Nederlands tijdschrift voor anesthesiologie · strijding , meten van kwaliteit van zorg maar ook de...

volume 27, september 2016 4

Officiële uitgave vande Nederlandse Verenigingvoor Anesthesiologie

Abstracts 13de Wetenschapsdag9 Reguliere presentaties10 Korte presentaties9 E-posters

• Onderzoek van hoge kwaliteitE.A.J. Joosten

• Campus Woudestein, the place to be… R.J. Stolker

• PhD thesis summary: Minimally invasive monitoring in patients under general anesthesiaJ.J. Vos, T.W.L. Scheeren

• Ambiguous policies in anaesthetic pain management in laparoscopic colonic surgery: A national surveyE.E. van Houwelingen, M.V. Koning, A.J.W. Teunissen, R.J. Stolker

Wetenschapsspecial

anesthesiologieNederlands tijdschrift voor

Prof. Dr. E.A.J. Joosten, hoofdredacteur Prof. Dr. B. Preckel, plaatsvervangend hoofdredacteur

93 nederlands tijdschrift voor anesthesiologie | september ’16

anesthesiologieNederlands tijdschrift voor

inhoud

editorial 95Onderzoek van hoge kwaliteitE.A.J. Joosten

editorial 98Campus Woudestein, the place to be…R.J. Stolker

programma wetenschapsdag 2016 96

abstracts wetenschapsdag 2016 99

regulier e p r e se ntati e 99

Safety, tolerability, and immunomodulatory effects of EA-230 in humansR. van Groenendael, L.T. van Eijk, G.P. Leijte, B Koeneman, M Kox, P. Pickkers


Angiopoietin-1 mimetic restores microcirculatory perfusion after cardiopulmonary bypass in a rat modelN.A.M. Dekker, C.E. van den Brom, A.L.I. van Leeuwen, , N.J. Koning, A.B.A. Vonk, M. van Meurs, Boer C.


Change of mitochondrial function in vivo during human endotoxemia: preliminary dataJelle Zwaag, M.A. Wefers Bettink, M. Kox, E.G. Mik


Making safer preoperative arrangements for patients using vitamin K antagonistsJ. Willems, J.M.K. van Fessem, S.E. Hoeks, R.J. Stolker


The influence of age on quality of life one year after cardiac surgery: a historical cohort studyL. Verwijmeren, P.G. Noordzij, E.J. Daeter, B. van Zaane, L.M. Peelen, E.P.A. van Dongen

reguliere pres en tatie 102

Delayed effect of High-frequency Spinal cord stimulation in experimental chronic painful diabetic polyneuropathyM. van Beek, M. van Kleef, B. Linderoth, S.M.J. van Kuijk, W.M. Honig, E.A. Joosten


Preferred frequencies and waveforms for spinal cord stimulation in patients with complex regional pain syndrome: a multicenter, double-blind, randomized and placebo-controlled crossover trialN. Kriek, J. G. Groeneweg, D.L. Stronks, D. de Ridder, F. J.P.M. Huygen


Minimal invasive determinations of oxygen delivery (do2) and consumption (vo2) in cardiac surgeryD.T.M. Burtman, A. Stolze, A.A. Vonk, Ch. Boer

korte pres en tatie 104

Viral reactivation as marker for a persistent anti-inflammatory phenotype and increased risk for secondary infections in trauma patientsR. M. Koch, M.Kox, J.C. Rahamat-Langendoen, K. Timmermans, J.G. van der Hoeven, P. Pickkers,

korte presentatie 105

Angiopoietin-1 mimetic protects against microcirculatory perfusion disturbances and microvascular leakage during hemorrhagic shockM. Trieu, M. van Meurs, A.L.I. van Leeuwen, L.M.G. Geeraedts, C. Boer, C.E. van den Brom


Minimally invasive treatment for lumbar spine related pain disordersC.W.J. van Tilburg, F.A. Schuurmans, D.L. Stronks, J.G. Groeneweg, F.J.P.M Huygen


Genetic polymorphisms and their association with the prevalence and severity of chronic postsurgical painR.R.I. van Reij, D. M.N. Hoofwijk, B.P. Rutten, G. Kenis, N. J. van den Hoogen, W.F.F.A. Buhre, E. A. Joosten


Reproducibility of corneal confocal microscopy in a multicenter study with a new tool to estimate neuropathy in patients with painful neuropathy and healthy controlsM.D. Nieuwenhoff, H. Nguyen, F.J.P.M. Huygen, S.P. Niehof, A. Verma, J. Geelhoed, A.F.S. Petzold, A.C. Moll, G.J. Groeneveld,


Painful procedures during neonatal development: short- and long-term consequences on spinal nociceptive processingN.J. van den Hoogen, C.H.T. Kwok, M. Fitzgerald, J. Patijn, D. Tibboel, E.A. Joosten,


The prognostic value of postoperative high-sensitive troponin T in patients with different stages of kidney disease undergoing noncardiac surgeryV.G.B Liem, S.E. Hoeks, F. Grüne, F.H.I.M. Wesdorp, R.J. Stolker, F. van Lier


The effect of clonidine as an additive to local anaesthetics on the duration of postoperative analgesia after orthopaedic foot surgery: a randomized clinical trialP.A. Ramsodit, L. Timmerman


Evaluating non-invasive mitochondrial function assay vs muscle biopsies in an endotoxemic model in ratM.A. Wefers Bettink, N. Dollee, R.J. Stolker, E.G. Mik


Endotoxin challenge does not influence the immune response induced by a subsequent challenge with live-attenuated influenza vaccine in humans in vivoR.M. Koch, M.Kox, E.J.M. Thijs, J.C. Rahamat-Langendoen, J. Gerretsen, D. Diavatopoulos, J. G. van der Hoeven, M.I. de Jonge, Peter Pickkers,

poster presentatie 111

Quality Indicators (QI) from the Perspective of Chronic Pain Patients; the QiPPP-listP. de Meij, A. Köke, , T. van der Weijden, M. van Kleef


poster p r e se ntati e 112

The effect of pulsed radiofrequency treatment applied adjacent to the dorsal root ganglion in an experimental model for chronic neuropathic pain: behavioral assessmentG. Franken, W. Honig, E.A. Joosten

poster p r e se ntati e 112

Assessment of anesthesiology residents: a systematic reviewJ. Kaldeway, E. Booij, M.F. van der Schaaf, R.G. Hoff

poster presen tatie 113

Anesthetics and analgesics, and their impact on anti-tumor immune responsesT.K. Raaijmakers, M.H. den Brok, G.J. Scheffer, G.J. Adema

poster presen tatie 113

Perioperative and postoperative adverse cardiac events in patients undergoing vascular surgery: External validation of prognostic risk modelsM.S. Erkamp, F. van Lier, S.E. Hoeks

poster presenatie 114

Prevalence and determinants of medication non-adherence in chronic pain patientsL. Timmerman, D.L. Stronks, J.G. Groeneweg, F.J.P.M. Huygen


The effect of midazolam on the quality of postoperative recoveryS. van Beek, J. Kroon, H.J. Mijderwijk, M. Klimek, R.J. Stolker


Potential pathways leading to postoperative fatigue. Structural equation modelling in daycase surgery patientsH. Mijderwijk, E.W. Steyerberg, H.J. Duivenvoorden, M. Klimek, R.J. Stolker

samenvatting PhD thesis 116PhD thesis summary: Minimally invasive monitoring in patients under general anesthesiaJ.J. Vos, T.W.L. Scheeren

onderzoek 124Ambiguous policies in anaesthetic pain management in laparoscopic colonic surgery: A national surveyE.E. van Houwelingen, M.V. Koning, A.J.W. Teunissen, R.J. Stolker

september ’16 | nederlands tijdschrift voor anesthesiologie 95

editorial colofon

Geachte lezer,

Het is najaar. In de maanden augustus en septem-ber wordt de oogst binnen gehaald en kan er bepaald worden of het achterliggend jaar een goed of minder goed jaar is geweest. Wij kunnen dat ook. De abstracts ingediend voor de Wetenschapsdag 2016 (30 september te Rotterdam) zijn ingediend en allen afgedrukt in dit issue. Een hele mooie mix van basaal experimenteel tot klinisch wetenschappelijk onderzoek uit de we-reld van de anesthesiologie en pijnbe-strijding vormt de oogst van dit jaar. We kunnen trots zijn op de kwaliteit van ons onderzoek. Enkele jaren geleden was de, destijds, editor-in-chief van het toonaan-gevende tijdschrift Anesthesiology, Prof. James Eisenach, gastspreker bij onze We-tenschapsdag. Hij was toen diep onder de indruk van het niveau en kwaliteit maar ook de diversiteit van het Nederlandse anesthesiologisch onderzoek. Dit was heel mooi om te horen en zulke opmer-kingen stimuleren. Ik denk dan ook dat we die hoge kwaliteit van ons onderzoek hebben weten vast te houden en mis-schien nog wel verbeterd hebben. De oogst is goed dit jaar en kwaliteit prima. Ik nodig u dan ook uit de astracts te lezen om daarmee een beeld te krijgen van het onderzoek binnen de anesthesiologie en pijnbestrijding. De abstracts geven daar-naast een beeld in welke richting het on-

derzoek (en daarmee ook de kliniek van de toekomst) zich beweegt en mogelijk verder zal gaan: genetica en pijnbe-strijding , meten van kwaliteit van zorg maar ook de ontwik-keling van nieuwe methoden en technieken (bijvoorbeeld om DO2 en VO2 te meten).

Naast de abstracts voor de 13e Weten-schapsdag een tweetal artikelen. Een samenvatting van een zeer interessant proefschrift over minimale invasieve monitoring bij patiënten onder algehele anesthesie door collega Vos (Universitair Medisch Centrum Groningen) alsmede een bijdrage van collega van Houwelin-gen (Erasmus Universiteit Rotterdam) die een samenvatting beschrijft van een nationaal onderzoek naar het Neder-landse anesthesiologische management bij laparoscopische colonchirurgie. Beide artikelen zijn state-of-the-art en geven gelijktijdig een beeld van wat en hoe goed wetenschappelijk onderzoek in Nederland uitgevoerd wordt. Beiden hebben daarnaast een directe klinische impact.Al met al bevat dit nummer genoeg wetenschappelijke en praktijkgerichte informatie om eens goed voor te gaan zitten.Ik wens u, namens de gehele redactie, veel leesplezier,

Bert JoostenHoofdredacteur

Onderzoek van hoge kwaliteit

E.A.J. Joosten, Prof. Dr.Hoofdredacteur NTvAMaastricht [email protected]

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 overzichts artikelen, klinische en laboratoriumstudies en casuïstiek, de verspreiding van kennis betreffende de anesthesiologie en gerelateerde vakgebieden te bevorderen.

REDACTIEHoofdredacteur: Prof. Dr. E.A.J. Joosten. Plaatsvervangend hoofdredacteur: Prof. Dr. B. Preckel.Redacteuren: Dr. P. van Beest, Dr. J. Bijker, Dr. A. Bouwman, Dr. P. Bruins, Prof. Dr. A. Dahan, Dr. H. van Dongen, Dr. J.P. Hering, Dr. S. Dieleman, Dr. J.S. Jainandunsing, Prof. Dr. M.W. Hollmann, Dr. R.V. Immink, Dr. M. Klimek, Dr. A. Koopman, Dr. M. Kox, Dr. M.D. Lancé, Dr. F. Van Lier, Prof. Dr. S.A. Loer, Prof. Dr. G.J. Scheffer, Dr. M.F. Stevens, Dr. B. in ’t Veld, Dr. M. van Velzen, Prof. Dr. K. Vissers.

Voor informatie over adverteren en het reserveren van advertentieruimte in het Nederlands Tijdschrift voor Anesthesiologie: www.breener.nl

REDACTIE-ADRESNederlandse Vereniging voor AnesthesiologieDomus Medica, Mercatorlaan 1200, 3528 BL Utrecht; www.anesthesiologie.nl

INZENDEN VAN KOPIJRichtlijnen voor het inzenden van kopij vindt u op www.anesthesiologie.nl of kunt u opvragen bij de redactie of de uitgever: [email protected]

OPLAGE2.500 exemplaren, 5x per jaar

Het NTvA wordt uitsluitend toegezonden aan leden van de NVA. Adreswijzigingen: Nederlandse Vereniging voor Anesthesiologie, Postbus 20063, 3502 LB Utrecht, T 030-2823385, F 030-2823856, Email [email protected]

PRODUCTIEEldering Studios: Ontwerp: Dimitry de BruinEindredactie & bladcoördinatie: Monique de Mijttenaere

AUTEURSRECHT EN AANSPRAKELIJKHEIDNederlands Tijdschrift voor Anesthesiologie® is een wettig gedeponeerd woordmerk van de Ne-derlandse 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 vooraf-gaande schriftelijke toestemming.


Wetenschapsdag 30 september 2016 programma

korte presentatie

09.40 - 09.50

Genetic polymorphisms and their association with the prevalence and severity of chronic postsurgical painR.R.I. van Reij, D. M.N. Hoofwijk, B. P. Rutten, G. Kenis, N. J. van den Hoogen, W.F.F.A. Buhre, E. A. Joosten

- Department of Anesthesiology and Pain Medicine, Maastricht University Medical Center+, Maastricht

- School for Mental Health and Neuroscience (MHeNs), Faculty of Health, Medicine and Life Sciences, Maastricht University Medical Centre, Maastricht

reguliere presentaties

09.50 - 10.10

Safety, tolerability, and immuno modulatory effects of EA-230 in humansR. van Groenendael 1, 2, L.T. van Eijk 1, 2, GP Leijte 1, B Koeneman 1, M Kox 1, P Pickkers 1

1 Department of Intensive Care Medicine, Radboudumc, Nijmegen

2 Department of Anesthesiology, Radboudumc, Nijmegen

10.10 - 10.30

Angiopoietin-1 mimetic restores microcirculatory perfusion after cardiopulmonary bypass in a rat modelN.A.M. Dekker 1, 3, C.E. van den Brom 1,

2, A.L.I. van Leeuwen 1, 2, 3, N.J. Koning 1, A.B.A. Vonk 2, M. van Meurs 4, Boer C. 1

1 Departments of Anesthesiology, Cardiothoracic Surgery and Physiology, VU University Medical Center, Amsterdam, The Netherlands.

