anesthesiologie Nederlands tijdschrift voor Wetenschap special volume 22, september Selectie van abstracts C. Boer Abstracts Wetenschapsdag 2010

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1 Advertentie Nederlands tijdschrift voor anesthesiologie Wetenschap special volume 22, september Selectie van abstracts C. Boer Abstracts Wetenschapsdag 2010 Dr. M. Klimek, hoofdredacteur Dr. C. Boer, plaatsvervangend hoofdredacteur Officiële uitgave van de Nederlandse Vereniging voor Anesthesiologie

2 Zo vader, zo zoon Effectieve pijnstilling voor volwassenen van elke leeftijd 1 Geen specifieke cardiovasculaire & gastro-intestinale complicaties 1 Uitstekend te combineren met lage dosering NSAID 2,3,4 NU OOK ALS BRUISTABLET Zie productinformatie elders in dit tijdschrift ZAL-ADV Zeker Zaldiar

3 1 nederlands tijdschrift voor anesthesiologie september 10 inhoud Nederlands tijdschrift voor anesthesiologie volume 22 Nummer 4 september 2010 Coverbeeld: Shutterstock editorial 5 Selectie van abstracts C. Boer abstracts wetenschapsdag o r a l p r e s e n tat i o n 7 Benzethonium increases the cytotoxicity of S(+)- ketamine in lymphoma, neuronal and glial cells F. Stevens, R. Werdehausen, N. Gaza, H. Hermanns, M.W. Hollmann, S. Braun o r a l p r e s e n tat i o n 7 The impact of morphine on tumor progression and metastasis formation in a preclinal mouse model of metastatic breast cancer C.W. Doornebal, M. Ciampricotti, Cheei-Sin Hau, M.W. Hollmann, J. Jonkers, K.E. de Visser o r a l p r e s e n tat i o n 8 Effect of spinal cord stimulation on tactile hypersensitivity is potentiated by a sub- effective dose of ketamine in an animal model of chronic neuropathic pain M. Truin, S.P.M. Jannsen, R. Deumens, M. van Kleef, E.A.J Joosten o r a l p r e s e n tat i o n 8 The effect of helium on the immune system ex-vivo G.T.M.L. Oei, K.F. Smit, D. van de Vondervoort, N.C. Weber, M.W. Hollmann, B. Preckel o r a l p r e s e n tat i o n 9 Reversion of high-fat diet normalizes myocardial function and sphingolipid levels in rats C.E. van den Brom, R.A. Bouwman, M.H. Graeler, D.M. Ouwens, M. Diamant, C. Boer o r a l p r e s e n tat i o n 10 Effect of ketamine on endogenous pain modulation in healthy volunteers M. Niesters, E.Y. Sarton, A. Dahan p o s t e r d i s c u s s o n 10 Population pharmacokinetic-pharmaco dynamic modeling of ketamine- induced pain relief of chronic pain M.J. Sigtermans, E. Olofsen, A. Dahan posterdiscussion 10 Increased perioperative complications after major vascular surgery in patients with a preoperative abnormal exercise blood pressure response I. de Liefde, G.M.J.M. Welten, H.J.M Verhagen, R.T. van Domburg, R.J. Stolker, D. Poldermans posterdiscussion 11 Pharmacokinetics of a highly concentrated intranasal midazolam spray in healthy adult volunteers A.A. Fiddelers, N.M.L. Veldhorst, P-H.M. Van der Kuy, C. Neef, M.A.E. Marcus posterdiscussion 12 Myocardial contrast echocardiography for the study of perioperative myocardial perfusion C.S.E. Bulte, J. Slikkerveer, O. Kamp, S.A. Loer, C. Boer, R.A. Bouwman posterdiscussion 12 Prediction of early liver dysfunction after orthotopic liver transplantation using indocyanine green plasma disappearance rate J.J. Vos, T.W.L. Scheeren, J.K.G. Wietasch posterdiscussion 13 Safety of retransfusing shed blood after local infiltration analgesia in total knee arthroplasty B.J.W. Thomassen, L.D. Pool, R.E. van der Flier, R.D. Stienstra, B.A. in t Veld groep 1 - pijn 13 Pain symptoms accompanying chronic post sternotomy pain, a cross-sectional cohort study N.J. van Leersum, R.L. van Van Leersum, H.F. Verwey, R.J.M. Klautz groep 1: pijn 14 A reinforced microglial response as as mechanism underlying long-term changes in paijn sensitivity after neonatal repetitive pain L. Knaepen, R. Deumens, D. Tibboel, J. Patijn, E.A.J. Joosten groep 1: pijn 14 Translational research on central neuropathic pain and neuroinflamation after experimental spinal cord injury S.F.J. van Gorp, E.A.J. Joosten, P. Martínez-Martínez, M. Losen, M. de Baets, M. van Kleef, R. Deumens groep 1: pijn 15 Time-dependent plasticity of the spinal GABAergic system in relation to the degree of neuropathic pain S.P.M. Janssen, M. Truin, M. Van Kleef, Elbert A. Joosten groep 1: pijn 15 Opioid Chronopharmacology: Influence of Timing of Infusion on Fentanyl s Analgesic Efficacy M.C.A. Boom, J. Grefkens, E.L.A. van Dorp, E. Olofsen, L.P.H.J. Aarts, A. Dahan, E.Y. Sarton groep 1: pijn 16 Intrathecal delivery of VEGF165 following experimental spinal cord injury results in modest attenuation of mechanical allodynia S.G.A. van Neerven, E.A.J. Joosten, R. Deumens groep 1: pijn 16 Role of corticotropin-releasing factor and urocortin 1 systems in pain-induced maladaptation and comorbid diseases T.P.H. Rouwette, W.J.J.M Scheenen, E.W. Roubos, T. Kozicz, K.C. Vissers groep 2: divers 17 Decision support reduces PONV incidence in a general surgical population F.O. Kooij, T. Klok, M.W. Hollmann, J.E. Kal groep 2: divers 17 Arterial and Venous Pharmacokinetics of Morphine-6-Glucuronide and Impact of Sample Site on Pharmacodynamic Parameter Estimates E.L.A. van Dorp, E. E. Olofsen, A. Dahan

4 doppler guided intraoperative fluid management NHS Technology Adoption Centre, January N= % Decrease in Mortality Eleven Day Reduction in LOS within Critical Care Level 3 Three Day Reduction in Length of Stay Four Day Reduction in Post-op LOS 23% Decrease in CVC Insertion Rate 33% Decrease in Re-admission Rate 25% Decrease in Re-operation Rate Advertentie oraal of nasaal bewezen beter Hemodynamica & Vloeistofbeleid met ODM Oesophageal Doppler Monitoring geeft een lagere mortaliteit & een kortere opnameduur klinisch- & kosteneffectief* *evidence base n>2.200 patienten 9 peer reviewed randomized controlled clinical trials (986 patiënten) 4 meta-analyses 2 onafhankelijke hta s (ecri-us 2007 & nhs-uk 2009) 1 multicenter audit (nhs technology adoption centre 2010) Medical Technology Transfer BV adres J.F. Oltmansstraat 10, 7221 NA Steenderen tel +31 (0) fax +31 (0) mail info@mttnl.com web Meer informatie over onze methodieken, trainingsmaterialen en literatuur sturen wij u graag toe

