heller, S C Heller (2009)  The family-friendly hospital: (how) does it work?   Anaesthesist 58: 6. 571-581 Jun  
Abstract: The demographic development in Germany is heading towards a significant shortage in specialists within the next 10-15 years with an increased demand for health services at the same time. The three-stage model of family life planning (work, family phase, return) will also be gradually replaced by a model of simultaneous compatibility of family and work. This change in values, although initiated by the parents themselves, may turn out to be a crucial countermeasure in national economy against the demography-related loss of qualified personnel. For these three trends the economic need arises to minimize family-related absence of our well-trained, motivated and reliable doctors from the clinical departments through implementation of family-friendly human resources policies and supporting measures by the employers. In a representative survey 26% of respondents with children had in the past already changed their workplace to ensure a better match of work and family duties. In this regard the compatibility of family and professional responsibilities had a higher impact on the selection of the employer than a high income. Accordingly, a work-life competence oriented business plan will represent the crucial factor within the competition between universities, hospitals and professional disciplines to attract high potential bearers although a sustained change of the traditional hospital culture is mandatory. Anaesthesia-related fields of development regarding family-friendly corporate governance are working hours and organization of work, part-time jobs even for managers and fathers, and staff development. In the hospital daily routine, in particular, creative solutions meeting the local demands are deemed necessary that do not involve the use of high financial resources. Family-friendly personnel policy not only arises from altruistic enthusiasm but also pays off economically. This article discusses the necessity, opportunities and threads of family-oriented hospital management and fields of action for anaesthesia departments.
A R Heller, K R Bauer, M Eberlein-Gonska, D M Albrecht, T Koch (2009)  Regional anaesthesia as advantage in competition between hospitals. Strategic market analysis   Anaesthesist 58: 5. 459-468 May  
Abstract: BACKGROUND: The German Social Act V section sign 12 is aimed towards competition, efficiency and quality in healthcare. Because surgical departments are billing standard diagnosis-related group (DRG) case costs to health insurance companies, they claim best value for money for internal services. Thus, anaesthesia concepts are being closely scrutinized. The present analysis was performed to gain economic arguments for the strategic positioning of regional anaesthesia procedures into clinical pathways. METHODS: Surgical procedures, which in 2005 had a relevant caseload in Germany, were chosen in which regional anaesthesia procedures (alone or in combination with general anaesthesia) could routinely be used. The structure of costs and earnings for hospital services, split by types and centres of cost, as well as by underlying procedures are contained in the annually updated public accessible dataset (DRG browser) of the German Hospital Reimbursement Institute (InEK). For the year 2005 besides own data, national anaesthesia staffing costs are available from the German Society of Anaesthesiology (DGAI). The curve of earnings per DRG can be calculated from the 2005 InEK browser. This curve intersects by the cost curve at the point of national mean length of stay. The cost curve was calculated by process-oriented distribution of cost centres over the length of stay and allows benchmarking within the national competitive environment. For comparison of process times data from our local database were used. While the InEK browser lacks process times, the cost positions 5.1-5.3 (staffing costs anaesthesia) and the national structure adjusted anaesthesia staffing costs 2005 as published by the DGAI, were used to calculate nationwide mean available anaesthesia times which were compared with own process times. RESULTS: Within the portfolio diagram of lengths of stay for each DRG and process times most procedures are located in the economic lower left, in particular those with high case mix (length of stay and anaesthesia times below reimbursement relevant national mean). The driver of increased earnings is shortening length of stay. Our use of regional anaesthesia is 5 to 10-fold higher than national benchmarks and may contribute to our advantageous position in national competition. The annual increases in profit per DRG range between EUR 1,706 and EUR 467,359 and compensate by far the investment of regional anaesthesia derived pain management, besides the advantage of increased patient satisfaction and avoidance of complications. CONCLUSION: Regional anaesthesia is a considerable value driver in clinical pathways by shortening length of stay. The present analysis further demonstrates that time for regional block performance is covered by anaesthesia reimbursement within the DRG costing schedule.
Martina Wendel, Axel R Heller (2009)  Anticancer actions of omega-3 fatty acids--current state and future perspectives.   Anticancer Agents Med Chem 9: 4. 457-470 May  
Abstract: Omega-3 fatty acids (omega3-FA) were shown to attenuate growth and induce apoptosis in a variety of human cancer cell lines derived from colonic, pancreatic, prostate, and breast cancer. In addition, recent findings indicate that omega3-FA act synergistically with chemotherapeutic agents and may also be used to enhance tumour radiosensitivity. The mechanisms underlying the anti-tumour effects of omega3-FA are complex. Incorporation of omega3-FA in biological membranes alters the profile of lipid mediators generated during inflammatory reactions. Furthermore, omega3-FA act as ligands of nuclear peroxisome proliferator-activated receptors that attenuate transcription of NF-kappaB-dependent genes. Thereby, the cyclooxygenase-2/prostaglandin E(2)-dependent production of pro-angiogenic vascular endothelial growth factor and levels of anti-apoptotic bcl-2 and bcl-X(L) are decreased. Eicosanoid-independent pro-apoptotic pathways include enhanced lipid peroxidation, modulation of mitochondrial calcium homeostasis and enhanced production of reactive oxygen species as well as activation of p53. This review article will give a comprehensive overview over the pleiotropic actions of omega3-FA and will discuss the potential of omega3-FA and derivatives like conjugated eicosapentaenoic acid as important nutritional adjuvant therapeutics in the management of various human cancer diseases and the impact of nutritional omega-3 FA on cancer prevention.
Axel R Heller, Alexander Fuchs, Thomas Rössel, Oliver Vicent, Diana Wiessner, Richard H W Funk, Thea Koch, Rainer J Litz (2009)  Precision of traditional approaches for lumbar plexus block: impact and management of interindividual anatomic variability.   Anesthesiology 111: 3. 525-532 Sep  
Abstract: BACKGROUND: Traditional methods for approaching the lumbar plexus from the posterior rely on finding the intersection of lines that are drawn based on surface landmarks. These methods may be inaccurate in many cases. The aim of this study was to determine the accuracy of these traditional approaches and determine if modifications could increase their accuracy. METHODS: The lumbar plexus region of 48 cadavers (78 +/- 7 yr; 167 +/- 6 cm; 60 +/- 13 kg; men/women: 29/19) was dissected, and relevant anatomic structures were marked. Needle proximity curves were obtained by triangulation for the five traditional approaches and for vectors from the posterior superior iliac spine directed towards the lumbar spinous processes of L3 and towards L4. RESULTS: Proximity curves (mean +/- SD) showed that except Pandin's approach (13 +/- 5 mm too medial), all others were too lateral: Winnie (17 +/- 8 mm), Chayen (8 +/- 5 mm), Capdevila (6 +/- 4 mm), and Dekrey (17 +/- 6 mm). Further, the curves had a narrow parabolic shape and thus a narrow margin of error. Both diagonal vectors had a significantly higher proximity to the lumbar plexus as compared with traditional approaches with a wide parabola, indicating more error tolerance. Using the vector posterior superior iliac spine-L3 with a length between 1/6-1/3 (= 16-22 mm) of the distance posterior superior iliac spine-L3, a proximity to the lumbar plexus < 5.0 +/- 0.3 mm was reached. CONCLUSION: Improvement of both the proximity and the margin of error is possible by using diagonal landmark vectors. Relying on the position of the posterior superior iliac spine eliminates the sex and sided differences and individual body size, which can be problematic if firm metric distances are used in determining the entry point.
M Wendel, A R Heller, T Koch (2009)  Pathomechanisms of organ failure. Mitochondrial dysfunction in sepsis   Anaesthesist 58: 4. 343-352 Apr  
Abstract: Proinflammatory mediators as well as increased formation of reactive oxygen and nitrogen species impair cellular respiration during sepsis. In particular, the highly reactive peroxynitrite irreversibly damages lipids, proteins and nucleic acids and also inhibits enzyme complexes of the respiratory chain. In this way cellular metabolic functions and subsequently organ functions are also impaired. Repair of DNA by poly(ADP-ribose)polymerase consumes large amounts of nicotinamide adenine dinucleotide (NAD+) which leads to cellular NAD+ depletion further promoting inflammation. This article summarizes central aspects of the pathophysiology of mitochondrial dysfunction during sepsis and gives an overview about newly developed strategies which proved effective in experimental studies and may have a potential clinical application in the future.
M Adolph, A R Heller, T Koch, B Koletzko, K G Kreymann, K Krohn, E Pscheidl, M Senkal (2009)  Lipid emulsions - Guidelines on Parenteral Nutrition, Chapter 6.   Ger Med Sci 7: 11  
Abstract: The infusion of lipid emulsions allows a high energy supply, facilitates the prevention of high glucose infusion rates and is indispensable for the supply with essential fatty acids. The administration of lipid emulsions is recommended within < or =7 days after starting PN (parenteral nutrition) to avoid deficiency of essential fatty acids. Low-fat PN with a high glucose intake increases the risk of hyperglycaemia. In parenterally fed patients with a tendency to hyperglycaemia, an increase in the lipid-glucose ratio should be considered. In critically ill patients the glucose infusion should not exceed 50% of energy intake. The use of lipid emulsions with a low phospholipid/triglyceride ratio is recommended and should be provided with the usual PN to prevent depletion of essential fatty acids, lower the risk of hyperglycaemia, and prevent hepatic steatosis. Biologically active vitamin E (alpha-tocopherol) should continuously be administered along with lipid emulsions to reduce lipid peroxidation. Parenteral lipids should provide about 25-40% of the parenteral non-protein energy supply. In certain situations (i.e. critically ill, respiratory insufficiency) a lipid intake of up to 50 or 60% of non-protein energy may be reasonable. The recommended daily dose for parenteral lipids in adults is 0.7-1.3 g triglycerides/kg body weight. Serum triglyceride concentrations should be monitored regularly with dosage reduction at levels >400 mg/dl (>4.6 mmol/l) and interruption of lipid infusion at levels >1000 mg/dl (>11.4 mmol/l). There is little evidence at this time that the choice of different available lipid emulsions affects clinical endpoints.
Thomas Volk, Lars Engelhardt, Claudia Spies, Thorsten Steinfeldt, Bernd Kutter, Axel Heller, Christian Werner, Florian Heid, Hartmut Bürkle, Thea Koch, Oliver Vicent, Peter Geiger, Paul Kessler, Hinnerk Wulf (2009)  A German network for regional anaesthesia of the scientific working group regional anaesthesia within DGAI and BDA   Anasthesiol Intensivmed Notfallmed Schmerzther 44: 11-12. 778-780 Nov  
Abstract: Regional anaesthesia generally is considered to be safe. However, reports of complications with different severities are also well known. The scientific working group of regional anaesthesia of the DGAI has founded a network in conjunction with the BDA. With the aid of a registry, we are now able to describe risk profiles and associations in case of a complication. Moreover, a benchmark has been implemented in order to continuously improve complication rates.
Alysson R Carvalho, Peter M Spieth, Paolo Pelosi, Alessandro Beda, Agnaldo J Lopes, Boriana Neykova, Axel R Heller, Thea Koch, Marcelo Gama de Abreu (2009)  Pressure support ventilation and biphasic positive airway pressure improve oxygenation by redistribution of pulmonary blood flow.   Anesth Analg 109: 3. 856-865 Sep  
Abstract: BACKGROUND: Spontaneous breathing (SB) activity may improve gas exchange during mechanical ventilation mainly by the recruitment of previously collapsed regions. Pressure support ventilation (PSV) and biphasic positive airway pressure (BIPAP) are frequently used modes of SB, but little is known about the mechanisms of improvement of lung function during these modes of assisted mechanical ventilation. We evaluated the mechanisms behind the improvement of gas exchange with PSV and BIPAP. METHODS: Five pigs (25-29.3 kg) were mechanically ventilated in supine position, and acute lung injury (ALI) was induced by surfactant depletion. After stabilization, BIPAP was initiated with lower continuous positive airway pressure equal to 5 cm H2O and the higher continuous positive airway pressure titrated to achieve a tidal volume between 6 and 8 mL/kg. The depth of anesthesia was reduced, and when SB represented > or = 20% of total minute ventilation, PSV and BIPAP + SB were each performed for 1 h (random sequence). Whole chest helical computed tomography was performed during end-expiratory pauses and functional variables were obtained. Pulmonary blood flow (PBF) was marked with IV administered fluorescent microspheres, and spatial cluster analysis was used to determine the effects of each ventilatory mode on the distribution of PBF. RESULTS: ALI led to impairment of lung function and increase of poorly and nonaerated areas in dependent lung regions (P < 0.05). PSV and BIPAP + SB similarly improved oxygenation and reduced venous admixture compared with controlled mechanical ventilation (P < 0.05). Despite that, a significant increase of nonaerated areas in dependent regions with a concomitant decrease of normally aerated areas was observed during SB. In five of six lung clusters, redistribution of PBF from dependent to nondependent, better aerated lung regions were observed during PSV and BIPAP + SB. CONCLUSIONS: In this model of ALI, the improvements of oxygenation and venous admixture obtained during assisted mechanical ventilation with PSV and BIPAP + SB were explained by the redistribution of PBF toward nondependent lung regions rather than recruitment of dependent zones.