2 Department of Critical Care, University Medical Center Groningen, Groningen, The Netherlands.

10.30 - 10.50

Change of mitochondrial function in vivo during human endotoxemia: preliminary dataJelle Zwaag 1, M.A. Wefers Bettink 2, M. Kox 1, E.G. Mik 2

1 Intensive Care Research, Radboudumc, Nijmegen

2 Department of Anesthesiology, Erasmus MC, Rotterdam

10.50 - 11.10

Making safer preoperative arrangements for patients using vitamin K antagonistsJ. Willems, J.M.K. van Fessem, S.E. Hoeks, R.J. StolkerErasmus MC

11.10 - 11.40

Pauze

08.30 Ontvangst09.00 Welkom en opening door Robert Jan Stolker 09.20 Gastspreker: Frank Miedema

korte presentaties

11.40 - 11.50

Viral reactivation as marker for a persistent anti-inflammatory phenotype and increased risk for secondary infections in trauma patientsR. M. Koch 1, 3, M.Kox 1, 3, J.C. Rahamat-Langendoen 2, K. Timmermans 1, 3, J.G. van der Hoeven 1,

3, P. Pickkers 1, 3

1 Radboud university medical center, Radboud Institute for Molecular Life Sciences, Department of Intensive Care Medicine, Nijmegen

2 Radboud university medical center, Radboud Institute for Molecular Life Sciences, Department of Medical Microbiology, Nijmegen

3 Radboud center for Infectious Diseases (RCI), Nijmegen

11.50 - 12.00

Angiopoietin-1 mimetic protects against microcirculatory perfusion disturbances and microvascular leakage during hemorrhagic shockM. Trieu 1, 2, M. van Meurs 4, 5, A.L.I. van Leeuwen 1, 2, L.M.G. Geeraedts 3, C. Boer 1, C.E. van den Brom 2

1 Departments of Anesthesiology, Physiology and Trauma Surgery, VU University Medical Center, Amsterdam

2 Departments of Pathology and Medical Biology and Critical Care, University Medical Center Groningen, Groningen

12.00 - 12.10

Minimally invasive treatment for lumbar spine related pain disordersC.W.J. van Tilburg 1, F.A. Schuurmans 1, D.L. Stronks 2, J.G. Groeneweg 2, F.J.P.M Huygen 2

1 Bravis hospital

2 Erasmus MC University Medical Center

12.10 - 12.20

Reproducibility of corneal confocal microscopy in a multicenter study with a new tool to estimate neuropathy in patients with painful neuropathy and healthy controlsM.D. Nieuwenhoff 1, 2, H. Nguyen 3, F.J.P.M. Huygen 1, S.P. Niehof 1, A. Verma 4, J. Geelhoed 2, A.F.S. Petzold 3,

5, A.C. Moll 3, G.J. Groeneveld 2, 3

1 Department of Anesthesiology and Pain Medicine, Erasmus MC University Medical Center, Rotterdam

2 Centre for Human Drug Research, Leiden

3 Department of Ophthalmology VU University Medical Center, Amsterdam

4 Biogen, Cambridge, USA

5 Department of Neurology, VU University Medical Center, Amsterdam

12.20 - 12.30

Painful procedures during neonatal development: short- and long-term consequences on spinal nociceptive processingN.J. van den Hoogen 1, 2, C.H.T. Kwok 3, M. Fitzgerald 3, J. Patijn 1, D. Tibboel 4, E.A. Joosten 1, 2

1 Department of Anaesthesiology, Pain Management and Research Centre, Maastricht University Medical Centre

2 Department of Translational Neuroscience, School of Mental Health and Neuroscience, Maastricht University

3 Department of Neuroscience, Physiology and Pharmacology, University College London, London

4 Intensive Care and Department of Paediatric Surgery, Erasmus MC-Sophia, Rotterdam

12.30 - 13.15

Lunchpauze


13.15 - 13.35

The influence of age on quality of life one year after cardiac surgery: a historical cohort studyL. Verwijmeren 1, P.G. Noordzij 1, E.J. Daeter 1, B. van Zaane 2, L.M. Peelen 3, E.P.A. van Dongen 2

1 Departments of Anesthesiology, Intensive Care and Cardiothoracic Surgery, St Antonius Hospital, Nieuwegein

2 Departments of Anesthesiology, Intensive Care and Emergency Medicine University Medical Center Utrecht

3 Julius Center for Health Sciences and Primary Care

13.35 - 13.55

Delayed effect of High-frequency Spinal cord stimulation in experi-mental chronic painful diabetic polyneuropathyM. van Beek 1, M. van Kleef 1, B. Linderoth 1, 2, S.M.J. van Kuijk 3, W.M. Honig 1, E.A. Joosten 1

1 Pain Management and Research Center, Department of Anesthesiology, MUMC+, Maastricht

2 Functional Neurosurgery, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden

3 Department of Clinical Epidemiology and Medical Technology Assessment (KEMTA), MUMC+, Maastricht

13.55 - 14.15

Preferred frequencies and waveforms for spinal cord stimulation in patients with complex regional pain syndrome: a multicenter, double-blind, randomized and placebo-controlled crossover trialN. Kriek 1, J. G. Groeneweg 1, D.L. Stronks 1, D. de Ridder 2, F.J.P.M. Huygen 1

1 Center for Pain Medicine, Erasmus MC – University Medical Center Rotterdam

2 Department of Surgical Sciences, Section of Neurosurgery, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand

14.15 - 14.35



prijsuitreikingen

16.45 -16.55 Uitreiking beste korte en beste reguliere presentatie Uitreiking Young Investigator Grant 2016

16.55 - 17.00 Afsluiting Robert Jan Stolker

17.00 – 17.40 Borrel

e-posters

e-post ers worden tijdens de pauzes gep rojecteerd op het sche rm in de p lena ire za al.

Quality Indicators (QI) from the Perspective of Chronic Pain Patients; the QiPPP-listP. de Meij 1, A. Köke 2, 4, 5, T. van der Weijden 3, M. van Kleef1 Maastricht, UPCM, Department of Anaesthesiology

and Pain Management, Maastricht University Medical Centre

2 Department of Rehabilitation Medicine/CAPHRI, School for Public Health and Primary Care Maastricht University

3 Department of Family Medicine/CAPHRI, School for Public Health and Primary Care & Maastricht University Medical Centre

4 Adelante Centre of Expertise in Rehabilitation and Audiology, Hoensbroek

5 Zuyd University for Applied Sciences, faculty Health and Technology, Heerlen

The effect of pulsed radiofrequency treatment applied adjacent to the dorsal root ganglion in an experimental model for chronic neuropathic pain: behavioral assessmentG. Franken, W. Honig, E.A. Joosten- Department of Anesthesiology and Pain

Management, University Pain Clinic Maastricht (UPCM), Maastricht, The Netherlands

- Department of Translational Neuroscience, School for Mental Health and Neuroscience (MHeNS), Maastricht, The Netherlands

Assessment of anesthesiology residents: a systematic reviewJ. Kaldeway, E. Booij, M.F. van der Schaaf, R.G. HoffUniversitair Medisch Centrum Utrecht

Anesthetics and analgesics, and their impact on anti-tumor immune responsesT.K. Raaijmakers 1, 2, M.H. den Brok 1, G.J. Scheffer 2, G.J. Adema 1

1 Department of Tumor Immunology, Radboud University Medical Center, Nijmegen, The Netherlands.

2 Department of Anesthesiology, Pain management and Palliative Care, Radboud University Medical Center, Nijmegen, The Netherlands

Perioperative and postoperative adverse cardiac events in patients undergoing vascular surgery: External validation of prognostic risk modelsM.S. Erkamp, F. van Lier, S.E. HoeksDepartment of AnesthesiologyErasmus University Medical Center, Rotterdam, The Netherlands

Prevalence and determinants of medication non-adherence in chronic pain patientsL. Timmerman 1, D.L. Stronks 2, J.G. Groeneweg 2, F.J.P.M. Huygen 2 1 St Antonius Ziekenhuis, Nieuwegein2 Erasmus MC Rotterdam

The effect of midazolam on the quality of postoperative recoveryS. van Beek, J. Kroon, H.J. Mijderwijk, M. Klimek, R.J. StolkerErasmus MC Rotterdam

Potential pathways leading to postoperative fatigue. Structural equation modelling in daycase surgery patientsH. Mijderwijk 1, E.W. Steyerberg 2, H.J. Duiven-voorden 1, M. Klimek1, R.J. Stolker 1

1 Department of Anesthesiology, Erasmus University Medical Center

2 Department of Public Health, Erasmus University Medical Center

Departments of anesthesiology and cardiothoracic surgery of the VUmc, Amsterdam

14.35 - 14.55

Young Investigator Grant 2014 Matijs van MeursUniversitair Medisch Centrum Groningen

14.55 - 15.25

Pauze

15:25 - 16.05

Postoperative delirium and cognitive dysfunctionGastspreker: Claudia Spies

korte presentaties

16.05 - 16.15

The prognostic value of postoperative high-sensitive troponin T in patients with different stages of kidney disease undergoing noncardiac surgeryV.G.B Liem, S.E. Hoeks, F. Grüne, F.H.I.M. Wesdorp, R.J. Stolker, F. van LierErasmus MC Rotterdam

16.15 - 16.25

The effect of clonidine as an additive to local anaesthetics on the duration of postoperative analgesia after orthopaedic foot surgery: a randomized clinical trialP.A. Ramsodit, L. TimmermanSt. Antonius Ziekenhuis, Nieuwegein

16.25 - 16.35

Evaluating non-invasive mitochondrial function assay vs muscle biopsies in an endotoxemic model in ratM.A. Wefers Bettink, N. Dollee, R.J. Stolker, E.G. MikDepartment of Anesthesiology, Erasmus MC, Rotterdam

16.35 - 16.45

Endotoxin challenge does not influence the immune response induced by a subsequent challenge with live-attenuated influenza vaccine in humans in vivoR.M. Koch 1, 4, M.Kox 1, 4, E.J.M. Thijs 1, 4, J.C. Rahamat-Langendoen 2, J. Gerretsen 1, 4, D. Diavatopoulos 3, 4, J. G. van der Hoeven 1, 4, M.I. de Jonge 3, 4, Peter Pickkers 1, 4



3 Radboud university medical center, Radboud Institute for Molecular Life Sciences, Department of Pediatrics, Nijmegen



Geachte lezer,

Op 30 september 2016 orga-niseert de Raad van Hoogleraren de Wetenschapsdag van de Nederlandse vereniging voor Anesthesiologie. In het verleden werd deze dag meestal centraal in Nederland georganiseerd. Dit kostte aanzienlijke bedragen die ten koste zouden gaan van de jaarlijks toe te kennen Young Investigators Grant (groot 50.000 euro). Daarom is besloten de Wetenschapsdag steeds door een ander UMC te laten organiseren en om toegang te heffen. Op deze wijze kan de NVA en een wetenschapsprijs en een Wetenschapsdag blijven organiseren. Aan de opzet van het programma is eigenlijk weinig veranderd. We hebben twee gastsprekers en de rest van het programma wordt verzorgd door de on-derzoekers zelf. De gastsprekers zijn dit jaar Frank Miedema en Claudia Spies.Frank Miedema is decaan en vicevoorzitter van het UMC Utrecht. Op de Wetenschapsdag zal hij vertellen over de activiteiten van Science in transi-tion, een beweging waar hij mede aan de wieg heeft gestaan. Science in transition probeert de waardering van wetenschappelijke output verder te krijgen dan uitsluitend bibliometrische parameters als impact factoren en citatiescores.Claudia Spies is het afdelingshoofd van de afdeling Anesthesiologie van de Charité in Berlijn. Dit is het universiteitsziekenhuis van de vier gefuseerde uni-versiteiten in Berlijn. De titel van haar voordracht is Postoperative delirium and cognitive dysfunction, een

belangrijk onderwerp waar prof. Spies één van de coryfeeën van is. Zij is ook voorzitter van de Taskforce Postoperatief Delier van de European Society of Anaes-thesiology.Het overige programma wordt verzorgd door de researchers zelf. We hebben een keuze gemaakt uit het ruime aanbod en u krijgt presentaties van 20 minuten,

korte presentaties van 10 minuten en posterpre-sentaties te zien en te horen. Ik denk dat u een aardig overzicht krijgt wat er zoal in Nederland aan research wordt verricht. De gevarieerdheid van de onderwerpen is opvallend, een groot deel van het vak wordt gecovered. Het is goed om te zien dat er samenwerkingsverbanden zijn tussen UMC’s en algemene ziekenhuizen, tussen UMC’s onderling en dat er internationale contacten zijn. Wetenschap is iets dat je samen doet en de auteurslijsten reflec-teren dat. Wetenschap is de motor tot innovatie en innovatie is nodig om met de eisen van de tijd mee te kunnen gaan en ons vak toekomstbestendig te laten zijn. Op 30 september kunt u constateren dat de anesthesiologie in Nederland nog steeds aan de weg timmert.Dit jaar is het Erasmus MC aan de beurt om de We-tenschapsdag te organiseren. Het paviljoen van de Erasmus Universiteit Rotterdam op Campus Wou-destein (en niet het Erasmus MC) is de plaats van actie. Welkom op Woudestein!

Namens de Raad van Hoogleraren,Robert Jan Stolker

editorialProf. Dr. R.J. StolkerAfdelingshoofd Anesthesiologie, Erasmus MC, Rotterdam

Campus Woudestein, the place to be…



re guliere presentatie

Safety, tolerability, and immunomodulatory effects of EA-230 in humansR. van Groenendael 1, 2, L.T. van Eijk 1, 2, GP Leijte 1, B Koeneman 1, M Kox 1, P Pickkers 1

1 Department of Intensive Care Medicine, Radboudumc, Nijmegen

2 Department of Anesthesiology, Radboudumc, Nijmegen

IntroductionThe systemic inflammatory response syn-drome (SIRS) is characterized by injurious systemic inflammation in response to a vari-ety of inflammatory stimuli, including major surgery. SIRS often results in pronounced tissue damage with associated organ failure and mortality rates up to 30%. EA-230 is a newly developed synthetic linear tetrapep-tide derived from the β-human chorionic gonadotropin hormone (β-hCG), which has shown promising anti-inflammatory and tissue-protective effects in animal studies. We investigated the tolerability, safety and immunomodulatory effects of EA-230 in humans.

MethodsWe conducted a double blind, placebo controlled, dose-escalating randomized clinical trial in 60 healthy volunteers, in two phases. In the first phase (n=24), safety and tolerability was established for escalating doses of EA-230 (30, 90 and 180 mg/kg). In the second phase (n=36), the same doses were used to assess the effects of EA-230 on systemic inflammation during experimental endotoxemia. At t=0 hours, 2 ng/kg Esch-erichia Coli endotoxin was administered i.v. followed by a 2-hour continuous i.v. infu-sion of EA-230 or placebo. Levels of circulat-ing inflammatory mediators were assessed as well as body temperature and symptom scores. Furthermore, tissue protective ef-fects were assessed by measuring renal func-tion using plasma clearance of iohexol.

ResultsEA-230 was well tolerated and showed an excellent safety profile. Treatment with the highest dose of EA-230 resulted in a signifi-cant attenuation of the endotoxin-induced increase in circulating inflammatory me-diators (Figure 1), body temperature and symptom scores (Figure 2). Endotoxemia resulted in a marked increase in GFR, but no differences between groups were observed.

ConclusionOur study demonstrates that administration of EA-230 is safe and results in attenuation of the systemic inflammatory response in humans. These promising results pave the way to assess the effects of EA-230 in pa-tients with systemic inflammation following on-pump cardiac surgery.

abstracts 2016100 nederlands tijdschrift voor anesthesiologie | september ’16

reguliere presentatie

Angiopoietin-1 mimetic restores microcirculatory perfusion after cardiopulmonary bypass in a rat modelN.A.M. Dekker 1, 3, C.E. van den Brom 1, 2, A.L.I. van Leeuwen 1, 2, 3, N.J. Koning 1, A.B.A. Vonk 2, M. van Meurs 4, Boer C. 1

1 Departments of Anesthesiology 1, Cardiothoracic Surgery 2 and Physiology 3, VU University Medical Center, Amsterdam, The Netherlands.

2 Department of Critical Care, University Medical Center Groningen, Groningen, The Netherlands.

IntroductionCardiopulmonary bypass (CPB) during car-diac surgery impairs microcirculatory perfu-sion and is paralleled by microvascular leak-age. The Angiopoietin/Tie2 system might preserve endothelial barrier function and attenuate microvascular leakage. This study investigated the effects of an Angiopoietin-1 mimetic on microcirculatory perfusion in a rat CPB model.

MethodsMale rats were subjected to 75 minutes of CPB after treatment with an angiopoietin-1 mimetic (Ang1mim; n=5) or PBS (n=5) or underwent sham procedure. Intravital mi-crocirculatory perfusion was measured in the cremaster muscle at baseline and five time points until 60 minutes after CPB.

ResultsOnset of CPB resulted in comparable haematocrit levels (21.0±1.0%, P=0.02 and 18.8±0.9%, P< 0.001) in the PBS and Ang-1mim groups, respectively. In the PBS group, this was accompanied by reduced propor-tion of perfused capillaries from 86.6±2.6% to 59.5±5.3% P=0.002 and increased num-ber of stopped vessels from 12.1±3.1% to 40.1±5.1% P=0.002, which progressed after

CPB. In contrast, Ang1mim pretreated rats showed minimal reduction in perfused ves-sel proportion during CPB from 93.5±2.2% to 79.4±3.7% P=0.01 which restored after CPB to 80.9±5.9% P=0.07 vs. baseline. More-over, CPB-induced stopped vessels returned to baseline one hour after weaning from CPB in the Ang1mim group from 5.1±2.2 to 18.3±6.0 P=0.07 after CPB.

ConclusionIntervening with an Angiopoietin-1 mi-metic attenuates and restores CPB-induced microcirculatory perfusion disturbances suggesting that therapeutic targeting the Angiopoietin/Tie2 system may contribute to preserved microcirculatory function dur-ing extracorporeal circulation.


Change of mitochondrial function in vivo during human endotoxemia: preliminary dataJelle Zwaag 1, M.A. Wefers Bettink 2, M. Kox 1, E.G. Mik 2

1 Intensive Care Research, Radboudumc, Nijmegen2 Department of Anesthesiology, Erasmus MC,

Rotterdam

IntroductionMitochondrial dysfunction plays a role in the pathophysiology of sepsis but the lack of tools to monitor mitochondrial function hampers clinical research in this field. With the recent introduction of the COMET (Cellular Oxygen METabolism) monitoring device (Photonics Healthcare) a new diag-nostic test comes available for patients sus-pected of acute mitochondrial dysfunction. COMET measures mitochondrial oxygen tension and cellular oxygen consumption in skin. In the present study we evaluated COMET in healthy volunteers during ex-

perimental endotoxemia, a standardized controlled model of inflammation.

