Munich Intensive Care Outcome Study Group Physical, Cognitive and Emotional Consequences of Critical Illness and Extreme Stress Exposure Glucocorticoid - System

Endocannabinoid - System

Catecholaminergic - System

Ludwig – Maximilians University Munich, Germany Gustav Schelling, MD, PhD Josef Briegel, MD, PhD Erich Kilger, MD, PhD Shahnaz C. Azad, MD, PhD Florian Weis, MD Daniela Hauer, MS Isabel Briegel, MD Markus Landinger, MS Theresia Englmeier, MS Julia Liebke, MS

Till Krauseneck, Michael Vogeser, Lorenz Jäger, MD MD, PhD MD Jürgen Lutz, MD Frank Padberg, MD, PhD Florian Seemüller, MD

Department of Anesthesiology

Department of Psychiatry

Department of Department of Clinical Chemistry Radiology

International Cooperation Center for the Neurobiology of Learning and Memory, Department of Neurobiology and Behavior, University of California at Irvine, USA (Benno Roozendaal, PhD) Department of Psychiatry Research University of Zürich Switzerland (Dominique de Quervain, MD, PhD) Department of Physiology and Pharmacology, La Sapienza University of Rome, Rome, Italy (Patrizia Campolongo, PhD)

Description The purpose of our study group is to conduct outcome research in after intensive care treatment or other causes of extreme stress exposure. Our group currently focuses on emotional, cognitive and behavioural functioning of patients and individuals during and after an extreme stress exposure. Individuals studied include long-term survivors of sepsis, trauma and shock, patients during and after cardiac surgery, patients with stress-related chronic wide spread pain but also volunteers participating in isolation experiments, astronauts, parabolic flights or scientists working and living in Antarctic environment. Current clinical and experimental studies investigate the hormonal regulation of the stress response with a particular focus on traumatic memory. Neurobiologic systems we study include the catecholaminergic, the glucocorticoid and the endocannabinoid system as well as the interaction between these systems with regard to traumatic memory and stress-related disorders such as post-traumatic stress disorder (PTSD) or fibromyalgia. Furthermore, we increasingly study the effects of genetic single nucleotide polymorphisms (SNPs) on outcome of severe stress. As the population ages, the field of intensive care advances and the incidence of highly aversive events in the general population increases, it becomes more important to optimize outcome of extreme stress exposure and critical illness.

The aims of the Munich Intensive Care Outcome Study Group 1. To expand scientific knowledge and serve as a centre of research in the areas of outcomes after extreme stress and after ICU treatment. 2. To increase the understanding of basic neurohumoral mechanisms of traumatic memories and chronic stress disorders in patients after highly aversive experiences with the aim of developing approaches to prevention and treatment. 3. To disseminate research findings to the scientific community, health care policy makers, health-care providers, and members of the general public. 4. To assist clinicians in improving the quality and cost-effectiveness of patient care based on scientific evidence found in our investigations. 5. To improve and validate the methodology used to measure outcome including health-related quality of life and emotional, cognitive and behavioural functioning in patients after intensive care or extreme stress exposure.

Current Ongoing Clinical Studies and Trials • • • • •

Effect of Analgesia and Sedation on Outcome of Intensive Care Therapy (DFG Sche 573) Low-Dose Hydrocortisone for Fibromyalgia (ClinicalTrials.gov Identifier: NCT00236925) Glucocorticoid-Endocannabinoid Interaction in Patients undergoing Cardiac Surgery (ClinicalTrials.gov Identifier: NCT00490828) Diffusion Tensor Imaging Magnetic Resonance Imaging in Patients with Stress-Related Disorders Long-term Outcome of Catastrophic ARDS