5 september 10 nederlands tijdschrift voor anesthesiologie 3 inhoud g r o e p 2 : d i v e r s 18 Increased renal microvascular endothelial responsiveness to LPS in aged mice F.M. Wulfert, M. Meurs, van, N.F. Neng, R.M. Jongman, P. Heeringa, J.G. Zijlstra, M.M.R.F. Struijs, G. Molema g r o e p 2 : d i v e r s 18 The effects of major and minor surgery on the tryptophan kynurenine pathway, neopterin and IL-6 J.W. Hol, R.J. Stolker, M. Klimek, F. van Lier, D. Stronks, D. Fekkes g r o e p 2 : d i v e r s 19 Recovery discharge criteria after spinal anesthesia with articaine in day care surgery R.M. van Bockel, E.W. van den Bosch, M.M.R.F. Struys, R.H.G van den Brom g r o e p 2 : d i v e r s 20 Pulse Transit Time to assess the mechanism involved in CRPS-induced vasomotor dysfunction M.C. Kortekaas, S.P. Niehof, M.H.N. Van Velzen, R.J. Stolker, F.J.P.M. Huygen g r o e p 2 : d i v e r s 21 Postoperative Urinary Retention: a biased diagnosis? L.S. Wagenaar, J.K.G. Wietasch, T.A. Brouwer g r o e p 2 : d i v e r s 21 Endotracheal intubation using videolaryngoscopy causes less cardiovascular responses compared to classic direct laryngoscopy R.L.J.G. Maassen, B. Pieters, B. Maathuis, J. Serroyen, M.A.E. Marcus, A.A.J. Van Zundert g r o e p 3 : c a r d i o va s c u l a ir 22 Withdrawal of low dose aprotinin from anti-fibrinolytic therapy with tranexamic acid is associated with increased blood loss and transfusion requirements in cardiothoracic surgery M.I. Meesters, A.B.A. Vonk, J.W.A. Romijn, E.K. Jansen, C. Boer groep 3: cardiovasculair 22 Comparison of non-invasive continuous arterial waveform analysis (Nexfin HD) with transthoracic Doppler echocardiography for monitoring of cardiac output A.G.E. van der Spoel, R.A. Bouwman, A.C. Folkers, A.J. Voogel, C. Boer groep 3: cardiovasculair 23 Does pneumatic tube transport influence TEG and ROTEM thromboelastography/ -metry? M.C. Timmerman, R. Van Oerle, Y.M.C. Henskens, M.A.E. Marcus, M.D. Lancé groep 3: cardiovasculair 23 Blood volume measurements by contrast enhanced ultrasound and thermodilution: an in vitro comparison E.H.A. Maas, I.H.F. Herold, M.P.J. Kuenen, A.J.G.H. Bindels, M. Mischi, H.H.M. Korsten groep 3: cardiovasculair 24 Perioperatieve prohormone levels of atrial natriuretic peptide, adrenomedullin and vasopressin during cardiac surgery: an explorative study K.W.L. van Deutekom, A.B.A. Vonk, R.A. Bouwman, S.A. Loer, C. Boer groep 3: cardiovasculair 24 Development of phosphorescent nanovesicles for measuring microvascular PO2 S.I.A. Bodmer, M. Heger, M. Broekgaarden, T. Johannes, D. Gommers, R.J. Stolker, E.G. Mik groep 3: cardiovasculair 25 Helium induced early and late preconditioning in human endothelium K.F. Smit, G.T.M.L. Oei, N.C. Weber, E.S. Stroes, M.W. Hollmann, B. Preckel groep 4: divers 26 Effects of helium on H2O2 induced damage in HUVEC D. van de Vondervoort, K.F. Smit, M.W. Hollmann, B. Preckel, N.C. Weber groep 4: divers 26 Ultrasound assistance for positioning of epidural catheters in neonates and infants M.F. Grapenthin, A.R. Absalom, J.K.G. Wietasch, R.J. Steur groep 4: divers 27 Crystalloid Fluid restriction during pancreatic surgery has no measurable effect on delayed gastric emptying: the results of a double- blinded prospective trial (EPOR) G. van Samkar, O.R.C. Busch, R.J. Bennink, W.J. Eshuis, T.M. Van Gulik, M.G.W. Dijkgraaf, B. Preckel,S.G. De Hert, D.J. Gouma, M.W. Hollmann groep 4: divers 28 A Macintosh laryngoscope blade for videolaryngoscopy reduces stylet use in patients with normal airways R.J. Willems, A. Van Zundert, R. Maassen, R. Lee groep 4: divers 31 In vitro testing of a computer-driven model for Sevoflurane infusion through AnaConDa C.R.M. Barends, J.K. Oosterhuis, T. De Smet, M. Enlund, M.M.R.F Struys groep 4: divers 31 The effects of epidural analgesia on delivery in a dutch teaching hospital: does the rate of caesarean section or instrumental delivery increase? P. Bruins, A.C. Werger, L.S.M. Ribbert, M.E. Kars, H.P.A van Dongen groep 4: divers 32 Can sugammadex save a patient in a simulated cannot intubate cannot ventilate situation at a large teaching hospital? M.M.A. Bisschops, C Holleman, J.M. Huitink

6 FLOW-i PERFORMANCE WHEN YOU NEED IT MOST High-risk patients bring a wide variety of challenges to perioperative care. FLOW-i addresses the ventilatory challenge bringing high quality ventilatory support when needed. FLOW-i brings together high ventilation capabilities with modern anesthesia delivery features, thus enhancing the perioperative care of high risk and common patient categories alike. One of these features is the Volume Reflector tech nology allowing partial re-breathing of exhaled gases; when using low fresh gas flow settings, thanks to its reliability and in the presence of rapidly changing ventilatory conditions, clinicians will have better control to ensure diminished risk for hypoxic mixtures for the patient. The system s module-based design ensures that the unit can be upgraded and adapted as new functions become available, or as clinical needs change. Structural details and operability are based on the ergonomic requirements of busy staff. With FLOW-i, more patients today can benefit from excellent quality ventilation during anesthetic care, enabling high performance when you need it most. The product may be pending regulatory approval to be marketed in your country. Contact your local MAQUET representative for more information. MAQUET Netherlands B.V. Postbus AJ Hilversum ELDERLY PATIENT OBESE PATIENT NEONATAL PATIENT CRITICALLY ILL PATIENT THORACIC PATIENT