Methods4 male volunteers participated in a human en-dotoxemia experiment as controls receiving 2 ng/kg bodyweight lipopolysacharide (LPS) but no additional intervention. After cannu-lation of both the antecubital vein and the ra-dial artery of the same arm, subjects received 1.5 L prehydration (2.5%gluc/0.45%NaCl). Immediately after prehydration LPS was ad-ministered intravenously.Dynamic measurement of mitochondrial oxygen tension (mitoPO2) gave us the Oxy-gen Disappearance Rate (ODR), a measure of cellular oxygen metabolism. PpIX, nec-essary for the COMET measurement, was induced by affixing an 8mg 5-aminolevulinic acid plaster (Alacare) on sternal skin of the subjects.

ResultsAdministration of LPS resulted in a sharp increase in plasma levels of the pro-inflam-matory cytokines TNF-α, IL-6, and IL-8 as well as the anti-inflammatory cytokine IL-10. COMET measurements showed a tran-sient decrease in mitoPO2 (from 65.8±8.0 to 36.8±3,4 mmHg) and ODR (from -8.6±2.4 to -6.45±1.1 mmHg*s-1) 1:45 hours after LPS infusion, which restored 7 hours after LPS infusion.

ConclusionFor the first time we demonstrate a decrease in ODR after LPS administration in humans in vivo. These data provide the first evidence that the COMET is a promising new diag-nostic instrument for use in patients sus-pected of acute mitochondrial dysfunction.




Making safer preoperative arrangements for patients using vitamin K antagonistsJ. Willems, J.M.K. van Fessem, S.E. Hoeks, R.J. Stolker

Erasmus MC

IntroductionUse of vitamin K antagonists creates a risk for patient health and safety. The frame-work “Landelijke Standaard Ketenzorg Antistolling” propagates a shared plan and responsibility by surgeon and anesthesiolo-gist together in the preoperative setting. In our institution, this framework had not been implemented. Therefore, a quality-improvement project was started at the anesthesiology department to improve peri-operative safety.

MethodsAfter exploration of barriers, multiple in-terventions were carried out to encourage co-workers from the preoperative screening

department to take shared responsibil-ity: distribution of prints, adjustments in electronic patient records, introduction of a protocol and educative sessions. Efficacy was measured retrospectively performing a before-after study collecting perioperative data of patients using vitamin K antagonists. The primary outcome measure was the percentage of predefined safe preoperative plans. Secondary outcome measures were (1) incidence of postoperative bleeding and thrombo-embolic events within the first 24 hours after intervention and (2) necessity to preoperative correction of anticoagulation.

ResultsBefore intervention 64 (27%) safe, 91 (38%) partially unsafe and 82 (35%) unsafe plans were made. After the intervention these numbers were 72 (88%), 8 (10%) en 2 (2%), respectively: a significant 61% rise in safe

preoperative plans (P<0.001).No significant difference (P=0.609) was observed regarding bleeding and thrombo-embolic events: pre-intervention 12 (5%) cases of postop-erative bleeding were documented vs. 4 (5%) post intervention and the number of thrombo-embolic events was 5 vs. 0. Also, no significant differences concerning preop-erative correction of anticoagulation were observed: 11 (5%) vs. 5 (6%) (P=0.569).

ConclusionThis quality improvement project demon-strates a major improvement in safer pre-operative plans in our institution regarding vitamin K antagonists, using the described interventions. A significant effect on bleed-ing or thrombo-embolic events or necessity to correction of anticoagulation could not be demonstrated.


The influence of age on quality of life one year after cardiac surgery: a historical cohort studyL. Verwijmeren 1, P.G. Noordzij 1, E.J. Daeter 1, B. van Zaane 2, L.M. Peelen 3, E.P.A. van Dongen 2

1 Departments of Anesthesiology, Intensive Care and Cardiothoracic Surgery, St Antonius Hospital, Nieuwegein

2 Departments of Anesthesiology, Intensive Care and Emergency Medicine University Medical Center Utrecht

3 Julius Center for Health Sciences and Primary Care

IntroductionDue to an ageing society and improving medical techniques elderly patients undergo more high risk cardiac surgeries. Studies on postoperative health related quality of life (HRQoL) in relation to age are scarce but of importance for clinical decision making. This study aimed to evaluate the influence of age on HRQoL one year after coronary artery bypass grafting (CABG).

MethodsHistorical cohort study including 658 CABG patients between July 2011 and May 2014 who completed Short Form 12 question-naires before and 12 months after surgery. Outcome was a change in physical or mental

quality of life (QoL). For statistical analysis univariate and multivariate linear regression analysis was used.

ResultsMean age was 66 years (±9) and 82.6% was male. Mean preoperative physical and men-tal QoL were 39.2 (±5.4) and 48.9 (±13.1)

respectively. One year after surgery mean physical QoL improved 0.7(±6.6) points (P=0.007) and mean mental QoL gained 5.5 (±12.4) points (P<0.001) (Figure 1a and 1b). When stratified into age groups, physical QoL improved in the oldest age group and mental QoL was higher in all age groups (Figure 1). In univariate analysis, age was

Figure 1a. Physical quality of life for all patients according to age group

Figure 1b. Mental quality of life for all patients according to age group


positively associated with a change in physi-cal QoL (β 0.08 per year; 95% confidence interval (CI) 0.02 to 0.13). However, after correction for preoperative risk factors this association was lost (β 0.04 per year; 95% CI

-0.02 to 0.10). Age was not associated with mental QoL after surgery in univariate anal-ysis (β -0.05 per year; 95%CI -0.15 to 0.06) nor in a preoperative multivariate model (β 0.02 per year; 95% CI -0.15 to 0.06).

ConclusionTwelve months after CABG, patients experi-ence improved HRQoL. Especially mental health related quality of life. This effect oc-curred independently of age.


Delayed effect of High-frequency Spinal cord stimulation in experimental chronic painful diabetic polyneuropathyM. van Beek 1, M. van Kleef 1, B. Linderoth 1, 2, S.M.J. van Kuijk 3, W.M. Honig 1, E.A. Joosten 1

1 Pain Management and Research Center, Department of Anesthesiology, MUMC+, Maastricht

2 Functional Neurosurgery, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden

3 Department of Clinical Epidemiology and Medical Technology Assessment (KEMTA), MUMC+, Maastricht

IntroductionSpinal cord stimulation (SCS) has been shown to provide pain relief in painful dia-betic polyneuropathy (PDPN). As the vascu-lature system plays a great role in the patho-physiology of PDPN, a potential beneficial side effect of SCS is peripheral vasodilation, with high frequency (HF) SCS in particular.

We hypothesize that HF-SCS (500 Hz), compared with conventional (CON) or low frequency (LF)-SCS will result in increased alleviation of mechanical hypersensitivity in chronic experimental PDPN.

MethodsDiabetes was induced in eight week old fe-male Sprague Dawley rats with an intraperi-toneal injection of 65 mg/kg of streptozoto-cin (n=44). Rats with a significant decrease in mechanical withdrawal response to von Frey filaments over a period of 20 weeks were implanted with SCS electrodes (n=18). Rats were assigned to a cross over design with a random order of LF-, CON-, HF-, and sham SCS and mechanical withdrawal thresholds were assessed with von Frey testing.

ResultsThe average logarithmically transformed withdrawal threshold during LF-SCS was 0.32 higher compared with sham SCS (p=0.081), and 0.17 higher post-stimulation (p<0.001). For 50Hz, the average withdrawal threshold during and after stimulation were 0.42 (p=0.015) and 0.25 (p<0.001), respective-ly. HF-SCS resulted in an average difference in withdrawal threshold of 0.16 (p=0.182) during stimulation, and 0.42 after stimula-tion (p<0.001) as compared with sham SCS.

ConclusionWe demonstrated a delayed effect of HF-SCS on mechanical hypersensitivity in chronic PDPN animals compared with LF-, or CON-SCS.


Preferred frequencies and waveforms for spinal cord stimulation in patients with complex regional pain syndrome: a multicenter, double-blind, randomized and placebo-controlled crossover trialN. Kriek 1, J. G. Groeneweg 1, D.L. Stronks 1, D. de Ridder 2, F. J.P.M. Huygen 1

1 Center for Pain Medicine, Erasmus MC – University Medical Center Rotterdam

2 Department of Surgical Sciences, Section of Neurosurgery, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand

IntroductionConventional tonic spinal cord stimulation (SCS) is an effective treatment for patients with therapy- resistant Complex Regional Pain Syndrome (CRPS). Although the therapeutic effect of SCS can diminish over time due to tolerance, pain control can be regained by increasing the stimulation fre-quency. This multicenter, double-blind, ran-domized and placebo-controlled crossover trial was conducted to investigate whether more effective pain reduction is achieved with different frequencies. Trial registration

Current controlled trials ISRCTN 36655259.

MethodsThe investigated settings are: standard 40 Hz, 500 Hz, 1200 Hz, burst, and placebo stimulation. All five were programmed in random order during the 10-week crossover-period (2-weeks/setting). The primary out-come parameters were scores on the Visual Analogue Scale (VAS), McGill Pain Ques-tionnaire (MPQ) and the Global Perceived Effect (GPE); at the end of the crossover period patients decided which SCS setting they preferred. A Linear Mixed Models analysis was performed in 29 patients who completed the crossover trial.

ResultsSignificant pain reduction and GPE Satisfac-tion was achieved with four SCS settings

compared with placebo stimulation, and these four settings did not differ significant-ly from each other. Standard stimulation was preferred by 48% of the patients while 52% preferred non-standard stimulation. Other than pain reduction, factors such as user-friendliness, comfort and recharging time may have influenced the patient’s final decision for the preferred stimulation set-ting.

ConclusionApparently, for various reasons, patients have a preference for different SCS setting. Therefore, future neuromodulation should aim to implement customized individual patient care by incorporating all stimulation options in one device.





Departments of anesthesiology and cardiothoracic surgery of the VUmc, Amsterdam

IntroductionOxygen delivery (DO2) and consumption (VO2) measurements during cardiac surgery are frequently limited to patients with a pulmonary artery catheter (PAC). The aim of this study was to evaluate an alternative method for DO2 and VO2 measurements using a minimally invasive approach.

MethodsParallel measurements of invasive and mini-mally invasive parameters for the calcula-tion of DO2 and VO2 were performed after

anesthesia induction and PAC placement in adults undergoing cardiac surgery. The in-vasive approach included arterial and PAC-derived blood sampling and cardiac output (CO) measurements. The minimally invasive approach included pulse oximetry, point-of-care hemoglobin, non-invasive, Nexfin-based CO and central venous line-derived blood sampling. Level of agreement was determined using Bland-Altman analysis.

ResultsDO2 and VO2 levels were determined in 18 male and 4 female patients aging 72 ± 8 years. The mean DO2 and VO2 levels as-sessed by the invasive approach were 641.5 ± 191.6 ml/min and 148.8 ± 41.2 ml/min, respec-

tively. The bias for DO2 was 26.2 ± 160.3 ml/min with levels of agreement (LOA) ranging from -134.1 to 186.6 ml/min and a precision error of 25.0%. The bias for VO2 was 14.0 ± 52.6 ml/min with LOAs ranging from = -38.6 to 66.5 ml/min and a precision error of 35.3%.

ConclusionMinimally invasive determinations of DO2 levels showed a good agreement with invasive DO2 levels. The agreement be-tween minimally invasive and invasive VO2 measurements was however poor. Further elaboration of the value of non-invasive DO2 measurements may extend its value to patients admitted to the normal ward.


korte presentatie

Viral reactivation as marker for a persistent anti-inflammatory phenotype and increased risk for secondary infections in trauma patientsR. M. Koch 1, 3, M.Kox 1, 3, J.C. Rahamat-Langendoen 2, K. Timmermans 1, 3, J.G. van der Hoeven 1, 3, P. Pickkers 1, 3




IntroductionSepsis-induced immunosuppression in-creases patients’ vulnerability towards secondary infections[1]. Among others, immunosuppression is illustrated by viral reactivation[2], associated with an increased incidence of secondary infections and 90-day mortality in sepsis patients[1, 2]. Recently, we reported that immunosup-pression is also apparent in multiple-trauma patients, exemplified by elevated levels of the anti-inflammatory cytokine IL-10 and decreased HLA-DR expression, which was related to an increased incidence of bacterial infections[3]. Herein, we investigated viral reactivation in multi-trauma patients.

MethodsSamples of 31 multi-trauma patients with and without bacterial infections were ana-lyzed for reactivation of the viruses HSV, CMV and EBV, and for HLA-DR expression and plasma levels of IL-10.

Results6/12 patients who developed bacterial infec-tions showed viral reactivation, of whom all were positive for EBV, while viral reac-tivation was observed in only 3/19 patients without infections (p=0.06). Hospital length of stay appeared longer in patients with viral reactivation (median [IQR] 63 [30-143] vs. 21 [12-37] days). Furthermore, the difference in HLA-DR expression between Emer-gency Room admission and day 3 following trauma, a parameter which was previously shown to correlate with bacterial infec-tions[3], decreased in patients with viral reactivation, while it increased in patients without viral reactivation (mean±SEM ra-tios: 0.75±0.12 vs. 1.20±0.10, p=0.02). Finally, IL-10 levels at later time-points were higher in patients with viral reactivation and cor-related with the extent of EBV reactivation (see Figure 1).

ConclusionViral reactivation illustrates trauma-induced immunosuppression, which is more fre-quently encountered in patients who devel-oped bacterial infections. Furthermore, de-creased HLA-DR expression and increased plasma IL-10 are related to viral reactivation, suggesting a relationship between an anti-inflammatory phenotype and reactivation of viruses. These data indicate that viral re-activation may represent a promising novel marker for immunosuppression in trauma patients.

re fe re nce s

1. Grimaldi D., Llitjos J.F., Pene F., (2014) Post-infectious immune suppression: a new paradigm of severe infections. Medecine et maladies infectieuses 44: 455-463.

2. Walton A.H., Muenzer J.T., Rasche D., Boomer J.S., Sato B., Brownstein B.H., Pachot A., Brooks T.L., Deych E., Shannon W.D., Green J.M., Storch G.A., Hotchkiss R.S., (2014) Reactivation of multiple viruses in patients with sepsis. PLoS One 9: e98819.

3. Timmermans K., Kox M., Vaneker M., van den Berg M., John A., van Laarhoven A., van der Hoeven H., Scheffer G.J., Pickkers P., (2016) Plasma levels of danger-associated molecular patterns are associated with immune suppression in trauma patients. Intensive care medicine 42: 551-561.

Figure 1. Left panel: Plasma IL-10 levels of patients that displayed viral reactivation (VR+) compared with the patients that did not display viral reactivation (VR-) on day 5 and day 7 following trauma. Data are presented as Means. P-values are calculated usingt-tests on log-transformed data. Central and right panels: Pearson correlations between IL-10 plasma levels at days 5 and 7 following trauma and maximum EBV viral load of the 7 patients who displayed viral reactivation.

r =0.85p=0.02

0.0 0.5 1.0 1.5 2.00

1

2

3

4

log IL-10 day 5

log

max

EB

V

r =0.96p=0.0007

0.0 0.5 1.0 1.5 2.00

1

2

3

4

log IL-10 day 7

log

max

EB

V

VR+1

10

100

pg/m

L

VR-

day 5VR+ VR-

day 7

p=0.11 p=0.02


korte presentaties

k orte presentatie

Angiopoietin-1 mimetic protects against microcirculatory perfusion disturbances and microvascular leakage during hemorrhagic shockM. Trieu 1, 2, M. van Meurs 4, 5, A.L.I. van Leeuwen 1, 2, L.M.G. Geeraedts 3, C. Boer 1, C.E. van den Brom 2

1 Departments of Anesthesiology 1, Physiology 2 and Trauma Surgery 3, VU University Medical Center, Amsterdam

2 Departments of Pathology and Medical Biology 4 and Critical Care 5, University Medical Center Groningen, Groningen

IntroductionMicrocirculatory dysfunction following hemorrhagic shock (HS) is associated with multiple organ failure and unfavourable patient outcome. Although crystalloids are effective in restoring macrohemodynamics during HS, microcirculatory dysfunction often persists. Therapeutic targeting of the Angiopoietin (Ang)/Tie2 system might preserve microvascular integrity. This study investigated the effects of an Angiopoietin-1 mimetic (Ang1-mim) on microcirculatory perfusion and microvascular leakage during HS.