T Volk, L Engelhardt, C Spies, T Steinfeldt, D Gruenewald, B Kutter, A Heller, C Werner, F Heid, H Bürkle, P Gastmeier, K - D Wernecke, T Koch, O Vicent, P Geiger, H Wulf (2009)  Incidence of infection from catheter procedures for regional anesthesia: first results from the network of DGAI and BDA   Anaesthesist 58: 11. 1107-1112 Nov  
Abstract: BACKGROUND: To analyze safety issues of regional anaesthesia and analgesia in Germany only a few single center studies are available. Therefore, the German Society for Anaesthesiology and Intensive Care Medicine (Deutschen Gesellschaft für Anästhesiologie und Intensivmedizin, DGAI) and the Professional Association of German Anaesthetists (Berufsverband Deutscher Anästhesisten, BDA) initiated a network for safety in regional anaesthesia. From this the first results on infectious complications will be reported. MATERIALS AND METHODS: In a Delphi process the documentation of the setup and maintenance of regional anaesthesia and analgesia was agreed with the participants in a working group from the DGAI. After approval by the officially authorized representative for patient data privacy protection a registry was programmed to collect anonymous data. Up to October 2008 data from 6 centers could be analyzed. RESULTS: After testing for plausibility 8,781 regional anaesthesia procedures (22,112 catheter days) could be analyzed. The 5,057 neuraxial and 3,724 peripheral catheter-based procedures were in place for a median of 2.48 days (range 1.0-3.0 days) and 4 severe, 15 moderate and 128 mild infections were recorded. Diabetics were not found to show a statistically significant increase in risk (2.6% compared to 1.9% for non-diabetics: n.s.). Neuraxial procedures seem to have a higher rate of infections than peripheral procedures (2.7% vs. 1.3%, p<0.0001). Multiple punctures of the skin also seem to be associated with a higher infection rate than single skin punctures (4.1% vs. 1.6%, p<0.0001). CONCLUSIONS: Infectious complications of catheter-based regional anaesthesia are common. Strict hygienic standards must therefore be complied with. More data are necessary to calculate risk factors. The registry provided can also be used as a benchmark to reduce these rates further.
Ralf Konopke, Stephan Kersting, Marius Distler, Jeannine Dietrich, Jörg Gastmeier, Axel Heller, Eberhard Kulisch, Hans-Detlev Saeger (2009)  Prognostic factors and evaluation of a clinical score for predicting survival after resection of colorectal liver metastases.   Liver Int 29: 1. 89-102 Jan  
Abstract: BACKGROUND: Patient outcome after resection of colorectal liver metastases can be predicted by various prognostic factors. Aims: Development of a model for risk stratification based on analysis of prognostic factors. METHODS: Data of 201 patients were collected prospectively and included in a single-centre trial. A total of 20 factors were analysed as to their influence on recurrence-free and overall survival. Independent prognostic factors were entered into a model of a clinical risk score. RESULTS: Median recurrence-free survival reached 24 months for all patients; median overall survival was 50 months. Only a synchronous manifestation of primary colorectal carcinoma and liver metastases, the presence of four or more metastases and a carcino-embryonic antigen level of 200 ng/ml or more significantly influenced recurrence-free and overall survival in the multivariate analysis. The derived risk stratification grouped the patients according to the following criteria: low risk, zero prognostic factors (n=112); intermediate risk, one factor (n=74); high risk, two or more factors (n=15). The median recurrence-free survival for low, intermediate and high risk were 30.0, 23.0 and 11.0 months, respectively; the median overall survival was 94.0, 40.0 and 33.0 months. Compared with the low-risk group, patients with intermediate risk demonstrated an increased hazard ratio (HR) of 1.57-fold for recurrence (P=0.018) and 1.91-fold for mortality (P=0.007). For the high-risk group, the HR rose significantly to 3.26 for recurrence (P<0.0005) and to 3.10 for mortality (P=0.001). CONCLUSIONS: The presented clinical score may allow for patients with colorectal liver metastases to be stratified appropriately and for optimization of their subsequent therapeutic management.
Jörg U Bleyl, Axel R Heller (2008)  Standard operating procedures and operating room management: Improvement of patient safety and the efficiency of processes   Wien Med Wochenschr 158: 21-22. 595-602  
Abstract: Financial pressures have led the way more efficiency in health care management. To decrease hospital costs a more proficient use of personal resources is required. The drive to increase efficiency with the concomitant increase in workload can cause a reduction in quality of patient care and of patient security. A professional operating room (OR) management and the introduction of standard operating procedures (SOP) have helped to optimise workflow in and around the OR. OR management can control an efficient workflow and generate data concerning performance, costs and quality. SOPs lead to a standardisation of workflow in the OR and in patient treatment modalities. This guaranties a high quality in patient care and more safety despite an increase in work-load.
Sebastian N Stehr, Lilla Knels, Christian Weissflog, Johannes Schober, Dirk Haufe, Amelie Lupp, Thea Koch, Axel R Heller (2008)  Effects of IGM-enriched solution on polymorphonuclear neutrophil function, bacterial clearance, and lung histology in endotoxemia.   Shock 29: 2. 167-172 Feb  
Abstract: Immunological interventions in endotoxemia and sepsis have been tested in experimental and clinical studies. Our group evaluated the effects of an immunoglobulin (Ig)M-enriched solution in an established model of Gram-negative bacteraemia. Ten New Zealand White rabbits (2-3 kg) were randomized to a treatment or control group. In both groups, LPS was infused at a rate of 40 mg kg(-1) h(-1). Immunoglobulin M-enriched solution (Pentaglobin; 2 mL kg(-1) h(-1)) was applied in the intervention group 15 min after beginning LPS infusion. 1 x 10(8) colony forming units of Escherichia coli were injected 30 min after LPS infusion was commenced. Baseline hemodynamic and respiratory parameters, blood E. coli concentration (30 min before and 1, 15, 30, 60, 90, 120, and 180 min after E. coli injection), polymorphonuclear neutrophil oxidative burst activity, and phagocytosis dead space (both 30 min before and 1, 15, 60, 120, and 180 min postinjection) were measured. Ex vivo phagocytosis activity was measured in a separate experiment and evaluated by electron microscopy. Diffuse alveolar damage (DAD) was measured. Organ colonization (kidney, lung, liver, spleen) was assessed in aseptic organ samples. Hemodynamic parameters did not differ between the two groups. Bacterial blood clearance was not influenced by application of IgM-enriched solution. Liver and spleen colonization was significantly reduced in the IgM group. Immunoglobulin M-enriched solution reduced in vitro residual phagocytosis capacity at 30, 90, and 180 min and improved respiratory burst at 180 min. Correspondingly, ex vivo phagocytosis activity as documented by electron microscopy was increased in the IgM group. The sum of all weighted DAD scores (except overdistension) was significantly better in the IgM group (23+/-5 vs. 30+/-8). Immunoglobulin M-enriched solution significantly improved six of seven DAD score parameters and reduced liver and spleen E. coli count. Residual phagocytosis capacity was significantly decreased in the IgM group, whereas burst activity was increased, pointing to an increased in vivo phagocytosis efficiency. Short-term IgM-enriched solution intervention had an especially beneficial effect on LPS-induced pulmonary histological changes.
Rainer J Litz, Thomas Roessel, Axel R Heller, Sebastian N Stehr (2008)  Reversal of central nervous system and cardiac toxicity after local anesthetic intoxication by lipid emulsion injection.   Anesth Analg 106: 5. 1575-7, table of contents May  
Abstract: A 91-yr-old man (57 kg, 156 cm, ASA III) received an infraclavicular brachial plexus block for surgery of bursitis of the olecranon. Twenty minutes after infraclavicular injection of 30 mL of mepivacaine 1% (Scandicain) and 5 min after supplementation of 10 mL of prilocaine 1% (Xylonest) using an axillary approach, the patient complained of agitation and dizziness and became unresponsive to verbal commands. In addition, supraventricular extrasystole with bigeminy occurred. Local anesthetic toxicity was suspected and a dose of 200 mL of a 20% lipid emulsion was infused. Symptoms of central nervous system and cardiac toxicity disappeared within 5 and 15 min after the first lipid injection, respectively. Plasma concentrations of local anesthetics were determined before, 20, and 40 min after lipid infusion and were 4.08, 2.30, and 1.73 microg/mL for mepivacaine and 0.92, 0.35, and 0.24 microg/mL for prilocaine. These concentrations are below previously reported thresholds of toxicity above 5 microg/mL for both local anesthetics. Signs of toxicity resolved and the patient underwent the scheduled surgical procedure uneventfully under brachial plexus blockade.
Axel R Heller (2008)  Pharmaconutrition with omega-3 fatty acids: status quo and further perspectives.   Mini Rev Med Chem 8: 2. 107-115 Feb  
Abstract: Beneficial rapid onset effects of omega-3 fatty acids from fish oil on host defense compensatory fit into the comprehensive pathophysiology of critical illness. Because of balanced pro- and anti-inflammatory effects on a variety of host defense subsystems even septic patients had earlier recovery and improved survival. This review focuses in a compressed view on the beneficial aspects of omega-3 fatty acid supplementation on diverse organ functions, host defense and on balanced pro - and anti-inflammatory effects. Clinical impact of fish oil based pharmaconutrition during critical inflammation processes and immune response in humans is thoroughly discussed.
T Rössel, R J Litz, A R Heller, T Koch (2008)  Anesthesia for carotid artery surgery. Is there a gold standard?   Anaesthesist 57: 2. 115-130 Feb  
Abstract: Carotid endarterectomy (CEA) has remained the first choice of treatment in preventing ischemic stroke due to symptomatic stenosis of the internal carotid artery despite other new available options. During CEA patients are first and foremost at risk of cerebral as well as myocardial ischemia, therefore, maintenance of the oxygen supply to the brain and the myocardium is of outstanding importance requiring reliable monitoring of cerebral and cardiac function. The regional versus general anesthesia debate is an age-old one that has brought few definite answers regarding the impact on postoperative outcome of either anesthetic technique. Up to now, there is little evidence from only a few randomized clinical trials to demonstrate the superiority of either anesthetic technique with respect to outcome parameters. Because the level of evidence in favor of regional anesthesia during CEA can at least be rated between 1(-) and 2(+) the resulting recommendation is grade C. The purpose of the review is to highlight the characteristics and goals of anesthetic management during CEA.
A R Heller, J Rothermel, M A Weigand, K Plaschke, J Schmeck, M Wendel, H J Bardenheuer, T Koch (2007)  Adenosine A1 and A2 receptor agonists reduce endotoxin-induced cellular energy depletion and oedema formation in the lung.   Eur J Anaesthesiol 24: 3. 258-266 Mar  
Abstract: BACKGROUND AND OBJECTIVE: Tissue depletion of adenosine during endotoxaemia has previously been described in the lung. Therapeutic approaches to prevent adenosine depletion and the role of A1 and A2 receptor agonists, however, have not been investigated until now. METHODS: In isolated and ventilated rabbit lungs, it was tested whether pretreatment with adenosine A1 agonist 2-chloro-N6-cyclopentyladenosine (CCPA; 10(-7) mol, n = 6) or A2 receptor agonist 5'-(N-cyclopropyl)-carboxyamido adenosine (CPCA; 10(-7) mol, n = 6) prior to injection of lipopolysaccharide (LPS) (500 pg mL-1) influenced pulmonary artery pressure (PAP), pulmonary energy content and oedema formation as compared with controls, solely infused with LPS (n = 6). Release rates of adenosine and uric acid were determined by high-performance liquid chromatography. Pulmonary tissue concentrations of high-energy phosphates were measured and the adenine nucleotide pool, adenosine 5'-triphosphate (ATP)/adenosine 5'-diphosphate (ADP) ratio and adenylate energy charge of the pulmonary tissue were calculated. RESULTS: Administration of LPS induced increases in PAP within 2 h up to 20.8 +/- 2.9 mmHg (P < 0.01). While pretreatment with the A1 agonist merely decelerated pressure increase (13.8 +/- 1.1 mmHg, P < 0.05), the A2 agonist completely suppressed the pulmonary pressure reaction (9.6 +/- 1.0 mmHg, P < 0.01). Emergence of lung oedema after exclusive injection of LPS up to 12.0 +/- 2.9 g was absent after A1 (0.6 +/- 0.5 g) and A2 (-0.3 +/- 0.2 g) agonists. These observations were paralleled by increased adenosine release rates compared with LPS controls (P < 0.05). Moreover, tissue concentrations of ADP, ATP, guanosine 5'-diphosphate, guanosine 5'-triphosphate, nicotinamide-adenine-dinucleotide and creatine phosphate were significantly reduced after LPS. Consequently, the calculated tissue adenine nucleotide pool and the adenylate energy charge increased after adenosine receptor stimulation (P = 0.001). CONCLUSIONS: Adenosine A1- and A2-receptor agonists reduced LPS-induced vasoconstriction and oedema formation by maintenance of tissue energy content. Thus, adenosine receptor stimulation, in particular of the A2 receptor, might be beneficial during acute lung injury.
Martina Wendel, Rüdiger Paul, Axel R Heller (2007)  Lipoproteins in inflammation and sepsis. II. Clinical aspects.   Intensive Care Med 33: 1. 25-35 Jan  
Abstract: BACKGROUND: Systemic inflammation and sepsis are accompanied by severe metabolic alterations, including insulin resistance together with increased levels of triglycerides (TGs) and decreases in high- and low-density lipoproteins. Clinical studies have clearly established a link between lipid metabolism and systemic inflammation. Lipoproteins were shown to neutralize LPS and to exert direct anti-inflammatory actions. High- and low-density lipoproteins are thus thought to be important regulators of the host immune response during endotoxemia, which may also have the potential of improving the care of patients with Gram-negative sepsis. DISCUSSION: Nutritional lipids supplied during critical illness have been shown to modulate the host response to inflammation. In particular, inclusion of omega-3 fatty acids seems to have beneficial effects on cellular immunity and helps to maintain the balance between pro- and anti-inflammatory cytokines thereby preventing hyperinflammatory complications. In addition to improvements in the profile of lipid mediators generated, omega-3 fatty acids act as activating ligands of peroxisome proliferator-activated receptors and directly inhibit nuclear factor kappaB mediated proinflammatory signaling. We present an overview on the alterations in the metabolism of serum lipoproteins during sepsis and present data from clinical studies and discuss the significance of nutritional lipids and their role in immunomodulation with special emphasis on omega-3 fatty acids.