7 september 10 nederlands tijdschrift voor anesthesiologie 5 colofon Het Nederlands Tijdschrift voor Anesthesiologie is het officiële orgaan van de Nederlandse Vereniging voor Anesthesiologie. Het stelt zich ten doel om door middel van publicatie van overzichtsartikelen, klinische en laboratoriumstudies en casuïstiek, de verspreiding van kennis betreffende de anesthesiologie en gerelateerde vakgebieden te bevorderen. REDACTIE Kernredacteuren: Dr. C. Boer, Prof. Dr. A. Dahan, Dr. H. van Dongen, Dr. H.G.D. Hendriks, Prof. Dr. S. de Hert, Dr. M. Klimek, Prof. Dr. J. Knape, Prof. Dr. M.A.E. Marcus, Prof. Dr. G. Scheffer. Ondersteunend redacteuren: Drs. M. van der Beek, Drs. E. Bouman, Dr. P. Bruins, Drs. G. Filippini, Dr. D. Gommers, Prof. Dr. M. Hollmann, Dr. W. Klei, Dr. A. Koopman, Prof. Dr. S.A. Loer, Dr. S. Schiere, Dr. B. in het Veld, Dr. K. Vissers, Dr. J.K.G. Wietasch, Drs. E. Wiewel. Secretaresse: mw. W. van Engelshoven Voor informatie over adverteren en het reserveren van advertentieruimte in het Nederlands Tijdschrift voor Anesthesiologie: Mw W. van Engelshoven ntva@mumc.nl REDACTIE-ADRES Nederlands Tijdschrift voor Anesthesiologie, mw. W. van Engelshoven, Academisch Ziekenhuis Maastricht, Afdeling Anesthesiologie, Postbus 5800, 6202 AZ Maastricht; ntva@mumc.nl internet: INZENDEN VAN KOPIJ Richtlijnen voor het inzenden van kopij vindt u op of kunt u opvragen bij de redactie of de uitgever. OPLAGE exemplaren, 5x per jaar Het NTvA wordt uitsluitend toegezonden aan leden van de NVA. Adreswijzigingen: Nederlandse Vereniging voor Anesthesiologie, Postbus 20063, 3502 LB Utrecht, tel , fax , nva@anesthesiologie.nl PRODUCTIE Bladcoördinatie: Drs. Thomas Eldering ( ) Ontwerp: Dimitry de Bruin Eindredactie: Monique de Mijttenaere AUTEURSRECHT EN AANSPRAKELIJKHEID De Stichting tot Beheer van het Nederlands Tijdschrift voor Anesthesiologie Nederlands Tijdschrift voor Anesthesiologie is een wettig gedeponeerd woordmerk van de Nederlandse Vereniging voor Anesthesiologie. Alle rechten voorbehouden. Niets uit deze uitgave mag worden verveelvoudigd, opgeslagen in een geautomatiseerd gegevensbestand of openbaar gemaakt, in enige vorm of op enige wijzen, hetzij elektronisch, mechanisch, door foto kopieën, opnamen of enige andere manier, zonder voorafgaande schriftelijke toestemming. Selectie van abstracts Geachte lezer, Zeven jaar geleden nam ik voor het eerst deel aan de organisatie van de NVA Wetenschapsdag als lid van het Organiserend Comité Wetenschapsdag onder leiding van Gert-Jan Scheffer. De verwachtingen waren gespannen, maar de dag werd een groot succes. Het aantal deelnemers en bezoekers, de kwaliteit van de inzendingen en het niveau van de discussies steeg tijdens de daaropvolgende edities tot een hoog niveau. De NVA Wetenschapsdag biedt een platform aan jonge onderzoekers uit de experimentele en klinische setting, en na zeven jaar kunnen we concluderen dat het aantal (zeer) jonge onderzoekers dat aan deze dag deelneemt nog steeds toeneemt. Deze toename is onder andere een reflectie van de groeiende groep jonge anesthesiologen die structureel betrokken is bij onderzoek binnen ons vakgebied. Daarnaast is er in toenemende mate sprake van studenten geneeskunde die onderzoek doen binnen de perioperatieve setting en vervolgens doorstromen naar de opleiding anesthesiologie. De vraag is welke veranderingen hebben geleid tot de groeiende interesse in onderzoek binnen ons vakgebied. Niet alleen de verplichte wetenschappelijke bijdrage tijdens de opleiding tot anesthesioloog en de inzet van academische en perifere ziekenhuizen voor wetenschappelijk onderzoek binnen de OOR hebben hieraan bijgedragen. We observeren tevens een uitbreiding van de ingezonden manuscripten voor publicatie in het NTvA en een stijging in het aantal subsidies van organisaties als ZonMW en collectebusfondsen die worden toegekend aan een onderzoeksproject binnen de anesthesiologie. Maar bovenal is er een zichtbare toename in de interesse voor het doen van wetenschappelijk onderzoek editorial Christa Boer Plaatsvervangend hoofdredacteur onder AIOS en stafleden anesthesiologie. Immers, zonder onderzoek is er geen innovatie en kennisvermeerdering mogelijk, en hierop wordt in verschillende academische en perifere ziekenhuizen geanticipeerd. De groeiende aandacht voor wetenschappelijk onderzoek binnen de opleiding tot anesthesioloog biedt niet alleen de nieuwe generatie stafleden handen en voeten voor het opzetten van eigen projecten binnen de afdeling, maar motiveert ook ervaren stafleden om te participeren in wetenschappelijk onderzoek. Daarmee is een belangrijke stap gezet richting integratie van wetenschap met opleiding en klinische praktijk binnen het vakgebied Anesthesiologie. Dit jaar ontving het Organiserend Comité Wetenschapsdag dusdanig veel inzendingen voor de NVA Wetenschapsdag dat een selectie van abstracts moest worden gemaakt. De voor u liggende uitgave van het NTvA is geheel gewijd aan deze abstracts en aan de NVA Wetenschapsdag in het algemeen. Voor mij is deze uitgave van het NTvA niet alleen een prachtige illustratie van het stijgende niveau van perioperatief wetenschappelijk onderzoek in Nederland, maar tevens de eerste uitgave waaraan ik mag meewerken als plaatsvervangend hoofdredacteur. Ik hoop daarmee in de komende jaren nog op veelzijdige wijze te kunnen bijdragen aan het verbeteren van de infrastructuur en het omgevingsklimaat voor het doen van perioperatief wetenschappelijk onderzoek. Een voorbeeld hiervan vormt de geaccrediteerde nascholing die het NTvA in de toekomst zal aanbieden met als doel de kennis te verbreden rondom niet-alledaagse thematiek en nieuwe ontwikkelingen binnen ons vakgebied. Ik wens u veel plezier met het lezen van deze editie van het NTvA. Christa Boer

8 PSSST! Bij doorbraakpijn heb je geen tijd voor omwegen en kies je liever de snelste weg. Daarom is er nu Instanyl : de eerste intranasale toedieningsvorm van fentanyl. Instanyl maakt het mogelijk om doorbraakpijn zelf in de hand te houden. Meer weten? NIEUW! Tegen doorbraakpijn bij kanker Snel 1-3 Kortwerkend 2,3 Eenvoudig 4 HET NIEUWSTE SNUFJE TEGEN DOORBRAAKPIJN BIJ KANKER

9 september 10 nederlands tijdschrift voor anesthesiologie 7 oral presentations oral presentation Benzethonium increases the cytotoxicity of S(+)-ketamine in lymphoma, neuronal and glial cells F. Stevens 1, R. Werdehausen 2, N. Gaza 2, H. Hermanns 2, M.W. Hollmann 1, S. Braun 2 1 AMC, AMSTERDAM, the Netherlands 2 Universitätskliniken Düsseldorf, Düsseldorf, Germany Ketamine has been demonstrated to be neurotoxic in animals as well as in patients. Preservatives added to ketamine have been accused to induce neurotoxicity. Therefore, we investigated whether the most widely used preservative of ketamine - benzethonium chloride - enhances the toxicity of S(+)-ketamine in vitro in lymphoma, neuroblastoma cells and primary astrocytes. Human Jurkat T-Lymphoma-, neuroblastoma cells (SHEP) and primary rat astrocytes were incubated for 24h with commercially available S(+)-ketamine containing benzethonium, as well as only with S(+)-ketamine or benzethonium chloride alone. The rate of early- and late-apoptotic cells was evaluated after double-staining with Annexin V and 7AAD by flowcytometry. In a second step, the additivity of toxicity was investigated in neuroblastoma cells and astrocytes by means of isobolograms using a XTT assay to measure overall viability (mitochondrial activity). All experiments were performed three times and the results are presented as mean ± CI (95%). In all cell types benzethonium increased the toxicity of S(+)-ketamine. The main mechanism of toxicity was apoptosis as displayed by flowcytometry. The isobolograms of combined toxicity of benzethonium and S(+)-ketamine demonstrated additive toxicity in neuroblastoma cells (Fig. A) and astrocytes (Fig. B). The straight black line connects the LD50 of S(+)-ketamine and benzethonium as seen during pure additivity. The CI (95%) is represented by dashed lines. The black data point indicates the calculated halfmaximal concentrations (LD50) resulting from the experimentally observed doseresponse relationship of S(+)-ketamine and benzethonium in combination. We conclude that benzethonium increases the local toxicity of ketamine in cells of hematopoetic, neuronal and glial origin in an additive manner. Therefore, neuraxial application of ketamine alone and especially in solutions containing benzethonium should be restricted. oral presentation The impact of morphine on tumor progression and metastasis formation in a preclinal mouse model of metastatic breast cancer C.W. Doornebal 1, M. Ciampricotti 1, Cheei-Sin Hau 1, M.W. Hollmann 2, J. Jonkers 1, K.E. de Visser 1 1 Netherlands Cancer Institute, Amsterdam, the Netherlands 2 Academic Medical Center, Amsterdam, the Netherlands Opioid analgesics are the mainstay and most effective treatment of cancer-related pain. Nevertheless, two clinical studies recently reported an increased risk of recurrence or metastasis formation in surgical breast- and prostate cancer patients treated with morphine. These potentially deleterious side-effects might be explained by morphine s proangiogenic and immune inhibitory actions. Our aim was to test this hypothesis utilizing a novel preclinical mouse model of breast cancer metastasis formation. The effects of morphine on tumor progression and metastasis formation are tested in a transplantation-based mouse model of metastatic breast cancer. In this model, donor tumors derived from a conditional mouse model of spontaneous breast cancer formation are transplanted into mammary glands of wild-type FVB/N mice. Transplanted tumors are subsequently allowed to establish, after which mastectomy is performed. Following surgery, mice develop clinically overt metastases for which they eventually need to be sacrificed. Using this model, morphine s impact on two distinct phases in tumor development are studied by treating mice either during (a) primary tumor development or (b) post surgery while they are at risk for metastasis formation. Preliminary results suggest that effective analgesic doses of morphine do not accelerate primary tumor growth in our model (median tumor latencies 29 vs. 35 days for NaCl0.9% and morphinetreated animals, respectively). Likewise, immune profiles of peripheral blood and tumors were not quantitatively affected by morphine (influx of CD45+ cell into