MethodsRats underwent HS or sham surgery receiv-ing an Ang1-mim or PBS. HS was induced by blood withdrawal to achieve a mean arterial pressure (MAP) of 30mmHg for one hour, followed by resuscitation with crystalloids and blood until baseline MAP was reached. Microcirculatory perfusion was measured in the cremaster muscle using intravital microscopy and microvascular leakage by Evans Blue Dye extravasation. Plasma levels of Ang1, Ang2 and sTie2 were analysed by ELISA.

ResultsHS was characterized by a significant drop in MAP and heart rate, and metabolic aci-dosis. This was accompanied by a reduction of perfused capillaries and an increase in stopped vessels, which persisted during fluid resuscitation. In parallel, HS induced microvascular leakage in kidney and lung tissue, elevation of plasma Ang2 and sTie,

and a decrease of plasma Ang1.Administration of Ang1-mim had no ef-fect on the hemodynamic alterations and microcirculatory perfusion during shock. However, Ang1-mim restored microcircula-tory perfusion back to baseline during fluid resuscitation and attenuated microvascular leakage in kidney and lung tissue. Ang1-mim treatment additionally resulted in reduced resuscitation requirements following shock.

ConclusionAdministration of an Angiopoietin-1 mi-metic protects the microvasculature from impaired microcirculatory perfusion during HS and leads to reduced fluid resuscitation requirement, possibly due to less micro-vascular leakage. These results suggest that pharmacologic modulation of the Angiopoi-etin/Tie2 system might be a novel target in preventing microcirculatory disturbances, microvascular leakage in HS patients.

k orte presentatie

Minimally invasive treatment for lumbar spine related pain disordersC.W.J. van Tilburg 1, F.A. Schuurmans 1, D.L. Stronks 2, J.G. Groeneweg 2, F.J.P.M Huygen 2

1 Bravis hospital2 Erasmus MC University Medical Center

IntroductionThe assessment and interpretation of tests used to diagnose low back pain subtypes are often not standardised. Judging from spinal imaging tests regarding the cause of chronic low back pain can be challenging. The re-sults from trials investigating the efficacy of minimally invasive treatment are inconsis-tent. We conducted research into the effect on pain intensity and global perceived ef-fect (GPE) of minimally invasive treatment compared to a sham procedure for chronic lumbar spine related pain disorders.

MethodsThree RCT’s (60 patients per trial with low back pain lasting more than 3 months) in patients with medical history and physical examination suggestive of sacroiliac (SI) joint -, facet joint - or disc pain and a reduc-tion of 2 or more on a numerical rating scale after a diagnostic test block. Investigating the effect of a percutaneous radiofrequency heat lesion, applied to the lateral branches of L5-S4 nerve roots, medial branch of the primary dorsal ramus or ramus communi-cans. Inter-rater reliability study by three physicians, each and independently taking a physical examination in 100 patients. De-scribing presence of pathology on lumbar X-ray and MRI in 100 patients with positive – and negative diagnostic test block.

ResultsRegarding the SI joint trial, no statistically significant difference in pain level over time between the groups, nor in the group was found; when pooled together, the mean pain level was significantly reduced. No statisti-cally significant difference in the GPE scales was found. Results from the other trials will be published upon acceptance to the journals.

ConclusionIn the SI joint trial, the hypothesis of no dif-ference in pain reduction or in GPE between the treatment and sham group cannot be rejected. Conclusions from the other trials will be published upon acceptance to the journals.


korte presentatie

Genetic polymorphisms and their association with the prevalence and severity of chronic postsurgical painR.R.I. van Reij, D. M.N. Hoofwijk, B. P. Rutten, G. Kenis, N. J. van den Hoogen, W.F.F.A. Buhre, E. A. Joosten

- Department of Anesthesiology and Pain Medicine, Maastricht University Medical Center+, Maastricht

- School for Mental Health and Neuroscience (MHeNs), Faculty of Health, Medicine and Life Sciences, Maastricht University Medical Centre, Maastricht

IntroductionChronic postsurgical pain (CPSP) is a com-mon problem affecting between 10 and 60% of the patients undergoing surgery. Although demographic, clinical and psy-chological risk factors are well documented; little is known about genetic risk factors for CPSP. Single nucleotide polymorphisms (SNPs) might to play a crucial role in the de-velopment of CPSP. The aim of this study is

to investigate the association between SNPs and the prevalence and severity of CPSP. It is hypothesized that SNPs in some genes predispose to CPSP whereas other SNPs are associated with a protective effect.

MethodsTo assess current knowledge about the asso-ciation between SNPs and CPSP, a systemat-ic review following the PRISMA guidelines was conducted. For inclusion, the primary outcome of the study needed to be CPSP, defined as pain at least two months after the surgery. Studies performed exclusively in animals were excluded from the literature search. A total of 1001 studies were identified, of which 14 were included. The studies de-scribed 5269 participants combined in 17 cohorts.

The genes identified in the systematic review were selected as genes of interest. Moreover, the separate genes were assessed for their role in the development of CPSP.

ResultsAssociations with CPSP were reported for SNPs in the COMT gene, OPRM1, potas-sium channel genes, GCH1, CACNG, CHR-NA6, P2X7R, cytokine associated genes, HLA, DRD2, and ATXN1.

ConclusionSome of these genes are well known in the biological and psychological mechanisms of pain. This study and future studies should lead to a better understanding of the associ-ations between genetics and the prevalence and severity of CPSP.

k orte presentatie

Reproducibility of corneal confocal microscopy in a multicenter study with a new tool to estimate neuropathy in patients with painful neuropathy and healthy controlsM.D. Nieuwenhoff 1, 2, H. Nguyen 3, F.J.P.M. Huygen 1, S.P. Niehof 1, A. Verma 4, J. Geelhoed 2, A.F.S. Petzold 3, 5, A.C. Moll 3, G.J. Groeneveld 2, 3

1 Department of Anesthesiology and Pain Medicine, Erasmus MC University Medical Center, Rotterdam

2 Centre for Human Drug Research, Leiden3 Department of Ophthalmology VU University

Medical Center, Amsterdam4 Biogen, Cambridge, USA 5 Department of Neurology, VU University Medical

Center, Amsterdam

IntroductionThe diagnosis of neuropathy is still challeng-ing. Medical history taking, physical exami-nation, questionnaires, electrophysiological tests and skin biopsies are the main available tools to diagnose neuropathy. In vivo cornea confocal microscopy (CCM) of the subbasal corneal nerve plexus is an emerging non-invasive tool in determining peripheral neu-

ropathy in a large range of diseases. Studies show this technique has good intra- and inter-observer reproducibility. However, evidence is lacking on inter-center repro-ducibility, which is crucial when performing multi-center studies.The purpose of this study was to determine the inter-center reproducibility of corneal nerve fiber parameters in patients with dia-betes mellitus with and without painful neu-ropathy, patients with chronic idiopathic axonal neuropathy and healthy controls assessed with corneal confocal microscopy.

MethodsTwenty-eight subjects underwent CCM on two separate occasions at different centers and by different operators. Corneal nerve fiber density (CNFD), branch density (CNBD) and fiber length (CNFL) were calculated with automated image analysis

software (ACCMetrics v2.0). The intraclass correlation coefficient (ICC) was calculated to assess inter-center reproducibility.

ResultsCCM images were obtained for 27 subjects, in one subject CCM measurements were not successful. Inter-center ICCs were 0.77 for CNFD, 0.63 for CNBD, and 0.87 for CNFL.

ConclusionCorneal nerve fiber density and corneal nerve fiber length were highly reproduc-ible, even when assessed at different sites by different examiners. This new diagnostic tool may facilitate the diagnosis and man-agement of patients at risk for neuropathy including potential future multicenter trial settings.


korte presentaties

k orte presentatie

Painful procedures during neonatal development: short- and long-term consequences on spinal nociceptive processingN.J. van den Hoogen 1, 2, C.H.T. Kwok 3, M. Fitzgerald 3, J. Patijn 1, D. Tibboel 4, E.A. Joosten 1, 2

1 Department of Anaesthesiology, Pain Management and Research Centre, Maastricht University Medical Centre

2 Department of Translational Neuroscience, School of Mental Health and Neuroscience, Maastricht University

3 Department of Neuroscience, Physiology and Pharmacology, University College London, London

4 Intensive Care and Department of Paediatric Surgery, Erasmus MC-Sophia, Rotterdam

IntroductionIn the Neonatal intensive care unit (NICU), new-born babies routinely undergo painful procedures, approximately 10-14 times per day. Clinical and experimental data suggests that noxious stimulation at critical stages of development has both short- and long-term consequences on nociceptive processing in later life. Here, we use a model of repeated procedural pain as would be experienced in

the NICU. The aim of this study is to eluci-date the short- and long-term consequences of repetitive needle pricking in neonatal rats upon nociceptive circuits in central nervous system.

MethodsNeonatal rats received four needle pricks per day in the left hind-paw from postnatal day 0 to 7 as a model of procedural pain in infancy. Control pups were handled in the same way but did not receive pricks. At the age of 8 weeks, all animals received an ipsilateral hind-paw incision as a model for post-operative pain in adulthood. The effect of neonatal injury on adult pain sensitivity was quantified by: 1) mechanical sensitivity in behavioural tests; 2) excitability of spinal cord dorsal horn neurons in extracellular single unit recordings; and 3) immunola-belling of molecular markers, CGRP, 5HT, GluR1, and OPRM1 in spinal cord tissue.

ResultsNeonatal repeated needle pricks resulted in short term increases in mechanical hyper-sensitivity of the ipsilateral hind-paw, but by adulthood, baseline sensitivity was not different from controls. However, adult paw incision to the same dermatome resulted in significantly greater mechanical hypersen-sitivity than in controls. In the spinal cord, expression of molecular markers and activ-ity of dorsal horn neurons followed the same pattern of enhanced injury-induced sensi-tivity in adulthood.

ConclusionRepeated procedural pain during early life primes spinal nociceptive circuits and results in enhanced postoperative pain in adulthood.

korte presentatie

The prognostic value of postoperative high-sensitive troponin T in patients with different stages of kidney disease undergoing noncardiac surgeryV.G.B Liem, S.E. Hoeks, F. Grüne, F.H.I.M. Wesdorp, R.J. Stolker, F. van Lier

Erasmus MC Rotterdam

IntroductionEmerging evidence suggests that postopera-tive troponin release is a strong and inde-pendent predictor of short-term mortality. However, evaluating elevated troponins in patients with chronic kidney disease (CKD) is still controversial and is usually being disregarded. This study examines short and long-term mortality risk associated with el-evated high-sensitivity troponin T (hsTnT) in patients with different stages CKD under-going noncardiac surgery.

MethodsThis observational cohort comprised of 2119 patients aged ≥ 60 years who underwent noncardiac surgery. Postoperative hsTnT levels were divided in normal = reference (<14 ng/L), low (14-49 ng/L), moderate (50-149 ng/L) and high ≥ 150 ng/L). The study Figure 1


endpoints were 30-day and long-term all-cause mortality. Cox proportional hazard models were performed to assess the asso-ciation between postoperative hsTnT and study endpoints.

ResultsPostoperative hsTnT was associated with a stepwise increase of 30-day mortality

and long-term mortality risk: low hsTnT adjusted HR=1.5 (95% CI 1.1-1.9), moderate adjusted hsTnT HR 3.0 (95% CI 2.1-4.3), high hsTnT adjusted HR 5.5 (95% CI 3.7-8.1), inde-pendent of CKD. After stratification of the different stages of CKD, cumulative survival presented to be comparable between differ-ent levels of postoperative hsTnT irrespec-tive of preoperative renal function.

ConclusionElevated postoperative hsTnT is associated with a dose-dependent increase in 30-day mortality and long-term mortality risk, irre-spective of the stage of CKD. Postoperative hsTnT monitoring after surgery is justified and elevated hsTnT levels in patients with a decreased eGFR must not be disregarded.

k orte presentatie

The effect of clonidine as an additive to local anaesthetics on the duration of postoperative analgesia after orthopaedic foot surgery: a randomized clinical trialP.A. Ramsodit, L. Timmerman

St. Antonius Ziekenhuis, Nieuwegein

IntroductionA popliteal nerve block is frequently used for postoperative pain management after orthopaedic foot surgery. Popliteal nerve block may provide superior pain relief com-pared to systemic analgesic therapy, which is often accompanied by side effects of medication prescribed. Unfortunately, the analgesic effect is limited to the first hours after surgery, after which additional analge-sic therapy is often required. In this study, we assessed the ability of clonidine as an additive to local anaesthetics to prolong the analgesic effect of popliteal nerve block.

MethodsPatients scheduled for orthopaedic foot sur-gery (all osteotomies) were included in this randomized double-blind study. After in-formed consent, patients were randomized into a control or intervention group. Both groups received a popliteal nerve block with 30 cc levobupivacaine 5 mg/ml, in the intervention group clonidine 105 ugr was added to the local anaesthetic. All blocks were performed with ultrasound guidance and neurostimulation. After popliteal nerve block, patients received spinal or general anaesthesia. The primary endpoint of this study was the First Analgesic Request (FAR), the time after which additional pain medica-tion was requested. Secondary endpoints were pain intensity, side effects, occurrence of hypotension or bradycardia.

ResultsFrom August 2015 until December 2015, 68 patients were included. After analysis 7 pa-tients were excluded because of failed block (N=6) and not following study protocol (N= 1). Fifty-one patients were female (84%) and the mean age was 51,8 years. All participants had ASA physical status I/II. Eighty-two per-cent received general anaesthesia with the rest receiving spinal anaesthesia. The medi-an FAR (interquartile range) was 1320 (326) min and 1280 (245) min in the intervention

and control group, respectively (p=0.44; see Figure). The secondary endpoints pain intensity, frequency of side effects, hypoten-sion and bradycardia did not significantly differ between the study groups.

ConclusionThe use of clonidine as an additive to le-vobupivacaine for popliteal nerve block did not result in a significant difference in the duration of postoperative analgesia in or-thopaedic foot surgery.

Figure 1


korte presentaties

korte presentatie

Evaluating non-invasive mitochondrial function assay vs muscle biopsies in an endotoxemic model in ratM.A. Wefers Bettink, N. Dollee, R.J. Stolker, E.G. Mik

Department of Anesthesiology, Erasmus MC, Rotterdam

IntroductionMitochondrial dysfunction plays an im-portant role in the pathophysiology of sepsis. Endotoxemia diminishes the func-tion of mitochondria. By developing a new non-invasive mitochondrial assay based on measuring cellular oxygen consumption in skin, a new diagnostic test comes available for patients suspected of acute mitochon-drial dysfunction. A direct comparison of mitochondrial assay in muscle biopsies and the novel non-invasive technique was not performed until now.

MethodsOxygen disappearance rate (ODR) was mea-

sured by dynamic measurements of mito-chondrial oxygen tension (mitoPO2), based on delayed fluorescence lifetime measure-ments of protophorphyrin IX (PpIX). PpIX was induced by affixing 2.5% 5-aminolevu-linic acid cream on abdominal skin of anes-thetized and mechanically ventilated rats (n = 3 LPS, n=3 control). In the LPS group endotoxemia was induced by LPS infusion (dose 3mg/kg). At the end of the experiment leg muscle of the rat was collected for classic respirometry experiments in the O2K (Oro-boros Instruments). In the O2K a substrate-uncoupler-inhibitor titration protocol was followed, designed for measurement of total oxygen consumption, complex 1 (C1) and complex 2 (C2) activation.

ResultsPreliminary data of this ongoing study showed that LPS infusion decreased cutane-

ous ODR by 40±40% in the LPS- treated rats. In comparison, the ODR in control rats decreased by only 9,1±10%. The ex vivo mi-tochondrial assay in muscle biopsies showed no difference between LPS and control rats in absolute oxygen consumption and in C1 vs C2 activation.