Thomas Roessel, Diana Wiessner, Axel R Heller, Thomas Zimmermann, Thea Koch, Rainer J Litz (2007)  High-resolution ultrasound-guided high interscalene plexus block for carotid endarterectomy.   Reg Anesth Pain Med 32: 3. 247-253 May/Jun  
Abstract: BACKGROUND AND OBJECTIVES: High-resolution ultrasound imaging (HRUI) allows real-time visualization of peripheral nerves, needle insertion, and the spread of local-anesthetic (LA) solution. We evaluated the feasibility of performing a high interscalene brachial-plexus block for carotid endarterectomy by means of HRUI, thereby limiting the amount of LA to the dose required to sufficiently surround the relevant nerve structures. METHODS: The interscalene brachial plexus was localized in the interscalene groove at its most cephalad point in 14 patients undergoing carotid endarterectomy by use of an ultrasound device with a 17.5 MHz transducer. Up to 20 mL of ropivacaine 0.5% was injected. RESULTS: In all patients, HRUI allowed clear delineation of the upper part of the interscalene brachial plexus at the level of the 4th cervical vertebra appearing as 1 hypoechoic, roundish, hypodense node located in a distance of 1.5 +/- 0.3 cm to the skin, 1.5 +/- 0.2 cm lateral to the common carotid artery, and 0.6 +/- 0.2 cm from the transverse process of the spine. Likewise HRUI allowed a clear delineation of minor blood vessels and adjacent anatomic structures, as well as accurate placement of the needle close to the nerves. Real-time observation of LA spread during injection was possible, even in increments of less than 1 mL. CONCLUSIONS: High-resolution ultrasonic imaging allows clear depiction of the target tissues and facilitates accurate needle placement during high interscalene brachial-plexus blocks. This technique may minimize the risk of direct puncture-related complications, as well as accidental intravascular injection of LA. The observation of LA spread in all patients, even in small increments of less than 1 mL might enhance safety by limiting the injected LA to the actual demand. Well-placed LA spread could potentially avoid central nervous toxicity caused by intravascular injection or resorption of inadequately high dosages, in particular in nerve blocks of the highly vascularized neck region.
P Panousis, A R Heller, M Burghardt, J U Bleyl, T Koch (2007)  The effects of electromyographic activity on the accuracy of the Narcotrend monitor compared with the Bispectral Index during combined anaesthesia.   Anaesthesia 62: 9. 868-874 Sep  
Abstract: The Narcotrend is a monitor system for the assessment of depth of anaesthesia. The objective of this trial was to investigate the susceptibility of the Narcotrend to electromyographic (EMG) activity when compared with the Bispectral Index (BIS). We enrolled 33 patients undergoing major urological procedures under combined anaesthesia (thoracic epidural analgesia and general anaesthesia). Anaesthetic depth was assessed simultaneously by the BIS XP and Narcotrend. The intended anaesthetic depth ranged between 40 and 55 in the BIS and between D2 and D0 in the Narcotrend. BIS, but not Narcotrend, values correlated significantly (p < 0.0001) with EMG. BIS values between 70 and 80 occurred intermittently above an EMG activity of 35 dB, whereas the Narcotrend and the clinical signs remained unchanged during the period of elevated BIS values. None of the patients reported intra-operative awareness. Increased electromyographic activity does not affect Narcotrend values. Under combined anaesthesia, the Narcotrend monitor is more reliable when compared with the BIS regarding susceptibility to increased EMG activity.
M Carl, A Alms, J Braun, A Dongas, J Erb, A Goetz, M Göpfert, W Gogarten, J Grosse, A Heller, M Heringlake, M Kastrup, A Kröner, S Loer, G Marggraf, A Markewitz, M Reuter, D V Schmitt, U Schirmer, C Wiesenack, B Zwissler, C Spies (2007)  Guidelines for intensive care in cardiac surgery patients: haemodynamic monitoring and cardio-circulatory treatment guidelines of the German Society for Thoracic and Cardiovascular Surgery and the German Society of Anaesthesiology and Intensive Care Medicine   Thorac Cardiovasc Surg 55: 2. 130-148 Mar  
Abstract: Hemodynamic monitoring and adequate volume-therapy, as well as the treatment with positive inotropic drugs and vasopressors, are the basic principles of the postoperative intensive care treatment of patient after cardiothoracic surgery. The goal of these S3 guidelines is to evaluate the recommendations in regard to evidence based medicine and to define therapy goals for monitoring and therapy. In context with the clinical situation the evaluation of the different hemodynamic parameters allows the development of a therapeutic concept and the definition of goal criteria to evaluate the effect of treatment. Up to now there are only guidelines for subareas of postoperative treatment of cardiothoracic surgical patients, like the use of a pulmonary artery catheter or the transesophageal echocardiography. The German Society for Thoracic and Cardiovascular Surgery and the German Society for Anaesthesiology and Intensive Care Medicine made an approach to ensure and improve the quality of the postoperative intensive care medicine after cardiothoracic surgery by the development of S3 consensus-based treatment guidelines. Goal of this guideline is to assess available monitoring methods and their risks as well as the differentiated therapy of volume-replacement, positive inotropic support and vasoactive drugs, the therapy with vasodilators, inodilators and calcium-sensitizers and the use of intra-aortic balloon pumps. The guideline has been developed according to the recommendations for the development of guidelines by the Association of the Scientific Medical Societies in Germany (AWMF). The presented key messages of the guidelines were approved after two consensus meetings under the moderation of the Association of the Scientific Medical Societies in Germany (AWMF).
M Hübler, A R Heller, J U Bleyl, T Rössel, S N Stehr, T Koch (2007)  Spatial pulmonary flow distribution in rabbit isolated lungs is a poor representation of the situation in vivo.   Clin Exp Pharmacol Physiol 34: 4. 269-273 Apr  
Abstract: 1. Isolated lung preparations are established to investigate effects on pulmonary vascular tone and spatial pulmonary flow (Q (rel)) distribution. In the present study, we hypothesized that Q (rel) distribution in isolated lungs is only poorly correlated with the in vivo situation. 2. Fourteen rabbits were anaesthetized and mechanically ventilated with room air. Animals were held in an upright position for 15 min and Q (rel) was assessed using fluorescent microspheres (Q (rel-in vivo)). A second injection of microspheres was made after isolation of the lungs (Q (rel-ex vivo)). Lungs were dried, cut into 1 cm(3) cubes and spatial Q (rel) distributions were analysed. 3. The mean correlation of Q (rel-in vivo) and Q (rel-ex vivo) was 0.592 +/- 0.188 (95% confidence interval 0.493-0.690). The Q (rel) was redistributed to more ventral (the mean slope of Q (rel) vs the dorsal-ventral axis changed from -0.289 +/- 0.227 to -0.147 +/- 0.114; P = 0.03), cranial (mean slope of Q (rel) vs the caudal-cranial axis changed from -0.386 +/- 0.193 to -0.176 +/- 0.142; P < 0.001) and central (mean slope of Q (rel) vs the hilus-peripheral axis changed from 0.436 +/- 0.133 to -0.236 +/- 0.159; P = 0.003) lung areas. 4. The results obtained from studies investigating Q (rel) distributions in isolated lung models must be interpreted cautiously because the isolated lung set-up significantly affects the spatial distribution of pulmonary flow.
S N Stehr, A Pexa, S Hannack, A Heintz, A R Heller, A Deussen, T Koch, M Hübler (2007)  Insulin effects on myocardial function and bioenergetics in L-bupivacaine toxicity in the isolated rat heart.   Eur J Anaesthesiol 24: 4. 340-346 Apr  
Abstract: BACKGROUND AND OBJECTIVES: A positive effect of insulin-glucose-potassium infusion in severe bupivacaine-induced cardiovascular collapse has been described in vivo. It has been speculated that an antagonistic influence of insulin on sodium channel inhibition, transient outward potassium current, calcium-dependent adenosine triphosphatase or even improved myocardial energetics may be responsible for this effect. Using an isolated heart model, we therefore sought to further elucidate insulin effects in l-bupivacaine-induced myocardial depression. METHODS: An isolated rat heart constant-pressure perfused, non-recirculating Langendorff preparation was used. Hearts were exposed to l-bupivacaine 5 microg mL(-1) and insulin 10 mIU mL(-1). Heart rate, systolic pressure, the first derivative of left ventricular pressure (+dP/dt), coronary flow, double product, PR and QRS intervals were recorded. Hearts were freeze-clamped and high-performance liquid chromatography measurement of the total adenine nucleotide pool was performed. RESULTS: l-Bupivacaine led to a significant decrease in heart rate, +dP/dt, systolic pressure, coronary flow and double product, and to an increase in PR and QRS. Insulin exerted a positive inotropic effect, significantly augmenting +dP/dt and systolic pressure in both l-bupivacaine-treated and control hearts. Heart rate, coronary flow, total adenine nucleotides, PR and QRS were not significantly changed by the insulin intervention. CONCLUSION: Insulin did not have a significant effect on total adenine nucleotides in controls and in l-bupivacaine-treated hearts. However, it does exert a positive inotropic action in bupivacaine-induced myocardial depression. We conclude that the positive effect of insulin application lies in positive inotropic action and not in changes in total adenine nucleotides.
Sebastian N Stehr, Axel R Heller (2006)  Omega-3 fatty acid effects on biochemical indices following cancer surgery.   Clin Chim Acta 373: 1-2. 1-8 Nov  
Abstract: Epidemiological studies have indicated that a high intake of saturated fat and/or animal fat increases the risk of colon and breast cancer. Laboratory and clinical investigations have shown a reduced risk of colon carcinogenesis after alimentation with omega-3 fatty acids, as found in fish oil. Mechanisms accounting for these anti-tumor effects are reduced levels of PGE(2) and inducible NO synthase as well as an increased lipid peroxidation, or translation inhibition with subsequent cell cycle arrest. Further, omega-3 eicosapentaenoic acid is capable of down-regulating the production and effect of a number of mediators of cachexia, such as IL-1, IL-6, TNF-alpha and proteolysis-inducing factor. In patients with advanced cancer, it is possible to increase energy and protein intake via an enteral or parenteral route, but this seems to have little impact on progressive weight loss. Fish oil administration improved patients' conditions in cancer cachexia and during radio- and chemotherapy. In patients undergoing tumor resection surgery we observed improvement of liver and pancreas biochemical indices when omega-3 fatty acids were administered. This paper is a review of recent developments in the field of nutrition in cancer patients with emphasis on the acute phase response following cancer surgery and the beneficial aspects of fish oil administration.
Axel R Heller, Susann Rössler, Rainer J Litz, Sebastian N Stehr, Susanne C Heller, Rainer Koch, Thea Koch (2006)  Omega-3 fatty acids improve the diagnosis-related clinical outcome.   Crit Care Med 34: 4. 972-979 Apr  
Abstract: OBJECTIVE: Supplementation of clinical nutrition with omega-3 fatty acid in fish oil exerts immune-modulating and organ-protective effects, even after short-term application. The aim of this study was to evaluate dose-dependent effects of parenteral supplementation of a 10% fish oil emulsion (Omegaven, Fresenius-Kabi, Bad Homburg, Germany) on diagnosis- and organ failure-related outcome. DESIGN: Prospective, open label, multiple-center trial. PATIENTS AND METHODS: A total of 661 patients from 82 German hospitals receiving total parenteral nutrition for > or =3 days were enrolled in this study. The sample included 255 patients after major abdominal surgery, 276 with peritonitis and abdominal sepsis, 16 with nonabdominal sepsis, 59 after multiple trauma, 18 with severe head injury, and 37 with other diagnoses. The primary study end point was survival; secondary end points were length of hospital stay and use of antibiotics with respect to the primary diagnosis and the extent of organ failure. Multiple quasi-linear and logistic regression models were used for calculating diagnosis-related fish oil doses associated with best outcome. RESULTS: The patients enrolled in this survey were (mean +/- sd) 62.8 +/- 16.5 yrs old, with a body mass index of 25.1 +/- 4.2 and Simplified Acute Physiology Score (SAPS) II score of 32.2 +/- 13.6. Length of hospital stay was 29.1 +/- 18.7 days (12.5 +/- 14.8 days in the intensive care unit). Total parenteral nutrition, including fish oil (mean, 0.11, was administered for 8.7 +/- 7.5 days and lowered hospital mortality as predicted by Simplified Acute Physiology Score II from 18.9% (95% confidence interval, 17.4-20.4%) to 12.0% (p < .001). The fish oil did correlate with beneficial outcome (intensive care unit stay, hospital stay, mortality). Fish oil had the most favorable effects on survival, infection rates, and length of stay when administered in doses between 0.1 and 0.2 Lower antibiotic demand by 26% was observed when doses of 0.15-0.2 were infused as compared with doses of <0.05 After peritonitis and abdominal sepsis, multiple quasi-linear regression models revealed a fish oil dose for minimizing intensive care unit stay of 0.23 and an inverse linear relationship between dosage and intensive care unit stay in major abdominal surgery. CONCLUSION: Administration of omega-3 fatty acid may reduce mortality, antibiotic use, and length of hospital stay in different diseases. Effects and effect sizes related to fish oil doses are diagnosis dependent. In view of the lack of substantial study literature concerning diagnosis-related nutritional single-substrate intervention in the critically ill, the present data can be used in formulating hypotheses and may serve as reference doses for randomized, controlled studies, which may, for instance, confirm the value of omega-3 fatty acid in the adjunctive therapy of peritonitis and abdominal sepsis.