10 8 nederlands tijdschrift voor anesthesiologie september 10 abstracts 2010 the tumor: 17.9 ±3.1% vs. 16.7±1.5% for control and morphine-treated animals, respectively). We are currently addressing whether morphine has an effect on metastasis formation in vivo. s This study might provide a significant contribution to the recently evolved controversy regarding the use of morphine in cancer patients. In addition, potential effects of morphine on tumor progression and metastasis formation can be studied mechanistically in our model. oral presentation Effect of spinal cord stimulation on tactile hypersensitivity is potentiated by a sub-effective dose of ketamine in an animal model of chronic neuropathic pain M. Truin, S.P.M. Jannsen, R. Deumens, M. van Kleef, E.A.J Joosten AZM, MAASTRICHT, the Netherlands Although Spinal Cord Stimulation (SCS) is an established therapy for chronic neuropathic pain, still 60% of patients do not respond adequately to trial stimulation. These so called non-responders do not receive a permanent implantation for pain relief. The induction and maintenance of central sensitization, the origin for (chronic) neuropathic pain, is thought the be the resultant of the activation of the N-Methyl- D-Aspartate (NMDA) receptor in the dorsal horn. Blocking the NMDA receptor has been proven to attenuate neuropathic pain, although the undesirable side effects limits its use. The effect of SCS on the NMDA receptor is unknown and we therefore wanted to elucidate the possible role of the NMDA receptor in SCS induced pain relieve. Rats (n=15) received a partial ligation of the sciatic nerve for the induction of neuropathic pain. Behavioral signs of neuropathic pain were measured using von Frey monofilaments. After implantation of the electrodes, animals received 30 minutes of SCS (frequency 50 Hz, pulse width 0.2 ms). Non-responders to SCS received an intrathecal individual determined subeffective dose of the NMDA receptor antagonist ketamine and subsequently received SCS. Responders to SCS also received their individual determined subeffective dose of ketamine. All 15 animals developed chronic neuropathic pain. From these neuropathic animals 8 (53%) did not respond to SCS. However, the combined treatment of SCS and sub-effective dose of ketamine resulted in a significant pain relieve in all these eight previously non-responders. In the animals previously responding to SCS (n=7), subeffective ketamine combined with SCS resulted in a prolonged attenuation of the neuropathic pain compared to SCS alone. A sub-effective dose of intrathecal ketamine is able to convert non-responders to SCS into responders to SCS and prolong pain relieve. oral presentation The effect of helium on the immune system ex-vivo G.T.M.L. Oei, K.F. Smit, D. van de Vondervoort, N.C. Weber, M.W. Hollmann, B. Preckel AMC, AMSTERDAM, the Netherlands Experimental studies show that helium protects myocardial and neuronal tissue against ischemia/reperfusion damage. If helium is introduced to protect against clinical ischemia/reperfusion injury, it has to be evident that no effects on cytokines and chemokines pivotal for the defense against bacterial infections exist. From other organ protective inhalational gases such as volatile anesthetics and xenon, immunomodulatory effects are known. We investigated whether a 30-minute episode of helium breathing affects proinflammatory cytokines TNFalpha, IL-1beta and IL-6 and chemokine Il-8 in whole blood after stimulation with lipopolysaccharide (LPS). This study with cross-over design was approved by the ethical committee of the Academic Medical Center (METC). Healthy, male volunteers (n=12) inhaled heliox (79% helium and 21% oxygen) and air. Blood sampling was done at T0 (baseline), T1 (25 min inhalation), T2, T3, T4 and T5 (1 h, 2 h, 6h and 24 h after inhalation respectively). C-reactive protein (CRP) was measured at T0 of each experimental cycle, leukocyte counts and differentials were analyzed at T0, T3 and T5 of each cycle. After sampling, whole blood was immediately incubated with (LPS) or with RPMI (as control, CON) for 2, 4 and 24 hours. TNF-alpha, IL-1beta, IL-6 and Il-8 levels were analyzed by cytometric bead array. Statistical analysis: Wilcoxon test for matched samples, all data are shown as mean ± SEM. After 0, 2, 4 and 24 hours of incubation with LPS, the amount of TNF-alpha (see figure), Il-1beta, Il-6 and Il-8 (pg/ml) in whole blood was not affected by heliox inhalation in comparison to air at all timepoints. No differences in CRP, leukocyte counts and differentials were found between groups. A 30-minute episode of helium inhalation does not alter TNF-alpha, Il-1beta, Il-6 and Il-8 levels after incubation with LPS.

11 september 10 nederlands tijdschrift voor anesthesiologie 9 oral presentations Caption 1. Figure 1. oral presentation Reversion of high-fat diet normalizes myocardial function and sphingolipid levels in rats C.E. van den Brom 1, R.A. Bouwman 1, M.H. Graeler 2, D.M. Ouwens 3, M. Diamant 1, C. Boer 1 1 VU Medisch Centrum, AMSTERDAM, the Netherlands 2 Hannover Medical School, HANNOVER, Germany 3 German Diabetes Center, DüSSElDORf, Germany The dietary balance between carbohydrates and lipids influences the ischemic tolerance and sevoflurane-induced cardioprotection in the rat heart. These findings suggest that alterations in dietary intake may improve the sensitivity of the heart to stress. As a first step, we explored the possible beneficial effects of reversal of high-fat diet-induced metabolic imbalance on myocardial function. Male Wistar rats (n=8 per group) were exposed to a high-fat (HFD) or control diet (CD) for 8 weeks. A third group of HFDfed rats reversed after 4 weeks to CD for 4 consecutive weeks. Before sacrifice, rats underwent an oral glucose tolerance test and echocardiography. Myocardial function was evaluated by fractional shortening (FS), isovolumic relaxation time (IVRT) and E deceleration time (Edec). Left ventricular tissue was used for analysis of myocardial sphingolipid metabolism. Compared to controls, HFD feeding was associated with impaired glucose tolerance, decreased myocardial systolic function (FS, -23%, p<0.05) and impaired early diastolic function (IVRT +43% and Edec +21%, both p<0.05). This was accompanied by decreased myocardial sphingolipid levels including C18-ceramide (-36%), sphingomyelin (-30%), phosphatidylcholine (-67%) and sphingosine (-18%) (all p<0.05). Reversion of HFD to CD resulted in normalization of the glucose tolerance. Moreover, myocardial function improved as shown by increased FS (+12%, p<0.05) and shortened IVRT (-40%, p<0.05) and Edec (-11%, p<0.05) as compared to HFD-fed rats. This was accompanied by recovery of myocardial sphingolipid metabolism. HFD-induced metabolic alterations are associated with impaired myocardial sphingolipid metabolism and function, which could be normalized by a diet intervention. These results suggest that a dietary change may improve myocardial function. Further research is warranted to conclude on the effect of dietary changes on ischemic tolerance in diet-induced metabolic imbalance.

12 10 nederlands tijdschrift voor anesthesiologie september 10 abstracts 2010 oral presentation Effect of ketamine on endogenous pain modulation in healthy volunteers M. Niesters, E.Y. Sarton, A. Dahan LUMC, Leiden, the Netherlands Inhibitory and facilitatory descending pathways, originating at higher central nervous system sites modulate activity of dorsal horn nociceptive neurons, and thereby influence pain perception. Diffuse Noxious Inhibitory Control (DNIC) and Offset Analgesia (OA) are two mechanisms involved in descending inhibition. Dysfunction of inhibitory pathways or a shift in the balance between pain facilitation and pain inhibition has been associated with the development of chronic pain. The authors previously showed that the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine produces hyperalgesic responses to acute noxious experimental pain following the treatment period. The present study investigates the effect of a ketamine infusion on subsequent DNIC and OA responses to determine whether ketamine has an influence on descending pain control. Ten healthy subjects (4 men/6 women) received a 1-h placebo or S(+)- ketamine (40 mg per 70 kg) infusion on two separate occasions in random order. Upon the termination of the infusion DNIC and OA responses were obtained. After placebo treatment significant descending inhibition of pain responses was present for DNIC and OA. In contrast, after ketamine infusion, no DNIC was observed, but rather a significant facilitatory pain response (p < 0.01); the OA response remained unaffected. These findings indicate that the balance between pain inhibition and pain facilitation was shifted by ketamine towards pain facilitation and suggest that hyperalgesia following ketamine is associated with descending facilitatory modulation of spinal nociceptive responses. The absence of an effect of ketamine on OA indicates differences in the mechanisms and neurotransmitter influences between OA and DNIC. posterdiscusson Population pharmacokinetic-pharma- co dynamic modeling of ketamine-induced pain relief of chronic pain M.J. Sigtermans, E. Olofsen, A. Dahan LUMC, Leiden, the Netherlands Aims Pharmacological treatment of chronic (neuropathic) pain is often disappointing. In order to enhance our insight in the complex interaction between analgesic drug and chronic pain relief, we performed a pharmacokinetic-pharmacodynamic (PK-PD) modeling study on the effect of S(+)-ketamine on pain scores in Complex Regional Pain Syndrome type 1 (CRPS-1) patients. Sixty CRPS-1 patients were randomly allocated to received a 100-h infusion of S(+)-ketamine or placebo. The drug infusion rate was slowly increased from 5 mg/h (per 70 kg) to 20 mg/h based upon the effect/side effect profile. Pain scores and drug blood samples were obtained during the treatment phase and pain scores were further obtained weekly for another 11 weeks. A population PK-PD model was developed to analyze the S(+)-ketaminepain data. Plasma concentrations of S(+)-ketamine and its metabolite decreased rapidly upon the termination of S(+)-ketamine infusion. The chance for an analgesic effect from ketamine and placebo treatment was 70% and 20%, respectively. The pain data were well described by the PK-PD model with parameters C 50 = 10.5 ± 4.8 (population value ± SE) ng/ml (95% ci ng/ml) and t½ for onset/offset = 10.9 ± 4.0 days ( days). Discussions Long-term S(+)-ketamine treatment is effective in causing pain relief in CRPS-1 patients with analgesia outlasting the treatment period by 50 days. These data suggest that ketamine initiated a cascade of events, including desensitization of excitatory receptor systems in the central nervous system, which persisted but slowly abated when ketamine molecules were no longer present. posterdiscussion Increased perioperative complications after major vascular surgery in patients with a preoperative abnormal exercise blood pressure response I. de Liefde, G.M.J.M. Welten, H.J.M Verhagen, R.T. van Domburg, R.J. Stolker, D. Poldermans Erasmus MC, Rotterdam, the Netherlands Recent studies have shown that hypertensive or hypotensive blood pressure response during a preoperative treadmill exercise test in patients with peripheral arterial disease (PAD) is associated with a two fold increased risk of cardiovascular events and mortality. However, it is unknown if these patients also experience an increased complication risk during major vascular surgery. Between 1993 and 2006, 665 consecutive PAD patients underwent elective major vascular surgery (carotid endarterectomy, abdominal aorta repair or lower extremity revascularization surgery) in the Erasmus MC.