ConclusionA decline of ODR was measured after LPS infusion without changes in total oxygen consumption in the O2K. Furthermore, no changes in c1/c2 activity were found between the LPS group and the control group. Several explanations for this appar-ent discrepancy are possible. For example skin and muscle mitochondria might have different sensitivity for LPS, or mitochon-drial dysfunction in vivo precedes structural changes in mitochondria as measured in muscle biopsies.

k orte presentatie

Endotoxin challenge does not influence the immune response induced by a subsequent challenge with live-attenuated influenza vaccine in humans in vivoR.M. Koch 1, 4, M.Kox 1, 4, E.J.M. Thijs 1, 4, J.C. Rahamat-Langendoen 2, J. Gerretsen 1, 4, D. Diavatopoulos 3, 4, J. G. van der Hoeven 1, 4, M.I. de Jonge 3, 4, Peter Pickkers 1, 4



3 Radboud university medical center, Radboud Institute for Molecular Life Sciences, Department of Pediatrics, 6500 HB, Nijmegen


IntroductionBacterial sepsis induces immunosuppres-sion, impairing clearance of primary infec-tions and increasing vulnerability towards secondary infections[1]. However, whether bacterial sepsis affects the response to sub-sequent influenza infection is unknown, as is the safety of live-attenuated influenza vaccines (LAIVs) in immunocompromised patients. Experimental human endotoxemia

Figure 1. Plasma levels of the cytokines TNF-α, IL-6, and IL-10 over time in subjects that received an intravenousadministration of endotoxin or placebo at T=0. Data are represented as mean with SEM.

plasma cytokine levels

Time after endotoxin / placebo administration (h)

0 1 2 3 4 5 6 7 80

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200

300

400

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LPS IL-6

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induces systemic inflammation that mimics bacterial sepsis and subsequent immuno-suppression[2]. We investigated the effects of human endotoxemia on the immune response elicited by a subsequent challenge with the LAIV Fluenz surrogate for influ-enza infection[3]).

Methods30 healthy males received placebo or endo-toxin (2 ng/kg) intravenously, followed by intranasal Fluenz on day 7 in all subjects. Blood and nasal washes were obtained to measure seroconversion (≥fourfold in-crease in antibody titer for ≥1 of 4 influenza strains present in the vaccine, 4 weeks post-inoculation), viral loads, and inflammatory mediators.

ResultsEndotoxin, but not placebo administration increased plasma cytokine levels (see Figure 1). Following Fluenz, seroconversion oc-curred in 14/15 (93%) subjects in the placebo-Fluenz group vs. 10/15 (68%) subjects in the LPS-Fluenz group (p=0.17). Viral shedding for ≥1 of 4 influenza strains in nasal wash was 6/15 (40%) in the LPS-Fluenz group vs. 7/15 (47%) in the placebo-Fluenz group (p=1.00). The increase in viral loads in nasal wash was similar between groups (Figure 2). Likewise, Fluenz-induced increased levels of IP-10, IL-6 and G-CSF in nasal wash were similar in both groups (see Figure 2).

ConclusionWhile human endotoxemia severely at-tenuates the immune response to a second challenge with endotoxin[2], it does not influence the Fluenz-induced immune re-sponse. These data suggest that the immune response to a bacterial compound does not alter the response to a subsequent viral infection. Furthermore, it indicates that Fluenz is safe to administer in immunocom-promised patients.

re fe re nce s

1. Hotchkiss R.S., Monneret G., Payen D., (2013) Immunosuppression in sepsis: a novel understanding of the disorder and a new therapeutic approach. The Lancet infectious diseases 13: 260-268.

2. Leentjens J., Kox M., Koch R.M., Preijers F., Joosten L.A., van der Hoeven J.G., Netea M.G., Pickkers P., (2012) Reversal of immunoparalysis in humans in vivo: a double-blind, placebo-controlled, randomized pilot study. Am J Respir Crit Care Med 186: 838-845.

3. Carter N.J., Curran M.P., (2011) Live attenuated influenza vaccine (FluMist(R); Fluenz): a review of its use in the prevention of seasonal influenza in children and adults. Drugs 71: 1591-1622.

Fluenz Influenza A

Fold

chan

ge

LPSPlacebo

P=0.90

7 12 13 15 16 17 18 19 20 218 9 10 11 140.1

1

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100P=0.20

Influenza B

Fold

chan

ge

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LPSPlacebo

7 12 13 15 16 17 18 19 20 218 9 10 11 140.1

1

10

100

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Figure 2. Viral shedding in nasal wash of the two influenza A and two B strains present in the vaccine (upper panels) and levelsof IP-10, IL-6 and G-SCF in nasal wash (lower panels) following intranasal administration of Fluenz on day 7, in subjects thatwere administered endotoxin or placebo one week before. Data are presented as Geometric means with 95% CI. P-values arecalculated using two way ANOVAs on log-transformed data.

p=0.93

G-CSF in nasal wash

Time (days)

pg/m

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FluenzLPSPlacebo

7 1213 15 16171819 20218 9 1011 1410

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pg/m

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7 12 13 15 16 17 18 19 20 218 9 10 11 14100

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IL-6 in nasal wash

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7 1213 15 16171819 20218 9 1011 141

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20

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poster presentatie

pos ter presentatie

Quality Indicators (QI) from the Perspective of Chronic Pain Patients; the QiPPP-listP. de Meij 1, A. Köke 2, 4, 5, T. van der Weijden 3, M. van Kleef 1

1 University Pain Centre Maastricht, UPCM, Department of Anaesthesiology and Pain Management, Maastricht University Medical Centre

2 Department of Rehabilitation Medicine/CAPHRI, School for Public Health and Primary Care Maastricht University

3 Department of Family Medicine/CAPHRI, School for Public Health and Primary Care & Maastricht University Medical Centre

4 Adelante Centre of Expertise in Rehabilitation and Audiology, Hoensbroek

5 Zuyd University for Applied Sciences, faculty Health and Technology, Heerlen

IntroductionPatient involvement in developing quality indicators (QI) may lead to better processes and outcomes for care. The aim of the study is to develop QI from the perspective of chronic pain patients for the assessment of quality pain care.

MethodsQuality criteria as defined by chronic pain patients’ organizations (Samenwerkings-verband van pijnpatienten naar één stem & PijnPlatform) were prioritized and trans-formed into measurable QI. Additionally the QI were divided into quality domains. A first set of QI was tested and fine-tuned in a small sample of chronic pain patients, result-ing in the QiPPP-list.

ResultsA QiPPP-list was developed with process (n=28) and outcome (n=3) QI divided into 12 quality domains; contact patient-physician, one contact person for the patient, waiting-time, pain team information, pain question-naire, discussed treatment information, work and rehabilitation, patient decision in treatment, treatment purpose, treatment result, and result of the process of pain care.

ConclusionThe QiPPP-list is a first set of QI from the perspective of chronic pain patients. Where professionals emphasize more organiza-tional aspects of quality of health care, pa-

tient organizations underline indicators on process and outcome for quality pain care. Currently, about 600 chronic pain patients in five Dutch pain clinics tested the QiPPP-list in daily pain practice.


pos ter presentatie

The effect of pulsed radiofrequency treatment applied adjacent to the dorsal root ganglion in an experimental model for chronic neuropathic pain: behavioral assessmentG. Franken, W. Honig, E.A. Joosten

- Department of Anesthesiology and Pain Management, University Pain Clinic Maastricht (UPCM), Maastricht, The Netherlands

- Department of Translational Neuroscience, School for Mental Health and Neuroscience (MHeNS), Maastricht, The Netherlands

IntroductionAnalysis of the pain relieving effect of Pulsed RadioFrequency (PRF) treatment in experi-mental chronic neuropathic pain is often limited to reflex-based outcome measures, predominantly related to mechanical and thermal hypersensitivity. This study exam-ined the effect of PRF applied adjacent to the L5 Dorsal Root Ganglion (DRG) not only on mechanical and thermal hypersen-sitivity, but also on pain-induced gait using the CatWalk system.

MethodsMale Sprague-Dawley rats were sub-jected to Partial Sciatic Nerve Ligation (PSNL) and randomly assigned to a PRF (n=9) or sham group (n=6). PRF (pulse-frequency=4Hz, pulse-width=20ms, output voltage=45V, duration=2x180s and max temperature<42°C) was applied to the ipsi-lateral L5 DRG two weeks post-PSNL. Ani-mals were tested for mechanical (Von Frey) and thermal hypersensitivity (Hargreaves) and pain-induced gait (CatWalk) on base-line, days 3, 7 and 14 post-PSNL, and days 5, 8 and 15 post-PRF application. Stand phase, print area, mean intensity and max intensity of the ipsilateral hind paw were used as pa-rameters for pain-induced gait.

ResultsPSNL successfully induced chronic neu-ropathic pain, evidenced by increases in

mechanical and thermal hypersensitivity throughout the 14 days post-PSNL. Addi-tionally, significant decrease of stand phase of the ipsilateral hind paw was noted on all time points post-PSNL. The effect of PSNL was less obvious on CatWalk parameters mean intensity (decreased on post-PSNL day 3) and max intensity (decreased on post-PSNL days 3 and 7) of paw print. PRF treat-ment attenuated PSNL-induced mechanical hypersensitivity at all post-PRF time points and thermal hypersensitivity at post-PRF day 8. No effect of PRF was observed on CatWalk parameters, which might be due to a too small window for PRF treatment.

ConclusionMore research is needed to elucidate the mechanism of action underlying PRF and pain relief.

poste r presentatie

Assessment of anesthesiology residents: a systematic reviewJ. Kaldeway, E. Booij, M.F. van der Schaaf, R.G. Hoff

Universitair Medisch Centrum Utrecht

IntroductionA systematic review was conducted to cat-egorize and critically appraise what has been published on assessment of anesthesiology residents.

MethodsA search was performed in medical data-bases ‘Medline’, ‘Embase’ and ‘CINAHL’ for articles on performance assessment and en-trustment decision making within the do-main of anesthesiology from 1990 up to 2015. Articles were categorized using the AMEE

guide and validated with a framework based on the work of Messick (1995).

ResultsThe search yielded 535 results. 46 Articles were selected after screening and reference check. CATEGORIES: 67% focused on sim-ulation testing, the remainder on long and short practice observation. 50% investigated technical skills, 24% non-technical skills and 26% both. VALIDITY: 89% scored positive on the content aspect, 58% scored positive on the substantive aspect, 87% scored posi-tive on the structural aspect, 93% on the generalizability aspect, 54% scored positive on the external aspect and 76% on the con-sequential aspect.

ConclusionMore than two-thirds of the articles focus on simulated emergencies, tools to assess daily practice seem to be underrepresented. Non-technical skills are generally evaluated by validated frameworks, while technical skills are often evaluated by stand-alone scoring systems. The content, generaliz-ability and structural aspects of validity were often thoroughly investigated, but less emphasis was laid on the substantive and external aspects. The last two aspects may be harder to investigate or are given less priority.


poster presentatie

pos ter presentatie

Anesthetics and analgesics, and their impact on anti-tumor immune responsesT.K. Raaijmakers 1, 2, M.H. den Brok 1, G.J. Scheffer 2, G.J. Adema 1

1 Department of Tumor Immunology, Radboud University Medical Center, Nijmegen, The Netherlands.

2 Department of Anesthesiology, Pain management and Palliative Care, Radboud University Medical Center, Nijmegen, The Netherlands

IntroductionAnesthesia (narcotics) and analgesia (pain management) are often administered to cancer patients. These compounds are given during surgery, when (a part of ) the tumor is removed, or when in a later stage, the disease gives discomfort due to pain. Lo-cal or metastatic recurrence after surgical resection of primary tumors is common. A multitude of working mechanisms by which anesthetics and analgesics might affect tu-mor growth and metastasis have been pro-posed, e.g. changes in angiogenesis, direct anti-tumor toxicity, the immune system, metabolic stress and other factors. However,

especially the influence of anesthetics/anal-gesics on the immune system remains poorly defined. This also has implications for new immunotherapies, that are currently more and more implemented in the clinical field, and in which patients are also often exposed to anesthetics or analgesics. More insight in the interaction between anesthetics/an-algesics and the immune system is therefore urgently needed. In this project, we will in-vestigate the immunological effects of inha-lation or intravenous anesthetics and various analgesics (e.g. NSAIDs and opioids).

MethodsIn in vitro studies, we will study the effects of the compounds on functioning of rel-evant immune cells (e.g. cross-presentation and maturation of dendritic cells, and prim-ing and killing efficacy of T cells). Molecular interference with relevant receptors or im-munological pathways might help to iden-tify how the anesthetics/analgesics mecha-

nistically influence immunological outcome. In vivo, we will determine the interaction between the anesthetics/analgesics and the immune system using various immunothera-pies, including T cell checkpoint blockade and in situ tumor destruction, that have proven to be effective.

ResultsThe murine studies will provide insight in the influence of anesthetics and analgesics on the anti-tumor reactivity of the immune system, while the in vitro studies can help identify immunological targets that are key players in this interaction.

ConclusionThe obtained knowledge can improve clinical practice for immune or surgical anti-cancer therapies: the type of anesthesia and/or analgesia can be adapted to immunologi-cally support rather than counteract the treatment.

poste r presentatie (digitaal)

Perioperative and postoperative adverse cardiac events in patients undergoing vascular surgery: External validation of prognostic risk modelsM.S. Erkamp, F. van Lier, S.E. Hoeks

Department of AnesthesiologyErasmus University Medical Center, Rotterdam, The Netherlands

IntroductionCardiac complications are an important cause of morbidity and mortality after vas-cular surgery. The objective of the present study was to validate existing prognostic models on their performance to predict ad-verse cardiac outcome in a cohort of patients undergoing vascular surgery.

MethodsData were extracted from the local Vascular Surgery Outpatient Clinic Database at Eras-mus Medical Center. A total of 721 patients undergoing non-cardiac and non-emergent vascular surgery between 2012 and 2014 were

eligible for this study. Four sets of prognos-tic models were externally validated using discrimination (Area Under the receiver op-erating characteristics Curve, AUC) and cali-bration statistics (Hosmer and Lemeshow test and calibration plots): the American College of Surgeons National Surgical Qual-ity Improvement Program (ACS NSQIP), the Vascular Study Group of New England Cardiac Risk Index (VSG-CRI), the Gupta Perioperative Cardiac Risk Index (Gupta) and the Revised Cardiac Risk Index (RCRI).

ResultsPerioperative myocardial infarction and cardiac arrest was seen in 18 (2.8%) patients. Major adverse cardiac events occurred in 42 (6,6%) patients. AUC varied from 0.64 for the RCRI to 0.81 for the ACS NSQIP. External validation of the RCRI showed that

this model failed to properly predict major adverse cardiac events (calibration slope 0.51, intercept -0.27). External validity of the ACS NSQIP and the Gupta model in predicting myocardial infarction and/or cardiac arrest in patients undergoing vascular surgery showed good discrimination and calibration (AUC 0.81 and AUC 0.77, slope 1.35 and 1.08, respectively). Our results also showed good performance of the VSG-CRI model to pre-dict adverse cardiac events.

ConclusionThe prognostic models VSG-CRI, Gupta and ACS NSQIP possess good calibration and discriminative ability for prediction of the development of major cardiac events in patients undergoing non-emergent vascular procedures.


poste r presenatie (digitaal)

Prevalence and determinants of medication non-adherence in chronic pain patients: a systematic reviewL. Timmerman 1, D.L. Stronks 2, J.G. Groeneweg 2, F.J.P.M. Huygen 2

1 St Antonius Ziekenhuis, Nieuwegein2 Erasmus MC Rotterdam

IntroductionChronic pain is commonly treated with analgesic medication. Non-adherence to prescribed pain medication is very common and may result in suboptimal treatment out-come. The aim of this review is to investigate the prevalence of medication non-adherence and to present determinants that may help identify patients at risk for non-adherence to analgesic medication.

MethodsA search was performed in PubMed and Embase with systematic approach including

PRISMA recommendations. Individual risk of bias was assessed and systematic data ex-traction was performed.

ResultsTwenty-five studies were included. Non-adherence rates to pain prescriptions ranged from 8 to 62 percent with a weighted mean of 40 percent. Underuse of pain medication was more common than overuse in most studies. Factors that were commonly posi-tively associated with non-adherence were dosing frequency, polymedication, pain intensity, and concerns about pain medica-tion. Factors negatively associated with non-adherence were age, again pain intensity and quality of the patient-caregiver relationship. Underuse was positively associated with active coping strategies and self-medication,

and negatively associated with perceived need for analgesic medication. Overuse was positively associated with perceived need, pain intensity, opioid use, number of pre-scribed analgesics, a history of drug abuse and smoking.