Major publications related to the field 1. Roozendaal B, Schelling G, McGaugh JL (2008): Corticotropin-releasing factor in the basolateral amygdala enhances memory consolidation via an interaction with the beta-adrenoceptor-cAMP pathway: dependence on glucocorticoid receptor activation. J Neurosci 28: 6642-6651. 2. Kaufmann I, Eisner C, Richter P, Huge V, Beyer A, Chouker A et al (2007): Lymphocyte subsets and the role of TH1/TH2 balance in stressed chronic pain patients. Neuroimmunomodulation 14: 272-280. 3. Kaufmann I, Schelling G, Eisner C, Richter JC, Krauseneck T, Vogeser M et al (2008): Anandamide and Neutrophil Function in Patients with Fibromyalgia. Psychoneuroendocrinology 33: 676-685. 4. Schelling G (2007): Post-traumatic stress disorder in somatic disease: lessons from critically ill patients. Prog Brain Res 167: 229-237. 5. Kaufmann I, Eisner C, Richter P, Huge V, Beyer A, Chouker A et al (2007): Psychoneuroendocrine stress response may impair neutrophil function in complex regional pain syndrome. Clin Immunol 125: 103-111. 6. Vogeser M, Schelling G (2007): Pitfalls in measuring the endocannabinoid 2arachidonoyl glcyerol in biological samples. Clin Chem Lab Med 45: 1023-1025. 7. Briegel J, Kilger E, Schelling G (2007): Indications and practical use of replacement dose of corticosteroids in critical illness. Curr Opin Crit Care 13: 370-375. 8. Krauseneck T, Seemuller F, Krahenmann O, Schelling G, Padberg F (2006): [Psychiatric disorders in the ICU I: delirium]. Anasthesiol Intensivmed Notfallmed Schmerzther 41: 720-726. 9. Krauseneck T, Graz C, Krahenmann O, Schelling G, Padberg F (2007): [Psychiatric emergencies on ICU]. Anasthesiol Intensivmed Notfallmed Schmerzther 42: 10-13. 10. Krauseneck T, Krahenmann O, Heimendahl J, Schelling G, Padberg F (2007): [Psychiatric disorders in intensive care--part three: psychic reactions, affective and anxiety disorders]. Anasthesiol Intensivmed Notfallmed Schmerzther 42: 180-187. 11. Schelling G, Roozendaal B, Krauseneck T, Schmoelz M, DE QD, Briegel J (2006): Efficacy of hydrocortisone in preventing posttraumatic stress disorder following

critical illness and major surgery. Ann N Y Acad Sci 1071: 46-53. 12. Soravia LM, Heinrichs M, Aerni A, Maroni C, Schelling G, Ehlert U et al (2006): Glucocorticoids reduce phobic fear in humans. Proc Natl Acad Sci U S A 103: 55855590. 13. Schelling G, Roozendaal B, Krauseneck T, Schmoelz M, de Quervain DJ-F, Briegel J (2006): Efficacy of Hydrocortisone in Preventing Post-Traumatic Stress Disorder Following Critical Illness and Major Surgery. Ann NY Acad Sci 1071: 46-53. 14. Weis F, Kilger E, Roozendaal B, de Quervain DJ, Lamm P, Schmidt M et al (2006): Stress doses of hydrocortisone reduce chronic stress symptoms and improve healthrelated quality of life in high-risk patients after cardiac surgery: A randomized study. J Thorac Cardiovasc Surg 131: 277-282. 15. Schelling G, Hauer D, Azad SC, Schmoelz M, Chouker A, Schmidt M et al (2006): Effect of General Anesthesia on Anandamide Blood Levels in Humans. Anesthesiology 104: 273-277. 16. Krauseneck T, Rothenhausler HB, Schelling G, Kapfhammer HP (2005): [PTSD in Somatic Disease.]. Fortschr Neurol Psychiatr 73: 206-217. 17. Weis F, Kilger E, Roozendaal B, de Quervain DJ-F, Lamm P, Schmidt M et al (2006): Stress doses of hydrocortisone reduce chronic stress symptoms and improve health-related quality of life in high risk patients after cardiac surgery: a randomized study. The Journal of Thoracic and Cardiovascular Surgery 131: 277-282. 18. Krauseneck T, Rothenhausler HB, Schelling G, Kapfhammer HP (2005): [PTSD in Somatic Disease.]. Fortschr Neurol Psychiatr 73: 206-217. 19. Rothenhausler HB, Grieser B, Nollert G, Reichart B, Schelling G, Kapfhammer HP (2005): Psychiatric and psychosocial outcome of cardiac surgery with cardiopulmonary bypass: a prospective 12-month follow-up study. Gen Hosp Psychiatry 27: 18-28. 20. Schelling G, Roozendaal B, de Quervain DJ-F (2004): Can post-traumatic stress disorder (PTSD) be prevented with glucocorticoids? Ann NY Acad Sci 1032: 158166. 21. Kapfhammer HP, Rothenhausler HB, Krauseneck T, Stoll C, Schelling G (2004): Posttraumatic stress disorder and health-related quality of life in long-term survivors of acute respiratory distress syndrome. Am J Psychiatry 161: 45-52. 22. Azad SC, Monory K, Marsicano G, Cravatt BF, Lutz B, Zieglgansberger W, Rammes G: Circuitry for associative plasticity in the amygdala involves endocannabinoid signaling. Journal of Neuroscience 2004; 24: 9953-61 23. Marsicano G, Wotjak CT, Azad SC, Bisogno T, Rammes G, Cascio MG, Hermann H, Tang J, Hofmann C, Zieglgansberger W, Di M, V, Lutz B: The endogenous cannabinoid system controls extinction of aversive memories. Nature 2002; 418: 530-4