13 september 10 nederlands tijdschrift voor anesthesiologie 11 posterdiscussions Hypertensive blood pressure response at the preoperative treadmill exercise test, was defined as a difference between the exercise systolic blood pressure and resting systolic blood pressure of more than 55mmHg. Hypotensive blood pressure response was defined as a drop in exercise systolic blood pressure below resting systolic blood pressure. Perioperative complications (infection, myocardial infarction, angina pectoris, cardiac arrhythmia, heart failure, cerebrovascular accident or spinal cord ischemia, dialyses, amputation, thrombectomy, re-operation and death) occurring within one month of the major vascular surgery were collected using medical records. Myocardial infarction, angina pectoris, heart failure, new cardiac arrhythmia s and 30-day cardiac mortality together were classified as cardiac complications. Patients with a hypertensive blood pressure response during a preoperative exercise test (n=66) demonstrated a higher risk of thrombectomy (HR %CI ( )) compared to patients with a normal blood pressure response (n=582). Patients with a hypotensive blood pressure response (n=18) showed an increased risk of myocardial infarction (HR % CI ( )) and cardiac complications (HR % CI ( ). Patients with an abnormal blood pressure response have an increased risk of cardiovascular complications after elective major vascular surgery. posterdiscussion Pharmacokinetics of a highly concentrated intranasal midazolam spray in healthy adult volunteers A.A. Fiddelers 1, N.M.L. Veldhorst 1, P-H.M. Van der Kuy 2, C. Neef 1, M.A.E. Marcus 1 1 Maastricht Universitair Medisch Centrum, Maastricht, the Netherlands 2 Orbis Medisch Centrum Sittard, Sittard, the Netherlands Intranasally administered midazolam has been introduced as an alternative next to rectally administered diazepam for the acute treatment of epileptic seizures. In order to avoid first-pass elimination, a highly concentrated nosespray should be administered. The purpose of this study was to investigate pharmacokinetics and tolerability of midazolam in a new formulation, administered as a highly concentrated intranasal (IN) spray, compared with intravenous (IV) administration in healthy adult volunteers. Seven healthy volunteers were enrolled in a non-blind, randomised, crossover study. Subjects were given both IN and IV midazolam, with a washout period of at least five Figure 1. Intravenous and intranasal midazolam days between treatments. The newly developed IN midazolam formulation consisted of 5 mg midazolam base per 0.1 ml (one spray), and was once administered in one nostril. The IV midazolam solution (2.5 mg) was infused over 10 seconds. IV data were converted to 5.0 mg. Blood samples were taken before administration, and at regular intervals up to 240 minutes after dosing. Pharmacokinetic data (Cmax, Tmax, T1/2, AUC) were analysed using one-compartmental analysis. Mean bioavailability of IN midazolam was 80%. Cmax of 82 ng/ml was reached 46 minutes after IN administration, and Cmax was found 105 ng/ml after IV administration. For IN administration, a T1/2 of 1.8 hours (SD 0.35) was calculated, compared to 2.2 hours (SD 0.41) after IV administration. Few side effects were experienced by the subjects. A high concentration (60 ng/ml) was reached within 15 minutes after administration, which is comparable with results found in other studies. However, they found Tmax of minutes, while in our study Tmax was 46 minutes. This is probably due to nasoral absorption. Furthermore, bioavailability after IN administration of midazolam was high, showing that a highly concentrated midazolam solution is a good alternative for other administration forms.

14 12 nederlands tijdschrift voor anesthesiologie september 10 abstracts 2010 posterdiscussion Myocardial contrast echocardiography for the study of perioperative myocardial perfusion C.S.E. Bulte, J. Slikkerveer, O. Kamp, S.A. Loer, C. Boer, R.A. Bouwman VU medisch centrum, Amsterdam, the Netherlands General anesthesia is associated with increased activity of the sympathetic autonomic nervous system, which may lead to alterations in myocardial blood flow (MBF). Historically, the lack of suitable intraoperative noninvasive imaging techniques prohibited investigation of the influence of general anesthesia on MBF in healthy subjects. Myocardial contrast echocardiography (MCE) is a recently developed noninvasive method for assessment of MBF. In this feasibility study of intraoperative MCE, we investigated the effect of sympathetic stimulation on MBF and the effect of general anesthesia on this relation. Five cardiovascular healthy men (age years) scheduled for general anesthesia were included. Integrity of cardiovascular autonomic control was confirmed using autonomic function tests. MCE was performed before and during the administration of 1.0 MAC sevoflurane and included MBF measurements at rest, during adenosine-induced hyperemia and in response to sympathetic stimulation by cold pressor testing (CPT). MCE provides an estimate of MBF expressed in intensity units per second (IU/s) by analysis of replenishment curves obtained during continuous contrast infusion. Flow reserve was calculated by MBF hyperemia/cpt/mbf rest. Data are given as mean±sd. In the preoperative setting, basal MBF was 7.7±5.7 IU/s and increased to 16.4±5.1 IU/s during hyperemia and to 10.3±4.7 IU/s during CPT (both P<0.05). Intraoperatively, basal MBF was 8.4±5.2 IU/s, which was augmented to 21.4±14.2 IU/s during hyperemia (P=0.03) and to 15.0±10.5 IU/s during CPT (P=0.09). Alterations in MBF in response to stress and sympathetic stimulation were comparable for the preoperative and intraoperative measurements, indicated by flow reserves of 3.0±1.6 and 2.8±1.7 during hyperemia (P>0.05) and 1.7±0.7 and 1.9±0.9 during CPT (P>0.05). MBF measurements using MCE are feasible in the perioperative setting and provide a useful tool for studying the effect of general anesthesia on myocardial perfusion during hyperemia and increased sympathetic stimulation. posterdiscussion Prediction of early liver dysfunction after orthotopic liver transplantation using indocyanine green plasma disappearance rate J.J. Vos, T.W.L. Scheeren, J.K.G. Wietasch Universitair Medisch Centrum Groningen, Groningen, the Netherlands Although the 1 and 5 year survival after orthotopic liver transplantation (OLT) has risen above 85% and 75%, respectively, morbidity and mortality is mainly determined in the early post-operative period. During this period, using physical examination and conventional laboratory findings, it is yet not easy to adequately assess initial graft function. Indocyanine Green Plasma Disappearance Rate (PDR-ICG) has been shown to predict early post-operative complications following OLT when measured during the first postoperative days.(1)(2) We evaluated the predictive role of intraoperative PDR-ICG values in the prediction of early post-operative complications after OLT. In this study, we retrospectively analyzed data from 62 patients undergoing OLT. Early post-operative complications were defined as the occurrence of primary non-function, hepatic artery or portal vein thrombosis, sepsis, need for surgical re-intervention, acute rejection or early ischemic biliary lesions. PDR-ICG was measured non-invasively by pulse dye densitometry at the end of surgery and was correlated with postoperative complications. ROC analysis was performed to determine the accuracy and optimal cut-off value for predicting early liver dysfunction. PDR-ICG at the end of surgery was significantly lower in patients with than in patients without early post-operative complications (23,0 %/min ± 6,9 versus 27,2 %/min ± 8,2; p<0,05). ROC analysis revealed an area under the curve of 0,70 and a cut-off PDR-ICG value for predicting good early graft function was determined to be 23,9%/min with a sensitivity of 64,7% and a specificity of 72,7%. A further subgroup analysis could not determine specific complications to be predicted by intraoperative PDR-ICG measurements. Intraoperative measurement of PDR-ICG in OLT patients is a useful tool for prediction of early liver dysfunction. r e f e r e n c e s 1. Levesque E, et al. Liver Transpl 2009;15: Olmedilla L, et al. Liver Transpl 2009;15:

15 september 10 nederlands tijdschrift voor anesthesiologie 13 posterdiscussions posterdiscussion Safety of retransfusing shed blood after local infiltration analgesia in total knee arthroplasty B.J.W. Thomassen 1, L.D. Pool 2, R.E. van der Flier 2, R.D. Stienstra 3, B.A. in t Veld 4 1 MC Haaglanden, Den haag, the Netherlands 2 Afdeling Orthopedie, Medisch Centrum Haaglanden, Den haag, the Netherlands 3 Afdeling Anesthesiologie, St. Maartenskliniek, Nijmegen, the Netherlands 4 Afdeling Anesthesiologie, Medisch Centrum Haaglanden, Den haag, the Netherlands High volume infiltration with local anaesthetics (LIA) during totalkneearthroplasty (TKA) for postoperative pain relief may be beneficial as compared to traditional methods. Retransfusion drains are used in TKA as alternative for allogeneic blood transfusions. When combining both modalities, recollected blood may contain large doses of local anaesthetics potentially leading to systemic toxicity during retransfusion. We investigated the safety of combining LIA and retransfusion of shed blood. Twenty patients scheduled for primary TKA were included. During surgery two peri-articular injections with ropivacaine (total 375 mg) were given. Patients received an intraarticular retransfusion drain and a wound catheter for continuous infusion of ropivacaine (8 mg/hr) for 24 hours. Blood collected in the retransfusion device, was not retransfused but used for laboratory analyses. Patients blood samples were taken immediately after surgery, 3, 6 and 24 hours postoperatively. We predicted cumulative ropivacaine concentrations using patient and shed blood data from 6 hours postoperatively. Assuming instant retransfusion we estimated cumulative plasma concentrations. Total ropivacaine concentration was highest 24 hours postoperatively and unbound ropivacaine was maximal predominantly at 6 hours. Peak total ropivacaine concentrations ranged from 684 to 1886 mcg/l and the unbound ropivacaine concentrations varied between 32 and 105 mcg/l. At 6 hours on average 591 ml shed blood was collected. Assuming retransfusion, on average 13 mg (6-18mg) of unbound ropivacaine would have been administered intravenously. The model used to estimate cumulative ropivacaine plasma levels showed that instant retransfusion would have led to plasma levels of below 0.6 mg/l. Under the conditions in our study it is safe to use LIA in combination with continuous infusion of ropivacaine. Moreover, it also appears safe to retransfuse blood collected with the Bellovac ABT system in combination with LIA and continuous infusion of ropivacaine through an indwelling catheter, although formal testing is required. groep 1 - pijn Pain symptoms accompanying chronic post sternotomy pain, a cross-sectional cohort study N.J. van Leersum 1, R.L. van Van Leersum 2, H.F. Verwey 3, R.J.M. Klautz 3 1 MC Haaglanden, lok. Westeinde, Den haag, the Netherlands 2 Ziekenhuis Bronovo, Den haag, the Netherlands 3 LUMC, Leiden, the Netherlands Instruction Despite the technical developments in surgical procedures, the incidence of chronic post-sternotomy pain (CPSP) is 30%. Many theories for its cause have been proposed in literature, but the etiology is still not clear. The incidence and etiology of painfull sites unrelated to the chest wall incision (neck, shoulder, arms, back) has been poorly evaluated and considered a separate complication. This exploratory study was designed to evaluate all pain symptoms accompanying CPSP after cardiac surgery. Our hypothesis was that all pain symptoms post sternotomy were part of a united pain syndrome. A questionnaire was sent to 1097 patients that underwent sternotomy in the Leiden University medical centre. All patients that reported sternal pain and a random sample of patients without sternal pain were examined for pain of head, neck, back, chest and upper extremities. Pain symptoms in patients without sternal pain were contrasted with patients with sternal pain. A 36% incidence of CPSP was reported in the questionnaire. In 277 patients, all pain locations were compared in two groups: 189 patients with sternal pain and 88 patients without stermal pain. All patients with anamnestic paint, had a painful sternum on palpation. The incidence of pain of head (33%), neck (33%), shoulder (45%), between the scapulae (38%), chest wall (22%) and arms (21%) was high and significantly more common in patients with CPSP. No surgical or demographic factors, with exception of female gender, were consistent predictors of sternal pain. The results of this study show that CPSP is an extensive and complex pain syndrome which includes, alongside sternal pain, pain of the musculoskeletal components of the trunk, upper extremity, head and neck. In patients without a tender sternum, other pain symptoms were rarely seen.

16 14 nederlands tijdschrift voor anesthesiologie september 10 abstracts 2010 groep 1: pijn A reinforced microglial response as as mechanism underlying long-term changes in paijn sensitivity after neonatal repetitive pain L. Knaepen 1, R. Deumens 1, D. Tibboel 2, J. Patijn 1, E.A.J. Joosten 1 1 Maastricht University Medical Centre/ Anesthesiologie, Maastricht, the Netherlands 2 Erasmus-MC/Sophia Children s Hospital, Rotterdam, the Netherlands Neonates admitted to intensive care units and exposed to repetitive pain stimuli for diagnostic purposes, have long-term changes in pain sensitivity at baseline and in pathological conditions. Underlying mechanisms responsible for these changes are unknown. No experimental model mimicking both neonatal repetitive pain and adult inflammatory pain is currently available. Objectives 1. To develop an animal model for neonatal repetitive pain exposure and its long-term pain sensitivity consequences. 2. To investigate glial activation in the spinal cord as a possible underlying mechanism. Neonatal rat pups received four needle pricks per day during the first week of life into the left hind paw. Control rat pups received tactile stimuli. Eight weeks later all animals received an ipsilateral hind paw injection with complete Freund s adjuvant (CFA), resulting in painful inflammation. Mechanical pain thresholds were measured weekly during development and 24h following CFA injection in the adult rat. Lumbar spinal cord sections were stained for microglial (Iba1) and astroglial (GFAP) activation. Relative proinflammatory cytokine (IL1β, TNFα and IL6) mrna-concentrations were determined with RT-PCR. Neonatal needle pricking did not result in altered baseline thresholds to mechanical stimuli during development. Animals exposed to neonatal needle pricks showed increased pain sensitivity to mechanical stimuli following inflammation in adulthood. Microglial activation was apparent at the ipsilateral lumbar dorsal horn of these animals. Pro-inflammatory cytokine mrnaconcentrations did not differ between the groups. 1. Repetitive needle pricking in neonatal rats results in long-term consequences on inflammatory pain sensitivity, relating to clinical observations of increased pathological pain sensitivity in children which were exposed to neonatal pain. 2. Long-term changes in pain sensitivity following neonatal pain exposure might be related to altered microglial activation later in life. groep 1: pijn Translational research on central neuropathic pain and neuroinflamation after experimental spinal cord injury S.F.J. van Gorp 1, E.A.J. Joosten 2, P. Martínez-Martínez 3, M. Losen 3, M. de Baets 3, M. van Kleef 2, R. Deumens 2 1 Maastricht University Medical Centre, Maastricht, the Netherlands 2 Maastricht University Medical Center, Maastricht, the Netherlands 3 Department of Neuroscience, Maastricht University, Maastricht, the Netherlands Progression in therapeutic efficacy in Spinal Cord Injury (SCI) induced Central Neuropathic Pain (CNP) is hampered by lacunae in the comprehension of its pathophysiology. Importantly, SCI does not cause CNP per se, but, thus far, no predictors for CNP after SCI have been found. Data from animal studies indicate a role of specific neuroinflammatory processes in established CNP. However, it remains unknown (1) whether such neuroinflammatory processes are indeed differentially activated in CNP conditions and (2) which molecular cues may predict CPN following SCI. Objectives 1. To investigate whether an existing SCI animal model results in distinct CNP and non-cnp groups 2. To identify early neuroimmune-related predictors for the development of CNP (future plans) Method Adult Sprague Dawley rats ( grams) underwent either a moderate T9 spinal cord contusion injury (SCCI, n=19), a laminectomy (sham control, n=4), or no surgical procedure (naïve control, n=4). At baseline and early (two weeks) post-sci mechanical nociceptive thresholds of the hindpaws were assessed with a dynamic plantar linear aesthesiometer. Two groups were assigned with the k-means clustering method based on the relative decreases of the hindpaw withdrawal responses. The clustering method resulted in a CNP group (n=10), with a statistically significant decrease in nociceptive thresholds of 25.1% (SD±3.7%, P<0.01), and a non-cnp group (n=9), which remained at baseline values (+4.7%, SD±3.7%, P=0.30). Also, the control animals did not show any change in thresholds (-2.1% SD±6.8%, P=0.53), and between-group differences were only present between CNP vs. non-cnp and CNP vs. control animals (P<0.01 and P=0.01, respectively). A moderate T9-SCCI results in CNP and non-cnp rats. Therefore, analysis of the gene-expression in central nervous tissue from these animals can help defining specific (neuroinflammatory) molecular cues as predictors for CNP.