ConclusionNon-adherence to analgesic medication use is very common in the chronic pain population. The choice for pharmacological therapy should not only be based upon pain diagnosis, but should also take the risks of non-adherence into account. The value of adherence monitoring or adherence enhanc-ing interventions has to be investigated in future studies.

poste r presentatie (digitaal)

The effect of midazolam on the quality of postoperative recoveryS. van Beek, J. Kroon, H.J. Mijderwijk, M. Klimek, R.J. Stolker

Erasmus MC Rotterdam

IntroductionThe effects of anxiolytic premedication such as benzodiazepines on the quality of postop-erative recovery are unknown. Despite con-tradictory outcomes, premedication with benzodiazepines is a common practice in hospitals. Therefore we ev aluated the effect of midazolam as premedication on quality of recovery and psychological manifestations in laparotomy patients.

MethodsA randomized placebo controlled, double blinded clinical trial was performed in a single tertiary center from July 2014 to Sep-tember 2015 in patients aging > 18 years and scheduled for (semi)-elective laparotomy with a planned postoperative recovery of

≥ 3 days in the hospital. Exclusion criteria were insufficient command of the Dutch language, intellectual disability, preceding use of psycho-pharmaceuticals and contra-indications for midazolam. We randomized patients in two groups to receive Midazolam 3mg or NaCl 0.9% intravenously as pre-medication prior to surgery. Primary outcome: Quality of Recovery-40 (QoR-40). Secondary outcomes: State-Trait Anxiety Inventory (STAI-State/Trait); State-Trait Anger Scale (STAS-State/Trait); Multi-dimensional Fatigue Inventory (MFI); Hos-pital Anxiety and Depression Scale (HADS). Timing of evaluation: T0: preoperatively (all scales); T1: first postoperative day (STAI-State/Trait); T2: third postoperative day (QoR-40); T3: 7th day after surgery (all scales). Robust regression analysis was applied. Sta-tistical analyses were adjusted for the corre-sponding baseline value and sex.

Results192 patients were randomized; 190 patients were analyzed. Postoperative mean QoR-40 scores were better in the midazolam group at T2 (166.4 vs 163.9 P=0.3433) and T3 (172.9 vs 166.0 P=0.007). Postoperative mean HADS-anxiety score decreased more in the midazolam group at T3 (2.4 vs 3.5 P=0.046) and MFI scores increased less in the mid-azolam group (56.6 vs. 60.1 P= 0.05).

ConclusionMidazolam as premedication for laparotomy surgery patients improved quality of recov-ery. Midazolam had minor positive effects on postoperative anxiety and fatigue but had no effect on aggression or depressive feelings. Trial Registration: ClinicalTrials.gov-Identi-fier: NCT01993459.


poster presentatie

pos ter presentatie (digitaal)

Potential pathways leading to postoperative fatigue. Structural equation modelling in daycase surgery patientsH. Mijderwijk 1, E.W. Steyerberg 2, H.J. Duivenvoorden 1, M. Klimek1, R.J. Stolker 1

1 Department of Anesthesiology, Erasmus University Medical Center

2 Department of Public Health, Erasmus University Medical Center

Introduction Postoperative fatigue is common follow-ing surgery, however its etiology is still unknown. The most common theory to date is of psychological nature assuming that anxiety and depression are closely re-lated to fatigue. Although these factors are indeed strongly interrelated, direction of causality is currently not determined which is necessary for proper treatment. We tried to unravel the direction of these pathways using an appropriate statistical methodol-

ogy in order to find a target for treatment or prevention.

MethodsStructural equation modelling was used to unravel the pathways among fatigue, anxiety, and depression in 398 mixed adult patients undergoing ambulatory surgery. Assessments took place preoperatively and postopera-tively. Fatigue was measured using the Mul-tidimensional Fatigue Inventory, whereas anxiety and depression were measured using the Hospital Anxiety and Depression Scale. Standardized regression coefficients (B) were used as measures of relative importance.

ResultsThe most optimal path model showed that preoperative fatigue substantially predicted

postoperative fatigue (B=0.54, P=0.00), and that preoperative anxiety and depression were unimportant in predicting postopera-tive fatigue. Furthermore, at each single measurement moment fatigue significantly predicted anxiety and depression rather than vice versa. The model fit was adequate: chi2 16.10, df 9, P=0.06, CFI 0.991, TLI 0.979, SRMR 0.029, RMSEA 0.045.

ConclusionIn the ambulatory surgery population postoperative fatigue is likely induced via preoperative fatigue, and not a consequence of anxiety and depression. If an interven-tion for postoperative fatigue is considered, preoperative treatment tailored to reduce preoperative fatigue could be strategy of choice.


samenvatting PhD thesis

PhD thesis summaryMinimally invasive monitoring in patients under general anesthesia

summary Minimally invasive monitoring of patients under (general) anesthesia has emerged in recent decades following technologic advances. We investigated multiple aspects of novel minimally invasive moni-toring methods. At first, we demonstrated that in hemodynamically stable patients under general anesthesia, continuous arterial blood pressure measurement by the noninvasive volume-clamp technique is non-inferior to intermittent arm cuff oscillometry, the current clinical standard. At second, the current gold standard for determining fluid responsiveness (FR) – i.e. whether cardiac output increases after fluid administration – is the use of dynamic (preload) variables such as pulse pressure variation and stroke volume variation (PPV, SVV). We demonstrated that noninvasive dynamic variables (e.g. pleth variability index, PVI) are as good as their invasive counterparts in predicting FR. Yet, we demonstrated that the adequacy of predicting FR by dynamic preload variables is critically dependent on the actual definition of FR – which is an important issue to consider in the individual patient. At third, we observed that, with respect to the noninvasive monitoring of hemoglobin concentration, the agreement with invasive reference measurements is moderate, yet substantially influenced by the type of fluid infused. For instance, after colloid infusion, its agreement dropped substantially, which was not true after infusing crystalloids. Finally, we investigated minimally invasive liver function monitoring in patients undergoing orthotopic liver transplantation. We found that at the end of surgery, the plasma decay of indocyanine green (ICG) could pre-dict early postoperative complications, potentially allowing early interventions aimed at preserving transplant survival.

samenvatting Minimaal invasieve bewaking van de patiënt onder (algehele) anesthesie heeft de afgelo-pen jaren een enorme vlucht genomen dankzij technologische vooruitgang. Meerdere aspecten van minimaal invasieve bewaking hebben wij onderzocht. Allereerst hebben we aangetoond dat in hemodynamisch stabiele patiënten onder algehele anesthesie, continue arteriële bloeddrukmeting middels de volume-clamp techniek niet inferieur is ten opzicht van de huidige klinische standaard: intermitterende bloeddrukband oscillometrie. Ten tweede, de huidige gouden standaard voor het bepalen van volume responsiviteit – m.a.w. stijgt de cardiac output na vochttoediening – is het gebruik van dynamische (preload) variabelen, zoals pulse pressure variation en stroke volume variation (PPV, SVV). We laten zien dat noninvasieve dynamische variabelen (zoals pleth varia-bility index, PVI) net zo goed zijn in het voorspellen van volume responsiviteit als invasief bepaalde dynamische variabelen. Maar belangrijk is, dat we hebben laten zien dat de voorspelling van volume responsiviteit sterk afhankelijk is van de definitie hiervan, wat belangrijk is in het gebruik van zulke variabelen in de individuele pa-tiënt. Ten derde, we hebben laten zien dat in het geval van non invasieve bepaling van het hemoglobinegehalte, de overeenkomst hiervan met referentiewaarden redelijk is. Echter, na infusie van colloïden daalt deze overeen-komst sterk, wat niet optreedt na infusie van kristalloïden. Als laatste hebben we de minimaal invasieve meting van leverfunctie middels bepaling van de relatieve plasmacon-centratie van ICG onderzocht tijdens orthotope levertransplantaties. We vonden dat deze waarde, gemeten aan het einde van de operatie, geassocieerd is met het optreden van vroege postoperatieve complicaties. Dit biedt in poten-tie de kans om reeds peroperatief interventies uit te voeren ten behoeve van transplantaat-preservatie.

J.J. Vos 1

T.W.L. Scheeren 1

1 MD PhD, Afdeling anesthesiologie, Universitair Medisch Centrum Groningen

contactinformatieUniversitair Medisch Centrum Groningen Dr. J.J. VosAfdeling anesthesiologie Hanzeplein 1Postbus 30.0019700 RB GroningenT +31 (0) 50 361 61Email [email protected]


What is known?Recent technologic advances allow assessing many aspects of hemodynamics, such as blood pressure and flow – in a more minimally invasive fashion. Before clinical implementation however, a thorough valida-tion of these new devices is required.

What does this study add to that?This study investigates the adequacy of minimally in-vasively determined blood pressure, fluid responsiveness, hemoglobin concentration and liver function during general anesthesia. As such, it provides important information on the validation of these innovative monitoring methods.

Continuous and noninvasive measurement of arterial blood pressureMean arterial blood pressure (MAP) measurement is a mandatory part of hemodynamic monitoring in all patients undergoing any form of an-esthesia [1] and is usually measured intermittently by noninvasive arm cuff oscillometry (MAPiNIBP). Nevertheless, MAPiNIBP accuracy and precision can be substantially reduced, e.g. by incor-rect cuff positioning or inadequate cuff size [2]. Also, given the typical time-interval for MAPiNIBP measure-ment (3-5 min.), it only provides a snap shot impression of instantaneous hemodynamics. On the other hand, the invasive measurement of MAP (MAPinvasive, the gold standard) requires placement of an intra-arterial catheter and is usually reserved for either high-risk patients and/or patients undergo-ing high-risk surgery, as the benefits of its placement should outweigh its risks [3]. One of the newer continuous noninvasive alternatives for measuring blood pressure is the Nexfin device® (and its successor that is called the ClearSight monitor, Edwards Life-sciences, Irvine, USA) which provides a continuous “beat to beat” measure-ment of MAP (MAPcNIBP). Its technol-ogy is based on the Penaz principle

[4], and consists of an inflatable finger cuff together with a photoplethysmo-graph. At a rate of 1000Hz, the artery is clamped continuously at a diameter at which transmural pressure is zero (keeping arterial volume constant, ‘volume clamping’), and the generated pressure curve is reconstructed to a brachial artery pressure waveform [5]. As in the majority of anesthetic procedures MAP is monitored only intermittently using MAPiNIBP, it is of interest whether MAPcNIBP could replace this clinical standard. There-fore, we investigated the agreement of both MAPiNIBP and MAPcNIBP with MAPinvasive. A total of 112 patients under general anesthesia undergoing surgery were observed over a 30 minutes time period. The median difference (2.5th / 97.5th percentile) of MAPcNIBP at the start of measurements was 1 (-13/8) mmHg and 3 (-8 / 11) after 30 minutes. For MAPiNIBP, these values were -2 (-18 / 14) and -2 (-18 / 8), respectively. The bias (standard deviation) and limits of agreement of both MAPcNIBP and MAPiNIBP are shown in a Bland-Altman plot (see Figure 1.). Most importantly, these results demonstrate that mea-surement of MAP using the volume clamp technique is not inferior to the clinical standard using MAPiNIBP, and even tends to have a closer agreement

Figure 2. Receiver Operating Characteristics (ROC) Curve for the prediction of fluid responsiveness by stroke volume variation (SVV), pulse pressure variation (PPV) and pleth variability index (PVI). Given is the area under the ROC curve (AUROC) with its associated 95% confidence interval.

Figure 1. Modified Bland-Altman plot for repeated measurements. Given are the differences between MAPinvasive and either MAPcNIBP or MAPiNIBP, against the mean of these measure-ments. All values are shown are relative to MAPinvasive. The continuous horizontal line repre-sent bias, while dotted lines represent the limits of agreement (bias ±(1.96*SD))


to MAPinvasive. Therefore, MAPcNIBP us-ing the volume clamp technique offers an important alternative for the cur-rent clinical standard for monitoring MAP in patients undergoing anesthe-sia, with the obvious and important advantage of providing a continuous instead of intermittent monitoring modality. We would not advocate MAPcNIBP as an alternative for MAP-invasive, as its agreement is insufficient to pass two standardized validation criteria which were set up to evaluate blood pressure measurement devices, which was however also true for MAP-iNIBP [6, 7]. While both criteria were not designed to validate continuous blood pressure monitoring devices, it supports previous observations that MAPcNIBP is not interchangeable with its invasive gold standard [8, 9]. An important consideration is the fact that we studied patients under gen-eral anesthesia in a hemodynamically stable phase and as such, the observed non-inferiority of MAPcNIBP in compar-ison with MAPiNIBP is limited to these circumstances, and further research in ‘less’ hemodynamically stable circum-stances is required.

Minimally and noninvasive pre-diction of fluid responsivenessIt is well known that in the periopera-tive period, both hypo- and hyper-volemia are associated with increased morbidity and even mortality [10],

either due to the high risk of the patient (comorbidities) and/or due to high-risk surgery. In this context, static variables of cardiac preload, e.g. central venous pressure (CVP), have traditionally been used for guiding fluid management, although it became apparent in recent years that these variables fail to predict fluid respon-siveness (FR): i.e. these variables could not adequately predict whether car-diac output (CO) would increase fol-lowing fluid administration [11]. More recently, it was found that during positive pressure mechanical ventila-tion, circulatory variations secondary to respiratory-induced changes in intrathoracic pressure (i.e. heart-lung interaction), allow the calculation of dynamic preload variables [12]. The most well-known dynamic preload vari-ables, pulse pressure variation (PPV) and stroke volume variation (SVV) can be derived from a moving time inter-val (typically 20 seconds) from the arterial pressure waveform. While well validated [13], these variables still re-quire the use of an intra-arterial cath-eter. Therefore, we compared these invasive variables with newer, nonin-vasively derived dynamic variables in 30 patients under general anesthesia undergoing major hepatic resection in whom 15ml kg-1 fluid was administered directly after completion of hepatic parenchymal transection. Of the inves-tigated noninvasive dynamic preload

variables, the most important one was the commercially available ‘plethys-mographic variability index’ (PVI)[14], which is calculated continuously using the Masimo Radical 7 SET device (Ma-simo, Irvine, USA; software version V7.6.0.1, sensor version R2-25, Rev E) using a finger cuff. SVV was calculated by the FloTrac-Vigileo® device (V3.02; Edwards Lifesciences, Irvine, USA) and PPV was calculated off-line using dedicated software. FR was defined as an increase in stroke volume index > 20%. The ability of PPV, SVV and PVI to predict FR (17 responders, 13 non-responders) is depicted in the receiver operating characteristics (ROC) curve (see Figure 2.). Importantly, there were no significant differences be-tween the areas under the ROC curve of the investigated dynamic preload variables, although the confidence intervals of the areas under the ROC curve were wide, owing to the rela-tively low number of patients included (n=30). As such, noninvasive measurement of PVI, allows a similar ability to predict FR compared to the invasively mea-sured PPV and SVV. Nevertheless, the ability to track changes induced by fluid administration is another important clinical issue. In fluid responders, PPV and SVV decreased after the ad-ministration of fluid (from 24 (11)% to 10 (7)% and from 18 (8)% to 8(5)%, respectively), which was not true for

Figure 3a. Sensitivity (dashed curves) and specificity (solid curves) for predicting FR at the given thresholds. The small dashed horizontal lines at sensitivity / specificity of 0.9, show the intercepts of the grey zone limits for the associated thresholds.

Figure 3b. Sensitivity (dashed curves) and specificity (solid curves) for predicting FR at the given thresholds. The small dashed horizontal lines at sensitivity / specificity of 0.9, show the intercepts of the grey zone limits for the associated thresholds.