Axel R Heller, Katrin Zimmermann, Kristin Seele, Thomas Rössel, Thea Koch, Rainer J Litz (2006)  Modifying the baricity of local anesthetics for spinal anesthesia by temperature adjustment: model calculations.   Anesthesiology 105: 2. 346-353 Aug  
Abstract: BACKGROUND: Although local anesthetics (LAs) are hyperbaric at room temperature, density drops within minutes after administration into the subarachnoid space. LAs become hypobaric and therefore may cranially ascend during spinal anesthesia in an uncontrolled manner. The authors hypothesized that temperature and density of LA solutions have a nonlinear relation that may be described by a polynomial equation, and that conversion of this equation may provide the temperature at which individual LAs are isobaric. METHODS: Density of cerebrospinal fluid was measured using a vibrating tube densitometer. Temperature-dependent density data were obtained from all LAs commonly used for spinal anesthesia, at least in triplicate at 5 degrees, 20 degrees, 30 degrees, and 37 degrees C. The hypothesis was tested by fitting the obtained data into polynomial mathematical models allowing calculations of substance-specific isobaric temperatures. RESULTS: Cerebrospinal fluid at 37 degrees C had a density of 1.000646 +/- 0.000086 g/ml. Three groups of local anesthetics with similar temperature (T, degrees C)-dependent density (rho) characteristics were identified: articaine and mepivacaine, rho1(T) = 1.008-5.36 E-06 T2 (heavy LAs, isobaric at body temperature); L-bupivacaine, rho2(T) = 1.007-5.46 E-06 T2 (intermediate LA, less hypobaric than saline); bupivacaine, ropivacaine, prilocaine, and lidocaine, rho3(T) = 1.0063-5.0 E-06 T (light LAs, more hypobaric than saline). Isobaric temperatures (degrees C) were as follows: 5 mg/ml bupivacaine, 35.1; 5 mg/ml L-bupivacaine, 37.0; 5 mg/ml ropivacaine, 35.1; 20 mg/ml articaine, 39.4. CONCLUSION: Sophisticated measurements and mathematic models now allow calculation of the ideal injection temperature of LAs and, thus, even better control of LA distribution within the cerebrospinal fluid. The given formulae allow the adaptation on subpopulations with varying cerebrospinal fluid density.
M Müller, B Bergmann, T Koch, A Heller (2005)  Dynamic decision making in emergency medicine. Example of paraplegia after a traffic accident   Anaesthesist 54: 8. 781-786 Aug  
Abstract: Dynamic decision making is one of the key skills in crew resource management training in aviation. In emergency medicine it is important to practice this skill as a prerequisite for effective treatment of patients. We report a case of paraplegia after a road traffic accident and cervical spine injury. During the prehospital treatment the patient's state was re-evaluated at different times. Although the patient was initially unconscious the physician at the scene decided not to intubate the trachea as the level of consciousness improved during resuscitation. In the emergency room a C5 fracture and a prolapsed intervertebral disc were diagnosed and immediate decompression and stabilisation of the cervical spine were performed. Dynamic decision-making has been in practise for a long time in aviation, similarities to decisions in medicine and the psychological background are described on the basis of the case report.
A R Heller, R J Litz, D Wiessner, C Dammann, R Weissgerber, O W Hakenberg, M P Wirth, T Koch (2005)  Impact of thoracic epidural analgesia on revenue for G-DRG M01B, OPS-301 5-604.0 (radical retropubic prostatectomy).   Anaesthesist 54: 12. 1176-1185 Dec  
Abstract: INTRODUCTION: Using the surgical procedure OPS 5-604.0 (radical retropubic prostatectomy) as an example, our study identifies revenue-relevant patient characteristics and describes the impact of the perioperative application of thoracic epidural analgesia (TEA). METHODS: Factors affecting duration of stay were determined in 460 patients undergoing OPS 5-604.0 in the year 2001 and 2002 using multifactorial regression analysis. Preoperative parameters served as factors for matched-pair analysis of the effects of TEA. RESULTS: Characteristics significantly affecting length of postoperative hospital stay were ASA status, age, preoperative haemoglobin concentration, postoperative tachycardia, number of transfused packed red cells, wound infection and surgical revision. Based on identical matching criteria 27 pairs (with/without TEA) could be formed. While the induction time in the TEA group was 8+/-18 min longer (p=0.04), emergence was briefer by 3+/-9 min (p=0.045). Neither anaesthesia presence time nor anaesthesia costs or total costs of surgery differed significantly between the pairs. However, duration of epidural postoperative pain therapy was longer with TEA but in contrast, the postoperative length of hospital stay after TEA was reduced. Assuming a continuous demand for OPS 5-604.0 procedures, TEA enables 32 more procedures to be carried out per year with an increased yield on turnover of 2.7%. CONCLUSION: At first sight combined anaesthesia procedures require more human resources and material, however, as a result of shortened hospital stay and optimized pain therapy patient satisfaction increases and a substantial potential for increased revenue is gained.
Matthias Hübler, Axel R Heller, Jörg U Bleyl, Marcelo Gama de Abreu, Tobias Kroll, Thomas Rössel, Thea Koch (2005)  Perfluorohexane vapor has only minor effects on spatial pulmonary blood flow distribution in isolated rabbit lungs.   Anesth Analg 100: 4. 1122-1128 Apr  
Abstract: We tested the hypothesis that administration of perfluorohexane (PFH) vapor does not significantly affect the relative pulmonary blood flow (Qrel) distribution in isolated rabbit lungs. Fourteen isolated rabbit lungs were perfused with a Krebs-Henseleit buffer solution (flow 150 mL/min). Pulmonary afterload was set to 3 mm Hg. The lungs were ventilated with 4% CO(2) in room air using a small animal ventilator (respiratory rate, 30 breaths/min; tidal volume, 12 mL/kg body weight; positive end-expiratory pressure, 2 cm H(2)O). After a steady-state period, 18 vol. % of PFH vapor was administered to 9 lungs for 30 min. In a second set of experiments five lungs served as controls. Change in (Qrel) distribution was assessed using fluorescent-labeled microspheres. The unpaired Student's t-test was used to compare variables between groups. The paired Student's t-test, the one-sample Student's t-test, the Anderson-Hauck test of equivalence, and Pearson correlation were used to analyze changes within groups. The mean correlation coefficients of (Qrel) were 0.564 +/- 0.182 for the PFH group and 0.502 +/- 0.295 for the control group, respectively. No significant changes in (rel) distribution over time and between groups were found. However, in the PFH group a tendency towards redistribution of (Qrel) to more ventral lung areas was noted. Our results suggest that PFH vapor has no significant effects on redistribution of (Qrel) in isolated rabbit lungs.
A R Heller, M P Müller, M D Frank, J Dressler (2005)  Rigor mortis -- a definite sign of death?   Anasthesiol Intensivmed Notfallmed Schmerzther 40: 4. 225-229 Apr  
Abstract: In the past years an ongoing controversial debate exists in Germany, regarding quality of the coroner's inquest and declaration of death by physicians. We report the case of a 90-year old female, who was found after an unknown time following a suicide attempt with benzodiazepine. The examination of the patient showed livores (mortis?) on the left forearm and left lower leg. Moreover, rigor (mortis?) of the left arm was apparent which prevented arm flexion and extension. The hypothermic patient with insufficient respiration was intubated and mechanically ventilated. Chest compressions were not performed, because central pulses were (hardly) palpable and a sinus bradycardia 45/min (AV-block 2 degrees and sole premature ventricular complexes) was present. After placement of an intravenous line (17 G, external jugular vein) the hemodynamic situation was stabilized with intermittent boli of epinephrine and with sodium bicarbonate. With improved circulation livores and rigor disappeared. In the present case a minimal central circulation was noted, which could be stabilized, despite the presence of certain signs of death ( livores and rigor mortis). Considering the finding of an abrogated peripheral perfusion (livores), we postulate a centripetal collapse of glycogen and ATP supply in the patients left arm (rigor), which was restored after resuscitation and reperfusion. Thus, it appears that livores and rigor are not sensitive enough to exclude a vita minima, in particular in hypothermic patients with intoxications. Consequently a careful ABC-check should be performed even in the presence of apparently certain signs of death, to avoid underdiagnosing a vita minima. Additional ECG- monitoring is required to reduce the rate of false positive declarations of death. To what extent basic life support by paramedics should commence when rigor and livores are present until physician DNR order, deserves further discussion.
Sebastian N Stehr, Sören Weber, Susanne C Heller, Jutta Weikel, Matthias Hübler, Thea Koch, Axel R Heller (2004)  N(omega)-nitro-L-arginine methyl ester effects on neutrophil function and bacterial clearance.   Shock 22: 2. 180-185 Aug  
Abstract: Nitric oxide synthase (NOS) inhibitors are considered promising as a therapeutic option in severe septic shock. The aim of this study was to investigate the effects of N-nitro-L-arginine methyl ester (L-NAME) application on neutrophil (PMN) respiratory burst, phagocytosis, and elimination of Escherichia coli from blood and tissue in rabbits. Twenty-eight female chinchilla rabbits were randomized to a treatment and control group. To quantify the bacterial clearance process, 10 colony forming units (CFU) of E. coli were injected intravenously into anesthetized rabbits. Animals in the L-NAME group had a significantly higher mortality compared with controls. NOS inhibition resulted in a significant delay of bacterial clearance (P < 0.001). These findings correlated with a significant augmentation of all organ E. coli findings (P = 0.002-0.035). PMN phagocytosis activity was notably reduced by L-NAME treatment during the experimental observation. Neutrophil burst, on the other hand, was amplified by NOS inhibition (P = 0.008). Our findings point to an interference with the PMN-dependent immune mechanisms after L-NAME treatment. The augmented PMN burst reaction could be a compensatory mechanism, potentially leading to tissue damage. Therefore, in this model, we find sufficient evidence pointing to a possible cause for the deleterious effect of early nonselective NOS inhibition in critically ill patients.
Rainer J Litz, Oliver Vicent, Diana Wiessner, Axel R Heller (2004)  Misplacement of a psoas compartment catheter in the subarachnoid space.   Reg Anesth Pain Med 29: 1. 60-64 Jan/Feb  
Abstract: BACKGROUND AND OBJECTIVES: This case report describes an unusual cause of misplacement of an indwelling catheter in the subarachnoid space after primary psoas compartment block in a patient undergoing total knee arthroplasty. CASE REPORT: A 67-year-old woman presenting for total knee joint replacement received a combination of continuous psoas compartment block and sciatic nerve block. Neurostimulation and additional ultrasound guidance were used for identification of the lumbar plexus. After elicitation of a quadriceps motor response, a negative aspiration test, and an uneventful test dose, 20 mL ropivacaine 0.375% and 20 mL mepivacaine 1% were injected. Despite difficult ultrasound conditions because of intestinal air, local anesthetic spread was observed paravertebrally at the medial border of the psoas muscle as usual. A catheter was then advanced 7 cm through the insulated directional puncture needle. An additional sciatic nerve block was performed by using Labat's approach. Ten minutes after injection unilateral sensory block was noted and surgery was started. After uneventful surgery, bilateral sensory block to the T4 level and complete motor block in both lower limbs was detected. A second aspiration test was negative, and an epidural block was suspected. For verification of the catheter tip location, a computed tomography scan with contrast dye was performed revealing catheter placement in the subarachnoid space. The catheter was removed and showed a kink about 7 cm from the tip. After regression of the neuraxial block, lumbar plexus block persisted for another 2 hours. CONCLUSION: An additional test dose via the catheter is recommended if the indwelling catheter is inserted after injection of the local anesthetics through the puncture needle. If epidural anesthesia occurs, an x-ray of the catheter is advisable because negative aspiration via catheter does not rule out subarachnoid catheter location.
Axel R Heller, Thomas Rössel, Birgit Gottschlich, Oliver Tiebel, Mario Menschikowski, Rainer J Litz, Thomas Zimmermann, Thea Koch (2004)  Omega-3 fatty acids improve liver and pancreas function in postoperative cancer patients.   Int J Cancer 111: 4. 611-616 Sep  
Abstract: Epidemiologic studies have indicated that high intake of saturated fat and/or animal fat increases the risk of colon and breast cancer. Omega-3 PUFAs in fish oil (FO) can inhibit the growth of human cancer cells in vitro and in vivo. These effects are related to the uptake of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) into the cellular substrate pool and their competitive metabolism with arachidonic acid (AA) at the cyclooxygenase and 5-lipoxygenase levels. The metabolites of EPA and DHA have less inflammatory and immunosuppressant potency than the substances derived from AA. Based on previous experimental data, we hypothesized that FO supplementation after major abdominal cancer surgery would improve hepatic and pancreatic function. Ours was a prospective, randomized, double-blinded clinical trial on 44 patients undergoing elective major abdominal surgery, randomly assigned to receive total parenteral nutrition (TPN) supplemented with either soybean oil (SO 1.0 g/kg body weight daily, n = 20) for 5 days or a combination of FO and SO (FO 0.2 + SO 0.8 g/kg body weight daily, n = 24). Compared to pure SO supplementation in the postoperative period, FO significantly reduced ASAT [0.8 +/- 0.1 vs. 0.5 +/- 0.1 mmol/(l. sec)], ALAT [0.9 +/- 0.1 vs. 0.6 +/- 0.1 mmol/(l. sec)], bilirubin (16.1 +/- 5.3 vs. 6.9 +/- 0.6 mmol/l), LDH (7.7 +/- 0.4 vs. 6.7 +/- 0.4 mmol/(l. sec) and lipase (0.6 +/- 0.1 vs. 0.4 +/- 0.1 micromol/(l. sec) in the postoperative course. Moreover, patients with increased risk of sepsis (IL-6/IL-10 ratio >8) showed a tendency to shorter ICU stay (18 hr) under omega-3 PUFA treatment. Weight loss as encountered after the SO emulsion of 1.1 +/- 2.2 kg was absent in the FO group. After major abdominal tumor surgery, FO supplementation improved liver and pancreas function, which might have contributed to the faster recovery of patients.