17 september 10 nederlands tijdschrift voor anesthesiologie 15 groep 1 groep 1: pijn Time-dependent plasticity of the spinal GABAergic system in relation to the degree of neuropathic pain S.P.M. Janssen 1, M. Truin 1, M. Van Kleef 2, Elbert A. Joosten 2 1 Maastricht University, Maastricht, The Netherlands 2 Maastricht University Medical Centre, Maastricht, The Netherlands A decreased GABA inhibitory tone is known to contribute to a generalized state of neuropathic pain following peripheral neuropathy. Here we explore whether histological changes in the GABAergic system are related to the degree of mechanical allodynia in both acute and chronic neuropathic pain. Male Sprague Dawley rats were subjected to partial sciatic nerve injury and hind paw withdrawal thresholds to mechanical stimuli were determined before and after injury. Dorsal horn laminae I-III of the L4-L5 spinal cords of animals with different degrees of mechanical allodynia (mild: g (n=7) or moderate: 1,4-6.0 g (n=8)) were analyzed for GABA-immunoreactivity and the number of GABAergic cells at three (acute) or sixteen (chronic) days post-injury. Data (mean±sem) were compared to sham-operated animals (n=8) unless stated differently. No changes in GABA-immunoreactivity (89%±5% vs 100%±6%) or GABAergic cell numbers (44±3 vs 49±2) were observed in both acute mild and moderate allodynic rats. In contrast, GABA-immunoreactivity was increased in chronic neuropathic rats (119%±7% vs 100%±4%, p<0.05), without differences between mild and moderate allodynic animals (115%±13% vs 122%±8%). The number of GABAergic cells did not change when comparing mild and moderate allodynic animals to controls (50±3 vs 48±3 vs 47±2). There was no correlation between both GABA-immunoreactivity or the number of GABAergic cells and the degree of mechanical allodynia. Our histological data do not suggest an important role of the GABAergic system during the acute phase of neuropathic pain. In contrast, chronic neuropathic pain coincides with increased dorsal horn GABA-immunoreactivity which is not due to alterations in the GABAergic cell number. Changes in the GABAergic system were not related to the degree of chronic neuropathic pain. groep 1: pijn Opioid chronopharmacology: influence of timing of infusion on fentanyl s analgesic efficacy M.C.A. Boom 1, J. Grefkens 2, E.L.A. van Dorp 1, E. Olofsen 1, L.P.H.J. Aarts 1, A. Dahan 1, E.Y. Sarton 1 1 LUMC, Leiden, the Netherlands 2 Rijnland Ziekenhuis, Leiderdorp, the Netherlands Background Chronopharmacology studies the effect of the timing of drug administration on drug effect. Here we measured the influence of four timing moments on fentanyl-induced antinociception in healthy volunteers. Eight subjects received 2.1 μg/kg intravenous fentanyl at 2 PM and 2 AM, with at least 2 weeks between occasions, eight others at 8 AM and 8 PM. Heat pain measurements using a thermode placed on the skin were taken at regular intervals for 3-h and Verbal Analogue Scores (VAS) were then obtained. The data were modeled with a sinusoid function using the statistical package NONMEM. A significant circadian sinusoidal rhythm in the antinociceptive effect of fentanyl was observed. Variations were observed for peak analgesic effect, duration of effect and the occurrence of hyperalgesia. A peak in pain relief occurred late in the afternoon (5:30 PM) and a trough in the early morning hours (5:30 AM). The difference between the peak and trough in pain relief corresponds to a difference in VAS of 1.3 to 2 cm. Only when given at 2 AM did fentanyl cause a small but significant period of hyperalgesia following analgesia. No significant changes were observed for baseline pain, sedation or the increase in end-tidal CO 2. s The variations in fentanyl s antinociceptive behavior are well explained by a chronopharmacodynamic effect originating at the circadian clock in the hypothalamus. This may be a direct effect through shared pathways of the circadian and opioid systems or an indirect effect via diurnal variations in hormones or endogenous opioid peptides that rhythmically change the pain response and/or analgesic response to fentanyl.

18 16 nederlands tijdschrift voor anesthesiologie september 10 abstracts 2010 groep 1: pijn Intrathecal delivery of VEGF165 following experimental spinal cord injury results in modest attenuation of mechanical allodynia S.G.A. van Neerven, E.A.J. Joosten, R. Deumens Maastricht Universitair Medisch Centrum, Maastricht, the Netherlands Neurodegeneration and inflammatory responses in glial cells are thought to contribute to central pain following spinal cord injury. Neuroprotective therapies may therefore attenuate central pain by limiting tissue damage and inflammation. Vascular endothelial growth factor (VEGF) treatment has been shown to have neuroprotective effects following spinal cord injury, but effects on central pain remain unknown. Objective Investigate the effect of early VEGF treatment on mechanical allodynia and thermal hyperalgesia following spinal cord injury in the rat. Female Sprague Dawley rats were subjected to spinal cord contusion injury (SCCI) at low thoracic (T9) level and received daily intrathecal bolus injections of VEGF165 for one week following injury (n=9). Hindpaw withdrawal thresholds and latencies (for mechanical and thermal stimuli, respectively) were determined up to eight weeks post-injury. Tissues were processed for analysis of putative cellular and molecular mechanisms underlying the pain-related effects. SCCI reduced both the hind paw withdrawal threshold to mechanical stimulation and the withdrawal latency to thermal stimulation, which persisted for at least 2 months post-injury. Animals treated with VEGF165 showed a minor, but significant reduction in mechanical allodynia, but not thermal hyperalgesia. SCCI activates glia at lumbar levels, however this activation appeared unaffected in VEGF165 treated animals. At thoracic level, lesion size and glial scar formation remained unchanged; however VEGF165 induced neovascularisation at the lesion site. VEGF165 treatment after SCCI has small anti-allodynic effects. This behavioral effect could not be explained by changes in glial activation. However VEGF165 induced neovascularisation at thoracic levels, indicative of functionally active VEGF. groep 1: pijn Role of corticotropin-releasing factor and urocortin 1 systems in pain-induced maladaptation and comorbid diseases T.P.H. Rouwette 1, W.J.J.M Scheenen 2, E.W. Roubos 2, T. Kozicz 2, K.C. Vissers 3 1 UMCN, Nijmegen, the Netherlands 2 Radboud Universiteit Nijmegen, Nijmegen, the Netherlands 3 Radboud Universiteit Nijmegen Medical Centre, Nijmegen, the Netherlands Neuropathic pain patients have a high incidence of depression and anxiety and although the precise etiology of these painrelated mood alterations is not known, there is evidence for an involvement of the corticotropin-releasing factor (CRF) system. We hypothesize that neuropathic pain disrupts the homeostatic functioning of the CRF system of the hypothalamic paraventricular nucleus (PVN), the bed nucleus of the stria terminalis (BST), the central amygdala (CeA), and the urocortin 1 (Ucn1) system of the non-preganglionic Edinger-Westphal nucleus (npew), and consequently will trigger stress-related symptoms of depression and anxiety. Neuropathic pain is induced in rats by chronic constriction injury (CCI) of the sciatic nerve. Rats are tested for hyperalgesia/allodynia and anxiety/ depression. Brains are analyzed by quantitative immunohistochemistry and in situ hybridization. CCI leads to marked cold allodynia 24 days post-surgery and increased CRF mrna in the CeA and BST and higher CRFimmunoreactivity in the CeA. There are no changes in CRF and CRF mrna in the PVN. Also, the npew does not differ in Ucn1 and Ucn1 mrna. Corticosterone titers do not differ between shams and CCI-operated rats 24 days post-surgery. Our results indicate that neuropathic painlike behavior in rats leads to a habituated stress response with persistent increases in CRF in the CeA and BST, possibly leading to symptoms of depression and anxiety. This is in clear contrast to acute pain stress induced bij injection of formalin into the hind paw, which activates the PVN and npew, but not the CeA and BST. Taken together, our data show that acute and chronic pain comprise separate signaling cascades in different, stress-sensitive brain nuclei.