PVI, which was 16 (5)% before and 13 (7)% after fluid administration. The clinical relevance of this finding is that if an anesthesiologist were solely using PVI for monitoring FR, inappropriate amounts of fluids could be adminis-tered as the findings might incorrectly suggested the patient being a fluid non-responder. In this study, we found optimal cut-off values for PPV, SVV and PVI of 14, 15 and 12%, respectively, similar to values found previously [13]. While defin-ing such a cut-off value gives some guidance to clinicians to guide fluid management, it renders the decision to administer fluid or not ‘binary’, and may therefore be inappropriate in some patients. To overcome this issue, a ‘grey zone’ has been suggested previ-ously [15], i.e. a range of inconclusive values of dynamic variables around the optimal cut-off value. While this may improve the clinical applicabil-ity of dynamic preload variables (see further), one aspect infrequently taken into account in studies is the actual definition of FR. Therefore, we investigated the influence of multiple thresholds (definitions) of FR on the ability of PPV and SVV to predict FR in 90 patients undergoing general surgery. PPV and SVV were derived noninvasively using the Nexfin® de-vice; thresholds for defining FR were varied between 10-25% increase in stroke volume index. All patients were

administered a 500ml colloid bolus, as deemed required by the attending anesthesiologist on clinical suspicion of hypovolemia. The areas under the ROC curve of PPV and SVV gradually increased at higher FR thresholds: from 0.818 / 0.760 at 10% ↑SVI to 0.928 / 0.944 at 25% ↑SVI (data not shown). Interestingly, the limits of the grey zones – i.e. the areas of uncertainty around the optimal cut-off value – decreased for both PPV and SVV at higher thresholds for defining FR (Figure 3A for PPV, Figure 3B for SVV). Consequently, a larger propor-tion of patients was outside the grey zone (see Table 1.).Therefore, when implementing FR in clinical decision-making algorithms or in future studies – and even in the individual patient – it is important to keep the differences in FR defini-tions in mind. For instance, consider a patient with an aortic valve stenosis on the one hand, and a patient with pulmonary edema on the other hand. In the first case, hypovolemia would preferentially be prevented, while in the latter case this would be true for hypervolemia. The first case requires a high specificity, the latter a high sen-sitivity, or, to be more specific: a high ↑SVI threshold for the patient with an aortic valve stenosis, and a low ↑SVI threshold for the patient with pulmo-nary edema (see Figure 3.).Unfortunately, multiple criteria (dis-

cusses below) are required for a valid prediction of FR by dynamic preload variables [16], which hinder the rou-tine clinical use of these variables [17]. It is estimated [18] that only in about 23% of patients undergoing a surgical procedure, all criteria are met for al-lowing FR to be predicted by arterial pressure waveform derived dynamic variables, which is 39% for plethysmo-graphic waveform derived variables. In ICU patients, these percentages are likely to be even lower. Most importantly, positive pressure mechanical ventilation (without spon-taneous breathing activity) is required in a volume-controlled mode, prefer-ably with tidal volumes > 7 ml kg-1. Also, substantial cardiac arrhythmia (e.g. atrial fibrillation) should be ab-sent, the thorax should not be opened and the heart rate / respiratory rate ratio should be > 3.6 [16, 17]. Apart from the factors above that prohibit the clinical use of dynamic preload variables, it should also be respected that any of the dynamic pre-load variables – whether flow-derived (SVV), pressure-derived (PPV) or volume derived (PVI) – only provide a partial, simplified picture of the cir-culation (cardiac preload) without a quantification of volume status. Therefore, a more recent approach, which incorporates the mean circula-tory filling pressure (Pmsf ), might pro-vide more insight and a quantification

Figure 4. Receiver Operating Characteristics (ROC) Curve for the prediction of fluid responsiveness by the pressure for venous return (Pvr) and stroke volume variation (SVV) and pulse pressure variation (PPV). The blue dotted line, repre-sents the reference line.

A:↑SVI (%)threshold

No. of responders and non-responders

Limits of the grey zone (%)

Percentage patients below/within/above grey zone

10 56/25 9 – 16 21 / 48 / 3115 34/47 10 – 16 28 / 41 / 3120 22/59 14 – 17 54 / 17 / 2925 16/65 18 – 21 72 / 7 / 21

B:↑SVI (%)threshold

No. of responders and non-responders

Limits of the grey zone (%)

Percentage patients below/within/above grey zone

10 56/25 5 – 13 11 / 53 / 3615 34/47 7 – 14 18 / 51 / 3120 22/59 10 – 15 49 / 22 / 2925 16/65 14 – 16 69 / 6 / 25

Table 1A-B. Specification of the number of responders / non-responders, grey zone (=area of uncertainty) limits and percentage of patients within these limits for PPV (A) and SVV (B).Data are given for each definition of minimal relative increase in stroke volume index (↑SVI) for pulse pressure variation (A; PPV) and stroke volume variation (B; SVV).


of the circulation instead [19, 20]. Pmsf is determined by blood that “fills” the circulation (unstressed blood volume) and blood that builds up intravascular pressure (stressed blood volume) [21]. Furthermore, Pmsf is a major determi-nant of cardiac preload, and together with CVP, determines the pressure gradient for venous return (Pvr, cal-culated as Pmsf – CVP), and hence, CO. Unfortunately, Pmsf can only be measured when the circulation has stopped and arterial and venous pres-sure have equilibrated. Yet, based on an algorithm introduced in 1994 [22], an analogue of Pmsf (Pmsa) can be calculated using the formula: a(CVP) + b(MAP) + c(CO). Here, a and b are constant values (a+b = 1, based on a typical, but assumed arterio-venous compliance ratio), while c depends on anthropomorphic data. The inter-ested reader is referred to the original publication for more detailed infor-mation [22]. Pmsa has been validated both experimentally and clinically, and changes in Pmsa following fluid administration were comparable with alternative methods for assessing Pmsf [23, 24]. In a post-hoc analysis of patients (n=30) undergoing major hepatic re-section in whom we investigated the ability of dynamic variables to predict FR (defined as an increase in cardiac index>20%), we found that Pmsa was comparable between fluid respond-

ers (n=18) and non-responders (n=12) before fluid administration (13 ± 3 vs. 14 ± 4 mmHg; p=0.28). In both groups, Pmsa increased to 17 ± 4 mmHg (p<0.01) after fluid administration. While Pvr was lower in responders than in non-responders before fluid administration (6 ± 1 vs. 7 ± 1 mmHg, p=0.02), it only increased in respond-ers (from 6 ±1 to 8 ±1 mmHg, p<0.01). These differences allow a closer look at circulatory dynamics following fluid administration: Fluid increased Pmsa both in responders and non-respond-ers. However, in fluid responders, CVP did not change and as such, Pvr increased. The net increase in Pvr (as a driving pressure for venous return), al-lowed the heart to increase its output. In contrast, in non-responders CVP increased analogous to the increase in Pmsa and hence, Pvr did not change, and a further increase in venous re-turn is coped with by the increase in CVP. In these patients, the heart was obviously unable to handle the extra amount of fluid, or stated differently: it is likely that in these patients the heart operated (already) on the flat part of the Frank-Starling curve. This mechanism is further reflected by the observed changes in ‘heart efficiency’ (EH; calculated as Pvr / Pmsa): EH de-creased in non-responders (from 0.56 ± 0.17 to 0.45 ± 0.12), while it did not change in responders (0.52 ± 0.11 vs. 0.49 ± 0.12, p=0.16).

Importantly, Pmsa is a mathematically derived variable and on the basis of the algorithm used, is automatically increased if CO increases. Previous research found nevertheless that while the absolute value of Pmsa can differ to some extent from Pmsf, changes of both variables are linearly correlated and calibration can reduce a potential bias to zero [24]. Apart from the physiologic differen-tiation between fluid responders and non-responders, we observed that Pvr has a similar ability to predict FR as compared to dynamic preload vari-ables. The area under the ROC curve of Pvr was 0.75, which did not differ significantly from that of PPV (0.73) and SVV (0.72) (see Figure 4.). There-fore, Pvr might be considered as an alternative variable for predicting FR, especially if there are circumstances in which dynamic variables cannot be used (see above). It remains however to be demonstrated, whether an ‘opti-mal’ Pvr value exists which allows spe-cific guidance of fluid management.

Noninvasive measurement of hemoglobin concentrationAnother important goal in periopera-tive hemodynamic management is the maintenance of a sufficient Hemoglo-bin (Hb)- concentration, ultimately to provide a sufficient amount of oxygen to the patient. In the OR, the clinical standard for measuring Hb is point-

Figure 6. Coefficients of determination (R2 values, thick lines) of SpHb and Hbsatlab measure-ments during the dynamic phase, with a 5-minute time interval, for patients receiving crystalloids (red) and colloids (green). Also shown are the corresponding Hbsatlab values (dashed lines)

Figure 5. Correlation of Hbsatlab and SpHb for measurements obtained during the steady state phase (black circles) and dynamic phase (grey circles).


of-care satellite laboratory blood gas analysis (Hbsatlab) [25]. Hbsatlab measure-ments, however, are time-consuming, relatively expensive and most impor-tantly require drawing of a blood sam-ple. Also, it only allows a ‘snap shot’ as-sessment of actual Hb-concentration. Theoretically, noninvasive and contin-uous Hb-monitoring might therefore be advantageous, provided it allows an accurate and precise assessment of Hb. The Masimo Radical 7 device (Masimo Corp., Irvine, USA) uses a transcuta-neous, multi-wavelength analysis of Hb absorption. As such, it calculates total Hb-concentration (SpHb). We investigated the agreement of SpHb measurements with those of Hbsatlab in patients undergoing major hepatic resection (n=30). In these patients, we defined 2 phases: the first (steady state) phase was the fluid restrictive phase, lasting from surgical incision until hepatic parenchymal transection, dur-ing which patients were administered a fixed amount of 6ml kg-1 hr-1 crystal-loids. During the dynamic phase, pa-tients were randomized to be adminis-tered 15 ml kg-1 in 30 minutes of either crystalloids and colloids. In Figure 5., the overall correlation is shown between SpHb and Hbsatlab mea-surements for all data points (n=543), for which we noted no differences between the steady state and dynamic phase (R² 0.45 and 0.42, respectively). Also, Bland-Altman analysis revealed

that SpHb bias (absolute difference) and precision (1SD of the bias) were comparable between both phases (-0.27 (1.06) g dL-1 and -0.02 (1.07) g dL-1, respectively). During the dynamic phase – in which Hbsatlab was measured every 5 minutes, we observed a substantial drop in cor-relation between SpHb and Hbsatlab (R² 0.41 at the start, vs. 0.11 15 minutes thereafter), while in the crystalloid group R² increased from 0.72 to 0.82 15 minutes thereafter (see Figure 6.).The observed agreement between SpHb and Hbsatlab (or other reference measurements) in a steady state phase, is similar to previous research [26, 27]. Yet, it is of utmost importance that under ‘dynamic’ circumstances (which frequently occur periopera-tively), measurement of Hb is accurate and precise so that a correct decision whether or not blood should be trans-fused can be made. The observation that colloids – frequently admin-istered during blood loss – reduce SpHb accuracy dramatically, is obvi-ously highly relevant to the anesthe-siologist. In addition, other studies found that factors such as a reduced peripheral perfusion [28] and changes in FiO2, also decrease SpHb accuracy [29]. Therefore, in its current form SpHb measurements cannot yet re-place Hbsatlab monitoring [30].

Noninvasive assessment of liver functionThe anesthesiologist has the opportu-nity to monitor more than hemody-namics in a minimally invasive fashion, such as specific organ function. For instance, the elimination of Indo-Cy-anine Green (ICG) can be monitored non-invasively using a finger cuff, which allows an online assessment of perioperative liver function, e.g. in pa-tients with liver disease or in patients undergoing hepatic surgery (i.e. major hepatic resection, liver transplanta-tion), ICG is a non-toxic dye almost exclusively eliminated by the liver without metabolisation and its elimi-nation rate is considered to correlate with liver function [31, 32]. The noninvasive, finger-cuff based measurement of the plasma disap-pearance rate of ICG (PDRICG), is well correlated with invasive measure-ments of ICG elimination [33]. In a retrospective study in patients under-going orthotopic liver transplantation (n=62), we investigated the ability of intra-operatively measured PDRICG values to predict the occurrence of early postoperative complications. In those patients developing complica-tions (n=22), PDRICG was significantly lower at the end of the surgical pro-cedure compared to patients without (n=40) early postoperative complica-tions (PDRICG 21.0 % min-1 vs. 24.9% min-1, p=0.034). More interestingly,

Figure 7A. ROC-analysis for the prediction of absence of early postoperative complications of the intraoperative PDRICG values (measured 30 minutes after graft reperfusion and at the end of surgery) and values of the pH, lactate and PT shortly thereafter when the patient was admitted to the ICU. AUROC’s are shown in brackets. The bold green line, represents the reference line.

Figure 7B. ROC-analysis for the prediction of absence of early postoperative complications using postoperative measurements of serum bilirubin and PT at the 5th postoperative day. AUROC’s are shown in brackets. The bold green line, represents the reference line.


we found that for the prediction of absence of these complications, the area under the ROC curve of PDRICG was 0.70 (p<0.05), which was higher than other conventional laboratory tests measured directly after admission to the ICU, i.e. lactate, pH, PT, bilirubin and PT (see Figure 7.). As such, we determined a PDRICG cut-off value of 23.5% min-1 for predicting absence of early postoperative complications with a sensitivity of 72% and specific-ity of 71%. Therefore, a low PDRICG at the end of surgery might function as an early warning tool for the detec-tion of factors that impede adequate graft function, and subsequently both surgical and anesthetic optimization of potential graft compromising fac-tors are possible while still on the OR. Of note, it should be reckoned that, given the high hepatic extraction ratio of ICG, its elimination is dependent on hepatic blood flow and therefore, PDRICG only allows a reliable estima-tion of liver function in case of hemo-dynamic stability and adequate liver perfusion [34]. In many (mainly Asian) centers evalu-ating cirrhotic patients with hepato-cellular carcinoma, measurement of ICG elimination is implemented in

preoperative diagnostic algorithms to assess the (maximum) extent of hepatic resection [35] and mortality rates close to zero have been reported [36, 37]. It is unknown whether these results also apply to the European situation, where most hepatic surgical procedures are performed because of (colorectal) liver metastasis [38]. Despite extensive research in the past, none of the studies in which the perioperative measurement of ICG elimination has been evaluated, had a prospective and randomized study design. Therefore, while ICG elimina-tion can provide diagnostic informa-tion, it is still to be decided whether its use actually has a positive impact on patient’s outcome.

In conclusion, this thesis was aimed at minimally invasive monitoring of multiple important aspects of hemo-dynamics. With respect to monitor-ing MAP, continuous MAP CNIBP is an important alternative to the clinical standard, intermittent MAPINIBP. Also, guiding fluid management using dynamic preload variables can be established completely noninvasive. Importantly though, the defini-tion of fluid responsiveness should

be respected. Another important aspect of our specialty – Hb monitor-ing - can potentially be performed noninvasively, yet the agreement with reference values is critically dependent on the type of fluid infused. Finally, minimally invasively obtained PDRICG values during liver transplantation are predictive of postoperative outcome, and thus might allow optimization of graft function perioperatively. He-modynamic optimization of patients undergoing (major) surgery, remains a challenge to the anesthesiologist. The emerging availability of more minimally invasive hemodynamic monitoring methods, allows the clini-cian to evaluate hemodynamics both in a more continuous fashion and in a more complete fashion. Importantly though, a thorough validation in the appropriate patient population of whatever new variable is necessary before its clinical implementation. Eventually, the transition from tra-ditional (sometimes highly invasive) pressure-dominant monitoring, to more minimally invasive and flow-based monitoring, offers the potential to further improve perioperative out-come in a broad patient population.

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onderzoek

Ambiguous policies in anaesthetic pain management in laparoscopic colonic surgery: A national survey

abstract Background The goal of postoperative care is no longer solely adequate pain relief since other outcomes (e.g. mobilization, length of hospital stay) have become increasingly important. Enhanced Recovery After Surgery (ERAS)-guidelines recommend the use of epidural analgesia and Non-Steroidal Anti-Inflammatory Drugs (NSAIDs). However, this practice have been challenged, due to the association of epidural analgesia with prolonged recovery and the use of NSAIDs with anas-tomotic leakage. Aim of this survey was to investigate the extent of difference in postoperative pain management after colonic surgery. Methods Anaesthesiology departments from all 86 Dutch hospitals were contacted and a questionnaire was submitted. Respondents were questioned about pain manage-ment, which drugs are used and experience with intrathecal opioids in laparoscopic colonic surgery. Results The response rate was 85%. 55% of the hospitals used epidural analgesia and 21% used patient controlled analgesia as primary pain modality (P<0.01). Epidural analgesia was used more in general hospitals than in university hospitals (58% vs. 14% respectively, P = 0.045). NSAIDs were prescribed in 45 Dutch hospitals (62%). Overall use of intrathecal long acting opioids for postoperative pain was 22%. 48% was unfamiliar with the use of intrathecal opioids for laparoscopic colonic surgery. Conclusions Epidural analgesia is used in the majority of Dutch hospitals for laparoscopic colonic surgery. NSAID’s are predominantly used in combination with patient controlled analgesia. The use of single shot intra-thecal morphine is not common, especially not for laparoscopic surgery. This survey gives an adequate reflection of Dutch anaesthetic management in laparoscopic colonic surgery.

Key words: epidural analgesia, intrathecal morphine, laparoscopic colonic surgery, patient controlled analgesia.