A R Heller, R J Litz, T Koch (2004)  A fine balance--one-lung ventilation in a patient with Eisenmenger syndrome.   Br J Anaesth 92: 4. 587-590 Apr  
Abstract: A 38-yr-old woman with an atrial septum defect and Eisenmenger syndrome was scheduled for a lung biopsy via thoracoscopy during one-lung ventilation. Fluids were given to increase central venous pressure to 8 mm Hg, an epidural catheter was inserted at the sixth thoracic intervertebral space and ropivacaine 0.3%, 6 ml were given. Careful balance of systemic and pulmonary vascular resistance is crucial in Eisenmenger syndrome, so norepinephrine (0.14 mg kg(-1) min(-1)) was infused before general anaesthesia was started with fentanyl 4 mg kg(-1), ketamine 2 mg kg(-1), pancuronium 1 mg and succinylcholine 2 mg kg(-1). Anaesthesia was maintained with propofol 4-8 mg kg(-1) h(-1). To control pulmonary artery pressure, ventilation was performed with oxygen 100% and nitric oxide 20 ppm. Surgery and anaesthesia course were uneventful and the patient was extubated. However, pleural haemorrhage required treatment with blood components, re-intubation on the second postoperative day and removal of the haematoma by mini-thoracotomy. A step-by-step approach using a balanced combination of regional and general anaesthesia, controlled fluid administration, norepinephrine and inhaled nitric oxide preserved a stable circulation even during one-lung ventilation. The diagnostic value of lung biopsy must be weighed against the possibility of life-threatening haemorrhage.
Marcelo Gama de Abreu, Manuel Heintz, Axel Heller, Roswitha Széchényi, Detlev Michael Albrecht, Thea Koch (2003)  One-lung ventilation with high tidal volumes and zero positive end-expiratory pressure is injurious in the isolated rabbit lung model.   Anesth Analg 96: 1. 220-8, table of contents Jan  
Abstract: We tested the hypothesis that one-lung ventilation (OLV) with high tidal volumes (VT) and zero positive end-expiratory pressure (PEEP) may lead to ventilator-induced lung injury. In an isolated, perfused rabbit lung model, VT and PEEP were set to avoid lung collapse and overdistension in both lungs, resulting in a straight pressure-time (P-vs-t) curve during constant flow. Animals were randomized to (a) nonprotective OLV (left lung) (n = 6), with VT values as high as before randomization and zero PEEP; (b) protective OLV (left lung) (n = 6), with 50% reduction of VT and maintenance of PEEP as before randomization; and (c) control group (n = 6), with ventilation of two lungs as before randomization. The nonprotective OLV was associated with significantly smaller degrees of collapse and overdistension in the ventilated lung (P < 0.001). Peak inspiratory pressure values were higher in the nonprotective OLV group (P < 0.001) and increased progressively throughout the observation period (P < 0.01). The mean pulmonary artery pressure and lung weight gain values, as well as the concentration of thromboxane B(2), were comparatively higher in the nonprotective OLV group (P < 0.05). A ventilatory strategy with VT values as high as those used in the clinical setting and zero PEEP leads to ventilator-induced lung injury in this model of OLV, but this can be minimized with VT and PEEP values set to avoid lung overdistension and collapse. IMPLICATIONS: One-lung ventilation with high tidal volumes and zero positive end-expiratory pressure (PEEP) is injurious in the isolated rabbit lung model. A ventilatory strategy with tidal volumes and PEEP set to avoid lung overdistension and collapse minimizes lung injury during one-lung ventilation in this model.
Michael Froehner, Rainer Koch, Rainer Litz, Axel Heller, Sven Oehlschlaeger, Manfred P Wirth (2003)  Comparison of the American Society of Anesthesiologists Physical Status classification with the Charlson score as predictors of survival after radical prostatectomy.   Urology 62: 4. 698-701 Oct  
Abstract: OBJECTIVES: To compare the American Society of Anesthesiologists Physical Status (ASA) classification with the Charlson score in the radical prostatectomy setting. The ASA classification is a widely accepted way to evaluate perioperative risk. At present, the Charlson score is probably the most frequently used comorbidity measure to predict long-term survival after radical prostatectomy. METHODS: A total of 444 consecutive patients were enrolled in this study. The ASA classification was obtained from the anesthesia chart, and the Charlson score was assigned based on conditions noted during the preoperative cardiopulmonary risk assessment or mentioned on the discharge document. Kaplan-Meier time-event curves and Mantel-Haenszel hazard ratios were estimated for comorbid (noncancer) and overall survival. RESULTS: After a mean follow-up of 5.9 years, both classifications were able to predict comorbid and overall survival in dose-response patterns. The ASA classification was superior in terms of a clearer discrimination of the survival curves (lower P values, higher hazard ratios). Both classifications identified a high-risk group (ASA 3 and Charlson score 2 or more), but only the ASA classification sufficiently defined a low-risk group (ASA 1). CONCLUSIONS: In experienced hands, the ASA classification is a promising tool to improve the classification of prognostic comorbidity in the radical prostatectomy setting and may be used as an alternative to the Charlson score.
Axel R Heller, Fritz Fiedler, Philipp Braun, Sebastian N Stehr, Hans Bödeker, Thea Koch (2003)  Clusterin protects the lung from leukocyte-induced injury.   Shock 20: 2. 166-170 Aug  
Abstract: Clusterin (CLU) is a multifunctional 75- to 80-kDa glycoprotein that is upregulated during cellular stress and might represent a defense mechanism during local cellular damage. Mechanisms discussed are antiapoptotic, antioxidative, and anticomplement properties as well as chaperone-like features protecting stressed proteins. The aim of this study was to investigate potential protective effects of CLU on pulmonary vasculature after in situ PMN activation in isolated rabbit lungs. The experiments were performed on 24 isolated and ventilated rabbit lungs that were perfused with 200 mL of Krebs-Henseleit-10% blood buffer with a constant flow of 150 mL/min in a recirculating system. It was tested whether pretreatment with CLU (2.5 microg/ml; n = 8) or catalase (CAT, 5000 U/ml; n = 8) before N-formyl-Met-Leu-Phe (fMLP; 10(-8) M) injection influenced pulmonary artery pressure (PAP) peak airway pressures (PAW) and edema formation as compared with controls (n = 8). Baseline values of PAP were 9-11 mmHg and PAW 11-13 cm H2O. Application of fMLP resulted in an acute significant (P < 0.01) increase of PAP (48 +/- 29 mmHg) within 2 min in the control group and PAW increased to 35 +/- 7 cm H2O within 30 min. Pretreatment with CLU completely suppressed the PAP and PAW response as a result of the fMLP challenge (P < 0.001), whereas a transient PAW increase up to 27 +/- 15 mmHg was observed after CAT. Complement factor C3a release was suppressed by CAT, whereas CLU blocked the complement cascade at the level of C5b-9 formation. Moreover, generation of thromboxane A(2) was reduced after CLU and CAT. Lung edema occurred in the fMLP group but was absent (P < 0.001) after CLU and CAT treatment. Both CLU and CAT prevented fMLP-induced lung injury. Stabilizing effects of CLU, point towards complement regulating features at the level of the terminal complement sequence. Elevated levels of CLU during inflammation could reflect a compensatory organ protective mechanism. Further studies are required to elucidate the clinical impact of the observed organ-protective properties of CLU.
A R Heller, V K Meier, J Seifert, R J Litz (2003)  Thoracotomy and scoliosis surgery in a patient with a univentricular heart   Anaesthesist 52: 3. 218-223 Mar  
Abstract: We report the case of a 15-year-old boy with a single left ventricle who underwent total cavopulmonary connection (Fontan circulation). Due to a progredient idiopathic scoliosis he had to undergo two surgical correction procedures of the vertebral column. Fontan circulation is characterized by the functional absence of the right ventricle. Blood from the systemic circulation passively flows directly into the pulmonary artery. Therefore, central venous preload as well as pulmonary vascular resistance gain essential significance for cardiac output. After volume preload, in both procedures anaesthesia was induced with etomidate and maintained intravenously with propofol and fentanyl but without N(2)O. Increases of the systemic and pulmonary vascular resistance were avoided. A central venous pressure of 20 mmHg was clinically associated with the most stable haemodynamics. In view of the elective nature of the present surgical procedures and with regard to an individual advantage vs risk estimation, tactical algorithms of action must be predefined on the basis of the individual physiology/pathophysiology to keep reaction times for necessary interventions brief.
Axel R Heller, Susanne C Heller, Annette Borkenstein, Sebastian N Stehr, Thea Koch (2003)  Modulation of host defense by hydrocortisone in stress doses during endotoxemia.   Intensive Care Med 29: 9. 1456-1463 Sep  
Abstract: OBJECTIVE: To investigate the effects of low-dose hydrocortisone (HC) on neutrophil respiratory burst, phagocytosis, and elimination of E. coli from blood and tissue under endotoxemic and non-endotoxemic conditions. DESIGN. Randomized, controlled trial. SETTING: Experimental laboratory, university hospital. SUBJECTS: Forty-eight female chinchilla rabbits ( n=8 in six groups A-F). INTERVENTIONS: In order to quantify the bacterial clearance process, defined numbers [10(8) colony forming units (CFU)] of Escherichia coli were injected intravenously into all anesthetized rabbits. Group A did not receive further intervention. Group B received bolus administration of HC 1.4 mg/kg and group C 14 mg/kg. Endotoxin (LPS, 40 microg/kg/h) was given to groups D, E, and F. Group E received additional bolus administration of HC 1.4 mg/kg and group F 14 mg/kg. All HC groups (B, C, E, and F) were continuously infused with HC 0.18 mg/kg/h. MEASUREMENTS: Monitored parameters were neutrophil respiratory burst and phagocytosis activity, rates of bacterial elimination from the blood, arterial blood pressure, serum lactate and LPS concentrations, as well as nitrite and nitrate levels. Tissue samples of liver, kidney, spleen, and lung were collected for bacterial counts. MAIN RESULTS: In controls HC significantly delayed elimination of injected E. coli from the blood (P<0.01). LPS also prolonged bacterial elimination but additional HC did not further delay removal of E. coli from the blood. Under endotoxemia HC depressed respiratory burst, whereas phagocytosis functions remained unaltered. Moreover, bacterial colonization of organs was reduced after HC in the LPS groups. Significance, however, was reached only in the liver (P<0.05). Due to HC, clearance from LPS (P<0.01) and lactate (P<0.05) were improved. Levels of nitrite and nitrate did not differ among the groups. CONCLUSION: HC demonstrated immunomodulatory effects even in stress doses. In endotoxemic states use of low-dose HC seems to be favorable, although not in non-septic conditions.
Axel R Heller, Hermann J Theilen, Thea Koch (2003)  Fish or chips?   News Physiol Sci 18: 50-54 Apr  
Abstract: Cell membranes are not simply barriers separating intracellular from extracellular space. Rather, they represent a dynamic high-turnover system that adapts to current demands. During inflammation, prostaglandins and leukotrienes are formed from membrane-derived phospholipids. Encouraging improvements in critically ill patients were observed after nutritional replacement of long-chain omega-6 fatty acids with long-chain omega-3-fatty acids, contained in fish oil.
A R Heller, S Fischer, T Rössel, S Geiger, G Siegert, M Ragaller, T Zimmermann, T Koch (2002)  Impact of n-3 fatty acid supplemented parenteral nutrition on haemostasis patterns after major abdominal surgery.   Br J Nutr 87 Suppl 1: S95-101 Jan  
Abstract: In various diseases n-3 fatty acids exert anti-inflammatory properties. These effects seem to be related to the uptake and incorporation of eicosapentaenoic acid (EPA) into the cellular substrate pool after dietary intake of EPA, which is contained in fish oils (FO). In the state of inflammation EPA is released to compete with arachidonic acid (AA) for metabolism at the cyclo-oxygenase and the 5-lipoxygenase level. The metabolites of EPA have less inflammatory and chemotactic potency than the substances derived from AA. In addition to positive effects, early studies pointed towards prolonged bleeding times after dietary intake of n-3 fatty acids. This study was undertaken to address the issue of potential coagulation disturbances associated with postoperative parenteral FO administration. This was a prospective, randomised, double blinded clinical trial, carried out in two operative intensive care units (13 and 16 beds) in a university hospital. Forty-four patients undergoing elective major abdominal surgery participated in the trial. Patients were randomly assigned to receive total parenteral nutrition (TPN) supplemented with either soybean oil (SO, Lipovenoess 10% PLR; 1.0 g/kgBW per day; n = 20) for five days or with a combination of FO and SO (FO, Omegaven; 0.2 g/kgBW per day plus SO, Lipovenoes 10% PLR; 0.8 g/kgBW per day, n = 24), respectively. Blood samples were taken preoperatively (day -1), prior to (day 1) during (days 2-5) and after TPN (day 6). The coagulation parameters thromboplastin time (Quick), activated partial thromboplastin time (aPTT), fibrinogen and antithrombin III were measured. To differentially assess activation levels of extrinsic and intrinsic coagulation pathway, factors VIIa and XIIa were quantified. Moreover platelet function was determined by resonance thrombography. Baseline values of coagulation and platelet function were comparable in both groups, but coagulation activity dropped after surgery. Over the observation period of 6 days, however, physiological levels were regained. No clinically significant differences were observed between the SO- and SO + FO- group. These findings suggest that infusion of fish oil in doses up to 0.2 g/kgBW per day is safe regarding coagulation and platelet function.