19 september 10 nederlands tijdschrift voor anesthesiologie 17 groep 1 groep 2: divers Decision support reduces PONV incidence in a general surgical population F.O. Kooij 1, T. Klok 2, M.W. Hollmann 1, J.E. Kal 2 1 Academisch Medisch Centrum, Amsterdam, the Netherlands 2 Onze Lieve Vrouwe Gasthuis, Amsterdam, the Netherlands Guidelines to minimize the incidence of PONV have been implemented in many hospitals. In previous studies, we have demonstrated that guideline adherence is suboptimal and can be improved using decision support. 1,2 In this study, we demonstrate that decision support not only improves physician behaviour, but also improves patient outcome. Medical information of surgical patients is routinely entered in our anesthesia information management system (AIMS), which includes automated reminders for PONV management based on the simplified risk score by Apfel. 3 This study included consecutive adult patients undergoing general aneshthesia for elective non-cardiac surgery which were treated according to normal clinical routine. The presence of PONV was recorded in the AIMS both during the recovery period and at 24 hours. Two periods were studied: one period without the use of decision support (control period) and one period with the use of decision support (support period). Decision support consisted of reminders on PONV both in the pre-operative screening clinic and at the time of general anesthesia. In the control period 971 patients, of which 302 (31%) were high risk patients, received general anaesthesia. Overall 328 (34%) patients experienced PONV within 24 hours. In the support period 1750 patients, of which 575 (33%) had a high risk for PONV, received general anaesthesia. In this period, only 401 (22%) patients experienced PONV within 24 hours postoperatively. Automated reminders can improve patient outcome by improving guideline adherence. r e f e r e n c e s 1. Kooij et al, Anesthesia & Analgesia (3): Kooij et al, European Journal of Anesthesia (2): Apfel et al, British Journal of Anaesthesia (2):234 groep 2: divers Arterial and venous pharmacokinetics of morphine-6-glucuronide and impact of sample site on pharmacodynamic parameter estimates E.L.A. van Dorp 1, E. E. Olofsen 2, A. Dahan 2,, 1 LUMC, Leiden, the Netherlands 2 Leids Universitair Medisch Centrum, Leiden, the Netherlands In pharmacokinetic-pharmacodynamic modeling studies venous plasma samples are sometimes used to derive pharmacodynamic model parameters. In the current study the extent of arteriovenous concentration differen ces of morphine-6-glucuronide (M6G) was quantified. Simulations studies were applied to estimate possible biases in pharmacodynamic model parameters when linking venous versus arterial concentrations to effect. Seventeen healthy human volunteers received an intravenous 90-s infusion of 0.3 mg/kg M6G. Arterial and venous blood samples, from the radial artery and cubital vein, respectively, were obtained. An extended pharmacokinetic model was constructed linking arterial and venous compartments. The extent of bias in pharmacodynamic model parameter estimates was explored in simulation studies with NONMEM, simulating M6G effect using first-order effect-compartment inhibitory sigmoid EMAX models. M6G effect was simulated at various values for the arterial blood-effect-site equilibration halflifes (t1/2ke0), ranging from 5 to 240 min. Arteriovenous concentration differences were apparent, with higher arterial plasma concentrations just after infusion while at later times (greater than 60 min) venous M6G concentrations exceeded arterial concentrations. The extended pharmacokinetic model adequately described the data and consisted of three arterial compartments, one central and one peripheral venous compartment. The simulation studies revealed large biases in model parameters derived from venous concentration data. The biases were dependent on the value of t1/2ke0. Assuming that the true values of M6G t1/2ke0 range from min (depending on the endpoint measured), we would have underestimated t1/2ke0 by 30%, while the potency parameter would have been overestimated by about 40%, when using venous plasma samples. Due to large arteriovenous differences in M6G plasma concentration, biases in pharmacodynamic model parameters will occur when linking venous concentration to effect, using a traditional effectcompartment model. In order to obtain optimal PD parameters for use in clinical practice, a pharmacodynamic model needs to be derived from arterial samples.

20 18 nederlands tijdschrift voor anesthesiologie september 10 abstracts 2010 Caption 1. Model in terms of volumes and clearances. Caption 2. Model in terms of rate constants and compartments groep 2: divers Increased renal microvascular endothelial responsiveness to LPS in aged mice F.M. Wulfert, M. Meurs, van, N.F. Neng, R.M. Jongman, P. Heeringa, J.G. Zijlstra, M.M.R.F. Struijs, G. Molema UMCG, Groningen, the Netherlands Incidence of acute kidney injury (AKI) following severe sepsis is higher in the elderly than in younger patients. We hypothesize that the microvascular endothelium is primed by ageing. Sepsis thus represents a second hit resulting in augmented responses causing more severe microvascular complications in the elderly. Interaction between activated neutrophils and endothelial cells is considered to play a role in the pathophysiology. We analyzed expression of adhesionmolecules and neutrophils in kidney in response to sepsis in young and aged mice 3 month and 18 month old female mice were i.p. injected with 1,500 endotoxinunits/gram lipopolysaccharide(lps), and sacrificed after 8 hours. Neutrophil numbers in plasma were determined by flow cytometry. In kidney tissue we assessed neutrophil influx by immunohistochemical staining of Ly6G. qrt-pcr and immunohistochemistry were used to analyze mrna and protein of E-selectin, and P-selectin. The baseline neutrophil count was significantly lower in young compared to elderly mice (2.5 [SD 1.8] in 3 month versus 6.5 [SD 2.6] % in 18 month old mice), and the relative increase in response to LPS in neutrophil fraction was lower in young compared with aged mice (47.2 [SD 7.8] in 3 month versus 69.6 [SD 4.5] % in 18 month old mice). mrna analysis showed significantly higher upregulation of P-selectin, and E-selectin 8 hours after LPS in kidney of elderly mice. Furthermore, increased neutrophil influx in LPS treated aged mice was observed. Aged mice showed an increase in circulating neutrophils. Furthermore, aged mice subjected to LPS showed increased renal influx of neutrophils, accompanied by an increased expression of adhesion molecules E-selectin and P-selectin. The higher neutrophil count, higher upregulation of adhesion molecules, and higher tissue influx of neutrophils in aged mice subjected to LPS may play a role in increased morbidity and mortality, which will be addressed in future studies. groep 2: divers The effects of major and minor surgery on the tryptophan kynurenine pathway, neopterin and IL-6 J.W. Hol, R.J. Stolker, M. Klimek, F. van Lier, D. Stronks, D. Fekkes Erasmus MC, Rotterdam, the Netherlands Background Anesthesia has wide ranging immunomodulatory properties of which the mechanism is poorly understood. In order to better understand the effect of surgery and anesthesia on inflammation, we designed a longitudinal observational study investigating three inflammatory profiles of two separate patient groups undergoing surgery of differing severity while undergoing general anesthesia. In addition to measuring the well known inflammatory markers neopterin and IL-6, we also investigated the product of tryptophan, kynurenine. This study was a prospective, single center, two-armed observational study involving 28 female patients. Plasma levels of tryptophan, kynurenine, and IL-6 were determined from samples taken at: 24hrs pre-operative, prior to induction, thirty minutes before the operation was expected to end, and at 24 as well as 96 hours post operative in patients undergoing major abdominal surgery and vulvectomy. 15 and 13 patients were included in the vulvectomy and major abdominal