24. Aerni A, Traber A, Hock C, Roozendaal B, Schelling G, Papassotiropoulos A et al (2004): Low-dose cortisol treatment reduces symptoms of post-traumatic stress disorder. Am J Psychiatry 161: 1488-1490. 25. Roozendaal B, de Quervain DJ-F, Schelling G, McGaugh JL (2003): A Systemically Administered Beta-Adrenoceptor Antagonist Blocks Corticosterone-induced Impairment of Contextual Memory Retrieval in Rats. Neurobiol Learn Mem 81: 150154. 26. Bouillon B, Kreder HJ, Eypasch E, Holbrook TL, Kreder HJ, Mayou R et al (2002): Quality of life in patients with multiple injuries--basic issues, assessment, and recommendations. Restor Neurol Neurosci 20: 125-134. 27. Schelling G, Kilger E, Roozendaal B, Briegel J, Dagge A, Rothenhausler HB et al (2004): Stress doses of hydrocortisone, traumatic memories and post-traumatic stress disorder in patients after cardiac surgery: a randomized study. Biol Psychiatry 55: 627-633. 28. Schelling G (2002): Effects of Stress Hormones on Traumatic Memory Formation and the Development of Posttraumatic Stress Disorder in Critically Ill Patients. Neurobiology of Learning and Memory 78: 596-609. 29. Rothenhausler HB, Ehrentraut S, Kapfhammer HP, Lang C, Zachoval R, Bilzer M et al (2002): Psychiatric and psychosocial outcome of orthotopic liver transplantation. Psychother Psychosom 71: 285-297. 30. Schelling G, Richter M, Roozendaal B, Rothenhausler H, Stoll C, Nollert G et al (2003): Exposure to high stress in the ICU may have negative effects on healthrelated quality of life outcomes after cardiac surgery. Crit Care Med 31: 1971-1980. 31. Rothenhausler HB, Ehrentraut S, Stoll C, Schelling G, Kapfhammer HP (2001): The relationship between cognitive performance and employment and health status in long-term survivors of the acute respiratory distress syndrome: results of an exploratory study. Gen Hosp Psychiatry 23: 90-96. 32. Schelling G, Stoll C, Vogelmeier C, Hummel T, Behr J, Kapfhammer HP et al (2000): Pulmonary function and health-related quality of life in a sample of longterm survivors of the acute respiratory distress syndrome. Intensive Care Med 26: 1304-1311. 33. Schelling G, Stoll C, Kapfhammer HP, Rothenhausler HB, Krauseneck T, Durst K et al (1999): The effect of stress doses of hydrocortisone during septic shock on posttraumatic stress disorder and health-related quality of life in survivors. Crit Care Med 27: 2678-2683. 34. Schelling G, Stoll C, Haller M, Briegel J, Manert W, Hummel T, Lenhart A, Heyduck M, Polasek J, Meier M, Preuss U, Bullinger M, Schüffel W, Peter K: Health-Related Quality of Life and Post-Traumatic Stress Disorder in Survivors of the Acute Respiratory Distress Syndrom (ARDS). Crit Care Med 1998; 25: 651-9

Scientific Meetings and Workshops Workshop Munich 2006: Emotional Memory Regulation by Stress Hormones and Endocannabinoids

Workshop Munich 2005: Glucocorticoids and Endocannabinoids in the Amygdala Workshop Munich 2002: Post-traumatic stress disorder (PTSD): From terrorist acts to intensive care treatment and critical illness: Neurobiological mechanisms and pharmacological approaches for prevention and therapy Workshop Munich 2000: Stress und Stresshormone, traumatische Erinnerungen und posttraumatische Belastungsstörungen nach Intensivtherapie

Major grants • • •

Else Kröner-Fresenius Foundation Deutsche Forschungsgemeinschaft (Sche 573) Eli - Lilly International Foundation

Prizes and Awards • • • •

Hans Roemer Award, Deutsches Kollegium für Psychosomatische Medizin, 2001. Prize Award, Kongress der Deutschen Gesellschaft für Psychiatrie, Psychotherapie und Nervenheilkunde 2000. Prize Award, 10th European Congress on Intensive Care Medicine 1997. Prize Award, 9th European Congress on Intensive Care Medicine 1996.

Contact Prof. Dr.med. Gustav Schelling Department of Anesthesiology Ludwig - Maximilians Universität Klinikum Großhadern 81377 München Germany Phone: +49897095-1 Fax: +49897098882 E-mail: [email protected]