A R Heller, G Groth, S C Heller, R Breitkreutz, T Nebe, M Quintel, T Koch (2001)  N-acetylcysteine reduces respiratory burst but augments neutrophil phagocytosis in intensive care unit patients.   Crit Care Med 29: 2. 272-276 Feb  
Abstract: OBJECTIVE: The antioxidant N-acetylcysteine (NAC) has been shown to attenuate septic tissue injury. To evaluate whether NAC affects host defense mechanisms in critically ill patients, thus predisposing to increased risk of infection, the current study focuses on neutrophil phagocytotic and burst activity after treatment with NAC. DESIGN: Prospective, randomized, clinical trial. SETTING: Twelve-bed operative intensive care unit in a university hospital. PATIENTS: Thirty patients diagnosed with sepsis/systemic inflammatory response syndrome, or multiple trauma. INTERVENTIONS: Patients were randomly assigned to receive either NAC (n = 15) for 4 days in increasing dosages (day 1: 6 g; day 2: 12 g; days 3 and 4: 18 g) or a mucolytic basis dosage of NAC (3 x 300 mg/day [control]; n = 15), respectively. MEASUREMENTS AND MAIN RESULTS: Blood samples were taken before NAC high-dose infusion (day 1), after increasing doses of NAC (days 3 and 5) and 4 days after the last high-dose treatment (day 8). Neutrophil oxidative burst activity after stimulation with Escherichia coli and polymorphonuclear phagocytosis were determined in a flow cytometric assay. Baseline values of polymorphonuclear functions were comparable in both groups. NAC high-dose treatment resulted in a significantly improved phagocytosis activity compared with control patients. In contrast to this, polymorphonuclear burst activity was significantly reduced in the NAC high-dose treated group on day 3. CONCLUSION: These findings suggest that infusion of NAC in high doses affects granulocyte functions in critically ill patients. Antimicrobial host defense requires the effective sequence of cell adhesion, phagocytosis, and bactericidal respiratory burst. The enhanced phagocytotic activity might be a compensatory mechanism in states of impaired respiratory burst to maintain tissue sterility. For certain mechanisms of disease, the effects observed might be favorable (e.g., ischemia/reperfusion, endothelial cell activation), for others (infection) this might be detrimental.
A Heller, M Kunz, A Samakas, M Haase, M Kirschfink, T Koch (2000)  The complement regulators C1 inhibitor and soluble complement receptor 1 attenuate acute lung injury in rabbits.   Shock 13: 4. 285-290  
Abstract: Because activation of the complement system plays a major role in the pathogenesis of acute lung injury, the availability of new specific complement inhibitors represents a promising therapeutic approach. In the present study we investigated pulmonary edema formation and pulmonary artery pressure (PAP) in acute complement-induced lung injury for possible therapeutic impact of the complement regulators C1 inhibitor and soluble complement receptor 1. Eighteen isolated and ventilated rabbit lungs were perfused with pooled normal human serum (NHS, final concentration 35%) in Krebs-Henseleit buffer in a recirculating system. Lung weight gain and PAP were continuously recorded. Complement activation was blocked by the addition of C1 inhibitor (1.0 U/mL, n = 6) or sCR 1 (2.0 microg/mL, n = 6). Lungs that received NHS without inhibitors served as controls (n = 6). This study was performed according to the Helsinki Declaration and approved by the local government. Application of NHS resulted in an increase of PAP within 20 min from 8+/-2 to 42+/-6 mmHg, which was significantly (P < 0.05) decreased by C1-Inh (25+/-5 mmHg) and sCRI (20 +/-3 mmHg). Moreover, pulmonary edema formation after NHS, as assessed by overall weight gain, was reduced by both C1-Inh and sCR1, compared with controls. These findings were paralleled with significantly decreased thromboxane release rates and reduced tissue deposition of C3c and C5b-9. C1 inhibitor and sCR1 attenuate the complement-induced pulmonary capillary leakage and PAP increase, indicating the protective effect of complement inhibition in isolated perfused rabbit lungs.
A Heller, T Koch (2000)  Immunonutrition with omega-3-fatty acids. Are new anti-inflammatory strategies in sight?   Zentralbl Chir 125: 2. 123-136  
Abstract: In the early phase of sepsis and SIRS an overwhelming activation of humoral and cellular mediator systems can alter vascular resistance and causes capillary leakage increasing the risk of organ dysfunction. omega-6-arachidonic acid is released from lipid pools of cellular membranes during inflammation and is metabolized to pro-inflammatory prostaglandins and leukotriens, which are key mediators in the pathogenesis of organ dysfunction. omega-3-eicosapentaenoic acid-derived lipid mediators present altered biologic effects. Thus, omega-3-fatty acid application enables anti-inflammatory intervention on the level of lipid mediators. The current article reviews experimental and clinical data on omega-3-fatty acids. Besides the decrease of pro-inflammatory mediators, fish oil supplementation lowered post operative infection rates and showed a tendency to reduce hospital stay in surgical patients. It is believed that the decreased formation of LTB4 and TXA2 during sepsis after administration of omega-3-fatty acids accounts for improved microcirculatory perfusion and declined lactate acidosis.
A Heller, J Schmeck, S Heller, H Phan, T Nebe, R Urbaschek, T Koch (2000)  Endothelin-1 impairs neutrophil respiratory burst and elimination of Escherichia coli in rabbits.   Crit Care Med 28: 5. 1515-1521 May  
Abstract: OBJECTIVE: During systemic inflammation, elevated levels of endothelin (ET)-1 have been reported. The aim of this study was to investigate the effects of ET-1 on neutrophil (PMN) respiratory burst, phagocytosis, and elimination of Escherichia coli from blood and tissues. DESIGN: Prospective, randomized, controlled trial. SETTING: Experimental laboratory in a university hospital. SUBJECTS: A total of 18 female chinchilla rabbits. INTERVENTIONS: To quantify the clearance process, defined numbers (10(8) colony-forming units) of E. coli were injected intravenously into anesthetized rabbits, 60 mins after onset of continuous 0.2 microg/kg/min ET-1 administration (n = 9) and after saline infusion (control group, n = 9), respectively. To evaluate potential effects of ET-1 on bacterial elimination and killing, blood clearance of E. coli and colonization of different organs were investigated. MEASUREMENTS: Variables monitored were neutrophil respiratory burst and phagocytosis activity, rates of bacterial elimination from the blood, arterial blood pressure, blood gases, serum lactate concentrations, and nitrite and nitrate levels. The animals were killed 3 hrs after bacterial injection and tissue samples of liver, kidney, spleen, and lung were collected for bacterial counts. MAIN RESULTS: Compared with the control group, ET-1 significantly impaired PMN respiratory burst (p < .05) and prolonged elimination of injected E. coli from the blood (p < .01), whereas phagocytosis functions remained unaltered. The reduced PMN burst activity after ET-1 was associated with a higher bacterial colonization of all organs (lung, p < .01; spleen, p < .05). Endothelin-1 induced increases in mean arterial pressure (p < .01) and serum lactate concentrations, whereas nitrite and nitrate levels remained unaltered. CONCLUSION: Endothelin-1 impairs respiratory burst and bacterial clearance from the blood and tissue. Thus, elevated levels of ET-1 during sepsis could induce organ hypoperfusion and cause disturbances in immune functions, increasing the risk of bacterial infections.
A Heller, T Koch (2000)  The complement system: an old story or target of new therapeutic approaches?   Anasthesiol Intensivmed Notfallmed Schmerzther 35: 4. 207-213 Apr  
Abstract: The complement system is a multifactorial protein cascade system which is essentially involved in the early unspecific immune response. Its major function is the activation of cellular defense mechanisms, opsonisation of foreign particles and the destruction of target cells. While the impact of the different complement components for bacterial elimination still remains controversial, overwhelming activation of the complement cascade, however, can induce life threatening tissue damage due to the effective cytotoxic properties. In the last years a variety of studies demonstrated beneficial, organ protective effects of complement modulation in models of severe inflammation. Attempts to control the complement system include the application of endogenous complement inhibitors e.g. C1-inhibitor (C1-INH) or the administration of recombinant complement receptors such as the soluble complement receptor 1 (rsCR1). Moreover antibodies against key proteins (C3, C5), against their activation products (C5a) or against complement receptor 3 (CR3, CD18/11b) mediated adhesion of leukocytes to the vascular endothelium, represent effective options of complement modulation. Besides this, insertion of membrane bound human complement regulators (DAF- CD55, MCP- CD46 or CD59) into xenogenic donor organs has proven effectiveness to prevent xenograft rejection. The described interventions protected from severe organ damage in various animal models of sepsis, myocardial and intestinal ischaemia-reperfusion injury, ARDS, nephritis, and xenograft rejection. With respect to recent clinical data, complement inhibition could represent a useful therapeutic strategy to control overwhelming inflammation. Own experiments demonstrated protective effects of complement modulation with C1 INH and rsCR1 in a model of complement induced pulmonary injury. With respect to sufficient host defense, however, the use of complement inhibitors must be considered carefully.
A R Heller, R J Litz, I Djonlagic, A Manseck, T Koch, M P Wirth, D M Albrecht (2000)  [Combined anesthesia with epidural catheter. A retrospective analysis of the perioperative course in patients ungoing radical prostatectomy] .   Anaesthesist 49: 11. 949-959 Nov  
Abstract: Patients requiring radical prostatectomy (rPE), including retroperitoneal lymphadenectomy are often aged and have coexisting cardiopulmonary diseases, increasing the risk of perioperative complications. The aim of the present study was to evaluate our perioperative anaesthesiologic regimen over the last five years, in terms of safety and patients comfort. Records of 433 patients who underwent rPE between 1994 and 1999 in our hospital were retrospectively reviewed. Patients were divided in those who received: 1. general anaesthesia (GA) alone, 2. a combination of lumbar epidural anaesthesia (LEA) + GA or, 3. thoracic epidural anaesthesia (TEA) + GA. General anaesthesia was performed as balanced anaesthesia, and epidural administered local anaesthetics were bupivacaine 0.25% or ropivacaine 0.2%, 8-12 ml/h. In terms of intra- and postoperative numbers of tachycardiac and hypertensive episodes, a reduced stress response was observed under epidural anaesthesia (EA). Moreover, the weaning duration was shorter under EA and onset of gastrointestinal motility was found earlier ([h] GA: 50.6 +/- 11.1/LEA: 39.3 +/- 13.6/TEA: 33.8 +/- 13.0). Furthermore, a trend to rarer phases of postoperative vomiting and a significant decrease of in hospital stay of about one day ([d] GA: 12.4 +/- 5.8/LEA: 11.1 +/- 3.1/TEA: 11.5 +/- 3.8) was observed. The duration of personnel binding in the OR did not differ significantly between GA and TEA ([min] GA: 222.9 +/- 43.5/LEA: 238.2 +/- 41.8/TEA: 227.0 +/- 46.2), but ICU stay was shortened under TEA. Besides this, TEA reduced the number of pathologic postoperative thorax-x-rays. Senso-motor blockades, decreases of SaO2 and cardiac complications were experienced more frequent under LEA as compared with TEA. Combination of GA and EA, especially TEA, appears to improve perioperative care of patients undergoing rPE, in terms of patients safety and comfort.
J Schmeck, A Heller, A Gröschler, A Recker, H Neuhof, R Urbaschek, T Koch (2000)  Impact of endothelin-1 in endotoxin-induced pulmonary vascular reactions.   Crit Care Med 28: 8. 2851-2857 Aug  
Abstract: OBJECTIVES: Elevated endothelin-1 (ET-1) levels have been detected during sepsis. The aim of the study was to examine the role of thromboxane A2 (TXA2) and ET-1 in pulmonary vascular reactions after endotoxin (LPS) challenge. DESIGN: Prospective experimental study in rabbits. SETTING: Experimental laboratory in a university teaching hospital. SUBJECTS: Twenty-four adult rabbits of either sex. INTERVENTIONS: Experiments were performed on 30 isolated and ventilated rabbit lungs, which were perfused with a saline solution containing 10% autologous blood. MEASUREMENTS AND MAIN RESULTS: Pulmonary arterial pressure and lung weight gain were continuously registered. Perfusate samples were drawn intermittently to determine ET-1, TXA2, and prostacyclin (PGI2) concentrations. LPS isolated from Escherichia coli (0.5 mg/mL; n = 6) was added to the perfusate. A marked pulmonary arterial pressure increase followed by massive edema formation after 60 mins was observed after LPS injection. At the same time, elevated TXA2 and PGI2 levels in the perfusate were measured. ET-1 was detected 30 mins after LPS infusion (13.4+/-2.6 fmol/L). Pretreatment with the ET(A) receptor antagonist LU135252 (10(-6) M; n = 6) almost completely suppressed the pressure reaction after endotoxin injection (p < .01 at 50 and 60 mins) and reduced edema formation (p < .05). The cyclooxygenase inhibitor diclofenac (10 microg/mL; n = 6) was as effective as LU135252 in preventing vascular reactions after LPS injection. CONCLUSIONS: Pretreatment with the ET(A) receptor antagonist LU135252 and the cyclooxygenase inhibitor diclofenac reduced pulmonary vascular reactions after LPS challenge. Based on the current data, we conclude that the pulmonary arterial pressure increase and edema formation after LPS injection are related to an ET-1- and TXA2-dependent mechanism.