E.E. van Houwelingen 1, 2

M.V. Koning 1

A.J.W. Teunissen 2

R.J. Stolker 1

1 Department of Anaesthesiology, Erasmus University Medical Centre, Rotterdam

2 Department of Anaesthesiology, Maasstad Ziekenhuis, Rotterdam

contactinformationDept. of AnaesthesiologyErasmus University Medical CentreE.E. van Houwelingen‘s Gravendijkwal 2303015 CE RotterdamEmail [email protected]

Conflict of interest: none.

mailto:[email protected]


IntroductionThe goal of postoperative care is no longer solely adequate pain relief since other outcomes (e.g. mobilization, length of hospital stay, return of bowel function and prevention of adverse events) have become increasingly im-portant. This is reflected in guidelines for Enhanced Recovery After Surgery (ERAS) after colonic surgery [1]. In this guideline it is recommended to use as few opioids as possible by administer-ing multimodal analgesia with Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) and epidural analgesia.

Regarding postoperative pain manage-ment in laparoscopic colonic surgery, controversies arose in the past years. Laparoscopic surgery is still associated with high postoperative pain intensities in the first 24 hours after surgery [2]. However, some reported that epidural analgesia prolongs length of hospital stay (LOS) after surgery [4-7]. Other modalities of pain management, such as patient controlled analgesia (PCA) or single shot spinal anesthesia with long acting opioids might be attractive al-ternatives due to the high effectiveness of analgesia and less effect on length of hospital stay and mobilization [5, 8, 9]. Another controversy is the use of NSAIDs. Some retrospective reports state that the use of NSAIDs is associ-ated with increased anastomotic leak-age, although two recent meta-analyses could not confirm this statement [10, 11].

The Dutch guideline of postoperative pain management leaves space for local variation [12]. We undertook a national survey to study the practice of pain management in laparoscopic colonic surgery. The objective of this survey is to investigate the extent of difference in pain management, the familiarity with intrathecal analgesia for laparoscopic colonic surgery and the rationale for their preferred method of analgesia. With this knowledge, we aim to give insight in daily practice and consider-ations with regard to anaesthetic pain management in laparoscopic colonic surgery.

MethodsThe survey was conducted from No-vember 2014 to March 2015. The attend-ing anesthesiologists from all 86 anaes-thesiology departments in the Neth-

erlands were contacted by telephone to ask for cooperation with the survey. The questionnaire could be answered by telephone or by email. Up to three reminders were send when the respon-dent opted for cooperation. Anonymity was guaranteed for the publication of data, however the investigators were not blinded. The respondents were questioned about the following aspects of pain management in laparoscopic colonic surgery patients:• What kind of pain management is

used in your hospital in what per-centage of the patients?

· Which drugs are used?· Why is the chosen pain management

preferred? · Which co-analgesics are given? In order to investigate the familiarity

with intrathecal opioids the respon-dents were asked:

· Are intrathecal long-acting opioids given for any type of surgery?

· What experience do you have with long acting opioids?

· If long acting opioids are adminis-tered, are there any specific arrange-ments or precautions undertaken?

· What would be necessary to admin-ister single shot long acting opioids as a standard pain management in laparoscopic colonic surgery pa-tients?

· Are you familiar with single shot long acting opioids in pain manage-ment of laparoscopic colonic surgery patients?

The full questionnaire is included in appendix A. It was emphasized that the

answers should reflect departmental policies rather than individual practice. Based on the first question, the respon-dents were classified according to pri-mary technique. Primary technique was defined as the technique used in 75% or more of the patients. It was categorized as “Epidural”, “PCA”, “combination” and “other”. The combination group con-sisted of hospitals which used epidural and PCA-analgesia, but neither one was a primary technique. The category of “other” consisted of hospitals which used oral or intramuscular opioids, sometimes combined with ketamine and/or gabapentinoids. Data are pre-sented as percentages or numbers of respondents. For categorical data a Fisher’s exact test is performed by SPSS 23.0 (IBM, Armonk, NY, U.S.A.).

ResultsThe overall response rate by mail (9) or telephone (64) of the questionnaire was 85% (73 hospitals in the Netherlands). 7 of the 8 Dutch university hospitals responded (88%).

Current pain management in laparoscopic colonic surgeryTable 1 displays the frequency of the used analgesic modality. Fifty-five per-cent of the hospitals used epidural an-algesia and 21% used PCA-administered opioids as a primary modality. The most used drugs for epidural analgesia were bupivacaine (56%), ropivacaine (36%) and levobupivacaine (8%). Except one, all hospitals used bupivacaine/ropiva-caine in combination with an opioid (sufentanil 86%, morphine 8%, fentanyl

Epidural PCA Combination OtherwiseAll Hospitals 40 (55%) 15 (21%) 10 (13%) 8 (11%)

Academic 1 (14%)* 2 (29%) 3 (43%) 1 (14%)General 39 (58%)* 13 (20%) 7 (11%) 7 (11%)

Co-analgesiaNSAIDs 19 (48%)^ 13 (87%)^ 6 (60%) 7 (88%)Only paracetamol 21 (52%) 2 (13%) 4 (40%) 1 (12%)

Table 1. The frequencies of primary technique of analgesia (defined as >75% of the patients) are presented as n(%). PCA: Patient Controlled Analgesia, NSAID: Non-Steroidal Anti-Inflammatory Drugs. * p=0.045, ^ p=0.013 with Fisher’s exact-test.

Epidural PCA Other analgesicsFast return of bowel function (49%) Epidural not indicated (40%) PCA/epidural not necessary (57%)High success rate (33%) Non-invasive nature (33%) Non-invasive nature (43%)ERAS-protocol (26%) High success rate (20%) High success rate (29%)Less systemic opioids (26%) Low-risk modality (13%) Convenience for nursing staff

(14%)

Table 2.The reported reasons why an analgesic modality was chosen. Percentage is the percentage of respondents reporting that argument. Multiple arguments per respondent was possible. PCA: Patient Controlled Analgesia. ERAS: Enhanced Recovery After Surgery.


4%). One hospital added clonidine to a mixture of a local anesthetic and an opioid. The most commonly used combi-nation was bupivacaine 0.125% with suf-entanil 0.5-2mcg/ml. Eleven percent used other analgesics than epidural analgesia or PCA, which were predominantly oral oxycodone or subcutaneous opioids. An-other 13% had no primary technique and was applying various methods of analgesia between patients, most often epidural analgesia and PCA. General hospitals used epidural analgesia more often than univer-sity hospitals as a primary modality (58% vs. 14%, P=0.045). Only 1 of all 73 hospitals administered intrathecal opioids in 1-25% of the patients for elective laparoscopic colonic surgery.

Co-analgesics All hospitals prescribed paracetamol as a co-analgesic. However, NSAIDs were prescribed in 45 Dutch hospitals (62%), without a difference between the uni-versity and general hospitals (71% vs 61% respectively, p=0.70). Table 1 also shows that NSAIDs were prescribed less when epidural analgesia was the primary form of pain management when compared with PCA (48% and 87%, P=0.013). In 8 hospitals (11%) other pain medication was prescribed, such as ketamine, cloni-dine or gabapentinoids in addition to paracetamol, NSAIDs and opioids per requisite as standard pain management.

Reasons for using primary techniqueTable 2 displays the percentage of re-ported reason for using a primary modal-ity. The return of bowel function was the most reported argument for epidural analgesia. In general, when epidural anal-gesia is not the primary technique, non-invasiveness is an important argument.

Familiarity with intrathecal opioidsThe overall use of intrathecally admin-istered long acting opioids in Dutch hospitals was 22%, it was mostly used in orthopedic surgery and cesarean sec-tions and morphine was the only opioid reported. Dosage ranged from 100 to 500 µg. The most associated or feared adverse effects of intrathecal long acting opi-oids were pruritus (70%), nausea (29%), respiratory insufficiency (18%), urinary retention (5%), hypotension (3%) and dos-age errors (3%). Respiratory insufficiency appeared to be reported less by hospitals that used intrathecal morphine when compared to hospitals that did not (7% vs. 22%, p=0.177). Sixty-nine percent of the

hospitals take no additional measures for postoperative monitoring. In 6% of the hospitals, patients stayed on the intensive care unit for one night and in 13% patients got a urinary catheter.

Implementation of intrathecal long acting opioids for laparoscopic colonic surgery48% of the respondents were unfamiliar with the use of intrathecal opioids for laparoscopic colonic surgery. For imple-mentation the respondents reported that more research was needed (52%), a guideline was desirable (19%) and 26% reported that intrathecal opioids were not necessary at all. The hospitals with experience with intrathecal morphine seem to request more often additional research before implementation (55% vs 36%, p=0.152).

DiscussionThis national survey has a high response rate. Key findings of this survey were the clear differences in policies concerning pain management in laparoscopic colonic surgery in Dutch hospitals. In most of the Dutch hospitals (59%) epidural analgesia is the primary technique, while PCA is the second most used modality (21%).

In the past decennium several studies investigated pain management for lapa-roscopic surgery. Laparoscopic surgery is still associated with high postoperative pain intensities in the first 24 hours after surgery [2]. And although the use of epi-dural analgesia gives excellent pain relief during the initial period after surgery, this benefit is limited by a relatively high failure rate [13, 14]. Another perceived benefit of epidural analgesia is its positive effect on bowel function, as showed by a meta-analysis [15]. However this conclu-sion is based predominantly on two stud-ies without an ERAS-program and with a relatively long length of hospital stay [15-17]. Epidural analgesia was associated with prolonged length of hospital stay and delayed medical recovery when an ERAS-program was followed. This was due to the need of vasoactive medication treating hypotension [4, 5]. Furthermore, it probably serves no benefit for gastroin-testinal function in laparoscopic surgery as opposed to laparotomic surgery [18]. Even though these studies indicate that the benefits of epidural analgesia may not outweigh the disadvantages, it still re-mains the most common method of an-algesia in the Netherlands. Interestingly, the most reported reason in this survey for

using epidural analgesia (enhanced return of bowel function) is not supported by literature.

A difference was seen in the use of epi-dural analgesia between general hospitals and university hospitals (58% vs. 14% re-spectively, P=0.045). This difference might have numerous explanations, such a dif-ference in success rate of epidural analge-sia, perhaps due to young residents, local experience, type of surgery, co-morbidity of patients and its related medications (e.g. anticoagulants) or an earlier transla-tion of recent research findings [4, 5] into clinical practice in the academic hospitals. However, this remains speculation since this study was not designed to comment on this difference.

NSAIDs were used in 48% of the hospitals when epidural analgesia is the primary technique, while they were prescribed in 87% of the hospitals which used predomi-nantly PCA. The use of NSAIDs is recently challenged because a claimed association with anastomotic leakage [10, 19, 20]. Especially non-selective NSAIDs may be associated with anastomotic leakage compared to selective cyclooxygenase-2-inhibitors after colorectal surgery [21]. However, this association is based on non-randomized prospective and retro-spective studies. In a recent meta-analysis, the power of these pooled results was too low to detect any significant difference in anastomotic leakage [11]. Moreover, in randomized controlled trials the use of NSAIDs have demonstrated to lower pain scores, decreased use of systemic opi-oids, shorten length of hospital stay and reduce postoperative bowel impairment after colonic surgery [22, 23]. For epidural analgesia, however, one can question the addition of NSAIDs. In cesarean sections it appears that the addition of NSAIDs to epidural analgesia leads to less or delayed use of rescue analgesics but it made no difference in pain perception, patient sat-isfaction or functional recovery [24, 25].

Intrathecal opioids for laparoscopic surgery were used in only one hospital. The only long acting intrathecal opioid reported to be used in the Netherlands is morphine. It is administered in 22% of the hospitals, in particular in orthopaedic surgery and cesarean sections in doses of less than 500 micrograms. Respondents associated intrathecal morphine with pruritus, nausea, respiratory insufficiency and urinary retention. Assumedly, these


side effects may limit it widespread use in Dutch practice, while in other European countries it is more commonly used [26, 27]. Regarding the side effects, pruritus is more common after intrathecal administra-tion of morphine with relative risk of 1.8 (95%-CI 1.4-2.2), but nausea and vomiting are not more common than with intrave-nous opioids when a dose <300 mcg is used [28]. Furthermore, both 5-HT3 receptor antagonists and droperidol are effective and recommended in the prophylaxis of pruritus due to intrathecal opioids [29, 30]. There is a large variance in the incidence of respiratory depression, due to the lack of a clear definition and a large variance in ad-ministered dosage. Two meta-analysis re-ported two different conclusions. Meylan et al. stated that there is an increased risk in respiratory depression, although they did not search for a dose-dependent effect [31]. Gehling et al. stated that an intrathe-cal dose < 300 mcg of morphine does not lead to an increased incidence of respira-tory depression, while larger doses did so indeed [28]. A dose < 300 mcg of morphine is also recommended in abdominal surgery [32]. Another concern are medication er-rors which are easily made when morphine has to be diluted to lower concentrations.

Ten percent of the respondents feels that ready to use ampoules should be available and that this could lower the probability of a medication error. Urinary retention is indeed a common side effect of intrathecal morphine use [33]. Intrathecal morphine in a dose of ≤ 300mcg could be a promising technique of analgesia for laparoscopic gastrointestinal surgery [5-7, 28, 32]. Still, its benefit has yet to be proven in regard to patient satisfac-tion or functional recovery after surgery. We initiated a randomized controlled trial to investigate this in Dutch practice (reg-istered at clinicaltrials.gov with number NCT02284282). Remarkable is that many respondents (26%) stated that implementa-tion of intrathecal morphine as a analgesic modality is not necessary, even if it proves to lead to enhanced recovery and better patient satisfaction. Even though this sur-vey leads to an insight in Dutch practice it has several limitations. One limitation is that almost all respondents were ap-proached by telephone during daytime, which could lead to rushed interviews. However, an internet based questionnaire was offered, as well as phone call on a dif-ferent day. Furthermore, the telephonic in-terview has the advantage for elaboration,

explanations and clarification of questions or answers. Another limitation was the fact that only one representative in a hospital was questioned instead of the entire de-partment. However, it was emphasized that the answers should reflect hospital policies rather than individual practice. We have chosen this strategy in order to achieve a high response rate, which we believe gives an adequate reflection of common practice in Dutch hospitals.

In conclusion, this survey shows that epi-dural analgesia is used in the majority of Dutch hospitals for laparoscopic colonic surgery, despite recent investigations challenging the superiority of this form of pain management. Despite some concerns, NSAIDs are commonly used, predomi-nantly in combination with PCA. Single shot intrathecal morphine is not common in Dutch hospitals, especially not for lapa-roscopic surgery. It is a remarkable finding that despite evidence 26% of the respon-dents finds it not necessary to implement the use of intrathecal opioids. This survey gives an adequate reflection of Dutch anaesthetic management in laparoscopic colonic surgery.

appendix a. Questionnaire (translated from Dutch).

1. Please state how often the following an-algesia methods are applied in your hos-pital for laparoscopic gastro-intestinal surgery (e.g. Hemicolectomy, (partial) gastric resections, sigmoidectomy, etc.). Please give in percentage of the patients.

- PCA … % - Epidural analgesia …% - Spinal analgesia …% - Otherwise ...% (such as:……)

2. Which medication and what dose do you use per method applied in question 1.

3. What is the reason for the preference of the most applied method of analgesia (multiple answers are possible):- non-invasive nature- high successive rate - sympathic blockade- positive effect on bowel function- too limit the use of systemic opioids - the lack of necessity for postopera-

tive visits - otherwise, such as:…..

4. Which coanalgetics are prescribed:- Acetaminophen- NSAID’s- Metamizole- Others (gabapentin/pregabalin/ket-

amine/lidocaine/ketamine/clonidine)- Others (not yet mentioned), such

as:….

5. Do you use intrathecal long acting opi-oids (such as morphine) for any type of surgery?- Yes/No

6. If so, which opioid, what dose and which indications?

7. Which effects do you see/associate with intrathecal long acting opioids? (mul-tiple answers are possible)- Nausea- Beneficial effect on pain- Hypotension- Pruritus- A limited effect on pain- Respiratory depression- Otherwise, such as….

8. Do you take postoperative measures or precautions when intrathecal long act-ing opioids are used?

9. What would be necessary to implement intrathecal long acting opioids as anal-gesia for laparoscopic gastro-intestinal surgery?- More research/scientific articles- A national guideline with recommen-

dations for dose and indication- Ready to use ampoules- More or prolonged postoperative

monitoring abilities- Others, such as….

10. Were you familiar with the use of a sin-gle shot intrathecal injection with long acting opioids as method of analgesia for laparoscopic surgery? - Yes/No


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