A R Heller, M Ragaller, T Koch (2000)  Epidural abscess after epidural catheter for pain release during pancreatitis.   Acta Anaesthesiol Scand 44: 8. 1024-1027 Sep  
Abstract: BACKGROUND: Despite knowledge about compromised host defence in the course of diabetes mellitus and pancreatitis, epidural analgesia (EA) is recommended for pain management during pancreatitis. CASE REPORT: We present the case of a diabetic patient with pancreatitis who developed an epidural abscess after 3 days with an epidural catheter. Natural killer and T-helper cell counts were distinctively reduced in the absence of HIV serology. Furthermore, a synthesis failure of the liver was observed and evidenced by low cholinesterase, low whole protein fraction and low antithrombin III in the peripheral blood. CONCLUSION: We suggest that the combination of pancreatitis, diabetes and compromised immunity might be a contraindication to epidural analgesia.
J Schmect, P Krafft, A Gröschler, A Heller, H Neuhof, K van Ackern, T Koch (1999)  Characterization and distribution of endothelin receptors in the pulmonary circulation: investigation of isolated, perfused, and ventilated rabbit lungs.   Shock 12: 4. 247-254 Oct  
Abstract: The aim of the study was to investigate the distribution of 2 subtypes of endothelin-receptors, mediating the effects of endothelin-1 (ET-1) in the pulmonary circulation. Until now, it is still unclear, whether ET(A) receptors or ET(B) receptors or even both are localized in pulmonary vessels. The experiments were performed on 72 isolated and ventilated rabbit lungs that were perfused with a cell- and plasma-free buffer solution. The arterial pressure and the lung weight gain were continuously registered. Intermittently perfusate samples were taken for determination of thromboxane A2 (TXA2) and prostacyclin (PGI2). The injection of ET-1 (10(-8) M, n = 6) resulted in a biphasic increase in pulmonary arterial pressure (PAP) that was accompanied by the generation of TXA2 and PGI2. Pretreatment with the ET(A)-receptor antagonist LU135252 (10(-6) M, n = 6) suppressed the pressure response after ET-1 application (P < 0.01 at 120 min) and reduced the generation of TXA2 (P < 0.05 at 120 min) and PGI2 (P < 0.05 at 120 min). Pretreatment with the cyclooxygenase inhibitor diclofenac (10 microg/mL; n = 6) also reduced the PAP increase after ET-1 injection. In contrast to this, the pulmonary vascular pressure reaction after ET-1 application was elevated, when ET(B)-receptor antagonist BQ788 (10(-6) M; n = 6) was given. Furthermore, the PGI2 to TXA2 ratio was shifted from 2.3 to 0.9, reflecting a predominance of vasoconstrictive TXA2. The simultaneous application of LU135252 and BQ788 significantly reduced the PAP increase after ET-1 application, but no beneficial effects were observed compared with the application of LU135252 solely. The injection of the ET(B)-receptor agonist sarafotoxin S6c (S6c; 10(-8) M, n = 6) also induced an increase in PAP that was not attenuated by pretreatment with the ET(B)-receptor antagonist BQ788 (10(-6) M, n = 6). LU135252 (n = 6) as well as the application of LU135252 in combination with BQ788 (n = 6) failed to suppress the pressure response after S6c, whereas the cyclooxygenase inhibitor diclofenac (10 microg/mL, n = 6) alone and in combination with LU135252 and BQ788 (n = 6) was able to prevent the PAP increase after S6c injection (P < 0.001). The results demonstrate that the ET-1-induced increase in pulmonary vascular resistance is mainly mediated via ET(A) receptors, whereas ET(B) receptors seem to mediate vasodilation, which was shown by an imbalance of TXA2 and PGI2 generation. On the other hand, the ET(B)-receptor agonist S6c induced vasoconstriction, which was only attenuated by the cyclooxygenase inhibitor diclofenac. From the current results we conclude that, apart from vasoconstrictor ET(A) receptors, at least 2 ET(B)-receptor subtypes are expressed in the pulmonary circulation, one mediating vasoconstriction, which was not blocked by BQ788, and one mediating vasodilation, which was influenced by BQ788.
J Schmeck, A Heller, T L Phan, R Urbschek, T Koch (1999)  Effects of endothelin-1 on bacterial clearance in rabbits.   Eur J Anaesthesiol 16: 3. 169-175 Mar  
Abstract: As elevated endothelin-1 (ET-1) levels have been reported in systemic inflammatory diseases, the role of ET-1 as a promoter of inflammatory reactions is currently under investigation. The purpose of this study was to investigate the potential influence of ET-1 on systemic vascular pressure and immune function in terms of blood clearance and organ distribution of injected Escherichia coli in a rabbit model. To enable quantification of the clearance process, defined numbers of exogenous E. coli (10(8) cfu) were injected intravenously 60 min after starting the infusion of ET-1 (0.2 microgram kg-1 min-1; n = 9) or after saline infusion (controls, n = 9). Parameters monitored were arterial blood pressure, airway pressure, serum lactate concentrations and rates of bacterial elimination from the blood. At 180 min after E. coli injection, the animals were killed, and tissue samples of liver, kidney, spleen and lung were collected for bacterial counts. ET-1 infusion produced an increase in mean arterial pressure (83.9 +/- 3.9 mmHg vs. 50.1 +/- 4.1 mmHg at 120 min; P < 0.01) associated with higher serum lactate concentrations (12.6 +/- 1.3 vs. 5.4 +/- 0.3 mg dL-1; P < 0.001) and a delayed bacterial elimination from the blood compared with controls. Furthermore, there was increased colonization of the lungs (3.6 +/- 0.5 x 10(3) cfu vs. 745 +/- 120 cfu; P < 0.01), spleen (142.4 +/- 45.4 x 10(3) cfu vs. 227 +/- 5.2 x 10(3) cfu; P < 0.05) and kidney (758 +/- 329 vs. 357 +/- 151 cfu; NS), reflecting a reduced bacterial killing function.
S Heller, K Weber, A Heller, R Urbaschek, T Koch (1999)  Pentoxifylline improves bacterial clearance during hemorrhage and endotoxemia.   Crit Care Med 27: 4. 756-763 Apr  
Abstract: OBJECTIVE: The aim of this study was to investigate whether the methylxanthine-derivative pentoxifylline (PTX) affects bacterial clearance of the organism in states of hemorrhage and endotoxemia. DESIGN: Prospective, randomized, controlled trial. SETTING: Experimental laboratory in a university hospital. SUBJECTS: Fifty-four female chinchilla rabbits. INTERVENTIONS: To quantify the clearance process, defined numbers (10(7) CFO) of Escherichia coli bacteria were injected intravenously into anesthetized rabbits, 60 mins after induction of hemorrhage (n = 9 + 3) or infusion of endotoxin (lipopolysaccharide [LPS]; 40 microg/kg/hr; n = 9 + 3) and after saline infusion (control; n = 9), respectively. Hemorrhage was induced by bleeding, standardized by defined reduction of mean arterial pressure (30% of baseline value). To evaluate the potential effects of PTX on bacterial elimination and killing, in states of hemorrhage and endotoxemia, blood clearance of E. coli and colonization of different organs were investigated after pretreatment with PTX (30 mg/kg) as a bolus injection followed by continuous infusion of PTX (50 mg/kg/hr) in hemorrhagic (n = 9) and endotoxemic rabbits (n = 9). Three additional experiments were performed to evaluate the effects attributable to PTX itself. MEASUREMENTS AND MAIN RESULTS: Parameters monitored were rates of bacterial and LPS elimination from the blood, arterial blood pressure, blood gases, and serum lactate concentrations. Additionally, flow cytometric analysis of respiratory burst activity was performed. Three hours after bacterial injection, the animals were killed, and tissue samples of liver, kidney, spleen, and lung were collected for bacteriologic examinations. Compared with the controls, hemorrhage and endotoxemia resulted in a significantly prolonged elimination of injected E. coli from the blood. The delayed blood clearance was associated with a significantly (p < .01) higher bacterial colonization of all organs, which was most pronounced in the lung. Pretreatment with PTX slightly enhanced blood clearance of E. coli as well as of LPS, and significantly reduced (p < .05) the colonization of lung and kidney after hemorrhage and endotoxemia. Furthermore, PTX suppressed polymorphonuclear neutrophil respiratory burst activity. CONCLUSIONS: Hemorrhage and endotoxemia induce impaired bacterial clearance from blood and tissue. Treatment with PTX may reduce the risk of bacterial infections by attenuating bacterial colonization of organs in states of hemorrhage and endotoxemia.
A Heller, F Fiedler, J Schmeck, V Lück, J L Iovanna, T Koch (1999)  Pancreatitis-associated protein protects the lung from leukocyte-induced injury.   Anesthesiology 91: 5. 1408-1414 Nov  
Abstract: BACKGROUND: Severe pancreatitis is often complicated by shock and acute lung failure. Little is known about the pathophysiologic impact of the 16.6-kD lectine, named pancreatitis-associated protein (PAP), which is expressed during pancreatitis and which reduces mortality in a rat model with severe pancreatitis. Therefore, the aim of this study was to investigate the effects of PAP on the pulmonary vasculature after leukocyte activation with N-formyl-Met-Leu-Phe (fMLP). METHODS: The experiments were performed in buffer-perfused isolated rabbit lungs. Mean pulmonary artery pressure, weight gain, and thromboxane A2 synthesis of the lungs were monitored. PAP was obtained by affinity chromatography of pancreas juice from pancreatitic rats. The authors tested whether treatment with PAP (260 microg/l, n = 9; or 500 microg/l, n = 6) before fMLP injection (10(-6) M) influences mean pulmonary artery pressure and edema formation. Lungs that were treated only with fMLP (n = 6) served as controls. Additional experiments in which PAP was applied were performed to study whether PAP (260 microg/l, n = 3; 500 microg/l, n = 3; 1,000 microg/l, n = 3) itself effects lung vasculature. RESULTS: Application of fMLP resulted in an increase of mean pulmonary artery pressure (+/- SD) from 8 +/- 2 mmHg up to 26 +/-13 mmHg (P < 0.01) at a flow of 150 ml/min. Pretreatment with PAP reduced the peak pressure developed after fMLP to 15 +/- 7 mmHg (PAP 260 microg/l; P < 0.05) and to 9 +/- 4 mmHg (PAP 500 microg/l), respectively. In addition, the fMLP-induced lung weight gain of 9 +/- 7 g in the controls was prevented by pretreatment with PAP after 150 min in either concentration. In parallel to the attenuated pressure increase, thromboxane A2 release was significantly suppressed in the 260-microg/l (200 +/- 220 pmol x ml(-1) x min(-1); P < 0.01) and 500-microg/l (285 +/- 70 pmol x m(-1) x min(-1); P < 0.05) PAP groups compared with controls (1,138 +/- 800 pmol x ml(-1) x mi(-1)). Treatment with PAP alone in either concentration did not induce any changes in mean pulmonary artery pressure, weight gain, or thromboxane A2 release. CONCLUSION: Clinically relevant concentrations of PAP prevented fMLP-induced vasoconstriction and edema formation in the lung. These findings point toward a protective effect of PAP on polymorphonuclear neutrophil leukocyte-mediated lung injury.
A Heller, M Ragaller, J Schmeck, H Flüth, M Müller, D M Albrecht, T Koch (1998)  Role of NO and endothelin in hemoglobin-induced pulmonary vasoconstriction.   Shock 10: 6. 401-406 Dec  
Abstract: The underlying mechanisms of hemoglobin (Hb)-induced vasoconstriction are not yet well understood. The aim of this study was to elucidate the influence of nitric oxide (NO) and endothelin (ET) on Hb-induced pulmonary vasoconstriction. Therefore, an autologous Hb preparation was administered into isolated rabbit lungs, in which pulmonary artery pressure (PAP) and weight gain was monitored. Either glyceroltrinitrate (GTN; 10(-5) M; n=6), L-arginine (10(-2) M; n=6), L-NAME (10(-4)M; n=6), ET(A)- or ET(B)-receptor antagonists (BQ,23, 10 6M, n=6) or (BQ788, 10(-6) M, n=6) were added to the perfusion fluid and NOx and thromboxane A2 levels were measured. RESULTS: In the control group the Hb-stimulation resulted in a pressure response up to 25.1+/-2.1 mmHg (p < .05), which was 136+/-6% of the reference value. The PAP increase was significantly (p < .05) blunted after GTN (71+/-5%), L-arginine (93+/-6%) and BQ788 (88+/-7%). Pretreatment with L-NAME (139+/-13%) or BQ123 (115+/-9%) did not show significant changes in PAP. CONCLUSION: The reduction of the Hb-induced pulmonary hypertension by NO-donors points toward the inactivation of NO by free hemoglobin. Likewise, ET(B)-receptor mediated vasoconstrictive effects without changes in NOx concentrations seem to play a pathogenetic role in the Hb-induced pulmonary vasoconstriction.
A Heller, S Heller, S Blecken, R Urbaschek, T Koch (1998)  Effects of intravenous anesthetics on bacterial elimination in human blood in vitro.   Acta Anaesthesiol Scand 42: 5. 518-526 May  
Abstract: BACKGROUND: Since anesthetics are widely used in critically ill patients, this study investigates anesthetic effects on neutrophil and monocyte function concerning bacterial elimination in human whole blood. METHODS: The effects of thiopental (20 and 200 microg/ml), propofol (5 and 50 microg/ml), midazolam (0.15 and 1.5 microg/ml) and ketamine (3 and 30 microg/ml) on elimination of Escherichia (E.) coli from whole blood were investigated in vitro after incubation for 1 h in both clinical (1) (n=10) and 10-fold higher (h) (n=11) concentrations. These data were compared to neutrophil and monocyte phagocytosis (1; n=6) and burst activity (1; n=10, h; n=11), measured by flow cytometry. To enable quantification of the clearance process, a defined number of 10(5) colony forming units of E. coli were added to the blood assays and bacterial growth was determined. RESULTS: All anesthetics delayed bacterial clearance from the blood in the 10-fold concentration (P<0.05). Thiopental (1+h) and propofol (h) suppressed neutrophil (59+/-3% and 38+/-6%) and monocytic (45+/-6% and 30+/-11%) oxidative burst (P<0.01). Phagocytosis was reduced even after propofol (1) in polymorphonuclear leukocytes (PMN) (34+/-9%; P<0.05) and monocytes (35+/-11%). Ketamine (h) prolonged bacterial elimination (P<0.01), which did correlate with inhibition of monocytic phagocytosis, by 26+/-14%. Midazolam application (h) resulted in an inhibition of PMN-respiratory burst by 19+/-6% (P<0.05) and impaired bacterial clearance (P<0.05). CONCLUSION: Thiopental, propofol, midazolam and ketamine affect E. coli clearance and neutrophil and monocyte oxidative burst and phagocytosis in vitro only in high concentrations, while thiopental inhibited monocytic burst and propofol impaired PMN phagocytosis even in clinically used concentrations. These data suggest that i.v. anesthetics in concentrations recommended for general anesthesia seem to have minor influence on the investigated host defense mechanisms.
J Schmeck, T Koch, B Patt, A Heller, H Neuhof, K van Ackern (1998)  The role of endothelin-1 as a mediator of the pressure response after air embolism in blood perfused lungs.   Intensive Care Med 24: 6. 605-611 Jun  
Abstract: OBJECTIVE: It is well known that lung embolism is associated with an increase in pulmonary vascular resistance. Since the mechanisms of pulmonary vascular reactions during embolism are still unclear, the aim of this study was to investigate the potential involvement of endothelin-1 (ET-1) and thromboxane A2 (TXA2) as mediators of the pulmonary artery pressure (PAP) increase after embolism using the selective ETA receptor antagonist LU135252 [1], the ETB receptor antagonist BQ788 [2], and the cyclooxygenase inhibitor diclofenac. DESIGN: Prospective experimental study in rabbits. SETTING: Experimental laboratory in a university teaching hospital. SUBJECTS: 36 adult rabbits of either sex. INTERVENTIONS: The experiments were performed in 36 isolated and ventilated rabbit lungs which were perfused with a buffer solution containing 10% of autologous blood. Embolism was induced by the injection of 0.75 ml air into the pulmonary artery. MEASUREMENTS AND RESULTS: PAP and lung weight, reflecting edema formation, were continuously recorded. Perfusate samples were drawn intermittently to determine TXA2 and ET-1 concentrations. Air injection resulted in an immediate increase in PAP up to 22.8 +/- 1.4 mm Hg at 2.5 min (control, n = 6), which was parallelled by an enhanced generation of TXA2. No relevant edema formation occurred during the observation period. Pretreatment with the ETA receptor antagonist LU135252 significantly reduced the pressure reaction after air embolism (p < 0.001) whereas the ETB receptor antagonist BQ788 (n = 6) was without marked effects. The administration of diclofenac (n = 6) did not alter the PAP increase 2.5 min after embolism, but significantly reduced the pressure reaction during the further observation period (p < 0.001). The application of LU135252 and diclofenac together (n = 6) also significantly reduced the PAP increase from 2.5 min during the total observation period (p < 0.001). CONCLUSIONS: The acute pressure reaction after air embolism is mainly mediated via ET-1 by an ETA receptor related mechanism. TXA2 seems to maintain this reaction for a longer time.
A Heller, T Koch, J Schmeck, K van Ackern (1998)  Lipid mediators in inflammatory disorders.   Drugs 55: 4. 487-496 Apr  
Abstract: During the past few decades, intensive collaborative research in the fields of chronic and acute inflammatory disorders has resulted in a better understanding of the pathophysiology and diagnosis of these diseases. Modern therapeutic approaches are still not satisfactory and shock, sepsis and multiple organ failure remain the great challenge in intensive care medicine. However, the treatment of inflammatory diseases like rheumatoid arthritis, ulcerative colitis or psoriasis also represents an unresolved problem. Many factors contribute to the complex course of inflammatory reactions. Microbiological, immunological and toxic agents can initiate the inflammatory response by activating a variety of humoral and cellular mediators. In the early phase of inflammation, excessive amounts of interleukins and lipid-mediators are released and play a crucial role in the pathogenesis of organ dysfunction. Arachidonic acid (AA), the mother substance of the pro-inflammatory eicosanoids, is released from membrane phospholipids in the course of inflammatory activation and is metabolised to prostaglandins and leukotrienes. Various strategies have been evaluated to control the excessive production of lipid mediators on different levels of biochemical pathways, such as inhibition of phospholipase A2, the trigger enzyme for release of AA, blockade of cyclooxygenase and lipoxygenase pathways and the development of receptor antagonists against platelet activating factor and leukotrienes. Some of these agents exert protective effects in different inflammatory disorders such as septic organ failure, rheumatoid arthritis or asthma, whereas others fail to do so. Encouraging results have been obtained by dietary supplementation with long chain omega-3 fatty acids like eicosapentaenoic acid (EPA). In states of inflammation, EPA is released to compete with AA for enzymatic metabolism inducing the production of less inflammatory and chemotactic derivatives.
A Heller, T Koch (1998)  Pharmacologic aspects of polyunsaturated fatty acids in parenteral nutrition   Anasthesiol Intensivmed Notfallmed Schmerzther 33: 2. 77-87 Feb  
Abstract: Despite immense progress in intensive-care medicine, mortality rates of 30-70% in sepsis and SIRS are still an unresolved problem. Particularly the failure of respiratory and other vital functions is a major cause of death. Besides infectious stimuli (viruses, bacteria, fungi) a variety of non-infectious triggers (tissue damage, immune complexes, complement activation, etc.) can initiate the development of organ failure. These inflammatory reactions aim physiologically towards inactivation and removal of the stimulating agents as well as the induction of reparative processes. In states of prolonged activation of humoral and cellular mediator systems the natural host defence mechanisms react in an uncontrolled manner causing tissue damage and organ failure. So far there are no efficient therapeutic strategies to influence these complex inflammatory reactions. In the development of SIRS and sepsis, pro-inflammatory lipid mediators play a crucial role. Omega-3-fatty acids (omega-3-PUFAs) have shown anti-inflammatory and antithrombotic properties in a great number of experimental and clinical studies. These effects seem to be related to the uptake of eicosapentaenoic acid (EPA) into cellular membrane lipid pools and its subsequent metabolisation. After inflammatory activation EPA is released besides arachidonic acid (AA) and competes with AA for metabolisation via the cyclo- and lipoxygenase pathway. Compared to AA the derivatives of EPA have less pro-inflammatory and chemotactic characteristics. With regard to prophylactic and therapeutic consequences it appears reasonable to supplement omega-3-PUFAs to attenuate the inflammatory response by modulating the generation of lipid mediators during inflammation.
T Koch, S Heller, K Weber, A Heller, R Urbaschek (1997)  Effects of human i.v. immunoglobulin on bacterial clearance and granulocyte function in endotoxinemia   Anasthesiol Intensivmed Notfallmed Schmerzther 32: 7. 420-425 Jul  
Abstract: PURPOSE: The therapeutic impact of intravenous immunoglobulins (ivIG) in septic patients remains controversial. Until now, the mechanisms of action have not been fully elucidated. Since polymorphonuclear neutrophils (PMN) play a key role in host defence, this study focuses on the effects of ivIG on bacterial clearance and PMN respiratory burst activity during endotoxinaemia. For this purpose, it was investigated whether ivIG improves blood clearance and organ colonisation as well as PMN functions after experimentally induced bacteraemia in rabbits. METHODS: The experiments were performed in 30 anaesthetised rabbits. To determine quantification of bacterial killing in vivo, defined numbers of exogenous Escherichia (E.) coli 1.3 x 10(8) CFU) were injected intravenously in untreated animals (n = 10) or 60 min after infusion of endotoxin (LPS: 40 micrograms/kg/h) in groups without (n = 10), and after pretreatment with ivIG (Sandoglobulin, 0.5 g/kg body weight, n = 10), respectively. Parameters monitored were rates of bacterial elimination from the blood, LPS clearance, arterial pressure, blood gases and white blood cell counts, PMN burst activity was determined using a flow cytometry assay. Samples of liver, kidney, spleen and lung were collected for bacterial counts 180 min following E. coli injection. RESULTS: Compared to controls, endotoxinaemia resulted in a prolonged elimination of the injected E. coli out of the blood associated with a significantly (p < 0.01) higher colonisation of all organs. Pretreatment with ivIG improved LPS clearance and significantly reduced bacterial colonisation of lung and kidney (p < 0.01). This was paralleled by an enhanced PMN respiratory burst activity compared to untreated animals (p < 0.05). CONCLUSION: The reduced bacterial colonisation of lung and kidney in correlation with an increased PMN bactericidal activity in endotoxinaemia suggest an improved granulocyte-dependent bacterial killing due to ivIG application.
J Groschel, A Heller, M Muller, K F Waschke (1996)  Present use and future perspectives of the Internet for anaesthesiologists   ANASTHESIOLOGIE & INTENSIVMEDIZIN 37: 12. 654-660 DEC  
Abstract: The development of the internet is described from its beginning to the introduction of the World Wide Web (WWW), which offers graphic user interfaces, hypertext and the integration of pictures, sound and video, Examples demonstrate the present use of the WWW for anaesthesiologists, such as online-literature retrieval, anaesthesiology textbooks and discussion groups as well as information about anaesthesiological departments, Furthermore, support for the development of a clinic's own home page is presented, Future perspectives such as online conferences and interactive multimedia computer-based training programs are discussed, The evolution of the internet with its multiple opportunities will certainly influence daily anaesthesiological practice in the future.
I Breil, T Koch, A Heller, E Schlotzer, A Grünert, K van Ackern, H Neuhof (1996)  Alteration of n-3 fatty acid composition in lung tissue after short-term infusion of fish oil emulsion attenuates inflammatory vascular reaction.   Crit Care Med 24: 11. 1893-1902 Nov  
Abstract: OBJECTIVES: To investigate whether modulation of the fatty acid profile can be achieved by the short-term infusion of a fish oil emulsion which may attenuate the pulmonary response to inflammatory stimulation. Changes of fatty acid pattern in-lung tissue and perfusate were analyzed and correlated with physiologic data after a 3-hr infusion of fish oil in comparison with a soybean oil preparation. DESIGN: Prospective, randomized, controlled trial. SETTING: Experimental laboratory in a university teaching hospital. SUBJECTS: Forty standard breed rabbits of either gender. INTERVENTIONS: Isolated lungs from anesthetized rabbits were ventilated and recirculation-perfused (200 mL/min) with 200 mL of cell-free buffer solution to which either 2 mL of saline (control, n = 6), 2 mL of a 10% soybean oil preparation (n = 6), or 2 mL of a 10% fish oil emulsion (n = 6) were added. Samples of perfusate and lung tissue were collected for analysis of fatty acid composition. Tissue and perfusate fatty acid composition were analyzed by capillary gas chromatography. To study metabolic alterations in states of inflammatory stimulation, lungs of each group were stimulated with small doses of the calcium ionophore, A23187 (10(-8) M), during the 180-min lipid perfusion period and again after washing out the lipids by exchanging the perfusion fluid. Pulmonary arterial pressure and lung weight gain were monitored, and eicosanoids were analyzed in the perfusate. MEASUREMENTS AND MAIN RESULTS: Free eicosapentaenoic acids increased several-fold in lung tissue and perfusate during a 3-hr infusion with fish oil. The intravenously administered n-3 fatty acids were rapidly hydrolyzed, as indicated by the appearance of substantial quantities of eicosapentaenoic acid in the perfusate free fatty acid fraction. This increase of perfusion levels of eicosapentaenoic acid was paralleled by an attenuated pressure increase and edema formation due to calcium ionophore challenge and an altered eicosanoid spectrum determined in the perfusate compared with soybean oil-treated lungs. CONCLUSION: Short-term n-3 lipid application (fish oil emulsion) exerts anti-inflammatory effects on lung vasculature, which may be due to the metabolism of eicosapentaenoic acid resulting in the generation of less potent inflammatory eicosanoids.
T Koch, H P Duncker, A Heller, R Schaible, K van Ackern, H Neuhof (1994)  Effects of stroma-free hemoglobin solutions on pulmonary vascular resistance and mediator release in the isolated perfused rabbit lung.   Shock 1: 2. 146-152 Feb  
Abstract: The aim of this study was to evaluate the effect of an ultrapure bovine stroma-free hemoglobin (SFH) on pulmonary vascular resistance and mediator release and to analyze potential mechanisms of action in the isolated perfused rabbit lung model. Repetitive bolus applications of small amounts of bovine SFH were examined which resulted in a reproducible acute increase of pulmonary vascular resistance of approx. 9 mmHg (controls, n = 6). It was tested whether the platelet-activating factor (PAF) antagonist WEB 2086 (50 microM; n = 6), the cyclooxygenase blocker diclofenac (10 micrograms/ml; n = 6), the iron-chelating agent deferoxamine (500 micrograms/ml, n = 6) and the radical scavenger catalase (5000 U/ml; n = 6) exert a protective effect on vasoconstrictor response to SFH. The pressure increase was completely suppressed in the lungs pretreated with WEB 2086, whereas diclofenac, deferoxamine and catalase failed to inhibit the vasoconstriction due to SFH. No significant differences in either TXB2 generation or in histamine release were found in the WEB 2086 group compared with untreated lungs. The results point towards the crucial role of PAF in mediation of vasoconstrictor side effects due to SFH.
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